tacrolimus and Postoperative-Complications

End-stage kidney disease (ESKD) is a main public health problem, the prevalence of which is continuously increasing worldwide. Due to adverse effects of renal replacement therapies, kidney transplantation seems to be the optimal form of therapy with significantly improved survival, quality of life and diminished overall costs compared with dialysis. However, post-transplant patients frequently suffer from post-transplant diabetes mellitus (PTDM) which an important risk factor for cardiovascular and cardiovascular-related deaths after transplantation. The management of post-transplant diabetes resembles that of diabetes in the general population as it is based on strict glycemic control as well as screening and treatment of common complications. Lifestyle interventions accompanied by the tailoring of immunosuppressive regimen may be of key importance to mitigate PTDM-associated complications in kidney transplant patients. More transplant-specific approach can include the exchange of tacrolimus with an alternative immunosuppressant (cyclosporine or mammalian target of rapamycin (mTOR) inhibitor), the decrease or cessation of corticosteroid therapy and caution in the prescribing of diuretics since they are independently connected with post-transplant diabetes. Early identification of high-risk patients for cardiovascular diseases enables timely introduction of appropriate therapeutic strategy and results in higher survival rates for patients with a transplanted kidney.

Topics: Animals; Cardiovascular Diseases; Cyclosporine; Diabetes Mellitus; Heart Disease Risk Factors; Humans; Immunosuppressive Agents; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Postoperative Complications; Prevalence; Renal Dialysis; Tacrolimus; TOR Serine-Threonine Kinases; Transplant Recipients

A traditional narrative review was performed to evaluate clinical studies that have examined the clinical implications, risk factors, and prevention of calcineurin inhibitors (CNIs) nephrotoxicity with stress on a belatacept-based rescue regimen.. The Cochrane Library, PubMed/MEDLINE, EBSCO (Academic Search Ultimate), ProQuest (Central), and Excerpta Medical databases and Google scholar were searched using the keywords (CNI AND Nephrotoxicity prevention) OR ("Calcineurin inhibitor" AND Nephrotoxicity) OR (Tacrolimus AND Nephrotoxicity) OR (Ciclosporin AND Nephrotoxicity) OR (cyclosporine AND Nephrotoxicity) OR (Belatacept) OR (CNI Conversion) for the period from 1990 to 2020. Fifty-five related articles and reviews were found.. A better understanding of the mechanisms underlying calcineurin inhibitor nephrotoxicity could help in the individualization of therapy for and prevention of CNI nephrotoxicity. Identification of high-risk patients for CNI nephrotoxicity before renal transplantation enables better use and selection of immunosuppression with reduced adverse effects and, eventually, successful treatment of the kidney recipients. Belatacept conversion is a good and safe option in patients with deteriorating renal function attributed to CNI nephrotoxicity.

Topics: Abatacept; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Tacrolimus

Introduced in 1995, mycophenolate mofetil (MMF) would become the most powerful antiproliferative agent in the field of organ transplantation, thereby supplanting azathioprine, the first antiproliferative agent introduced in the early 1960s. Its association with tacrolimus greatly improved kidney transplant (KT) prognosis by significantly reducing the incidence of posttransplant acute rejection. MMF is also reputed to be a safe medication, but the frequency of the gastrointestinal complications associated with it, even minor ones, has induced the marketing of a second molecule called enteric-coated mycophenolate sodium. This late form of mycophenolate was supposed to be better tolerated thanks to its pharmacokinetic properties but the studies did not show significant differences between the two molecules. Otherwise, the combination of MMF with tacrolimus has significantly increased the risk of infections, particularly viral, and of neoplasia. To reduce this risk and avoid any situation of under or overexposure while remaining effective, only a strict and long-term monitoring of MMF allows the maintenance of already established therapeutic targets within the predefined ranges. In KT, individualizing the prescription and targets of MMF according to immunologic risk, global immunosuppression, and posttransplant period, as for other immunosuppressants, is open to discussion and may be beneficial.

Topics: Adult; Drug Interactions; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Virus Diseases

Although, liver transplantation serves as the only curative treatment for patients with end-stage liver diseases, it is burdened with complications, which affect survival rates. In addition to clinical risk factors, contribution of recipient and donor genetic prognostic markers has been extensively studied in order to reduce the burden and improve the outcomes. Determination of single nucleotide polymorphisms (SNPs) is one of the most important tools in development of personalized transplant approach. To provide a better insight in recent developments, we review the studies published in the last three years that investigated an association of recipient or donor SNPs with most common issues in liver transplantation: Acute cellular rejection, development of new-onset diabetes mellitus and non-alcoholic fatty liver disease, hepatocellular carcinoma recurrence, and tacrolimus concentration variability. Reviewed studies confirmed previously established SNP prognostic factors, such as PNPLA3 rs738409 for non-alcoholic fatty liver disease development, or the role of CYP3A5 rs776746 in tacrolimus concentration variability. They also identified several novel SNPs, with a reasonably strong association, which have the potential to become useful predictors of post-transplant complications. However, as the studies were typically conducted in one center on relatively low-to-moderate number of patients, verification of the results in other centers is warranted to resolve these limitations. Furthermore, of 29 reviewed studies, 28 used gene candidate approach and only one implemented a genome wide association approach. Genome wide association multicentric studies are needed to facilitate the development of personalized transplant medicine.

Topics: Cytochrome P-450 CYP3A; End Stage Liver Disease; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lipase; Liver Transplantation; Male; Membrane Proteins; Polymorphism, Single Nucleotide; Postoperative Complications; Prognosis; Tacrolimus; Treatment Outcome

Liver transplantation has been widely accepted as an effective intervention for end-stage liver diseases and early hepatocellular carcinomas. However, a variety of postoperative complications and adverse reactions have baffled medical staff and patients. Currently, transplantation monitoring relies primarily on nonspecific biochemical tests, whereas diagnosis of multiple complications depends on invasive pathological examination. Therefore, a noninvasive monitoring method with high selectivity and specificity is desperately needed. This review summarized the potential of endogenous small-molecule metabolites as biomarkers for assessing graft function, ischemia-reperfusion injury and liver rejection. Exogenous metabolites, mainly those immunosuppressive agents with high intra- and inter-individual variability, were also discussed for transplantation monitoring.

Topics: Biomarkers; Carcinoma, Hepatocellular; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Metabolome; Mycophenolic Acid; Postoperative Complications; Prognosis; Reperfusion Injury; Tacrolimus

Tacrolimus, a potent posttransplant immunosuppressant, has been associated with major neuropsychiatric complications, including catatonia and psychosis. We report a novel case of tacrolimus-induced encephalopathy that developed 16 years after renal transplantation while the drug was at a therapeutic level. Discontinuation of tacrolimus and switching to an alternative immunosuppressant resulted in significant clinical improvement over 1 week. Our experience illustrates the possibility of acute neurotoxicity from tacrolimus even when the patient has tolerated the drug for 16 years and drug levels are within the therapeutic range. This case also highlights the importance of collaboration between psychiatry and transplant clinicians.

Topics: Aged; Antipsychotic Agents; Catatonia; Cyclosporine; Electroencephalography; Female; GABA Modulators; Humans; Immunosuppressive Agents; Kidney Transplantation; Lamotrigine; Lorazepam; Postoperative Complications; Tacrolimus

Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents (in particular, immunosuppression) added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification (for example, diet, exercise, and smoking cessation) or by pharmacological means (for example, statins, anti-hyperglycemics, and so on). Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article.

Topics: Antiviral Agents; Cardiovascular Diseases; Diabetes Mellitus; Hepatitis C, Chronic; Humans; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Mortality; Neoplasms; Postoperative Complications; Risk Factors; Tacrolimus

Resistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene).. We describe our experience in management of R-CMV after renal transplant at our center (2012-2016).. We encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks).. Resistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple, Viral; Female; Foscarnet; Ganciclovir; Humans; Induction Chemotherapy; Kidney Transplantation; Male; Middle Aged; Mutation; Postoperative Complications; Recombinant Fusion Proteins; Tacrolimus; Valganciclovir; Virus Replication

Early detection of post-transplantation diabetes mellitus (PTDM) allows prompt clinical and pharmacological interventions, reducing the chance of adverse outcomes. We conducted a systematic review and meta-analysis to determine the overall diagnostic accuracy of glycated hemoglobin (HbA1c) for the diagnosis of renal PTDM.. We searched MEDLINE, Embase and SCOPUS up to June 2016. Studies that included adults without previous diabetes were selected if they reported an oral glucose tolerance test as a reference test, HbA1c levels measured by standardized methods and data necessary for drawing 2 × 2 tables. A bivariate model was used to calculate the pooled estimates.. Based on 2057 kidney recipients from six studies, an HbA1c cut-off point of 6.5% in early months after transplant resulted in sensitivity of 0.48 [95% confidence interval (95% CI) 0.31-0.65], specificity of 0.96 (95% CI 0.95-0.97), positive likelihood ratio (PLR) of 12.0 (95% CI 7.4-19.5) and negative likelihood ratio (NLR) of 0.54 (95% CI 0.38-0.77). Based on 1888 kidney recipients from four studies, an HbA1c cut-off point of 6.2% early after transplant resulted in sensitivity of 0.76 (95% CI 0.49-0.91), specificity of 0.89 (95% CI 0.86-0.92), PLR of 7.18 (95% CI 5.29-9.75) and NLR of 0.27 (95% CI 0.11-0.65).. HbA1c cut-off points of 6.5% and 6.2% presented high specificity but low/moderate sensitivity to diagnose PTDM.

Topics: Adrenal Cortex Hormones; Cyclosporine; Diabetes Mellitus; Glucose Tolerance Test; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sensitivity and Specificity; Tacrolimus

Post-transplant diabetes mellitus is a significant risk factor for cardiovascular disease in solid organ transplantation. The main underlying pathophysiological mechanism of PTDM is pancreatic beta cell dysfunction in the context of insulin resistance, but the relative importance of each of these important components of glycemic metabolism is under intense debate.. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials to January 15, 2015. We selected systematic reviews and meta-analyses and randomized clinical trials. When no such reports were found for a given topic or drug, observational studies were included in the assessment.. There are agents with known diabetogenic effects: corticosteroids, calcineurin inhibitors including tacrolimus and cyclosporine, as well as the mammalian target of rapamycin inhibitors (sirolimus and everolimus). The association between the use of induction agents and PTDM is very scarce. No diabetogenic effects have been found with the use of azathioprine, mycophenolate mofetil and its derivatives.. Immunosuppression is the major modifiable risk factor for development of PTDM but risk versus benefit analysis is required to balance risk of developing PTDM versus rejection. Caution is advisable in immunosuppressant adjustments in the event that PTDM develops based on current evidence. Physicians should choose and use immunosuppression regimens shown to have the best outcome for patient and graft survival, irrespective of PTDM risk.

Topics: Adrenal Cortex Hormones; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Everolimus; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

Topics: Allografts; Antioxidants; Calcineurin Inhibitors; Cardiovascular Agents; Cytomegalovirus Infections; Everolimus; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

Annually, about 8000 heart and lung transplantations are successfully performed worldwide. However, morbidity and mortality still pose a major concern. Renal failure in heart and lung transplant recipients is an essential adverse cause of morbidity and mortality, often originating in the early postoperative phase. At this time of clinical instability, the kidneys are exposed to numerous nephrotoxic stimuli. Among these, tacrolimus toxicity plays an important role, and its pharmacokinetics may be significantly altered in this critical phase by fluctuating drug absorption, changed protein metabolism, anemia and (multi-) organ failure. Limited understanding of tacrolimus pharmacokinetics in these circumstances is hampering daily practice. Tacrolimus dose adjustments are generally based on whole blood trough levels, which widely vary early after transplantation. Moreover, whole blood trough levels are difficult to predict and are poorly related to the area under the concentration-time curve. Even within the therapeutic range, toxicity may occur. These shortcomings of tacrolimus monitoring may not hold for the unbound tacrolimus plasma concentrations, which may better reflect tacrolimus toxicity. This review focuses on posttransplant tacrolimus pharmacokinetics, discusses relevant factors influencing the unbound tacrolimus concentrations and tacrolimus (nephro-) toxicity in heart and lung transplantation patients.

Topics: Drug Monitoring; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Postoperative Complications; Prognosis; Tacrolimus; Tissue Distribution

Skin is the most immunogenic component of a vascularized composite allograft (VCA) and is the primary trigger and target of rejection. The skin is directly accessible for visual monitoring of acute rejection (AR) and for directed biopsy, timely therapeutic intervention, and management of AR. Logically, antirejection drugs, biologics, or other agents delivered locally to the VCA may reduce the need for systemic immunosuppression with its adverse effects. Topical FK 506 (tacrolimus) and steroids have been used in clinical VCA as an adjunct to systemic therapy with unclear beneficial effects. However, there are no commercially available topical formulations for other widely used systemic immunosuppressive drugs such as mycophenolic acid, sirolimus, and everolimus. Investigating the site-specific therapeutic effects and efficacy of systemically active agents may enable optimizing the dosing, frequency, and duration of overall immunosuppression in VCA with minimization or elimination of long-term drug-related toxicity.

Topics: Animals; Drug Compounding; Graft Rejection; Humans; Immunosuppression Therapy; Neovascularization, Physiologic; Plastic Surgery Procedures; Postoperative Complications; Skin Transplantation; Tacrolimus; Transplantation, Homologous

Renal transplantation is the best therapy for patients with end-stage renal disease. To avoid graft rejection, adequate immunosuppressive therapy is crucial. Tacrolimus is approved for prophylaxis of transplant rejection in liver, kidney or heart allograft recipients and for the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products.. The objective of this review is to summarize the clinical efficacy of tacrolimus in renal transplantation with special emphasis on acute rejection, refractory rejection and nephrotoxicity and post-transplant diabetes mellitus as typical adverse effects of the drug.. Since its approval in 1994, tacrolimus has proven its efficacy as a cornerstone of modern immunosuppressive therapy not only in numerous randomized clinical trials but also in standard clinical care. Compared with cyclosporine, the use of tacrolimus in renal transplant recipients is associated with a reduced risk for acute rejection, a reduction in the occurrence of steroid-resistant rejection and a better graft function. The avoidance of nephrotoxicity and especially post-transplant diabetes mellitus are of major interest in long-term care of renal transplant recipients.

Topics: Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Mycophenolic Acid; Organ Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft failure among kidney transplant recipients. Chronic allograft dysfunction (CAD) is a multifactorial process associated with progressive interstitial fibrosis and tubular atrophy. Current Data confirms that an additive series of time-dependent immunological factors such as acute and chronic antibody- and/or cell-mediated rejection and nonimmunological factors are involved in development of interstitial fibrosis and tubular atrophy as the fundamental parts of CAD. The use of calcineurin inhibitors has produced a major impact on achieving successful organ transplantation; however, although this assumption has been doubted recently, calcineurin inhibitors are deemed to be associated with nephrotoxicity and subsequent interstitial fibrosis, tubular atrophy, and kidney dysfunction. The early fibrotic changes are due to implantation stress, T-cell-mediated rejection, and infection; however, usually they do not lead to progressive fibrosis and allograft dysfunction per se. In the setting of CAD, many factors occurring lately after 1 year, such as chronic antibody-mediated rejection, recurrent or de novo glomerulonephritis, and nonadherent adequately address the existence of ongoing injuries and progression to fibrosis. Identification of patients who are at risk, close clinical monitoring, and optimization and individualization of their maintenance immunosuppressive regimen are among the means that could help us to improve the long-term outcome of kidney transplantation.

Topics: Calcineurin Inhibitors; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Primary Graft Dysfunction; Tacrolimus; Transplantation, Homologous

Endoplasmic reticulum (ER) stress is a situation caused by the accumulation of unfolded proteins in the endoplasmic reticulum, triggering an evolutionary conserved adaptive response termed the unfolded protein response. When adaptation fails, excessive and prolonged ER stress triggers cell suicide. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including diabetes, hypoxia, ischemia/reperfusion injury, neurodegenerative and heart diseases. The implication of the ER stress is not well recognized in solid organ transplantation, but increasing evidence suggests its implication in mediating allograft injury. The purpose of this review is to summarize the mechanisms of ER stress and to discuss its implication during tissue injury in solid organ transplantation. The possible implications of the ER stress in the modifications of cell functional properties and phenotypic changes are also discussed beyond the scope of adaptation and cell death. Increasing the understanding of the cellular and molecular mechanisms of acute and chronic allograft damages could lead to the development of new biomarkers and to the discovery of new therapeutic strategies to prevent the initiation of graft dysfunction or to promote the tissue regeneration after injury.

Topics: Animals; Apoptosis; Cyclosporine; Diabetes Mellitus, Type 2; Drug Delivery Systems; Endoplasmic Reticulum; Graft Survival; Humans; Insulin Resistance; Islets of Langerhans; Kidney Transplantation; Liver Transplantation; Mice; Organ Preservation; Postoperative Complications; Reperfusion Injury; Tacrolimus; Transplantation; Transplantation, Homologous; Unfolded Protein Response

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Diabetic Nephropathies; Disease Progression; Epstein-Barr Virus Infections; Fatal Outcome; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Lumbar Vertebrae; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Pancreas Transplantation; Plasmacytoma; Postoperative Complications; Prednisone; Reoperation; Rituximab; Spinal Neoplasms; Tacrolimus; Thalidomide

Four months after receiving an orthotopic liver transplant, a 51-year-old man was admitted for progressive liver failure and severe hepatocellular necrosis thought to be due to tacrolimus. During his hospitalization he experienced bloodstream infections including fungemia due to Trichosporon mucoides and prolonged undulating fever despite antifungal and antibacterial treatment. He underwent removal of the allograft and implantation of another liver. Fever continued postoperatively until therapy with posaconazole was initiated. Initiation of posaconazole led to clinical improvement until the patient's demise from bacteremic vancomycin-resistant enterococcal peritonitis. Trichosporonosis appears to be an emerging fungal infection among immunocompromised individuals (including both hematological and solid organ transplant recipients). T. mucoides is a rare cause of systemic infection. When it occurs, trichosporonosis usually is associated with hematological malignancies and, to the best of our knowledge, has not been previously reported in a liver transplant recipient. The optimal treatment is not well defined. We report here the first case using posaconazole for treatment of trichosporonosis in a liver transplant recipient caused by T. mucoides.

Topics: Antifungal Agents; Enterococcus faecium; Fatal Outcome; Fungemia; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycoses; Peritonitis; Postoperative Complications; Tacrolimus; Triazoles; Trichosporon; Vancomycin; Vancomycin Resistance

Advances in liver transplantation (LT), particularly in immunosuppression and intensive care treatment have had increased the number of long-term survivors following liver transplantation. In order of more long-term survivors, reports about neurological complication following liver transplantation are increasing. Neurological complications are not uncommon in liver transplant recipients, which contribute to a longer ICU- and in-hospital stay. Every effort should be focused on early detection to prevent the patient from this life-threatening event, which is often associated with poor life quality.

Topics: Brain; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Early Diagnosis; Hepatic Encephalopathy; Humans; Immunosuppressive Agents; Liver Transplantation; Neurotoxicity Syndromes; Postoperative Complications; Tacrolimus

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.

Topics: Antiviral Agents; BK Virus; Cystitis; Cytomegalovirus Infections; Fatal Outcome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatorenal Syndrome; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoma, Follicular; Male; Middle Aged; Myelodysplastic Syndromes; Nephritis, Interstitial; Polyomavirus Infections; Postoperative Complications; Reoperation; Tacrolimus; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous

Tacrolimus and cyclosporine are the 2 major immunosuppressants for lung transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this meta-analysis of randomized controlled trials (RCTs) was to compare the beneficial and harmful effects of tacrolimus and cyclosporine as the primary immunosuppressant for lung transplant recipients.. We conducted searches of electronic databases and manual bibliographies. We performed a meta-analysis of all RCTs comparing tacrolimus with cyclosporine as primary immunosuppression for lung transplant recipients. Extracted, pooled data for mortality, acute rejection, withdrawals, and adverse events were analyzed using Mantel-Haenszel tests with a random effects model.. Three RCTs including 297 patients were assessed in this study. Mortality at 1 year or more was comparable between lung recipients treated with tacrolimus and cyclosporine (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.42-2.10; P = .88). Tacrolimus-treated patients experienced fewer incidences of acute rejection (MD = -0.14; 95% CI, -0.28 to -0.01; P = .04). Pooled analysis showed a trend toward a lower risk of bronchiolitis obliterans syndrome (BOS) among tacrolimus-treated patients, although it did not reach significances (OR, 0.53; 95% CI, 0.25-1.12; P = .10). Fewer patients stopped tacrolimus than cyclosporine (OR, 0.12; 95% CI, 0.03-0.48; P = .003). The rate of new-onset diabetes was higher among the tacrolimus group (OR, 3.69; 95% CI, 1.17-11.62; P = .03). The incidence of hypertension and renal dysfunction were comparable in these 2 groups (OR, 0.24; 95% CI, 0.03-1.70; P = .15; and OR, 1.67; 95% CI, 0.70-3.96; P = .25, respectively). There was a trend toward lower risk of malignancy in tacrolimus-treated patients, although it did not reach significance either (OR, 0.19; 95% CI, 0.03-1.13; P = .07). The incidence of infection was comparable in these 2 groups (MD = -0.29, 95% CI, -0.68 to 0.11; P = .16).. Using tacrolimus as primary immunosuppressant for lung transplant recipient resulted in comparable survival and reduction in acute rejection episodes when compared with cyclosporine.

Topics: Adult; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infections; Lung Transplantation; Odds Ratio; Postoperative Complications; Randomized Controlled Trials as Topic; Registries; Survival Rate; Tacrolimus; Treatment Outcome

Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, have had a potent impact on the success of organ transplantation. However, the nephrotoxicity associated with CNI can cause renal dysfunction, which is an independent risk factor for graft loss and mortality after kidney transplantation (KTx). Thus, the search for an optimal immunosuppressive therapy continues to be crucial in KTx. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We conducted a literature review (PubMed, Medline) on this issue. Maximum reduction in CNI is associated with a modest improvement in renal function; however, the kidney damage is observed as long as CNIs are maintained. Avoidance of CNI is associated with high acute rejection rates. CNI withdrawal may be the optimal strategy because it reduces early immunologic graft injury after KTx, particularly when CNI withdrawal is initiated before irreversible renal damage. These strategies seem feasible with mycophenolate acid, sirolimus and induction therapy with interleukin-2 receptor antibodies as concurrent immunosuppressants.

Topics: Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Postoperative Complications; Tacrolimus

The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCT) to compare the effectiveness and safety of induction with and without antithymocyte globulin (ATG) combined with cyclosporine/tacrolimus-based immunosuppression in renal transplantation.. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane controlled trials register, Cochrane Renal Group Specialized Register of RCTs, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality, and then extracted data. Data were extracted for patient and graft survival, acute rejection, the incidence of Banff, cytomegalovirus (CMV) infection, leukopenia, and thrombocytopenia. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CI).. Four RCTs (892 patients) were identified. The data showed that induction with ATG was more beneficial than no induction with ATG to reduce the incidence of chronic rejection (RR 0.70; 95% CI, 0.57-0.84) and acute rejection within 6 months (RR 0.68; 95% CI, 0.49-0.96) and at 12 months (RR 0.67; 95% CI, 0.50-0.89) as well as Banff II episodes (RR 0.53; 95% CI, 0.30-0.91), but increased the incidences of CMV infection (RR 1.61; 95% CI, 1.27-2.04) and leukopenia (RR 3.88; 95% CI, 2.80-5.38) and thrombocytopenia (RR 2.92; 95% CI, 1.77-4.04). There was no statistical difference between patient or graft survival rates at 6 and 12 months, as well as the incidences of Banff III or Banff I after transplantation.. Based on available data induction with ATG was more efficient to reduce the rate of acute rejection episodes and chronic rejection responses after renal transplantation, but was associated with increased side effects, particularly CMV infections. It is important to provide the most benefit for an individual patient.

Topics: Adult; Antilymphocyte Serum; China; Confidence Intervals; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Randomized Controlled Trials as Topic; Registries; Risk; Survival Rate; Survivors; Tacrolimus

In this article there were regarded the most frequent side effects that appear in the patients who have been treated with topical tacrolimus, and the association between topical tacrolimus and the development of tumors is unfolded. The irritation in the site of application of the tacrolimus can manifiest as pruritus, sensation of burning and/or eritema located to the area of the application. It is the most frequent side effect, independently of the duration of the study. The cutaneous infections, especially the viral ones, tend to be more numerous in patients with atopic dermatitis that receive topic tacrolimus. After reviewing the medical literature one concludes that nowadays there doesn t exist scientific evidence of an increase of skin cancer, lymphomas or systemic immunosuppression in those patients that use or have used topical tacrolimus. Nevertheless, it is not possible to exclude the possibility that there appear cutaneous and/or systemic long-term side effects.

Topics: Administration, Cutaneous; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Flushing; Humans; Immunosuppressive Agents; Neoplasms; Neoplasms, Experimental; Organ Transplantation; Postoperative Complications; Pruritus; Retrospective Studies; Skin Absorption; Skin Diseases, Viral; Spain; Tacrolimus

With increasing survival rates, intestinal transplantation (ITx) and multivisceral transplantation have reached the mainstream of medical care. Pediatric candidates for ITx often suffer from severe multisystem impairments that pose challenges to the medical team. These patients frequently require intensive care preoperatively and have unique intensive care needs postoperatively.. We reviewed the literature on intensive care of pediatric intestinal transplantation as well as our own experience. This review is not aimed only at pediatric intensivists from ITx centers; these patients frequently require ICU care at other institutions.. Preoperative management focuses on optimization of organ function, minimizing ventilator-induced lung injury, preventing excessive edema yet maintaining adequate organ perfusion, preventing and controlling sepsis and bleeding from varices at enterocutaneous interfaces, and optimizing nutritional support. The goal is to extend life in stable condition to the point of transplantation. Postoperative care focuses on optimizing perfusion of the mesenteric circulation by maintaining intravascular volume, minimizing hypercoagulability, and providing adequate oxygen delivery. Careful monitoring of the stoma and its output and correction of electrolyte imbalances that may require renal replacement therapy is critical, as are monitoring for and aggressively treating infections, which often present with only subtle clinical clues. Signs of intestinal rejection may be non-specific, and early differentiation from other causes of intestinal dysfunction is important. Understanding of the expanding armamentarium of immunosuppressive agents and their side-effects is required.. As outcomes of ITx improve, transplant teams accept patients with higher pre-operative morbidity and at higher risk for complications. Many ITx patients would benefit from earlier referral for transplant evaluation before severe liver disease, recurrent central venous catheter-related sepsis and venous thromboses develop.

Topics: Child, Preschool; Critical Care; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestines; Liver Transplantation; Pediatrics; Postoperative Care; Postoperative Complications; Preoperative Care; Tacrolimus

Topics: Acute Disease; Chronic Disease; Clinical Trials as Topic; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Postoperative Complications; Sirolimus; Tacrolimus

Calcineurin inhibitors (ciclosporin and tacrolimus) can cause acute and chronic nephrotoxicity. The serum levels of these drugs do not correlate well with the extent of renal damage caused, and the clinical manifestation is nonspecific. Renal biopsy is a reliable tool with which to diagnose calcineurin-inhibitor-induced nephrotoxicity. Ciclosporin and tacrolimus produce identical lesions, which are focal in nature and can be overlooked, necessitating the evaluation of serial tissue sections. Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation. In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy. As maintenance doses of calcineurin inhibitors in renal transplant recipients have been lowered during the past decade, the incidence of acute toxicity has decreased markedly. Chronic toxicity, however, is still prevalent, and causes chronic allograft damage.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Tacrolimus

Pediatric heart transplantation is a surgical therapy for dilated cardiomyopathy and for complex congenital heart defects with low pulmonary artery resistance. However, it is still discussed as controversial because of uncertain long-term results. We report our experience with pediatric heart transplantation in a heterogeneous population.. Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 +/- 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.. Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 +/- 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.. Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.

Topics: Adolescent; Antiviral Agents; Bacterial Infections; Cardiomyopathy, Dilated; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Female; Follow-Up Studies; Ganciclovir; Germany; Graft Rejection; Heart Defects, Congenital; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Life Tables; Lymphoma, Non-Hodgkin; Male; Mycophenolic Acid; Pneumonia, Pneumocystis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Vascular Resistance; Virus Diseases

The most prominent side effect of tacrolimus is the induction of posttransplant diabetes mellitus (PTDM). In this review, the authors discuss the incidence, mechanism, prevention, and treatment of tacrolimus-induced PTDM in renal patients.

Topics: Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Risk Factors; Tacrolimus

Liver transplantation has become the standard therapy for patients with end-stage liver disease or acute liver failure, with excellent outcomes in terms of quality of life and length of survival. The use of immunosuppressive agents, without any doubt, has played a crucial role in the establishment of this technique and improved short- and long-term survival rates. Eventually, mortality from acute or chronic rejection may be entirely eliminated. Minimizing the adverse effects of immunosuppressive agents is essential to improve long-term survival and quality of life. In this chapter, we review the history of immunosuppressive agents for liver transplantation with consideration of the pre- and the postcyclosporine eras. We also review the development and contributions of cyclosporine, the excellent outcomes from C2 monitoring, comparisons between the cyclosporine microemulsion and the oil-based formula, as well as between cyclosporine microemulsion versus tacrolimus. In addition, details are provided on the newer immunosuppressive agents: mycophenolate mofetil, sirolimus, and the IL-2 receptor antagonists, as well as agents in development: CAMPATH 1-H, thymoglobulin, everolimus, FT720, and FK778.

Topics: Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Survival Analysis; Tacrolimus

In our series of 1374 renal transplantations performed between February 1970 and December 2002, we observed 6 cases of infection due to Nocardia asteroides. There were 4 males and 2 females, aged 49.8 +/- 12 years (29 to 63 years). One patient received his first transplantation and the 5 others retransplants. Three patients had PRA > 80%, one 28% and one 40%. One patient was diabetic and two had HCV infection. Two of 6 patients experienced acute rejection episodes. Nocardiosis localisation was pulmonary in 5 cases, cerebral in two and mediastinal in one. All patients recovered after reduction of immunosuppression and appropriate antibiotherapy with trimethoprim-sulfamethoxasole (TMP-SMX). When we analyzed the role of immunosuppression, we observed that only two cases were observed in the 933 recipients transplanted between 1985 and 2002 and receiving cyclosporin, contrasting with 4 cases among 174 recipients transplanted between 1996 and 2002 and receiving tacrolimus. Our data suggest that high immunologic risk patients, heavy immunosuppression, and perhaps tacrolimus-based immunosuppression are risk factors of nocardial infection. Early diagnosis of this severe infection, reduction of immunosuppression and appropriate therapy with TMP-SMX resulted in complete recovery in all our patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Azathioprine; Cyclosporine; Diabetes Complications; Disease Susceptibility; Female; Graft Rejection; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nocardia asteroides; Nocardia Infections; Postoperative Complications; Reoperation; Risk Factors; Tacrolimus; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Cyclosporine; Cytomegalovirus Infections; Diabetes Mellitus; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Cyclosporine; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Liver Transplantation; Lung Transplantation; Lymphocyte Activation; Organ Transplantation; Pancreas Transplantation; Postoperative Complications; T-Lymphocytes; Tacrolimus; Time Factors; Tissue and Organ Harvesting; Tissue Donors; Transplantation Immunology; Waiting Lists

B19 virus infection with persistent anaemia has been reported in organ transplant recipients. Detection of B19 virus DNA in serum is the best direct marker of active infection.. The present study evaluated the incidence and clinical role of active B19 virus infection in renal transplant recipients presenting with anaemia.. Forty-eight such recipients were investigated by nested PCR on serum samples. The controls were 21 recipients without anaemia. Active HCMV infection was also investigated as a marker of high immunosuppression.. In 11/48 (23%) patients B19 virus DNA was demonstrated in serum versus only 1/21 (5%) of the controls. Ten of these 11 patients had already been seropositive at transplantation and active infection occurred in eight of them during the first 3 months after transplantation. The remaining patient experienced a primary infection 9 months after transplantation. Eight (73%) of these 11 patients displayed a concomitant HCMV infection and four (36%) showed increasing serum creatinine levels but none developed glomerulopathy; 3/11 (27%) recovered spontaneously from anaemia whereas 8/11 (73%) needed therapy. In conclusion, the relatively high occurrence (23%) of B19 virus infection in patients presenting with anaemia, suggests that it should be considered in the differential diagnosis of persistent anaemia in renal transplant recipients. Presence of the viral DNA should be assessed early from transplantation and the viral load should be monitored to follow persistent infection and better understand the relation between active infection and occurrence of anaemia, and to assess the efficacy of IVIG therapy and/or immunosuppression reduction in clearing the virus.

Topics: Anemia; Antibodies, Monoclonal; Antibodies, Viral; Antilymphocyte Serum; Basiliximab; Cyclosporine; Cytomegalovirus Infections; Diagnosis, Differential; Disease Susceptibility; DNA, Viral; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interleukin-1; Kidney Transplantation; Male; Mycophenolic Acid; Parvoviridae Infections; Parvovirus B19, Human; Phosphoproteins; Polymerase Chain Reaction; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Retrospective Studies; T-Lymphocytes; Tacrolimus; Viral Load; Viral Matrix Proteins; Viremia; Zidovudine

Early after renal transplantation (RT) a rapid decrease in bone mineral density at the lumbar spine, femoral neck, and femoral shaft has been documented. In addition, an appreciable proportion of patients still remain losing bone late after RT. As a consequence, RT patients are at a high risk of bone fractures as compared to general population. Most fractures involve appendicular skeleton, particularly the feet and ankles, and the diabetic patient is at increased risk of fractures. Thus, early institution of preventive measures and treatment of established osteoporosis are central. The major cause of post-transplantation bone loss is corticosteroid treatment, and this should be used at the lower dose compatible with graft survival. Preexisting hyperparathyroidism also affects the early cancellous bone loss at the spine, and post-transplantation bone loss reflects variable individual susceptibility, resembling the polygenic determination of bone mineral density in general. Clinical trials have demonstrated that bisphosphonates or vitamin D plus calcium supplementation, prevent post-transplantation bone loss during the first 6-12 months. However, their role in preventing bone fractures has not been proven. Finally, recommendations for management, prevention and treatment, are summarized.

Topics: Absorptiometry, Photon; Adrenal Cortex Hormones; Animals; Biomarkers; Bone and Bones; Bone Density; Calcineurin Inhibitors; Calcium; Diphosphonates; Diuretics; Female; Fractures, Spontaneous; Genetic Predisposition to Disease; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Male; Osteoporosis; Postoperative Complications; Prospective Studies; Rats; Renal Dialysis; Risk; Tacrolimus; Vitamin D

Bowel perforation is an uncommon but serious complication of peritoneoscopic peritoneal dialysis (PD) catheter insertion. The approach to diagnosis of bowel perforation utilizing this technique has not been previously published. The authors report their experience with the diagnosis and management of bowel perforation in the context of peritoneoscopic placement of PD catheters.. The authors retrospectively reviewed the records of 750 PD catheters inserted over a 12-year period (January 1991 to May 2003) utilizing peritoneoscopic technique.. Six (0.8%) patients experienced bowel perforation during the procedure. The diagnosis was made immediately during the procedure in 5 (83%) of the 6 patients. Of these 5, peritoneoscopy confirmed intrabowel position of the cannula by visualizing bowel mucosa (n = 3) and hard stool (n = 1). The fifth patient showed extrusion of fecal matter upon trocar withdrawal before peritoneoscopy. All 5 had emanation of foul-smelling gas through the cannula. Bowel rest and broad-spectrum intravenous antibiotics were initiated. Of the 5, 1 required surgery, whereas the others were discharged home after 3 days. The sixth patient had fever, severe peritoneal irritation, and polymicrobial peritonitis the morning after the procedure. In this patient, no evidence of bowel injury was noted during the procedure except for brief emanation of foul-smelling gas. He required surgical intervention.. Bowel perforation can be diagnosed immediately in most patients undergoing peritoneoscopic PD catheter insertion. A majority of these patients can be treated medically. The surgical team should be consulted if the patient shows clinical deterioration or has signs of peritoneal irritation.

Topics: Abdomen, Acute; Adult; Aged; Anti-Bacterial Agents; Catheterization; Combined Modality Therapy; Diabetic Nephropathies; Drug Therapy, Combination; Feces; Female; Gases; Humans; Immunosuppressive Agents; Intestinal Perforation; Kidney Failure, Chronic; Laparoscopy; Lung Transplantation; Male; Middle Aged; Peritoneal Dialysis; Peritonitis; Postoperative Complications; Retrospective Studies; Surgical Instruments; Tacrolimus

Intestinal transplantation has been gradually instituted in the management of intestinal failure. More than 200 cases including isolated intestinal transplant, liver/intestinal transplant, and multivisceral transplant have been performed worldwide,with 1-year graft and patient survival rates of 66% and 54%,respectively. Indications for the procedure include short bowel syndrome and functional abnormalities secondary to a variety of diseases or conditions. Tacrolimus-based immunosuppression regimens have been used universally with improved outcomes. The major contributors to the morbidity and mortality include rejection,infection, and technical complications. Of those, control of rejection remains the most difficult dilemma and it will be the key to improved patient and graft survival.

Topics: Digestive System Surgical Procedures; Graft Rejection; Humans; Intestines; Liver Transplantation; Patient Selection; Postoperative Care; Postoperative Complications; Short Bowel Syndrome; Survival Rate; Tacrolimus; Tissue Donors; Treatment Outcome

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Postoperative Complications; Sirolimus; Tacrolimus; Transplantation Immunology

The high incidence of hypertension after renal transplantation contributes to the risk of cardiovascular morbidity and mortality in renal transplant recipients. Although cyclosporine has been influential in the improvement of transplant outcome, it has emerged as a major cause of hypertension after organ transplantation. The underlying pathophysiological mechanisms of cyclosporine-induced hypertension include enhanced sympathetic nervous system activity, renal vasoconstriction, and sodium/water retention. Hypertension is also significantly associated with reduced graft survival and thereby requires aggressive treatment intervention. Calcium channel blockers may offer some advantages over angiotensin-converting enzyme inhibitors for the treatment of hypertension in stable renal transplant recipients. Nevertheless, selection of the most appropriate antihypertensive agent should take into account the possibility of pharmacokinetic interactions with immunosuppressive agents. There is evidence to suggest that the use of tacrolimus-based immunosuppression induces less hypertension compared with cyclosporine. Not only do patients receiving tacrolimus tend to require less antihypertensive therapy, but converting patients from cyclosporine to tacrolimus has been shown to result in significant reductions in blood pressure. Thus, tacrolimus may be associated with an improved cardiovascular risk profile in renal transplant recipients.

Topics: Antihypertensive Agents; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

Substitution of cyclosporin with tacrolimus should be considered for paediatric liver transplant recipients with cyclosporin-associated complications such as hypertension, gum hyperplasia, hirsutism, gynaecomastia and growth retardation, as well as recurrent or refractory acute rejection, chronic duct injury or chronic rejection. Continued experience with well tolerated drug administration and careful monitoring during drug substitution has limited drug toxicity associated with tacrolimus to a level comparable to or less than that associated with cyclosporin. Successful outcome with long term graft salvage has been reported in up to 80% of patients converted to tacrolimus because of acute rejection and 50% of patients converted because of chronic rejection. Nearly all children converted because of cyclosporin-related complications have a successful outcome. Additional benefits of conversion to tacrolimus include improvement in growth and resolution of hypertension, hirsutism and cushingoid facies. Complete corticosteroid withdrawal is possible in up to 78% of children post-conversion. Long term outcome in these patients may be optimised by conversion to tacrolimus at an early stage of acute or chronic transplant rejection in order to minimise the cumulative amount of immunosuppression. Avoidance of cyclosporin-related toxicity and minimisation of corticosteroid therapy may further improve patient compliance to drug therapy.

Topics: Child; Cyclosporine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

Skin cancer is the most common malignancy arising in the posttransplantation setting. Multiple factors contribute to the high risk for cutaneous carcinoma in immunosuppressed organ-transplant recipients. We review the phenomenon of skin cancer in solid-organ transplant recipients and further delineate the problem in the context of liver transplantation. Skin cancer is a significant medical and surgical problem for organ-transplant recipients. With prolonged allograft function and patient survival, the majority of solid-organ transplant recipients will eventually develop skin cancer. Although squamous cell carcinoma is the most common cutaneous malignancy in this population, basal cell carcinoma, melanoma, and Kaposi's sarcoma, as well as uncommon skin malignancies, may occur. Highly susceptible patients may develop hundreds of squamous cell carcinomas, which may be life threatening. Management strategies focus on regular full-skin and nodal examination, aggressive treatment of established malignancies, and prophylactic measures to reduce the risk for additional photodamage and malignant transformation. Skin cancer is a substantial cause of morbidity and even mortality among solid-organ transplant recipients. As a byproduct of immunosuppression, liver transplant recipients experience a high incidence of skin cancer and should be educated and managed accordingly.

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Keratosis; Liver Transplantation; Postoperative Complications; Skin Neoplasms; Tacrolimus

Clinical liver transplantation became an established therapy of end-stage liver disease since the first at least medium-term successful liver transplantation in 1967. Clinical studies have played a major part in improving peri- and postoperative therapy in liver transplantation. In this article clinical studies of major impact are presented. Main topics are studies dealing with immunosuppressants, improvements in surgical techniques, viral infections and tumor diseases. Controlled randomized multicentric studies are rare; most of the studies are unicentric. Further studies in the fields of reducing side effects of immunosuppression, the introduction of monoclonal antibodies and improvement of the therapy of viral hepatitis would be helpful. These studies should be controlled, randomized and multicentric.

Topics: Carcinoma, Hepatocellular; Cyclosporine; Cytomegalovirus Infections; Double-Blind Method; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Multicenter Studies as Topic; Postoperative Complications; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Tacrolimus

Between 10%-28% of patients who receive the immunosuppressant cyclosporine (CsA) experience some form of neurotoxic adverse event. Both sensorial motoric functions may be adversely affected, and thus patients present with a wide range of neurological and psychiatrical disorders. Mild symptoms are common and include tremor, neuralgia, and peripheral neuropathy. Severe symptoms affect up to 5 % of patients and include psychoses, hallucinations, blindness, seizures, cerebellar ataxia, motoric weakness, or leukoencephalopathy. Tacrolimus is associated with similar neurotoxic adverse events. Neurotoxicity may result in serious complications for some patients, particularly recipients of orthotopic liver transplants. Factors that may promote the development of serious complications include advanced liver failure, hypertension, hypocholesterolemia, elevated CsA or tacrolimus blood levels, hypomagnesemia, and methylprednisolone. Occipital white matter appears to be uniquely susceptible to the neurotoxic effects of CsA; injury to both the major and minor vasculature may cause hypoperfusion or ischemia and local secondary toxicity in the white matter. Calcineurin inhibition by CsA and tacrolimus alters sympathetic outflow, which may play a role in the mediation of neurotoxic and hypertensive adverse events. The symptoms of CsA- and tacrolimus-associated neurotoxicity may be reversed in most patients by substantially reducing the dosage of immunosuppressant or discontinuing these drugs. However, some patients have experienced permanent or even fatal neurological damage even after dose reduction or discontinuation. CsA-sparing and tacroli-mus-sparing drug regimens that use the immunosuppressant mycophenolate mofetil, which has no neurotoxic effects, may reduce the incidence and severity of neurotoxic adverse events while maintaining an adequate level of immunoisuppression.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Mental Disorders; Nervous System Diseases; Neurotoxins; Postoperative Complications; Tacrolimus; Transplantation Immunology

Hemolytic-uremic syndrome (HUS) is a rare, but well-described complication in organ transplant recipients maintained on cyclosporine immunosuppression. Tacrolimus is a newer agent with similar immunosuppressant efficacy. In cases of cyclosporine-related HUS in renal transplant recipients, tacrolimus has been used successfully without recurrence of HUS. Tacrolimus has been reported to cause HUS in renal and more recently in cardiac transplant patients. We report a case of HUS in a lung transplant recipient receiving tacrolimus who was subsequently converted to cyclosporine without recurrence of HUS.

Topics: Cyclosporine; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Lung Transplantation; Middle Aged; Postoperative Complications; Tacrolimus

Legionella micdadei (Pittsburgh pneumonia agent) is the second most common cause of Legionella pneumonia, and occurs predominantly in immunocompromised hosts. L micdadei is the cause of nosocomial pneumonia in renal transplant recipients, but has not been described in other adult solid organ transplant recipients. This report describes the first case of L micdadei pneumonia in an adult liver transplant recipient on immunosuppressive therapy. Importantly, this case highlights the difficulties in establishing the diagnosis, as the Legionella urinary antigen is negative, and special culture conditions are required. Furthermore, this case illustrates several atypical clinical features of L micdadei pneumonia in a transplant recipient, including a community acquired mode of transmission, occurrence several years after organ transplantation, and lung abcess formation. The patient was successfully treated with limited surgical resection and quinolone antimicrobial monotherapy.

Topics: Adult; Anti-Infective Agents; Bronchoalveolar Lavage Fluid; Ciprofloxacin; Diabetes Mellitus, Type 2; Hepatitis B; Humans; Immunosuppressive Agents; Legionellosis; Liver Transplantation; Lung Abscess; Male; Pneumonia, Bacterial; Postoperative Complications; Tacrolimus; Tomography, X-Ray Computed

Topics: Coronary Disease; Cyclosporine; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppression Therapy; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mycophenolic Acid; Polyenes; Postoperative Complications; Sirolimus; Tacrolimus

Topics: Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Survival Rate; Tacrolimus

Credit for the first pediatric heart transplant is given to Kantrowitz and colleagues who, in 1967, transplanted the heart of an anencephalic infant into a 3-week-old with tricuspid atresia (1). Although the infant only survived a few hours after surgery, this pioneering procedure emphasized the technical feasibility of heart transplantation in childhood. Over the next decade, enthusiasm for heart transplantation declined in both adults and children, as it became apparent that the therapeutic armamentarium for controlling acute allograft rejection was inadequate for achieving graft and patient survival. Towards the end of the 1970s, several advances led to renewed interest in human heart transplantation. These included topical cooling of the donor heart to protect the myocardium from ischemia (and enabling distant procurement), the technique and interpretation of endomyocardial biopsy for the diagnosis of allograft rejection (2) and, most importantly, the introduction of cyclosporine into human clinical trials (3). Cyclosporine was the first oral agent specifically to inhibit T lymphocytes, the principal mediators of allograft rejection. The favorable impact on survival of adult heart transplant recipients was immediately apparent (4) and led to renewed interest in pediatric heart transplantation. The pediatric heart transplant program at the University of Pittsburgh commenced in 1982, drawing on the experience of the adult program which had begun two years earlier. It rapidly became apparent that children present unique problems for the transplant physician and surgeon. This review draws on many of the lessons learned in our program over the last 15 years and reviews some of the prospects for the future of pediatric thoracic organ transplantation.

Topics: Child; Contraindications; Graft Rejection; Heart Diseases; Heart Transplantation; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoproliferative Disorders; Patient Selection; Pennsylvania; Postoperative Complications; Survival Analysis; Tacrolimus; Tissue Donors

Topics: Antimetabolites; Bone Density; Cyclosporine; Glucocorticoids; Heart Transplantation; Humans; Immunosuppressive Agents; Osteoporosis; Postoperative Complications; Tacrolimus

Tacrolimus (FK 506) is a macrolide immunosuppressant which possesses similar but more potent immunosuppressant properties compared with cyclosporin, inhibiting cell-mediated and humoral immune responses. Like cyclosporin, tacrolimus demonstrates considerable interindividual variation in its pharmacokinetic profile. This has caused difficulty in defining the optimum dosage regimen and has highlighted the usefulness of therapeutic drug monitoring. Most clinical studies with tacrolimus have neither been published in their entirety nor subjected to extensive peer review; there is also a paucity of published randomised investigations of tacrolimus versus cyclosporin, particularly in renal transplantation. Despite these drawbacks, tacrolimus has shown notable efficacy as a rescue or primary immunosuppressant therapy when combined with corticosteroids in adult and paediatric recipients following liver or kidney transplantation. Indeed, graft salvage rates in patients experiencing rejection or drug-related toxicity were > or = 50%, although data in renal transplantation are limited. Compared with cyclosporin as a primary immunosuppressant, tacrolimus showed comparable or greater patient/graft survival rates in liver allograft recipients (where cost savings associated with reduced hospitalisation costs were evident in one study), and comparable patient/graft survival in patients following kidney transplantation. Worthy of note was the efficacy of tacrolimus as a primary immunosuppressant in patients who received en bloc kidney allografts. The incidence of rejection was largely reduced following rescue therapy with tacrolimus and was generally lower (notably for refractory rejection) than that observed for cyclosporin, at least in liver allograft recipients. This was reflected in less need for adjunct immunotherapy including antilymphocyte preparations for the treatment of rejection episodes. The potential for reduction or withdrawal of corticosteroid therapy with tacrolimus appears to be a distinct advantage compared with cyclosporin, and this may be enhanced by the reduced incidence of infectious complications and of hypertension and hypercholesterolaemia reported by some investigators. In other respects, however, the tolerability profile of tacrolimus appears to be broadly similar to that of cyclosporin. Against this background, preliminary data indicate that tacrolimus provides a valuable therapeutic alternative to retransplantation in patients experiencing liv

Topics: Adult; Child, Preschool; Humans; Kidney Transplantation; Liver Transplantation; Postoperative Complications; Tacrolimus; Treatment Outcome

Renal dysfunction often complicates the course of liver transplant recipients. Preoperative renal dysfunction, including hepatorenal syndrome (HRS) may be present. Assessment of renal function in the pretransplant patient with end-stage liver disease is fraught with pitfalls. Direct measurement of GFR by a method other than creatinine clearance is recommended wherever possible. Preoperative renal biopsy should also be considered in those patients with renal dysfunction in whom the diagnosis of HRS is not definite. With the routine use of veno venous bypass, renal perfusion is maintained and intraoperative events generally do not play a significant role in the development of postoperative dysfunction. Postoperatively immunosuppressive medications such as CsA or FK506 account for most of the renal dysfunction that is observed. Other factors such as graft dysfunction, sepsis, and nephrotoxic drugs may also participate in renal impairment. The exact mechanism of cyclosporine or FK506 nephrotoxicity remains unknown. In liver transplant recipients, no convincing therapeutic strategies exist to combat nephrotoxicity other than dose reduction of immunosuppressive therapy. Patients with HRS can be successfully treated by liver transplantation with recovery of renal function and with patient survival rates comparable to recipients without HRS, despite increased morbidity.

Topics: Cyclosporine; Glomerular Filtration Rate; Hepatorenal Syndrome; Humans; Intraoperative Period; Kidney; Kidney Diseases; Liver Failure; Liver Transplantation; Postoperative Complications; Preoperative Care; Tacrolimus

BACKGROUND At present, there is no ideal conventional triple regimen that can effectively treat gastrointestinal (GI) complications in patients after kidney transplantation. We aimed to investigate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids, compared with regimens containing standard-dose tacrolimus, corticosteroids, plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after renal transplantation. MATERIAL AND METHODS Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplant recipients with MPA-related GI complications were enlisted in a single-center, prospective, randomized, control study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group, 37 recipients were assigned to the low-dose EC-MPS group, and 39 recipients were assigned to the standard-dose MZR group. We analyzed the Gastrointestinal Symptom Rating Scale (GSRS), estimated glomerular filtration rate (eGFR), graft rejection, serum creatinine, human leukocyte antigen (HLA) antibody, and the occurrence of adverse events among the 3 groups. RESULTS Compared with baseline, gastrointestinal symptoms improved significantly in all 3 groups. The reduction in mean subscale scores from baseline to month 3 was more significant in the standard-dose MZR group compared with the other 2 groups. The low-dose EC-MPS plus low-dose MZR group had better renal function. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection, as well as the incidence of hyperuricemia, in the low-dose EC-MPS plus low-dose MZR group were all significantly reduced. CONCLUSIONS This quadruple regimen may be equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplant, and is also advantageous for kidney function, graft rejection, and the rates of adverse events.

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome; Young Adult

To describe the incidence of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving an mTOR-inhibitor-containing immunosuppressive regimen without prophylactic CMV treatment.. This single-center retrospective cohort analysis included all de novo kidney transplant recipients (09/15/2015-07/31/2017) receiving 3 mg/kg single dose of rabbit antithymocyte globulin induction, tacrolimus, everolimus, and prednisone. Preemptive therapy was initiated only in patients deemed at higher risk for CMV infection: (a) D+/R- CMV patients; (b) after treatment for acute rejection (ARt); and (c) after everolimus discontinuation (EVRd).. Of 230 patients, there were no episodes of CMV disease among 217 (94%) without criteria to initiate preemptive therapy. Of 77 (33.5%) patients initiating preemptive therapy, 13 were D+/R-, 30 were ARt, and 34 were EVRd. The overall incidence of first CMV infection/disease was 6% (46.1% in D+/R-, 13.3% ARt [all patients had also discontinued everolimus], and 11.8% after early [<90 days] EVRd). The incidence of biopsy-proven acute rejection was 5.6%, and median glomerular filtration rate at month 12 was 47 mL/min/1.73m. This study suggests that everolimus-containing immunosuppressive regimen reduces the need for preventive strategies for CMV infection in the majority of kidney transplant recipients, reducing antiviral drug-associated toxicities and healthcare-related expenditures.

Topics: Adult; Antilymphocyte Serum; Brazil; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein.. Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout.. The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7).. In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation.

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Organ Transplantation; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Transplant Recipients

Transplant nurse (RN) coordinators review tacrolimus levels frequently and would be capable of making dose adjustments autonomously if not limited by their license. Collaborative practice agreements could be an answer; thus, the aim of this evaluation was to determine if an RN-driven protocol could be used safely and effectively to manage tacrolimus in ambulatory kidney transplant (KTX) recipients.. This was a retrospective review of all solitary adult KTX recipients between August 1, 2016, and July 29, 2017. The primary objective was to evaluate protocol adherence and frequency of use, and secondary objectives were to evaluate the utility of the protocol both overall and based on ethnicity.. A total of 173 patients were included in the evaluation (59% African American [AA], 41% non-African American [non-AA). RN coordinators followed the protocol for 75% of tacrolimus adjustments; however, they only responded to 27% of the overall levels. There was no difference in 180-day tacrolimus-associated readmission (15% AA vs 5% non-AA, P = .06), biopsy-proven acute rejection (4% AA vs 7% non-AA, P = .363), or hyperkalemia (34% AA vs 32% non-AA, P = .87) between groups.. Transplant nurse coordinators are capable of accurately following a protocol for tacrolimus dosage adjustment in a large, racially diverse kidney transplant center.

Topics: Adult; Aged; Black or African American; Delivery of Health Care, Integrated; Disease Management; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Nursing Care; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; South Carolina; Tacrolimus; Young Adult

Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins; however, little data exist using high-intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus.. This single-center, retrospective analysis included adult HT recipients from January 1, 2005, to December 31, 2015, who received HI statin therapy during posttransplant follow-up. The primary outcome, tolerability, was defined as the absence of myalgias, hepatotoxicity, rhabdomyolysis, or HI statin dose reduction/discontinuation. The secondary end point was the mean reduction in total and LDL cholesterol.. Among the 24 patients included, one experienced myalgias and therapy discontinuation (4%; P > 0.99). No other HI statin dose reduction/discontinuation occurred, and no instances of rhabdomyolysis or hepatotoxicity were observed. The average reduction in total and LDL cholesterol after conversion to HI statin was 35 mg/dL (P = 0.02) and 19 mg/dL (P = 0.10), respectively.. High-intensity statin therapy appears safe and efficacious in HT recipients receiving tacrolimus and is a reasonable option for the treatment of refractory hyperlipidemia.

Topics: Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Diseases; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Immunosuppressive Agents; Incidence; Male; Maximum Tolerated Dose; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Tacrolimus; United States

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.

Topics: Adult; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus; Transplant Recipients; Transplantation, Homologous; United States

This was a single-center, randomized controlled trial assessing the impact of a 3-month (10-16 weeks) conversion to everolimus with low-exposure tacrolimus, as compared to remaining on full exposure tacrolimus with mycophenolate (NCT02096107). Adult kidney transplant recipients with a functioning graft were eligible for participation. Goal troughs in the intervention arm were 2-5 ng/mL for tacrolimus and 3-8 ng/mL for everolimus, with tacrolimus maintained at 5-12 ng/mL in the control arm; 60 were randomized (30 in each arm) and were well matched at baseline; mean age was 51 years and 57% were African-American. At 12-months, fibrosis scores (27.8% tacrolimus/mycophenolate vs 22.9% tacrolimus/everolimus, P = .391), acute rejection rates (7% tacrolimus/mycophenolate vs 3% tacrolimus/everolimus, P = .554), and graft function (mean eGFR tacrolimus/mycophenolate 56 ± 15 vs tacrolimus/everolimus 59 ± 14 mL/min/1.73 m

Topics: Adult; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Survival Rate; Tacrolimus

Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires retransplantation. This study evaluates the incidence and outcome of the patients with CR at a large living donor liver transplant (LDLT) center.. Data of patients with CR were retrospectively analyzed in 1232 adult (age >18 years) LDLT on tacrolimus (mainly)-based immunosuppression. Sirolimus/everolimus (mammalian target of rapamycin [mTOR] inhibitors) was added to baseline immunosuppression as rescue therapy in patients with CR. Data are shown as median (interquartile range [IQR]).. Twenty-three patients (22 males), aged 42 (IQR 45-56) years, had biopsy-proven chronic rejection at 21 (8-44) months after liver transplantation. The incidence of chronic rejection was 1.9% in this cohort. The patients with CR (n = 23) had a significantly higher incidence of cytomegalovirus (CMV) viremia, acute cellular rejection, and history of anastomotic biliary strictures as compared to patients without CR. Five patients were noncompliant with immunosuppression before the diagnosis of CR. Twelve patients (52%) responded to addition of mTOR inhibitors, whereas 11 did not respond and had poor outcome.. The incidence of chronic rejection is low in LDLT. Treatment with mTOR inhibitors can reverse graft dysfunction in approximately half of the patients.

Topics: Adult; Chronic Disease; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; India; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus

Tacrolimus (TAC) increases the risk of posttransplant diabetes (PTDM) compared with cyclosporine A (CYC). The present 12-month, multicenter, investigator-driven, prospective, randomized study was designed to assess whether conversion from tacrolimus to CYC can reverse PTDM after renal transplantation. Predominantly white patients with PTDM according to the 2005 American Diabetes Association criteria were randomized to either replacement of TAC with CYC or continuation of their TAC-based regimen after stratification for type of glucose-lowering therapy, steroid therapy, and hepatitis C status. At 12 months, 14 of 41 patients with complete data in the CYC arm (34%; 95%CI 19%-49%) were free of diabetes, whereas this was the case in only 4 of 39 patients (10%; 95%CI 3%-20%) in the TAC arm (P = .01). At 12 months, 39% of patients in the CYC arm were off glucose-lowering medication vs 13% of patients in the TAC arm (P = .01). The CYC group decreased glycated hemoglobin level during the 12-month follow-up, resulting in significantly lower levels compared with the TAC group (6.0 ± 0.9% vs 7.1 ± 1.7% at 12 months; P = .002). In conclusion, replacement of TAC with CYC significantly improves glucose metabolism and has the potential to reverse diabetes during the first year after conversion. (EU Clinical Trials Register No. 2006-001765-42).

Topics: Cyclosporine; Diabetes Mellitus; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucose; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus

We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation.. In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF.. At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation.. Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function.

Topics: Adult; BK Virus; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Polyomavirus Infections; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Tumor Virus Infections; Viremia; Young Adult

Graft survival following pancreas transplant alone (PTA) is inferior to other pancreas transplants. Steroid elimination is appealing, but a two-drug maintenance strategy may be inadequate. Additionally, recipients tend to have diabetic nephropathy and do not tolerate nephrotoxic medications. A three-drug maintenance strategy permits immunosuppression through different mechanisms as well as an opportunity to use lower doses of the individual medications. Induction consisted of five doses of rabbit antithymocyte globulin (1 mg/kg/dose). As of October 2007, a single dose of rituximab (150 mg/m

Topics: Adult; Animals; Antilymphocyte Serum; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prognosis; Rabbits; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus

Although various strategies for steroid withdrawal after transplantation have been attempted, there are few reports of the long-term results of steroid withdrawal regimens in kidney transplantation. Earlier, we reported on a 5-year prospective, randomized, single-center trial comparing the safety and efficacy of cyclosporine (CsA) plus mycophenolate mofetil (MMF) with that of tacrolimus (TAC) plus MMF, when steroids were withdrawn 6 months after kidney transplantation in low-risk patients. We now report the 10-year observational data on the study population. We collected data from the database of the Organ Transplantation Center, Samsung Medical Center for 5 years after completion of the original study (TAC group n = 62; CsA group n = 55). The 10-year patient survival, death-censored graft survival, and acute rejection-free survival did not differ between groups (98% vs 96%; P = 0.49, 78% vs 85%; P = 0.75 and 84% vs 76%; P = 0.14 in the TAC group vs CsA group, respectively). In low-risk patients, there was no difference in long-term patient and graft survival between TAC- and CsA-based late steroid withdrawal regimens that included MMF treatment. More long-term randomized clinical trials are needed to clarify the benefits of late steroid withdrawal in kidney transplantation.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Postoperative Complications; Prognosis; Prospective Studies; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Withholding Treatment

Radical prostatectomy (RP) is associated with erectile dysfunction, largely mediated through cavernous nerve injury. There are robust pre-clinical data supporting a potential role for neuromodulatory agents in this patient population. This study assessed tacrolimus in improving erectile function recovery rates after RP (ClinicalTrials.gov number, NCT00106392).. To define the utility of oral tacrolimus in improving erectile function recovery after nerve sparing radical prostatectomy.. A randomized, double-blind trial compared tacrolimus 2-3 mg daily and placebo in men undergoing RP. Patients had localized prostate cancer and excellent baseline erectile function, underwent bilateral nerve-sparing RP, and were followed up for at least 18 months after RP. Patients received study drug for 27 weeks and completed the International Index of Erectile Function erectile function domain (EFD) questionnaire at baseline and serially after surgery.. International Index of Erectile Function erectile function domain score.. Data were available for 124 patients (59 tacrolimus, 65 placebo); mean age was 54.6 ± 6.2 years. No patient experienced permanent creatinine or potassium elevation. At baseline, mean EFD scores were 28.6 ± 2.1 (tacrolimus group) and 29 ± 1.5 (placebo group). By week 5, mean EFD scores had dropped to 8 ± 9.4 (tacrolimus) and 9 ± 10.7 (placebo). At 18 months, mean EFD scores were 16.0 ± 11.3 (tacrolimus) and 20.2 ± 9.0 (placebo) (P = .09). Tacrolimus failed to meet significance (hazard ratio = 0.83; P = .50), with no difference in: (i) percentage of patients achieving normal spontaneous erectile function (EFD score ≥24), (ii) time to normalization of EFD score (≥24), (iii) percentage of patients capable of intercourse in response to phosphieserase type 5 inhibitor (PDE5i), and (iv) time to achieve response to PDE5i.. Despite positive animal data, oral tacrolimus as used in this trial failed to improve erectile function after nerve sparing radical prostatectomy.. The study is limited by a high attrition rate. The strengths include a randomized, placebo controlled design, extensive patient monitoring, use of medication diaries and a validated instrument as the primary outcome measure.. Despite supportive animal data, tacrolimus used in this fashion in the RP population failed to demonstrate any superiority over placebo. Mulhall JP, Klein EA, Slawin K, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy. J Sex Med 2018;15:1293-1299.

Topics: Aged; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Neurotransmitter Agents; Penile Erection; Postoperative Complications; Prostatectomy; Prostatic Neoplasms; Recovery of Function; Surveys and Questionnaires; Tacrolimus; Treatment Outcome; United States

Tacrolimus (TAC) is available as a twice-daily capsule (TAC-BID), once-daily capsule (TAC-QD), and once-daily tablet. Recipients with ABO-incompatible/anti-human leukocyte antigen (HLA)-incompatible transplantation were excluded in previous trials and have thus not been evaluated. We conducted a 5-year trial to determine whether TAC-QD is noninferior to TAC-BID for transplant outcomes. Adults who underwent de novo living kidney transplantation were randomly assigned (62 TAC-QD; 63 TAC-BID). We did not exclude ABO-/HLA- incompatible transplantation. TAC was initiated 7 days preoperatively (0.10 mg/kg/d). Mycophenolate mofetil, methylprednisolone, and basiliximab were administered. The primary endpoint was graft failure (non-censored for death). We performed a noninferiority test. The noninferiority margin was 10% in risk difference. Five-year graft failure rates were 6.5% and 9.5% for TAC-QD and TAC-BID, respectively (noninferiority, P = 0.009). The estimated glomerular filtration rates were similar between the groups (noninferiority, P < 0.001). TAC-QD did not have point estimates of risk difference above the inferiority margin in any assessed endpoints. However, a tendency of interaction was observed between biopsy-proven acute rejection and the follow-up period. In a living kidney transplant population with 40% of patients with ABO/HLA incompatibility, the effect of TAC-QD was not appreciably worse on various clinical transplant outcomes than that of TAC-BID over 5 years.

Topics: ABO Blood-Group System; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus

BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies.. Forty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively (P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively (P = .47).. Conversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance.

Topics: Adult; Aged; BK Virus; Drug Substitution; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Substance Withdrawal Syndrome; Tacrolimus; Tumor Virus Infections; Viremia

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m

Topics: Adolescent; Adult; Aged; Equivalence Trials as Topic; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Safety; Tacrolimus; Young Adult

A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open-label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low-dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time-normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy-proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3-8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients.. NCT01025817.

Topics: Adolescent; Adult; Aged; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Transplant Recipients; Young Adult

Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.

Topics: Adult; Aged; Body Weight; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Genotype; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Netherlands; Polymorphism, Single Nucleotide; Postoperative Complications; Prevalence; Prognosis; Prospective Studies; Risk Factors; Tacrolimus; Young Adult

Immunosuppressive protocols containing everolimus (EVR) preserve good renal function in kidney transplantation (KT), although they are often complicated by several adverse events. We have evaluated the efficacy and safety of a protocol with late (1 month after KT) EVR introduction.. This study randomized 49 de novo patients undergoing KT between September 2012 and June 2014 into 2 groups: group A (n = 24) with late EVR introduction and tacrolimus reduction, and group B (control group; n = 25) with a standard immunosuppressive regimen. Primary aims were 1-year patient and graft survivals and acute rejection rates. Secondary aims were related to wound, metabolic, and hematologic complications.. Patient and graft survivals were similar in both groups. One year after KT, median serum creatinine was inferior in group A (1.4 vs 1.8 mg/dL; P = .004). Late acute rejection (8.3 vs 12.0%; P = 1.0) and wound complication (4.2 vs 4.0%; P = 1.0) rates were similar. Higher cholesterol and triglycerides and lower platelets and hemoglobin levels were observed in group A.. In our experience, delayed introduction of EVR shows similar results with respect to its early introduction, contemporaneously presenting fewer wound complications and lymphoceles. A higher rate of metabolic and hematologic complications are, however, observed in patients under EVR therapy. Further multicenter studies should be performed to confirm these preliminary results.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Everolimus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Time Factors; Treatment Outcome

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Tacrolimus; Transplant Recipients; Treatment Failure; Weaning; Young Adult

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids).. eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

Topics: Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus

The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Steroids; Tacrolimus; Young Adult

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r-ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end-point was the incidence of first CMV infection/disease in the intention-to-treat population at 12 months. Patients treated with r-ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037-0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13-0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound-healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced-dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate (ClinicalTrials.gov NCT01354301).

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Treatment Outcome

Tremor is a common side effect of tacrolimus correlated with peak-dose drug concentration. LCPT, a novel, once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ~30% dose reduction vs. immediate-release tacrolimus. In this phase 3b study, kidney transplant recipients (KTR) on a stable dose of tacrolimus and with a reported clinically significant tremor were offered a switch to LCPT. Tremor pre- and seven d post-conversion was evaluated by independent, blinded movement disorder neurologists using the Fahn-Tolosa-Marin (FTM) scale and by an accelerometry device; patients completed the QUEST (quality of life in essential tremor) and the Patient Global Impression of Change. There were 38 patients in the mITT population. A statistically and clinically significant improvement in tremor (FTM score, amplitude as measured by the accelerometry device and QOL [p-values < 0.05]) resulted post-conversion. Change in QUEST was significantly (p = 0.006) correlated (R = 0.44) with change in FTM; 78.9% of patients reported an improvement after switching to LCPT (p < 0.0005). To our knowledge this is the first trial in KTR that utilizes a sophisticated and reproducible measurement of tremor. Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose reduction of immediate-release tacrolimus for patients experiencing tremor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Area Under Curve; Delayed-Action Preparations; Drug Administration Schedule; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Tacrolimus; Treatment Outcome; Tremor; Young Adult

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Topics: Antihypertensive Agents; Calcineurin Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Proteinuria; Ramipril; Risk Factors; Sirolimus; Tacrolimus

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in heart transplant (HTx). Our aim was to analyze the rate of CMV infection in HTx patients receiving treatment with cyclosporine (CsA) or tacrolimus (Tac). Ninety-five patients were randomized to receive either CsA (53.7%) or Tac (46.3%). We performed prophylaxis with valganciclovir in patients with the highest risk of CMV infection. We considered CMV infection as an increased viral load or the presence of CMV in histological samples. We analyzed baseline characteristics, CMV infection, and other complications. Event-free rates were calculated using the Kaplan-Meier method. There were no significant differences in baseline characteristics between both groups. CMV infection was detected in 31.6% of patients (in 66.7% due to asymptomatic replication). The group treated with Tac had a lower rate of CMV infection (15.9% vs. 45.1%, p = 0.002) and longer CMV infection-free survival time (1440 vs. 899 d, p = 0.001). No differences were observed in the complications analyzed in both groups. The independent risk factors for infection identified in the multivariate analysis were treatment with CsA and bacterial infections. This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

Topics: Adult; Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Survival Rate; Tacrolimus; Valganciclovir

Post-transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post-transplantation. We conducted a single-center, open-label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). Analyses were on intention-to-treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI -1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA-IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Diarrhea; Female; Glucose Tolerance Test; Graft vs Host Disease; Humans; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Magnesium; Magnesium Deficiency; Magnesium Oxide; Male; Middle Aged; Postoperative Complications; Prediabetic State; Receptor, Insulin; Severity of Illness Index; Tacrolimus

Use of generic tacrolimus in liver transplantation (LT) could result in cost savings. Generic tacrolimus has been shown to be bioequivalent to innovator tacrolimus in healthy volunteers and renal transplant patients. There are limited data on the de novo use of generic tacrolimus in LT. This study aimed to determine whether the de novo use of generic tacrolimus (Adoport, Sandoz,UK) was associated with differences in outcomes, safety, and cost compared with innovator tacrolimus (Prograf, Astellas, Japan).. Patients were studied before and after a programmatic change from de novo IS with Prograf to Adoport. Outcomes, tacrolimus levels, doses, and costs were compared for the first-yr post-LT.. Ninety-four patients were studied, 46 Prograf, 48 Adoport. No significant differences in rejection, cytomegalovirus infection, acute kidney injury, sepsis, or graft loss were observed between groups. Tacrolimus costs were significantly reduced with the de novo use of Adoport. Day 14 dose normalized levels in Adoport patients showed significant variation but at the day 30 and one yr, there were no significant differences in the doses or levels of tacrolimus between groups.. Adoport is safe and effective compared to Prograf when used de novo in LT patients. Tacrolimus costs were significantly reduced by the use of Adoport.

Topics: Adult; Drugs, Generic; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Japan; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Retrospective Studies; Risk Factors; Tacrolimus

This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.

Topics: Adult; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Time Factors

Cyclosporine and tacrolimus (TAC) are the most potent immunosuppressants. TAC is considered less nephrotoxic, but may be an important factor in chronic graft dysfunction. The aim of the study was to evaluate kidney function and cardiovascular risk profile in 2 groups of low immunological risk kidney allograft recipients receiving 2 TAC dosages.. Patients were randomly assigned to 2 TAC-based treatments (group I [n = 14], standard dose; group II [n = 15], reduced dose). Patient and graft survival, graft function, occurrence of cardiovascular events (cardiac death, myocardial infarction, stroke), incidence of new-onset diabetes mellitus after transplantation, and cardiovascular risk factors were assessed over a 5-year period.. Patient demographics and transplant characteristics were not statistically different between groups. TAC trough levels were significantly higher in group I for 24 months post transplant. Patient survival did not differ, but there were more acute rejection episodes and graft losses in group II. There were no significant differences in the rate of cardiac events. Graft function measured as serum creatinine levels and calculated glomerular filtration rate did not differ between groups. The same applies to new-onset diabetes mellitus after transplantation incidence. Office blood pressures were numerically higher in group I up to 24 months but this difference did not reach significance at any time. Similar results were obtained for serum lipids.. Immunosuppression based on low doses of tacrolimus seems to be safe in the group of low immunological risk patients but in the 60-month follow-up does not offer any clear benefits in terms of potential nephrotoxicity or cardiovascular risk.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Risk Factors; Tacrolimus; Treatment Outcome; Young Adult

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 μg/L) and low-level sirolimus (SIR, 3-7 μg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 μg/L) and high-level SIR (8-12 μg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Sirolimus; Steroids; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

The sensitivity of fasting plasma glucose (FPG) in screening for new-onset diabetes after transplantation (NODAT) has been questioned, particularly in the presence of moderate-dose prednisolone, where peak plasma glucose occurs 7 to 8 hr after administration. Oral glucose tolerance testing (OGTT) has been mooted as an alternative but is inconvenient for patients.. We compared sensitivity of screening tests for NODAT at 6 weeks, 3 months, and 12 months after kidney transplantation in recipients receiving prednisolone, mycophenolate, and tacrolimus.. At 6 weeks, NODAT (capillary blood glucose [CapBG] ≥11.1 mmol/L, FPG ≥7.0 mmol/L, 2-hr plasma glucose ≥11.1 mmol/L, or glycated hemoglobin [HbA1c] ≥6.5%) was detected in 46% with CapBG versus 12% with OGTT (P=0.013), 4% with HbA1c (P<0.001), and 0% with FPG (P<0.001; n=26). At 3 months, NODAT was present in 14% with HbA1c versus 20% with OGTT (P=0.600) and 2% with FPG (P=0.059; n=50), whereas, at 12 months, NODAT was found in 4% with HbA1c versus 6% with OGTT (P=1.00) and 2% with FPG (P=0.618; n=51). Combining 3- and 12-month data, OGTT recorded NODAT in 14% and impaired glucose tolerance in 28%, whereas HbA1c detected NODAT in 10% and impaired glucose tolerance (from ≥5.7 to <6.5%) in 51%. Employing HbA1c as a screening test and reserving OGTT for those with impaired glucose tolerance would detect NODAT with a sensitivity more than 94%, avoiding the need for OGTT in 49% of patients.. This study confirms the inadequacy of FPG screening for NODAT in the first 6 weeks after transplantation, at which time 4 p.m. CapBG also outperformed OGTT. From 3 months, HbA1c had similar sensitivity to OGTT and represents a convenient alternative.

Topics: Adult; Blood Glucose; Circadian Rhythm; Cross-Sectional Studies; Fasting; Female; Glucocorticoids; Glucose Tolerance Test; Glycated Hemoglobin; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Mass Screening; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sensitivity and Specificity; Tacrolimus

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone-free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow-up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy-proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone-free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.

Topics: Adult; Allografts; Anti-Inflammatory Agents; Calcineurin Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Prognosis; Prospective Studies; Sirolimus; Survival Rate; Tacrolimus; TOR Serine-Threonine Kinases

New-onset diabetes mellitus (NODAT) is a serious complication following renal transplantation. In this cohort study, we studied 118 nondiabetic renal transplant recipients to examine whether indices of insulin resistance and secretion calculated before transplantation and at 3 months post-transplantation are associated with the development of NODAT within 1 year. We also analysed the long-term impact of early diagnosed NODAT. Insulin indices were calculated using homeostasis model assessment (HOMA) and McAuley's Index. NODAT was diagnosed using fasting plasma glucose. Median follow-up was 11 years. The cumulative incidence of NODAT at 1 year was 37%. By logistic regression, recipient age (per year) was the only significant pretransplant predictor of NODAT (OR 1.04, CI 1.009-1.072), while age (OR 1.04, CI 1.005-1.084) and impaired fasting glucose (OR 2.97, CI 1.009-8.733) were significant predictors at 3 months. Pretransplant and 3-month insulin resistance and secretion indices did not predict NODAT. All-cause mortality was significantly higher in recipients developing NODAT within 1 year compared with those remaining nondiabetic (44% vs. 22%, log-rank P = 0.008). By Cox's regression analysis, age (HR 1.075, CI 1.042-1.110), 1-year creatinine (HR 1.007, CI 1.004-1.010) and NODAT within 3 months (HR 2.4, CI 1.2-4.9) were independent predictors of death. In conclusion, NODAT developing early after renal transplantation was associated with poor long-term patient survival. Insulin indices calculated pretransplantation using HOMA and McAuley's Index did not predict NODAT.

Topics: Blood Glucose; Cyclosporins; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin Resistance; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Logistic Models; Male; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Survival Analysis; Tacrolimus; Time Factors; Transplantation Immunology; Treatment Outcome

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.

Topics: Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Tacrolimus

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure.. This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance.. In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period.. Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Topics: Adaptor Proteins, Signal Transducing; Aged; Cyclosporine; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Scandinavian and Nordic Countries; Sirolimus; Tacrolimus; Time Factors

The calcineurin inhibitors cyclosporine and tacrolimus are implicated in post-transplant complications such as new-onset diabetes after transplantation. The relative contribution of each calcineurin inhibitor to new-onset diabetes after transplantation remains unclear. We sought to compare the impact of cyclosporine and tacrolimus on glucose metabolism in humans.. Eight haemodialysis patients received 8-10 days of oral treatment followed by 5-h infusions with cyclosporine, tacrolimus and saline in a randomized, investigator-blind, crossover study. Glucose metabolism and β-cell function was investigated through: a hyperinsulinaemic-euglycaemic clamp, an intravenous glucose tolerance test and insulin concentration time series.. Cyclosporine and tacrolimus decreased insulin sensitivity by 22% (P = 0.02) and 13% (P = 0.048), respectively. The acute insulin response and pulsatile insulin secretion were not significantly affected by the drugs.. In conclusion, 8-10 days of treatment with cyclosporine and tacrolimus impairs insulin sensitivity to a similar degree in haemodialysis patients, while acute insulin responses and pulsatile insulin secretion remain unaffected.

Topics: Body Mass Index; Calcineurin; Cross-Over Studies; Cyclosporine; Denmark; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.

Topics: Cardiovascular Diseases; Cyclosporine; Diabetes Complications; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus

The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients.. From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis C virus (HCV) patients were reevaluated.. After 5 years, the following parameters were comparable in both groups: patient survival (P=0.236), organ survival (P=0.509), and acute rejections (P=0.409). Steroid-free immunosuppression lead to a higher rate of chronic rejections (P=0.023). Six months after OLT, there was a difference in rates of posttransplant diabetes mellitus (PTDM) (P=0.024) and hypercholesterolemia (P=0.002). However, 5 years after OLT, there was no difference in hypertension (P=0.647), PTDM (P=0.453), hypercholesterolemia (P=0.412), and osteoporosis (P=0.624). In HCV patients, we could not find any differences in patient survival (P=0.096), organ survival (P=0.424), time free from recirrhosis (P=0.647). The rate of recirrhosis was influenced by steroid bolus therapy (P=0.01) but not by avoiding continuous steroid therapy.. Early tapering down of steroids to a tacrolimus monotherapy is possible with comparable acute rejection rates. During steroid therapy, PTDM and hypercholesterolemia are cumulative. These side effects are reversible. The recirrhosis in HCV patients is not influenced by continuous steroid therapy but more frequent in HCV patients receiving a steroid bolus therapy.

Topics: Adrenal Cortex Hormones; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Graft Survival; Hepatitis C; Humans; Hypercholesterolemia; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Recurrence; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

We sought to reduce the risk of infectious complications and nonrelapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (aGVHD) in patients undergoing reduced-intensity conditioning (RIC) transplantation. As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n = 39) to 6.0 mg/kg of ATG (r-ATG) (n = 33) in association with fludarabine (Flu) and busulfan (BU) RIC transplantation and then monitored patients for adverse events, relapse, and survival. Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in posttransplantation full donor-cell chimerism rates were observed between the 2 ATG-dose groups (P > .05). When R-ATG versus r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II-IV aGVHD (32% versus 27%; P = .73) or grade III-IV aGVHD (23% versus 11%; P = .28). However, the r-ATG group had significantly less cytomegalovirus (CMV) reactivation (64% versus 30%; P = .005) and bacterial infections (56% versus 18%; P = .001), a better 1-year cumulative incidence of NRM (18% versus 3%; P = .03), and a trend for better 1-year overall survival (OS) (64% versus 84%; P = .07) compared to R-ATG patients. A seemingly modest reduction in the dose of rabbit ATG did not compromise control of aGVHD or achievement of donor chimerism, but led to a significant decrease in the risk of serious infections and NRM in high-risk RIC allograft recipients.

Topics: Adult; Aged; Animals; Anti-Infective Agents; Antilymphocyte Serum; Busulfan; Disease Susceptibility; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Infection Control; Infections; Male; Medical Audit; Methotrexate; Middle Aged; Myeloablative Agonists; Patient Isolation; Postoperative Complications; Rabbits; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

Several interventions can cure posttransplant lymphoproliferative disease (PTLD); a sequential approach is usual, starting with reduction in immunosuppressives (RI). The efficacy of RI remains poorly defined, particularly in adults. We assessed an algorithm starting with a defined course of RI in all patients, escalating to interferon (IFN) alpha2b, and finally to chemotherapy, in a prospective multicenter phase II study of adult solid organ transplant recipients. The design predated rituximab.. Reduction in immunosuppressives: cyclosporine or tacrolimus reduction by 50% for 2 weeks; a further 50% reduction for 1 week if not in complete remission (CR). Intravenous acyclovir was given for the duration of all RI. Patients with less than CR, or any rejection, resumed immunosuppressives and proceeded to IFN 3 MIU/m(2)/day for up to 3 months; if less than CR, ProMACE-CytaBOM chemotherapy.. Twenty patients were registered over 60 months; 16 patients with biopsy-proven PTLD were eligible (13 heart, 3 kidney recipients). Median age was 47 (24-75) years. Reduction in immunosuppressives resulted in only 1 of 16 partial responses (12.5%), no CR. Progressive disease occurred in 8 of 16 (50%) and 6 of 16 (38%) experienced rejection. Only 1 of 13 (7%) patients achieved durable CR with IFN. Seven eligible patients received ProMACE-CytaBOM chemotherapy, five of seven (67%) achieving CR, four of five durable beyond 2 years.. Reduction in immunosuppressives produced no CR, progressive disease and rejection were frequent; response to IFN was rare. A strong case can be made for adding rituximab to RI as initial therapy. Chemotherapy resulted in 57% durable CR, data that are relevant for the up to two thirds of PTLD patients who are refractory to rituximab.

Topics: Acyclovir; Adult; Aged; Antineoplastic Agents; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Remission Induction; Tacrolimus

The incidence of severe graft-vs-host disease (GVHD) in unmanipulated human leukocyte antigen (HLA) 2-3 antigen-mismatched bone marrow transplantation (BMT) using cyclosporine and methotrexate as GVHD prophylaxis is 80% to 90%. We investigated whether pharmacological GVHD prophylaxis consisting of four drugs, including a steroid, effectively suppressed GVHD in this transplantation setting.. Thirty patients who had hematologic malignancies at an advanced stage or with poor prognosis underwent allogeneic BMT using a myeloablative preconditioning regimen consisting of cyclophosphamide (60 mg/kg x 2), total body irradiation (8-10 Gy), and fludarabine (30 mg/m(2) x 4) with or without cytosine arabinoside (2 g/m(2) x 4), and GVHD prophylaxis consisting of a combination of tacrolimus, methotrexate, mycophenolate mofetil, and methylprednisone (2 mg/kg). Early therapeutic intervention for GVH reaction or grade I GVHD was performed, and steroid was slowly tapered.. All patients achieved donor-type engraftment. Neutrophil (>0.5 x 10(9)/L) and platelet (>20 x 10(9)/L) engraftment was achieved on day 13 and on day 30, respectively. Seventeen patients (56.7%) had no GVHD. Eleven patients (36.7%) developed grade II-III acute GVHD. Seven patients (23.3%) died of transplant-related toxicity, including fungal or viral infections and thrombotic microangiopathy, and four patients died of disease progression. Estimated relapse rate at 3 years was only 20.9%. The probability of survival at 3 years was 49.9%.. These data suggest that, in unmanipulated HLA-haploidentical allogeneic BMT, this GVHD prophylactic regimen, which includes methylprednisolone 2 mg/kg, and early therapeutic intervention for GVH reaction suppress the incidence of severe GVHD to an acceptable level, while preserving the graft-vs-leukemia effect.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Living Donors; Methotrexate; Methylprednisolone; Mycophenolic Acid; Myeloablative Agonists; Postoperative Complications; Tacrolimus; Transplantation Conditioning; Whole-Body Irradiation

One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy.. Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects.. At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped.. SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.

Topics: Adult; Albuminuria; Autoantibodies; C-Peptide; Cell Transplantation; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Lymphocyte Count; Male; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged < or =5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age < or =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Cyclosporine; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Multivariate Analysis; Postoperative Complications; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/microL) and platelet recovery (>20,000/microL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD.

Topics: Adult; Aged; Blood Component Transfusion; Bone Marrow Transplantation; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Female; Filgrastim; Graft Survival; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hemoglobinuria, Paroxysmal; Histocompatibility; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Recombinant Proteins; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Posttransplant diabetes mellitus (PTDM) occurs in approximately 15% to 20% of renal transplant patients. It has important clinical implications for graft function and survival. Anticalcineurin drugs are associated with an increased risk of developing PTDM. There is a little evidence that conversion from tacrolimus to cyclosporine (CsA)-based immunosuppression improves glucose metabolism and reverses diabetes. This prospective study included nine renal transplant patients (mean age of 34 +/- 20) with PTDM under immunosuppression with tacrolimus. Five were switched directly to CsA and the other four (glycemia > 250 mg/dL) required insulin and were simultaneously switched to CsA. Basal blood levels of tacrolimus were 7.9 +/- 1.9 ng/dL. Conversion was associated with an early, significant improvement of glycemia and HbA1c blood levels (P < .01). At the end of the follow-up, the glycemia (105 +/- 20 mg/dL) and Hb1Ac (5.1 +/- 0.4 mg/dL) were normal. Insulin was discontinued between 3 and 6 months in all patients who required it at the beginning. Cholesterol did not change significantly and triglycerides decreased significantly (basal 210 +/- 85 mg/dL, at 12 months 125 +/- 29, P < .01). Graft function was stable with a mean serum creatinine of 1.7 +/- 0.2 mg/dL. CsA blood levels remained stable during all follow-up periods (P = NS). There were neither episodes of acute rejection nor secondary effects related to the medication. In summary, renal transplant patients receiving tacrolimus who develop PTDM may display better control of hyperglycemia by a switch to CsA.

Topics: Adolescent; Adult; Blood Glucose; Cyclosporine; Diabetes Mellitus; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Tacrolimus

Prior retrospective studies have suggested that tacrolimus monotherapy is an option associated with excellent outcomes and reduced toxicities.. We conducted a prospective, randomized, 2-center study of tacrolimus combination therapy vs monotherapy. From April 16, 2004, to September 15, 2005, 58 adult heart transplant patients were studied. All received oral tacrolimus, mycophenolate mofetil, and corticosteroids. Patients were then randomized to a group where mycophenolate was maintained (COMBO) or to a group where it was discontinued (MONO) 14 days post-transplant. Corticosteroids were rapidly withdrawn in both groups between 8 and 12 weeks.. The primary end point (mean 6-month International Society of Heart and Lung Transplantation biopsy score) was 0.44 +/- 0.04 in the MONO group and 0.60 +/- 0.05 in the COMBO group (p = 0.013, unpaired Student's t-test). The freedom from rejection grade of 2R or higher at 6 and 12 months was 93.3% with MONO and 92.9% with COMBO (p = NS).. Tacrolimus monotherapy appears to be safe and efficacious in heart transplant recipients and is not associated with excess rejection in the first year post-transplant. Further studies of this approach are warranted.

Topics: Adrenal Cortex Hormones; Adult; Aged; Cytomegalovirus Infections; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Treatment Outcome

Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation.. HCV-infected cirrhotic patients randomised to tacrolimus monotherapy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over 3 months.. Twenty-seven patients (MT) and 29 (TT)--median follow up 661 days (range, 1-1603). Rejection episodes (protocol/further biopsies) within first 3 months and use of empirical treatment were evaluated. New rejection was diagnosed if repeat biopsy (5-day interval) did not show improvement. Treated rejection episodes: 20 MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs. 24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and 46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and more moderate rejection (22% vs. 41%). The MT group had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, and death were not significantly different.. Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infected liver transplant recipients.

Topics: Adult; Aged; Azathioprine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Secondary Prevention; Survival Analysis; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.

Topics: Adult; Age of Onset; Aged; Antibodies; Antifungal Agents; Aspergillosis; B-Lymphocytes; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Prospective Studies; Risk Factors; Sirolimus; Spain; T-Lymphocytes; Tacrolimus; Treatment Outcome; United States

Subclinical inflammation is related to adverse events in patients with coronary artery disease. In the present study, we determined the changes in hemostatic parameters and inflammatory markers in a large cohort of dyslipidemic cardiac transplant recipients compared with dyslipidemic healthy controls, and the effect of cyclosporin microemulsion (CsA) vs. tacrolimus immunoprophylaxis on these parameters.. Stable cardiac transplant recipients (n=129) aged 56.7+/-10.1 years, 79+/-42 months postcardiac transplantation, and 26 mildly dyslipidemic healthy control subjects had serum measurements for lipids and lipoproteins, hemostatic parameters, and selected inflammatory markers. Transplant recipients were randomized to either continuation of CsA maintenance or conversion to tacrolimus immunoprophylaxis and were reassessed after six months.. CsA-maintained cardiac transplant recipients exhibited a significant elevation in Factor VIII, Von Willebrand factor, fibrinogen and PAI-I compared with healthy control subjects (all P<0.05). Similarly, cardiac transplant patients yielded a significantly elevated C-reactive protein (CRP) (4.11+/-6.25 [transplant group (TX)] vs. 2.09+/-2.21 mg/L [control group (CTL)]; P=0.0195), and homocysteine (19.2+/-8.8 [TX] vs. 9.70+/-2.45 microM [CTL]; P<0.001). VCAM, ICAM, E- and P-selectins were also significantly higher in transplant patients than in controls (all P<0.05). The conversion from CsA to tacrolimus resulted in a significant decrease in uric acid, total- and LDL-cholesterol, apolipoprotein B, creatinine, and homocysteine levels (all P<0.05).. Stable long-term CsA-maintained cardiac transplant patients exhibit a significant and general increase in hemostatic parameters and markers for subclinical inflammation. Tacrolimus conversion improved the patient lipid profile and decreased serum creatinine, uric acid, and homocysteine without any significant effect on the other markers.

Topics: Adult; Aged; Biomarkers; Blood Pressure; C-Reactive Protein; Cyclosporine; Dyslipidemias; Emulsions; Heart Transplantation; Hemostasis; Humans; Immunosuppressive Agents; Inflammation; Middle Aged; Postoperative Complications; Tacrolimus; Thrombosis

This study compared early postoperative complications in kidney transplant recipients treated with either a sirolimus-based calcineurin inhibitor (CNI)-free regimen or a tacrolimus-based steroid-free regimen. We used a single-center, prospective, sequential but nonrandomized study design. Consecutive recipients of primary cadaveric or non-HLA identical kidney transplant recipients received either a CNI-free regimen, consisting of sirolimus 5 mg daily beginning postoperative day 3, mycophenolate mofetil 1 gm twice a day, and methylprednisolone 500 mg intraoperatively, then prednisone 30 mg daily tapered to 10 mg daily at 3 months, or a prednisone-free regimen, consisting of methylprednisolone 500 mg, 250 mg, and 125 mg from days 0 to 2, then no further steroids, tacrolimus 0.075 mg/kg twice a day, and mycophenolate mofetil 1 g twice a day. All patients received thymoglobulin induction 6 mg/kg total dose. Outcome measures were patient and graft survival, BPAR, surgical and wound complications, viral infections and posttransplant diabetes mellitus (PTDM). Both groups had excellent early outcomes with no significant difference in patient or graft survival, early renal function, BPAR, surgical or wound complications, or viral infections between the two groups. Patients in the sirolimus-based CNI-free group had a significantly higher incidence of PTDM and a trend toward more discontinuation due to drug toxicity. Whether either regimen improves long-term outcomes awaits longer follow-up.

Topics: Adrenal Cortex Hormones; Adult; Cadaver; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Graft Survival; Histocompatibility Testing; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Postoperative Complications; Racial Groups; Survival Analysis; Tacrolimus; Tissue Donors; Treatment Outcome

We have previously shown that high pretransplant regulatory autoantibodies are associated with better kidney graft outcome. To analyze the effect of intravenous immunoglobulin (IVIG) induction therapy on these regulatory antibodies, we performed a prospective randomized study in 50 renal transplant recipients who were randomly assigned to receive 7 x 10 g IVIG or 7 x 10 g IV albumin infusions. Basic immunosuppressive therapy consisted of tacrolimus/azathioprine (n = 24) and tacrolimus/mycophenolate mofetil (n = 26), respectively. ELISA was used to assess IgG-/IgA-anti-Fab, -anti-F(ab)2 and -anti-hinge regulatory antibodies. IVIG induction therapy resulted in upregulation of serum IgG and IgA levels within the first 20 days posttransplant (P = .001, IgG; P = .04, IgA), so that a significant IgG deficiency was found only in non-IVIG patients (day 10: IgG <6 g/L: 7/25 (28%) non-IVIG versus 0/25 IVIG patients; P = .005). As the IVIG charges contained all of the regulatory antibodies tested, intravenous administration of these antibodies explain the elevated IgG- and IgA-anti-F(ab)2 antibody levels found in IVIG compared to non-IVIG patients on day 10 (P = .005 and P = .04, respectively). Our data indicated that IVIG induction prevented severe IgG deficiency in the early posttransplant period but had no impact on severe infectious complications. IVIG induction enhanced immunoregulatory antibody levels early posttransplant, which might provide graft protective effects.

Topics: Azathioprine; Drug Therapy, Combination; Histocompatibility Testing; Humans; Immunoglobulin A; Immunoglobulin M; Immunoglobulins; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The ideal immunosuppressive treatment for African-American kidney transplant recipients has not been established. We performed a long-term prospective randomized trial comparing the results of tacrolimus (TAC) and cyclosporine (CSA) in the African-American population. Thirty-five African-American primary cadaveric renal transplant (CRT) recipients were enrolled in the study. Group I (n = 14) received TAC and group II (n = 21) received CSA; mean follow up was 78 months. We found no difference in patient/graft survival rates between the groups. Twelve patients in the CSA group were converted to TAC, mostly because of hypercholesterolemia or as a rescue for an acute rejection episode. Significant lower creatinine and cholesterol levels were seen at 1 year post-transplant, but this difference lost significance at 3 and 5 years, possibly because of conversion of most patients from CSA to TAC. In conclusion, African-American recipients of primary CRTs can achieve excellent long-term results with TAC-based immunosuppression.

Topics: Acute Disease; Adult; Black or African American; Cholesterol; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Postoperative Complications; Tacrolimus

Simultaneous pancreas-kidney (SPK) transplantation is an accepted therapy for type 1 diabetic patients with end-stage renal disease. This study analyses the occurrence of rejection episodes in patients undergoing SPK.. The study population was obtained from 205 patients enrolled in the Euro-SPK 001 study and randomized to receive tacrolimus- (n = 103) or cyclosporin microemulsion (ME)-based (n = 102) immunosuppressive therapy. All patients received concomitant antibody induction therapy, mycophenolate mofetil and short-term corticosteroids.. After 3 years of follow-up, rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving cyclosporin-ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93 and 90%, respectively) and in most cases were treated with corticosteroids alone (88 vs 90%). Actuarial rejection-free kidney and/or pancreas graft survival was similar for tacrolimus (54%) and cyclosporin-ME (44%). Human leukocyte antigen (HLA) compatibility (P = 0.003) and graft vessel extension (P = 0.000001) had a significant influence on rejection-free graft survival. Also, rejection influenced pancreas graft survival (P = 0.01), and pancreas graft loss due to rejection influenced patient survival (P = 0.02). In the intent-to-treat analysis of early rejection, significantly fewer tacrolimus- than cyclosporin-ME-treated patients had (i) more than one rejection episode (11 out of 40 vs 24 out of 47; P = 0.03); (ii) first moderate to severe rejection (one out of 40 vs 12 out of 47; P = 0.004); and (iii) refractory rejection (two out of 40 vs 10 out of 47; P = 0.03). Pancreas survival was lower in late rejectors (53%) than non-rejectors (86%; P = 0.002). Also, serum creatinine was highest in late rejectors.. Tacrolimus-based immunosuppressive therapy demonstrates significant advantages over cyclosporin-ME in terms of the severity of acute rejection in SPK transplant patients.

Topics: Adolescent; Adult; Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease-Free Survival; Drug Therapy, Combination; Emulsions; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Postoperative Complications; Tacrolimus

Simultaneous pancreas-kidney transplantation (SPK) has evolved as an effective treatment for patients with end-stage nephropathy due to type 1 diabetes mellitus. This report analyses the spectrum of surgical complications among patients receiving tacrolimus and cyclosporin microemulsion (ME)-based therapy for SPK transplantation.. The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporin-ME (n = 102) in the Euro-SPK 001 study. Surgical complications were defined as any intervention in the 3-month post-operative course related to the transplant procedure.. In the tacrolimus vs cyclosporin-ME group, repeat laparotomy was required by fewer patients (26 vs 43%, respectively; P = 0.01) and at a later stage post-transplant (26+/-26 vs 14+/-17 days; P = 0.05). Also, thrombosis of graft vessels (2 vs 9%; P = 0.03) and repeat laparotomy for intra-abdominal haemorrhage within the first 3 months (8 vs 22%; P = 0.005) occurred significantly less frequently with tacrolimus vs cyclosporin-ME. A donor age of > or =45 years was a significant determinant for surgical complications requiring repeat laparotomy, regardless of the type of immunosuppression. Portal anastomosis was the safest method of endocrine venous drainage, and Roux-en-Y loop for enteric exocrine drainage was associated with a higher re-operation rate than duodenoenterostomy. Repeat laparotomy had no impact on patient survival, but significantly reduced kidney and pancreas graft survival in the cyclosporin-ME group (kidney: P<0.01; pancreas: P<0.001) and in both groups combined (P < or = 0.05 and P<0.001, respectively).. The immunological benefits of tacrolimus compared with cyclosporin-ME treatment result in a lower incidence of repeat laparotomies post-transplant and a reduced in-hospital stay. Fewer repeat laparotomies translate into improved pancreas and kidney graft survival.

Topics: Adult; Age Factors; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Europe; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Israel; Kidney Failure, Chronic; Kidney Transplantation; Laparotomy; Middle Aged; Pancreas Transplantation; Postoperative Complications; Prospective Studies; Reoperation; Survival Rate; Tacrolimus; Treatment Outcome

Topics: Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Japan; Kidney Function Tests; Kidney Transplantation; Living Donors; Postoperative Complications; Ribonucleosides; Survival Analysis; Tacrolimus; Time Factors

Between September 2002 and February 2004, 40 kidney transplant (27 from deceased and 13 from living donors) recipients (25 male and 15 female, aged 50.3 +/- 15.1 years) were treated with Campath 1H (C 1H; 30 mg/dose IV) for biopsy-proven steroid-resistant rejection (SRR) or rejections equal to or worse than Banff 1B. All transplantations occurred between August 2001 and May 2003. All patients had received antibody preconditioning (RATG 5 mg/kg, n = 34; C 1H 60 mg, n = 4; C 1H 30 mg, n = 2) preoperatively and were treated with Tacrolimus monotherapy (target level 10 ng/ml) postoperatively and subsequent spaced weaning. Elevated creatinine levels at follow-up were evaluated by renal transplant biopsy. Rejection was treated with steroids, reversal of weaning, addition of sirolimus, and/or antibody treatment, depending on grade of rejection. The mean duration of follow-up was 453 +/- 163 days after C 1H administration. Twenty-nine patients received C 1H for SRR and 11 patients for Banff 1B or worse rejections; 26 patients received more than 1 dose of C 1H. Graft survival was 62.5% (25 patients); 6 of the 15 allografts (40%) that failed had presented with rejections because of noncompliance. Graft survival in compliant patients with SRR or rejections equal to or worse than Banff 1B was 73.5% (25 of 34). Fourteen patients (35%) had infectious complications, of whom 2 patients (5%) died. C 1H is an effective agent for SRR and Banff 1B or worse rejections, with 95% patient survival and 73.5% graft survival (in compliant patients). The number of doses of 30 mg C 1H should be restricted to two, as there is a high incidence of potentially fatal infectious complications.

Topics: Acute Disease; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Biopsy; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Posttransplantation diabetes (PTDM) is a frequent complication of tacrolimus (TAC)-based immunosuppressive therapy after kidney transplantation. We investigated whether immediate conversion from TAC to Cyclosporine (CSA) could reverse or at least improve new-onset PTDM. Between February 2002 and February 2004, 28 adult kidney transplant recipients maintained on TAC were diagnosed with new-onset PTDM. Eight adult patients with new-onset PTDM were enrolled in the study and converted from TAC to CSA, the remaining 20 patients served as controls and were continued on the TAC-based immunosuppression. The conversion to CSA was performed immediately after establishing the diagnosis of PTDM at an average of 11 months posttransplantation. We did not document any episodes of acute rejection or worsening renal function after conversion. After conversion to CSA, among the 3 patients started on insulin, 1 has come completely off antidiabetic medications, whereas 1 required decreased doses of insulin, and the third has been converted to oral medications. Of the 5 patients originally on oral medications, 3 completely discontinued therapy, whereas the other 2 were well controlled on single-drug therapy at reduced doses. After a mean follow-up of 17 months, in the control group 9 of the 16 patients started on oral antidiabetics ultimately required insulin treatment and no patient could stop antidiabetic or insulin therapy. These findings indicate that conversion from TAC to CSA is a simple, safe, and efficacious way to reverse or at least improve PTDM.

Topics: Adult; Cyclosporine; Diabetes Mellitus; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus

Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.

Topics: Cardiovascular Diseases; Cholesterol; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Risk Factors; Tacrolimus

In an open, prospective, multicenter study, stable renal graft recipients were converted to tacrolimus because of cyclosporine-related side effects. Seventy-five patients were switched primarily because of hyperlipidemia. After the switch to tacrolimus, mean total cholesterol was reduced by 15% at month 6. One hundred seventy-seven additional patients were switched primarily for other indications: hypertrichosis, gingival hyperplasia, and arterial hypertension, and these symptoms also improved after the switch. In this analysis, serum lipid levels were categorized according to a modified standard classification of lipid parameters for renal transplant patients (published by the NKF Work Group). The aim was to estimate the proportion of patients reaching normal lipid levels after the conversion to tacrolimus therapy. In patients with primary indication hyperlipidemia, the proportion with normal cholesterol levels increased significantly from 5.6% at baseline to 37.5% at month 6 (P < .05). For LDL cholesterol, the increase was from 54.1% at baseline to 64.9% at month 6, and for triglycerides the improvement was from 25.4% to 33.8%. HDL cholesterol levels remained stable. Similar changes of lipid parameters were also observed in the subgroups of patients converted to tacrolimus primarily because of other indications. After conversion from cyclosporine to tacrolimus, a significantly higher proportion of stable renal graft recipients reached normal total cholesterol levels. For LDL cholesterol and triglycerides, a trend for normalization was observed. Thus, the improvement of serum lipid levels resulted for many patients in a change to a better level class and improved or normalized their cardiovascular risk parameters.

Topics: Cholesterol, LDL; Cohort Studies; Cyclosporine; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Postoperative Complications; Prospective Studies; Tacrolimus; Treatment Outcome

Cardiovascular disease is the leading cause of death in renal transplant recipients. Arterial wall properties are surrogate markers for arteriosclerosis. Previous investigations have shown that the cardiovascular risk profile is better with tacrolimus compared to cyclosporine. Renal function, blood pressure, and lipid levels improve. The hypothesis is that arterial wall properties will improve after conversion from cyclosporine to tacrolimus. Thirty-four stable renal recipients were converted from cyclosporine microemulsion to tacrolimus without changing concomitant medication. Before and after conversion we performed wall track ultrasounds of the carotid and the brachial arteries; pulse wave velocity (PWV); laboratory investigations; 24-hour ABPM; estimates of renal function; and Framingham risk scores. After conversion the 24-hour ambulatory blood pressure monitoring (ABPM) did not change. Total cholesterol, LDL cholesterol, and triglycerides improved significantly. Renal function (Cockroft) improved. There were no significant changes in arterial wall properties, or in PWV. Framingham comparative risk scores improved only significantly in patients not receiving statins. In conclusion, 3 months after conversion from cyclosporine to tacrolimus total cholesterol, LDL cholesterol, and triglycerides were significantly decreased and renal function significantly improved. Contrary to expectation, ABPM did not change, probably due to prolonged use (>10 years) of cyclosporine. There was also no difference in arterial wall properties.

Topics: Adult; Aged; Arteries; Blood Pressure; Cholesterol; Cholesterol, LDL; Cyclosporine; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Triglycerides

Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients.. From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months.. Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group (P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well (P = .004).. Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.

Topics: Adrenal Cortex Hormones; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Glucocorticoids; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Survival Analysis; Tacrolimus; Time Factors

The purpose of this study is to find out whether basiliximab administration will improve postoperative renal function by delaying the start of tacrolimus and decreasing of dosage requirement for tacrolimus in adult living donor liver transplantation (LDLT). Forty-five adult LDLT recipients were enrolled in the study. The induction group (n = 27) was given basiliximab 20 mg on days 0 and 4; tacrolimus administration was delayed until renal function improved. The control group (n = 18) did not receive basiliximab; tacrolimus was given on the first postoperative day. Trough levels of tacrolimus in the induction and control groups were aimed to be maintained at 5-10 ng/ml and 10-15 ng/ml during the first week after transplant, respectively. The median follow-up was 22 months (range 10-34 months). The preoperative conditions were poorer in the induction group (Child C, 56% vs. 33%, P = 0.01; UNOS 2a, 15% vs. 0%, P = 0.02). The intraoperative blood loss was also higher in the induction group than in the control group (median 2,180 ml vs. 495 ml, P < 0.01). The median delay in tacrolimus administration in the induction group was 36 hours (range 24-108 hours). Serum creatinine levels at second and third postoperative months were significantly lower in the induction group. The creatinine clearance rate in the induction group was higher at the third month posttransplant (median 72 vs. 57 ml/minute, P = 0.04). The incidence of renal insufficiency was significantly lower in the induction group at the third month posttransplant (26% vs. 67%, P < 0.01). Blood cholesterol level at the sixth month posttransplant was lower in the induction group (median 152 vs. 196 mg/dl P = 0.03). The incidences of acute cellular rejection, bacteremia, and cytomegalovirus (CMV) infection were similar in both groups. In conclusion, for pretransplant critical patients with more intraoperative blood loss, basiliximab induction could prevent early renal dysfunction by delaying the start of tacrolimus and reducing the dose requirement of tacrolimus without increasing graft rejection and infection. Furthermore, it also improved renal function as well as lowered cholesterol levels within 6 months after transplantation.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Creatinine; Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Recombinant Fusion Proteins; Tacrolimus; Treatment Outcome

Although hyperuricemia is a well-known adverse effect of cyclosporine (CsA) treatment, there are contradictory data regarding the effect of tacrolimus on uric acid levels. The aim of this study was to examine the influences of CsA and tacrolimus-based treatment regimens on serum uric acid levels in 155 renal transplant recipients with normal allograft function who underwent renal transplantation between 1999 and 2002. Serum uric acid levels were recorded at 1, 6, 12, 18, and 24 months follow-up. The patients were treated with CsA-based (n = 73), tacrolimus-based (n = 47), or conversion from CsA-based to tacrolimus-based (n = 35) immunosuppressive regimens. Serum uric acid levels for patients in the CsA and tacrolimus groups were 6.3 +/- 1.6 versus 7.9 +/- 1.9 mg/dL and 6.5 +/- 1.8 versus 8.0 +/- 1.8 mg/dL at the study outset and 24 months, respectively. Both of the treatment regimens showed progressively increasing serum uric acid levels (P < .001). Serum uric acid levels of patients with treatment conversion from CsA to tacrolimus were 8.6 +/- 2.8 mg/dL before conversion and 8.1 +/- 1.9 mg/dL after conversion. There was no alteration in serum uric acid levels after the change of treatment (P > .05). These findings indicate that, compared with CsA, tacrolimus offers no advantage for serum uric acid levels in renal transplant recipients.

Topics: Adult; Cyclosporine; Female; Humans; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Tacrolimus; Uric Acid

Itraconazole is often given for fungal prophylaxis to lung transplant recipients after transplantation. The aim of this study was to determine the extent of interaction between tacrolimus and itraconazole in lung transplant recipients and the efficacy of itraconazole prophylaxis.. The study group included 40 lung transplant recipients followed for at least 12 months. All received prophylactic itraconazole, 200 mg twice a day, for the first 6 months after transplantation. Tacrolimus levels and dosage requirements were compared during and after itraconazole therapy. Rejection rate, fungal infection rate, and renal function were assessed. The mean cost per daily treatment of the itraconazole/tacrolimus combination and tacrolimus alone was calculated.. The mean tacrolimus dose during itraconazole treatment was 3.26 +/- 2.1 mg/day compared with 5.74 +/- 2.9 mg/day after itraconazole was stopped (p < 0.0001) for a mean total daily dose elevation of tacrolimus of 76%. When the cost of itraconazole was taken into account, the average total daily cost of the combined treatment was US5.86 dollars less than the treatment with tacrolimus alone. No differences in the rejection or fungal infection rate, or in renal toxicity, were observed between the periods with and without itraconazole treatment, although less positive fungal isolates were identified during itraconazole therapy.. Prophylaxis therapy with itraconazole is highly effective. Itraconazole reduces the dose of tacrolimus and therefore lowers the cost of therapy without causing an increase in rejection rate and with renal function preservation.

Topics: Antifungal Agents; Drug Costs; Drug Interactions; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Itraconazole; Kidney; Lung Transplantation; Mycoses; Postoperative Complications; Tacrolimus

Omeprazole is a proton pump inhibitor with a number of pharmacokinetic drug interactions due to interference with cytochrome P450. Some studies show absence of relevant interaction between omeprazole and cyclosporine, but little is known about possible interactions between omeprazole and tacrolimus. In vitro studies suggest such interference, but no clinical data are available so far. We assessed interactions between omeprazole and tacrolimus among patients fulfilling two criteria: (1) renal allograft recipients receiving immunosuppression based on tacrolimus and acid-related disorder prophylaxis with omeprazole 20 mg/d since the day of the transplant procedure and (2) stopped omeprazole when it was considered unnecessary. Fifty-one transplant recipients received concomitant immunosuppression with MMF-prednisone (n = 47) or azathioprine-prednisone (n = 1), or rapamycin-prednisone (n = 2) or only prednisone (n = 1). omeprazole was stopped after 6.2 +/- 3 months of treatment. Tacrolimus doses and levels were recorded during 3 outpatient visits before omeprazole withdrawal (Pre3/Pre2/Pre1), at the withdrawal visit (Susp), and at 3 visits after withdrawal (Pos1/Pos2/Pos3). Weight gain was significant (72.5 +/- 13 kg Pre3; 73.4 +/- 13 kg Susp; 74 +/- 12.9 kg Pos3, P < .0001) and serum creatinine (SCr) decreased (1.70 +/- 0.49 mg/dL Pre3; 1.63 + 0.49 Susp; 1.58 +/- 0.48 Pos3, P < .0001). The progressive decrease in tacrolimus doses and levels was significant (ANOVA including the 7 visits <0.01 in all cases); whereas the level/dose ratio remained constant. Tacrolimus doses and levels continued a slow, progressive and significant decrease without any relevant change between visits during on versus off omeprazole. This clinical-analytical study supported the conclusion that an omeprazole-tacrolimus interaction is not clinically relevant. Despite possible competition or interaction at the molecular level, clinical management was not significantly affected in renal allograft recipients.

Topics: Anti-Ulcer Agents; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Omeprazole; Postoperative Complications; Tacrolimus

In an attempt to reduce chronic calcineurin inhibitor induced allograft nephropathy in first cadaver and human leukocyte antigen non-identical living-donor renal transplantation, sirolimus (Siro) or mycophenolate mofetil (MMF) was tested as adjunctive therapy, with planned dose reductions of tacrolimus (Tacro) over the first year postoperatively. Adjunctive Siro therapy with a similar dose reduction algorithm for Neoral (Neo) was included for comparison.. The detailed dose reduction plan (Tacro and Siro, group A; Tacro and MMF, group B; Neo and Siro, group C) is described in our companion report in this issue of Transplantation. The present report documents function, patient and graft survival, protocol compliance, and adverse events.. As mentioned (in companion report), group demographics were similar. The present study shows no significant differences in 1-year patient and graft survival but does show a trend that points to more difficulties in group C by way of a rising slope of serum creatinine concentration (P=0.02) and decreasing creatinine clearance (P=0.04). There were more patients who discontinued the protocol plan in group C. Thus far, no posttransplant lymphomas have appeared, and infectious complications have not differed among the groups. However, a greater percentage of patients in group C were placed on antihyperlipidemia therapy, with an (unexpected) trend toward a higher incidence of posttransplant diabetes mellitus in this group. Group A required fewer, and group B the fewest, antihyperlipidemia therapeutic interventions (P<0.00001).. This 1-year interim analysis of a long-term, prospective, randomized renal-transplant study indicates that decreasing maintenance dosage of Tacro with adjunctive Siro or MMF appears to point to improved long-term function, with reasonably few adverse events.

Topics: Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Kidney Function Tests; Kidney Transplantation; Lymphocele; Mycophenolic Acid; Patient Compliance; Postoperative Complications; Sirolimus; Surgical Wound Infection; Tacrolimus; Time Factors

Although tacrolimus (Prograf) is the calcineurin inhibitor usually employed in simultaneous pancreas-kidney transplantation (SPKTx), no prospective randomized studies have compared its efficacy to cyclosporine (Neoral), when either drug is used in combination with mycophenolate mofetil (MMF) and the pancreas is drained into the portal vein.. Between May 2001 and June 2003, 16 SPKTx recipients were randomized to be prescribed Neoral and 17 Prograf in addition to basiliximab, steroids, and MMF. All pancreata were drained into the portal vein.. After a median follow-up of 15.6 months, six kidney acute rejection episodes were observed with Prograf (36.5%; one steroid-resistant) and one Neoral (n = 1, 6.2%; P =.04). No pancreas rejection episode was recorded. Two infections occurred in two recipients from each group. No major adverse events were noted other than a severe hematological toxicity (Prograf). Metabolic parameters were equivalent in the two groups, save for higher total cholesterol (212 +/- 39 mg/dL vs 173 +/- 23 mg/dL; P =.008), LDL (129 +/- 33 mg/dL vs 101 +/- 21 mg/dL; P =.029), and triglyceride (191 +/- 86 mg/dL vs 126 +/- 40 mg/dL; P =.028), values with Neoral, although the same differences were already present at baseline. One recipient (Neoral) died with functioning grafts. Patient, pancreas, and kidney survival rates were all 94% for Neoral versus 100% for Prograf.. Although a larger series and a longer follow-up are needed, Neoral and Prograf used in combination with MMF seem to achieve equivalent success rates among primary SPKTx when the pancreas is drained into the portal vein.

Topics: Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation; Pilot Projects; Postoperative Complications; Tacrolimus; Time Factors

Evidence suggests that steroid sparing in renal transplantation is associated with good outcomes, although there are limited data regarding steroid sparing in Tacrolimus and Mycophenolate Mofetil (MMF)-based regimes. In this study we describe the use of these agents in 101 consecutive patients undergoing renal transplantation using only a 7-day course of prednisolone. Median follow-up was 33 months (range 18-44). Patient and graft survival at 1 year were 100% and 98%, respectively. The acute rejection rate at both 6 and 12 months was 19%, with two episodes beyond 12 months. Anti-CD25 monoclonal antibody (anti-CD25 mAb) was administered to 25 patients at high immunological risk: a trend toward a lower rejection rate was seen in these patients compared with those at lower risk but not receiving induction therapy (8% vs. 22%; p = 0.11). Two patients experienced recurrent rejection. Of the twenty-three rejection episodes in total, 26% showed vascular involvement. Allograft function was preserved at 12 months with a mean creatinine of 144 micromol/L and mean estimated glomerular filtration rate (GFR) of 55 mL/min. At 12 months, the incidence of post-transplant diabetes mellitus was 3.5%. This steroid-sparing regime is associated with excellent patient and graft outcomes, and a low incidence of side effects.

Topics: Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethnicity; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Racial Groups; Recurrence; Survival Analysis; Tacrolimus; Time Factors

Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years.. The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF.. All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

Topics: Acute Disease; Azathioprine; Cadaver; Creatinine; Cyclosporine; Drug Therapy, Combination; Florida; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Probability; Racial Groups; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

Interindividual variability in dosage requirements of the calcineurin inhibitor immunosuppressive agents cyclosporine and tacrolimus after liver transplantation may result from differences in the CYP3A activity of the liver graft. Early postoperative erythromycin breath test (ERMBT) is an in vivo measure of graft CYP3A activity. This study evaluates the usefulness of an early postoperative ERMBT in predicting early morbidity in liver transplant recipients.. In 26 liver transplant recipients, ERMBT was performed within 2 hr after transplantation. Main end points were the occurrence of cyclosporine and tacrolimus nephrotoxicity, episodes of early graft rejection, early graft function, and graft survival.. Cyclosporine and tacrolimus nephrotoxicity were associated with low postoperative ERMBT values (mean 0.63%+/-0.25% 14C/hr vs. 1.35%+/-0.84% 14C/hr, P=0.02). No significant association between early graft rejection and ERMBT values was demonstrated. There was a significant inverse correlation between postoperative ERMBT values and the time to normalization of international normalized ratio as a measure of early graft function (r=-0.78, P<0.001). Graft loss was associated with low postoperative ERMBT values (0.21%+/-0.15% 14C/hr vs. 1.09%+/-0.72% 14C/hr, P=0.002).. An early postoperative ERMBT may be useful in predicting the development of cyclosporine and tacrolimus nephrotoxicity, severe graft dysfunction, or even graft loss in liver transplant recipients when calcineurin inhibitors are administered according to protocols. Whether ERMBT results may be used to individualize dosage of calcineurin inhibitors needs to be explored.

Topics: Adult; Anti-Bacterial Agents; Aryl Hydrocarbon Hydroxylases; Breath Tests; Cyclosporine; Cytochrome P-450 CYP3A; Erythromycin; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Liver; Liver Transplantation; Male; Middle Aged; Oxidoreductases, N-Demethylating; Postoperative Complications; Predictive Value of Tests; Tacrolimus

Optimal immunosuppression is essential to maintain kidney allograft viability but minimizing toxicity is also fundamental.. This article compares immunosuppressants, corticosteroids, cyclosporine, tacrolimus, and basiliximab, which are used in the treatment regimens for renal transplantation. The analyses evaluated their effectiveness to prevent acute rejection episodes and to reduce the appearance of other complications, mainly infectious disease complications.. Ninety-five patients were analysed during the first year after primary renal transplantation. These patients were included in a random way in 3 different groups according to the immunosuppressant drug therapy: Group I (35 patients) received corticosteroids + CsA; Group II (35 patients) received corticosteroids + CsA + Basiliximab; Group III (25 patients) received corticosteroids + Tacrolimus + Basiliximab.. Among the 95 patients, 9 presented with an acute rejection episode in Group I. None in Group II, and one in group III. With reference to the infectious disease complications, the incidence of oral herpes was one case in Group I, 4 cases in Group II, and 2 cases in group III.. Treatment with Basiliximab produced a significantly lower incidence of acute rejection cases and an increase in infectious disease complications, such as lip herpes.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Herpes Labialis; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Postoperative Complications; Recombinant Fusion Proteins; Tacrolimus

Topics: Adult; Aged; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Recombinant Fusion Proteins; Survival Analysis; Tacrolimus; Time Factors

The aim of this retrospective study was to assess the incidence of acute rejection episodes (AR), diabetes mellitus (DM), and serum creatinine (SCr) among renal transplant recipients treated with tacrolimus (Tac), steroids (S), and mycophenolate mofetil (MMF) or azathioprine (Aza).. Seventy-five renal allograft recipients enrolled in the COSTAMP study were followed for a period of 3 years. Patients were randomized to receive either Tac and MMF (n = 41) or Tac and Aza (n = 34) concomitantly with steroids. Follow-up assessments were performed at 3, 6, 12, 24, and 36 months.. Patient survival at month 36 was 91.18% in the Tac/Aza/S group and 97.56% in the Tac/MMF/S group. Graft survival at month 36 was 82.35% and 85.37%, respectively. During the study period, 22 cases of biopsy-proven AR were diagnosed in 17 patients (22.6%). After 36 months the total number of AR was 11 in the Aza-treated group (32.4%) and 11 in the MMF-treated group (26.8%). DM was diagnosed de novo in 17 individuals (22.6%). During 36 months, 10 patients from Aza-treated group (29.4%) and seven from MMF-treated group developed DM (17.1%). Serum creatinine values were not significantly different in both arms of the study. Comparison of arterial blood pressure and total cholesterol revealed no significant changes in any of the studied groups.. We conclude that combinations of steroids, tacrolimus, and azathioprine or MMF provide good results with regard to renal function.

Topics: Adrenal Cortex Hormones; Azathioprine; Creatinine; Diabetes Mellitus; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

To compare the efficacy and safety of tacrolimus (FK506)- versus cyclosporine (CsA)-based immunosuppression protocol in the treatment of patients with renal transplantation for diabetic end-stage renal disease.. A total of 64 patients with end-stage renal disease were randomized into FK506 (n=33) and CsA (n=31) group after cadaveric renal transplantation, the former group adopting small-dose FK506 therapy with low trough concentration, and the latter receiving CsA therapy. The dose of insulin was adjusted according to blood glucose level of the patients after the operation. The incidence of acute rejections, blood glucose level, the dose of insulin and changes in blood pressure, lipid metabolism and liver function were compared between the two groups.. The 1-year patient/graft survival rates were 96.97%/93.94% in FK506 group and 96.77%/90.32% in CsA group. Four patients (12.12%) developed acute rejection in the FK506 group, while 11 (35.48%) did in the CsA group during the first year after the operation (P<0.05). The dose of the insulin of the FK506 group (34.35 U/d, 14.09 U/d) was not significantly different from that in the CsA group (28.15 U/d, 13.05 U/d) at the first month and 1 year after the operation (P>0.05). One year after the operation, 21 patients (63.63%) required anti-hypertension treatment, 5 (15.15%) needed anti-hyperlipidemia treatment and 3 (9.09%) had abnormal liver function in FK506 group, while in the CsA group, 28 patients (90.32%) needed anti-hypertension therapy, 13 (41.94%) received anti-hyperlipidemia treatment and 11 (35.48%) showed signs of abnormal liver function, with significant differences between the two groups.. Small-dose FK506 therapy with low concentrations is effective in the postoperative management of patients with renal transplantation for diabetic end-stage renal disease, with only mild adverse effect. FK506 is comparable with CsA in terms of the effect on glucose metabolism of the patients.

Topics: Aged; Diabetic Nephropathies; Female; Graft Rejection; Humans; Immunosuppressive Agents; Islets of Langerhans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Corticosteroids have been invariant transplant immunosuppressives with numerous adverse effects. We previously reported 6-month results in 10 patients using extended daclizumab induction to safely eliminate steroid use in pediatric renal transplantation. This expanded pilot series discusses immunosuppression dosing modification to further minimize drug toxicity without sacrificing regimen efficacy.. Fifty-seven pediatric renal transplant recipients were enrolled in the pilot steroid-free protocol. Extended daclizumab induction, tacrolimus, and mycophenolate mofetil (MMF) were intended maintenance drugs. Fourteen patients were equal to or younger than 5 years, and 43 patients were older than 5 years of age at transplantation. There were seven protocol breaks. Study patients underwent serial protocol transplant biopsies (n=246), and serum daclizumab and mycophenolic acid (MPA) trough levels were evaluated. In this efficacy study, controls were 50 historical-matched steroid-based children receiving tacrolimus with 100% 2-year graft survival and without delayed graft function.. Mean follow-up was 20 (range, 4.5-41) months with 98% overall graft and patient survival. At 1 year of analysis, steroid-free recipients showed significant improvements for clinical acute rejection (8%), graft function, hypertension, and growth, without increased infectious complications. Leukopenia, anemia, and allograft nephrotoxicity were addressed by solely decreasing MMF and tacrolimus dosing and/or by replacing MMF with sirolimus, without increasing acute rejection. Early daclizumab levels of more than 5 microg/mL were observed for the first time in children of all ages.. Pediatric renal transplantation is safe without steroids. Daclizumab first-dose doubling and extended use for 6 months replaces steroids effectively without evidence of overimmunosuppression and may be the pivotal cause for the reduced acute rejection seen in this trial. This pilot study provides preliminary data to test this protocol in a prospective, multicenter randomized study.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Pressure; Child; Child, Preschool; Daclizumab; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Hematocrit; Histocompatibility Testing; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Kidney Transplantation; Mycophenolic Acid; Pilot Projects; Postoperative Complications; Steroids; Tacrolimus; Time Factors; Treatment Outcome

The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned.. Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus.. All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function.. We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemia; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Postoperative Complications; Reproducibility of Results; Sirolimus; Tacrolimus; Time Factors

Topics: Cyclosporine; Drug Therapy, Combination; Europe; Follow-Up Studies; Graft Rejection; Graft Survival; Half-Life; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Survival Analysis; Tacrolimus; Time Factors

Topics: Cause of Death; Cyclosporine; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

Topics: Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Thrombocytopenia; Time Factors

Topics: Adult; Creatinine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus

Topics: Adult; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Immunosuppressive Agents; Incidence; Liver Transplantation; Postoperative Complications; Prednisone; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C; Humans; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Prospective Studies; Tacrolimus; Time Factors

Topics: Adult; Antilymphocyte Serum; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Incidence; Kidney Transplantation; Postoperative Complications; Tacrolimus

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Middle Aged; Postoperative Complications; Spain; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Pilot Projects; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Brazil; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Postoperative Complications; Protozoan Infections; Tacrolimus; Time Factors

Topics: Cyclosporine; Diltiazem; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emulsions; Europe; Female; Humans; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Survival Analysis; Tacrolimus

Topics: Adult; Cyclosporine; Cytomegalovirus Infections; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Postoperative Complications; Tacrolimus; Treatment Failure

Topics: Adult; Aged; Creatinine; Diabetes Mellitus; Fasting; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Postoperative Complications; Tacrolimus

Topics: Adolescent; Blood Glucose; Child; Child, Preschool; Cholesterol; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Hyperlipidemias; Kidney Transplantation; Lipids; Male; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Triglycerides

No data are currently available that describe the clinical outcomes associated with Thymoglobulin (rabbit polyclonal anti-thymocyte globulin) induction in pediatric renal transplant recipients. We report the outcomes of 17 pediatric renal transplant recipients (mean age 10.1+/-5.2 years) transplanted between 1 August 1999 and 31 July 2001. Eleven patients (65%) were Caucasian and 6 (35%) were African-American. Eleven (65%) recipients received cadaveric allografts. Two patients (12%) were second allograft recipients. One patient had primary allograft non-function secondary to vascular thrombosis. Two patients (12%) had delayed allograft function. Immunosuppression consisted of Thymoglobulin induction (mean number of doses 6+/-1.7) with tacrolimus (62%) or cyclosporine A (38%), mycophenolate mofetil, and prednisone. One year post transplant, patient and graft survival was 100% and 93%, respectively. No acute rejection episodes occurred during the first 6 months after transplantation in any of the recipients. Additionally, no rejection episode occurred among the 14 patients followed for 1 year after transplant. The incidences of asymptomatic cytomegalovirus (CMV) and Epstein-Barr virus (EBV) seroconversion at 1 year in seronegative recipients with a seropositive donor were 100% of 4 patients and 0% of 4 patients, respectively. No symptomatic CMV or EBV infections and no post-transplant lymphoproliferative disease have occurred in any patient. These short-term data suggest that Thymogobulin induction is safe and effective in combination with triple immunosuppressive therapy for preventing early rejection in pediatric renal transplant recipients.

Topics: Acute Disease; Adolescent; Animals; Antilymphocyte Serum; Child; Child, Preschool; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Rabbits; Tacrolimus; Treatment Outcome

Topics: Blood Pressure; Creatinine; Cyclosporine; Drug Therapy, Combination; Humans; Hypertension; Incidence; Kidney Transplantation; Postoperative Complications; Tacrolimus

This prospective, randomized, multicentre study investigated the efficacy and safety of two tacrolimus-based regimens and their potential to withdraw steroids.. In total 489 patients were randomised to receive either tacrolimus and MMF (n = 243) or tacrolimus and azathioprine (n = 246) concomitantly with steroids in both treatment groups. The initial oral dose of tacrolimus was 0.2 mg/kg/day, MMF dose was 1 g/day, azathioprine was administered at 1-2 mg/day. Steroids were tapered from 20 mg/day to 5 mg/day. From month 3 onwards, steroids were withdrawn in patients who were free from steroid-resistant rejection and who had serum creatinine concentrations < 160 mumol/L. Study duration was 6 months.. Patient survival at month 6 was 98.3% (Tac/MMF/S) and 98.4% (Tac/Aza/S), graft survival at 6 month was 95.0% (Tac/MMF/S) and 93.5% (Tac/Aza/S). The 6-month incidences of biopsy-proven acute rejection were 18.9% (Tac/MMF/S) compared with 26.8% (Tac/Aza/S), p = 0.038. The 6-month incidences of steroid-resistant acute rejection were 2.1% (Tac/MMF/S) and 4.9% (Tac/Aza/S), p = ns. At the end of month 3, steroid withdrawal was performed in 60.5% (Tac/MMF/S) and 48.8% (Tac/Aza/S) of patients, p < 0.01. During months 4-6, 2.7% of patients in the Tac/MMF group had a biopsy-confirmed acute rejection compared with 0.8% of patients in the Tac/Aza group. In patients who continued to receive steroids, the incidences of biopsy-proven acute rejections during months 4-6 were 3.5% (Tac/MMF/S) and 7.1% (Tac/Aza/S). At study end, the steroid-free patients had an excellent kidney function, the median serum creatinine concentration was 119.5 mumol/L (Tac/MMF) and 115.1 mumol/L (Tac/Aza); the median serum creatinine of the total study group was 130.5 mumol/L (Tac/MMF/S) and 132.8 mumol/L (Tac/Aza/S).. Both tacrolimus regimens are efficacious and safe. The combination of Tacrolimus and MMF achieved a lower rejection rate and permitted a higher proportion of steroid-free patients. The overall incidence of acute rejection was low and kidney function was good.

Topics: Adult; Azathioprine; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Reoperation; Steroids; Tacrolimus; Tissue Donors

With tacrolimus-based immunosuppression, it appears safe to withdraw steroids 3 to 6 months after renal transplantation. We hypothesized whether steroids could also be safely withdrawn early after transplantation.. Sixty-two patients (first or second transplant, with no previous immunological failure, and current panel reactive human leucocyte antigen [HLA] antibodies [PRA]<50%), treated with tacrolimus, were prospectively randomized to stop steroids (10 mg prednisolone) after day 7 posttransplantation (stop group [STOP], n=28) or to gradually wean off steroids in 3 to 6 months (tapering group [TAP], n=34). Analyses were performed on an intention-to-treat basis.. After a median follow-up of 2.7 years, patient and graft survival were 97 and 90% and comparable between both groups (P =0.11 and P=0.13, respectively). The incidence of acute rejection was 29 (STOP) versus 33% (TAP) ( P=0.30). The time to the first rejection was a median of 35 days (STOP) versus 11 days (TAP) ( =0.19). The severity of the rejections (1997 Banff classification) was comparable (P =0.57). Creatinine clearance and proteinuria were similar (P >0.70). The incidence of infections was comparable ( P>0.10). The incidence of new-onset diabetes mellitus, defined as the use of antidiabetic medication, was 8.0 (STOP) versus 30.3% (TAP) (P =0.04). All cases occurred in the STOP group after 1 year, while all cases occurred in TAP in the first 4 months ( P<0.001).. Compared with tapering in 3 to 6 months, stopping steroids 1 week posttransplantation results in comparable patient and graft survival and in a similar incidence of acute rejections. The incidence of new-onset diabetes may be reduced. The immunosuppressive benefit of adding 10 mg prednisolone to tacrolimus seems to be limited.

Topics: Acute Disease; Adult; Aged; Anti-Inflammatory Agents; Creatinine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Incidence; Infections; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prednisolone; Prospective Studies; Proteinuria; Risk Factors; Tacrolimus

Hepatitis C is the most common indication for liver transplantation (LT) in the United States. Recurrence of hepatitis C virus (HCV) infection post-LT remains a problem for which there is no completely satisfactory treatment. The aim of the present study is to evaluate mycophenolate mofetil (MMF), which has both immunosuppressive and antiviral properties, to determine whether it is associated with a difference in the rate of HCV recurrence and also examine its impact on patient and graft survival. Between August 1995 and May 1998, a total of 106 patients who were HCV positive before LT were randomized to tacrolimus (TAC) and prednisone versus TAC, prednisone, and MMF therapy. The rate of recurrence of HCV, patient and graft survival, incidences of rejection, and histological findings were examined. Fifty six patients were randomized to TAC and steroid therapy (double [D] drug; group D), and 50 patients were randomized to TAC, steroid, and MMF therapy (triple [T] drug; group T). Liver biopsies were performed when liver function was abnormal; protocol liver biopsies were not performed. Mean follow-up was 4.3 +/- 0.8 years. Actuarial patient survivals at 4 years were 72.6% in group D and 73.8% in group T (P = not significant). Actuarial graft survivals at 4 years were 65.6% in group D and 65.4% in group T. One patient in group D and 2 patients in group T underwent a second LT for recurrent HCV. One patient in each group died of recurrent HCV without re-LT. Twenty-six patients in group D (46.4%) and 23 patients in group T (46.0%) showed signs of recurrent HCV. Mean hepatitis activity index (HAI) scores were 7.4 +/- 2.7 in group D and 7.0 +/- 3.4 in group T, and mean fibrosis scores were 2.9 +/- 1.7 in group D and 2.6 +/- 1.1 in group T. The rate of rejection was 0.57/patient in each group for the entire follow-up period. None of these values reached statistical significance. Rates of HCV recurrence, graft loss or death from recurrent HCV, and 4-year actuarial patient and graft survival were not different between the groups. In liver transplant recipients with HCV, MMF has no impact on patient survival, graft survival, rejection, or rate of HCV recurrence based on biochemical changes and histological findings. In addition, there was no difference in HAI or fibrosis score between the two groups. Either MMF has no anti-HCV effect or its immunosuppressive properties overwhelm its antiviral effect in the clinical setting.

Topics: Adult; Aged; Cause of Death; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Secondary Prevention; Tacrolimus

Topics: Adrenal Cortex Hormones; Azathioprine; Cadaver; Cholesterol; Creatinine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Transplantation; Postoperative Complications; Spain; Survival Rate; Tacrolimus; Time Factors; Tissue Donors

Topics: Adrenal Cortex Hormones; Age Factors; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Postoperative Complications; Prednisone; Tacrolimus; Time Factors; Transplantation, Homologous

Pediatric donor (PD) livers have been allocated to adult transplant recipients in certain situations despite size discrepancies. We compared data on adults (age > or = 19 years) who underwent primary liver transplantation using livers from either PDs (age < 13 years; n = 70) or adult donors (ADs; age > or = 19 years; n = 1,051). We also investigated the risk factors and effect of prolonged cholestasis on survival in the PD group. In an attempt to determine the minimal graft volume requirement, we divided the PD group into 2 subgroups based on the ratio of donor liver weight (DLW) to estimated recipient liver weight (ERLW) at 2 different cutoff values: less than 0.4 (n = 5) versus 0.4 or greater (n = 56) and less than 0.5 (n = 21) versus 0.5 or greater (n = 40). The incidence of hepatic artery thrombosis (HAT) was significantly greater in the PD group (12.9%) compared with the AD group (3.8%; P =.0003). Multivariate analysis showed that preoperative prothrombin time of 16 seconds or greater (relative risk, 3.206; P =.0115) and absence of FK506 use as a primary immunosuppressant (relative risk, 4.477; P =.0078) were independent risk factors affecting 1-year graft survival in the PD group. In the PD group, transplant recipients who developed cholestasis (total bilirubin level > or = 5 mg/dL on postoperative day 7) had longer warm (WITs) and cold ischemic times (CITs). Transplant recipients with a DLW/ERLW less than 0.4 had a trend toward a greater incidence of HAT (40%; P <.06), septicemia (60%), and decreased 1- and 5-year graft survival rates (40% and 20%; P =.08 and.07 v DLW/ERLW of 0.4 or greater, respectively). In conclusion, the use of PD livers for adult recipients was associated with a greater risk for developing HAT. The outcome of small-for-size grafts is more likely to be adversely affected by longer WITs and CITs. The safe limit of graft volume appeared to be a DLW/ERLW of 0. 4 or greater.

Topics: Adolescent; Adult; Cholestasis; Graft Survival; Hepatic Artery; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Multivariate Analysis; Organ Size; Postoperative Complications; Prothrombin Time; Risk Factors; Safety; Tacrolimus; Thrombosis; Tissue Donors

Topics: Adult; Analysis of Variance; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Lung Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Tacrolimus; Time Factors

Topics: Azathioprine; Biopsy; Blood Pressure; Cholesterol; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Triglycerides

Topics: Antilymphocyte Serum; Azathioprine; Bacterial Infections; Cytomegalovirus Infections; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Mycoses; Postoperative Complications; Prednisolone; Prospective Studies; Sepsis; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Antilymphocyte Serum; Azathioprine; Calcineurin; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Patient Selection; Postoperative Complications; Reoperation; Steroids; Survival Rate; Tacrolimus; Time Factors

A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years.. Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years.. The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF.. All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.

Topics: Administration, Oral; Adolescent; Adult; Antilymphocyte Serum; Azathioprine; Black People; Cadaver; Child; Cross-Over Studies; Cyclosporine; Diabetes Mellitus; Drug Monitoring; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Kidney Function Tests; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Mycophenolic Acid; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; United States; White People

In the past, enteric drainage or the omission of induction immunotherapy has been shown to be predictive of suboptimal outcomes of simultaneous pancreas-kidney (SPK) transplantation. We have reassessed the need for bladder drainage and induction immunotherapy to optimize the outcome of SPK transplantation.. One hundred consecutive recipients of SPK transplants who received mycophenolate mofetil and tacrolimus immunosuppression were studied. The first 50 recipients had bladder-drained pancreas allografts and received induction immunotherapy. The results were compared with the next 50 recipients who had enteric-drained pancreas allografts, which included a subgroup (n = 17 patients) who were randomized to receive no induction immunotherapy.. The 1-year actuarial patient, kidney, and pancreas survival rates in the bladder-drainage group were 98.0%, 94.0%, and 94.0%, respectively. The 1-year actuarial patient, kidney, and pancreas survival rates in the enteric-drainage group were 96.8%, 96.8%, and 89.4%, respectively. In the enteric-drainage group, the incidence of rejection at 1 year was 6.1% in recipients who received induction therapy versus 23.5% in recipients who did not receive induction therapy. The average number of readmissions per recipient was 1.8 in the bladder-drainage group versus 0.9 in the enteric-drainage group.. Primary enteric drainage of the pancreas allograft in recipients of SPK transplantation is the preferred surgical technique in the tacrolimus/mycophenolate mofetil era.

Topics: Adult; Bacterial Infections; Drainage; Female; Graft Rejection; Graft Survival; Humans; Hypertension, Renal; Immunosuppressive Agents; Incidence; Intestines; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Patient Readmission; Postoperative Complications; Survival Analysis; Tacrolimus; Treatment Outcome; Urinary Bladder

Topics: Administration, Oral; Azathioprine; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

Topics: ABO Blood-Group System; Adult; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Tacrolimus; Time Factors

Topics: Adult; Aged; Antilymphocyte Serum; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Postoperative Complications; Prednisolone; Prospective Studies; Tacrolimus; Time Factors

Tacrolimus is an effective immunosuppressant in the rescue of liver allograft patients in whom conventional immunosuppression failed. Efficacy and safety were examined in a multicenter trial of liver transplant recipients converted to tacrolimus because of rejection despite cyclosporine (CyA) therapy or intolerance to CyA. Six hundred seventy-seven patients were enrolled onto the study; 475 patients for rejection, 197 patients for intolerance, and 5 patients treated compassionately. The mean daily dose of tacrolimus was less in the intolerance (Int) patients throughout the study: 0.22 versus 0.17 mg/kg at 1 week and 0.14 versus 0.11 mg/kg at 24 months in rejection (Rej) and Int patients, respectively. Mean blood levels paralleled dosing in both groups, but were greater in the Rej patients (10.7 v 8.3 ng/mL at 18 months). Kaplan-Meier estimates of patient and graft survival were similar in the two groups. Patient survival rates were 80.1% and 81.5%, and graft survival rates were 72.7% and 73.9% at 24 months in the Rej and Int patients, respectively. Most adverse events occurred with a similar incidence in the two groups. Those with a 4% or greater incidence were fever, viral hepatitis, and pneumonia. The incidence of sepsis, gastrointestinal hemorrhage, kidney failure, and convulsion was greater in the Int group. The incidence of abnormal liver function test results, hyperglycemia, headache, and abnormal kidney function was greater in the Rej group. Mean liver function test results decreased with time postrescue in both groups. Mean serum creatinine level increased from baseline to 18 months postrescue in both groups (1.44 to 1.51 mg/dL for Int patients, 1.14 to 1.48 mg/dL for Rej patients). We conclude tacrolimus is safe and effective rescue in liver transplant recipients with rejection or CyA intolerance.

Topics: Adult; Child; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Function Tests; Liver Transplantation; Postoperative Complications; Tacrolimus

The recent U.S. multicenter randomized trial of FK506 versus cyclosporine (CsA) demonstrated equivalent patient and graft survival in patients treated with FK506 and statistically fewer rejection episodes in the first year posttransplant.. To determine if more effective posttransplant immunosuppression was associated with an increased risk of cytomegalovirus (CMV) or posttransplant lymphoproliferative disease (PTLD), we examined the incidence of these two opportunistic infections during 3 years of follow-up.. CMV infection occurred in 40 (19.5%) FK506 and 40 (19.3%) CsA-treated patients. The incidence of CMV disease was 9.3% in FK506 and 6.8% in CsA-treated recipients; the most common site of CMV disease was the gastrointestinal tract. A multivariate analysis of several risk factors demonstrated that a CMV- recipient of a CMV+ donor was at greatest risk for CMV infection. The incidence of posttransplant lymphoproliferative disease was equal in the two treatment arms: six CsA- and five FK506-treated recipients.. The results of this study suggest that the superior efficacy of FK506 in the prevention of acute rejection was not associated with an increased risk of CMV or posttransplant lymphoproliferative disease compared with CsA.

Topics: Cyclosporine; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Multivariate Analysis; Opportunistic Infections; Postoperative Complications; Tacrolimus

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Cadaver; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Tissue Donors

Topics: Adrenal Cortex Hormones; Belgium; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Luxembourg; Male; Middle Aged; Mycophenolic Acid; Netherlands; Postoperative Complications; Reoperation; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Europe; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Spain; Survival Rate; Tacrolimus

Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation.. Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6).. A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group.. Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

Topics: Adult; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Cyclosporine; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Postoperative Complications; Tacrolimus; Triglycerides

Results of a multicenter, randomized, clinical trial demonstrated that tacrolimus was more effective than cyclosporine in preventing acute rejection in cadaveric renal transplant patients. As African-Americans comprised approximately 25% of the study population, their outcome was analyzed relative to the experience of Caucasian patients.. Of the 205 patients randomized to tacrolimus, 56 (27.3%) were African-American and 114 (55.6%) were Caucasian. Of the 207 patients randomized to cyclosporine, 48 (23.2%) were African-American and 123 (59.4%) were Caucasian. The efficacy variables were 1-year patient survival, graft survival, and incidence of acute rejection.. The incidence of acute rejection was significantly lower in African-American and Caucasian patients treated with tacrolimus than with cyclosporine. Additionally, no African-American patient who was treated with tacrolimus experienced moderate or severe acute rejection, as determined by blinded independent review. The incidence of nephrotoxicity, cardiovascular and gastrointestinal events, malignancies, and opportunistic infections was similar between treatments and race groups. However, there was an increased incidence of posttransplant diabetes mellitus in tacrolimus-treated patients, particularly in African-Americans, and tacrolimus was associated with significantly lower lipid levels in both Caucasians and African-Americans. African-American patients required a 37% mean higher dose of tacrolimus than Caucasian patients to achieve comparable blood concentrations.. Tacrolimus is more effective than cyclosporine in preventing acute rejection in both African-American and Caucasian patients. However, tacrolimus was associated with an increased risk of posttransplant diabetes mellitus, particularly in African-Americans, which was reversible in some patients.

Topics: Adult; Black or African American; Black People; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors; United States; White People

Immunosuppression in patients with hepatitis C virus (HCV) following orthotopic liver transplantation can lead to significant increases in serum viral loads. Our aim was to analyze the effect of a randomized study of two immunosuppressive agents (tacrolimus vs. microemulsion cyclosporine) on the outcome of HCV patients following orthotopic liver transplantation.. From December 1995 to September 1996, 50 adult patients transplanted for HCV cirrhosis were randomly assigned to receive tacrolimus (Prograf) (group 1, 25 patients) or microemulsion cyclosporine (Neoral) (group 2, 24 patients). All patients received alpha-interferon after transplantation, and the overall steroid doses were no different between the groups. Serum RNA levels were measured by signal amplification of Chiron. Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens.. There were more episodes of rejection in the Neoral group, but there were no differences in bacterial and viral infections, nor in the rate of HCV recurrence between the two groups. There were seven deaths in group 1 and eight in group 2. Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68% and 67 and 64%, respectively.. (a) Both immunosuppression regimens had similar HCV recurrence rates; (b) there were no differences in bacterial or opportunistic infections; and (c) patient and graft survival was similar between the two groups.

Topics: Adult; Aged; Cyclosporine; Emulsions; Female; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Reoperation; RNA, Viral; Survival Rate; Tacrolimus

Topics: Adolescent; Adult; Aged; Creatinine; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus

Topics: Adolescent; Adult; Blood Transfusion; Cadaver; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Prednisolone; Survival Rate; Tacrolimus; Time Factors; Tissue Donors

Topics: Adolescent; Adult; Aged; Antilymphocyte Serum; CD3 Complex; Child; Communicable Diseases; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Survival Rate; T-Lymphocyte Subsets; Tacrolimus

Topics: Bias; Black People; Cadaver; Cross-Over Studies; Cyclosporine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Hypoglycemic Agents; Immunosuppression Therapy; Immunosuppressive Agents; Insulin; Kidney Transplantation; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; United States; White People

Topics: Adult; Azathioprine; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Postoperative Complications; Prednisone; Prospective Studies; Survival Rate; Tacrolimus; Time Factors

Immunosuppressive efficacy of Neoral and Prograf following primary hepatic transplantation was comparable. Incidence of rejection episodes, infectious complications, hypertension, and postoperative diabetes mellitus was comparable. Although clinical use of both immunosuppressants was associated with early compromise in renal function, no progressive renal dysfunction was observed.

Topics: Analysis of Variance; Azathioprine; Creatinine; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Liver Transplantation; Postoperative Complications; Prednisone; Prospective Studies; Regression Analysis; Survival Rate; Tacrolimus; Time Factors

Topics: Communicable Diseases; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Prednisone; Tacrolimus

Topics: Adult; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Premedication; Tacrolimus

Topics: Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone Hemisuccinate; Muromonab-CD3; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Premedication; Tacrolimus

Five patients with cyclosporin-related haemolytic uraemic syndrome (HUS) following cadaveric renal transplantation were converted from cyclosporin- to tacrolimus-based immunosuppression. All patients had biochemical, haematological and biopsy evidence of HUS at the time of conversion. Four of the patients showed complete resolution of the syndrome within 1 week of conversion with normalisation of haemoglobin, platelets and lactate dehydrogenase levels. In the fifth patient renal function stabilised with slow resolution of the haematological and biochemical parameters. Four of the five patients are still taking tacrolimus, one having converted back to cyclosporin due to marked hair loss. We conclude that conversion to tacrolimus appears to be an effective treatment for cyclosporin-related HUS following renal transplantation.

Topics: Adult; Cyclosporine; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

We conducted an analysis of biopsy specimens of non-episode renal allografts from patients treated with tacrolimus (FK506) or cyclosporine (CsA) to evaluate chronic drug-induced nephropathy in stable allografts. A total of 38 biopsy specimens from stable functioning renal allografts were examined. The patients had been treated with FK506 (n = 16) or CsA (n = 18) as main immunosuppressant for 0.3 to 7.4 years. Of the 38 biopsy specimens, 15 showed mild drug-induced arteriolopathy (hyalinosis or insudative change of arterioles and small arteries) with striped-form interstitial fibrosis, 10 showed minimum interstitial cellular infiltration (borderline rejection), 2 showed IgA nephropathy, 4 showed evidence of chronic rejection (transplant nephropathy) and 12 showed no abnormal findings. Of 34 renal allograft biopsy specimens with stable function, 22 (65%) showed pathological evidence of drug-induced nephropathy. There were no significant qualitative or quantitative differences between FK506- and CsA-associated nephropathy.

Topics: Biopsy; Cyclosporine; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Tacrolimus; Vascular Diseases

Following renal transplantation, the long-term use of cyclosporine can cause nephrotoxicity. This small study of ten patients looks at the effects of tacrolismus rescue therapy over a 6-month period. After conversion to tacrolismus, renal function improved in seven patients, progressive graft dysfunction slowed and almost stabilized in two patients, and, in the remaining patient, deterioration continued and hemodialysis treatment was initiated at the end of the study period. A greater number of patients and a longer follow up are necessary to confirm these initially impressive results.

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Tacrolimus

Tacrolimus (FK506) is an effective and relatively safe novel immunosuppressant able to revert refractory rejection after pediatric liver transplantation (LTx). Between April 1993 and October 1996, 20 pediatric patients were converted to tacrolimus for biopsy-proven, steroid-resistant liver rejection. The mean follow-up was 18 months. The median time from LTx to switch was 20 days. Tacrolimus was administered per os at a mean dosage of 0.23 mg/kg per day to maintain median blood levels of 10.8 ng/ml at 1 week and 9.2 ng/ml at 1 year from the switch. Of the 20 patients, 15 are alive and they all recovered from rejection without the need of OKT3 after conversion. The major causes of death were: one multiorgan failure, two infections (cytomegalovirus Aspergillus), one bowel perforation, and one posttransplant lymphoproliferative disease. One patient experienced late side effects and was reconverted to cyclosporine when she was already rescued from hepatic allograft rejection. The results confirm that an earlier conversion to tacrolimus should be recommended after pediatric liver transplantation in order to revert hepatic allograft rejection with the best safety profile.

Topics: Child, Preschool; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Postoperative Complications; Tacrolimus

Following primary liver transplantation, immunosuppressive efficacy of Neoral and Prograf was similar and superior to that of Sandimmune. Rejection incidence was statistically increased with Sandimmune therapy. Incidence of hypertension, posttransplant diabetes mellitus, and infectious complications was not statistically different. Although early compromise in renal function was associated with Sandimmune, Neoral, and Prograf immunosuppression, no progressive renal dysfunction was identified.

Topics: Adult; Analysis of Variance; Azathioprine; Communicable Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Function Tests; Liver Transplantation; Methylprednisolone Hemisuccinate; Postoperative Complications; Regression Analysis; Retrospective Studies; Tacrolimus

Topics: Adolescent; Adult; Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Methylprednisolone; Middle Aged; Neoplasms; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

Arterial hypertension, which represents a common problem in patients with renal transplant, contributes to the cardiovascular morbidity and mortality of these patients. The most usual immunosuppressive drugs (cyclosporine and FK-506) collaborate on the development of hypertension. Calcium channel blockers are the most habitually used antihypertensive drugs in this population, although its long-term hemodimamycs effects could be deleterious especially in transplanted patients with chronic graft nephropathy. Losartan, a specific blocker of angiotensin II (AT1) receptors, has demonstrated a potent antihypertensive effect with a good safety and tolerance profile. The glomerular effects of losartan could be useful in transplanted patients. The present open, prospective and multicenter study evaluated the efficacy and safety of losartan in the treatment of hypertension in a group of patients with a renal transplant. Seventy-six patients with systolic blood pressure > or = 140 and/or diastolic blood pressure > or = 90 mm Hg, and/or patients on therapy with one antihypertensive drug and related side effects were included. After inclusion, therapy with losartan 50 mg/24 hr was started, discontinuing the previous antihypertensive therapy and/or therapy which caused the side effects. At four weeks, if blood pressure (BP) was not controlled, hydrochlorothiazide 25 mg or furosemide 40 mg/24 hr was added. At baseline and at weeks 2, 4, 8 and 12, the following parameters were monitored: BP, creatinine, hematocrit, hemoglobin, glucose, ions, uric acid, cholesterol, triglycerides, bilirubin, SGOT, SGPT, GGT, LDH, calcium, phosphate, alkaline phosphatase, proteinuria, and both cyclosporine and FK-506 levels in whole blood. Sixty-seven patients completed the 12-week study period. Mean blood pressure decreased from 113 +/- 10 to 102 +/- 9 mm Hg at the end of the study (P < 0.0001); 38 of the 67 patients (56.7%) who completed the study had a SBP lower than 140 mm Hg and a DBP lower than 90. These blood pressures were obtained in 30 patients on monotherapy with losartan (78.9%). Proteinuria decreased significantly at week 4 and was confirmed at week 12, especially in patients with proteinuria > or = 300 mg/24 hr. Nine patients were withdrawn during the study period for different reasons. Serum creatinine showed a slight, non-clinically significant increase at week 4, remaining stable until the end of the study. Two patients developed a mild normocytic anemia, and three others

Topics: Adult; Antihypertensive Agents; Blood Pressure; Cyclosporine; Drug Interactions; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Losartan; Male; Postoperative Complications; Tacrolimus

Eleven children, 4 males and 7 females, with biliary atresia receiving living related liver graft were studied. The mean age was 1.8 years and the mean body weight was 10.3 kg. The donors were 4 fathers and 7 mothers. The graft was the lateral segment or left lobe. ABO blood group matching was compatible in 9 and incompatible in 2. All patients except one were crossmatch negative. Immunosuppression at induction was triple therapy (cyclosporine, azathioprine and steroid) or FK506 plus steroid. Acute rejection episodes were treated with pulse steroids. When the signs of rejection persisted despite steroid pulse therapy, 15-deoxyspergualin (DSG) was added. The survival rate of the patients was 73%. Three patients died of portal vein thrombosis, hepatic artery thrombosis and sepsis respectively. Other major complications included hyperbilirubinemia, bile duct stenosis, bile leakage and portal vein anastomosis narrowing. Complications of the donor were sepsis in one, and liver dysfunction in two. Although there are some complications related to graft size mismatch and operative procedure, living related partial liver transplantation is an effective therapy in countries where donor source is restricted.

Topics: ABO Blood-Group System; Biliary Atresia; Child, Preschool; Female; Graft Rejection; Guanidines; Histocompatibility; Humans; Immunosuppressive Agents; Infant; Japan; Liver Transplantation; Living Donors; Male; Postoperative Complications; Survival Rate; T-Lymphocytes; Tacrolimus

The efficacy and safety of the new immunosuppressant agent, FK506 (tacrolimus), was assessed in pediatric renal transplant recipients over a mean 12-month follow-up period.. Twenty pediatric renal transplant recipients received oral FK506 therapy (0.3 mg/kg/d) in combination with azathioprine (1 to 2 mg/kg/d) and low-dose prednisone as primary therapy (n = 11) or were converted from cyclosporine-based therapy (n = 9) for complications including cyclosporine toxicity (n = 2), acute refractory rejection (n = 4), and chronic rejection (n = 3). Patients were then followed-up prospectively to evaluate effectiveness of therapy and complications.. In the primary treatment group, 45% of patients had one or more rejection episodes. Two required OKT3 therapy (18%) for persistent rejection, with one (9%) graft loss at 3 months. All other episodes were treated effectively with FK506 dose adjustment and steroid pulses. Patient and graft survival was 100% and 91%, respectively, at 12 months mean follow-up. In the FK506 conversion group, two teenage girls with intractable acne and hirsutism were converted with complete resolution and no change in renal function. Four patients were converted for acute rejection: two who did not respond to steroid pulse and two who did not respond to both steroids and OKT3. All four grafts were salvaged (mean follow-up, 12 months; mean Creatinine [Cr], 1.1). Three patients were converted for biopsy-proven chronic rejection at 3, 10, and 12 years after transplant (mean Cr, 2.4) with two of three of patients stable with functioning grafts at 1 year after conversion. Complications of FK506 therapy included temporary insulin-dependent diabetes mellitus (10%), neurological complications (25%), renal toxicity (15%), and hypertension (85%). There were no cases of gastrointestinal toxicity, hepatic dysfunction, lymphoproliferative disorders, or life threatening viral infection. All symptoms of toxicity responded to dose adjustment. No patient required conversion from FK506 to other agents.. This early experience indicates that FK506 in combination with low-dose steroids and azathioprine appears to provide safe and effective immunosuppression in the pediatric age group as a primary agent and may salvage grafts in patients with refractory steroid and OKT3 resistant rejection. Graft and patient survival is comparable to that seen with conventional cyclosporine-based immunosuppression.

Topics: Adolescent; Adult; Azathioprine; Child; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Postoperative Complications; Prednisone; Prospective Studies; Tacrolimus

From 1988 to 1993, UCLA completed 938 first and 1,146 total orthotopic liver transplants (OLT). Race analysis demonstrated a 1-year patient survival of 89% in Blacks (n = 45) versus 80% in Whites (n = 492, p < 0.02), with no significant difference shown between Hispanics (n = 278) and Whites. The 1-year patient survival in Asians was 50% (n = 58, p < 0.02 vs. Whites) even when hepatitis B was excluded (59%, n = 43). The 1-year patient survival of hepatitis B surface antigen positive Asians (n = 15) was only 21% (p < 0.02 vs. all others). OLT patients whose panel reactive antibody (PRA) was < 10% (n = 339) demonstrated no graft or patient survival advantage versus recipients whose PRA was > 10% (n = 71). A positive antidonor flow cytometry crossmatch (> 30 mean channel shifts, n = 76) was associated with a decreased 1-year graft survival (56% vs. 73%, p < 0.05) when compared to flow negative recipients (n = 185). Graft survival for 0 DR mismatches was 74% at 1 year compared with 57% for 1 DR mismatches (p < 0.02) and 59% for 2 DR mismatches (p < 0.02).

Topics: Adult; Antibody Specificity; Asian People; Azathioprine; Child; Child, Preschool; Cohort Studies; Cyclosporine; Flow Cytometry; Graft Rejection; Hepatitis B Surface Antigens; Hispanic or Latino; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Liver Transplantation; Postoperative Complications; Prospective Studies; Steroids; Tacrolimus; White People

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Azathioprine; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Kidney Transplantation; Middle Aged; Postoperative Complications; Prednisone; Prospective Studies; Reoperation; Survival Rate; Tacrolimus; Time Factors

Topics: Bacterial Infections; Blood Pressure; Cadaver; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Kidney Transplantation; Male; Mycoses; Patient Selection; Postoperative Complications; Prednisolone; Tacrolimus; Time Factors; Tissue Donors; Virus Diseases

We analyzed the relation between FK506 trough levels (ELISA: patients 1-41, IMx: patients 42-70) and rejection and/or viral infection episodes, retrospectively, in the first 70 consecutive cases of living related liver transplantation. Twenty patients (28.6%) had rejection episodes. Of the 13 patients who had evidence of rejection during the first 3 months, 6 patients without infection and 7 patients with viral infection showed low concentrations of FK506 (< 5 ng/ml). Twelve patients were treated and improved with high dose steroid administration and an increase in the FK506 dosage. One patient died of refractory rejection. Nine patients had evidence of rejection after the first 3 months. In 3 patients, weaning from FK506 initiated the rejection episodes. Five patients repeated rejection and 4 patients required a third immunosuppressant (azathioprine). Viral infection included CMV (11 cases), EBV (13 cases), HZV (3 cases), and HSV (1 case). Excess immunosuppression might have been the cause, but no clear correlation was found. We propose that the optimal dosage of FK506 obtained by monitoring the trough levels using the IMx method should maintain a 10-20 ng/ml level during the first month, and a 5-10 ng/ml level at the second and third months.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Female; Graft Rejection; Humans; Infant; Liver Transplantation; Male; Postoperative Complications; Retrospective Studies; Tacrolimus; Virus Diseases

Previous clinical evaluation of FK506 in renal transplantation has demonstrated equivalent patient and graft survival when compared with cyclosporine-based regimens. However, lower steroid and anti-hypertensive mediation requirements and lower serum cholesterol levels have been seen in patients receiving FK506. In August, 1991, a prospective, randomized trial was begun, comparing FK506/prednisone with FK506/azathioprine/prednisone. Two-hundred-and-four adults were entered into this trial between August 1, 1991, and October 11, 1992. The mean recipient age was 43.8 +/- 13.7 years, with a range of 17.6-78.0 years. Sixty-one (30%) recipients received a 2nd, 3rd or 4th transplant, while 35 (17%) had a PRA greater than 40% at the time of transplant. Thirty-three (16%) of the transplants were in recipients over 60 years of age, Thirteen percent of the kidneys were from living donors; 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 +/- 8.4 hours, and the mean donor age was 34 +/- 2.10 years, with a range from 4 months to 75 years. With a mean follow-up of 9 +/- 4 months, the 1-year actuarial patient survival is 93%; for the two-drug group it is 95%, and for the three-drug group it is 91% (p = NS). One-year actuarial graft survival is 86%; in the two-drug group it is 90%, while in the three-drug group it is 82% (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actuarial Analysis; Adult; Azathioprine; Cadaver; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Kidney Transplantation; Postoperative Complications; Prednisone; Prospective Studies; Survival Rate; Tacrolimus; Time Factors; Tissue Donors

A prospective randomised study was conducted to evaluate the efficacy and safety of FK 506 administered with corticosteroids compared with a cyclosporin A-based immunosuppressive regimen in patients undergoing primary liver transplantation. 545 patients were recruited in eight European centres, of whom 267 were randomised to FK 506 therapy and 273 to cyclosporin A-based therapy. The estimated Kaplan-Meier patient and graft survival figures of 82.9% and 77.5% respectively in the FK 506 group were higher than the comparable figures in the cyclosporin A group (77.5% and 72.6%, respectively). These differences did not reach statistical significance. Retransplantation rates, time to first rejection episode and number of rejection episodes were all lower (P < 0.001) in the FK 506 group. The infection rates were comparable between the two groups. During the study, the dose of FK 506 was reduced; this did not compromise efficacy and reduced the associated toxicity. FK 506 provides effective immunosuppression in patients undergoing primary liver transplantation and is associated with a lower incidence of rejection.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

Neurotoxicity is a serious complication following orthotopic liver transplantation leading to increased morbidity and mortality. Neurotoxicity may be evoked by various perioperative factors, or may be due to drug-specific toxicity of immunosuppression. In the present study we evaluated the incidence of central nervous system (CNS) toxicity occurring within the early postoperative period of 121 patients, 61 randomly assigned to FK 506- and 60 to CsA-based immunosuppression as part of a multicentre study. The incidence of moderate or severe CNS toxicity was higher in patients treated with FK 506 (21.3%) than in patients receiving CsA (11.7%). The duration of symptoms was also greater in patients treated with FK 506 than in patients receiving CsA. The incidence of moderate or severe neurotoxicity after retransplantation was markedly greater in patients treated with FK 506 (100% of the patients).

Topics: Central Nervous System Diseases; Cyclosporine; Dose-Response Relationship, Drug; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Postoperative Complications; Reoperation; Tacrolimus; Time Factors

In a retrospective study, we analysed the FK 506 dosage used in primary liver graft recipients enrolled in the European FK 506 multicenter trial conducted from September 1990 to January 1992. In addition, a second cohort of patients treated more recently in a single centre was investigated. The impact of different dosing strategies on the clinical course of the patients was analysed with special emphasis on the incidence of rejection episodes and FK 506 side-effects. Among the patients enrolled in the European FK 506 multicenter trial, those patients enrolled during the "early" phase of the study received a higher oral FK 506 dose [mean oral dosage on day 7 = 0.19 mg/kg body weight (bw) per day, n = 134] compared to patients enrolled during the "late" period of the study (mean oral dosage on day 7 = 0.14 mg/kg bw per day, n = 133). This lower dosage was the result of several protocol amendments performed to reduce the incidence of FK 506 side-effects. Lowering of the FK 506 dosage was accompanied by a reduction in the long-term prevalence of side-effects such as diabetes (n. s.) or hypertension (P < 0.05), while patient survival and rejection frequency remained constant. Patients treated in centres with online FK 506 blood level monitoring experienced significantly less hypertension, less episodes of diabetes and less rejection episodes compared to patients treated in centres without. The clinical course of those patients enrolled in the multicentre trial was compared with the course of a cohort of liver-grafted patients treated with FK 506 more recently in a single centre. These patients had a further reduction in the FK 506 dosage (0.10 mg/kg bw per day p.o. or less according to whole blood levels, with no intravenous FK 506 administration). When compared to patients enrolled in the multicentre trial, these patients experienced less side-effects (nephrotoxicity, hypertension, serious early neurotoxicity) while adaequate immunosuppression was maintained.

Topics: Administration, Oral; Adult; Diabetes Mellitus; Dose-Response Relationship, Drug; Europe; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Infusions, Intravenous; Liver Transplantation; Male; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus

Long-term renal function was compared in 49 liver recipients [25 patients received cyclosporin (CyA) and 24 patients received FK 506] followed for a period of 1 year. Creatinine (CR) and glomerular filtration rate (GFR) pretransplantation (pre-Tx) and at 1, 3, 5, and 12 months post-Tx were recorded, as well as incidences of hyperkalemia, post-Tx hypertension, and insulin-dependent diabetes mellitus (IDDM) in the two groups. At 1 year post-Tx, the mean Cr had risen from baseline by 56% and 60% in the FK and CyA groups, respectively; the mean GFR had dropped by 32% in FK patients and by 27% in CyA patients. Acute nephrotoxicity occurred in 7/25 CyA patients (2/7 required dialysis) and 9/26 FK patients (7/9 required dialysis; 2/7 were switched to CyA). None remained on dialysis at 3 months. Renal insufficiency persisted at 1 year in 7/16 patients with early toxicity (CyA, 4; FK, 3) and in 3 of the remaining 36 pts (P < 0.001). Hyperkalemia occurred in 4/25 CyA, and in 12/24 FK patients (P < 0.025), post-Tx hypertension occurred in 15 CyA, and 7 FK patients (P < 0.05), and IDDM occurred in 4 CyA and 7 FK patients (P = ns). FK 506 and CyA, thus, exerted similar chronic renal effects. Although acute renal insufficiency improved upon dose reduction, renal impairment was permanent in some cases.

Topics: Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Postoperative Complications; Tacrolimus; Time Factors

Eighty-one liver recipients were randomised to FK 506 or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-seven FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-sparing effect.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Bacterial Infections; Cyclosporine; Female; Follow-Up Studies; Humans; Liver Transplantation; Male; Mycoses; Postoperative Complications; Tacrolimus; Virus Diseases

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient.

Topics: Adult; Female; Graft Rejection; Heart; Heart Transplantation; Humans; Immunosuppression Therapy; Infections; Kidney; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Tacrolimus

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft-versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection.

Topics: Adult; Alprostadil; Child, Preschool; Female; Gastrointestinal Motility; Graft Rejection; Graft vs Host Disease; Humans; Infant; Intestinal Absorption; Intestinal Diseases; Intestine, Small; Intestines; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Parenteral Nutrition; Postoperative Complications; Short Bowel Syndrome; Surgical Wound Infection; Survival Rate; Tacrolimus

Patient and primary graft survival for 2,090 patients who received primary liver transplants at the University of Pittsburgh from 1984 through 1990 are presented. Observed (actual) 3- and 12-month patient and primary graft survival rates were compared for 3 periods: 1) January 1984 to September 1987 (cyclosporine, OKT3, and Euro-Collins preservation period); 2) October 1987 to December 1988 (University of Wisconsin solution preservation period); and 3) January 1989 to December 1990 (FK506 period). Data for results according to age group, medical urgency, and primary diagnosis are provided. In addition, estimated survivor and cumulative hazard functions (life-table method) for patient and primary graft survival out to 60 months after transplantation are presented. Overall results have improved significantly in recent experience. Most notable are the improved results seen in liver transplantation for patients with biliary atresia (especially in infants), primary sclerosing cholangitis, fulminant hepatic failure, and chronic active hepatitis B. For all but a few conditions, most of the mortality after liver transplantation occurred in the first 3 months after surgery. Less than 2% of patients were lost in each 6-month interval beyond the first 6 months after transplantation. Outcome was related to patient condition at the time of surgery. Observed survival rates at 3 and 12 months for patients called in the hospital to receive a transplant were 88.6% and 86.5%, respectively, compared with 81.9% and 73.7% for patients in critical condition. The continuing shortage of organs for transplantation, which often forces patients to wait longer for an organ than they can afford to, continues to impose a significant penalty.

Topics: Adolescent; Age Factors; Body Weight; Child; Child, Preschool; Cyclosporine; Graft Survival; Hepatic Encephalopathy; Humans; Immunosuppression Therapy; Infant; Liver Function Tests; Liver Transplantation; Postoperative Complications; Prednisone; Reoperation; Survival Rate; Tacrolimus

Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC [PBMC] ) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3 + T lymphocytes (TAC [CD3] ) and CD14 + monocytes (TAC [CD14] ) with acute rejection after kidney transplantation.. From a total of 61 samples in this case-control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3 + T lymphocytes and CD14 + monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured.. The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC [CD3] was significantly lower than TAC [CD14] (median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC [PBMC] (48.5 versus 44.4 pg/million cells; P = 0.82), TAC [CD3] (13.4 versus 12.5 pg/million cells; P = 0.28), and TAC [CD14] (90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC [PBMC] than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors.. Differences in TAC [CD3] and TAC [CD14] between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC [PBMC] between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.

Topics: Case-Control Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Leukocytes, Mononuclear; Monocytes; Postoperative Complications; Retrospective Studies; T-Lymphocytes; Tacrolimus

There is paucity of data on neurological complications (NCs) and its predisposing factors, in pediatric liver transplant (PLT) recipients.. Records of seventy-one children who underwent LT between October 2018 and November 2019 were reviewed. Patients were categorized into group A: with NC and group B: without NC in the post-LT period. Various risk factors contributing to NC were studied.. In total, 15 (21.1%) had NC (group A) and 56 (78.9%) had no NC in the post-LT period. NC included cerebrovascular accident (n = 1), seizures (n = 5; 4 generalized, 1 focal), central pontine myelolysis (CPM) (n = 1), diaphragmatic palsy (n = 2), peripheral neuropathy (n = 1), extrapyramidal movements (n = 3), and encephalopathy beyond 96 h (n = 2). The median onset of NC was at 8.5 days post-LT (1-58 days). Ten (66.7%) patients in group A had grades 2-4 hepatic encephalopathy (HE) prior to LT. Eight (14.3%) patients in group B also had pre-LT neurological issues including HE in six, epilepsy and spastic diplegia in one each. On univariate analysis, pre-existing HE, high PELD/MELD score, pre-LT ventilation, pre-LT infection, higher day 1 post-operative bilirubin (all p < .05), and higher tacrolimus were found to predict post-operative NC whereas on multivariate analysis, pre-LT HE was the only predictive factor. Median follow-up was 15.5 months. Four patients died in each group (survival log-rank p = .369). All the surviving patients in group A (n = 11) fully recovered from the NC.. Pre-transplant HE was the single most significant predisposing factor for post-LT neurological complications.

Topics: Child; Hepatic Encephalopathy; Humans; Liver Transplantation; Postoperative Complications; Retrospective Studies; Risk Factors; Seizures; Tacrolimus

Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers.

Topics: Diabetes Mellitus; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Opportunistic infections remain a significant cause of morbidity and mortality after kidney transplantation. This retrospective cohort study aimed to assess the incidence and predictors of post-transplant DNA virus infections (CMV, EBV, BKV and JCV infections) in kidney transplant recipients (KTR) at a single tertiary centre and evaluate their impact on graft outcomes.. KTR transplanted between 2000 and 2021 were evaluated. Multivariate logistic regression analysis and Cox proportional hazard analyses were used to identify factors associated with DNA virus infections and their impact on allograft outcomes respectively. A sub-analysis of individual viral infections was also conducted to describe the pattern, timing, interventions, and outcomes of individual infections.. Data from 962 recipients were evaluated (Mean age 47.3 ± 15 years, 62% male, 81% white). 30% of recipients (288/962) had infection(s) by one or more of the DNA viruses. Individually, CMV, EBV, BKV and JCV viruses were diagnosed in 13.8%. 11.3%, 8.9% and 4.4% of recipients respectively. Factors associated with increased risk of post-transplant DNA virus infection included recipient female gender, higher number of HLA mismatch, lower baseline estimated glomerular filtration rate (eGFR), CMV seropositive donor, maintenance with cyclosporin (rather than tacrolimus) and higher number of maintenance immunosuppressive medications. The slope of eGFR decline was steeper in recipients with a history of DNA virus infection irrespective of the virus type. Further, GFR declined faster with an increasing number of different viral infections. Death-censored graft loss adjusted for age, gender, total HLA mismatch, baseline eGFR and acute rejection was significantly higher in recipients with a history of DNA virus infection than those without infection (adjusted hazard ratio (aHR, 1.74, 95% CI, 1.08-2.80)). In contrast, dialysis-free survival did not differ between the two groups of recipients (aHR, 1.13, 95% CI, 0.88-1.47).. Post-transplant DNA viral infection is associated with a higher risk of allograft loss. Careful management of immunosuppression and close surveillance of at-risk recipients may improve graft outcomes.

Topics: Adult; Cytomegalovirus Infections; Female; Humans; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Airway Obstruction; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Medical Illustration; Postoperative Complications; Tacrolimus

Topics: Abatacept; Adult; Aged; Diabetes Mellitus; Female; Glucose Tolerance Test; Graft Rejection; Humans; Immunosuppressive Agents; Insulin Resistance; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Pretransplant desensitization protocols, including plasmapheresis, intravenous immunoglobulin, induction antibody therapy, and intensive maintenance immunosuppression, are generally employed in kidney transplant recipients who have positive status for donor-specific anti-HLA antibody (DSA). To avoid serious infectious complications, the authors designed a novel low-dose protocol in Thai patients undergoing DSA+ living-related kidney transplantation (LRKT).. A retrospective cohort study of the patients who underwent DSA+ LRKT was conducted. The novel protocol consisted of 3 to 5 sessions of pretransplant double-filtration plasmapheresis (DFPP) with or without low-dose intravenous immunoglobulin together with low-dose anti-thymocyte globulin (ATG) induction (1-1.5 mg/kg/d for 3-4 days) and low-dose tacrolimus (Tac) (trough level 5-10 ng/mL), mycophenolate, and prednisolone.. The study included 17 patients. The lymphocyte crossmatch via complement-dependent cytotoxicity was negative in 12 patients and positive for B cell immunoglobulin M in 5 patients. The novel desensitization protocol resulted in a decrease of at least 50% of DSA mean fluorescence intensity from baseline (from 4320 ± 549 before DFPP to 1601 ± 350 before transplantation, P < .005) and successful kidney transplantation with good allograft function in all cases. Early DSA rebound was observed in 3 patients after transplantation, and kidney biopsy revealed subclinical antibody-mediated rejection in 1 patient and diffuse C4d staining without cell infiltration in 2 patients. There were good long-term outcomes in patient and graft survival (100% and 94.1%, respectively). Only 1 allograft loss occurred because of nonadherence. The majority of patients have stable allograft function with serum creatinine less than 1.5 mg/dL. However, infections, including CMV and other organisms, were commonly observed.. Desensitization protocol with DFPP, low-dose ATG, and Tac provides excellent outcomes in living donor kidney transplantation in highly sensitized Asian populations.

Topics: Adult; Antilymphocyte Serum; Asian People; Cohort Studies; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Living Donors; Male; Middle Aged; Plasmapheresis; Postoperative Complications; Retrospective Studies; Tacrolimus; Transplant Recipients; Young Adult

To compare everolimus (EVR) plus low-dose tacrolimus (TAC) with mycophenolic acid (MPA) plus standard-dose TAC with regards to rates of cytomegalovirus (CMV) disease in de novo kidney-transplant recipients (KTRs).. This single-center retrospective study included 187 de novo KTRs; 59 patients (31.6%) received EVR/low-dose TAC (group 1); 128 patients (68.4%) received MPA with standard-dose TAC (group 2). All received anti-thymocyte globulins as the induction therapy, and steroid-sparing strategy. Valganciclovir prophylaxis was mandatory for CMV D+/R- KTRs (seronegative recipients of a seropositive donor) in both groups and for R+ seropositive recipients (only in group 2).. The 2-year incidence of CMV disease was low and comparable between groups: 6.8% and 7.0% in groups 1 and 2, respectively (p = 0.94). There was no statistical difference in CMV serostatus (p = 1). However, CMV disease tended to be less frequent, though not statistically different, in R+ KTRs receiving EVR without prophylaxis (3.7% vs. 8.5% in groups 1 and 2, respectively) and in patients without EVR discontinuation (2.6% vs. 6.9% in patients who did not discontinue MPA (p = 0.29). Two-year graft function was good and comparable between groups (median eGFR of 54.2 and 53.0 mL/min in groups 1 and 2, respectively; p = 0.47); incidence of immunological events was low. Significantly more patients in group 1 discontinued EVR because of adverse events than patients that discontinued MPA in group 2 (35.6% in group 1 vs. 10.2% in group 2; p < 0.001).. Everolimus plus low-dose TAC given to de novo KTRs was associated with low rates of CMV disease, especially in R+ patients with no CMV prophylaxis.

Topics: Adult; Aged; Cytomegalovirus Infections; Drug Combinations; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

Topics: Acute Disease; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Medical Illustration; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Tacrolimus

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in 2019; thereafter, the COVID-19 outbreak became a health emergency of international concern. The impact of COVID-19 on liver-transplant recipients is unclear. Thus, it is currently unknown whether liver-transplant recipients are at a higher risk of developing complications related to COVID-19. Here, we report the case of liver-transplant recipients who were infected with SARS-CoV-2. A 20-year-old man who had undergone living-donor liver transplantation from his father at 5 years of age because of congenital biliary atresia was referred to our hospital for SARS-CoV-2 infection. Chest computed tomography did not show any abnormalities; however, laboratory results revealed liver dysfunction. He received tacrolimus as maintenance therapy that was continued at the same dose. He has not developed severe pulmonary disease and was discharged after 10 days of hospitalization. Limited data are available on post-transplant patients with COVID-19, and this case of a young patient without metabolic comorbidities did not show any association of severe COVID-19 under tacrolimus treatment. The progression of COVID-19 in liver-transplant recipients is complex, and COVID-19 risk should be evaluated in each patient until the establishment of optimal guidelines.

Topics: Adult; COVID-19; COVID-19 Testing; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Postoperative Complications; SARS-CoV-2; Tacrolimus; Transplant Recipients; Treatment Outcome; Young Adult

Acute kidney injury (AKI) is a common complication after lung transplantation (LTx) which is closely related to the poor prognosis of patients. We aimed to explore potential risk factors and outcomes associated with early post-operative AKI after LTx.. A retrospective study was conducted in 136 patients who underwent LTx at our institution from 2017 to 2019. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Univariate and multivariate analyses were conducted to identify risk factors related to AKI. The primary outcome was the incidence of AKI after LTx. Secondary outcomes were associations between AKI and short-term clinical outcomes and mortality.. Of the 136 patients analyzed, 110 developed AKI (80.9%). AKI was associated with higher baseline eGFR (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00-1.03)) and median tacrolimus (TAC) concentration (OR 1.15 (95% CI: 1.02-1.30)). Patients with AKI suffered longer mechanical ventilation days (. Our results suggested early post-operative AKI may be associated with higher baseline eGFR and TAC concentrations. AKI stage 1 may have no influence on survival rate, whereas AKI stage 2-3 may be associated with increased mortality at 1-year.

Topics: Acute Kidney Injury; Aged; Female; Glomerular Filtration Rate; Humans; Incidence; Length of Stay; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Respiration, Artificial; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus; Time Factors

Tacrolimus, an immunosuppressant prescribed to reduce the risk of organ rejection, is metabolized by cytochrome P450 and is a substrate for P-glycoprotein. Many medications affect tacrolimus concentrations, making it difficult to maintain exposure within its narrow therapeutic index. Clotrimazole troches, prescribed to posttransplant recipients immediately for the first 30 days for oral candidiasis prevention, are considered nonsystemic. However, data suggest a potential drug interaction, affecting tacrolimus exposure. To assess the magnitude of the effect of clotrimazole on tacrolimus trough levels, 97 kidney transplant recipients, on a stable dose of tacrolimus, were retrospectively evaluated. Tacrolimus trough concentrations were analyzed 7 and 14 days before and after discontinuation of clotrimazole. The median change in tacrolimus trough level was -1.3 ng/mL (confidence interval, -2.5, -1.0; P < .001) at day 7 and -2.8 ng/mL (confidence interval, -3.3, -1.6; P < .001) at day 14 after clotrimazole discontinuation, from a median baseline of 8.9 ng/mL. Overall, a reduction in tacrolimus level was observed in 60% of patients after discontinuation of clotrimazole. When assessing the effect of race and sex, no influence was found on the degree of change in tacrolimus level after clotrimazole discontinuation. In conclusion, clotrimazole exerts a significant interaction on tacrolimus where close monitoring of tacrolimus trough levels after discontinuation of clotrimazole is warranted.

Topics: Adult; Aged; Antifungal Agents; Clotrimazole; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycoses; Postoperative Complications; Retrospective Studies; Tacrolimus; Young Adult

Topics: Abnormal Karyotype; Adult; Antigens, CD; Biomarkers, Tumor; Burkitt Lymphoma; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lung Transplantation; Lymph Nodes; Male; Postoperative Complications; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocyte Subsets; Tacrolimus

Acute kidney injury (AKI) is common after liver transplantation (LT). Induction with interleukin-2 receptor antagonists is often used as a "renal-sparing" strategy. The aim of this study was to assess this approach in a real-world setting in an LT center.. A retrospective cohort analysis of LTs between 2011 and 2018 was performed to assess the impact of a renal-sparing strategy using basiliximab in conjunction with mycophenolate mofetil and corticosteroids from day 0 post-LT along with delayed introduction of tacrolimus. This was compared with a group receiving tacrolimus, mycophenolate mofetil, and corticosteroids from the outset.. The renal-sparing regimen was associated with significantly lower incidence of all-stage AKI at day 7 post-LT (36% vs 55%, P = .006) and less decline in renal function at 3 months (39% vs 57%, P = .01). No further significant differences in renal outcomes were observed at other time points on follow-up to 1 year post-LT. There was no significant difference in the incidence of acute cellular rejection, inpatient length of stay or graft survival. The decision to adopt a renal-sparing regimen was predominantly made on a clinically reactive basis within the first 24 hours post-LT in 77%, and was preordained in 23%. Cost-effectiveness analysis did not find evidence of a significant cost saving when using a renal-sparing strategy.. This study provides real-world analysis of the use of a renal-sparing immunosuppression regimen in LT. Although improvements in incidence of AKI in the short term were demonstrated, this did not translate to cost savings or improved renal outcomes after 3 months.

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Adult; Basiliximab; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Retrospective Studies; Tacrolimus; Treatment Outcome

High intra-patient variability (IPV) of tacrolimus trough concentrations is increasingly recognized as a predictor of poor long-term outcomes in kidney transplant. However, there is a lack of information regarding the association between tacrolimus IPV and graft outcomes according to immunological risk. We analyzed tacrolimus IPV using the coefficient of variability from months 6-12 after transplantation in 1080 kidney transplant recipients. Patients were divided into two immunological risk groups based on pre-transplant panel reactive antibodies and donor-specific antibodies. High immunological risk was defined as panel reactive antibodies ≥ 20% or the presence of donor-specific antibodies. The effects of tacrolimus IPV on graft outcomes were significantly different between low and high immunological risk patients. A multivariable Cox regression model confirmed that high tacrolimus IPV was an independent risk factor for graft failure in the high risk group (HR, 2.90; 95% CI, 1.42-5.95, P = 0.004). In the high risk group, high tacrolimus IPV was also significantly associated with increased risk of antibody-mediated rejection (P = 0.006). In contrast, death-censored graft survival and antibody-mediated rejection in the low immunological risk group was not significantly different by tacrolimus IPV. High tacrolimus IPV significantly increases the risk of graft failure and antibody-mediated rejection in patients with high immunological risk.

Topics: Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus

Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.

Topics: Adult; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Postoperative Complications; Renal Dialysis; Tacrolimus; Treatment Outcome

Infectious complications remain a common cause of mortality after kidney transplantation (KTx). Goal of effective immunosuppressive treatment (IS) must be balanced between decreasing incidence of acute kidney rejection (AKR) and avoiding the incidence of infections, at the same time.. The aim of our analysis was to identify the risk of fixed daily dose (DD) of mycophenolic acid (MPA) and levels of tacrolimus (TAC) in the development of a single, recurrent infection and AKR after KTx.. Our analysis consisted of 100 patients after KTx (66 males, 34 females). MPA DD > 1080 mg was a risk factor (RF) for recurrent infection in general (OR 1.2964;P = 0.0277), for recurrent bacterial infection from 1. MPA DD > 1080 mg as a RF for recurrent infection starting in the 1

Topics: Adult; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Reinfection; Retrospective Studies; Tacrolimus

To examine and characterize post-transplant eosinophilic gastrointestinal disorders (PTEGID) and post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients.. This is a single center retrospective study of all liver transplant recipients aged 0-18 years from 1999 to 2019 who received tacrolimus as their primary immunosuppressant. Demographic data and clinical/laboratory data including PTEGID, PTLD, liver transplant types, Epstein-Barr virus status, and blood eosinophil count were reviewed. Analysis was done with logistic regression and Mann-Whitney U test.. Ninety-eight pediatric liver transplant recipients were included with median age at transplantation of 3.3 years (IQR: 1.1-9.3). The major indication for transplantation was biliary atresia, 51 (52%) cases. Eight (8%) children had PTLD and 14 (14%) had PTEGID. Receiving liver transplantation at an age of ≤1 year was associated with developing PTEGID (OR = 11.9, 95% CI = 3.5-45.6, p < 0.001). Additionally, eosinophilic count of ≥500/μL was associated with having PTLD (OR = 10.7, 95% CI = 1.8-206.0, p = 0.030) as well as having at least one liver rejection (OR = 2.8, 95% CI = 1.2-7.0, p = 0.024). The frequency of food-induced anaphylaxis significantly increased post-transplantation (p = 0.023).. PTEGID and PTLD are common in this cohort and are associated with certain risk factors that help screen children to improve recipient survival. Further studies are needed to evaluate the clinical benefits of these findings.

Topics: Child; Epstein-Barr Virus Infections; Gastrointestinal Diseases; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Retrospective Studies; Tacrolimus

Functional capacity (FC) is known to affect morbidity and mortality in kidney transplantation. Despite this important role, little is known about the variables influencing post-transplant FC. Our study aims at identifying these crucial associations.. Our study included 16,684 renal transplant recipients (RTR). Patients had transplant between 1 September 2018 and 1 September 2019. Mild functional impairment was defined as those with a KPSS score > or = 80; moderate functional impairment was defined as those with a KPSS score between 50 and 70 and severe functional impairment was defined as those with a KPSS score < or =40. The outcome measured was FC at follow-up one-year post-transplant. Abnormal FC at follow-up was defined as those with KPSS score less than 80%. Normal FC at follow-up was defined as those with KPSS score equal or above 80%. Multivariate logistic regression was used to assess with the relationship between patient characteristics and abnormal functional status post-transplant.. Three groups were identified; those with none-to-mild functional impairment at time of transplant (Group A;. Kidney transplantation is associated with substantial improvement in all stages of FC in KTRs. Glucocorticoid withdrawal and diabetes mellitus are potentially modifiable factors of FC and merit further considerations during pre-transplant workup and post-transplant immunosuppressive therapeutic planning.Key messagesKidney transplantation is associated with substantial improvement in all stages of FC in KTRs.Glucocorticoid withdrawal and diabetes mellitus are potentially modifiable factors of FC and merit further considerations during pre-transplant workup and post-transplant immunosuppressive therapeutic planning.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus; Female; Functional Status; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus

To improve the long-term outcomes following renal transplantation, prevention of renal-allograft interstitial fibrosis (IF), mainly due to calcineurin inhibitors, is an important therapeutic target. Everolimus (EVR) was reported to have antifibrotic effects. We aimed to investigate the safety, efficacy, and IF of our modified immunosuppressive regimen, which includes early introduction of EVR and reduced-exposure tacrolimus (Tac) (EVR group), and compare it with the standard-exposure tacrolimus-based regimen (Tac group) in de novo living-donor renal recipients.. In this retrospective, single-center cohort study, we compared the 2-year clinical courses between the two groups according to intention to treat. Additionally, in patients in whom biopsies were obtained at 1 h, 3 months, and 12 months post-transplant, we compared IF between the groups using imaging analysis.. Overall, 47 patients were included (EVR group, n = 22; Tac group, n = 25). There were no significant differences in renal function and incidences of rejection and viral infections between the groups at the 2-year post-transplant follow-up. However, pathologic imaging analysis (n = 34) revealed chronological progression of IF in the Tac group during the first year post-transplant and no changes in the EVR group (fibrosis rate at 3 months: 20.8 vs. 13.6%, p < 0.001; at 12 months: 24.7 vs. 14.7%, p < 0.001, respectively).. Our modified immunosuppressive regimen may have an antifibrotic effect on transplanted kidneys without loss of safety and efficacy.

Topics: Adult; Everolimus; Female; Fibrosis; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus

Extended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK).. This is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 100∗standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively.. There was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07).. Significantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.

Topics: Adult; Creatinine; Delayed-Action Preparations; Female; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreas Transplantation; Postoperative Complications; Tacrolimus; Transplant Recipients

The efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear.. This retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010-June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone. High-risk patients not undergoing 3-month protocol biopsy were continued on triple immunosuppression.. Steroid withdrawal could be safely achieved in low immunological risk recipients with IL2 receptor antibody induction. The incidence of biopsy-proven acute rejection was 15.1% in the low-risk and 13.9% in the high-risk group (including sub-clinical rejection detected at protocol biopsy). One- year graft survival was 93.3% and patient survival 98.5% in the low-risk group, and 97.3 and 100% respectively in the high-risk group. Graft function was similar in each group at 1 year (mean eGFR 61.2 ± 23.4 mL/min low-risk and 64.6 ± 19.2 mL/min high-risk).. Immunosuppression regimen comprising basiliximab induction, tacrolimus, MMF and prednisolone with early steroid withdrawal in low risk patients and MMF withdrawal in high risk patients following a normal 3-month protocol biopsy is effective in limiting acute rejection episodes and produces excellent rates of patient survival, graft function and complications.

Topics: Adult; Aged; Azathioprine; Basiliximab; Drug Administration Schedule; Female; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Postoperative Care; Postoperative Complications; Prednisolone; Receptors, Interleukin-2; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Tacrolimus; Young Adult

The decline of allograft kidney function in the long term remains a significant issue in renal transplantation, with drug nephrotoxicity and cardiovascular complications as important risk factors. Our study aimed to evaluate the estimated glomerular filtration rate (eGFR) trend and metabolic cardiovascular risk factors over 10 years in a cohort of kidney transplant (KT) recipients converted from twice-daily (TD) tacrolimus (Tac) to once-daily (OD)-Tac. We enrolled 55 consecutive KT recipients who had been at the outpatient clinic between 2009 and 2011. Thirty-seven reached the 10-year follow-up. We compared the observed eGFR with the expected eGFR trend described in KT-recipients and monitored blood pressure and metabolic cardiovascular risk factors. The observed eGFR remained stable throughout the complete follow-up (P = .188). The observed decline of eGFR was significantly lower compared with the expected decline for KT patients (P < .001). The blood pressure was maintained within target values. The monitoring of plasma glucose levels demonstrated the stability of median values (P = .686), as well as cholesterol level (P = .250), high-density lipoprotein (HDL) cholesterol (P = .294), and triglycerides (P = .592) throughout the follow-up. The monitoring of tacrolimus plasma level demonstrated that median trough levels remained constant (median values 4.4-5.5 ng/mL) throughout the entire follow-up period (P = .149). We suggest that the reasonable control of metabolic risk factors for cardiovascular disease over long-term follow-up may significantly contribute to the preservation of eGFR compared with the decline expected in KT recipients.

Topics: Adult; Allografts; Cardiovascular Diseases; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Postoperative Period; Risk Factors; Tacrolimus; Transplantation, Homologous; Treatment Outcome

A 58-year-old woman developed rapidly progressive neurological symptoms and finally loss of vigilance 5 weeks following primarily successful lung transplantation. A posterior reversible encephalopathy syndrome (PRES) under treatment with tacrolimus as well as hyperammonemia due to sepsis with Ureaplasma urealyticum could be identified as the causes. Infections with Ureaplasma, bacteria which produce ammonia as a product of metabolism, are increasingly being identified in immunocompromised people by specific PCR (polymerase chain reaction) procedures and should routinely be taken into consideration as the cause of unspecific neurological symptoms.

Topics: Brain Edema; Female; Humans; Hyperammonemia; Immunocompromised Host; Lung Transplantation; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Status Epilepticus; Tacrolimus; Ureaplasma Infections; Ureaplasma urealyticum

We report a patient who has been on tacrolimus for bilateral lung transplantation and presented with a brachial plexus injury (BPI), with unusual improvement of lower trunk innervated hand function. The lower trunk injury with resultant left hand paralysis had developed after his sternotomy 18 months ago. He has been treated with tacrolimus as part of his immunosuppression protocol since the surgery, without severe side effects. Physical examination at 18 months demonstrated unusual excellent grip pattern and full opposition of his thumb with slight claw deformity of his ulnar two digits. While the neurotoxic effects of tacrolimus are more emphasised, the neuroregenerative properties have been recently explored. The recovery in this patient is unique and unusual after BPI and is most likely as a result of the low dose tacrolimus treatment.

Topics: Brachial Plexus Neuropathies; Hand; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Transplantation is not only the best method for treating end-stage failure of many organs but also the way to improve the quality of life of patients. For women of childbearing age, an organ transplant often brings a restoration of regular reproductive functions, which means, among other things, the possibility of having biological offspring.. The aim of the study was to analyze the medical records and assess the impact of a liver transplant on the course of pregnancy and labor.. The research was carried out from March to May 2019 in the Nephrology and Transplant Clinic Medical University of Warsaw. The study group consisted of 19 women after liver transplantation. Medical records were analyzed, and laboratory test results routinely performed on patients were also used for the study.. The mean age of conception of the patients following transplantation was 30 ± 4 years old. In the analyzed period, 6 patients gave birth to 2 children each, and 8 patients to 1 child each. Only 3 patients experienced premature birth. Twelve patients gave birth by caesarean delivery. Fourteen patients took tacrolimus.. Pregnancy is possible in patients following a liver transplant and does not appear to have a damaging effect on liver functionality. There is an increased risk of pre-eclampsia, intensified hypertension, and premature birth among patients following a transplant, which is why it is essential for these patients to remain under the care of a specialistic therapeutic team.

Topics: Adult; Female; Humans; Hypertension; Liver Transplantation; Postoperative Complications; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Quality of Life; Tacrolimus; Treatment Outcome

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

Topics: Antibiotics, Antineoplastic; Bacteremia; BK Virus; Cardiomyopathy, Dilated; Cardiotoxicity; COVID-19; COVID-19 Nucleic Acid Testing; Doxorubicin; Graft Rejection; Gram-Positive Bacterial Infections; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Male; Malnutrition; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus Infections; Postoperative Complications; Prednisone; Renal Dialysis; SARS-CoV-2; Staphylococcal Infections; Surgical Wound Infection; Tacrolimus; Tracheostomy; Tumor Virus Infections; Vancomycin-Resistant Enterococci; Viremia; Water-Electrolyte Imbalance

Autoimmune encephalitis is a rare spectrum of disease that can be a complication of chronic immunosuppression. Diagnosis often requires the presence of antineuronal antibodies, but many causative antibodies have not yet been identified. Antibody-negative autoimmune encephalitis (AbNAE) is especially difficult to diagnose and must rely largely on exclusion of other causes. In chronically immune-suppressed transplant recipients, the differential is broad, likely resulting in underdiagnosis and worse outcomes. Here, we present a 58-year-old liver transplant recipient taking tacrolimus for prevention of chronic rejection who presented with 5 days of confusion, lethargy and lightheadedness. He was diagnosed with AbNAE after an extensive workup and recovered fully after high-dose corticosteroids. Our case highlights the importance of recognising the association between chronic immunosuppression and autoimmune encephalitis. Autoimmune encephalitis, even in the absence of characterised antibodies, should be considered when transplant recipients present with central neurologic symptoms.

Topics: Antibodies; Encephalitis; Hashimoto Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Time Factors

Chronic kidney disease (CKD) is a common late complication in liver-transplanted patients who have received long-term therapy with calcineurin inhibitors (CNIs). Aims: To analyze kidney disease progression after liver transplantation.. We analysed the clinical data of adult single-organ liver transplant recipients performed at our centre between October 2003 and September 2009. The patients with the estimated glomerular filtration rate (eGFR) greater than 60 ml/min/1.73 m. 69 patients with complete follow-up data were analysed. We found that eGFR at 1 or 2 years after liver transplantation correlated well with eGFR at 5 years. In addition, our results showed that patients whose eGFR declined below 60 at 2 years after liver transplantation would develop an irreversible renal injury in the following years. At 2 years, 12 patients had an eGFR less than 60, which were maintained in 11 patients at 5 years (Sensitivity = 11/12, 91.67%; Specificity = 57/58, 98.28%, Youden's index = 89.95%). The annual rate of eGFR reduction of the tacrolimus group was greater than that of the tacrolimus sparing group based on the value-time variation curve in our study. Moreover, the tacrolimus concentration influenced the CKD progression at 1 and 2 years with an under the ROC curve of 0.73 and 0.78 when Youden's index was at its maximum and the tacrolimus concentrations were 8.55 and 5.96 ng/ml, respectively.. We confirmed that eGFR at 2 years after liver transplantation is useful for observing a meaningful change in eGFR and renal damage. Obtaining the appropriate serum concentration of an early decrease of the dose of CNIs and transforming non-nephrotoxic immunosuppressants would help improve renal function to prevent CKD progression and end-stage renal disease (ESRD).

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Calcineurin Inhibitors; Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency, Chronic; Risk Factors; Tacrolimus

Post-transplant liver fibrosis (PTLF) is a common and severe complication in liver recipients. In this study, we assessed the impact of donor liver genetics on the development of PTLF. A total of 232 patients undergoing liver transplantation were included. Twenty-two single nucleotide polymorphisms (SNPs) associated with liver fibrosis were analyzed. Univariate analysis revealed seven donor SNPs to be associated with PTLF. In a multivariate analysis, independent risk factors of PTLF were genetic variation of donor GRP78 rs430397 (OR = 8.99, p = 0.003), GSTP1 rs1695 (OR = 0.13, p = 0.021), miRNA-196a rs12304647 (OR = 16.01, p =0.001), and TNF-α rs1800630 (OR = 79.78, p = 0.001); blood tacrolimus levels at maintenance > 7 ng/ml (OR =7.48, p <0.001); and post-transplant diabetes mellitus (OR = 7.50, p = 0.001). A predictive model that included donor SNPs showed better prognostic ability for PTLF than a model with only clinical parameters (AUROC: 0.863 vs 0.707, P < 0.001). Given that donor gene SNPs are associated with an increased risk of PTLF, this model integrated with donor gene polymorphisms may help clinicians predict PTLF.

Topics: Adult; Diabetes Mellitus; Endoplasmic Reticulum Chaperone BiP; Female; Genetic Predisposition to Disease; Glutathione S-Transferase pi; Graft Rejection; Heat-Shock Proteins; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Male; MicroRNAs; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Tumor Necrosis Factor-alpha

In nonimmunized patients, similar rejection rates are observed for patients who have undergone thymoglobulin (antithymocyte globulins [ATG]) or basiliximab (BSX) therapy. While ATG may improve delayed graft function, it may also be associated with higher infection rates and malignancy risk. We compared survival and clinical outcomes in elderly recipients with low immunological risk according to their induction therapy.. We conducted a multicentric study on nonimmunized patients ≥65 years of age receiving a first kidney transplant between 2010 and 2017. The principal outcome was patient and graft survival. Secondary outcomes were cumulative probabilities of infection, first acute rejection episode, malignancy, de novo donor specific antibody, posttransplant diabetes (PTD), cardiac complications, estimated glomerular filtration rate, and occurrence of delayed graft function. Cox, logistic, or linear statistical models were used depending on the outcome studied, and models were weighted on the propensity scores.. Two hundred and four patients were included in the BSX group and 179 in the ATG group with the average age of 71.0 and 70.5 years, respectively. Patient and graft survival at 3 years posttransplantation were 74% (95% CI, 65%-84%) and 68% (95% CI, 60%-78%) in ATG and BSX group, respectively, without significant difference. Occurrence of PTD was significatively higher in BSX group (23% versus 15%, P = 0.04) due to higher trough levels of Tacrolimus on month 3 (9.48 versus 7.30 ng/mL, P = 0.023). There was no difference in other evaluated outcomes.. In elderly recipients, ATG does not lead to poorer outcomes compared with BSX and could permit lower trough levels of Tacrolimus, thus reducing occurrence of PTD.

Topics: Age Factors; Aged; Aged, 80 and over; Antilymphocyte Serum; Basiliximab; Delayed Graft Function; Diabetes Mellitus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Prospective Studies; Tacrolimus; Transplantation Conditioning; Treatment Outcome

Topics: Acute Disease; Anemia, Sickle Cell; Antisickling Agents; beta-Thalassemia; Bradycardia; Budd-Chiari Syndrome; Cardiopulmonary Resuscitation; Cholestasis, Intrahepatic; Glucocorticoids; Graft Rejection; Heart Arrest; Humans; Hydroxyurea; Immunosuppressive Agents; Liver Failure, Acute; Liver Transplantation; Male; Postoperative Complications; Prednisone; Tacrolimus; Young Adult

Motherhood is the greatest privilege that nature gives to women. Although pregnancy is a physiological event for women, every pregnancy is a risky pregnancy. During a normal pregnancy, the health of mother and baby are monitored. In post-transplantation pregnancies, the function of the transplanted organ, along with the mother and the infant, must be monitored, since the continuation of pregnancy depends on both the maternal and infant health and an organ functioning within normal limits. The desire is for every baby to be born in due time and at normal weight, but this is not always possible in pregnancies after transplants. Publications about the pharmocokinetics of tacrolimus are very limited. In this study, we wanted to share our experiences with pregnancy in our clinic.. Patients who used tacrolimus during their pregnancies after renal transplantation (RT) at Antalya Medicapark Organ Transplantation Unit, during November 2008 to July 2018 were included in the study. Patient's gestational age, pregnancy, drug levels, is charge, and labor creatinine clearances were examined.. Four thousand six hundred thirty-five RT occurred between November 2008 to July 2018; 786 of the patients were female between the ages 18 and 45. Thirty-one pregnancies went full term. Twenty-six pregnant women, who used tacrolimus after RT, were included in the study. Five patients had pre-eclampsia, 1 patient had abortus immines, 2 patients had hypertansion due to pregnancy, and 1 patient had aplated placenta. There was a breech presentation in 1 patient with preeclampsia. Acute rejection developed in 3 postpartum patients, but renal values normalized with medical treatment. All the babies were born alive and healthy; postpartum graft loss was not observed.. If planning to become pregnant after RT,our center recommends waiting at least 2 years after the RT, when graft function should be normal and without any signs of HT and proteinuria. Our recommendation regarding the level of tacrolimus after RT is 4.5 to 7 μg.

Topics: Adolescent; Adult; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Middle Aged; Postoperative Complications; Postoperative Period; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus; Young Adult

The Social Security System of our country reimburses only paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD) regime in treatment-naive patients with hepatitis C regardless of kidney disease. Most of our renal transplant (RT) recipients were treated with PrOD. The aim of the present study was to investigate the efficacy and safety of PrOD in RT patients with hepatitis C virus (HCV) infection in a single center real-life experience.. RT recipients with a post-transplant follow-up of at least 1 year were included in the study. The patients were treated and monitored according to the guidelines. Blood levels of immunosuppressive patients were closely followed up and adjusted.. A total of 21 (12 male and nine female) patients were assessed. The age of the patients was 50.8±8.5 years. Ten patients were infected with G1a, 10 patients with G1b, and one patient with G4 HCV. Two patients had compensated cirrhosis. Eighteen patients were treatment-naive, and three were peginterferon+ribavirin-experienced. Sustained virologic response (SVR12) was achieved in all patients. None of the patients discontinued the treatment. Cyclosporine (Csa) and tacrolimus (Tac) doses were reduced to once a day to once a week to maintain the blood level within normal range. The most common adverse effect was anemia in patients receiving ribavirin. Renal functions did not change during the treatment period.. In this real-life experience, all of the 21 PrOD-treated RT recipients reached SVR12. Tac or Csa serum levels were maintained within the normal range with close monitoring. PrOD regime can be successfully and safely used in RT recipients with HCV infection with close follow-up.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cyclosporine; Female; Hepacivirus; Hepatitis C; Humans; Kidney Transplantation; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Postoperative Complications; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Tacrolimus; Uracil; Valine

Epithelial to mesenchymal transition (EMT) occurs when cells lose morphological features of epithelial cells, such as cell-to-cell adhesion, and gain features of mesenchymal cells, including elongation and flattening. These cells also lose expression of epithelial immunohistochemical markers. In this report, we present a 55-year-old Caucasian male patient who underwent orthotopic heart transplant and immunosuppressant therapy with tacrolimus and mycophenolic acid. Seven and a half months later, an endomyocardial biopsy revealed a hypercellular, atypical lesion. Evaluation was negative for acute cellular rejection and post-transplant lymphoproliferative disorder. Histopathologic features and immunohistochemical stains were consistent with EMT. We subsequently identified four additional cases of EMT in patients who underwent orthotopic heart transplantation and received a similar immune suppression regimen. EMTs have been reported to occur in lung and kidney allografts; however, this is the first known report describing this entity in a heart transplant recipient.

Topics: Colitis; Diagnosis, Differential; Endocardium; Epithelial-Mesenchymal Transition; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus

There is little evidence about whether mammalian target of rapamycin (mTOR) inhibitor could prevent post-kidney transplant (KT) urothelial carcinoma (UC) or not. The aim of this study is to analyze the role of mTOR inhibitor add-on in tacrolimus-based kidney transplant recipients.. The data were obtained from the Kaohsiung Chang Gung Memorial Hospital using the Chang Gung Research Database and retrospectively reviewed from January 2000 to December 2015. Patients then were categorized into 2 groups: group FK (more than 2-year tacrolimus [FK] prescription) and group FK + mTOR inhibitor (more than 2-year tacrolimus plus at least 6-month continued sirolimus prescription). The primary end point is post-KT UC development. The secondary end point is mTOR inhibitor add-on effect on renal function deterioration episode.. There were 140 patients with tacrolimus-based immunosuppressant (group FK) and 82 patients with tacrolimus-based and add-on mTOR inhibitor regimen (group FK + mTOR inhibitor). The follow-up duration, sex distribution, and combined mycophenolate mofetil rate are similar in both groups. Younger age, lower tacrolimus trough level, lower UC incidence, and longer KT-to-UC interval were observed. Short- to intermediate-term results revealed noninferior graft outcome by creatinine level or creatinine deterioration.. In our preliminary result, mTOR inhibitor add-on in patients with tacrolimus-based regimen revealed less post-KT UC occurrence. In addition, noninferior graft outcome was also observed. In Taiwan, a high UC prevalence area, mTOR inhibitor add-on strategy can be considered as a preventive strategy for UC after KT.

Topics: Adult; Carcinoma, Transitional Cell; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Taiwan; TOR Serine-Threonine Kinases

Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain.. We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant.. Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy (. The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy; however, it was only effective when administered within 24 hours.

Topics: Adult; Aged; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Creatinine; Everolimus; Female; Glucocorticoids; Graft Rejection; Heart Transplantation; Humans; Immunity, Cellular; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Renal Insufficiency; Tacrolimus

Obliterative bronchiolitis (OB) is the major complication limiting the long-term survival of allografts after lung transplantation. In this study, we investigated the effect of tacrolimus (FK506) combined with GM6001，a matrix metalloproteinase (MMP) inhibitor， on the formation of OB using a mouse heterotopic tracheal transplantation model.. Syngeneic tracheal grafts were transplanted heterotopically from BALB/c mice to BALB/c mice. Allografts from C57BL/6 mice were transplanted to BALB/c mice. Isograft group, allograft group, allograft+FK506 group, allograft +GM6001 group and allograft+FK506 + GM6001 group was given respectively intraperitoneal injection of saline, saline, FK506, GM6001 and FK506 + GM6001 once a day. At 28 day after transplantation, OB incidence was determined by hematoxylin-eosin staining and the expressions of MMPs and cytokines were assessed using enzyme linked immunosorbent assay, immunohistochemical assays and western blot assay.. The tracheal occlusion rates of isograft group, allograft group, allograft+FK506 group, allograft+GM6001 group and allograft+FK506 + GM6001 group were 0, 74.1 ± 9.79%, 34.4 ± 6.04%, 40.3 ± 8.77% and 26.5 ± 5.73% respectively. There were significant differences between the latter two groups (P < .001). The serum MMP-8 and MMP-9 levels of allograft group were significantly higher than those of isograft group (P < .05) and had no significant decrease when treated by FK506. The serum MMP-8 and MMP-9 levels of allograft+FK506 + GM6001 group were significantly lower than those of allograft+FK506 group (P < .05). MMP-8 and MMP-9 protein expression in the grafts of allograft+FK506 + GM6001 group were lower than those of allograft+FK506 group verified by immunohistochemical staining and western blotting.. FK506 combined with GM6001 could alleviate tracheal obliteration in mouse heterotopic tracheal transplantation model, due to its inhibitory effect on MMPs.

Topics: Airway Obstruction; Animals; Bronchiolitis Obliterans; Dipeptides; Disease Models, Animal; Drug Therapy, Combination; Graft Survival; Humans; Lung Transplantation; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Postoperative Complications; Tacrolimus; Trachea; Transplantation, Heterotopic; Transplantation, Homologous

Gastrointestinal bleeding after kidney transplantation is a complication that can occur from immunosuppressant use. We present a case of refractory small bowel bleeding treated successfully with thalidomide after multiple failed attempts of conventional treatment. A 65-year-old male patient with diabetic nephropathy underwent living donor kidney transplantation. The surgery was uneventful, however, he developed immunosuppressant-induced melena with unstable vital signs 11 days later. There were a total of 4 bleeding episodes until the 90th postoperative day, and he received a total of 290 units of red blood cell transfusion during this period. Endoscopic clipping, transarterial embolization, and 2 surgical interventions failed to stop the bleeding. A trial of thalidomide 100 mg per day finally stopped the bleeding and the patient was discharged on the 110th postoperative day with a functioning renal graft. This case shows that thalidomide can be a safe option to treat immunosuppressant-induced refractory gastrointestinal bleeding in the setting of kidney transplantation. Additionally, this is the first case that reports the survival of a renal graft after more than 3000 mL of transfusion.

Topics: Aged; Angiogenesis Inhibitors; Gastrointestinal Hemorrhage; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Melena; Middle Aged; Postoperative Complications; Tacrolimus; Thalidomide

The vigilance of tacrolimus (TAC) trough levels is an essential part of renal transplant follow up. Reduced TAC trough levels and high variability are related to adverse outcomes. The aim of this study was to evaluate the impact of brand changes on tacrolimus (TAC) subtherapeutic (SubT) trough levels, acute rejection (AR), and kidney function.. This is a prospective, observational cohort study of renal transplant recipients, between January 2016 and October 2018. Tacrolimus trough levels and brand used by the patient were both registered at every consult. Tacrolimus values ≤3.5 ng/mL were considered SubT.. 445 patients were included. The median number of TAC brand changes was 2 (IQR, 1-4). Patients were grouped according to the number of brand changes: Group 1 = 0 (n = 107), Group 2 = 1-4 (n = 236), and Group 3 = ≥5 (n = 102). Patients with the greatest number of brand changes had a greater proportion and number of SubT TAC trough levels (Group 1 = 36.4%, average 0.53; Group 2 = 39.8%, average 0.65, Group 3 = 59.8%, average 1.17, P < .001) and AR (Group 1 = 0.9%, Group 2 = 11%, Group 3 = 14.7%, P < .001). On multivariate analysis, SubT levels and the number of brand changes were related to AR.. In Mexico, changes in TAC brand are associated with an elevated frequency of SubT levels. Brand changes and SubT levels are independently associated with acute rejection. The supply policies on TAC brands in Mexico require revision to avoid changing brands as much as possible.

Topics: Adult; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus; Transplant Recipients

Topics: Adult; Benzhydryl Compounds; Calcineurin Inhibitors; Diabetes Mellitus; Female; Glucosides; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Tacrolimus; Treatment Outcome

Post-transplant diabetes mellitus (PTDM) is a serious and frequent metabolic complication after the transplantation of solid organs. PTDM incidence 12 months after the transplantation is 2.5%-25%.. It is a retrospective analysis with 6-month follow-up of patients after liver transplantation without diabetes mellitus type 1 or 2 at the time of transplantation. We recorded all known risk factors for PTDM; however, only patients with tacrolimus in standard immunosuppression protocol were included in the analysis.. The PTDM incidence in the group of 102 patients was 18.6%. We identified following independent risk factors for PTDM: alcohol-related liver disease (Hazard Ratio 1.8261 [1.2246-2.723], P = .0031) and average level of tacrolimus ≥ 10 ng/mL (2.5482 [1.1592-5.6019], P = .0199). PTDM was diagnosed in average 2.5 months after the liver transplantation.. PTDM leads to infections, cardiovascular disease, and decreased survival. The mechanism by which alcohol-related liver disease influences the development of PTDM remains unclear.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Vascularized composite allotransplantation represents as an emerging field in reconstructive surgery. However, some complications can be associated with the procedure. The authors describe a case of bone infarctions of the bilateral hip joints following the first hand allotransplantation in Taiwan. A 45-year-old man who experienced a traumatic amputation of the distal third of his forearm received a hand transplantation from a brain-dead donor. Immunosuppression included antithymocyte globulins, and bolus methylprednisolone (Solu-Medrol) was used for the induction. The maintenance therapy protocol included systemic tacrolimus, mycophenolate mofetil, and prednisone. The patient discontinued the systemic steroid 15 months after surgery. Two episodes of acute rejections were observed at 105 and 810 days after surgery. These signs disappeared after pulse therapy with Solu-Medrol, titration with tacrolimus, and topical immunosuppressive creams (tacrolimus and clobetasol). However, the patient felt pain in both hips after long periods of standing 30 months after the transplantation. A pelvic radiograph and magnetic resonance imaging revealed avascular necrosis (AVN) in both hip joints. Because of the progressive worsening of the pain, the patient underwent a decompression surgery on the left hip involving a fibula bone graft. The patient underwent a right hip hemi-arthroplasty with a bipolar prosthesis 3 months later. The patient remained in good health without major complications. These findings indicate that systemic steroids and tacrolimus might be the major predisposing factors for the induction of AVN after hand allotransplantation.

Topics: Administration, Topical; Amputation, Traumatic; Arthroplasty, Replacement, Hip; Clobetasol; Femur Head Necrosis; Forearm Injuries; Graft Rejection; Hand Injuries; Hand Transplantation; Hip; Humans; Infarction; Magnetic Resonance Imaging; Male; Middle Aged; Postoperative Complications; Tacrolimus; Vascularized Composite Allotransplantation

BACKGROUND Patients with massive ascites (MA) after liver transplantation (LT, defined here as daily ascitic drainage more than 1000 ml per day for more than 7 days after liver transplantation) are at increased risks of infection, hypoalbuminemia, graft loss, and even mortality. The aim of this retrospective cohort study was to investigate the effects of somatostatin on patients with MA after LT. MATERIAL AND METHODS Twenty-eight patients with liver cirrhosis or hepatocellular carcinoma who underwent LT complicated by MA postoperatively were included. Ten participants were receiving somatostatin therapy. The postoperative course and adverse drug effects were investigated. Daily postoperative ascitic drainage and urine output were also recorded and compared to those in the non-somatostatin group. RESULTS The somatostatin group had significantly less ascites drainage after LT compared to the non-somatostatin group (p=0.002). Urine output was significantly increased after somatostatin administration (p<0.001). No serious adverse effects influencing graft function or fatal complications occurred after somatostatin therapy. CONCLUSIONS Somatostatin treatment is beneficial for the management of MA after liver transplantation.

Topics: Adrenal Cortex Hormones; Adult; Aged; Ascites; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Somatostatin; Tacrolimus; Treatment Outcome

This study is aimed to investigate the risk factors and clinical characteristics of posttransplant lymphoproliferative disorder (PTLD) after conducting Epstein-Barr virus (EBV) viral load monitoring in pediatric liver transplant (LT) patients in Taiwan, where EBV infection is endemic.. From 2007 to 2013, pediatric LT recipients who underwent EBV viral load monitoring within 3 months after LT were recruited in this study. The impact of clinical parameters-including age at LT, sex, peak EBV viral load and immunosuppressant levels after LT-on the risk of PTLD were assessed.. A total 39 patients underwent LT at a median age of 1.3 years (range: 0.6-14.0 years), and 5 patients developed PTLD during follow-up. Cox's proportional-hazards model identified two predictors of PTLD: peak EBV viral load within 3 months of LT >4100 copies/μg peripheral blood mononuclear cells (PBMC) DNA and peak tacrolimus level within 3 months of LT >14.8 ng/mL (Hazard ratio = 17.14 and 11.54, P = 0.02 and 0.03, respectively). Kaplan-Meier survival analysis revealed significant higher cumulative incidence rates of PTLD (27.3% and 41.8% at 0.3 and 1.2 years after LT) in subjects with peak EBV viral load >4100 copies/μg PBMC DNA within 3 months after LT. (P = 0.001, log-rank test).. Close monitoring of EBV viral load within 3 months after LT is helpful to predict a high risk of PTLD. Tapering of immunosuppressants is suggested if the EBV viral load is >4100 copies/μg PBMC DNA in LT children.

Topics: Adolescent; Child; Child, Preschool; DNA, Viral; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Kaplan-Meier Estimate; Leukocytes, Mononuclear; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Proportional Hazards Models; Tacrolimus; Taiwan; Viral Load

Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single-center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Monitoring; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Young Adult

There are conflicting data about the role of transplant nephrectomy and immunosuppression withdrawal on the development of allosensitization and the impact on re-transplantation. We divided 109 first graft recipients into two groups according to whether they underwent nephrectomy (NX+, n = 61) or their graft was left in situ (NX-, n = 48). Sera were assessed for HLA-A/B/Cw/DR/DQ antibodies at the time of NX/transplant failure and after 3, 6, 12, 24 months. The NX+ group showed a higher rate of donor specific antibody (DSA) and non-DSA human leukocyte antigen (HLA) antibody production at all the time points. Multivariable analysis showed that nephrectomy was a strong, independent risk factor for the development of DSAs after 12 and 24 months (P = 0.005 and 0.008). In the NX- group, low tacrolimus levels correlated with DSA formation (AUC 0.817, P = 0.002; best cut-off level 2.9 ng/ml). Analysis with a standardized pool of UK donors showed a more difficult grade of HLA matchability following nephrectomy compared with the NX- group. Nephrectomy is followed by the long-term production of DSA and non-DSA HLA antibodies and negatively impacts on the chances of finding a HLA-compatible kidney. Tacrolimus levels ≥3 ng/ml are protective against the development of allosensitization and could facilitate re-transplantation in the NX- group.

Topics: Adult; Aged; Female; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Nephrectomy; Postoperative Complications; Retrospective Studies; Tacrolimus; Transplantation Immunology

Allergy and other immune-mediated diseases are more frequently reported in children who have undergone liver transplantation. Furthermore, autoantibodies are also prevalent, suggesting a state of immune dysregulation in these patients. Whether or not these processes occur simultaneously in the same individual has not been studied previously.. A cohort of 43 children who had undergone liver transplantation for nonautoimmune liver disease at median age of 1.3 years was investigated for allergy and autoimmune disease. Sensitization to food and inhalant allergens was assessed, and autoantibodies were measured.. The prevalence of food allergy was 26% and that of respiratory allergy was 23%, whereas 33% and 26% of the subjects were sensitized to food and inhalant allergens, respectively. Autoimmune disease (ie, autoimmune hepatitis) occurred in a single individual (2%), whereas autoantibodies were present in 44% of the children. Food allergy and autoantibodies occurred concomitantly in 19% of the children, which was almost twice the frequency expected by chance (11%, P = 0.04). Respiratory allergy and the presence of autoantibodies were unrelated (12% concurrence versus the expected 10%, P = 0.73). In the logistic regression analysis, autoantibody formation was associated with discontinued immunosuppression and food allergy, with odds ratios of 13 (P = 0.01) and 7.1 (P = 0.03), respectively.. In contrast to respiratory allergy, food allergy and autoantibody formation occurred together in the same children who underwent liver transplantation at a frequency higher than would be expected by chance. This may reflect an underlying immune dysregulation that impairs immune tolerance to both food allergens and autoantigens.

Topics: Adolescent; Allergens; Autoantibodies; Autoantigens; Autoimmune Diseases; Biliary Atresia; Child; Child, Preschool; Cross-Sectional Studies; End Stage Liver Disease; Female; Follow-Up Studies; Food Hypersensitivity; Humans; Immunosuppression Therapy; Infant; Liver Transplantation; Male; Odds Ratio; Postoperative Complications; Prevalence; Tacrolimus

Everolimus (EVR) is a mammalian target of rapamycin (mTOR) inhibitor commonly used for immunosuppression (IS) after liver transplantation (LT). However, there are concerns about whether mTOR inhibitors may move the hemostatic balance toward a higher likelihood of thrombosis. The present study aimed to investigate potential coagulation disorders after the administration of EVR. We evaluated 54 patients after conversion to an EVR-based IS regimen (n = 26) and compared those patients with patients who were switched to extended-release tacrolimus (TAC) but had never received EVR (n = 28). At baseline and again at 1 month and 6 months after conversion, we measured international normalized ratio, activated partial thromboplastin time, and anticoagulation and fibrinolysis factors, and we performed rotational thromboelastometry (ROTEM). Data were analyzed with a Mann-Whitney U test, a repeated-measure analysis of variance, and a Fisher's exact test. Statistical significance was set at the level of P ≤ 0.05. Plasma levels of von Willebrand factor, fibrinogen, and factor VIII were significantly higher than baseline levels at 1 month and 6 months after conversion of IS to EVR (P < 0.001); plasma levels of protein C, protein S, and plasminogen also increased significantly (P < 0.001). ROTEM confirmed a significant increase in maximum clot firmness in EXTEM, INTEM, and FIBTEM assays (P < 0.001). In all assays, maximum lysis was significantly lower than baseline levels at 1 month and 6 months after conversion to EVR. Patients converted to IS with extended-release TAC exhibited no significant changes in coagulation variables. Retrospective analysis showed a significantly higher incidence of thromboembolic complications among patients treated with EVR-based IS than among those treated with extended-release TAC (P < 0.01). In conclusion, the administration of EVR after LT seems to modify hemostasis to a procoagulant state. Thrombophilia screening before conversion may determine which patients will benefit from conversion to EVR-based IS.

Topics: Adult; Aged; Blood Coagulation; Blood Coagulation Tests; Delayed-Action Preparations; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Thromboembolism

Physicians are faced with a growing number of patients after renal transplantation undergoing graft-unrelated surgery. So far, little is known about the postoperative restitution of graft function and the risk factors for a poor outcome.. One hundred one kidney transplant recipients undergoing graft-unrelated surgery between 2005 and 2015 were reviewed retrospectively. A risk analysis was performed and differences in creatinine, GFR and immunosuppressive treatment were evaluated. Additional, a comparison with a case-matched non-transplanted control group were performed.. Preoperative creatinine averaged 1.88 mg / dl [0.62-5.22 mg / dl] and increased to 2.49 mg / dl [0.69-8.30 mg / dl] postoperatively. Acute kidney failure occurred in 18 patients and 14 patients had a permanent renal failure. Significant risk factors for the development of postoperative renal dysfunction were female gender, a preoperative creatinine above 2.0 mg / dl as well as a GFR below 40 ml / min and emergency surgery. Patients with tacrolimus and mycophenolate mofetil treatment showed a significant lower risk of renal dysfunction than patients with other immunosuppressants postoperatively. Contrary to that, the risk of patients with cyclosporine treatment was significantly increased. Transplanted patients showed a significantly increased rate of postoperative renal dysfunction.. The choice of immunosuppressant might have an impact on graft function and survival of kidney transplant recipients after graft-unrelated surgery. Further investigations are needed.

Topics: Acute Kidney Injury; Adult; Aged; Case-Control Studies; Creatinine; Cyclosporine; Emergency Treatment; Female; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Risk Factors; Sex Factors; Tacrolimus

Tacrolimus has been widely used for immunosuppressive therapy in solid organ transplantation (SOT) and allo-geneic stem cell transplantation (allo-SCT) over the past 2 decades. Pancreatitis caused by tacrolimus was rarely reported in kidney transplantation previously.. Here we presented a case of a 45-year-old male who underwent kidney transplantation and received immunosuppressive therapy of tacrolimus, on day + 67 after transplantation he developed acute pancreatitis with extremely high blood concentration of tacrolimus. We excluded other possible causes and speculated tacrolimus was the probable inducer of pancreatitis. After tacrolimus was discontinued and alternated with cyclosporine, he gradually recovered and was discharged home with no relapse.. Tacrolimus can be a probable cause of pancreatitis after kidney transplantation. We recommended clinicians to be aware of the possibility of tacrolimus-induced pancreatitis during tacrolimus treatment.

Topics: Cyclosporine; Drug Monitoring; Drug Substitution; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreatitis; Postoperative Complications; Tacrolimus; Treatment Outcome

The practice of induction therapy with either rabbit anti-thymocyte globulin (r-ATG) or interleukin-2 receptor antagonists (IL-2RA) is common among heart transplant recipients. However, its benefits in the setting of contemporary maintenance immunosuppression with tacrolimus/mycophenolic acid (TAC/MPA) are unknown.. We compared post-transplant mortality among three induction therapy strategies (r-ATG vs IL2-RA vs no induction) in a retrospective cohort analysis of heart transplant recipients maintained on TAC/MPA in the Organ Procurement Transplant Network (OPTN) database between the years 2006 and 2015. We used a multivariable model adjusting for clinically important co-morbidities, and a propensity score analysis using the inverse probability weighted (IPW) method in the final analysis.. In multivariable IPW analysis, r-ATG (HR = 1.23; 95% CI = 1.05-1.46, P = 0.01) remained significantly associated with a higher mortality. There was a trend toward having a higher mortality in the IL2-RA (HR = 1.11; 95% CI = 1.00-1.24, P = 0.06) group. Subgroup analyses failed to show a patient survival benefit in using either r-ATG or IL2-RA among any of the subgroups analyzed.. In this contemporary cohort of heart transplant recipients receiving TAC/MPA, neither r-ATG nor IL2-RA were associated with a survival benefit. On the contrary, adjusted analyses showed a significantly higher mortality in the r-ATG group and a trend toward higher mortality in the IL2-RA group. While caution is needed in interpreting treatment effects in an observational cohort, these data call into question the benefit of induction therapy as a common practice and highlight the need for more studies.

Topics: Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Resource Allocation; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.. The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.. All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.. The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.. Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Topics: Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Hypertension; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk; Skin Neoplasms; Tacrolimus; Time Factors

Improving long-term renal allograft survival remains an important unmet need. To assess the extent of histologic injury at 10 years after transplantation in functioning grafts, we studied 575 consecutive adult solitary renal transplants performed between 2002 and 2005: 77% from living donors and 81% maintained on tacrolimus-based immunosuppression. Ten-year graft survival was 59% and death-censored graft survival was 74%. Surveillance allograft biopsies were assessed at implantation, 5 years, and 10 years from 145 patients who reached 10 years. At implantation, 5% of biopsies had major histologic abnormalities (chronic transplant glomerulopathy score > 0, other chronic Banff scores ≥ 2, global glomerulosclerosis > 20%, or mesangial sclerosis ≥ 2). This increased to 54% at 5 years and 82% at 10 years. Major lesions at 10 years included the following: arteriolar hyalinosis (66%), mesangial sclerosis (67%), and global glomerulosclerosis > 20% (43%), with 48% of grafts having more than one major lesion. Transplant glomerulopathy and moderate-to-severe interstitial fibrosis were uncommon (12% each). Major lesions were associated with increased proteinuria and decreased graft function. In patients with diabetes at baseline, 52% had diabetic nephropathy/mesangial sclerosis at 10 years. We conclude that almost all renal allografts sustain major histologic injury by 10 years after transplantation. Much damage appears nonimmunologic, suggesting that new approaches are needed to decrease late injury.

Topics: Adult; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Transplantation, Homologous

Individualized tacrolimus treatment can improve drug safety and efficacy. In this study, we aimed to investigate the association of donor and recipient small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphisms with tacrolimus elimination and the potential mechanism.. A total of 297 liver transplant patients were enrolled in the study. CYP3A5 rs776746 and SUMO4 rs237025 were genotyped using TaqMan SNPs assays. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase assay. The expressions of CYP3A5 were detected by qRT-PCR and western blotting.. Tacrolimus C/D ratios was significantly lower for donor SUMO4 rs237025 AA carriers than AG/GG carriers at weeks 1, 2, 3. In multivariate analysis, donor and recipient CYP3A5 rs776747, donor SUMO4 rs237025 and total bilirubin were independent predictors of tacrolimus C/D ratios in the early post-transplantation period both in Cohort A and Cohort B. When combined donor CYP3A5 rs776746 and donor SUMO4 rs237025 genotypes, tacrolimus C/D ratios was highly significant at all investigated time points within the four groups. CYP3A5 mRNA expression in liver tissues was significantly higher for AA carriers than AG/GG patients under inflammatory stimuli after liver transplantation (LT). Furthermore, we demonstrated that SUMO4 rs237025 G allele could increase NF-κB transcriptional activity under inflammatory condition. And activation of NF-kB suppressed the expression of pregnane X receptor (PXR)-mediated CYP3A5 gene.. Donor SUMO4 rs237025 genetic variant was associated with higher Tac C/D ratios in the early period after LT, which might be related to the down-regulation of CYP3A5 enzyme through the NF-kB signalling pathway.

Topics: Adult; Aged; Alleles; China; Cohort Studies; Cytochrome P-450 CYP3A; Female; Humans; Immunosuppressive Agents; Linear Models; Liver Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Tacrolimus; Tissue Donors; Transplant Recipients

Topics: Delayed-Action Preparations; Drug Administration Schedule; Female; Follow-Up Studies; Germany; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Maximum Tolerated Dose; Medication Adherence; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus; Transplant Recipients

Topics: Aged; Amputation, Surgical; Combined Modality Therapy; Debridement; Dermatomycoses; Fatal Outcome; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Piperacillin; Postoperative Complications; Prednisone; Scedosporium; Tacrolimus; Tazobactam

Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2-year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6 months (13% vs 0%; P = .016) compared to 24 months (13% vs 7%; P = .521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12 mg/day) compared to nonexpressers (8 mg/day; P < .001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P = .006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5 mL/min vs 50.0 mL/min; P = .003) at 24 months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.

Topics: Aged; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Genotype; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Polymorphism, Genetic; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus

To investigate the association between tacrolimus (TAC) blood concentration and the risk of post-transplantation diabetes mellitus (PTDM) development after living donor liver transplantation (LDLT).. This study reviewed the clinical data of 158 adult LDLT recipients. A cut-off of mean trough concentration of TAC (cTAC) value at the sixth month postoperatively was identified using a receptor operating characteristic curve. Other clinical complications rates were compared between different cTAC groups.. Thirty-four (21.5%) recipients developed PTDM during follow-up period. Recipients with PTDM suffered lower 1-, 5- and 10-year overall survival rates (85.2%, 64.9%, and 55.6% vs 92.4%, 81.4%, and 79.1%, p < 0.05) and allograft survival rates (87.9%, 76.9%, and 65.9% vs 94.1%, 88.5%, and 86.0%, p < 0.05) than those without PTDM. The best cut-off value of mean cTAC was 5.9 ng/mL. Recipients with higher cTAC (>5.9 ng/mL) were more likely to develop hyperlipidemia (39.6% vs 21.9%, p < 0.05), cardio-cerebral events (7.5% vs1.0%, p < 0.05), and infections (37.7% vs19.0%, p < 0.05) than recipients exposed to low cTAC (≤5.9 ng/mL). However, the two groups showed no difference in the incidence of acute and chronic rejection.. Higher mean cTAC at the sixth month postoperatively is related to increased risk of PTDM in LDLT recipients.

Topics: Adult; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Tacrolimus

Post-transplant diabetes mellitus (PTDM) is a major complication of immunosuppressive therapy, with many risk factors reported in adults with renal transplantation. The objective of this study was to investigate potential non-genetic and genetic risk factors of PTDM in children with renal transplantation treated with tacrolimus.. A national database was screened for patients developing PTDM within 4 years following tacrolimus introduction. PTDM was defined as glucose disorder requiring anti-diabetic treatment. PTDM patients were matched to "non-PTDM" control transplanted children according to age, gender, and duration of post-transplant follow-up. Patients were genotyped for six selected genetic variants in POR*28 (rs1057868), PPARa (rs4253728), CYP3A5 (rs776746), VDR (rs2228570 and rs731236), and ABCB1 (rs1045642) genes, implicated in glucose homeostasis and tacrolimus disposition.. Among the 98 children with renal transplantation enrolled in this multicentre study, 18 developed PTDM. None of the clinical and biological parameters was significant between PTDM and control patients. Homozygous carriers of POR*28 or wild-type ABCB1 (rs1045642) gene variants were more frequent in PTDM than in control patients with differences close to significance (p = 0.114 and p = 0.066 respectively). A genetic score based on these variants demonstrated that POR*28/*28 and ABCB1 CC or CT genotype carriers were at a significantly higher risk of developing PTDM after renal transplantation.. Identification of PTDM risk factors should allow clinicians to allocate the best immunosuppressant for each patient with renal transplantation, and improve care for patients who are at a higher risk.

Topics: Adolescent; ATP Binding Cassette Transporter, Subfamily B; Child; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diabetes Mellitus; Female; France; Genetic Predisposition to Disease; Genotype; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pharmacogenetics; Postoperative Complications; PPAR alpha; Receptors, Calcitriol; Retrospective Studies; Risk Factors; Tacrolimus

The impact of CYP3A5 polymorphisms on clinical outcomes is controversial. The present study investigated the impact of CYP3A5 genetic differences on the development of interstitial fibrosis (IF) from 0 h to 1 year post-transplantation in biopsy sections from 96 living kidney recipients under the same target trough regimen of tacrolimus. The relationships between CYP3A5 polymorphisms and long-term graft function and death-censored graft survival were also examined. A quantitative analysis of IF was performed using computer-assisted imaging on virtual slides. Percent IF (%IF) in the cortical region at 0 h was defined as the baseline, and increases in the ratio of %IF 1 year post-transplantation were calculated. The relationships between CYP3A5 genetic differences and the development of IF, the incidence of clinical events, and the long-term function and death-censored survival of grafts were assessed. The mean increase in the ratio of %IF from 0 h to 1 year was 1.38 ± 0.74-fold. Despite therapeutic drug monitoring (TDM), trough levels of tacrolimus were lower in carriers with the CYP3A5*1 allele (expressers) than in those with the CTP3A5*3/*3 genotype (non-expressers) throughout the 1-year post-transplantation period. However, CYP3A5 genetic differences were not associated with the development of IF, any clinical events, or the long-term function and survival of grafts. The clinical impact of CYP3A5 genetic differences may be small under the current immunosuppressive regimen consisting of mycophenolate mofetil, steroids, basiliximab, and lower target trough levels of tacrolimus with suitable TDM in a low immunological risk population.

Topics: Adult; Aged; Aged, 80 and over; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Female; Fibrosis; Genotype; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Polymorphism, Genetic; Postoperative Complications; Renal Insufficiency; Survival Analysis; Tacrolimus; Treatment Outcome

Over the years, survival after liver transplantation has increased and metabolic complications are becoming more common, contributing to patients' morbidity and mortality. The objectives of this study were to describe a population of patients with hepatic transplantation and diabetes mellitus (DM), evaluate the frequency of metabolic complications, and assess the impact of a multidisciplinary team on DM management.. This was a retrospective study involving interview and medical record analysis of 46 consecutive patients followed at the diabetes mellitus and liver transplantation unit of a tertiary university hospital, all evaluated by a multidisciplinary team.. Of all patients, 76.1% were men, with a median age 60 years old (interquartile range: 56 to 65 years) and liver transplantation time of 5 years (interquartile range: 0.6-9 years). Hypertension, hypercholesterolemia, hypertriglyceridemia, alcoholism, and smoking were present in 47.8%, 34.8%, 23.9%, 34.8%, and 30.4% of the patients, respectively. The most frequent immunosuppressant in use was tacrolimus (71.1%). Regarding nutritional status, 37.9% of patients were classified as overweight according to body mass index, and 41.2% were considered overweight according to the triceps skin fold. The median glycosylated hemoglobin and weight before and after intervention of the multidisciplinary team in all 46 patients were, respectively, 7.6% (5.7% to 8.8%) versus 6.5% (5.7% to 7.7%); P = .022 and 70.5 kg (64.7 to 82.0 kg) versus 71.6 kg (65.0 to 85.0 kg); P = .18.. Hypertension and dyslipidemia were common in transplanted patients with DM. Intervention of the multidisciplinary team resulted in a significant improvement in glycosylated hemoglobin without significant weight gain.

Topics: Aged; Body Mass Index; Body Weight; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nutritional Status; Patient Care Team; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Tacrolimus

There is mutual influence between the liver and thyroid hormone metabolism. Patients with diabetes mellitus (DM) also have an increased prevalence of thyroid disorders (TDs). The objectives of this study were to evaluate the frequency of TD before and after liver transplantation (LT) in a population of patients with DM as a whole and when categorized by sex.. This was a retrospective study involving interview and medical record analysis of 46 consecutive patients followed at the diabetes mellitus and liver transplantation unit of a tertiary university hospital.. Of all patients, 76.1% were men with a median age of 60 years old (interquartile range: 56 to 65 years) and time since LT of 5 years (range, 0.6 to 9 years). Hypertension, hypercholesterolemia, hypertriglyceridemia, alcoholism, and smoking were present in 47.8%, 34.8%, 23.9%, 34.8%, and 30.4% of the patients, respectively. The most frequent immunosuppressant in use was tacrolimus (71.1%). TD was present in 4.3% and 13% before and after LT, respectively (P = .058). In women and men, these frequencies were 9.1% and 18.2% (P = .563), and 2.9% and 11.8% (P = .045), respectively.. Frequency of TD was high both before and after LT. After transplantation, prevalence of TD increased in men and differences between males and females almost disappeared. Further studies are needed to assess if screening for TD before and after LT in patients with DM might be beneficial, especially in men.

Topics: Aged; Diabetes Complications; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Thyroid Diseases

Cytomegalovirus (CMV) infection is a relevant cause of morbidity and mortality in transplantation patients. Its major incidence is in the first year and viral replication is related to acute rejection, survival reduction, and graft vascular disease.. This study aims to evaluate retrospectively whether a high dose of calcineurin inhibitors correlates with CMV-positive polymerase chain reaction (PCR), need for treatment, and death in cardiac transplantation patients.. This is a case-control study including patients who underwent transplantation between 2014 and 2016. They were separated into two groups (positive or negative PCR) and evaluated for dosage serum levels of cyclosporine and tacrolimus. Patients were classified with adequate dose of immunosuppressant or high dose, and was analyzed that there was any association with those and positive CMV-PCR, need for treatment for CMV, and deaths. For statistical analysis, the Student t test was used for the quantitative variables and the Fisher's Exact Test for qualitative variables. To show CMV-free survival, the Kaplan-Meier curve was used. The level of significance was set at 5%.. CMV-positive PCR in the sample was 72% for a total of 50 individuals. Positive PCR correlated with a high dose of calcineurin inhibitors in a statistically significant way (P = .002), as did a high dose of cyclosporine (P = .004); however, a high dose of tacrolimus had no such association (P = .17). When a high dose was assessed with a need for treatment, the chance of needing treatment increased more than eight times (P = .024; odds ratio = 8.25; 95% CI = 1.33 to 51.26), which was different from results found with high-dose tacrolimus (P = 1.0). However, no significant association was found in relation to deaths.. Tacrolimus serum levels showed no association with CMV-PCR, which was different from serum cyclosporine, which showed association with CMV-PCR positivity, increasing the need for treatment approximately 8-fold, without association with death.

Topics: Adult; Calcineurin Inhibitors; Case-Control Studies; Cyclosporine; Cytomegalovirus Infections; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Biologic agents are a beneficial therapy for juvenile idiopathic arthritis (JIA). However, there is a lack of evidence with regard to management of these agents for JIA patients who undergo kidney transplantation (KTx). A 36-year-old woman with JIA who was treated with tocilizumab targeting interleukin-6 (IL-6) receptor underwent ABO-incompatible kidney transplantation (ABOi KTx). To prevent over-immunosuppression, tocilizumab was discontinued before ABOi KTx. Rituximab, tacrolimus, mycophenolate mofetil, everolimus, and methylprednisolone were used for immunosuppression. Clinical remission of joint pain was maintained for over 3 years despite complete discontinuation of tocilizumab. Both serum IL-6 and soluble IL-6 receptor levels were markedly decreased, suggesting that multitargeted immunosuppression for ABOi KTx induced long-term clinical remission of JIA through inhibition of the IL-6 pathway. However, levels of C-reactive protein (CRP) and matrix metalloproteinase-3 (MMP-3) gradually increased thereafter and abatacept was initiated to prevent joint deterioration. These levels decreased without any adverse events. The patient's renal graft function was well maintained.

Topics: Abatacept; ABO Blood-Group System; Adult; Antibodies, Monoclonal, Humanized; Arthritis, Juvenile; Blood Group Incompatibility; Everolimus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Rituximab; Tacrolimus; Transplants

The incidence and impact of anti-human leukocyte antigen donor-specific alloantibodies (DSAs) developing after liver transplantation (LT) remains controversial and not extensively studied. The aim of the present study was to assess the incidence of DSAs, to identify risk factors for the development of DSAs, and to understand the impact of DSAs in a large population of adult LT recipients. This single-center retrospective study included all adult patients who underwent a first LT between 2000 and 2010 in our center. The study population mainly consisted of male patients, the mean age was 52.4 years, and the main indication was alcoholic cirrhosis (54.1%). From the 297 patients included in the cross-sectional study, 14 (4.7%) had preformed DSAs, and 59 (19.9%) presented de novo DSAs (12.2% at 1 year, 13.4% at 5 years, and 19.5% at 10 years). Multivariate analysis found that female donor sex (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.12-2.01; P = 0.01) and delay between LT and DSA screening (HR, 1.10; 95% CI, 1.01-1.20; P = 0.03) were associated with occurrence of de novo DSAs. From the 190 patients included in the subgroup longitudinal analysis, exposure to tacrolimus (mean trough level during the periods 0-2 years and 0-3 years) was significantly lower for patients having DSAs at 5 years. Concerning histology, only acute rejection (P = 0.04) and portal fibrosis ≥2 (P = 0.02) were more frequent at 1 year for patients with DSAs. Patient survival and graft survival were not significantly different according to the presence or not of DSAs at 1 year. Among the 44 patients who had de novo or persistent preformed DSAs, the diagnosis of antibody-mediated rejection was made in 4 (9.1%) patients after 1, 47, 61, and 74 months following LT. In conclusion, the results of the present study suggest that DSAs are observed in a minority of LT adult patients, with limited overall impact on graft and patient outcome.

Topics: Adult; Cross-Sectional Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Isoantibodies; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus; Transplant Recipients; Treatment Outcome

Post-transplantation diabetes mellitus (PTDM) is a serious metabolic complication after kidney transplantation. The aim of this study was to explore the association of clinical variables and five selected single nucleotide polymorphisms (SNPs) with PTDM in Chinese Han renal allograft recipients taking tacrolimus (TAC).. A total of 129 non-diabetic, primary, Chinese Han renal allograft recipients treated with TAC were enrolled. Five SNPs (CYP3A5 rs776741, rs776746, rs15524, CYP24A1 rs2296241, and PPARG rs1801282) were genotyped and analyzed.. Among 129 recipients, 17 (13.2%) developed PTDM. Both univariate and multivariate analysis demonstrated that age over 50 years old and CYP24A1 rs2296241 A allele were independently correlated with the development of PTDM, while no significant differences was observed in TAC pharmacokinetics and CYP3A5, PPARG polymorphisms between two groups.. Patients with advanced age and CYP24A1 rs2296241 A allele had an increased risk of PTDM after kidney transplantation.

Topics: Adult; Age Factors; Alleles; China; Cytochrome P-450 CYP3A; Diabetes Mellitus; Female; Genetic Association Studies; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; PPAR gamma; Risk; Tacrolimus; Transplantation, Homologous; Vitamin D3 24-Hydroxylase

Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC

Topics: Allografts; Anti-Inflammatory Agents; Biomarkers; Calcineurin; Calcineurin Inhibitors; Case-Control Studies; Female; Follow-Up Studies; Gene Expression Profiling; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Prognosis; Prospective Studies; Risk Factors; Tacrolimus

Corticosteroids (CS) are traditionally used as part of the basal immunosuppression (IS) following liver transplantation (LT) but are known to be associated with an increased risk of new-onset diabetes mellitus (NODM), cardiovascular morbidity and mortality. The aim of this study was to retrospectively compare the incidence of transient as well as persistent NODM, rejection rate and patient- and graft survival between patients receiving steroid-based and steroid-free maintenance IS.. A total of 238 patients liver transplanted (2008-2011) with deceased donor livers were divided into two groups, one group that received steroid-based IS (tacrolimus (TAC), corticosteroids (CS), ± mycophenolate mofetil (MMF); n = 155) (2008-2011) and another group of non-autoimmune recipients that received steroid-free IS (TAC, MMF; n = 83) according to our new maintenance IS-protocol starting January 2010. The primary and secondary end-points were patient- and graft survival, rejection rates and the incidence of NODM. The median follow-up times were 1248 days and 681 days, respectively.. The one-year patient- and graft survival in the steroid-based and steroid-free group was 92.7% and 93.3% (ns) and 87.6% and 84.9% (ns), respectively. The incidence of biopsy proven acute rejection (BPAR) was 27.7% in both groups (ns) during follow-up. The overall incidence of persistent NODM in the two groups were 16.8% and 2.9%, respectively (p < .01).. The results show that steroid-free low-dose tacrolimus-based IS following LT is safe and decreases the incidence of NODM significantly.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Steroids; Sweden; Tacrolimus; Young Adult

Topics: Administration, Cutaneous; Aged; Diverticulitis, Colonic; Female; Humans; Ileostomy; Interleukin-8; Ointment Bases; Postoperative Complications; Pyoderma Gangrenosum; Skin; Tacrolimus; Treatment Outcome

Little is known about the endothelial injury caused directly by circulating donor-specific antibodies (DSAs) during antibody-mediated rejection. von Willebrand factor (vWF) is a highly thrombotic glycoprotein stored in Weibel-Palade bodies in endothelial cells. It has been shown that its secretion is triggered by allostimulation. Calcineurin-like phosphatases regulate pathways involved in vWF secretion. Therefore, we hypothesized that tacrolimus would prevent alloantibody-induced glomerular lesions, in part via inhibition of vWF secretion from endothelial cells. Here, we used a human in vitro model of glomerular endothelium expressing HLA class I and II antigens and demonstrated that anti-HLA class II antibodies elicit a higher endothelial release of vWF than do anti-HLA class I antibodies in cell supernatants. We observed that tacrolimus treatment decreased vWF secretion after stimulation with both classes of anti-HLA antibodies and decreased platelet adhesion on allostimulated endothelial cells in a microfluidic chamber. In kidney recipients, tacrolimus trough levels were negatively associated with vWF blood levels. These results indicate that direct disruption of hemostasis via vWF secretion is a potential mechanism of antibody-mediated injury in patients with DSAs. Our results further suggest that the targeting of microcirculation hemostasis may be beneficial to prevent the development of microangiopathic lesions in antibody-mediated rejection.

Topics: Cells, Cultured; Endothelium, Vascular; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Tissue Donors; von Willebrand Factor

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that T-cell-depleting agents should be used only for kidney transplant (KT) recipients at high immunologic risk. However, the effects of thymoglobulin induction therapy in low-immunologic risk KT recipients on tacrolimus, mycophenolic acid, and steroid have not been elucidated yet.. We retrospectively collected 6 months postoperative clinical data, for low-immunologic risk KT recipients at Soonchunhyang University Hospital. Recipients were divided into thymoglobulin and basiliximab groups, based on the induction agent used. Low-immunologic risk recipients were defined as those with panel-reactive antibody level <30% at the time of kidney transplantation. The incidence of biopsy-proven acute rejection and borderline change was compared between the two groups.. Of the 46 low-immunologic risk patients, 25 received thymoglobulin. The incidence of biopsy-proven acute rejection was 0% (n = 0) and that of borderline change was 8% (n = 2) in the thymoglobulin group. The basiliximab group had a significantly higher incidence of rejection (23.8%; n = 5; P = .015) and borderline change (42.9%; n = 9; P = .006). No significant difference in estimated glomerular filtration rate was found between the two groups at 6 months after kidney transplantation. Cytomegalovirus (CMV) infection occurred more frequently in the thymoglobulin group than in the basiliximab group. All patients with CMV infection in both groups were effectively treated with pre-emptive intravenous ganciclovir therapy.. In low-immunologic risk KT recipients who received tacrolimus, mycophenolic acid, and steroid therapy, thymoglobulin induction therapy significantly reduced the incidence of biopsy-proven acute rejection and borderline change compared with basiliximab induction therapy.

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Induction Chemotherapy; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

Exploration of fecal microbiota transplantation in the treatment of refractory diarrhea after renal transplantation.. Summarize the etiology of 120 cases with diarrhea after renal transplantation from 2014 to 2017 in our hospital. There were 4 recipients of refractory diarrhea who accepted fecal microbiota transplantation with informed consent, and we collected clinical data of stool and bacterial culture, gut microbiota analysis, graft function, electrolytes, immunosuppressant concentrations of prognostic evaluation of patients with fecal transplantation.. The absorption of electrolyte is slightly higher and concentration of tacrolimus and creatinine were not significantly changed compared with before.. Fecal microbiota transplantation provides a new choice to refractory diarrhea after renal transplantation as an innovative treatment, but the effectiveness of fecal microbiota transplantation needs long-term observation and further evaluation through large sample data.

Topics: Adult; Aged; Diarrhea; Fecal Microbiota Transplantation; Feces; Female; Gastrointestinal Microbiome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Tacrolimus; Treatment Outcome; Young Adult

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

Topics: Adult; Drug Monitoring; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Tissue Distribution

Topics: Combined Modality Therapy; Delirium; Diagnosis, Differential; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Middle Aged; Pancreas Transplantation; Postoperative Complications; Severity of Illness Index; Tacrolimus; Treatment Outcome

The aim of the study was to assess the frequency of infections caused by Pneumocystis jiroveci, Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae among lung transplant recipients in the context of immunosuppression.. The study group consisted of 94 patients (37 women and 57 men; mean age 42.03 years) transplanted between 2009 and 2016 at the Silesia Center for Heart Diseases (SCCS). Immunosuppressive treatment (induction and maintenance therapy) was assessed. The immunofluorescence methods were used to detect the P. jiroveci, L. pneumophila, C. pneumoniae, and M. pneumoniae antigens in samples obtained from the respiratory tract.. Thirty-two of 94 graft recipients developed atypical or opportunistic infection. The median time of its occurrence was 178 days after transplantation. P. jiroveci was responsible for 84.38% of first infections. Five patients developed infection with P. jiroveci and C. pneumoniae. None of the infections occurred during induction of immunosuppression. An opportunistic or atypical infection developed in 19.35% of the patients treated with a tacrolimus-based regimen, and in 43.33% of patients on a cyclosporine-based regimen.. Infection with P. jiroveci is a recognized problem after lung transplantation and should be monitored. The percentage of infected patients is higher in patients treated with a cyclosporine-based regimen in comparison to those treated with tacrolimus.

Topics: Adult; Chlamydophila Infections; Chlamydophila pneumoniae; Cyclosporine; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Legionella pneumophila; Legionnaires' Disease; Lung Transplantation; Male; Middle Aged; Mycoplasma pneumoniae; Opportunistic Infections; Pneumocystis carinii; Pneumonia, Mycoplasma; Pneumonia, Pneumocystis; Postoperative Complications; Tacrolimus; Transplant Recipients

BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end-stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC. CASE REPORT The data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up. CONCLUSIONS Liver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT.

Topics: Child; Child, Preschool; Cholestasis, Intrahepatic; Diarrhea; Disease Progression; Fatty Liver; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Colchicine; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Postoperative Complications; Prognosis; Tacrolimus; Transplantation, Homologous

Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability.. Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients' number of CYP3A5 loss-of-function alleles was assessed.. Acute rejection was associated with greater CV of dose in AA (P < 0.001) and EA recipients (P = 0.012). Graft failure was associated with a greater CV of dose (P = 0.022) and trough (P < 0.001) in AA, and higher CV of trough (P = 0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (P = 0.0042) and increased CV of dose (P < 0.0001).. CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Black or African American; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Genotype; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Minnesota; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus; White People; Young Adult

To treat organ transplant patients with mycobacterial infection, physicians need to pay attention to interaction between drugs used against mycobacteria and immunosuppressants. The purpose of this report is to describe the clinical features of and treatment for mycobacterial infection in lung transplant (LTx) recipients.. To investigate the incidence, treatment, and outcome for mycobacterial infection, we retrospectively reviewed 100 LTx recipients in our program since 2000.. Four recipients (4.0%) developed mycobacterial infection. Three recipients took tacrolimus, and 1 received cyclosporine with mycophenolate mofetil and a steroid for immunosuppression. Tuberculosis (TB) was isolated from 2 recipients, and non-tuberculous mycobacteriosis (NTM) was detected in the other 2. We treated the patients with levofloxacin + isoniazid + pyrazinamide + ethambutol (EB) for TB and clarithromycin (CLM) + EB for NTM to avoid interaction of calcineurin inhibitors (CNI: 8-10 ng/mL in trough level) with rifampicin (RFP). In treating the patients with NTM, we were able to maintain an adequate blood concentration of CNI by decreasing the dosage from one-half to one-quarter. All mycobacterial infections were controlled with treatment. In 1 patient with chronic obstructive pulmonary disease (COPD) infected with TB in the native lung, the forced expiratory volume in 1 second (FEV1) unexpectedly increased from 1890 mL before infection to 2320 mL possibly due to organization of the native lung.. We were able to manage the mycobacterial infections using drugs other than RFP without any cases of acute rejection under adequate immunosuppression. Organization of the native lung with TB infection unexpectedly resulted in improvement of FEV1 in a COPD patient.

Topics: Adult; Anti-Bacterial Agents; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Middle Aged; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Mycophenolic Acid; Nontuberculous Mycobacteria; Postoperative Complications; Retrospective Studies; Rifampin; Tacrolimus; Tuberculosis

Calcineurin inhibitors are a commonly used immunosuppressive drug and over 80% of lung transplant (LTx) recipients use tacrolimus. Sustained-release tacrolimus (SRT) was developed as a once-daily formulation, resulting in slower release and reduction in peak concentration compared with twice-daily immediate-release tacrolimus (IRT). Previous reports indicate that SRT may carry fewer side effects than IRT; however, the impact of SRT in bronchiolitis obliterans syndrome (BOS) after LTx is unclear.. Our study objective was to evaluate the effect of SRT in BOS after LTx.. We investigated the effect of SRT for BOS among 75 LTx recipients who were alive in 2017 in our LTx program. All analyses were carried out using student t test or F test.. Thirty-five recipients took IRT, 32 recipients used SRT, 7 recipients used cyclosporine, and 1 patient who received bone marrow and a lung graft from the same donor did not use a calcineurin inhibitor. The most frequent reason for conversion of IRT to SRT was kidney dysfunction, followed by other IRT complications. Five recipients underwent conversion of IRT to SRT because of decline of forced expiratory volume in 1 second (FEV1) with fluctuation of the tacrolimus trough level. After induction of SRT, the fluctuation of the tacrolimus trough level was significantly reduced in 4 of 5 patients (P < .05). Before drug form conversion, the FEV1 in these 5 patients was significantly decreased; however, this exacerbation of FEV1 was attenuated after SRT induction (P < .05).. SRT appeared to stabilize decline of FEV1 in patients with BOS possibly due to reducing the fluctuation of tacrolimus trough blood concentration.

Topics: Adolescent; Adult; Bronchiolitis Obliterans; Calcineurin Inhibitors; Cyclosporine; Delayed-Action Preparations; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Respiratory Function Tests; Tacrolimus; Young Adult

Posttransplantation diabetes mellitus (PTDM) is a frequent metabolic complication following solid organ transplantation and was proven to be associated with adverse outcome. This study aimed to identify the incidence and risk factors of PTDM under the background of relative-living renal transplantation in China.. We conducted a retrospective cohort study that included 358 recipients who underwent relative-living donor kidney transplantation in the Organ Transplant Institute of 309th Hospital of People's Liberation Army between January 1, 2010, and December 31, 2014. PTDM was defined based on American Diabetes Association criteria. Demographics and laboratory results were compared between patients with PTDM and non-PTDM; multivariate analysis was performed using a logistic regression model.. One hundred ten out of a total of 358 recipients were diagnosed with PTDM (30.72%) within 3 years after transplantations. Seven risk factors for PTDM were identified in multivariate analysis: body mass index ≥25 (odds ratio [OR] 1.905, 95% confidence interval [CI]: 1.114-3.258), family history of diabetes (OR 1.898, CI: 1.051-3.258), hypomagnesemia pretransplantation (OR 1.871, CI: 1.133-3.092), acute rejection episodes in 3 months posttransplantation (OR 2.312, CI: 1.015-5.268), tacrolimus use (OR 1.952, CI: 1.169-3.258), impaired fasting glucose diagnosed pretransplantation (OR 1.807, CI: 1.091-2.993), and hyperglycemia in the first week posttransplantation (OR 1.856, CI: 1.133-3.043).. Our study suggests high body mass index, family diabetes history, hypomagnesemia pretransplantation, acute rejection episodes within the first 3 months after transplantation, tacrolimus use, impaired fasting glucose diagnosed pretransplantation, and hyperglycemia within the first week after transplantation are independent risk factors of PTDM in relative-living donor transplantation.

Topics: Adult; Body Mass Index; China; Cohort Studies; Diabetes Mellitus; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

This study aims to verify the new-onset diabetes after kidney transplant (NODAT) incidence in recipients within 1 year after kidney transplantation from a single center in Southern Brazil and to assess the associated conditions.. A retrospective study of 258 post-renal transplant patients was performed. Demographic (gender, age, ethnic background) and clinical (origin of graft, associated infections, body mass index (BMI) at transplant time and 6 and 12 months after, causes of renal failure, and comorbidities) data were analyzed. All patients were on tacrolimus, mycophenolate mofetil, and prednisone treatment. Patients with and without NODAT were compared.. A NODAT incidence of 31.2% was noted 1 year post transplantation. In the univariate analysis, patients with NODAT were older (p = 0.001), mostly had African-American ethnic background (p = 0.02), and had renal failure secondary to high blood pressure (HBP) (p = 0.001). The group of patients with NODAT also had more incidence of post-transplant HBP (p = 0.01), heart failure (p = 0.02), and dyslipidemia (p = 0.001). Logistic regression showed that African-American ethnic background, post-transplant HBP, and dyslipidemia were independently associated with NODAT.. This study shows a NODAT incidence that is greater in patients with African-American ethnic background and that is associated with HBP and dyslipidemia.

Topics: Adult; Brazil; Diabetes Mellitus; Dyslipidemias; Female; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Transplantation; Logistic Models; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Statistics, Nonparametric; Tacrolimus

Aim of the article was to present a case of post transplantation invasive aspergillosis, successfully treated with conservative and surgical treatment.. Patient, male, 44 years old, with second kidney transplant, required special preparation therapy, because he was sensitized, with concentration of Panel Reactive Antibody (PRA) class I 11% and PRA class II 76%. On the day of transplantation, induction was done with. Although highly sensitized patients, those who are on hemodialysis, in preparation for transplantation, receive intensive immunosuppressive therapy that suppress the immune system. Occurrence of secondary fungal infections especially infection by aspergillosis, is cause of high mortality of infected. Application GM test that detects existence of antibodies against Aspergillus antigens and usage of different type of immunosuppressive preparation can increase longevity of graft and patients in solid organ transplantation program. Aspergillosis is treated with voriconazole and surgery, and sometimes graft-nephrectomy if needed. Recommendation is that in all immunocompromised hosts and organ transplant recipient should have been tested with GM test.

Topics: Adult; Antifungal Agents; Caspofungin; Humans; Immunocompromised Host; Immunosuppressive Agents; Invasive Pulmonary Aspergillosis; Kidney Transplantation; Male; Plasmapheresis; Pneumonectomy; Postoperative Complications; Tacrolimus; Treatment Outcome; Voriconazole

AR is lower in pKTx recipients on Tac vs CsA. Data comparing infection outcomes for children treated with these agents are limited. We retrospectively studied infection outcomes in 96 pKTx recipients on a RDP. PS, DCGS, AR, and infection-free survival were assessed using Kaplan-Meier/log-rank tests and proportional hazards models. There were no differences in 1-year PS, DCGS, or AR between Tac and CsA recipients. After adjusting for AR, the hazard of CMV viremia was 4.0 times higher (95%CI: 1.04, 15.5; P = .044) and that of BK viremia was 3.8 times higher (95%CI: 1.5, 10.2; P = .007) in Tac recipients. The incidence of EBV viremia was similar between the groups (P = .56). PostTx lymphoproliferative disease was only observed in Tac recipients (3%). There was no difference in the incidence of pneumonia, urinary tract, or Clostridium difficile infections between Tac and CsA recipients. Among KTx recipients on RDP, the hazards of CMV and BK viremia within 1 year post-KTx were significantly higher in Tac recipients compared to CsA. Regular assessment for infections and lower Tac trough levels may be warranted in Tac recipients.

Topics: Adolescent; Bacterial Infections; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Male; Postoperative Complications; Prednisone; Proportional Hazards Models; Retrospective Studies; Tacrolimus; Treatment Outcome; Virus Diseases

Polyomavirus nephropathy (BKVN) is an important cause of chronic allograft dysfunction (CAD). Recipient determinants (male sex, white race, and older age), deceased donation, high-dose immunosuppression, diabetes, delayed graft function (DGF), cytomegalovirus infection, and acute rejection (AR) are risk factors. Reducing immunosuppression is the best strategy in BKVN. The objective of our study was to evaluate CAD progression after therapeutic strategies in BKVN and risk factors for graft loss (GL).. Retrospective analysis of 23 biopsies, from patients with CAD and histological evidence of BKVN, conducted over a period of 10 years. Glomerular filtration rate was <30 mL/min in 16 patients at the time of the BKVN diagnosis.. BKVN was histologically diagnosed in 23 recipients (19 men, 4 women). All patients were white, with age of 51.2 ± 12.1 years (6 patients, age >60 years), and 22 had a deceased donor. Diabetes affected 4 patients, DGF occurred in 3, cytomegalovirus infection in 2, and AR in 15. All patients were medicated with calcineurin inhibitors (CNI) (95.7% tacrolimus) and corticoids, and 16 also received an antimetabolite. One year after antimetabolite reduction/discontinuation and/or CNI reduction/switching and/or antiviral agents, graft function was decreased in 11 patients, increased/stabilized in 10, and unknown in 2. GL occurred in 9 patients. Older age (hazard ratio, 1.76; 95% confidence interval, 0.94-3.28) and DGF (hazard ratio, 2.60; 95% confidence interval, 0.54-12.64) were the main risk factors for GL. The lower GFR at the time of the BKVN diagnosis was associated with an increased risk of initiation of dialysis.. GL occurred in 39.1% of patients with BKVN and DGF; older age and lower GFR at the time of diagnosis were important risk factors. Early diagnosis of BKVN is essential to prevent GL.

Topics: Adult; Allografts; BK Virus; Calcineurin Inhibitors; Delayed Graft Function; Disease Progression; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppression Therapy; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polyomavirus; Polyomavirus Infections; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

BACKGROUND Development of post-transplant diabetes mellitus after kidney transplant (PTDM) significantly increases kidney graft loss and mortality. Several risk factors for PTDM have been reported, including Hispanic ethnicity and the use of calcineurin inhibitors and corticosteroids. The incidence and impact of PTDM in the Hispanic kidney transplant population is unknown. MATERIAL AND METHODS We retrospectively reviewed the medical records of 155 Hispanic and 124 Caucasian patients, who were not diabetics and underwent kidney transplant between January 2006 and December 2011. We analyzed their clinical outcomes at 12 months post-transplant, including the incidence of PTDM, acute rejection rates, and patient and graft survival. RESULTS Hispanics who developed PTDM (n=22) were more than 10 years older and had higher body mass index (BMI) than Hispanics without PTDM (p<0.001 and p=0.001, respectively). Caucasians with PTDM (n=13) were non-significantly older (2.5 years) and had higher BMI than Caucasians without PTDM (p=0.526, p=0.043, respectively). The incidence of PTDM was not significantly different between Hispanics and Caucasians treated with tacrolimus-based immunosuppression (14.2% and 10.5%, respectively). CONCLUSIONS PTDM did not cause significant difference in short-term outcomes after kidney transplant in Hispanics or Caucasians. Larger multicenter prospective and long-term clinical trials are needed to validate these findings.

Topics: Adult; Age Factors; Body Mass Index; Diabetes Mellitus; Female; Hispanic or Latino; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; White People

BK polyomavirus-associated nephropathy is an important cause of post-transplantation renal failure. We present two cases of BK polyomavirus-associated nephropathy who were submitted to contrasting strategies of clinical follow-up to BK polyomavirus reactivation, but progressed to a similar final outcome.. Case 1 is a 37-year-old white man whose graft had never presented a good glomerular filtration rate function, with episodes of tacrolimus nephrotoxicity, and no urinary monitoring for BK polyomavirus; stage B BK polyomavirus-associated nephropathy was diagnosed by biopsy at 14 months post-transplant. Despite clinical treatment (dosage decrease and immunosuppressive drug change), he progressed to stage C BK polyomavirus-associated nephropathy and loss of graft function 30 months post-transplant. Case 2 is a 49-year-old mulatto man in his second renal transplantation who was submitted to cytological urinary monitoring for BK polyomavirus; he presented early, persistent, and massive urinary decoy cell shedding and concomitant tacrolimus nephrotoxicity. Even with decreasing immunosuppression, he developed BK polyomavirus-associated nephropathy 1-year post-transplant. Loss of graft function occurred 15 months post-transplant.. Cytological urinary monitoring was an efficient strategy for monitoring BK virus reactivation. Decoy cell shedding may be related to BK polyomavirus-associated nephropathy when extensive and persistent. The presence of associated tacrolimus nephrotoxicity may be a confounding factor for the clinical diagnosis of BK polyomavirus-associated nephropathy.

Topics: Adult; BK Virus; Dose-Response Relationship, Drug; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Renal Dialysis; Tacrolimus; Transplant Recipients; Treatment Outcome; Virus Activation

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Disease Progression; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Liver; Liver Cirrhosis; Liver Transplantation; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus

Heart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors.. This is a retrospective study of all children aged 0-18 years who underwent heart transplantation in Gothenburg from 1989 to 2014.. A total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0-17). The mean post-transplant follow-up time was 5.5 years (0.5-21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02-25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein-Barr virus infection - that is, a positive donor-negative recipient (p⩽0.0001) - and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028). Discussion This study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.

Topics: Adolescent; Child; Child, Preschool; Female; Heart Defects, Congenital; Heart Transplantation; Heart Ventricles; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphoma; Lymphoproliferative Disorders; Male; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sternotomy; Sweden; Tacrolimus

Tacrolimus is an immunosuppressive agent well known to be capable of producing renal impairment. Acute renal failure with right heart failure caused by tacrolimus is rarely described. We report the findings of one such case in which tacrolimus caused acute renal failure with severe tricuspid regurgitation and right ventricular failure documented by echocardiography.

Topics: Acute Disease; Aged; Echocardiography, Doppler; Female; Heart Failure; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

Parvovirus B19 infection should be contemplated as one of the differential diagnoses of persistent anemia in transplanted patients. There must be high index of suspicion of Parvovirus B19, when post-transplant patients present with refractory and severe anemia with reticulocytopenia and all the other common causes of anemia such as blood loss, adverse effects of immunosuppressant agents and graft dysfunction has been ruled out. In suspected patients, diagnosis is confirmed by serological tests (IgM and IgG), PCR from blood and/or bone marrow and by bone marrow biopsy finding of pure red cell aplasia. Intravenous immunoglobulin (IVIG) is the treatment of choice and highly rewarding. Here we are reporting two cases of post-transplant Parvovirusinfection, one in an adult lady and second in an adult man who underwent live renal transplantation recently.

Topics: Adult; Anemia; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Male; Parvoviridae Infections; Parvovirus B19, Human; Polymerase Chain Reaction; Postoperative Complications; Red-Cell Aplasia, Pure; Tacrolimus; Transplant Recipients; Treatment Outcome

Topics: Antibodies, Viral; Drug Substitution; Erythema; Everolimus; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sarcoma, Kaposi; Tacrolimus; Thoracic Neoplasms; Tissue Donors; Viremia

Induction therapy with a T cell-depleting agent followed by mycophenolate mofetil and tacrolimus is presently the most frequently used immune suppression (IS) regimen in islet transplantation. This study assesses its safety and tolerability in nonuremic type 1 diabetic recipients.. Fifty-one patients (age, between 29 and 63 years) with high glycemic variability and problematic hypoglycemia received intraportal islet grafts under anti-thymocyte globulin-mycophenolate mofetil-tacrolimus protocol. They were followed up for over 48 months for function of the implant and adverse events.. Severe hypoglycemia and diabetic ketoacidosis were absent in patients with functioning graft. Immune suppressive therapy was maintained for 48 months in 29 recipients with sustained function (group A), whereas 16 patients stopped earlier due to graft failure (group B) and in 6 for other reasons. Group A was significantly older at the time of implantation and achieved higher graft function at posttransplantation month 6 under similar dose of IS. Prevalence of IS-related side effects was similar in groups A and B, occurring predominantly during the first year posttransplantation. IS-related serious adverse events (SAE) were reported in 47% of patients, with 4 presenting with cytomegalovirus infection and 4 (age, 42-59 years) diagnosed with cancer. Except in 1 patient with cancer, all SAEs resolved after appropriate treatment.. These risk/benefit data serve as a basis for clinical decision-making before entering an intraportal islet transplantation protocol. A longer benefit is observed in recipients of higher age (≥40 years), but it is not associated with more side effects and SAE.

Topics: Adult; Antilymphocyte Serum; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

The cause of post-transplant CNI-NCs is multifactorial and not ascribed solely to CNI toxicity. A total of 90 children (aged <20 years) who underwent LDLT were evaluated to investigate the predictive factors associated with CNI-NCs. Twelve patients (13.3%) developed CNI-NCs after LDLT (age range, 2-15 years). The symptoms of CNI-NCs were seizures, VD, and stupor. The median onset of CNI-NCs was 10 days (range, 5-30 days) post-transplant. In the univariate analysis, higher recipient age at LDLT, donor age and recipient's BW, lower actual GV/SLV and TAC dosage/BW, and higher mean T-Bil and sodium level for 7 days after transplantation were independently significantly associated with TAC-NCs. Multivariate analysis showed that the T-Bil level in the first week after LDLT was the only significant independent predictive factor for TAC-NCs (HR, 1.588; 95% CI, 1.042-2.358; P=.031). In conclusion, CNI-NCs occurred most frequently in children over 5 years and were associated with hyperbilirubinemia for 7 days post-transplant, regardless of TAC levels. The transplant team should refer to a neurologist to define the diagnosis and to collaborate to resolve the neurological problems.

Topics: Adolescent; Age of Onset; Bilirubin; Body Weight; Calcineurin Inhibitors; Child; Child, Preschool; Female; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Male; Multivariate Analysis; Nervous System Diseases; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stupor; Tacrolimus

It is now known that post-transplant graft function after deceased-donor liver transplantation and living-donor liver transplantation (LDLT) differ; however, there is no report assessing the relationship between graft function and the development of new-onset diabetes mellitus after transplantation (NODAT). We conducted this study to identify the predictive risk factors for NODAT, including graft function after LDLT.. The subjects of this study were 175 adult recipients who underwent LDLT at Kyoto University Hospital between 2006 and 2010, and survived for more than 3 months (median observation period, 1046 days).. The 1-, 2-, and 3-year incidences of NODAT after LDLT were 26.1, 32.0, and 33.4%, respectively. Pre-transplant diabetes was associated with poor survival (p = 0.0048), whereas NODAT was not associated with patient survival. In the multivariate analysis, recipient age ≥40, a tacrolimus trough level ≥8 ng/mL 3 months after LDLT, and cholinesterase (ChE) <185 IU/L 3 months after LDLT were the independent risk factors for NODAT.. Poor graft synthetic function 3 months after LDLT as well as older age of the recipient and a higher tacrolimus concentration were strongly associated with NODAT development after LDLT.

Topics: Adolescent; Adult; Aged; Cholinesterases; Diabetes Mellitus; Female; Forecasting; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Young Adult

To clarify the incidence rate of post-transplant diabetes mellitus and associated risk factors in Japanese kidney transplant recipients, and to explore which treatment components are most effective in reducing post-transplant diabetes mellitus.. We analyzed 849 Japanese non-diabetic adult recipients who had undergone living kidney transplantation and had received tacrolimus-based immunosuppression from 1996 to 2013 with a median follow-up of 5 years.. In all, 127 patients developed post-transplant diabetes mellitus during the follow-up period. The incidence rate of post-transplant diabetes mellitus was 15.1% (95% confidence interval 12.7-17.5) at 5 years. Recipient age (hazard ratio 1.05, 95% confidence interval 1.05-1.06, P < 0.001 for every 5-year increase), obesity (hazard ratio 1.70, 95% confidence interval 1.06-2.73, P = 0.028), tacrolimus trough level at 2 weeks post-transplantation (hazard ratio 1.06, 95% confidence interval 1.03-1.09, P < 0.001 for a 1-ng/mL increase) and mycophenolate mofetil use (hazard ratio 0.46, 95% confidence interval 0.28-0.77, P = 0.003) were significant predictors of post-transplant diabetes mellitus. Estimated 5-year predicted incidence rate after adjusting for age and obesity was 9.4% for recipients with a low tacrolimus trough level, and receiving mycophenolate mofetil and 38.4% for recipients with a high tacrolimus trough level and not receiving mycophenolate mofetil.. Post-transplant diabetes mellitus is a common complication in Japan, similar to that in other Western countries. The present results show that an appropriate immunosuppressive regimen with a combination of tacrolimus and mycophenolate mofetil can reduce the likelihood of developing post-transplant diabetes mellitus. Clinical trials are required to confirm these findings.

Topics: Adult; Diabetes Mellitus; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus

New-onset diabetes after transplantation (NODAT) is a significant co-morbidity following kidney transplantation. Lower post-transplant serum magnesium levels have been found to be an independent risk factor for NODAT in adult kidney transplant recipients.. We undertook a retrospective analysis of risk factors for NODAT in pediatric renal transplant recipients at our institution with the aim of determining if hypomagnesemia confers a significant risk of developing NODAT in this patient population.. A total of 173 children with a median age at transplantation of 7.0 (range 1.3-17.5) years were included. Hypomagnesemia was found to be a significant independent risk factor for NODAT (p = 0.01). High trough tacrolimus levels were also independently associated with NODAT (p < 0.001). There was no significant association between NODAT and body mass index at the time of transplantation, monthly cumulative steroid dose or post-transplant cytomegalovirus viremia (p = 0.9, 0.6 and 0.7, respectively).. This study identifies hypomagnesemia as a significant independent risk factor for the development of NODAT in pediatric renal transplant recipients. Given the clear association between hypomagnesemia and NODAT in both adults and children following renal transplantation, further studies are merited to clarify the etiology of this association and to examine the effect of magnesium supplementation on NODAT.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Cytomegalovirus Infections; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Magnesium Deficiency; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Steroids; Tacrolimus; Transplant Recipients

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Cyclosporine; Diabetes Mellitus, Type 1; Dyslipidemias; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prevalence; Prospective Studies; Risk Factors; Severity of Illness Index; Spain; Survival Analysis; Tacrolimus; Transplant Recipients

Topics: Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents; Female; Humans; Ileostomy; Inflammation; Postoperative Complications; Silver Nitrate; Surgical Stomas; Tacrolimus

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

Topics: Antifungal Agents; Biomarkers; Cytochrome P-450 CYP3A; Drug Interactions; Female; Follow-Up Studies; Genotype; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Polymorphism, Single Nucleotide; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Triazoles; Voriconazole

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an extremely rare cause of hyponatremia post-liver transplantation. A 15-year-old Japanese girl with recurrent cholangitis after Kasai surgery for biliary atresia underwent successful living donor liver transplantation. Peritonitis due to gastrointestinal perforation occurred. Hyponatremia gradually developed but improved after hypertonic sodium treatment. One month later, severe hyponatremia rapidly recurred. We considered the hyponatremia's cause as SIADH. We suspected that tacrolimus was the disease's cause, so we used cyclosporine instead, plus hypertonic sodium plus water intake restriction, which improved the hyponatremia. Symptomatic hyponatremia manifested by SIADH is a rare, serious complication post-liver transplantation.

Topics: Adolescent; Cholangitis; Diagnosis, Differential; Female; Humans; Hyponatremia; Immunosuppressive Agents; Inappropriate ADH Syndrome; Liver Transplantation; Postoperative Complications; Tacrolimus; Vasopressins

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Drug Substitution; Etoposide; Humans; Ifosfamide; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Living Donors; Lymphoma, Extranodal NK-T-Cell; Methotrexate; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Remission Induction; Tacrolimus; Transplant Recipients

Topics: Adult; Aged; Carbamates; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Isoquinolines; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Pyrrolidines; Recurrence; Sampling Studies; Sulfonamides; Tacrolimus; Valine

Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet-after-kidney transplantation in patients with type 1 diabetes using an alemtuzumab-based induction regimen leads to considerable islet allograft function and improvement in glycemic control.

Topics: Alemtuzumab; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucose Tolerance Test; Glycemic Index; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney Function Tests; Kidney Transplantation; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Prognosis; Risk Factors; Tacrolimus

The aim of the study is to assess the relationship between the introduction of biologic and immunosuppressant therapy and the number of patients undergoing surgery for ulcerative colitis (UC).. A questionnaire survey about patients undergoing surgery for UC was sent to 26 teaching hospitals throughout Japan. The questionnaire period spanned from 2008 to 2013, to account for the introduction of tacrolimus (2009) and infliximab (2010).. The total number of patients who underwent surgery was 297, 291, 273, 255, 300, and 305 in 2008, 2009, 2010, 2011 2012, and 2013, respectively. The emergency surgery rate remained stable at 32-34 % each year. The proportion of patients who underwent surgery for cancer increased from 13.8 % in 2008 to 20 % in 2013. In 2013, 41, 38, and 6 % of patients who underwent surgery had received treatment with a biologic, tacrolimus, and cyclosporine, respectively. No institution reported an increase in postoperative complications among patients treated with immunosuppressive drugs.. The number of patients undergoing surgery decreased temporarily soon after infliximab and tacrolimus first became widely available, but subsequently increased again. The emergency surgery rate remained unchanged throughout the study period. These data show that immunosuppressive drugs have had little effect on the risk of postoperative complications.

Topics: Biological Factors; Colitis, Ulcerative; Cyclosporine; Digestive System Surgical Procedures; Hospitals, Teaching; Humans; Immunosuppressive Agents; Infliximab; Japan; Postoperative Complications; Risk; Surgery Department, Hospital; Surveys and Questionnaires; Tacrolimus; Time Factors

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Black or African American; Child; Child, Preschool; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Genome-Wide Association Study; Genotype; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Tissue Donors; Transplant Recipients; White People; Young Adult

PRES is a neuro-clinical and radiological syndrome that can result as a consequence of several different conditions including hypertension, fluid overload, and immunosuppressive treatment. Herein, we report two children who received kidney and combined liver-kidney transplantation as treatment for renal hypodysplasia associated with bilateral vesico-ureteral reflux and methylmalonic acidemia, respectively. Early after surgery (seven and 10 days), both patients presented with hypertension and seizures. The patients' immunosuppressive regimen included steroid and calcineurin inhibitors (tacrolimus and cyclosporine, respectively) and basiliximab and one with anti-IL2 receptor. In both cases, the imaging strongly supported the diagnosis of PRES. In details, the CT scan showed hypodensities in the posterior areas of the brain, and brain MRI demonstrated parieto-occipital alterations indicative of vasogenic edema. Treatment with calcineurin inhibitors was temporally discontinued and restarted at lower dosage; arterial hypertension was treated with Ca-channel blockers. Both children fully recovered without any neurological sequels. In conclusion, in children undergoing solid organ transplantation, who develop neurological symptoms PRES, should be carefully considered in the differential diagnosis and once the diagnosis is ruled in, we recommend strict arterial blood pressure control and adjustment or withholding of calcineurin inhibitor therapy should be considered based upon blood levels.

Topics: Amino Acid Metabolism, Inborn Errors; Antibodies, Monoclonal; Basiliximab; Child; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Magnetic Resonance Imaging; Male; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Receptors, Interleukin-2; Recombinant Fusion Proteins; Renal Insufficiency; Tacrolimus; Time Factors; Treatment Outcome; Vesico-Ureteral Reflux

The widespread use of immunosuppressive agents has significantly increased the rates of successful solid-organ and stem cell transplants, especially with liver and kidney. Cyclosporine and tacrolimus are most commonly used for this purpose. Although these agents have different mechanisms of action, both have various adverse effects, including nausea, vomiting, headache, hypertension, nephrotoxicity, and rarely epileptic seizures. In our first case, a patient presented with epileptic seizures and hemiparesis after a liver transplant, and posterior reversible encephalopathy syndrome related to cyclosporine toxicity was considered. Once cyclosporine levels in the blood decreased, the patient had both clinical and radiologic improvements. In our second case, a patient presented with delirium after a liver transplant. Again, when cyclosporine levels in the blood decreased, the patient showed improvement in clinical findings. Neurologic complications may develop after liver transplant, and these complications are encountered most frequently within the first postoperative month. Neurologic complications are multifactorial; insufficient graft function, intracranial bleeding, cerebral infarcts, infections, and immunosuppressive drug toxicity (tacrolimus and cyclosporine) may be considered among these factors. As shown in our presented cases, most neurologic complications can be successfully treated by correcting the underlying factor.

Topics: Cyclosporine; Epilepsy; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Muscle Weakness; Paresis; Postoperative Complications; Reflex, Babinski; Tacrolimus

Post-transplant diabetes mellitus (PTDM) is a common complication after solid organ transplantation, especially in recipients treated with calcineurin inhibitors. Previous studies suggest that chronic inflammation and chemokines play an important role in the pathogenesis of diabetes. Single-nucleotide polymorphisms (SNPs) can increase or decrease transcriptional activity and can change the production of chemokines. The aim of this study was to examine the association between CCL2 and CCL5 gene polymorphisms and the development of post-transplant diabetes mellitus. The study included 315 patients who received kidney transplants and were treated with calcineurin inhibitors. Patients were divided into two subgroups: with PTDM (n=43) and without PTDM (n=272). An additive model of univariate Cox regression analysis showed that the hazard of PTDM development was significantly positively associated with the number of CCL2 rs1024611 G alleles (HR 1.65; 95%CI 1.08-2.53; p=0.021). Multivariate Cox regression analysis, taking into the account the recipient's sex, age and BMI, as well as the number of G alleles of the CCL2 rs1024611 polymorphism, revealed that this polymorphism is an independent risk factor for post-transplant diabetes. The results of our study suggest an association between the CCL2 gene rs1024611 G allele and PTDM in patients treated with tacrolimus or cyclosporine.

Topics: Calcineurin Inhibitors; Chemokine CCL2; Chemokine CCL5; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Polymorphism, Single Nucleotide; Postoperative Complications; Tacrolimus

Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self-report of skin biopsy (n = 170). Controls without SCSC (n = 324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.23-5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR = 0.45, 95% CI 0.29-0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR = 0.52, 95% CI 0.32-0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus.

Topics: Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Skin Neoplasms; Tacrolimus; Washington

The calcineurin inhibitor (CNI) tacrolimus (Tac) is an effective immunosuppressant used after liver transplantation (LTx), but is often associated with CNI nephrotoxicity. Currently, there is no simple clinical predictor for CNI nephrotoxicity after LTx. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-LTx renal impairment.. We analyzed the relationship between the C/D ratio and post-transplant renal function in 179 patients who underwent LTx between 2000 and 2012 and were initially immunosuppressed with Tac, mycophenolate mofetil, and prednisolone. Six months after LTx, 115 patients were categorized into 1 of 2 groups based on their Tac C/D ratio (<1.09 or ≥1.09): fast (n=58) or slow (n=57) metabolizers. The renal function was determined 36 months after LTx using the estimated glomerular filtration rate (eGFR) as described by Cockcroft and Gault.. At the time of LTx there was no statistically significant difference between the eGFR of fast and slow metabolizers. Six months (P=0.016), 12 months (P=0.001), and 36 months (P=0.018) after LTx, fast Tac metabolizers had significantly more impaired renal function than slow metabolizers. Because of a presumption of CNI nephrotoxicity, 32.8% of fast metabolizers and 14.0% of slow metabolizers were switched from Tac to other immunosuppressants (P=0.027).. In this study, the Tac metabolism rate appears to influence renal function after LTx, suggesting that a C/D ratio of <1.09 is associated with increased CNI nephrotoxicity in LTx recipients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Inactivation, Metabolic; Liver Transplantation; Male; Middle Aged; Outcome Assessment, Health Care; Postoperative Complications; Renal Insufficiency; Retrospective Studies; Tacrolimus; Young Adult

Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy.. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, χ(2), and Fisher tests with the SPSS 18.0 statistical program.. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 ± 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75-41.16, P = .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45-416.17, P = .003) than those treated with tacrolimus.. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Cyclosporine; Female; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Young Adult

To determine risk factors for early neurologic complications (NCs) after liver transplantation from perspective of recipient, donor, and surgeon.. In all, 295 adult recipients were enrolled consecutively between August 2001 and February 2014 from a single medical center in Taiwan. Any NC in the first 30 d post-liver transplantation, and perioperative variables from multiple perspectives were collected and analyzed. The main outcome was a 30-d NC. Generalized additive models were used to detect the non-linear effect of continuous variables on outcome, and to determine cut-off values for categorizing risk. Risk factors were identified using multiple logistic regression analysis.. In all, 288 recipients were included, of whom 142 (49.3%) experienced at least one NC, with encephalopathy being the most common 106 (73%). NCs prolonged hospital stay (35.15 ± 43.80 d vs 20.88 ± 13.58 d, P < 0.001). Liver recipients' age < 29 or ≥ 60 years, body mass index < 21.6 or > 27.6 kg/m(2), Child-Pugh class C, history of preoperative hepatoencephalopathy or mental disorders, day 7 tacrolimus level > 8.9 ng/mL, and postoperative intra-abdominal infection were more likely associated with NCs. Novel risk factors for NCs were donor age < 22 or ≥ 40 years, male-to-male gender matching, graft-recipient weight ratio 0.9%-1.9%, and sequence of transplantation between 31 and 174.. NCs post- liver transplantation occurs because of factors related to recipient, donor, and surgeon. Our results provide a basis of risk stratification for surgeon to minimize neurotoxic factors during transplantation.

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Body Mass Index; Brain Diseases; Case-Control Studies; Consciousness Disorders; Delirium; Female; Graft Rejection; Hepatic Encephalopathy; Humans; Immunosuppressive Agents; Intraabdominal Infections; Length of Stay; Liver Transplantation; Male; Mental Disorders; Middle Aged; Mycophenolic Acid; Myelinolysis, Central Pontine; Neurotoxicity Syndromes; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Preoperative Period; Psychotic Disorders; Risk Assessment; Risk Factors; Seizures; Sex Factors; Stroke; Tacrolimus; Taiwan; Tissue Donors

HUS is a well-known entity primarily associated with bacterial infection and is characterized by a classic triad of anemia, thrombocytopenia, and kidney injury. Its atypical form has been associated with calcineurin inhibitors and has been extensively discussed in renal transplantation. We present a case of tacrolimus-associated HUS in a pediatric heart transplant recipient, which we believe to be previously unreported in the literature.

Topics: Child, Preschool; Female; Heart Transplantation; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Postoperative Complications; Tacrolimus

Cardiovascular diseases are among the most frequent causes of patient death after liver transplantation. The aim of this retrospective clinical study was to estimate the prevalence of arterial hypertension among patients after successful liver transplantation and the role of immunosuppressive drugs in the pathogenesis of hypertension in these patients.. A total of 88 patients (age 47 .5 ±  12.1 years; 33 women and 55 men) who had undergone successful liver transplantation and completed 24 months follow-up were studied. The results are presented as means with standard deviations.. At 1, 12, and 24 months after liver transplantation, the prevalences of hypertension were 44.3%, 54.5%, and 62.5%, respectively. Systolic and diastolic blood pressure in these months were 124.1 ± 14.8, 132.8 ± 19.1, and 135.2 ± 17.3 mm Hg and 83.3 ± 12.0, 87.3 ± 11.1, and 87.9 ± 11.1 mm Hg, respectively. The estimated glomerular filtration rates were 77.8 ± 32.3, 80.3 ± 30.8, and 78.8 ± 29.1 mL/min/1.73 m(2), respectively. Arterial hypertension was significantly more frequent in patients treated with cyclosporine A than in those treated with tacrolimus (P = .004) or everolimus (P = .005). In patients treated with tacrolimus, a positive correlation was found between tacrolimus blood concentration and systolic blood pressure (R = 0.34; P = .01) and a negative correlation was found between estimated glomerular filtration rate and systolic blood pressure (R = -0.28; P = .02).. Based on study findings, the following conclusions were drawn: arterial hypertension occurs in more than 50% of patients after liver transplantation (significantly higher frequency than in the general population); calcineurin inhibitors may participate in the pathogenesis of arterial hypertension in patients after successful liver transplantation; and the clinical importance of these findings and the influence on cardiovascular outcome of the liver transplant recipients need further investigation.

Topics: Adult; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; End Stage Liver Disease; Everolimus; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Blood Specimen Collection; Emergency Service, Hospital; Humans; Immunosuppressive Agents; Postoperative Complications; Tacrolimus; Time Factors; Transplant Recipients

Hepatitis C virus (HCV) still has significant prevalence in kidney transplant (KT) recipients and is related to poor recipient and graft survival. New direct-acting antivirals (DAA) are leading to a radical change in the problem.. We studied HCV prevalence at the time of transplantation and in follow-up patients, the way cases are handled, and the results of DAA.. A total of 2,001 KT had been performed in our center since 1978. Pre- or post-transplantation HCV serology was present in 1,880 cases and was positive in 13.4%. A total of 1,195 transplant recipients were still being monitored by us, with only 60 (5%) HCV+ and 45 (3.6%) RNA+ cases. Of these 45 HCV+/RNA+, 25 had been or were being treated, 7 were about to begin treatment, 1 was awaiting new DAA treatment owing to low glomerular filtration rate (GFR), 3 were being evaluated, 2 had been excluded owing to high comorbidity, 2 refused to be treated, 2 needed to return to hemodialysis, and 1 was lost to follow-up. Except 1 case where Viekira Pak was used because of low GFR, all cases included sofosbuvir as the main drug associated with either ledipasvir (70%) or daclatasvir (25%). Ribavirin was added as coadjuvant in 35% of cases. Twenty-one patients had completed treatment (84%). Two patients had to interrupt DAA therapy (8%), one because of hepatotoxicity and the other as a result of a liver transplantation. In every case, the graft maintained function and negativization of viral replication occurred.. Side effects have been low, anemia related to ribavirin being the main one. Just one case needed to be interrupted at the 7th week of DAA therapy due to hepatotoxicity. It has frequently been necessary to adjust immunosuppression treatment with the use of higher doses of tacrolimus.

Topics: Adult; Antiviral Agents; Female; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Ribavirin; Sofosbuvir; Tacrolimus

Renal transplantation has been established as the treatment of choice for end-stage renal disease (ESRD) due to diabetic nephropathy. This study aimed to investigate the risk factors for recurrence of diabetic nephropathy (RDN) in renal allografts.. We studied 1,011 renal transplant patients from 1986 to 2003, of which 95 had ESRD due to diabetic nephropathy. We retrospectively analyzed the clinical characteristics and outcomes of RDN after renal transplantation.. Of the 95 recipients with ESRD due to diabetic nephropathy, 41 developed RDN and 11 of those 41 underwent graft biopsy. The mean durations from transplantation to RDN and to renal replacement therapy was 81.58 months (range, 54-120 mo), and 109.66 months (range, 27-188.4 mo), respectively. At 5 years, treatment on statins and renin-angiotensin-aldosterone system (RAAS) blockers were associated with a higher survival free from RND (82.2% vs 63.2% [P = .070] and 100% vs 80% vs 0.6% [P = .013], respectively). Compared with cyclosporine, tacrolimus was associated with a higher risk for RND (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.75-5.13; P = .047). High doses of prednisone (>0.06 mg/kg) were also associated with a higher risk of RDN (OR, 3.03; 95% CI, 1.19-8.30; P = .029). The combination of calcineurin inhibitor and mammalian target of rapamycin inhibitor (mTORi) demonstrated the highest risk of RDN (OR, 14.08; 95% CI, 3.72-53.29; P < .01).. Treatment with tacrolimus and mTORi is the most diabetogenic immunosuppressive regimen. Treatment with tacrolimus entails a greater risk of RDN than with cyclosporine. The administration of statins or RAAS blockers could delay the progression of RDN.

Topics: Adult; Anti-Inflammatory Agents; Biopsy; Cyclosporine; Diabetic Nephropathies; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Recurrence; Retrospective Studies; Risk Factors; Tacrolimus

BACKGROUND Thrombotic microangiopathy (TMA) is a severe life-threatening complication associated with solid organ transplantation. We retrospectively investigated the incidence, risk factors, and appropriate treatment of TMA following adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The subjects were 129 adult patients who underwent LDLT in our department from 1997 to 2014. Patients with TMA were identified retrospectively based on diagnostic criteria. We calculated the incidence of TMA and performed a risk factor analysis for TMA occurrence. We also assessed our past treatments for TMA and sought to identify the most appropriate form of treatment. RESULTS Thirteen patients were identified as having TMA. The incidence of TMA in the study cohort was 10.1% but was especially high (37.9%) among ABO-incompatible cases. A univariate analysis revealed that ABO incompatibility, usage of tacrolimus, usage of rituximab, and cold ischemic time ≥50 minutes are risk factors for occurrence of TMA (p<0.10). Multivariate analysis demonstrated that ABO incompatibility was the only independent risk factor for TMA (p=0.009). Initiation of treatment on the day of TMA diagnosis was associated with better survival. CONCLUSIONS ABO incompatibility is an independent risk factor for TMA following adult LDLT. Our results suggest that early initiation of treatment is crucial for improving the outcomes.

Topics: ABO Blood-Group System; Adult; Aged; Blood Group Incompatibility; Female; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Rituximab; Tacrolimus; Thrombotic Microangiopathies; Young Adult

Thrombotic microangiopathy (TMA) is a rare complication associated with the use of calcineurin inhibitors in lung transplantation, irrespective of the underlying disease of the graft recipient. It usually occurs in incomplete forms, complicating and delaying diagnosis until damage is already irreversible. It is unrelated to time from transplantation and often presents with concomitant infection, which tends to confound diagnosis. The cases discussed here have a common causative agent and all present with concomitant infection. Treatment recommendations have changed in recent years with the introduction of plasmapheresis or, more recently, the availability of the antibody eculizumab. Notwithstanding, the most cost-effective measure is withdrawal or switching of the calcineurin inhibitor. TMA is an underdiagnosed clinical entity that should be considered in the management of transplantation patients.

Topics: Abscess; Candida glabrata; Candidiasis; Creatinine; Disease Susceptibility; Drug Substitution; Erythrocytes, Abnormal; Everolimus; Female; Hemoglobins; Humans; Immunosuppressive Agents; L-Lactate Dehydrogenase; Lung Transplantation; Male; Middle Aged; Myositis; Nocardia Infections; Platelet Transfusion; Pneumonia; Postoperative Complications; Tacrolimus; Thrombotic Microangiopathies; Young Adult

Immunosuppressive therapy after kidney transplant is necessary to prevent allograft rejection and it is the cause of several gastrointestinal (GI) disorders that have been scantily studied.. This study was aimed at investigating the influence of triple immunosuppressive therapy on GI transit in renal transplant patients by employing a biomagnetic technique.. Twenty-one renal transplant patients underwent triple therapy, which included either tacrolimus (TAC) or cyclosporin A (CsA) associated with prednisone and azathioprine. They were all evaluated, and fifteen other healthy individuals formed the control group. After a standardized meal, GI transit of magnetic markers was assessed using Alternating Current Biosusceptometry (ACB).. Patients taking TAC had significantly accelerated gastric emptying and colonic arrival (p ≤ 0.001) when compared with those taking CsA and those in the control group. However, no differences were observed in small bowel transit among the groups studied. Overall, the inter-subject coefficients of variation for gastrointestinal transit parameters were higher for the TAC group and similar for the CsA and control groups.. This study demonstrated that ACB is a suitable methodology when evaluating the influence of different immunosuppressive therapies on gastrointestinal transit after renal transplantation. Pronounced inter-individual variation was found in patients treated with tacrolimus, thus showing the prokinetic effect of this drug on GI motility. Studies of motility patterns in this population could be useful as complementary information toward determining the mechanisms and the relationship between motility and therapeutic doses.

Topics: Adult; Cyclosporine; Drug Therapy, Combination; Female; Gastric Emptying; Gastrointestinal Transit; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Magnetics; Male; Middle Aged; Monitoring, Ambulatory; Pilot Projects; Postoperative Complications; Tacrolimus

The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs, which are typically employed in the field of organ transplantation. Both drugs have narrow therapeutic indices, highly variable pharmacokinetics, and are associated with severe adverse effects. In current clinical routine, the dose finding of CNIs is based on the measurement of their blood concentrations. However, this method is limited in its ability to determine the biological impact of the drug. Alternative monitoring strategies, focusing on the pharmacodynamics of CNIs, could help to personalize drug dosing and optimize the treatment with CNIs. Therefore, we analyzed the relationship between pharmacokinetic and pharmacodynamic of the CNIs CsA (n = 9) and Tac (n = 8) in stable renal transplant patients during a 12-h dosing period. We observed a significant decrease in the drug-blood concentration during the course of the day and in parallel a significant recovery of T cell function. In addition, our data document that analysis of intracellular interleukin (IL)-2 production and determination of the IL-2 release are accurate parameters for monitoring the pharmacodynamics of CNIs.

Topics: Calcineurin Inhibitors; Cyclosporine; Drug Monitoring; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Tissue Distribution

Obesity has been a relative contraindication for renal transplantation. This study evaluates the impact of pretransplant body mass index (BMI) on renal transplant outcomes in a single institution in the era of modern immunosuppression.. A 10-y retrospective analysis was undertaken of 454 consecutive patients who received a renal transplant at Westmead Hospital from January 1, 2001 to December 31, 2010. The role of pretransplant BMI on patient survival, graft survival, surgical complications, and postoperative complications was studied.. The mean age of transplant of this study population was 45.4 ± 13.0 y. Live donation rate was 53.5%, and 60.6% were male. The median preoperative BMI was 25.6 (range, 14.3-51.4). One-year and 5-y patient survival were 97.4% and 86.6%, respectively, whereas 1-y and 5-y death-censored graft survival were 97.1% and 91.9%, respectively. Patients with BMI >30 did not exhibit any significant difference in survival or graft failure but had higher surgical wound infection rates (hazard ratio 3.95, P < 0.01). Patients with preoperative BMI <18.5 were associated with a six-fold increase in both death and death-censored graft failure (P < 0.01).. Pretransplant obesity increases wound infection but is not a contraindication to renal transplantation. Future prospective studies are required to further define the impact of low preoperative BMI <18.5.

Topics: Adult; Body Mass Index; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; New South Wales; Obesity; Postoperative Complications; Retrospective Studies; Tacrolimus

New Onset Diabetes after Transplantation (NODAT) is defined as sustained hyperglycemia developing in patients without diabetes history before transplantation. A cohort study was performed to access the effects of tacrolimus on insulin secretion and insulin sensitivity and consequently in the development of NODAT in kidney transplant recipients. Then, we further investigated the association between NODAT and single-nucleotide polymorphisms of IRS-1 and IRS-2 in renal allograft recipients. One hundred and fifty-eight kidney transplant patients, receiving tacrolimus as the base immunosuppressant, were divided into two groups: with or without NODAT. Plasma levels of fasting insulin concentration (FINS) and C-peptide were determined by enhanced chemiluminescence immunoassay and ADVIA Centaur C peptide assay, respectively. The genotypes of Gly1057Asp in IRS-2 and Gly972Arg in IRS-1 were detected through polymerase chain reaction fragment length polymorphism in NODAT and non-NODAT patients. It was found that the concentrations of fasting plasma insulin and C-peptide in NODAT and non-NODAT patients treated with tacrolimus were higher than that in healthy volunteers (p < 0.05). Fasting plasma insulin concentration in NODAT was significantly elevated compared with than that in non-NODAT group (p < 0.05). But there are no statistical differences in fasting plasma C-peptide concentrations between NODAT and non-NODAT groups. The allele and genotype frequencies of IRS-2 Gly1057Asp and IRS-1 Gly972Arg in NODAT patients were not significantly different from non-NODAT patients (p > 0.05). In conclusion, insulin resistance is the primary cause of tacrolimus-induced NODAT. The IRS-2 Gly1057Asp and IRS-1 Gly972Arg genotypes are not related to NODAT.

Topics: Adult; Cohort Studies; Diabetes Mellitus; Fasting; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Kidney Transplantation; Male; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Colostomy; Dermatitis; Diagnosis, Differential; Humans; Male; Postoperative Complications; Prednisone; Pyoderma Gangrenosum; Skin Neoplasms; Skin Ulcer; Surgical Stomas; Tacrolimus

Atypical hemolytic uremic syndrome (aHUS) is a serious hematologic disorder with high mortality if left untreated. A comprehensive literature review revealed only two cases of aHUS post-heart transplantation. In both cases the disease developed after induction of calcineurin inhibitor therapy. We report a case of immediate post-heart transplantation aHUS, manifested before the induction of, and therefore not associated with, calcineurin inhibitors.

Topics: Aged; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Biomarkers; Calcineurin Inhibitors; Creatinine; Dialysis; Early Diagnosis; Female; Haptoglobins; Heart Transplantation; Humans; L-Lactate Dehydrogenase; Plasma Exchange; Platelet Count; Postoperative Complications; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Postoperative Complications; Tacrolimus; Thrombotic Microangiopathies

BK virus infection accompanied with plasma cell-rich infiltrates is a dilemma in renal transplant recipients. One young female patient diagnosed as BK virus-associated nephropathy with plasma cell-rich infiltrates at 16 months after renal transplant was treated with bortezomib and a sequential immuno-suppressive protocol of tacrolimus combined with leflunomide. After a short period of reduction, her serum creatinine increased slowly with stable BK viruria. The patient underwent repeat biopsy. The histologic changes showed a decrease in plasma cells and CD20+ cells in the allograft, but the other mononuclear cells showed no difference from the first biopsy. The immunosuppressive protocol was converted to tacrolimus combined with enteric-coated mycophenolate sodium. Her serum creatinine decreased gradually during 6 months of follow-up. We speculate that bortezomib can be used in BK virus-associated nephropathy accompanied with plasma cell-rich infiltrates, and this effect might be mediated through a decrease of plasma cells and CD20+ cells in the allograft. The dosage and time of therapy need to be explored in the future; additional studies of large samples are needed.

Topics: Adult; Antineoplastic Agents; BK Virus; Bortezomib; Female; Humans; Isoxazoles; Kidney Diseases; Kidney Transplantation; Leflunomide; Plasma Cells; Polyomavirus Infections; Postoperative Complications; Tacrolimus; Tumor Virus Infections

Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low-dose SRL combined with a CNI could still prevent cancer in renal transplant recipients.. A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271).. The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 ± 37.5 months and 81.7 ± 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation.. De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients.

Topics: Adult; Calcineurin Inhibitors; Case-Control Studies; Cyclosporine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Neoplasms; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate; Tacrolimus; Taiwan; Treatment Outcome

Nodular lymphoid hyperplasia (NLH) of the gastrointestinal tract is a rare disease usually reported in patients with congenital or acquired immunodeficiency and chronic gastrointestinal infections. However, no case of NLH in a patient receiving immunosuppressive therapy has been reported to date. We describe the case of a woman who developed chronic diarrhea related to NLH 9 years after liver transplantation. Other causes of diarrhea and NLH were excluded. Her immunosuppressive regimen consisted on mycophenolate mofetil (MMF) and tacrolimus. Reduction of MMF dose improved symptoms but led to a rising aminotransferase level. Given the risk of graft rejection, MMF at full dose was resumed and she was started on symptomatic treatment for diarrhea. The role of immunosuppressive drugs in the pathogenesis of NLH may be related to the reduction of T- and B-lymphocyte proliferation and decreasing antibody production. NLH will further develop to compensate functionally inadequate lymphoid tissue, as reported in congenital immunodeficiency states.

Topics: Diarrhea; Duodenum; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Hyperplasia; Immunosuppressive Agents; Intestinal Mucosa; Liver Transplantation; Lymph Nodes; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus

Topics: Delayed Diagnosis; Herpesvirus 8, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus; Thorax

Generic immunosuppressants may offer economic advantages, but their use is still controversial. At our center, 55 heart transplant patients were switched from CellCept(®) to Myfenax Teva(®) (MT) (n = 51, 18% female, 8.1 ± 6.6 yr post-transplantation) and/or Prograf(®) to Tacrolimus Sandoz(®) (TS) (n = 17, 41% female, 6.6 ± 5.8 yr post-transplantation).. We conducted an acute monitoring and a retrospective follow-up with regard to safety and efficacy. Acute cellular rejections (ACRs) on endomyocardial biopsies (EMBs) four wk after the MT switch were specifically compared to a matched retrospective control group.. Tacrolimus C0 levels (TS switch) as well as hemoglobin, leukocytes, and thrombocytes (MT switch) did not change (p = NS) during the three wk after each respective switch (8.7 ± 2.9 vs. 8.4 ± 1.9 μg/L, 129.1 ± 12.6 vs. 130.1 ± 12.8 g/L, 6.3 vs. 6.2 × 10(9) /L, and 217.4 ± 56.6 vs. 219.3 ± 61.8 × 10(9) /L, respectively). 0% of the EMBs in the MT switch vs. 3% of the EMBs in the control group showed ACR>grade 1R (p = NS). After six months, survival was 96% (MT switch) and 100% (TS switch), and the frequency of severe ACR was low. Safety parameters measured at the next annual follow-up were also stable following each switch.. Switching to MT and/or TS several years after heart transplantation appeared safe in the short-term perspective, showing no detectable changes in tacrolimus C0 levels, safety or efficacy, during an average follow-up of six months.

Topics: Adolescent; Adult; Aged; Child; Drugs, Generic; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Safety Management; Survival Rate; Tacrolimus; Young Adult

There is no literature on the use of belatacept for sensitized patients or regrafts in kidney transplantation. We present our initial experience in high immunologic risk kidney transplant recipients who were converted from tacrolimus to belatacept for presumed acute calcineurin inhibitor (CNI) toxicity and/or interstitial fibrosis/tubular atrophy. Six (mean age = 40 years) patients were switched from tacrolimus to belatacept at a median of 4 months posttransplant. Renal function improved significantly from a peak mean estimated glomerular filtration rate (eGFR) of 23.8 ± 12.9 mL/min/1.73 m(2) prior to the switch to an eGFR of 42 ± 12.5 mL/min/1.73 m(2) (p = 0.03) at a mean follow-up of 16.5 months postconversion. No new rejection episodes were diagnosed despite a prior history of rejection in 2/6 (33%) patients. Surveillance biopsies performed in 5/6 patients did not show subclinical rejection. No development of donor-specific antibodies (DSA) was noted. In this preliminary investigation, we report improved kidney function without a concurrent increase in risk of rejection and DSA in six sensitized patients converted from tacrolimus to belatacept. Improvement in renal function was noted even in patients with chronic allograft fibrosis without evidence of acute CNI toxicity. Further studies with protocol biopsies are needed to ensure safety and wider applicability of this approach.

Topics: Abatacept; Adult; Aged; Allografts; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Post-transplant diabetes mellitus (PTDM) is a common metabolic complication after organ transplantation and may be associated with the use of calcineurin inhibitors (tacrolimus and cyclosporine). Leptin and adiponectin are adipokines and play an important role in the regulation of insulin secretion as well as glucose and lipid metabolism.. The aim of this study was to examine the association between adiponectin and leptin gene polymorphisms and development of PTDM.. The study included 323 patients who received kidney transplants and were treated with calcineurin inhibitors (tacrolimus or cyclosporine).. The association between adiponectin and leptin gene polymorphisms and PTDM was studied in three models of Cox regression analysis--additive, dominant and recessive. In these three models, the LEP rs2167270 gene polymorphism was statistically significantly associated with increased risk of PTDM. The association between the LEP rs2167270 polymorphism and PTDM was confirmed by multivariate regression analysis.. The results of our study suggest an association between the leptin rs2167270 gene A allele and PTDM. Original submitted 27 February 2015; Revision submitted 22 May 2015.

Topics: Adiponectin; Adult; Alleles; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leptin; Male; Middle Aged; Polymorphism, Genetic; Postoperative Complications; Risk; Tacrolimus

ABO-incompatible (ABOi) kidney transplantation (KTx) has become an accepted therapeutic option in renal replacement therapy for patients without a blood group-compatible living donor. Using different desensitization strategies, most centers apply B-cell depletion with rituximab and maintenance immunosuppression (IS) with tacrolimus and mycophenolic acid. This high load of total IS leads to an increased rate of surgical complications and virus infections in ABOi patients. Our aim was to establish ABOi KTx using an immunosuppressive regimen, which is effective in preventing acute rejection without increasing the risk for viral infections. Therefore, we selected a de novo immunosuppressive protocol with low-dose calcineurin inhibitor and the mTOR inhibitor everolimus for our ABOi program. Here, we report the first 25 patients with a complete three-yr follow-up treated with this regimen. Three-yr patient survival and graft survival were 96% and 83%. The rate of acute T-cell-mediated rejections was low (12%). Cytomegalovirus (CMV) infection was evident in one patient only (4%). Surgical complications were common (40%), but mild in 80% of cases. We demonstrate that ABOi KTx with a de novo mTOR inhibitor-based regimen is feasible without severe surgical or immunological complications and a low rate of viral infections.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular atrophy, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to everolimus.

Topics: Allografts; Amyloidosis; Diagnosis, Differential; Everolimus; Female; Humans; Immunoglobulin G; Immunoglobulin lambda-Chains; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Middle Aged; Paraproteinemias; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Proteinuria; Tacrolimus; TOR Serine-Threonine Kinases

Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy.

Topics: Alveolitis, Extrinsic Allergic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Cyclophosphamide; Cytarabine; Etoposide; Heart Transplantation; Humans; Hydrocortisone; Immunoblastic Lymphadenopathy; Immunocompromised Host; Immunophenotyping; Immunosuppressive Agents; Kartagener Syndrome; Lymphoma, T-Cell; Methotrexate; Mycophenolic Acid; Oculomotor Nerve Diseases; Postoperative Complications; Prednisone; Remission Induction; T-Lymphocyte Subsets; Tacrolimus; Vincristine

Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty-four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX-R/EX-D (n = 21), EX-R/NEX-D (n = 8), NEX-R/EX-D (n = 8) and NEX-R/NEX-D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX-R/EX-D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX-R/EX-D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under- and over-immunosuppression.

Topics: Bacterial Infections; Child, Preschool; China; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Male; Pharmacogenetics; Postoperative Complications; Regression Analysis; Risk Factors; Tacrolimus; Treatment Outcome; Virus Diseases

To evaluate the efficacy and safety of salvage therapy, and to identify risk factors of operative complications among hospitalized ulcerative colitis (UC) patients.. We evaluated 88 UC patients hospitalized at our center between April 2010 and November 2012. We compared characteristics of corticosteroid-refractory patients treated with calcineurin inhibitor and those with infliximab as second-line therapy. Furthermore, we compared the characteristics of operative and nonoperative patients. The association between perioperative treatments and complications was also investigated.. Calcineurin inhibitor and infliximab were used in 42 and 22 patients, respectively. We found no difference in the clinical background between them. Efficacy rates were 67 and 50%, respectively. Eight out of 10 nonresponders of each treatment were treated with the other drug as third-line therapy. The efficacy rates of calcineurin inhibitor and infliximab as the third-line therapy were 75 and 50%, respectively. Operative patients had more severe disease (87.5 vs. 31%, p < 0.01), higher Lichtiger score (14.1 vs. 11.5, p < 0.01), higher Rachmilewitz endoscopic index (10.5 vs. 8.4, p < 0.01), higher C-reactive protein (7.6 vs. 4.0, p = 0.015) and lower serum albumin (3.1 vs. 3.6, p = 0.014) than nonoperative patients. Complications were observed in 7 out of 16 (44 %) operative patients. Postoperative complications were not increased even when patients were treated with second- or third-line therapy. However, the complication rate in corticosteroid users was 54.5 (6/11) and 20% (1/5) in nonusers.. Third-line salvage therapy is effective and tolerable in carefully selected UC patients. Perioperative use of corticosteroids may lead to more adverse outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Calcineurin Inhibitors; Colitis, Ulcerative; Cyclosporins; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Salvage Therapy; Tacrolimus; Treatment Outcome; Young Adult

Racial differences among kidney transplant recipients may impact the total daily tacrolimus dose required to achieve therapeutic tacrolimus concentrations. Previous studies suggest that African Americans require higher doses to achieve similar therapeutic drug concentrations compared with Caucasians. Data were collected on a total of 147 de novo kidney transplant recipients. Tacrolimus total daily dose (TDD) requirements (mg/kg/d) and tacrolimus concentrations were retrospectively reviewed at discharge and at days 30, 60, and 90 after transplant. TDD requirements in African-American and Caucasian patients were 0.14 mg/kg/d and 0.11 mg/kg/d, respectively (p = 0.005), at day 30. TDD requirements at day of hospital discharge and days 60 and 90 following transplant were significantly higher in African-American patients vs. Caucasian patients, with similar tacrolimus concentrations at all time points. This study suggests that when compared to Caucasians, African Americans require significantly higher TDD of tacrolimus to achieve similar tacrolimus concentrations. These findings provide transplant clinicians with a sense of certainty to more rapidly titrate daily tacrolimus doses in African-American patients to achieve therapeutic concentrations.

Topics: Anti-Inflammatory Agents; Black or African American; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Transplant Recipients; White People

Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (≥60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL.

Topics: Adult; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus

We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.

Topics: Abatacept; Adolescent; Anemia, Hemolytic; B7-1 Antigen; B7-2 Antigen; Calcineurin; CTLA-4 Antigen; Graft Rejection; Hemolysis; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Plasmapheresis; Postoperative Complications; Recurrence; Tacrolimus; Treatment Outcome

Recurrence of cytomegalovirus (CMV) infection following solid organ transplantation causes mortality and morbidity in allograft recipients. The aim of this study was to evaluate prevalence and risk factors of recurrent CMV infection in kidney transplant patients.. Four hundred and twenty-seven consecutive kidney transplant recipients were included in this retrospective cohort study. Both donors and recipients were CMV seropositive. Recurrent CMV infection (symptomatic or asymptomatic) was defined as detection of CMV infection in a patient who has had previously documented infection and who had not have virus detected for an interval of at least 4 weeks during active surveillance.. Of 427 recipients, 71 (16.6%) had CMV infection, of which 19 (4.4%) were recurrent infection. Donor source, dialysis duration before transplantation, recipient and donor age and sex, and administration of antithymocyte globulin and prophylactic treatment ganciclovir were not associated with CMV infection or recurrence. The use of tacrolimus in the immunosuppressive regimen as compared to cyclosporine was an independent risk factor for CMV infection but not recurrent infection.. Intensive immunosuppressive regimen, such as using tacrolimus, might be associated with a higher risk for CMV infection, but this study was not able to document the same association for recurrent CMV disease. In patients receiving immunosuppressive regimens that include tacrolimus and antithymocyte globulin, prophylactic treatment for CMV disease with ganciclovir is recommended.

Topics: Adolescent; Adult; Aged; Antilymphocyte Serum; Antiviral Agents; Cytomegalovirus Infections; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Retrospective Studies; Risk Factors; Secondary Prevention; Tacrolimus; Young Adult

Concomitant administration of the triazole antifungals, voriconazole or itraconazole, with tacrolimus can result in significant drug interaction in the transplant recipient. Limited published information exists regarding tacrolimus dosing when transitioning from voriconazole to itraconazole. The objective of this study was to evaluate the extent of the drug interaction with antifungal prophylaxis using voriconazole followed by a change to itraconazole in lung transplant recipients receiving tacrolimus.. This prospective study included lung transplant recipients receiving antifungal prophylaxis with voriconazole followed by a switch to itraconazole. Patients were followed from the time of transplant until two months after converting to itraconazole. All patients received standard immunosuppression with tacrolimus, mycophenolate mofetil, and a corticosteroid. Tacrolimus dose normalized concentrations using concentration/dose ratio were compared while receiving voriconazole versus itraconazole.. Twenty lung transplant recipients were included in the final analysis. No difference was found with the tacrolimus dose normalized concentrations on voriconazole 254 ± 28 (ng/mL)/(mg/kg) compared with itraconazole 234 ± 34 (ng/mL)/(mg/kg), p = 0.65.. Tacrolimus dosage adjustments were not necessary when converting from voriconazole to itraconazole. Validation in a larger population is needed to confirm these findings.

Topics: Adult; Aged; Antibiotic Prophylaxis; Antifungal Agents; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Itraconazole; Lung Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Prognosis; Prospective Studies; Tacrolimus; Voriconazole

To summarize the clinical characteristics, early diagnosis, comprehensive treatment and prognosis of 6 cases of children with post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation.. Data of 6 cases with PTLD seen between January 2011 and December 2013 were retrospectively analyzed. The anti-rejection drug dose adjustments, the effect of rituximab, antiviral therapy and comprehensive treatment program after surgery were explored.. (1) The diagnosis of PTLD was confirmed by histologic findings. Six cases of PTLD including 3 males and 3 females were diagnosed as congenital biliary atresia and underwent split liver transplantation. The occurrence rate of PTLD was 2.9%. (2) The median time to the development of PTLD was less than 6 months. The initial symptom of PTLD in all patients was fever and clinical manifestations of PTLD were non-specific, depending on the involving organs. Five cases of PTLD developed gastrointestinal symptoms, including diarrhea, abdominal pain, and abdominal distension. One case developed respiratory symptoms, including cough and tachypnea. Three cases had lymph node involvement. In 2 cases pathophysiology involved polymorphic lymphocyte proliferation and in 4 cases B lymphocyte proliferation. (3) Two cases died, in whom EBV DNA was not detected and were diagnosed as PTLD by surgical pathology before death. Four survived cases had high EBV-DNA load and then were diagnosed as PTLD by biopsy pathology. (4) Of the 6 cases of PTLD, 2 cases died and 4 cases survived. The overall mortality was 33%. The dead cases were only treated with laparotomy because of intestinal obstruction or perforation and the survived cases were treated with tacrolimus at reduced doses or discontinuation and rituximab. In 2 cases antiviral therapy (acyclovir) was continued, including 1 cases of intestinal obstruction treated with surgical repair. All the survived patients were followed up for 4 months to 1 year and no evidence has been found.. EBV infection is the high risk factor for PTLD after liver transplantation. Close clinical surveillance of EBV DNA for pediatric liver transplantation was important for the early diagnosis of PTLD. Reducing doses of immunosuppressive agents and rituximab is the initial therapy for PTLD. A reduction in the dose of tacrolimus is suggested. Operation therapy can also play a role in the management of local complications.

Topics: Antiviral Agents; Biliary Atresia; DNA, Viral; Drug Therapy, Combination; Early Diagnosis; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Pediatrics; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus

The study was conducted to assess serious infectious complications in five hand allograft recipients (four males, one female, age 40 ± 10 years), transplanted between 2006 and 2010. All donors and recipients were positive but one for cytomegalovirus (CMV) immunoglobulin G. All recipients received immunosuppressive therapy basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone. Until May 2013, there were four cases of severe infections requiring hospitalization. One patient developed CMV infection on the 28th postoperative day. Despite therapy with ganciclovir and prophylaxis with valganciclovir, reinfection episodes occurred both 4 weeks and 7 months later. The female recipient developed CMV infection 8 months after hand transplantation. After 3 weeks of ganciclovir treatment, the polymerase chain reaction results remained negative. We found that the CD4/CD8 T lymphocytes ratio differs in those two patients who had developed CMV disease in the past in comparison to the three remaining hand transplant recipients (mean 0.46 versus 1.7, respectively). Moreover, the ratio of patients who were CD4-8 negative to total T lymphocytes in CMV recovered patients was two-fold higher compared to the remaining recipients (10.0 versus 4.4, respectively). The female recipient was also hospitalized because of acute tonsillitis 25 months after hand transplantation, and successfully treated with amoxicillin clavulanate. The third recipient was hospitalized because of severe acute pain involving right lower limb, especially foot, 74 months after hand transplantation. After 48 hours, a painful vesicular rash occurred on the plantar as well as dorsal surface of right foot and herpes zoster was diagnosed. Immunosuppressive therapy after hand transplantation may be complicated by serious infections. CMV disease was associated with persistent alterations in T lymphocyte subsets.

Topics: Adult; Allografts; Antiviral Agents; Cytomegalovirus Infections; Female; Hand Transplantation; Humans; Immunosuppression Therapy; Male; Middle Aged; Poland; Postoperative Complications; Retrospective Studies; T-Lymphocyte Subsets; Tacrolimus; Transplantation, Homologous; Vascularized Composite Allotransplantation

Liver transplantation (LT) in adult patients is associated with a higher incidence of cardiovascular risk factors (CVRF), chronic kidney disease (CKD), and cardiovascular disease mortality than the general population. Available information about these problems in adult patients with LT from a pediatric age is limited. The aim of this study was to analyze the incidence of CVRF, risk of developing CKD, and risk of 10-year coronary event in adult patients who received LT in childhood.. Thirty adult patients (11 female, 19 male; mean age, 29.3 years) who underwent LT in childhood were analyzed, and CVRF, estimated glomerular filtration rate, and current immunosuppressive regimen were recordered. The risk of 10-year coronary event was calculated with the use of validated equations (Framingham and Regicor) and compared with the estimated risk in the general population.. None of the patients had CVRF before LT, except 1 patient who received a transplant because of familial hypercholesterolemia. Median age of patients at the time of study was 28.6 years (range, 19.3-43.1 y), and mean follow-up after LT was 17.83 ± 5.21 years. Twenty-nine patients (96.7%) were receiving a calcineurin inhibitor (69% tacrolimus, 31% cyclosporine), along with steroids in 13 of them. The average CVRF per patient was 2, and 11 patients (43.33%) had ≥3. Thirteen patients (43.33%) had CKD. The estimated risk of developing a coronary event at 10 years according to the Framingham score was 3%, higher than expected in the general population of same age and sex. With the use of the Regicor equation, adapted to the Spanish population, the estimated cardiovascular risk was 1.6%, corresponding to Spanish men without CVRF aged 50-55 years. None of the patients had cardiovascular events during the follow-up.. Our data show a high incidence of CVRF and CKD in young adults who received LT in childhood, resulting in an increased risk of cardiovascular disease.

Topics: Adult; Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Postoperative Complications; Risk Factors; Survivors; Tacrolimus; Young Adult

Although kidney transplantation is by far the best method of renal replacement therapy, organ receiver is still not spared of eventual toxic consequences of drugs that are in charge of keeping the transplanted kidney functional. Both calcineurin inhibitors, of which tacrolimus more often, occasionally lead to neurotoxic side effects, mostly mild and reversible and dose-dependent in nature, but they can also be very severe or even fatal. It is very important to be aware of possible neurotoxic effects, to confirm them radiologically, and to prevent or reduce drug effects on nervous system. Sometimes the reduction of dose or substitution with another drug with similar mechanism effect is sufficient to terminate the neurotoxic effects of the drug and still not jeopardize the function of transplanted organ.

Topics: Adolescent; Brain; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Renal Dialysis; Seizures; Tacrolimus; Treatment Outcome

Post-transplant diabetes mellitus (PTDM) is a common and serious metabolic complication. Genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes have been reported to be related to diabetes mellitus and insulin sensitivity; however, the role of these genes in the development of PTDM is not known. For this purpose, we investigated the association of ACE and AGT genetic polymorphisms with PTDM.. A total of 302 subjects without previously diagnosed diabetes who had received kidney transplants were included. One ACE single nucleotide polymorphism (SNP) (rs4291) and two AGT SNPs (rs 699 and rs 4762) were genotyped from genomic DNA with direct sequencing.. PTDM developed in 49 (16.2%) of 302 subjects. Subjects in the PTDM were older than those in the non-PTDM. There was a significant difference between the two groups in tacrolimus use (p=0.03). Of the three SNPs, the rs4762 of the AGT gene was significantly associated with the development of PTDM in the dominant models (p = 0.03) after adjusting for age and tacrolimus usage.. AGT gene rs4762 polymorphisms may serve as genetic markers for the development of PTDM. The exact molecular mechanisms still need to be clarified.

Topics: Aged; Angiotensinogen; Asian People; Diabetes Mellitus; DNA Primers; Female; Gene Frequency; Genotype; Haplotypes; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Postoperative Complications; Republic of Korea; Tacrolimus

Bronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T cell proinflammatory cytokines and increased T cell granzyme B. Repeated antigen-driven proliferation down-regulates T cell CD28. We hypothesized that down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules (CD134, CD137, CD152 and CD154) on T cells may be associated with BOS. Co-stimulatory molecules, granzyme B, perforin and intracellular cytokines were measured by flow cytometry on T cells from stable lung transplant patients (n = 38), patients with BOS (n = 20) and healthy controls (n = 10). There was a significant increase in the percentage of CD4/28(null) and CD8/28(null) T cells producing granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α in BOS compared with stable patients. Down-regulation of CD28 was associated with steroid resistance and up-regulation of CD134, CD137, CD152 and CD154 on CD4(+) T cells and CD137 and CD152 on CD8(+) T cells. There was a significant correlation between increased CD28(null) /CD137 T cells producing IFN-γ, TNF-α with BOS grade (r = 0·861, P < 0·001 for CD28(null) /CD137 IFN-γ/CD8) and time post-transplant (r = 0·698, P < 0·001 for CD28(null) /CD137 IFN-γ/CD8). BOS is associated with down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules on steroid-resistant peripheral blood proinflammatory CD4(+) and CD8(+) T cells. Therapeutic targeting of alternate co-stimulatory molecules on peripheral blood CD28(null) T cells and monitoring response using these assays may help in the management of patients with BOS.

Topics: Adult; Bronchiolitis Obliterans; Case-Control Studies; CD28 Antigens; CD40 Ligand; Costimulatory and Inhibitory T-Cell Receptors; CTLA-4 Antigen; Cyclosporine; Female; Granzymes; Humans; Immunosuppressive Agents; Interferon-gamma; Lung Transplantation; Lymphocyte Activation; Male; Middle Aged; Perforin; Postoperative Complications; Receptors, OX40; T-Lymphocyte Subsets; Tacrolimus; Tumor Necrosis Factor Receptor Superfamily, Member 9; Tumor Necrosis Factor-alpha; Up-Regulation

New-onset diabetes after transplantation (NODAT) occurs commonly. Prior NODAT definitions have been inconsistent. Based on the American Diabetic Association criteria, we propose a new approach to defining NODAT.. Analysis of 1416 at-risk transplant recipients was performed. Data from three de novo Astellas registration transplant studies (two kidney and one liver) evaluated NODAT in 634 at-risk patients receiving tacrolimus, 630 at-risk patients receiving tacrolimus extended release, and 152 at-risk patients receiving cyclosporine. NODAT was defined as a composite endpoint consisting of first occurrence of one of four parameters: (i) two fasting plasma glucose levels ≥ 126 mg/dL (≥ 7.0 mmol/L) ≥ 30 days apart, (ii) oral hypoglycemic agent use for ≥ 30 consecutive days, (iii) insulin therapy for ≥ 30 consecutive days, and (iv) hemoglobin A1c ≥ 6.5%. We evaluated each of the above parameters, as well as the composite endpoint, in an attempt to establish an appropriate clinical approach to the diagnosis of NODAT.. The composite definition results in a 1-year NODAT incidence of 30% to 37% in kidney and 44% to 45% in liver transplant recipients treated with tacrolimus. NODAT incidence was significantly higher with tacrolimus than cyclosporine; there was no difference between the two tacrolimus formulations.. Based on these analyses, the proposed composite definition for NODAT, incorporating broader criteria, is recommended for clinical trials. Appropriate definitions of NODAT allow for a better understanding of the incidence of this complication and may result in earlier initiation of therapy with improved long-term outcomes.

Topics: Clinical Trials as Topic; Cyclosporine; Diabetes Mellitus, Type 2; Female; Graft Survival; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Prevalence; Registries; Risk Factors; Tacrolimus; Terminology as Topic

PTLDs are a well-recognized and potentially fatal complication after intestinal transplantation. We analyzed the incidence, clinical features, and outcome in a 63 intestinal transplantation series performed in our unit between October 1999 and July 2011. Types of graft included ISB (n = 23), LSB (n = 20), and MV (n = 20). Patients were categorized into three groups of immunosuppression: I (n = 43) received basiliximab, tacrolimus, and steroids; II (n = 11) thymoglobulin and tacrolimus, and III (n = 9) alemtuzumab and tacrolimus. EBV status was serially assessed. All PTLD cases were biopsied to establish histopathological diagnosis. The incidence of PTLD was 14.2% (9/63). Median onset of PTLD after transplant was four months (range: 0.5-28), within first postoperative year in 6 (66.6%) patients. Fever was the most common symptom. Graft removal was needed in four patients (44%). The patient survival rate was 66.6% (6/9). We have not found any association between PTLD and immunosuppression regimen or transplant type. However, there was a statistical association with EBV active infection.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Intestines; Lymphoproliferative Disorders; Male; Postoperative Complications; Postoperative Period; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus; Transplantation; Treatment Outcome

We prospectively screened 609 consecutive kidney (538) and kidney-pancreas (71) transplant recipients for BK viremia over a 4-year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥ 10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥ 10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30-50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus-associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22-744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.

Topics: Adult; Aged; Biopsy; BK Virus; Female; Humans; Immunosuppression Therapy; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Tacrolimus; Tumor Virus Infections; Viral Load

Long-term graft deterioration remains a major obstacle in the success of pancreatic islet transplantation (PITx). Antigen-independent inflammatory and innate immune responses strengthen subsequent antigen-dependent immunity; further, activation of nuclear factor (NF)-κB plays a key role during these responses. In this study, we tested our hypothesis that, by the inhibition of NF-κB activation, the suppression of these early responses after PITx could facilitate graft acceptance.. Full major histocompatibility complex (MHC)-mismatched BALB/c (H-2) mice islets were transplanted into streptozotocin-induced diabetic C57BL/6 (B6: H-2) mice. The NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) was administered for either 3 or 14 days after PITx. To some PITx recipients, tacrolimus was also administered. Islet allograft survival, alloimmune responses, and in vitro effects of DHMEQ on dendritic cells (DCs) were assessed.. With a vehicle treatment, 600 islet allografts were promptly rejected after PITx. In contrast, 3-day treatment with DHMEQ, followed by 2-week treatment with tacrolimus, allowed permanent acceptance of islet allografts. The endogenous danger-signaling molecule high mobility group complex 1 (HMGB1) was elevated in sera shortly after PITx, whereas DHMEQ administration abolished this elevation. DHMEQ suppressed HMGB1-driven cellular activation and proinflammatory cytokine secretion in mouse bone marrow-derived DCs and significantly reduced the capacity of DCs to prime allogeneic T-cell proliferation in vitro. Finally, the DHMEQ plus tacrolimus regimen reverted the diabetic state with only 300 islet allografts.. Inhibition of NF-κB activation by DHMEQ shortly after PITx suppresses HMGB1, which activates DCs and strengthens the magnitude of alloimmune responses; this permits long-term islet allograft acceptance, even in case of fewer islet allografts.

Topics: Animals; Benzamides; Cyclohexanones; Cytokines; Dendritic Cells; Graft Survival; HMGB1 Protein; Islets of Langerhans Transplantation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; NF-kappa B; Postoperative Complications; Tacrolimus; Transplantation, Homologous

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Infections; Inflammation; Intestinal Mucosa; Intestine, Small; Intestines; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Neuromuscular Diseases; Postoperative Complications; Regeneration; Short Bowel Syndrome; Tacrolimus; Transplantation; Treatment Outcome

Topics: Antiviral Agents; Drug Interactions; Hepatitis C, Chronic; Humans; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Postoperative Complications; Proline; Protease Inhibitors; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Treatment Outcome

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2(b) ) donor tracheas were orthotopically transplanted into CBA.J(H2(k) ). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real-time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration [34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05]. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL-12, IL-4, IL-6, TNF-α, TGF-β, PDGFβ, MCP1, P-/E-selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor-specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.

Topics: Animals; Blood Platelets; Bronchiolitis Obliterans; Calcineurin Inhibitors; Clopidogrel; Cytokines; Everolimus; Gene Expression Regulation; Immunohistochemistry; Isoantibodies; Lung Diseases; Lung Transplantation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Microscopy, Fluorescence; Models, Animal; Platelet Aggregation; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; T-Lymphocytes; Tacrolimus; Ticlopidine; Time Factors; TOR Serine-Threonine Kinases; Trachea

The management of hepatitis C virus (HCV) recurrence after liver transplantation (LTx) is a major challenge in patient care. For patients with HCV GT1, treatment standard with pegylated interferon (PEG-IFN) and ribavirin (RBV) has been augmented in 2011 by first generation protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC). We report our first experiences with TVR-based triple therapy in patients with GT1-reinfection of the graft.. 13 patients with histologically proven HCV GT1-reinfection of the graft received 12 weeks of PEG-IFN/RBV/TVR followed by 12 weeks of PEG-IFN/ RBV only. During the triple therapy phase immune suppression was tightly monitored, and the patients were also closely monitored for side effects.. The dosage of immunosuppressants had to be reduced significantly (TAC: 30-fold; CSA 3,5-fold). Stable levels were achieved by daily or over-daily dosing of a special size application of 0,1 mg tacrolimus (Tac) bid or a minimal dose of 10 mg cyclosporine (CSA) bid or qd, respectively. In all patients hematological side effects were observed, 65 % of which required RBV dose reduction, administration of erythropoietin or blood transfusions. Increase of kidney retention values requiring infusions occurred in 50 %. All side effects were reversible. There were no early discontinuations of therapy. An early viral response (EVR) with viral decline below limit of detection was noted at week 12 in 9/13 patients and at week 12 in further 3 patients.. Our preliminary results show high EVR response rates of TVR-based triple therapy in LTx patients with HCV-GT1 re-infection.

Topics: Adult; Antiviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Postoperative Complications; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Viral Load

An increase in the number of circulating endothelial cells (CEC) indicates endothelial damage and the risk of cardiovascular disease. The aim of our study was to investigate the association of CEC with various clinical parameters in pediatric renal transplant recipients.. CEC, defined as CD45(-)CD146(+), were enumerated by flow cytometry from the peripheral blood of 50 pediatric renal transplant recipients and 20 healthy controls. Clinical parameters, including renal function tests, fasting blood glucose, serum cholesterol and triglyceride, cyclosporine A (CsA) (trough and 2nd-hour) and tacrolimus (tac) trough blood levels and their association with CEC numbers were analyzed.. CEC numbers of patients were higher than those of controls (respectively, 128 ± 89 cells/ml (42-468 cells/ml), 82 ± 33 cells/ml (32-137 cells/ml), p = 0.024). There was a statistically significant negative correlation between CEC numbers and glomerular filtration rate (GFR) (r = -0.300, p = 0.012). There was also a statistically positive association between CEC numbers and transplant duration as well as cyclosporine trough level (respectively, r = 0.397, p = 0.004, r = 0.714, p = 0.004). CEC numbers in patients on tac and CsA were similar (p = 0.716).. Our results demonstrate that renal transplant recipients with high CsA trough blood level, longer transplant duration, and lower GFR, are at greater risk of developing endothelial damage.

Topics: Adolescent; Biomarkers; Case-Control Studies; CD146 Antigen; Cell Count; Child; Cyclosporine; Endothelial Cells; Female; Flow Cytometry; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Common Antigens; Male; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

To evaluate whether the combination of the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (ImmuKnow assay: IMK assay) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for monitoring of immunological aspects in the patient followup of more than one year after living donor liver transplantation (LDLT).. Forty-nine patients, who underwent LDLT more than one year ago, were randomly screened by using IMK assay from January 2010 to December 2011, and the complete medical records of each patient were obtained. The CYP3A5 genotypes were examined in thirty-nine patients of them.. The mean ATP level of the IMK assay was significantly lower in the patients with infection including recurrence of hepatitis C (HCV) (n = 10) than in those without infection (n = 39): 185 versus 350 ng/mL (P < 0.001), while it was significantly higher in the patients with rejection (n = 4) than in those without rejection (n = 45): 663 versus 306 ng/mL (P < 0.001). The IMK assay showed favorable sensitivity/specificity for infection (0.909/0.842) as well as acute rejection (1.0/0.911). CYP3A5 genotypes in both recipient and donor did not affect incidence of infectious complications.. In the late phase of LDLT patients, the IMK assay is very useful for monitoring immunological aspects including bacterial infection, recurrence of HCV, and rejection.

Topics: Adenosine Triphosphate; Adult; Aged; CD4-Positive T-Lymphocytes; Cytochrome P-450 CYP3A; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Transplantation Immunology; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Delayed Diagnosis; Dermatitis; Diagnostic Errors; Drug Substitution; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Prednisone; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tacrolimus; Vinblastine

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.

Topics: Antigens; Calcineurin; Calcineurin Inhibitors; Cell Proliferation; Epstein-Barr Virus Infections; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Immunologic Memory; Immunosuppression Therapy; Immunotherapy, Adoptive; Interferon-gamma; Leukocytes, Mononuclear; Lymphoma; Mutation; Organ Transplantation; Phenotype; Postoperative Complications; Retroviridae; T-Lymphocytes; T-Lymphocytes, Cytotoxic; Tacrolimus

Post-transplant lymphoproliferative disorders of T-cell origin are quite uncommon, and the vast majority represent neoplasms of mature, post-thymic T- or natural killer cells. Here, we report a rare case of T-cell acute lymphoblastic leukaemia (T-ALL), which occurred in an 18-year-old man who had undergone three liver transplants, initially for biliary atresia and subsequently for graft failure due to chronic rejection. He had received immunosuppression with cyclosporine and tacrolimus, as well as short-term treatment with OKT3. The T-ALL occurred 16 years after the first liver transplant. This case highlights the challenge for classifying rare neoplasms occurring in recipients of solid organ transplants that are currently not recognized to lie within the spectrum of post-transplant lymphoproliferative disorders. Given the long interval between the liver transplants and the development of T-ALL, a coincidental occurrence of the leukaemia cannot be ruled out. However, the potential roles of immunosuppressive therapy and other co-morbid conditions of the individual as possible risk factors for the pathogenesis of T-ALL are discussed.

Topics: Adolescent; Biliary Atresia; Causality; Clone Cells; Comorbidity; Cyclosporine; Diagnosis, Differential; Disease Susceptibility; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Radiation-Induced; Liver Transplantation; Lymphoproliferative Disorders; Male; Muromonab-CD3; Postoperative Complications; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Remission Induction; Reoperation; Tacrolimus; Time Factors

Antifungal prophylaxis with liposomal amphotericin B in high-risk liver transplant recipients is recommended, but experience with amphotericin B lipid complex (ABLC, Abelcet(®)) in this setting is limited. Data from 615 liver transplants performed during 1999-2005 were analyzed retrospectively. High-risk patients (n = 146) received a mean cumulative ABLC dose of 955 ± 609 mg (mean duration of 23.3 ± 11.9 days). Low-risk patients (n = 469) received no prophylaxis. During a mean follow-up of 43.8 ± 29.2 months, fungal infections occurred in 32.2% of ABLC patients versus 43.5% of non-prophylaxis patients (P = 0.015). The overall rate of invasive fungal infection was 12.3% in the ABLC group versus 15.6% in the non-prophylaxis patients (P = 0.34). Any Candida infection (ABLC 29.5%, non-prophylaxis 41.2%, P = 0.011), probable or proven invasive Candida infection requiring systemic antifungal treatment (ABLC 18.5%, non-prophylaxis 32.4%, P = 0.001) and invasive abdominal candidiasis during the first 3 months (ABLC 4.1%, non-prophylaxis 9.2%, P = 0.049) were significantly less frequent in the ABLC group. There was no significant difference between groups in the incidence of Aspergillus infections. The ABLC group showed no evidence of nephrotoxicity. In conclusion, the marked and significant differences in infection rates and requirement for systemic treatment in this large population suggest that targeted use of low-dose ABLC therapy to high-risk patients is a valid prophylactic strategy following liver transplantation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Cyclosporine; Female; Follow-Up Studies; France; Humans; Immunosuppressive Agents; Kidney; Liposomes; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Retrospective Studies; Safety; Tacrolimus; Treatment Outcome

To report postoperative complications of keratolimbal allograft (KLAL) transplantation in patients with bilateral total limbal stem cell deficiency.. In this retrospective observational case series, medical charts of 45 patients with at least 6 months of follow-up were reviewed. The main outcome measure was postoperative complications including graft-related issues (thickness, position, and alignment) and immunologic rejection.. Sixty-six KLALs were performed on 45 eyes. The mean follow-up period was 26.1 ± 11.8 months (range, 6-48 months). Primary failure occurred in 5 eyes primarily as a result of ocular surface exposure and severe dry eyes. Graft-related complications included misalignment (4 eyes), buttonhole (4), inner-edge tear (4), inadvertent limbal trephination (2), and thick KLAL (2). Postoperatively, regional thinning of the graft was observed in 8 KLALs as a result of exposure, regional ischemia, and after epithelial rejection. Acute rejection was diagnosed 16 times in 8 eyes, whereas chronic rejection was observed in 24 eyes. At last follow-up, 12 cases (26.6%) had failed because of recurrent acute rejection (4), chronic rejection (5), refractory herpetic keratitis (1), exposure (1), and refractory papillomavirus keratitis (1).. KLAL may be complicated by several adverse events. The most important complications are immunologic rejections, chronic ocular surface exposure, and graft-related complications.

Topics: Adolescent; Adult; Cell Transplantation; Child; Corneal Diseases; Drug Therapy, Combination; Epithelium, Corneal; Female; Graft Rejection; Humans; Immunosuppressive Agents; Limbus Corneae; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Stem Cell Transplantation; Tacrolimus; Tissue Donors; Transplantation, Homologous; Young Adult

Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Male; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Tacrolimus

Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventy-five renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23-39 days), compared with 12 days (95% CI, 10-15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (C(min)/[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to CYP3A5*1/*3 or CYP3A5*1/*1 genotype. Recipients with CYP2C19*2/*2 genotype also showed allograft delayed function (acute tubular necrosis in 3 patients). Genotyping of CYP3A5 and CYP2C19 in renal transplantation should be considered to be of interest when treating with tacrolimus and omeprazole, because CYP2C19*2/*2 variant indirectly elicits an increase of tacrolimus blood levels and, in our study population, the adverse effects described.

Topics: Aryl Hydrocarbon Hydroxylases; Chi-Square Distribution; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Enzyme Induction; Enzyme Inhibitors; Female; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Length of Stay; Male; Middle Aged; Nod2 Signaling Adaptor Protein; Omeprazole; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Postoperative Complications; Proton Pump Inhibitors; Substrate Specificity; Tacrolimus

Posterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.

Topics: Cerebral Hemorrhage; Child; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Subarachnoid Hemorrhage; Tacrolimus

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5-5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49-year-old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition-related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12-15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus-associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.

Topics: Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Prognosis; Recurrence; Sirolimus; Tacrolimus

Topics: Adult; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Tacrolimus

Topics: BK Virus; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Polyomavirus Infections; Postoperative Complications; Risk Factors; Tacrolimus; Tumor Virus Infections; Viremia; Virus Replication

Posterior reversible encephalopathy syndrome (PRES) is a rare disease characterized by altered mental status, seizures, headache, vomiting and visual disturbances, most often described after transplantation and immunosuppressive therapy. PRES is commonly first diagnosed by the neuroradiologist, rather than the clinician, as it is characterized by very typical magnetic resonance imaging (MRI) features, i.e., hyperintense lesions in the territories of the posterior cerebral artery. Here we report our experience in the Intensive Care Unit (ICU) with a case of tacrolimus-related PRES after liver transplant, presenting with sudden neurological deterioration and diffuse and massive hyperintensities upon brain MRI. Discontinuation of tacrolimus, as prompted by the established literature, permitted the patient to eliminate tacrolimus-associated toxicity, whereas its substitution with everolimus and mycofenolic acid allowed the maintenance of immunosuppression while avoiding acute organ rejection and reducing the dosage of corticosteroids. The lowering of blood pressure with drugs reported in the literature for use in PRES proved to be effective but challenging, requiring the use of multiple drugs and only slowly leading to proper control of hypertensive peaks. Nonetheless, hypertension management and supportive therapy allowed for a complete neurological restitutio ad integrum of the patient. In conclusion, tacrolimus-related brain adverse events need to be promptly recognized, especially during the first months after transplantation. When tacrolimus-related PRES occurs, immunosuppressive therapy may be safely and efficiently switched to everolimus and mycofenolic acid. This strategy may help not only to avoid acute organ rejection but also to reduce the dosage of corticosteroids, which might interfere with proper control of hypertension.

Topics: Brain; Critical Care; Electroencephalography; Humans; Immunosuppressive Agents; Intensive Care Units; Liver Cirrhosis; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Tacrolimus

Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia-reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Complement C3; Creatinine; Cytokines; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Postoperative Complications; Premedication; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sirolimus; Tacrolimus

We report a case of a renal transplant patient who was maintained on tacrolimus and diltiazem therapy and developed tacrolimus toxicity leading to reversible acute kidney injury when started on ranolazine. A 62-year-old Caucasian male status post renal transplant in 2009 (on prednisone and tacrolimus) was evaluated for ischemic heart disease and was initiated on ranolazine 500 mg tablets twice daily, which was later increased to 1000 mg twice daily. After 2 weeks, he developed fatigue, loss of appetite, tremors, and decreased urine output and was admitted to our hospital. His other significant medications included enalapril 2.5 mg and diltiazem 240 mg daily. The patient was awake and alert, but lethargic. He was found to be bradycardic with a heart rate of 42/min. The rest of his physical examination was benign. His electrocardiogram revealed sinus bradycardia. Laboratory studies revealed serum creatinine of 2.4 mg/dL from a baseline of 1.5 mg/dL (stable for the past 2 years). The tacrolimus trough was elevated at 14 ng/mL, which decreased after stopping ranolazine, reaching 7 ng/mL after 3 days, while continuing the same dose of tacrolimus. His creatinine trended downward and reached his baseline of 1.5 mg/dL over the next 2 days. His bradycardia and other symptoms resolved after cessation of ranolazine. He was discharged to follow up, to initiate an alternate agent for ischemic heart disease. Specific pharmacokinetic studies are warranted to study these drug interactions, and tacrolimus levels should be closely monitored in transplant patients who initiate ranolazine treatment.

Topics: Acetanilides; Acute Kidney Injury; Calcium Channel Blockers; Diltiazem; Drug Interactions; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Piperazines; Postoperative Complications; Ranolazine; Tacrolimus

A 71-year-old patient presented with very painful ulcers after uterus-resection with the da Vinci® Surgical System 3 months before. The anamnesis revealed that in the past 10 months similar wounds had appeared after osteosynthesis of a humerus fracture and after breast biopsy. The patient had been unsuccessfully treated with different antibiotics and wound dressings for several months for a suspected superinfected, postoperative disturbed wound healing. None of the wounds became smaller or healed completely. After exclusion of relevant differential diagnoses pyoderma gangrenosum (PG) could be diagnosed and systemic immunosuppressive therapy was initiated. The pain improved rapidly and complete wound healing was achieved. Pyoderma gangrenosum is a rarely diagnosed autoimmune disease which often occurs after physical trauma such as surgical interventions. Because a correct diagnose is usually made late it is important to be aware of this disease to treat it early and correctly.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Combined Modality Therapy; Cyclosporine; Diagnosis, Differential; Female; Humans; Hysterectomy, Vaginal; Immunosuppressive Agents; Postoperative Complications; Prednisolone; Pyoderma Gangrenosum; Robotics; Surgery, Computer-Assisted; Surgical Wound Infection; Tacrolimus

Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity.. We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant.. Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04-2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400-500 mg) and 228 ng/mL (190-272 ng/mL) in the cyclosporine group, and 6 mg (4-8 mg) and 12.6 ng/mL (10.2-15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity.. We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcineurin Inhibitors; Cyclosporine; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; Proportional Hazards Models; Prospective Studies; Risk Factors; Tacrolimus; Young Adult

The purposes of this study were to investigate the effects of topically administrated Tacrolimus and Octreotide on modulation of postoperative scarring in experimental glaucoma filtration surgery and to compare the antifibrotic properties of these agents with mitomycin-C (MMC).. A total of 28 New Zealand rabbits weighing 2.5-3 kg were randomly divided into a surgical control (SC) group and three experimental groups. Standard filtration surgeries were performed on the right eyes of all the rabbits. The rabbits in the SC group received only vehicle after the surgeries, whereas the rabbits in the three experimental groups were treated either with 0.4 mg/mL MMC during the surgery (MMC group) or with 0.3 mg/mL Tacrolimus drop four times a day (TT group) or with 10 µg/mL Octreotide drop three times a day (OT group) for 14 days. The animals were killed on day 14, eyes were enucleated and histologically and immunohistochemically analyzed.. In SC group mean fibroblast, mononuclear cell number and fibroblast growth factor-β (FGF-β), transforming growth factor-β (TGF-β) immunostaining intensity was higher than all treatment groups. In OT group mean fibroblast number was lesser than MMC (p < 0.01) and TT (p < 0.05) group. In TT group mean fibroblast number was lesser than MMC group (p < 0.05). Mean mononuclear cell number was similar between MMC, OT and TT groups (p > 0.05). In MMC, OT and TT groups mean TGF-β and FGF-β immunostaining intensity was similar (p > 0.05).. Topically administration of Tacrolimus and Octreotide effectively reduced the subconjuntival scarring response 2 weeks after experimental glaucoma filtration surgery.

Topics: Administration, Topical; Alkylating Agents; Animals; Cicatrix; Conjunctival Diseases; Disease Models, Animal; Fibroblast Growth Factor 2; Fibroblasts; Fibrosis; Filtering Surgery; Glaucoma; Immunoenzyme Techniques; Immunosuppressive Agents; Leukocyte Count; Mitomycin; Octreotide; Ophthalmic Solutions; Postoperative Complications; Rabbits; Tacrolimus; Transforming Growth Factor beta

This retrospective case series reviews our center's experience with sirolimus and a CNI as alternative therapy for the treatment of PTAH. It also characterizes regulatory T cells (Tregs) in PTAH. LT recipients with PTAH who had received or were receiving treatment with sirolimus were retrospectively identified (n = 12). Liver enzymes, immunohistochemistry, and histology were compared in all 12 patients. Immunophenotyping for Tregs in peripheral blood mononuclear cells was performed on LT recipients with PTAH on conventional therapy with CNI, azathioprine ± prednisone (CT) (n = 11), recipients with PTAH on sirolimus, CNI ± prednisone (n = 8), recipients without PTAH (n = 25), and pre-transplant patients (n = 5). Severity of necro-inflammatory changes markedly improved with sirolimus. Treg frequency and number were significantly lower in recipients with PTAH on CT compared to (i) those on sirolimus (p = 0.002 and p = 0.01, respectively), and (ii) recipients without PTAH (p = 0.07 and p = 0.009, respectively). Treg frequency was significantly higher in recipients with PTAH on sirolimus compared to recipients without PTAH under CNI therapy (p = 0.027). Sirolimus in addition to a CNI is successful in reversing inflammation in LT recipients with PTAH. This is associated with significantly higher circulating Tregs.

Topics: Azathioprine; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver; Liver Transplantation; Male; Postoperative Complications; Prednisone; Retrospective Studies; Single-Blind Method; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Treatment Outcome

Immunosuppressive (IS) medication is needed to avoid graft rejection in porcine transplantation models. An ideal IS therapy should have no side-effects, but increased susceptibility to infections, disturbed intestinal microflora and toxic effects on organs and tissues are commonly reported. The aim of the present study was to design an IS protocol with tacrolimus and mycophenolic acid to be used for maintenance therapy in the post-transplant period. An eligible whole blood trough value for tacrolimus was 5-15 μg/L. Conventional specific pathogen-free pigs were fitted with an indwelling catheter under general anaesthesia, and after the acclimatization period three groups were formed: group A (n= 4) received 0.15 mg/kg body weight (BW) twice daily tacrolimus and 500 mg twice daily mycophenolic acid; group B (n= 4) received 0.3 mg/kg BW twice daily tacrolimus and 500 mg twice daily mycophenolic acid; group C (n= 2) did not receive any medication. Daily clinical examinations and analyses of blood concentrations of tacrolimus and glucose were performed. Total and differential white blood cell counts, enzyme activities, bilirubin and electrolyte concentrations were measured every fourth day. At the end of the experiment, the pigs were killed with an overdose of pentobarbital intravenously and a necropsy was performed immediately. All animals seemed to tolerate the IS treatment well. No alterations in their clinical state of health were observed throughout the study and daily weight gain was similar for the three groups. The necropsy did not reveal any pathological findings related to medication. The study showed that 0.25 mg/kg BW twice daily tacrolimus and 500 mg twice daily mycophenolic acid would be an appropriate maintenance dosage for conventional pigs.

Topics: Administration, Oral; Animals; Clinical Protocols; Disease Models, Animal; Drug Administration Schedule; Graft Rejection; Immunosuppressive Agents; Islets of Langerhans Transplantation; Mycophenolic Acid; Postoperative Complications; Specific Pathogen-Free Organisms; Swine; Tacrolimus; Toxicity Tests

This retrospective single-center study evaluated long-term renal function after conversion from calcineurin inhibitors to sirolimus-based immunosuppression in kidney transplant recipients.. From 2001 to 2009, one hundred fifty kidney transplant recipients were converted from calcineurin inhibitors to sirolimus at least 3 months after transplant.. After a mean follow-up of 171 weeks, 56.7% of converted patients remained on sirolimus. The 5-year survival rate of the patients (including intent-to-treat) and grafts was 85.5% and 83.6%. Patients on sirolimus showed significant improvement in renal function with a creatinine clearance of 50.9 ± 20.7 and 52.9 ± 20.8 mL/minute at month 0 and month 24. Independent predictive factors associated with a stable estimated glomerular filtration rate at the last follow-up of sirolimus patients were (1) having a living donor, (2) absence of anti-HLA alloantibodies at month 0, and (3) cyclosporine versus tacrolimus used before conversion. Adverse effects were reported in 134 patients (89.3%). They included (1) hospitalization for infection (n=52), (2) de novo proteinuria (n=40), and (3) eight patients with biopsy-proven acute rejection. Sirolimus was stopped and replaced by calcineurin inhibitors in 37 patients after a mean of 16 months treatment. After stopping sirolimus, renal-allograft function remained stable at 2 years.. Conversion of calcineurin inhibitors to sirolimus in kidney transplant recipients was associated with improved renal function. The reintroduction of calcineurin inhibitors was safe in patients who were withdrawn from sirolimus owing to adverse effects.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Opportunistic Infections; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tacrolimus

Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis (PD), but only a few cases have been described in the pediatric patient population. There is no established medical treatment, and surgery has been reported with variable success. The number of reports of EPS being successfully treated with tamoxifen, based on its anti-fibrotic effects, are increasing. The role of sirolimus, an mTOR inhibitor with immunomodulatory and anti-proliferative properties, has been less well-defined.. A 17-year-old kidney transplant recipient, with a previous cumulative time on PD of 8 years and 3 months, developed severe bowel obstruction 8 months after undergoing a second kidney graft. Her immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisolone. The patient underwent laparotomy, which revealed multiple thick leathery adhesions with an encapsulated small bowel. Enterolysis was performed, and total parenteral nutrition was commenced after surgery to provide an adequate food intake. Treatment with tamoxifen was initiated, but the patient developed significant liver toxicity 2 weeks later, and the drug was withdrawn. The immunosuppressive regimen was changed to an increased dose of prednisolone, and tacrolimus was replaced with sirolimos. At 20 months of follow-up, the patient remains symptom-free, with a functioning kidney transplant.. Although EPS is a very rare condition in the pediatric population, it should be considered when a child or adolescent with a long-term history of PD presents with nonspecific gastrointestinal symptoms or with signs of bowel obstruction. There is an urgent need for alternative immunosuppressive protocols. The use of sirolimus in this group of patients remains controversial.

Topics: Adolescent; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Peritoneal Dialysis; Peritoneal Fibrosis; Postoperative Complications; Prednisolone; Sirolimus; Tacrolimus

Pyoderma gangrenosum (PG) is often associated with inflammatory bowel disease even after bowel surgery, but it remains an extremely rare pathology. The purpose of this study was to investigate the clinical features and treatment of PG and to consider proper management for peristomal PG.. Demographic data for patients who underwent colorectal surgery with ostomy creation at Hyogo College of Medicine between July 2007 and July 2011 were prospectively collected. The main outcome measures were postoperative occurrence of peristomal PG by type: explosive and rapidly spreading type (type R) and indolent and gradually spreading type (type G).. Overall prevalence was 11/738 (1.5%), with type R in 5 patients and type G in 6. Type R and type G were significantly more common in ulcerative colitis and Crohn's disease, respectively (p = 0.01). Type R developed within 6 days after surgery. Type G developed a mean of 52 days after surgery. Complete healing required a long time in both types, with means of 69 days for type R and 48 days for type G.. Although peristomal PG was a rare complication after surgery, differences in the development of PG were observed between ulcerative colitis and Crohn's disease. Careful observation and knowledge of PG are needed.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Enterostomy; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prednisolone; Pyoderma Gangrenosum; Risk Factors; Surgical Stomas; Surgical Wound Infection; Tacrolimus

De novo autoimmune hepatitis (AIH) describes the development of hepatitis with autoimmune features in liver transplant (LT) patients without prior diagnosis of AIH. We aimed to evaluate the incidence and risk factors for de novo AIH.. A cohort of 576 patients with LT for aetiologies other than AIH was evaluated.. De novo AIH was diagnosed in 17 patients (3%) with an overall incidence of 4.0 cases per 1000 patient-years. By univariate Cox analysis, patients who received cyclosporine A had lower risk (HR 0.24, 95% CI 0.07-0.80, P = 0.02), whereas patients who had female donors (HR 3.03, 95% CI 1.11-8.25, P = 0.03), donors ≥40-years (HR 6.95, 95% CI 1.93-25.03, P = 0.003), and those who received tacrolimus (HR 4.39, 95% CI 1.47-13.13, P = 0.008) and mycophenolate mofetil (HR 6.37, 95% CI 1.62-25.13, P = 0.008) had higher risk. Survival was similar in patients with de novo AIH compared with the LT population (mean survival time, 17 ± 1.5 vs. 16 ± 0.5 years, Log-rank test; P = 0.4).. The incidence of de novo AIH is low and does not impact on long-term survival. Recipients of female or older donor grafts, or recipients using tacrolimus, or mycophenolate mofetil as part of their immunosuppressive regimen have a higher risk of de novo AIH, whereas LT recipients maintained on cyclosporine A have a lower risk.

Topics: Adolescent; Adult; Age Factors; Aged; Canada; Child; Child, Preschool; Cohort Studies; Cyclosporine; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Risk Factors; Sex Factors; Survival Rate; Tacrolimus; Tissue Donors; Young Adult

Whole genome gene expression profiles were correlated with renal function and histology in a well-established animal model of chronic allograft nephropathy (CAN). Kidneys of F344 rats were transplanted into LEW recipients treated with a brief dose of FK506 (BFK). Blood and urine samples were collected weekly. Kidney grafts were harvested at an early (day 6) or late (days 30-90) phase after transplantation. BFK kidney grafts showed remarkable changes in function, histology, and gene expression profiles when compared to the isograft controls. In the early phase, renal function and histology were barely affected, yet the expression levels of 225 genes were significantly changed, reflecting both immune and non-immune pathways. In the late phase, however, 826 genes were affected in the BFK kidney grafts, including genes in the pathways of extracellular matrix and cell adhesion. Of these genes, 214 appear to be key factors for development of CAN, since they were affected at both early and late phases, including genes involved in the immune response, the inflammatory response, apoptosis, and metabolism. Kinetic studies with gene expression profiling can identify genes involved in the progressive development of chronic allograft rejection, leading to more detailed therapeutic approaches or useful biomarkers in clinical transplantation.

Topics: Animals; Cell Adhesion; Disease Models, Animal; Gene Expression Profiling; Graft Rejection; Humans; Immunity; Kidney Transplantation; Male; Microarray Analysis; Oligonucleotide Array Sequence Analysis; Postoperative Complications; Rats; Rats, Inbred F344; Rats, Inbred Lew; Tacrolimus

Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation.. A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25-0.43 versus 0.07-0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21-0.51; P<0.0001).. Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial.

Topics: Adult; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tacrolimus

We sought to study the prevalence, risk factors, and long-term prognosis of posttransplant diabetes mellitus.. We studied all patients with end-stage renal disease without diabetic nephropathy who received a kidney transplant and were followed-up at our center since 1983 (n=218; age, 44.3 ± 13.1 y). Patients with new-onset diabetes after transplant were compared to kidney transplant recipients without risk factors for diabetes mellitus. Patients with new-onset diabetes after transplant were divided into subgroups according to time of onset (early; < 90 d vs late, ≥ 90 d).. In total, 73/218 patients (33%) developed new-onset diabetes after transplant. Patients with new-onset diabetes after transplant were significantly older (51.2 ± 11.4 vs 40.7 ± 12.5 y; P < .001) and had a tendency to have a higher body mass index (29.6 ± 8.7 vs 21.6 ± 7.8 kg/m2; P =.05) than those that did not have new-onset diabetes after transplant. In multivariate analysis, age (P < .001), hepatitis C virus infection (P < .05), family history of diabetes mellitus (P < .03), and tacrolimus use (P < .001) were independent risk factors. Five- and 10-year death censored patient survival rates were worse in those that had new-onset diabetes after transplant compared with controls (log rank, 0.04), whereas there was no difference in outcomes between the early and late subgroups.. The prevalence of new-onset diabetes after transplant was 33%. Age, body weight at time of transplant, tacrolimus use, family history of diabetes mellitus, and hepatitis C virus infection are independent risk factors for new-onset diabetes after transplant. New-onset diabetes after transplant has a negative effect on patient survival, irrespective of the time of onset and duration of diabetes.

Topics: Adult; Age Distribution; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Prevalence; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Biomarkers, Tumor; Carcinoma, Renal Cell; Glomerulonephritis, Membranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney; Kidney Diseases, Cystic; Kidney Neoplasms; Kidney Transplantation; Male; Mucin-1; Mycophenolic Acid; Nephrectomy; Postoperative Complications; Reoperation; Tacrolimus

BK viremia can lead to nephritis, which can progress to irreversible kidney transplant failure. Our prospective study provides management and outcome of BK viremia in renal transplant recipients.. Two hundred forty de novo kidney-only recipients were enrolled from July 2007 to July 2010 and followed for 1 year. Standard immunosuppression with Thymoglobulin/interleukin 2 receptor blocker and mycophenolate mofetil/tacrolimus (Tac)/prednisone was employed. Quantitative BK virus (BKV) DNA surveillance in plasma/urine was performed at 1, 3, 6, 12, and 24 months after transplantation. Patients with significant viremia (defined as ≥10,000 viral copies/mL) underwent renal biopsy and treated with 30% to 50% reduction in doses of both mycophenolate mofetil and Tac without antiviral therapy. The target 12-hr Tac trough levels were lowered to 4 to 6 ng/mL in the significant viremia group, whereas the target levels remained unchanged at 5 to 8 ng/mL for all other groups.. Sixty-five patients (27%) developed BK viremia; 28 (12%) of whom had significant viremia. A total of five (21%) of the 23 (of 28) patients who underwent biopsy presented with subclinical BKV nephritis. The mean plasma BKV DNA declined by 98% (range, 76%-100%) at 1 year after peak viremia. Acute cellular rejection seen in four (14%) of 28 patients, responded to bolus steroids. There was no decline in estimated glomerular filtration rate over time from 1 month after transplantation to 1 year after peak viremia (P=0.57).. Reduction in immunosuppression alone resulted in the successful resolution of viremia with preservation of renal function and prevention of clinical BKV nephritis and graft loss.

Topics: Adult; Aged; Biopsy; BK Virus; Female; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Tacrolimus; Treatment Outcome; Tumor Virus Infections; Viral Load; Viremia

Topics: Adult; Humans; Immunosuppressive Agents; Intracranial Hemorrhages; Kidney Transplantation; Male; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Tacrolimus

Topics: Adult; Colectomy; Colitis, Ulcerative; Endoscopy, Gastrointestinal; Enteritis; Female; Humans; Immunosuppressive Agents; Jejunum; Postoperative Complications; Tacrolimus; Tomography, X-Ray Computed

Systemic complications in patients after renal or liver transplantation may be localized in the oral cavity. Calcium-phosphate disturbances may affect the structure and metabolism of mandible bones, promote calcification of dental pulp, and in children may cause developmental defects of teeth. The aim of this study was to evaluate the incidence of dental and bone abnormalities in children and adolescents after kidney and liver transplantation with respect to the type of the transplanted organ and maintenance immunosuppression.. Overall, 23 kidney and 25 liver recipients (mean age: 13.95±4.2 yrs) were evaluated. Twenty patients received ciclosporin A (CsA) and 28 tacrolimus (TAC). Twenty-one kidney and 14 liver recipients were treated with steroids. Mean time after transplantation was 3.62±2.98 years.. The severity of caries and percentage of odontogenic abnormalities (76.0% vs. 60.86%) was higher in liver transplant recipients. Positive correlations were found between discoloration of the deciduous teeth and liver transplantation, between enamel hypoplasia and kidney transplantation, and between treatment with CsA and its dose and blood concentration (p<0.05). Pulp stones were present in 13.04% of kidney vs. 8.0% in liver recipients, more often in those treated with CsA than with TAC. Jaw bone abnormalities were present in 30.43% kidney recipients vs. 12% liver recipients.. Both kidney and liver recipients present dental and bone abnormalities. The incidence of specific types of oral lesions is different in renal and liver graft recipients; however, it is also correlated with specific immunosuppression.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Dental Caries; Dental Enamel Hypoplasia; Dental Pulp Calcification; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Jaw Diseases; Kidney Transplantation; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Tooth Discoloration; Tooth Diseases

The aim of this trial was to evaluate the impact of conversion from a calcineurin-inhibitor (CNI)-based immunosuppressive regimen to mycophenolate mofetil (MMF) and reduced-dose CNI on long-term renal function and survival in a series of 63 liver transplant patients with CNI-induced renal dysfunction.. CNI dosage was significantly tapered after introduction of 2,000 mg MMF per day. Renal function was assessed by determination of serum creatinine levels and calculated creatinine clearance (CCl). The impact of relevant clinical parameters on renal function and survival post-conversion was analyzed by univariate and multivariate analysis.. At 60 months post-conversion, mean creatinine level had significantly declined from 197.2±58.3 μmol/l at baseline to 160.0±76.5 μmol/l, and mean CCl has significantly increased from 38.4±13.4 ml/min at baseline to 47.9±21.1 ml/min (p<0.001), respectively. Forty-six patients (73.1%) demonstrated sustained renal response to modified immunosuppression. Full-dose MMF medication (p=0.006) and the early conversion (p=0.02) were identified as independent predictors of persistent renal function improvement. Sustained renal response to MMF plus reduced-dose CNI was identified as the most relevant independent promoter of long-term survival (hazard ratio 6.9). Five-year survival rate post-conversion was 93.9% in renal responders and 64.3% in renal non-responders (log rank<0.001).. Sustained renal response to MMF and CNI dose reduction promotes long-term survival in liver transplant patients with CNI-induced renal dysfunction.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Retrospective Studies; Survival Rate; Tacrolimus

Topics: Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus

In liver transplantation (LT), modern immunosuppressive protocol is focused on early corticosteroid (CS) weaning. The aim of the study was to investigate all early transplant-related complications using Clavien grading system, in order to identify a significant relation in two homogenous groups of consecutive liver transplanted patients, only different for steroid avoidance in immunosuppressive regimen.. One group was treated with a tacrolimus-based CS-free immunosuppressive protocol, the other one underwent tacrolimus plus low dose CS therapy. The preoperative continuous variables analyzed were age, gender, model for end-stage liver disease (MELD) score, and the pre-allocation score for predicting survival following liver transplantation (P-SOFT).. There were 39 patients in Group A (CS free) (37.9%), and 64 patients in Group B (CS on board) (62.1%). No statistically significant differences between the two groups were detected regarding the incidence and Clavien grade of complications (P = 0.116). No significant relation was revealed between Clavien rate of complications and tacrolimus-based CS-free immunosuppressive protocol, comparing the two subgroup of patient with P-SOFT score < 6 and ≥ 6 (P = 0.193). This association was noted comparing the two subgroups on tacrolimus plus low dose CS regimen (P = 0.013).. In this series, the use of CS in sick patient is associated with higher morbidity identified by the Clavien classification.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Young Adult

To report the first histopathologic description of optic nerve demyelination from tacrolimus (FK 506) toxicity in the absence of toxic levels of tacrolimus in a patient presenting with asymmetric bilateral visual loss after 5 years of tacrolimus therapy.. We report a patient status post cardiac and renal transplantation who developed severe, progressive and asynchronous bilateral visual loss after prolonged treatment with tacrolimus. Orbital MRI showed an enlarged left optic nerve that enhanced with gadolinium.. After extensive negative work up, biopsy of one optic nerve was performed. Microscopic analysis showed extensive demyelination in the absence of vasculitis, neoplastic or infectious etiologies. Our patient illustrates that demyelination of the optic nerve causing asynchronous vision loss can be associated with tacrolimus toxicity in the absence of toxic drug levels.

Topics: Biopsy; Demyelinating Diseases; Diabetes Complications; Disease Progression; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Optic Nerve; Optic Nerve Diseases; Postoperative Complications; Risk Factors; Tacrolimus; Visual Acuity

Posttransplant diabetes mellitus (PTDM) is a common, serious complication of renal transplantation. The aim of this retrospective study was to estimate the incidence and to identify potential factors predisposing to PTDM.. We evaluated 296 adult nondiabetic patients who underwent kidney transplantation at our center. PTDM was defined according to 2003 international consensus guidelines. Potential factors predisposing to PTDM were analyzed individually and simultaneously using a logistic regression model.. Over 2054.5 years of cumulative follow-up, 51 patients (17.2%) developed diabetes corresponding to an annual incidence of 2.5%. PTDM was diagnosed after a median of 2.9 months (range: 0.2-168). The mean age of affect individuals was 33.3±7.4 years. Patients with PTDM were significantly older (P<.0005) and showed an higher body mass index (BMI; P<.004). Univariate analysis revealed that age, BMI, family history of diabetes, vascular nephropathy, and hepatitis C infection were associated with PTDM. Multivariate analysis rescaled the roles of age (relative risk [RR]=1.046/y; P<.04), BMI (RR=1.107/kg/m2, P<.05), vascular nephropathy (RR=7.06, P<.03), and hepatitis C infection (RR=2.72, P<.03) as independent factors predisposing to PTDM.. Among our relatively young kidney transplant recipients, in whom only 8% received tacrolimus, PTDM was a frequent complication. We suggest that the use of oral glucose tolerance tests to screen patients identifies those predisposed to develop this complication.

Topics: Adult; Diabetes Complications; Female; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Multivariate Analysis; Postoperative Complications; Regression Analysis; Retrospective Studies; Risk Factors; Tacrolimus

Bone fractures are a frequent complication after kidney transplantation, for which various predisposing factors have been identified. It has been suggested that human leukocyte antigen (HLA) mismatch increases the risk.. Data on hip fractures occurring in the first 5 years posttransplant were analyzed among kidney transplants from deceased donors performed between 1995 and 2008 and reported to the Collaborative Transplant Study.. In the 20,509 patients analyzed, the cumulative rate of hip fracture by year 5 posttransplant was 0.85%. Cox regression analysis identified the following risk factors: female recipients aged 40 to 59 years (hazard ratio [HR] 2.26, P=0.029), female recipients 60 years or older (HR 5.14, P<0.001), male recipients 60 years or older (HR 2.39, P=0.028), and donor age more than or equal to 60 years (HR 1.75, P=0.009). Using the rate of fractures in recipients with zero HLA-DR mismatch as the reference, the risk of hip fracture increased for grafts with one HLA-DR mismatch to HR 1.85 (95% confidence interval [CI] 1.18-2.89, P=0.007) and with two HLA-DR mismatches to HR 2.24 (CI 1.25-4.02, P=0.007). There was a significant association between the number of HLA-DR mismatches and the diagnosis of osteoporosis 5 years after transplantation: one HLA-DR mismatch risk ratio 1.26 (CI 1.12-1.43, P<0.001) and two HLA-DR mismatches risk ratio 1.45 (CI 1.20-1.74, P<0.001).. The risk of hip fracture after kidney transplantation seems to be markedly exacerbated by HLA-DR mismatching. These findings add to the growing base of evidence that HLA-DR matching influences morbidity after kidney transplantation.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Diabetic Nephropathies; Female; Graft Rejection; Hip Fractures; Histocompatibility Testing; HLA-DR Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

This study investigated the increase in interstitial fibrosis (IF) from 0 hr to 1 month and 1 year posttransplantation in biopsy sections and assessed the risk of developing IF in 118 living kidney recipients.. A quantitative analysis of IF was performed using computer-assisted imaging. The percent IF (%IF) in the cortical region at 0 hr was defined as the baseline, and the increases in %IF at 1 month and 1 year were calculated. Demographics, higher (regimen 1) and lower (regimen 2) target trough concentrations of tacrolimus, and the cytochrome P450 (CYP) 3A5 polymorphism were tested as risk factors.. The mean %IF at 0 hr, 1 month, and 1 year was 10.3%+/-4.2%, 15.0%+/-5.8%, and 19.0%+/-7.7%, respectively. %IF increased 1.7- and 2.2-fold from 0 hr to 1 month and 1 year posttransplantation, respectively. At 1 year, the increase was higher in patients with the CYP3A5*3/*3 genotype (nonexpressers), those treated with regimen 1, and those with a lower estimated glomerular filtration rate and higher body mass index. In a multivariate analysis, CYP3A5 nonexpression correlated with the development of IF (odds ratio 2.63, P=0.018). Tacrolimus blood levels in the early stage posttransplantation were higher in nonexpressers than CYP3A5 expressers in both regimens 1 and 2, despite therapeutic drug monitoring.. The higher concentrations of tacrolimus, especially in the nonexpressers treated with regimen 1, might influence the development of IF. This study suggested that a new regimen with lower and narrow target trough levels of tacrolimus or a dosing strategy based on the CYP3A5 genotype is needed to reduce the risk of developing IF.

Topics: Adult; Aged; Body Mass Index; Chronic Disease; Cohort Studies; Cytochrome P-450 CYP3A; Female; Fibrosis; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Treatment Outcome; Young Adult

Leukoencephalopathy syndrome is a neurologic complication after organ transplantation caused predominantly by the neurotoxic effects of immunosuppressive agents on cerebral white matter. We determined the incidence and features of leukoencephalopathy syndrome in recipients after living-donor liver transplantations.. We retrospectively investigated 205 patients who had a living-donor liver transplantation performed at our institution between August 1998 and October 2008.. Leukoencephalopathy syndrome developed in 7 of 205 patients (3.9%) and in 4.7% of the 150 patients treated with tacrolimus-based immunosuppression after their living-donor liver transplantation. The underlying diseases were alcoholic cirrhosis in 3 cases, viral cirrhosis in 2, biliary atresia in 1, and Wilson disease in 1. Time to clinical onset after tacrolimus medication was 15.6 days (range, 6-30 days). The neurologic symptoms included headache, confusion, myoclonus, seizures, and visual disturbances. The mean serum trough level of tacrolimus at clinical onset was not very high (11.7 ng/mL [range, 6.0-14.2 ng/mL]). T2-weighted magnetic resonance imaging in all cases showed diffuse high signal in the white matter of the frontal, parieto-occipital, and temporal lobes. Treatment with antihypertensives, anticonvulsants, and withdrawal of tacrolimus resulted in amelioration of symptoms and magnetic resonance imaging abnormalities. Six patients showed complete recovery, while the seventh had residual rigidity and cognitive impairment caused by hypoxia during a convulsion.. Tacrolimus neurotoxicity can occur despite low trough levels; it depends on variations in pharmacokinetics, such as absorption and maximum concentration level. Early diagnosis and treatment of leukoencephalopathy syndrome should contribute to complete remission.

Topics: Anticonvulsants; Antihypertensive Agents; Biliary Atresia; Child; Contraindications; Female; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Syndrome; Tacrolimus; Treatment Outcome

Beginning in March 2002, we initiated steroid-free lymphocyte depleting immunosuppression with rabbit anti-human thymocyte globulin (rATG) for all children who received an intestinal transplant (ITx). The purpose of the present study was to determine whether this treatment regimen supported growth. Because steroids were used for rejection episodes only, we hypothesized that improved growth would be observed in steroid-free rATG-treated children.. Nutrition outcomes in patients who received an ITx between December 1996 and February 2007 were retrospectively reviewed. Nutritional analysis included evaluation of differences in weight and height z scores between transplantation and 2 years post-ITx by the type of immunosuppressant therapy received.. A total of 109 children received an ITx during the evaluation period. Of these, 29 received a transplant before March 2002 and received an induction regimen that included anti-T-cell immunosuppressant, tacrolimus (TAC), with prednisone (steroid). The remaining 80 children received an induction regimen of rATG and TAC without steroids (steroid-free). Steroid-free children met their full nutritional requirements enterally or orally in a median of 2 months, whereas children treated with the steroid regimen reached nutritional autonomy 7 months after transplant (P < 0.001). A positive trend in z score values over time for height was observed in 48% of steroid-free patients versus 44% in the steroid regimen. The change in mean z score for linear growth over time was most positive (0.55) in the steroid-free group and <120 days of steroids during the follow-up period with 62% of patients in this group observed to have positive growth over time.. Nutritional autonomy was achieved rapidly, and positive growth was observed in the majority of patients with ITx who received steroid-free immunosuppression with rATG.

Topics: Animals; Antilymphocyte Serum; Body Height; Child; Child, Preschool; Clinical Protocols; Enteral Nutrition; Female; Glucocorticoids; Growth; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestine, Small; Male; Postoperative Complications; Prednisone; Rabbits; Retrospective Studies; T-Lymphocytes; Tacrolimus

Diabetic ketoacidosis in patients receiving tacrolimus in the post-transplant setting is rare. We describe two such cases in solid-organ transplant recipients. The first patient, a 17-year-old male, presented with severe diabetic ketoacidosis and was managed with intravenous fluids and insulin infusion. He was a known case of Laurence-Moon-Bardet-Biedl syndrome and had received a renal transplant 2 years ago and was receiving tacrolimus since then. Although diabetic ketoacidosis resolved in 24 hours, large doses of subcutaneous insulin (upto 130 units per day) were needed to keep serum glucose within the normal range. Substitution of tacrolimus with cyclosporine obviated the need for insulin or oral hypoglycaemics. The second patient, a 55-year-old woman, presented with a history of polyuria for 3 days. She had received a hepatic transplant 2 years ago and tacrolimus was being used since then. Mild diabetic ketoacidosis was managed with fluid resuscitation and subcutaneous insulin. Her insulin requirement after an uneventful recovery has been 54 - 70 units per day. Clinicians should be cognizant of the possibility of hyperglycaemic crisis presenting as sudden onset of diabetic ketocidosis in patients receiving tacrolimus. Use of an alternative calcineurin inhibitor may provide a safer solution to minimize future morbidity in such patients.

Topics: Adolescent; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Immunosuppressive Agents; Injections, Subcutaneous; Insulin; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Treatment Outcome

The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft.. Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2).. The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein-Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002).. When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft.

Topics: Adolescent; Aged; Antibodies, Viral; Azathioprine; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Steroids; Tacrolimus

Early calcineurin inhibitor-induced neurotoxicity (ECIIN) is considered when neurological symptoms occur within 4 weeks after liver transplantation (LT). Risk factors and clinical outcome of ECIIN remain largely unknown. We sought to estimate the incidence, risk factors, and outcome of ECIIN after LT. We retrospectively evaluated 158 patients that underwent LT in a 2-year period and received immunosuppression with calcineurin inhibitors (CNI) and prednisone. ECIIN was considered when moderate/severe neurological events (after excluding other etiologies) occurred within 4 weeks after LT and improved after modification of CNI. Demographic and clinical variables were analyzed as risk factors. Twenty-eight (18%) patients developed ECIIN and the remaining 130 patients were analyzed as controls. History of pre-LT hepatic encephalopathy (OR 3.16, 95% CI 1.29-7.75, P = 0.012), post-LT hyponatremia (OR 3.34, 95% CI 1.38-9.85, P = 0.028), and surgical time >7 h (OR 2.62, 95% CI 1.07-6.41, P = 0.035) were independent factors for ECIIN. Acute graft rejection and infections were more frequent in the ECIIN group. In addition, length of stay was longer in ECIIN patients. In conclusion, pre-LT hepatic encephalopathy, surgical time >7 h, and post-LT hyponatremia are risk factors for ECIIN. Clinical complications and a longer hospital stay are associated with ECIIN development.

Topics: Acute Disease; Aged; Calcineurin Inhibitors; Female; Graft Rejection; Hepatic Encephalopathy; Humans; Hyponatremia; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Variability of blood trough concentration (C0) in immunosuppressant leads to rejection and graft loss after kidney transplantation.. The aim of this study is to prospectively investigate the change of within-patient variability among stable kidney transplant recipients with conversion from twice-daily Prograf to the same milligram-for-milligram daily dose of once-daily Advagraf.. The mean age of 129 patients was 51.3±12.1 years. The conversion to Advagraf was administrated at 6.3±4.8 years after transplantation. The daily dose was changed from 4.7±2.0 mg to 4.9±2.1 mg after conversion. Only six patients increased daily dose by 16.7% to 25% to maintain target levels. The whole blood C0 of tacrolimus before conversion was 5.9±1.7 ng/mL. The mean C0 was significantly reduced after conversion to Advagraf; it was 4.9±1.5 ng/mL on the seventh day (P<0.001) and 5.4 to 5.5 ng/mL at 1 to 6 months (P<0.05). Forty-one (31.8%) patients have reduced C0 of more than 25% on the seventh day. The percent coefficient of variation of tacrolimus C0 more than 22.5% before conversion is associated with higher risk of reduced C0 after conversion (P<0.05). Compared with before conversion, less kidney transplant recipients have percent coefficient of variation more than 22.5% after conversion (3.1% vs. 17.4% with P<0.01).. The results support that conversion from Prograf to Advagraf among kidney transplant recipient leads to a significantly lower C0 and within-patient variability of tacrolimus C0. The within-patient variability of C0 before conversion influences C0 on the sevent day after conversion to Advagraf.

Topics: Adult; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Models, Statistical; Postoperative Complications; Prospective Studies; Regression Analysis; Reproducibility of Results; ROC Curve; Tacrolimus; Time Factors

Hypertension is an important cardiovascular risk factor that influences patient survival. This study sought to evaluate hypertension incidence and circadian rhythms of blood pressure (BP) among liver transplant recipients during the first posttransplant month. We also compared hypertension incidence according to clinical and automated blood pressure monitoring methods. BP was determined by clinical blood pressure monitoring (CBPM) methods and by automated blood pressure monitoring (ABPM) using the SpaceLabs device. We also assessed blood biochemistry, particularly kidney function parameters and immunosuppressive drug blood trough levels, among 32 white subjects (10 women and 22 men) of average age 47.58±14.19 years. The leading cause for transplantation was liver insufficiency due to viral hepatitis B and/or C infection (43.75%). The majority (93.75%) of patients was prescribed immunosuppressive treatment with tacrolimus. Although we observed hypertension in 28 patients (87.5%) by ABPM measurements and in 25 (78.12%) using CBPM method, the difference did not reach statistical significance. However, BP control was inadequate in 28 patients (87.5%) by ABPM assessment versus 3 (9.38%) according to CBPM readings (P=.025). The BP circadian rhythm was altered in 30 patients (93.75%) including 15 with higher nighttime BP readings. There was no correlation between tacrolimus blood levels and BP values or with kidney function as assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We concluded that prevalence of arterial hypertension among liver transplant recipients within 1 month after transplantation is high. The majority of the patients show disturbed circadian rhythms in the early period after liver transplantation with loss or even reversal of the normal nocturnal decrease in BP. Owing to the fact that ABPM enables more adequate daily assessment of BP values, it is an optimal method to adjust antihypertensive therapy to optimal levels.

Topics: Adult; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors

Postlaminectomy epidural fibrosis is the formation of scar tissue over the dura mater following posterior spinal surgery. This devastating complication is responsible for the substantial amount of failed back syndromes. MATERIAL and. Twenty male Wistar-Albino rats each weighing 350-400 grams were used. Following L3-L5 laminectomy, the rats were randomly divided into 2 groups, with 10 rats in each group. In the control group, only a laminectomy was performed. In the drug group, 5 mg/ml tacrolimus was topically applied with a cotton pad soaked with the drug solution for 5 minutes. The animals were killed on the 30th postoperative day injecting a lethal dose (250 mg/kg) of pentobarbital and the involved dural segments were removed for histopathological and ultrastructural evaluations.. Epidural scar thickness and the density were significantly lower in the animals treated with tacrolimus than those of the control group.. Promising evidence regarding the anti-scar potential of tacrolimus merits further research to optimize the dosage and the usage of the drug.

Topics: Administration, Topical; Animals; Cell Movement; Cicatrix; Disease Models, Animal; Dura Mater; Epidural Space; Failed Back Surgery Syndrome; Fibroblasts; Fibrosis; Immunosuppressive Agents; Laminectomy; Lumbar Vertebrae; Male; Microscopy, Electron; Neurosurgical Procedures; Postoperative Complications; Rats; Rats, Wistar; Spinal Canal; Tacrolimus; Treatment Outcome

Topics: Cardiomyopathies; Fusion Proteins, bcr-abl; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Male; Middle Aged; Philadelphia Chromosome; Platelet Count; Postoperative Complications; Tacrolimus

The aim of this paper was to report the case of type 2 diabetes and significant insulin resistance that improved dramatically after removal of a pheochromocytoma in a liver transplant recipient , and to provide a review of the relevant literature. We describe the clinical presentation, diagnostic results and management of the patient. In addition, we performed a PubMed search for related English language articles, to provide an overview of the pertinent literature. A 53 year old woman with a history of an orthotopic liver transplantation and insulin-requiring type 2 diabetes was admitted to the hospital with fever, diaphoresis, tachycardia and hypertension. A pheochromocytoma was diagnosed and removed. The patient subsequently developed hypoglycemia and required no further insulin therapy. Pheochromocytomas have been described to lead to hyperglycemia and diabetes, due to the suppression of insulin release and increased insulin resistance. Furthermore, a review of the literature revealed only 3 other reported cases of pheochromocytomas in organ transplant recipients. None of these pheochromocytomas were believed to have occurred de novo after transplantation. This is the first report of a pheochromocytoma in a liver transplant recipient and possibly the first case of a de novo pheochromocytoma in any organ transplant recipient. Moreover, this case showcases pheochromocytomas as a rare cause of diabetes mellitus.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Diabetes Mellitus, Type 2; Female; Glipizide; Glucocorticoids; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Liver Diseases, Alcoholic; Liver Transplantation; Middle Aged; Pheochromocytoma; Postoperative Complications; Remission Induction; Tachycardia; Tacrolimus

To identify the levels of functional immunity measured by the ImmuKnow assay in Chinese liver transplantation recipients and its application in monitoring the risk of posttransplant infection.. Forty-five apparent healthy Chinese and 106 adult liver transplant (LT) recipients were under investigation. LTs were grouped in stable status or infection according to their clinical diagnosis. Whole blood samples were collected freshly and cultured within 6 hr, the CD4(+) T cells were selected, and their adenosine triphosphate (ATP) value was assayed the next day. Before stimulation, we also examined the percentage of T-helper (Th; CD3(+) CD4(+)) and T-suppress (Ts; CD3(+) CD8(+)) lymphocyte subpopulations and the ratio of Th/Ts.. The average ImmuKnow assay in infectious LT recipients was 128 + or - 84 ng/mL, significantly lower (P<0.05) than that in stable LTs (305 + or - 149 ng/mL) or in normal adults (301+ or - 101 ng/mL). The ImmuKnow values in LTs had a good negative correlation to infection clinically (r = -0.6217, P<0.001). Infectious risk was high when the ImmuKnow value was less than 130 ng/mL (odds ratio=13, 95% confidence interval 6.0-29.4, P<0.01). The sensitivity of low ImmuKnow values in posttransplant infection was 85.2%, significantly higher than those of Th/Ts ratio and immunosuppressant trough levels (P<0.01); specificity was 76.3%, comparable with that of Th/Ts ratio (75.5%), but greatly higher than immunosuppressant trough levels (P<0.01). ImmuKnow ATP values had no correlation with Th/Ts ratio or immunosuppressant trough levels.. ImmuKnow ATP levels are lower in LT recipients with infection, which provides a new tool in monitoring posttransplant infection, and an index of tailoring immunosuppression clinically.

Topics: Adult; Aged; Carcinoma, Hepatocellular; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Environmental Monitoring; Epidemiological Monitoring; Female; Humans; Immunosuppressive Agents; Infections; Liver Neoplasms; Liver Transplantation; Lymphocytes; Male; Middle Aged; Postoperative Complications; Retrospective Studies; T-Lymphocytes, Helper-Inducer; Tacrolimus; Young Adult

Long-term oral corticosteroids have been a mainstay of maintenance immunosuppression in pediatric heart transplantation. In this study, we report early clinical outcomes in a cohort of pediatric heart transplant recipients managed using a steroid-avoidance protocol.. Of the 70 patients who underwent heart transplantation during the study period, 55 eligible recipients, including 49 non-sensitized and 6 sensitized (all 55 with negative crossmatch) patients, entered a steroid-avoidance immunosuppression protocol consisting of thymoglobin induction followed by a 2-drug, tacrolimus-based, corticosteroid-free regimen. The primary outcome variable was freedom from moderate rejection (International Society for Heart and Lung Transplantation [ISHLT] Grade 2R/3A or antibody-mediated rejection).. The median age at transplant was 7.1 years (range 2 weeks to 22 years) and median follow-up was 19 months (range 2 to 46 months). Fifty patients survived to discharge after transplantation. Of these patients, 2 (4%) were discharged on steroids and 8 (16%) started on maintenance steroids at follow-up. Rejection was diagnosed in 8 patients (Grade 2R cellular rejection in 3 and antibody-mediated rejection in 5). Freedom from rejection was 92% at 6 months (95% confidence interval [CI] 80% to 97%) and 87% at 1 year (CI 73% to 94%). Post-transplant survival was 91% at 6 months (CI 79% to 96%) and 88% at 12 and 24 months (CI 75% to 95%). There was 1 death due to rejection (antibody-mediated) 8 months after transplantation.. An immunosuppression protocol consisting of induction followed by corticosteroid avoidance appears to achieve acceptable rejection rates during the first year post-transplant in pediatric heart transplant recipients.

Topics: Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antilymphocyte Serum; Cause of Death; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Postoperative Complications; Survival Rate; Tacrolimus; Young Adult

Intensive glycemic control has been shown to positively impact outcomes in an intensive care setting. Whether this practice is beneficial after liver transplantation (LT) is not known.. A retrospective review of patients undergoing LT from February 2002 to July 2007 was conducted to analyze the association between perioperative hyperglycemia and outcomes after LT. Covariates included preexisting diabetes, mean glucose 3 months pre-LT, need for insulin drip post-LT, mean total glucose during the post-LT hospitalization, age, sex, type of transplant, and model for end-stage liver disease score. Outcomes within 1 year of LT included rejection, infection, rehospitalization, prolonged ventilation, and patient/graft survival.. One hundred thirteen LT and 31 liver-kidney recipients were included. By multivariate logistic regression adjusting for covariates, the rejection rate was significantly lower for patients with postoperative glucose levels less than 200 mg/dL (n=114) vs. more than 200 mg/dL (n=30) (odds ratio: 0.055; 95% confidence interval: 0.0154-0.200; P<0.001). The need for prolonged ventilation was more common in patients with glucose less than 200 vs. more than 200 mg/dL (odds ratio: 4.30; 95% confidence interval: 1.284-14.388; P=0.018). Although other outcomes, infection, rehospitalization, patient/graft survival, were not different among the glucose control groups, rejection was associated with increased rehospitalizations and infections.. Our data demonstrate an association between the immediate posttransplant glycemic control and the development of subsequent rejection. Prospective trials investigating the effects of perioperative glycemic control on outcomes and morbidity after LT are warranted.

Topics: Adult; Aged; Blood Glucose; Female; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Patient Selection; Postoperative Complications; Postoperative Period; Prednisone; Preoperative Care; Regression Analysis; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide.. Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept.. SII was performed 49.3+/-4.8 months (mean+/-SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076+/-492 vs. 9071+/-796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4+/-0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8+/-2.2 vs. 14.2+/-2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%+/-0.2% pre-SII vs. 6.1%+/-0.2% post-SII, P=0.005) and did not become immunosensitized.. Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Topics: Antilymphocyte Serum; Blood Glucose; C-Peptide; Drug Therapy, Combination; Etanercept; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Male; Postoperative Complications; Receptors, Tumor Necrosis Factor; Sirolimus; Tacrolimus

Graft-vs-host disease (GVHD) is a rare complication of transplantation of organs rich in immunocompetent cells. The goal of this study was to report the features of GVHD after small bowel transplantation (SBTx) in children.. The study involved a retrospective review of patients undergoing SBTx between 1999 and 2009 who had GVHD.. Of 46 children receiving 52 intestinal grafts (2 liver-intestine and 3 multivisceral), 5 (10%) developed GVHD. Median age at transplant was 42 (19-204) months. Baseline immunosupression consisted of tacrolimus and steroids supplemented with thymoglobulin (n = 2) or basiliximab (n = 3) for induction. Median time between transplantation and GVHD was 47 (16-333) days. All patients had generalized rash, 2 had diarrhea, and 2 had respiratory symptoms. Other symptoms were glomerulonephritis (n = 1) and conjunctivitis (n = 1). Four developed severe hematologic disorders. The diagnosis was confirmed by skin biopsy in 4 patients and supported by chimerism studies in two. Colonoscopy and opthalmoscopic findings were also suggestive in one. Treatment consisted of steroids and decrease of tacrolimus, with partial response in four. Other immunosuppressants were used in refractory or recurrent cases. Three patients died within 4 months after diagnosis.. Graft-vs-host disease is a devastating complication of SBTx, with high mortality probably associated with severe immunologic dysregulation.

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Child; Child, Preschool; Chimerism; Combined Modality Therapy; Female; Graft Rejection; Graft Survival; Graft vs Host Disease; Humans; Immune Tolerance; Immunosuppressive Agents; Infant; Intestine, Small; Male; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Treatment Outcome

Complications associated with kidney transplantation and immunosuppression can be prevented or treated effectively if diagnosed in the early stages by posttransplant monitoring. One of the major problems is diseases that occur during the first year after kidney transplantation. For this purpose, we used different classifiers to predict events of nephrotoxicity versus acute cellular rejection episodes. The classifiers were evaluated according to values of sensitivity, specificity and area under ROC curves (RCA). The classifier with better accuracy rate for nephrotoxicity achieved the value of 75.68% and RCA classifier reached the accuracy of 80.89%. These results are encouraging, with rates of accuracy and error consistent with work purpose.

Topics: Acute Disease; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Neural Networks, Computer; Patient Selection; Postoperative Complications; Retrospective Studies; ROC Curve; Tacrolimus; Waiting Lists

Posttransplant diabetes mellitus (PTDM) is considered to be a serious complication of kidney transplantation that may reduce patient and graft survival. The immunosuppressant tacrolimus (TAC) increases the risk of developing PTDM.. We sought to estimate the risk of PTDM among renal transplant recipients treated with TAC, to identify other risk factors for PTDM, and to describe its consequences.. We retrospectively analyzed 413 recipients of ages >or=18 years who were free of diabetes before kidney transplantation. They were treated with TAC, cyclosporine (CyA), or sirolimus (SIR) plus steroid therapy with a minimum follow-up posttransplant of 6 months. PTDM was diagnosed according to American Diabetes Association guidelines.. The mean age was 42.3 years and 230 (55.7%) were male. The initial immunosuppression for 171 (41.4%) patients was TAC; 221 (53.5%), CyA; and 21 (5.1%), SIR. PTDM occurred in 85/413 (20.6%) of patients. The median time to PTDM development was 54 days posttransplant. The cumulative incidence of PTDM was 24.6% and 17.2% for TAC and CyA treatment groups, respectively. In the intention-to-treat analysis, the proportion of patients receiving TAC who developed PTDM was significantly higher than that of CyA (HR = 1.6 [1.01-2.42]; P = .04). The Kaplan-Meier method showed that 78.5% patients taking TAC were free of PTDM at 6 months compared with 88.8% taking CyA (P = .003). The other independent risk factors were body mass index (BMI; P < .0001); recipient age (P < .0001) and acute rejection episodes (AE; P = .01). Three-year actuarial graft survivals were 85.5% for PTDM patients compared with 93.3% for those without diabetes (P = .021); patient survivals, 88.9% and 96.7%, respectively (P = .017).. The incidence of PTDM is associated with TAC use, recipient age, BMI, and ARE. Therefore, PTDM is an important risk factor for graft loss and mortality.

Topics: Adolescent; Adult; Body Mass Index; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Tissue Donors

The objective of this study was to identify the incidence of posttransplantation lymphoproliferative disease (PTLD) among children within 1 year after liver transplantation.. This retrospective review analyzed information in medical charts of pediatric (younger than 18 years of age) recipients of liver transplants between September 2000 and December 2007.. Seventy-one patients underwent a liver transplantation and 7 (9.85%) developed PTLD. Among this group, 6 children were girls and 1 was a boy. The median age at transplantation was 35.14 months. Indications that led the children to have their transplantation were 1 case of hemangioendothelioma, 1 case of autoimmune hepatic cirrhosis, 1 case of alpha-1-antitrypsin deficiency, and 4 cases of biliary atresia. The most frequent symptoms were splenomegaly, diarrhea, and fever. The median time from the first symptoms to the initial treatment was 9.7 days. The standard treatment was withdrawal of immunosuppression and close observation of tacrolimus levels and liver function tests associated with antiviral drugs and chemotherapy. Four among 7 children died; 3 children recovered. All 3 children who recovered has presented at the transplantation center within 5 days of initiation of symptoms (P = .033896).. Despite its rarity, when it occurs, PTLD shows a high mortality rate. Therefore, it is necessary to have interdisciplinary work between the medical team that performs the transplantation and those promoting the primary care to diagnose the disease early and treat it effectively.

Topics: alpha 1-Antitrypsin Deficiency; Biliary Atresia; Child; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Splenomegaly; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Bronchoalveolar Lavage Fluid; Diagnosis, Differential; Diarrhea; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Metronidazole; Mycophenolic Acid; Pneumonia; Pneumonia, Bacterial; Pneumonia, Viral; Postoperative Complications; Sirolimus; Tacrolimus; Tomography, X-Ray Computed

Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Cholestasis; Disease Progression; Fatal Outcome; Female; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Living Donors; Lung Transplantation; Methylprednisolone; Pneumonia, Bacterial; Postoperative Complications; Pseudomonas Infections; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

Mycophenolate mofetil (MMF) is routinely used at a fixed dose, but several factors interact to alter the blood level of mycophenolic acid (MPA), resulting in toxicity or treatment failure.. From January 2007 to December 2008, 85 kidney transplantation patients were given a fixed dose of 1.5 g/d of MMF in 12-hour intervals. MPA trough levels were measured on postoperative 1 week, 1 month, 3 months, 6 months, and 12 months.. Mean age of patients was 41 years. Thirty five cases were deceased donor kidney transplantations and 50 were living donor kidney transplantations. Mean trough levels of MPA were 1.04 microg/mL, 1.09 microg/mL, 1.28 microg/mL, 1.83 microg/mL, and 1.69 microg/mL at postoperative 1 week, 1 month, 3 months, 6 months, and 12 months, respectively. Mean trough levels of the subgroup of patients taking cyclosporine were 0.82 microg/mL, 0.94 microg/mL, 1.01 microg/mL, 1.56 microg/mL, and 1.46 microg/mL (n=36). Mean trough levels of the subgroup of patients taking tacrolimus were 1.19 microg/mL, 1.21 microg/mL, 1.56 microg/mL, 2.13 microg/mL, and 2.20 microg/mL (n=49). At 12 months, 31% of all patients experienced one or more opportunistic infections. Eight patients (9.4%) had cytomegalovirus infections, 14 patients (16.5%) had polyomavirus infections, and four patients (4.7%) had parvovirus infections. Ten patients (11.8%) experienced biopsy-proven acute rejection during the follow-up period.. Mean MPA trough levels of patients on 1.5 g/d of MMF reached 1.0 microg/mL within 1 week. Thirty one percent of patients experienced opportunistic infections, and 11.8% of patients had biopsy-proven acute rejections.

Topics: Adult; Cadaver; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Opportunistic Infections; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors

Topics: Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Secondary Prevention; Tacrolimus

Adenovirus is commonly isolated from pediatric small bowel transplant recipients, but its clinical consequences remain poorly understood.. The medical records of pediatric small bowel transplant recipients transplanted between January 2003 and December 2007 were reviewed. Thymoglobulin and basiliximab induction and tacrolimus-based immunosuppression were the standard of care. Logistic regression analysis was performed to determine risk factors for infection, descriptive analysis to determine adenovirus incidence, and Kaplan-Meier curve analysis to determine the timing of events after transplantation.. Ninety-eight patients were included; 38 were positive for adenovirus (incidence 23.5%), 23 for viral shedding, 23 for infections. Nine infections developed in the first month after transplantation and 8 during the following 5 months. The small bowel was involved in 19 cases. Younger age at transplantation was a risk factor for adenovirus infection (odds ratio=0.81, 95% confidence interval, 0.663-0.994, P=0.04). Treatment of rejection did not increase the risk of adenovirus infection. Cytomegalovirus D+/R- sero-status was a protective factor (odds ratio=0.26, 95% confidence interval, 0.06-1.089, P=0.04).. Adenovirus infections affected 24% of recipients and developed mostly during the first 6 months after transplantation. Small bowel is the most frequently involved site. Younger age at transplantation is a risk factor for adenovirus infection; whereas cytomegalovirus D+/R- sero-status seems to be protective.

Topics: Adenoviridae Infections; Antibodies, Monoclonal; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Child; Ganciclovir; Humans; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Postoperative Complications; Recombinant Fusion Proteins; Reoperation; Retrospective Studies; Risk Factors; Tacrolimus; Valganciclovir; Virus Shedding

Routine prophylaxis for CMV with valganciclovir is common in adult recipients but data to support its use in children are scarce. The aim of this study was to compare the efficacy and safety of valganciclovir vs. ganciclovir in a pediatric cohort. We performed a retrospective analysis of 92 children after KTx and/or LTx. All children have received IV ganciclovir for two wk, and then oral ganciclovir (TID; n = 41) before 2004, or valganciclovir (OD; n = 51) thereafter. Treatment was given for three months in R+/D+ or R+/D- recipients and for six months in R-/D+. Patients were followed for one yr post transplant. Both groups were comparable in their demographic and transplant-related history. Symptomatic CMV infection/disease developed in 13.7% vs. 19.5% of valganciclovir and ganciclovir groups, respectively (P-NS). Time-to-onset of CMV infection was comparable in both groups (P-NS); rates of acute allograft rejection were similar in both groups (3.9% vs. 9.8%). Risk factors for CMV infection included young age, serostatus of R-/D+, and allograft from cadaver donor. No significant side effects were noted in both groups. As in adults, valganciclovir appears to be as efficacious and safe as oral ganciclovir. Valganciclovir should be considered as a possible prophylactic treatment for CMV in pediatric recipients of KTx or LTx.

Topics: Administration, Oral; Adolescent; Antiviral Agents; Child; Child, Preschool; Cytomegalovirus Infections; Disease-Free Survival; Drug Therapy, Combination; Female; Ganciclovir; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Logistic Models; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome; Valganciclovir

Topics: Animals; Azathioprine; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Strongyloides stercoralis; Strongyloidiasis; Tacrolimus

Lymphocytic bronchiolitis (LB) has been shown to be an important factor for the subsequent development of obliterative bronchiolitis (OB). We have previously shown that OB, which limits long-term survival after lung transplantation, is associated with lack of suppression of peripheral blood T-cell granzyme B, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha. However, the role of these proinflammatory mediators in LB is unknown. We hypothesized that these proinflammatory mediators may also be increased during LB episodes despite standard immunosuppression regimens.. T-cell intracellular cytokine profiles and granzyme B were studied in whole blood, bronchoalveolar lavage samples, and bronchial brushings from stable lung transplant patients with LB and from healthy controls, using multiparameter flow cytometry.. There was a significant increase in peripheral blood T-cell granzyme B and CD8 T-cell IFN-gamma and TNF-alpha in patients with LB compared with control and stable groups and a decrease in CD25CD127CD3CD8 T regulatory cells in stable and LB transplant patients compared with controls. No changes were noted in the airways.. LB is associated with inadequate suppression of peripheral blood T-cell granzyme B, IFN-gamma, and TNF-alpha. Drugs that effectively reduce these proinflammatory mediators may improve current protocols for treating LB and possibly reduce subsequent progression to OB in lung transplant patients.

Topics: Bronchiolitis; Bronchoalveolar Lavage; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclosporine; Cytokines; Granzymes; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Leukocyte Count; Lung Transplantation; Postoperative Complications; Survival Analysis; T-Lymphocytes; T-Lymphocytes, Regulatory; Tacrolimus; Tumor Necrosis Factor-alpha

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Topics: Biliary Atresia; Child; Child, Preschool; Colonic Neoplasms; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymph Nodes; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisone; Retrospective Studies; Survivors; Tacrolimus

Reactivation of latent BK polyomavirus (BKV) infection is relatively common following renal transplantation and BKV-associated nephropathy has emerged as a significant complication. JC polyomavirus (JCV) reactivation is less well studied. The aim of the study was to determine reactivation patterns for these polyomaviruses in renal transplant recipients using an in-house quantitative real-time multiplex PCR assay and IgG serological assays using recombinant BK and JC virus-like particles.. Retrospective analysis of urine and plasma samples collected from 30 renal transplant patients from February 2004 to May 2005 at Leeds Teaching Hospitals NHS Trust. Samples were collected at 5 days and thereafter at 1, 3, 6 and 12 months post-transplantation.. Eight patients (26.7%) were positive for BK viruria; three of these patients submitted plasma samples and two had BK viraemia. Five patients (16.7%) were positive for JC viruria. A corresponding rise in BKV and JCV antibody titres was seen in association with high levels of viruria.. Different patterns of reactivation were observed: BK viruria was detected after 3-6 months, and JC viruria was observed as early as 5 days post-transplantation. One patient had biopsy-proven BKV nephropathy. No dual infections were seen. In order to ensure better graft survival, early diagnosis of these polyomaviruses is desirable.

Topics: Adult; Aged; Antibodies, Viral; BK Virus; Female; Humans; Immunosuppressive Agents; JC Virus; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Polyomavirus Infections; Postoperative Care; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tumor Virus Infections; Viral Load; Virus Activation

CKD is a major co-morbidity in pediatric lung transplant recipients. We report the prevalence of renal impairment post-lung transplant at a single center, using a modified, age-adjusted eGFR for the best approximation of true GFR, and investigated associations and possible predictors of decline in renal function post-transplant. Renal function was assessed by eGFR pre-transplant, three and 12 months post-transplant, and at last follow-up. Decline in renal function was analyzed as percentage fall in eGFR in two phases (0-3 and 3-12). Furthermore, we investigated impact of gender, age, pre-transplant diagnosis and renal function, transplant type, early post-transplant dialysis, and tacrolimus trough levels on decline in eGFR using multivariate analysis. Over a five-yr period, 30 transplants were performed. Mean eGFR pretransplant was 117 mL/min/1.73 m(2) (s.d. 35) with mean decline in eGFR during the first three months post-transplant of 33% (s.d. 31, p < 0.001). Thereafter, mean decline in eGFR was 8% (s.d. 18, p = 0.02). None of the factors assessed were significantly associated with decline in eGFR post-transplant. In conclusion, many children have decline in renal function following lung transplantation, particularly early post-transplant. Unlike in adults, we were unable to detect any predictors of renal impairment in pediatric lung transplant recipients.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Creatinine; Female; Glomerular Filtration Rate; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Postoperative Complications; Prevalence; Renal Insufficiency, Chronic; Retrospective Studies; Tacrolimus

De novo posttransplant thrombotic microangiopathy (TMA) is a complication of solid organ transplantation, which remains difficult to treat. In many cases, immunosuppressants and particularly calcineurin inhibitors, trigger TMA. Although withdrawing the offending drug may lead to resolution of TMA, graft and patient outcomes are poor. Specific treatments, including plasma exchange, have not gained widespread acceptance in those with fulminant disease and new approaches to the condition are urgently needed. We report a case of posttransplant de novo TMA presenting serially in association with ciclosporin, tacrolimus and sirolimus in a young recipient of a living donor kidney transplant. We describe a patient treated with belatacept, a novel CTLA4 Ig fusion protein, as ongoing maintenance immunosuppression to allow avoidance of conventional agents once associated with TMA. We report excellent early graft outcome, with no adverse events using this strategy. We suggest that belatacept may have a role in this traditionally difficult-to-treat group of patients.

Topics: Abatacept; Adult; Cyclosporine; Female; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus; Tacrolimus; Thrombosis; Tumor Necrosis Factor-alpha

Topics: Antiviral Agents; Fatal Outcome; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Jaundice; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Postoperative Complications; Recombinant Proteins; Ribavirin; Tacrolimus

The development of NODM is a common metabolic complication after liver transplantation. Presentation of post-liver transplant diabetes mellitus with DKA is rare especially among pediatric patients. We reported three pediatric patients who presented with DKA after liver transplantation. The underlying diseases leading to transplantation were cryptogenic liver cirrhosis, Wilson disease, and congenital hepatic fibrosis. None of the three patients had a history of diabetes prior to transplantation and all of them were cases of NODM after transplantation. All three patients presented with severe hyperglycemia, significant ketosis, and metabolic acidosis of variable severity. All of them received tacrolimus as one of the immunosuppressant agents. The patients received a liver transplant from a DD. The patients were treated with intravenous insulin injection (0.1 U/kg/h) and recovered from DKA, but one case expired in the intensive care unit because of bacterial sepsis after recovery from DKA. Our experience suggests that PTDM may result in ketoacidosis, and we emphasize the importance of paying more attention to glucose metabolism and risk of diabetes mellitus in patients with immunosuppressive therapy, especially tacrolimus.

Topics: Adolescent; Child; Diabetes Mellitus; Diabetic Ketoacidosis; Female; Humans; Immunosuppressive Agents; Insulin; Ketosis; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

We developed a novel sustained drug-eluting device using tacrolimus-eluting biodegradable nanofiber to prevent anastomotic stricture and evaluated the effects in a rat abdominal aortic anastomosis model.. In vitro and in vivo tacrolimus release tests for tacrolimus-eluting biodegradable nanofiber were performed to confirm its sustained release. To verify the prevention of anastomotic stricture, tacrolimus-eluting biodegradable nanofiber was placed around the end-to-end anastomosis of abdominal aorta in rats. Five rats were allocated to the following 5 groups: (1) control without tacrolimus-eluting biodegradable nanofiber, (2) 5 mg of nanofiber only (0 wt% of tacrolimus), (3) 5 mg of tacrolimus-eluting biodegradable nanofiber containing 0.04 wt% of tacrolimus, (4) 5 mg of tacrolimus-eluting biodegradable nanofiber containing 0.1 wt% of tacrolimus, and (5) 5 mg of tacrolimus-eluting biodegradable nanofiber containing 1.0 wt% of tacrolimus. Morphometric and histologic analyses including immunohistochemistry were performed in each of the groups 2 weeks after the operation.. The tacrolimus-eluting biodegradable nanofiber gradually released tacrolimus for at least 1 month in vitro and in vivo. The ratio of intimal area was significantly reduced in the 1.0 wt% tacrolimus-eluting biodegradable nanofiber group compared with the other groups (0.26, 0.24, 0.25, 0.21, and 0.08 in control, 0 wt%, 0.04 wt%, 0.1 wt%, and 1.0 wt%, respectively, P < .05). The cells, which constitute intimal hyperplasia, were positive for smooth muscle actin and SMemb, and factor VIII revealed that endothelial cells covered the surface of the aortic lumen even in the 1.0 wt% tacrolimus-eluting biodegradable nanofiber group in immunohistochemistry.. Tacrolimus-eluting biodegradable nanofiber reduced neointimal hyperplasia and preserved endothelialization. This device may be useful in the prevention of anastomotic stricture.

Topics: Anastomosis, Surgical; Animals; Aorta, Abdominal; Aortic Diseases; Biocompatible Materials; Constriction, Pathologic; Models, Animal; Nanostructures; Postoperative Complications; Rats; Rats, Wistar; Tacrolimus

There have been striking changes during the last 10 years concerning the choice of calcineurin inhibitor and antimetabolite agent prescribed after kidney transplantation.. A retrospective analysis of 51,303 patients undergoing deceased-donor kidney transplantation during 1998 to 2007 was performed using multivariate regression analysis. All patients received cyclosporine A (CsA) or tacrolimus (Tac) with azathioprine (AZA) or mycophenolic acid (MPA) on an intention-to-treat basis with corticosteroids plus/minus antibody induction. Graft survival rates and secondary outcomes were analyzed. A subanalysis was performed for transplants undertaken during 2002 to 2007, in which all patients were treated with MPA plus corticosteroids and CsA or Tac.. All-cause graft failure and death-censored graft failure to 5 years posttransplant did not differ significantly between Tac and CsA. We found no evidence in support of previous claims that MPA results in superior long-term graft survival compared with AZA treatment. At the end of year 1, Tac was associated with a lower risk for serum creatinine more than or equal to 130 mumol/L (P<0.001) and hypercholesterolemia (P<0.001) versus CsA, but a higher risk for de novo posttransplant diabetes (P<0.001). MPA treatment was associated with a lower risk of acute rejection (P<0.001) but a higher risk of hospitalization because of infection (P<0.001) versus AZA.. Five-year graft survival in deceased-donor kidney transplant recipients is equivalent in patients receiving CsA- or Tac-based immunosuppression, and in those receiving MPA or AZA. The absence of a survival benefit with modern agents is relevant in the current cost-conscious era of prescribing.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Regression Analysis; Reoperation; Retrospective Studies; Tacrolimus; Treatment Outcome

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.. Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.. PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.. Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Topics: Adolescent; Cadaver; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient.. A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed.. Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism.. Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Topics: Acute Kidney Injury; Anticholesteremic Agents; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Rhabdomyolysis; Simvastatin; Tacrolimus

Because morbidity early after hematopoietic cell transplantation (HCT) results in large part from the development of acute graft-versus-host disease (GVHD), we previously proposed that a longitudinal assessment of morbidity involving the skin, liver, and gastrointestinal (GI) tract might provide a more complete, objective approach for comparing 2 arms of open-label randomized clinical trials for acute GVHD prevention. In this study, we determined both morbidity across time and GVHD across time in a retrospective analysis of a database from an open-label randomized clinical trial comparing tacrolimus/methotrexate and cyclosporine/methotrexate after myeloablative conditioning and marrow transplantation from HLA-matched unrelated donors. The results confirm differences in overall morbidity across time in patients with peak grade II-IV GVHD compared with those with grade 0-I GVHD, but no significant differences in morbidity associated with grade II GVHD compared with grade 0-I GVHD. We observed less skin morbidity and a trend toward less liver morbidity across time in the tacrolimus group (P = .04 and .09, respectively), but not for GI morbidity or overall morbidity, despite significantly decreased skin and liver stages and overall grades of GVHD across time in this group. Thus, our objective assessment of differences in morbidity (regardless of cause) as a measure of acute GVHD in a randomized clinical trial of acute GVHD prevention has only limited utility. The difficulty of demonstrating clinical benefits from objective parameters, such as survival and morbidity, and the subjectivity of grading acute GVHD emphasize the need for blinded assessments in clinical trials of GVHD prevention.

Topics: Acute Disease; Clinical Trials, Phase III as Topic; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Liver Diseases; Methotrexate; Organ Specificity; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Diseases; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

There is evidence showing the importance of reaching immunosuppressant target concentrations as soon as possible. The aim of this study was to evaluate the relationship between tacrolimus trough concentrations within the first week after transplantation and the rate of acute rejection. In this descriptive-analytic study, we included 57 renal transplant patients receiving tacrolimus as the primary immunosuppressive drug. After univariate analysis, donor age, duration of hospital stay, and creatinine clearance (third month) showed significant differences between rejecters and nonrejecters. In addition, mean tacrolimus trough concentrations on day 5, day 7, mean of days 1-7, and mean of days 5-7 were found to be significantly lower in rejecters (P = 0.009, P = 0.012, P = 0.006, and P = 0.035, respectively). Receiver operating characteristic curve analysis with tacrolimus trough concentrations measured on days 5 and 7 was able to discriminate between patients with and without acute rejection (P = 0.028 and P = 0.048 after Bonferroni correction). The tacrolimus trough concentration with the best sensitivity-specificity balance was 9.3 ng/mL on day 5 and 8.7 ng/mL on day 7. In the Kaplan-Meier analysis, patients with tacrolimus trough concentrations below 9.3 mg/mL on day 5 showed a lower survival time without acute rejection (P = 0.048 after correction) in comparison with patients with tacrolimus trough concentrations above this concentration. After logistic regression, we obtained a model relating rejection with sex, donor age, and tacrolimus trough concentrations on day 5 (P = 0.004). No significant relationship between tacrolimus trough concentrations and delta creatinine clearance from week 1 to month 3 was obtained. These results confirm that tacrolimus trough concentrations during the first week are an important predictor of acute rejection. Therefore, it is critical to reach target blood concentrations of tacrolimus as soon as possible to improve allograft survival.

Topics: Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

A cyclosporine (CsA)-based immunosuppression is associated with an increased incidence of cholelithiasis after heart transplantation. It is not known if tacrolimus (Tac) has comparable biliary side effects in humans. We evaluated the incidence of gallbladder sludge and cholelithiasis under Tac-based immunosuppression by ultrasound examinations in 31 cardiac transplants (25 male, 6 female, mean age: 59 ' 11 years). Data were compared to 57 patients (47 male, 10 female, mean age: 58 ' 11 years) who received CsA-based immunosuppression. 6 patients receiving Tac and 6 patients receiving CsA had already gallstones prior to transplantation so that finally 25 patients of the Tac group and 51 patients of the CsA group could be evaluated. In the Tac group the incidence of biliary sludge was 4% (1 of 25), of gallstones 28% (7 of 25). In comparison, patients receiving CsA developed biliary sludge in also 4% (2 of 51) and gallstones in 25% (13 of 51). Nine of 42 males in the CsA group (21%) and eight of 20 males in the Tac group (40%) developed either gallstones or sludge (n.s). Six of nine females in the CsA group (67%), but none of five females in the Tac group (0%) developed either gallstones or sludge (p = 0.01). In summary, the incidence of biliary disease in patients with Tac is comparable with CsA-based immunosuppression. We recommend regular sonographical examinations to detect biliary diseases as early as possible. In cases of clinically, laboratory and sonographical signs of cholecystitis cholecystectomy is indicated. It seems that towards lithogenicity female patients benefit more from a Tac-based treatment because the occurrence of gallstones is rare.

Topics: Cholecystolithiasis; Cyclosporine; Female; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Tacrolimus

New-onset diabetes after transplantation is an important complication of renal transplantation. Few studies have examined nondiabetic renal transplant recipients for occult defects in insulin sensitivity or secretion. The aims of this study were to identify abnormalities of glucose metabolism in nondiabetic, tacrolimus-treated renal transplant recipients more than 6 months posttransplantation and characterize determinants.. Eighteen nondiabetic renal transplant recipients and 20 healthy control subjects were examined with a frequently sampled intravenous glucose tolerance test and meal tolerance test to derive first-phase insulin secretion (FPIR), insulin sensitivity, and second-phase insulin secretion.. FPIR was higher in controls compared with transplant recipients (2225 vs. 1173 pmol/L; P=0.003). In transplant subjects, there was a strong positive linear correlation between glomerular filtration rate (GFR) and FPIR (Pearson correlation r=0.7; P=0.002). There were strong negative correlations between trough tacrolimus concentration at study entry (r=-0.56; P=0.01) and 3-month tacrolimus exposure (r=-0.49; P=0.02) with GFR, but not with FPIR.. Nondiabetic renal transplant recipients had lower FPIR than controls with normal renal function. Declining FPIR predicts type 2 diabetes in the general population. Interpreting the relationship between FPIR and GFR requires exploration of dual tacrolimus toxicity on both renal and pancreatic beta-islet cell function.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incidence; Insulin; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Time Factors; Waist-Hip Ratio

Tacrolimus has been shown to be an important immunosuppressive agent in organ and bone marrow transplantation. Previously, we reported that there were no statistically significant differences between the pharmacokinetic parameters of the oral formulation of generic tacrolimus (TacroBell) and the conventional formulation (Prograf). This study was designed to evaluate the efficacy and safety of oral capsules of TacroBell in de novo renal transplantation.. Ninety-six renal transplant recipients from 9 transplantation centers in South Korea were enrolled between November 2005 and July 2007. De novo renal recipients ranged from 19-65 years old. Ninety-four patients who underwent renal transplantation were administered study drug at least one time in the intent-to-treat (ITT) analysis. This phase 4 clinical trial was a 26-week, open-label, noncomparative, multicenter study.. An acute rejection episode developed in 10/94 recipients (10.6%, 95% confidence interval, 4.4%-16.9%). There were no patient deaths during the study. The 6-month graft survival rate was 96.8%.. Based on this study, treatment with TacroBell is considered to be efficient and safe after primary renal transplantation.

Topics: Adult; Creatinine; Drugs, Generic; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pilot Projects; Postoperative Complications; Safety; Tacrolimus

Most reported data on posttransplantation diabetes mellitus (PTDM) are from Western countries with patients who underwent deceased donor liver transplantation. A retrospective study was performed to assess the prevalence and predictive factors of PTDM in the context of living donor liver transplantation (LDLT) in the Chinese population using the definition of PTDM proposed in 2003 by the World Health Organization and the American Diabetes Association. The prevalence of DM after LDLT in our study was 25% (21/84), and the incidence of PTDM was 14.9% (11/74) with 64% of cases diagnosed within 3 months after LDLT; 9.5% were observed to show impaired fasting glucose postoperatively. Multivariate analysis identified body mass index >or= 25 kg/m(2) before LDLT as the only independent risk factor for developing PTDM. Only one patient was operated for hepatitis C virus (HCV) infection. Hepatitis B virus (HBV)-related diseases were common in our study population, accounting for 78.6% of all patients. Both HCV and HBV infection status were not independent risk factors for developing PTDM. In addition, a greater tacrolimus trough blood level in the PTDM group versus no-DM group was observed at 3 months post-LDLT (11.03 ng/mL vs 4.87 ng/mL). The mean tacrolimus dose was not significantly different between the two groups. In conclusion, PTDM was prevalent among Chinese LDLT recipients.

Topics: Adult; Blood Glucose; China; Diabetes Mellitus; Female; Glucose Intolerance; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus

New-onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients. We conducted a retrospective single-center analysis (2002-2008) in order to assess NODAT the first year posttransplantation as defined by American Diabetes Association criteria. Serum magnesium (Mg) levels were defined as the median of all Mg levels registered during the first month posttransplantation. Patients with NODAT (N = 75; 29.5%) versus non-NODAT had lower Mg levels (p < 0.001). Patients with an Mg level < versus > or = 1.9 mg/dL showed a faster development of NODAT (log-rank p < 0.001). Mg levels were lower in patients on calcineurin inhibitors (CNI) versus no CNI patients (p < 0.001). Mg levels, albumin, BMI, triglycerides, posttransplantation hyperglycemia, tacrolimus levels and the use of sirolimus were predictors of NODAT in the multivariate analysis. Hypomagnesemia was an independent predictor of NODAT in renal transplant recipients. We confirm that the use of CNI is associated with NODAT, but, to a large extent, this effect seems attributable to the induction of hypomagnesemia. After adjustment for Mg, sirolimus was also associated with NODAT.

Topics: Aged; Body Mass Index; Calcineurin Inhibitors; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnesium; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Sirolimus; Tacrolimus; Triglycerides

Epstein-Barr virus (EBV)-driven posttransplantation lymphoproliferative disease (PTLD) is a serious complication of immunosuppression after either stem cell transplantation (SCT) or solid organ transplantation (SOT). Adoptive transfer of EBV-specific cytotoxic T lymphocytes (EBV-CTLs) is an effective prophylaxis and treatment for PTLD after SCT, but not for PTLD after SOT when pharmacologic immunosuppression cannot be discontinued. We report the generation of calcineurin (CN) mutants that render EBV-CTL resistant to the immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA): mutant CNa12 confers resistance to CsA but not FK506, and mutant CNa22 confers resistance to FK506 but not CsA, whereas mutant CNb30 renders CTLs resistant to both calcineurin inhibitors. Untransduced EBV-CTLs do not proliferate in the presence of FK506/CsA. However, EBV-CTLs transduced with a retroviral vector coding for these mutants retain the ability to both proliferate and secrete normal levels of interferon-gamma in the presence therapeutic levels of FK506 (CNa12), CsA (CNa22), or both (CNb30). The cytotoxicity and phenotype of EBV-CTL lines were unaffected by expression of these mutant CNs. This approach should allow effective immunotherapy with EBV-CTLs in the SOT setting without risking the graft by reduction in immunosuppression, and represents a generic approach to improving immunotherapy in the face of immunosuppression.

Topics: Adoptive Transfer; Calcineurin; Calcineurin Inhibitors; Cells, Cultured; Cyclophilin A; Cyclosporine; Cytotoxicity, Immunologic; Drug Resistance; Epstein-Barr Virus Infections; Genetic Vectors; Humans; Immunosuppressive Agents; Interferon-gamma; Jurkat Cells; Lymphoproliferative Disorders; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Organ Transplantation; Postoperative Complications; Protein Conformation; Protein Interaction Mapping; Recombinant Fusion Proteins; Retroviridae; T-Lymphocytes, Cytotoxic; Tacrolimus; Tacrolimus Binding Protein 1A

Fulminant hepatic failure is a rare complication of infection by varicella zoster virus that is favored by immunosuppression. Within 1 week, a 43-year-old male heart transplant recipient who was admitted with epigastric pain successively developed a generalized vesicular rash, hepatitis, and secondary multiorganic failure involving encephalopathy, despite treatment with acyclovir (since Day 2) and varicella zoster virus immunoglobulin (since Day 6). Emergency liver transplantation was performed on Day 9, and 36 months later, his heart and liver function are normal.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Cyclosporine; Heart Transplantation; Hemoglobinopathies; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunosuppressive Agents; Liver Failure, Acute; Liver Function Tests; Male; Postoperative Complications; Prothrombin Time; Tacrolimus; Treatment Outcome

Sirolimus, a macrolide with immunosuppressive properties, was introduced into clinical practice a decade ago. The optimal use of this drug remains controversial: It displays a wide range of organ and tissue toxicities owing to the critical role of its therapeutic site- the kinase mammalian target of rapamycin-in the signal transduction pathways of numerous cytokines, growth factors, hormones, and nutrients. However, it displays unique, recognized benefits for renal transplant recipients: synergistic interactions with cyclosporine and possibly tacrolimus, allowing marked reduction in exposure to the calcineurin inhibitor; reduction in the frequency of posttransplant malignancies, particularly lymphomas, Kaposi sarcomas, and hypernephromas; and modest nephrotoxicity in comparison with calcineurin inhibitors. Because of its inhibitory effects on endothelial and smooth muscle cell proliferation, sirolimus may be a useful tool to dampen chronic vasculo-obliterative processes that attenuate graft survival. With increasing experience with the drug, the true potential of sirolimus will be realized to be a critical element in the immunosuppressive matrix.

Topics: Calcineurin Inhibitors; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Sirolimus; Tacrolimus

Hepcidin is a small, defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. We studied correlations of hepcidin concentrations with markers of iron status, erythropoietin therapy, and markers of inflammation among 130 kidney allograft recipients. In addition, we assessed the prevalence of anemia and its relation to hepcidin. Soluble receptor of transferrin (sTfR), high-sensitivity C-reactive protein (hsCRP), TNF-alpha, interleukin (IL)-6, prohepcidin, and hepcidin were measured using commercially available kits. According to the WHO definition, the prevalence of anemia was 28%. Among anemic recipients we found a significantly higher values of serum creatinine, serum prohepcidin, hepcidin, (hsCRP), TNF-alpha, IL-6, ferritin, and proteinuria in addition to more frequent use of rapamycin and significantly lower use of CSA with lower CSA concentrations, as well as lower cholesterol, hemoglobin, and estimated glomerular filtration rate (eGFR) (by the Modification of Diet in Renal Disease equation). Serum prohepcidin significantly correlated with creatinine, GFR, time after transplantation, albumin, hsCRP, IL-6, and TNF-alpha, whereas hepcidin-25 correlated with serum iron, ferritin, hsCRP, IL-6, hemoglobin, transferrin saturation (TSAT), creatinine, and GFR. Multiple regression analysis showed that prohepcidin was independently related only to GFR and ferritin. Upon multiple regression analysis, predictors of serum hepcidin were eGFR, ferritin, and hsCRP, explaining 79% of the variation of hepcidin values. In conclusion, the prevalence of anemia was relatively high among a population of kidney allograft recipients. The pathogenesis of anemia is mulitfactorial. Elevated hepcidin levels among kidney transplant recipients may be due to low-grade inflammation, which is frequently encountered in this population, and mainly to impaired renal function, but it did not seem to be a major pathogenetic factor for anemia in this population.

Topics: Analysis of Variance; Anemia; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cholesterol; Creatinine; Cross-Sectional Studies; Cyclosporine; Drug Therapy, Combination; Erythrocyte Count; Glomerular Filtration Rate; Hematocrit; Hepcidins; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Prednisone; Regression Analysis; Tacrolimus; Transplantation, Homologous; Triglycerides; Urea

Topics: Adult; Antiviral Agents; Critical Care; Diagnosis, Differential; Disease Outbreaks; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza, Human; Intensive Care Units; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Opportunistic Infections; Oseltamivir; Postoperative Complications; Prednisone; Respiratory Insufficiency; Tacrolimus

A main cause for gastrointestinal (GI) complications in graft recipients is the routinely administered inosine monophosphate dehydrogenase inhibitor mycophenolic acid (MPA). MPA is available in two formulations, the prodrug mycophenolate mofetil (MMF) and the enteric-coated sodium salt (EC-MPS). Clinical results point to a better GI tolerability of EC-MPS as compared to MMF. We performed an open surveillance study in 397 organ graft recipients to investigate the clinical tolerability of EC-MPS in renal graft recipients who were converted from MMF to EC-MPS (maintenance) or who received EC-MPS as a new component of their immunsuppressive regimen (de novo). Physicians recorded GI symptoms (nausea, emesis, anorexia, diarrhea, abdominal cramps) at the start of EC-MPS treatment (visit 1) and at the next two visits in the clinic (visits 2 and 3); general tolerability (very good/good/moderate/poor) was assessed at visit 2 and 3. Two hundred seventy-five patients were on maintenance treatment with MMF and were converted to equimolar doses of EC-MPS, and 122 patients received EC-MPS de novo. The mean time since transplantation was 4.2 +/- 4.4 years. Median time until visit 2 was 28 days and until visit 3, 65 days. In 63.0% of patients, tolerability was rated as very good at visit 2 and in 64.7% at visit 3. Most patients who had suffered from GI complications during preceding MMF treatment reported improvement or total disappearance of their symptoms after conversion to EC-MPS. In conclusion, EC-MPS is a useful means to reduce GI complications in MPA-treated patients.

Topics: Adult; Cyclosporine; Female; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prodrugs; Tablets, Enteric-Coated; Tacrolimus; Tissue Donors

In renal transplant recipients, cyclosporine treatment appears to cause more frequent hyperlipidemia than tacrolimus usage. In this study, hyperlipidemic renal transplant recipients who use cyclosporine were investigated for changes in high-density lipoprotein (HDL)-2/3, apolipoprotein (Apo) A1/B, other lipid and biochemical parameters, and body mass index after prospective cyclosporine to tacrolimus switching.. Fifteen patients, including 9 females of overall mean age of 33.2 +/- 10.7 years and posttransplantation time of 78.06 +/- 42.93 months with a mean body mass index of 23.77 +/- 3.34 kg/m(2), were included if they were nondiabetic, hyperlipidemic, and had undergone renal transplantation between 1992 and 2000, using cyclosporine and candidates for a switch to tacrolimus due to hyperlipidemia. Before switching to tacrolimus and at 12 months of tacrolimus use we studied fasting blood samples for creatinine, uric acid, glucose, triglyceride, Apo A1, Apo B, low-density lipoprotein (LDL), HDL2, HDL3, and total cholesterol.. There were no significant differences in creatinine, uric acid, glucose levels, or body mass index before tacrolimus versus 12 months thereafter. It was observed that tacrolimus significantly decreased triglyceride, Apo A1, Apo B, LDL, HDL, and total cholesterol levels (P < .001; P = .006; P = .01; P < .001; P = .03; P .05).. Switching from cyclosporine to tacrolimus was associated with a more favorable cardiovascular risk profile by improving hyperlipidemia.

Topics: Adult; Body Mass Index; Cardiovascular Diseases; Cyclosporine; Female; Homocysteine; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Lipoprotein(a); Lipoproteins, HDL; Male; Patient Selection; Postoperative Complications; Tacrolimus; Treatment Outcome; Triglycerides; Young Adult

To clarify the demographic data, outcomes and complications of renal transplantation in children at Srinagarind (university) Hospital.. The authors reviewed the medical records of children with end-stage renal disease (ESRD) who received renal transplantation at Srinagarind Hospital, Khon Kaen, between August 2001 and July 2008.. Eight male and seven female patients were identified Their mean age was 12.8 +/- 3.2 years (range, 5.0-17.6). The major cause of ESRD was a congenital anomaly of the kidneys (53%). All of the children received cadaveric transplantations and none received induction therapy. Triple immunosuppressive drugs comprising cyclosporine, prednisolone and mycophenolate mofetil were administered to 12 patients. Tacrolimus, instead of cyclosporine, was given to three patients who had received a renal transplant since January 2008. The median follow-up time was 15 months (3 to 82 months). The most frequent complication was urinary tract infection (40%). Acute graft loss was found in one patient (6.7%) due to graft infarction. Other complications included herpes viral infection, chronic rejection, acute rejection, severe gingival hyperplasia, myopathy, lymphocele and transitional cell carcinoma of the bladder. Two patients returned to dialysis due to graft infarction and chronic rejection, respectively. The mean serum creatinine at the last follow-up of the remaining cases was 1.2 +/- 0.5 mg/dL (range, 0.6-2.3). All of the patients survived. The 1- and 5-year graft survival rates were 93.3% and 86.7%, respectively.. The present study demonstrates the potential for successful outcomes of pediatric renal transplantation in this resource-limited area.

Topics: Adolescent; Age Factors; Cadaver; Child; Child, Preschool; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Intensive Care Units, Pediatric; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Thailand

We identified pediatric liver transplant recipients with successful withdrawal of immunosuppression who developed tolerance in Korea.. Among 105 pediatric patients who received liver transplantation and were treated with tacrolimus-based immunosuppressive regimens, we selected five (4.8%) patients who had very low tacrolimus trough levels. Four of them were noncompliant with their medication and one was weaned off of immunosuppression due to life threatening posttransplant lymphoproliferative disorder. We reviewed the medical records with regard to the relationship of the donor-recipients, patient characteristics and prognosis, including liver histology, and compared our data with previous reports.. Four patients received the liver transplantation from a parent donor and one patient from a cadaver donor. A trial of withdrawal of the immunosuppressant was started a median of 45 months after transplantation (range, 14 months to 60 months), and the period of follow up after weaning from the immunosuppressant was a median of 32 months (range, 14 months to 82 months). None of the five patients had rejection episodes after withdrawal of the immunosuppression; they maintained normal graft function for longer than 3 years (median, 38 months; range, 4 to 53 months). The histological findings of two grafts 64 and 32 months after weaning-off of the medication showed no evidence of chronic rejection.. The favorable markers for successful withdrawal of immunosuppression were 1) long-term (> 3 years) stable graft function, 2) no rejection for longer than 1 year after withdrawal of immunosuppression, 3) non-immune mediated liver diseases, and 4) pediatric patients.

Topics: Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Korea; Liver; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

New-onset diabetes after transplantation (NODAT) has been associated with cardiovascular and thrombotic complications, acute rejection, and infection in transplant recipients. NODAT in kidney transplantation is well described; however, data are lacking in liver transplant recipients.. To evaluate the incidence of new-onset diabetes within 6 months postoperatively in adult liver transplant recipients. DESIGN, PARTICIPANTS, SETTING, AND INTERVENTIONS: Patients who underwent a liver transplantation at our institution between January 2004 and December 2005 were retrospectively evaluated. NODAT was defined according to the diagnostic criteria of the American Diabetes Association/World Health Organization, persistent hyperglycemia (serum glucose > or = 200 mg/dL occurring 2 weeks after initial steroid induction and persisting for more than 2 weeks), or the need for hypoglycemic agents upon discharge.. Incidence of NODAT within 6 months after transplantation in patients with poor glycemic control within the first 2 weeks after transplantation, acute rejection episodes, infections, hospital readmissions, and cardiovascular and thrombotic events.. Forty-five patients were evaluated. Within the first 6 months after transplantation, NODAT developed in 11 (24%). Acute rejection, infection, hospital readmissions, cardiovascular events, and thrombotic events did not differ between the groups.. Elevated fasting levels of blood glucose during the first 2 weeks after liver transplantation may be associated with an increased incidence of NODAT and may have predictive value. More studies are needed to determine the effects of recognition and treatment of hyperglycemia in recent transplant recipients.

Topics: Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Postoperative Period; Prognosis; Retrospective Studies; Risk; Tacrolimus; United States

New-onset post-transplantation food allergy has been described mainly after liver transplantation, and its pathogenesis was attributed to the immunomodulatory effects of tacrolimus therapy. The aim of the present study was to evaluate the association of food allergy with solid organ transplantation in our center. The medical records of children who underwent kidney transplantation and children who underwent liver or liver and kidney transplantation from 1986 to 2005 were reviewed. A total of 189 children (124 after kidney transplantation, 65 after liver or liver and kidney transplantation) received tacrolimus as part of the immunosuppressive regimen. New-onset post-transplantation food allergy was documented in four of them: two with liver transplants and two with combined kidney and liver transplants. The absence of new-onset food allergy in the children with isolated kidney transplants is compatible with other reports in the literature. This study supports the concept that the functioning liver itself, and not only tacrolimus immunosuppression, is a main contributor to food allergy in this patient population.

Topics: Adolescent; Child; Child, Preschool; Female; Food Hypersensitivity; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver; Liver Transplantation; Male; Postoperative Complications; Retrospective Studies; Tacrolimus

Transient hyperphosphatasemia was found in a 3-year-old male liver transplant recipient. The condition was associated with diarrheal disease due to the Epstein-Barr virus (EBV). Immunosuppression was tapered and valganciclovir prescribed for 3 months, after which the diarrhea resolved and the EBV polymerase chain reaction assays became negative. After 6 months, alkaline phosphatase levels normalized. Isolated elevation of alkaline phosphatase in conjunction with enteric infection is a rare condition. No further diagnostic or therapeutic interventions except treatment of the underlying infection are needed, as this has been shown to be a benign, transient condition.

Topics: Adult; Child, Preschool; Cholestasis; Enteritis; Epstein-Barr Virus Infections; Family; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Phosphoric Monoester Hydrolases; Phosphorus Metabolism Disorders; Postoperative Complications; Tacrolimus; Treatment Outcome

Bartonella henselae is the causative agent of cat-scratch disease and other disorders, including hepatosplenic granulomatosis. This infection has only rarely been reported after solid organ transplantation, where it can mimic the more common post-transplant lymphoproliferative disease. Here we present a case of asymptomatic B. henselae hepatic and lymph nodal granulomatosis in a pediatric patient who had received orthotopic liver transplant 2 months before; we hypothesize that the causative agent was transmitted from the donor. This infection developed early in the post-transplant period; the disease involved only the graft liver and the regional lymph nodes, and the patient did not have a cat or any history of contact, scratches, or bites by a cat. In our patient this infection resolved successfully with a combination of 2 associated antibiotics and reduction of immunosuppressive therapy.

Topics: Amikacin; Anti-Infective Agents; Antibodies, Bacterial; Azithromycin; Bartonella henselae; Cat-Scratch Disease; Child; Humans; Immunosuppressive Agents; Liver; Liver Neoplasms; Liver Transplantation; Lymph Nodes; Lymphomatoid Granulomatosis; Male; Postoperative Complications; RNA, Bacterial; RNA, Ribosomal, 16S; RNA, Ribosomal, 23S; Tacrolimus; Tissue Donors; Transplants; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Ultrasonography

Several groups identified pre-transplant factors which contribute to the development of new onset of diabetes after transplantation (NODAT).. To identify post-transplant risk factors for NODAT.. 55 stable renal transplant patients were divided into group A of 34 recipients with normoglycemia and group B of 21 recipients with impaired fasting glucose. Markers including insulin, pro-insulin, soluble receptors for advanced glycated end products (sRAGE), adiponectin, malondialdehyde, homeostasis model assessment of insulin resistance (HOMA-IR), and beta-cell function were calculated at the outset and correlated, thereafter, with the later development of NODAT after a follow-up duration of 14.98 +/- 3.97 months.. 11.8 and 19% of groups A and B respectively developed NODAT. Insulin, sRAGE, HOMA-IR and basal fasting plasma glucose correlated with the development of NODAT in univariate analysis. A baseline insulin level of 54.54 mU/l predicted the development of NODAT with a specificity of 95.45% and was the only significant factor in the multivariate analysis. beta-Cell function was not different among the three groups.. A long prodrome of insulin resistance (IR) exists prior to development of NODAT. 50% of patients with NODAT will remit to a normoglycemic state. IR, rather than beta-cell dysfunction, precedes the development of NODAT. Serum insulin in stable non-diabetic renal transplant patients can be used as a confirmatory test to the development of future NODAT.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Prospective Studies; Risk Factors; Sensitivity and Specificity; Tacrolimus

Orthotopic liver transplantation (OLT) is a successful therapy for patients with end-stage liver disease, and infection remains a significant cause of morbidity and mortality for patients undergoing this procedure. To assess humoral and cellular immunity markers as potential risk factors for development of infection, 46 consecutive liver transplant recipients (hepatitis C virus cirrhosis [n=17], alcoholic liver disease [n=15], hepatocellular carcinoma [n=9], autoimmune hepatitis [n=2], and other [n=3]) performed at a single center were prospectively studied. Maintenance therapy included tacrolimus (n=37) or cyclosporine (n=9) and prednisone. During follow-up, 27 patients had at least 1 episode of infection (58.7%). Pre-OLT immunoglobulin G (IgG) hypergammaglobulinemia (relative risk [RR] 2.78; 95% confidence interval [CI], 1.17-6.60, P=0.02), pre-OLT IgA hypergammaglobulinemia (RR 2.77, CI=1.24-6.19, P=0.012), and pre-OLT C3 hypocomplementemia (RR 3.02, CI=1.21-7.55, P=0.018) were associated with an increased risk for development of infection. Monitoring of Ig and complement levels might help to identify the risk of developing infection in OLT.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antibody Formation; Biomarkers; Communicable Diseases; Complement C3; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunity, Cellular; Immunoglobulins; Immunosuppression Therapy; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Lymphocyte Count; Male; Middle Aged; Monitoring, Immunologic; Postoperative Complications; Prednisone; Prognosis; Prospective Studies; Risk Factors; Spain; Survival Analysis; T-Lymphocytes; Tacrolimus

In this study we describe 3 single lung transplant recipients who developed unilateral pulmonary edema in the setting of cardiac and renal dysfunction. All 3 patients responded to diuresis with clinical and radiographic improvement. Unilateral cardiogenic pulmonary edema should be considered in the differential diagnosis of dyspnea and unilateral radiographic infiltrates in single lung transplant recipients.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Disease; Echocardiography, Doppler; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Edema; Radiography, Thoracic; Sirolimus; Tacrolimus; Treatment Outcome; Tuberous Sclerosis

The safety and efficacy of tacrolimus in transplantation are well established. However, tacrolimus (Pan Graf) has only been available in India for the last 2 years. We conducted this study to assess the safety and efficacy of tacrolimus in living related kidney transplantation. Herein we have reported our experience with tacrolimus as de novo therapy in a living related renal transplant program.. One hundred fifty-five consecutive recipients of living donor renal allografts were included in this study after consent and ethical clearance. Immunosuppression consisted of tacrolimus, mycophenolate mofetil or azathioprine, and steroids. The dose of tacrolimus was adjusted according to levels done on a regular basis. All patients were followed for periods ranging from 3 to 33 months. All episodes of graft dysfunction were evaluated by a graft biopsy. We evaluated the effects of this regimen on the incidence of graft rejection, graft survival, patient survival, and new onset diabetes mellitus. Six patients were diabetic prior to transplantation and 9 patients were hepatitis C virus (HCV) positive.. There were 137 male and 18 female patients. The incidence of acute rejection was 3.87%; 17.93% developed new onset diabetes mellitus; and 77.7% of HCV-positive patients and 14.07% of HCV-negative patients developed posttransplantation diabetes mellitus. The patient survival at the current follow-up was 94.19%.. This generic form of tacrolimus is a safe, effective immunosuppressant in living related renal transplantation.

Topics: Drugs, Generic; Family; Graft Survival; Humans; Immunosuppressive Agents; India; Kidney Transplantation; Living Donors; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus

The purpose of this study was to analyze the effects of immunosuppressants on hepatitis C virus (HCV) replication to establish optimal immunosuppressive therapy in HCV-positive renal transplantation.. Cyclosporine (CsA), tacrolimus (Tac), mycophenolate acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and methylprednisolone (MP) were administered to HCV replicon cells alone or in combination with interferon (IFN). HCV RNA was quantitatively determined. Of our 2064 recipients of renal transplantations between 1980 and 2005, 153 were HCV-positive. We analyzed changes in hepatic function and the efficacy of IFN therapy in these patients.. Only CsA strongly inhibited the growth of HCV RNA (13.1% at 1.0 microg/mL). MPA enhanced the inhibition of the growth of HCV RNA in the presence of IFN. Tac and MP reduced, rather than enhanced, the efficacy of IFN. Progression to chronic hepatitis occurred in a significantly smaller number of patients in the CsA than the Tac group (6 vs 19; P = .04). Serum alanine aminotransferase (ALT) levels were comparable pretransplantation and posttransplantation in the CsA group (24.8 +/- 20.5 vs 28.9 +/- 28.3 IU/L, respectively, while a significant elevation was noted in the Tac group (22.2 +/- 21.5 vs 32.6 +/- 30.8 IU/L, respectively; P = .024). Two of 4 patients who underwent combination therapy with IFN and ribavirin during treatment with CsA and MMF obtained an HCV-negative status for over 24 weeks.. CsA effectively prevents the progression of chronic hepatitis in HCV-positive renal transplant patients. A greater response rate can be expected by concurrent administration of CsA and MMF under IFN therapy.

Topics: Alanine Transaminase; Cyclosporine; Disease Progression; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Immunosuppressive Agents; Japan; Kidney Transplantation; Postoperative Complications; Retrospective Studies; RNA, Viral; Tacrolimus; Virus Replication

Central pontine myelinolysis (CPM) is the most serious central nervous system complication that could be seen after liver transplantation and represents an important source of mortality early after liver transplantation. CPM following liver transplantation was reported more and more in literatures, but the true incidence of CPM after living related liver transplantation (LDLT) remains unknown. However, with the introduction of magnetic resonance imaging (MRI), early recognition has become possible. In this report, we present a case of rapid resolution of CPM followed by MRI examinations.

Topics: Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Magnetic Resonance Imaging; Middle Aged; Myelinolysis, Central Pontine; Postoperative Complications; Tacrolimus

It has been suggested that avascular osteonecrosis (AVN) of the femoral head develops early after renal transplantation. We evaluated the relationship between risk of AVN and dose of steroids administered in different time periods.. Development of AVN was determined using MRI at 3-6 weeks, 9-12 weeks, 24 weeks, and 12 months after transplantation in 150 patients (96 males). We investigated possible associations between acute rejection reactions, the dose of cyclosporine, tacrolimus use, total steroid dose by the second, fourth, sixth, or eighth weeks after transplantation, and incidence of AVN.. There was no statistically significant difference between incidence of AVN and presence or absence of an acute rejection reaction. We found a statistically significant association between AVN incidence and the total dose of steroids administered during the first 2 months after transplantation, and there was a doseresponse relationship. No other statistically significant associations were found.. Our findings confirm that the total dose of steroids given within the first 2 months after renal transplantation has a great influence on the incidence of AVN.

Topics: Adolescent; Adult; Cyclosporine; Dose-Response Relationship, Drug; Female; Femur Head Necrosis; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Prednisolone; Risk Factors; Tacrolimus; Time Factors

The purpose of this study was to determine the utility of post-transplant serum soluble CD30 levels as a biomarker for the development of the bronchiolitis obliterans syndrome (BOS) after lung transplantation during a tacrolimus/mycophenolate mofetil-based regimen.. Soluble CD30 (sCD30) concentrations were measured prior to transplantation and in 175 samples taken after transplantation in 7 patients developing BOS and 7 non-BOS patients closely matched for age, underlying diseases, follow-up and gender.. High pre-transplant sCD30 levels dropped significantly after lung transplantation, but in the post-transplant samples no differences could be detected between patients developing BOS or not, and no changes were found prior to or during the development of BOS.. After transplantation, sCD30 levels are consistently suppressed, but BOS is not prevented, indicating that sCD30 cannot be used as a biomarker to predict BOS after transplantation in the regimen employed.

Topics: Adult; Antigens, CD; Biomarkers; Bronchiolitis Obliterans; Emphysema; Female; Graft Survival; Humans; Immunosuppressive Agents; Informed Consent; Ki-1 Antigen; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Tacrolimus

Topics: Child, Preschool; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Rotavirus Infections; Tacrolimus

To study the prevalence and clinical significance of polymorphisms in the CYP3A5 and MDR1 genes in liver transplant patients and their donors; to determine the relative importance of genes from the donor and the recipient; to assess the relationship of polymorphisms with the variability of concentration/dose of tacrolimus for optimization and individualization regimens.. This prospective study included 53 liver transplant recipients who received tacrolimus de novo. CYP3A5 and MDR1 gene polymorphisms were identified in the donors and recipients using polymerase chain reaction. We collected indicator variables of graft function and the patient for 3 months after the transplantation: days 0, 1, 3, 7, 14, 30, 60, and 90.. The frequencies of CYP3A5 polymorphisms were: 90.6% (G/G), 9.4% (G/A) and 0% (A/C) in donors and 88.7% (G/G), 11.3% (G/A), and 0% (A/A) in recipients. For the MDR1 gene, they were: 26.4% (C/C), 50.9% (C/T), and 22.6% (T/T) in donors and 17.0% (C/C), 71.7% (C/T), and 11.3% (T/T) in recipients. In the early days after transplant, G/A recipients from G/A donors did not reach the minimum drug levels. Between days 30 and 60, G/G recipients from G/A donors required higher tacrolimus doses. G/G recipients (CYP3A5) from C/T donors (MDR1) had a lower frequency of renal dysfunction, the same rejection rate, and a higher rate of diabetes than the other groups.. For CYP3A5, the presence of the A allele appeared to be related to greater requirements for tacrolimus in the early days after transplantation. Pharmacogenetics combined with pharmacodynamics may be a useful tool to adjust the concentration of tacrolimus depending on the absorption by the individual patient.

Topics: Adolescent; Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotransformation; Cytochrome P-450 CYP3A; Diabetes Mellitus; Dose-Response Relationship, Drug; Gene Frequency; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Postoperative Complications; Prospective Studies; Tacrolimus; Tissue Donors; Young Adult

To investigate the differential effects of cyclosporine (CsA) and tacrolimus (TAC) on renal expression of P-glycoprotein (P-gp) in a cohort of kidney transplant recipients.. We enrolled 78 cadaveric kidney transplant recipients recurring basal immunosuppressive protocol with prednisone + mycophenolate mofetil + calcineurin inhibitor (CsA or TAC).. We performed a 3-year analysis of 60 patients. There was no difference in age, gender, or cold ischemic time between two groups, Serum creatinine, urine protein, and blood fat levels of the CsA group were significantly higher than the TAC group (P < .05), while the creatinine clearance was remarkably lower than the TAC group (P < .05). The incidence of tubular atrophy, arteriohyalinosis, and interstitial fibrosis and nephrotoxic lesions among the CsA group were higher than the TAC group, as well as the chronic allograft nephropathy (CAN) Banff score (P < .05). P-gp was predominantly present in the a tubular apical membrane, basal membrane, and cytoplasm. The intensity and extent of tubular staining score in the CsA group were lower compared with the TAC group (P < .01 and P < .05, respectively).. Less P-gp expression in the CsA group than the TAC group may be the molecular action pathway of the high incidence of CsA nephrotoxicity and CsA-induced CAN. This study perhaps unraveled a novel interpretation that the differences of CsA and TAC on long-term allograft survival were due to increases dynamic effects of CsA at the exposures employed in this study.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Young Adult

Voriconazole is an anti-fungal agent active against Aspergillus infection that is used for prophylaxis and curative treatment in lung transplant patients. We present nine cases of painful neuromuscular disorders, an unusual and rare side effect of high-dose voriconazole in association with tacrolimus.

Topics: Adolescent; Adult; Aspergillosis; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Lung Transplantation; Male; Middle Aged; Neuromuscular Diseases; Pain; Postoperative Complications; Pyrimidines; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome; Triazoles; Voriconazole

Treatment of BK virus (BKV) infection in renal transplant recipients remains controversial. This retrospective analysis evaluated efficacy and safety of reducing immunosuppression without antiviral therapy.. This single center analysis included 24 patients diagnosed with BK viremia between September 2001 and December 2003. Sixteen patients (66%) presented with BKV nephritis and eight patients (34%) presented with viremia without evidence of nephritis on renal biopsy.. At time of diagnosis, mean plasma BKV DNA (copies/mL) was 460,409 (range 10,205-1,920,691). Mean doses reduction of mycophenolate mofetil and tacrolimus were 44% and 41%, respectively, from time of diagnosis of BKV infection to complete resolution of viremia. A decline in BK viral load was noticed within 15 to 30 days, with successful elimination of viremia over a mean period of 5.8 months (range, 1-9.5). Mean serum creatinine at time of diagnosis of BK viremia was 1.8 mg/dL (range, 1.2-2.8). Mean follow-up period is 30.9 months postdiagnosis. At the most recent visit, serum creatinine was 2.0 mg/dL (range, 1.0-3.6) (P=0.14). With reduction in immunosuppressive therapy, three patients (13%) developed acute cellular rejection and were treated successfully with intravenous bolus steroids. During follow-up, one patient had a relapse of BKV nephritis during pregnancy and lost her graft. After mean follow-up period of 43.5 months posttransplantation, all 24 patients are alive and 23 have a functioning graft. Seventeen patients (71%) have stable or improved graft function.. Our analysis shows that reduction in immunosuppression therapy alone results in clearance of the BK viremia with good long-term outcome.

Topics: Acute Disease; Adult; Aged; BK Virus; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Postoperative Complications; Prednisone; Tacrolimus; Tumor Virus Infections

Renal dysfunction is one of the most significant complications after liver transplant. It is attributed mainly to nephrotoxicity caused by calcineurin inhibitors. We evaluated the renal functioning in liver transplant recipients alive for at least 6 months after liver transplant.. One hundred seventy patients (108 male [63.5%], 62 female [36.5%]; mean age, 31.4 +/- 13.3 years; age range, 13-61 years) were included in this study. Patients who had undergone a liver transplant between 1994 and 2006 at the Organ Transplantation Center of the Shiraz University of Medical Sciences in Shiraz, Iran, and had been alive for at least 6 months after surgery were included. Data were collected regarding age, sex, body mass index, underlying liver disease, graft type, immunosuppressive medications, serum creatinine levels, and glomerular filtration rate before, 1, and 6 months after liver transplant. Renal dysfunction was defined as a serum creatinine level above 132.6 micromol/L or a glomerular filtration rate less than 60 mL/min/1.73 m2, based on our reference range. Glomerular filtration rate was calculated using the Schwartz formula (glomerular filtration rate mL/min/1.73 m2 = K x Ht (cm) / Cr mg/dL). Data were analyzed with SPSS software.. The mean follow-up was 25.9 +/- 23.5 months (range, 6-156 months). The main indications for liver transplant were cryptogenic cirrhosis (n=42), hepatitis B infection (n=34), autoimmune cirrhosis (n=30), Wilson's disease (n=21), and primary sclerosing cholangitis (n=18). The mean pretransplant glomerular filtration rate was 93.7 +/- 35.6 mL/min/1.73 m2. The mean glomerular filtration rates in the first and sixth months after liver transplant were 81.6 +/- 29.3 mL/min/1.73 m2 and 83.6 +/- 32.9 mL/min/1.73 m2. Sex, body mass index, type of immunosuppressive medication, and underlying liver disease were not predictors of renal dysfunction (P > .05). Posttransplant renal dysfunction was significantly more common in older patients (ie, those aged 38.8 years and older) (P = .0001) and those with a family history of renal disease (P < .05).. Renal dysfunction may be a significant problem for patients after liver transplant, and early detection of renal dysfunction in patients after liver transplant is important. Of all the risk factors studied here, only older age and family history of renal disease were correlated with development of renal dysfunction after liver transplant.

Topics: Adolescent; Adult; Body Mass Index; Creatinine; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Renal Insufficiency; Risk Factors; Tacrolimus

Posttransplant diabetes mellitus (PTDM) is common post transplantation and is associated with tacrolimus (TAC) and steroid therapy. The aim of the present study was to analyze the incidences of PTDM and associated risk factors.. We selected renal transplant recipients treated with TAC, mycophenolate mofetil (MM), and steroids. Exclusion criteria were recipients <18 years old, history of diabetes, recipients of kidney/pancreas, and/or those receiving cyclosporine or sirolimus. PTDM was defined as glucose >126 mg/dL, with or without drug therapy.. Among 67 patients who fulfilled the inclusion criteria, 18 (26.8%) developed PTDM within 2 months of transplantation. Compared with normal glucose patients, the PTDM group was older, male, received a kidney from deceased donors, and showed higher pretransplant glucose levels. No differences were noticed in renal function or daily dose of TAC or steroids. However, TAC trough levels in the first month were higher among the PTDM group, despite the lower dose per kilogram. After 1 year of follow-up, weight gain as well as daily TAC per kilogram dose was less among PTDM patients. Analysis of potential risk factors showed a higher incidence of hepatitis C virus infection in the PTDM group, as well as a higher frequency of HLA DR13.. The incidence of PTDM diagnosed in the early posttransplant period in the present series was 26.8%. Risk factors included older age, male gender, recipients of kidneys from deceased donors, hepatitis C virus infection, higher pretransplant glucose levels, and higher TAC trough levels during the first month posttransplant.

Topics: Adult; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors; Weight Gain

Few studies have evaluated the long-term use of MMF in liver transplanted children with renal dysfunction. The aim of this study is to report the experience of a pediatric transplantation center on the efficacy and security of long-term use of a MMF immunosuppressant protocol with reduced doses of CNIs in stable liver transplanted children with renal dysfunction secondary to prolonged use of CsA or Tac. Between 1988 and 2003, 191 children underwent OLT and 11 patients developed renal dysfunction secondary to CNIs toxicity as evaluated by biochemical renal function parameters. The interval between liver transplantation and the introduction of the protocol varied from one to 12 yr. Renal function was evaluated by biochemical parameters in five phases: immediately prior to MMF administration; 3, 6, 12 and 24 months after the introduction of MMF. Among the patients, nine of them (82%) showed improvement of renal function parameters in comparison with the pretreatment values. The two patients that did not show any improvement were patients in whom the interval of time between OLT and the introduction of MMF was longer. All parameters of liver function remained unchanged. No episodes of acute or chronic rejection or increases in infection rates during the period were detected. Two patients developed transitory diarrhea and leukopenia that were reverted with reduction of MMF dosage. In conclusion, in liver transplanted pediatric patients with CNI-induced chronic renal dysfunction, the administration of MMF in addition to reduced doses of CNIs promotes long-term improvement in renal function parameters with no additional risks.

Topics: Adolescent; Blood Urea Nitrogen; Child; Child, Preschool; Creatinine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Failure; Liver Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Uric Acid; Vaccination

Induction with the use of monoclonal antibodies targeting the alpha-chain (CD25) of the high-affinity IL2 receptor may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLT).. Forty-two consecutive deceased donor primary OLT were retrospectively analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after OLT) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels), and steroids (methylprednisolone 1 g intraoperatively followed by tapering doses). Mycophenolate mofetil (MMF) 1 g every 12 h was added to the drug combination as needed. The mean follow-up period was 19.3 months (range: 4.8-35.9 months).. The average Model for End-Stage Liver Disease score was 26 (range: 15-40). A total of 39 patients (93%) remained rejection-free during follow-up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 2 years was 93%. Twenty-five patients (60%) were completely off steroids within 3 months post-OLT (mean: 51.1 days, range: 10-90 days). By the 10th month post-OLT, 30/39 (77%) of the patients were completely off steroids. At last follow-up, 30/39 (77%) are on tacrolimus monotherapy with an average dose of 4 mg per day. Six patients (15%) are on double therapy, receiving a combination of tacrolimus and prednisone (two patients) or tacrolimus and MMF (two patients) or tacrolimus and mycophenolic acid (two patients). Only three patients (8%) are receiving triple therapy at last follow-up. Nine patients (21%) experienced at least one episode of infection. Only six (26%) of a total of 23 hepatitis C virus (HCV) recipients developed histology-proven HCV recurrence, with a mean onset of recurrence post-OLT of 3.2 months (range: 1.3-6.3 months). Of these six patients, two are presently undergoing treatment with interferon and ribavirin, one was treated and became HCV RNA negative, one was not treated, one declined treatment, and two died of HCV recurrence. None of the 42 study patients developed cytomegalovirus infection or posttransplant lymphoproliferative disease.. These preliminary data suggest that basiliximab, given in combination with a tacrolimus-based immunosuppressive regimen, is safe and associated with a low incidence of acute rejection and excellent short-term rejection-free graft and patient survival rate after OLT.

Topics: Acute Disease; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Interleukin-2 Receptor alpha Subunit; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Tacrolimus is a potent immunosuppressive agent widely used in renal and liver transplantations. Its potential side effects due to overdosing are variable. Most commonly toxic tacrolimus blood levels affect the central and peripheral nervous systems. Once absorbed, tacrolimus binds to plasma proteins and accumulates within erythrocytes. Current treatment strategies to overcome acute intoxications focus on the induction of hepatic cytochrome P450 enzymes to accelerate tacrolimus degradation. We report the case of a 69-year-old renal transplant recipient presenting with acute liver failure, septic shock, and tacrolimus intoxication. The intoxication was resolved by massive gastrointestinal bleeding and subsequent transfusion of packed erythrocytes. We concluded that exchange blood transfusions offer an alternative therapeutic approach for patients with severe liver function impairment and tacrolimus intoxication.

Topics: Aged; Diabetes Mellitus; Female; Gastrointestinal Hemorrhage; Hemofiltration; Hemoglobins; Hemorrhoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Renal Dialysis; Shock, Septic; Tacrolimus

The prevalence of inflammatory bowel disease (IBD) after renal transplantation is affected by the immune tolerance and the modality of immunosuppression. Mycophenolate mofetil (MMF) may have a promoting effect on the development of posttransplantation erosive enterocolitis and a Crohn's disease-like pattern of colitis. We have presented a 40-year-old man with end-stage renal disease due to chronic glomerulonephritis who commenced hemodialysis for 2 months before receipt of a live unrelated renal transplant. He developed early posttransplantation diabetes mellitus and an anti graft rejection episode, which responded to a methylprednisolone pulse and OKT3 treatment. His immunosuppressive regimen included prednisolone, MMF, and tacrolimus. Three years after transplantation, he developed mild constitutional symptoms, mouth ulcerations, and chronic intermittent bloody diarrhea. Colonoscopy showed active segmental colitis with aphthous ulcers, involving the proximal descending colon and the splenic flexure. Colonic biopsies showed distended and branched crypts in the ascending colon, moderate active chronic colitis with regenerative atypia, skipping appearance, and ulceration in the splenic flexure and descending colon. The edematous crypts were associated with ulcerations in the sigmoid colon and rectum. The features were highly suggestive of Crohn's disease. He was successfully treated with high-dose steroids and 5-aminosalicylic acid. Subsequently, he developed chronic transplant glomerulopathy and restarted hemodialysis. We concluded that de novo Crohn's disease may develop in renal transplant recipients despite immunosuppressive therapy especially with MMF immunosuppression.

Topics: Adult; Crohn Disease; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Renal Dialysis; Tacrolimus

This study aimed to investigate the pharmacokinetics after tacrolimus aerosol inhalation and to assess its efficacy to suppress acute and chronic airway allograft rejection. Orthotopic tracheal transplantations were performed and tacrolimus (4 mg/kg) was administered orally (PO) or via aerosol (AER). Tracheal tissue level AUCs(0-12) were similar in both treatment groups, but blood AUCs(0-12) were approximately 5.5-fold lower with AER (p < 0.001). Interestingly, only PO animals showed elevated BUN, cholesterol and triglycerides on POD 60 (p < 0.05). Histology of grafts harvested after 6 and 60 days revealed that both treatment groups were similarly effective in suppressing graft mononuclear infiltration (p < 0.001). Cellular immune activation (assessed by IFN-gamma- and IL-4-ELISPOTS), however, was far more effectively suppressed by tacrolimus PO (p < 0.001). In both treatment groups, the vigorous alloreactive IgM-antibody surge was effectively inhibited (p < 0.001). Due to the insufficient systemic cellular immunosuppression, discontinuation of tacrolimus AER resulted in a far stronger (3.5-fold) graft infiltration on POD 8 compared to PO (p < 0.001). Tacrolimus aerosol reduces systemic side effects and effectively protects the airway graft from early cellular rejection and chronic obliterative airway disease.

Topics: Administration, Inhalation; Airway Obstruction; Animals; Antibody Formation; Cytokines; Graft Rejection; Immunity, Cellular; Immunosuppressive Agents; Male; Postoperative Complications; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Trachea; Transplantation, Homologous

With the development of new immunosuppressive agents, the majority of transplant recipients are surviving for over a decade, and malignancy has become a major burden on long-term survival. Reducing the incidence of post-transplant malignancies is especially important in heart transplantation where the risk of malignancies is higher than in other organ transplants. Everolimus and sirolimus, the proliferation signal inhibitors (PSIs) or mammalian target-of-rapamycin (mTOR) inhibitors, now provide new strategies for immunosuppression because of their proven efficacy that translates to a reduction in doses of calcineurin inhibitors needed to prevent acute rejection. In addition, the anti-proliferative effects of this class of drugs raise the possibility that they may be effective for reducing the risk of malignancies after solid-organ transplantation. Despite the paucity of direct clinical evidence for this effect in heart transplant patients, observations from renal transplant recipients suggest that the anti-proliferative actions of PSIs/mTOR inhibitors may also protect against malignancies in heart transplant recipients. This potential for an anti-cancer effect is further supported by the emerging data on the use of PSIs/mTOR inhibitors in non-transplant oncology patients. Reviewed in this article are the incidence rates of malignancies after solid-organ transplantation, and the evidence for anti-cancer effects of PSIs/mTOR inhibitors in renal transplant recipients and in non-transplant patients. Also discussed are the implications of these observational data for future studies on the reduction of malignancies after heart transplantation.

Topics: Azathioprine; Cyclosporine; Enzyme Inhibitors; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Protein Kinases; Risk; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

Heart transplant recipients treated with long-term calcineurin inhibitors (CNIs) experience significant nephrotoxicity and transplant vasculopathy. Signal proliferation inhibitors might prevent the development of transplant vasculopathy. In an open, prospective pilot study, 33 primary heart transplant recipients received tacrolimus (Tac) and sirolimus (rapamycin, Rapa) with steroids. To reduce both nephrotoxicity and transplant vasculopathy at the same time, both Tac and Rapa exposure was kept low (6 to 8 ng/ml). Steroids were withdrawn successfully from all patients within 6 months. Just one acute rejection occurred at 54 days post-transplant, resulting in 0.03 acute rejection episode per patient at 1-year (primary end-point) and 2-year follow-up. Transplant vasculopathy assessed by angiogram was absent at 2 years. Graft and patient survival were 100% at 1 and 2 years. Accordingly, the survival estimate for freedom from first acute rejection, transplant vasculopathy, graft loss or death was 0.97 at 1 and 2 years. The regimen was well tolerated with only 3 patients requiring a change of study medication. Mean serum creatinine increased during the first year but returned to baseline at 2 years.

Topics: Adrenal Cortex Hormones; Adult; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Postoperative Complications; Prospective Studies; Sirolimus; Tacrolimus; Time Factors

Organ transplantation is a risk factor for atherogenesis that may be related to immunosuppressive therapy. Increased free radical generation may even aggravate atherogenesis. The aim of the study was to assess lipid metabolism in relation to risk factors for atherogenesis as well as carbohydrate metabolism and antioxidant status among children after liver transplantation. We studied 35 children at 3 to 5 years after liver transplant in whom the following parameters were assessed: total cholesterol; triglyceride; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol (LDL-C); very low-density lipoprotein cholesterol; apolipoproteins B, AI, E, lipoprotein (a); vitamin E; glutathione; glucose; insulin; and glutathione peroxidase activity. Three subgroups of patients were assessed according to the immunosuppressive therapy: cyclosporine (CsA), tacrolimus (Tac), or mycophenolate mofetil (MMF) in combination with low-dose CsA or Tac. We observed differences among the subgroups only in total cholesterol (CsA: 131.6 to 285.6; Tac: 144.0 to 181.61; MMF: 132.1 to 181.2) and LDL-C (CsA: 79.4 to 126.9; Tac: 42.2 to 118.8; MMF: 74.2 to 117.3). Lipid metabolism was not significantly disturbed among children after liver transplantation, an observation that does not point to a high risk of atherogenesis. CsA seems to have the strongest untoward effect on cholesterol metabolism. Decreased GSH concentration after liver transplantation may be related to slightly impaired liver function, but GPx activity and vitamin E concentrations remained normal.

Topics: Antioxidants; Atherosclerosis; Child; Child, Preschool; Cyclosporine; Dietary Carbohydrates; Dietary Fats; Drug Therapy, Combination; Follow-Up Studies; Glutathione; Glutathione Peroxidase; Humans; Immunosuppressive Agents; Lipoproteins; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adolescent; Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Male; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Tacrolimus

Describe the safety and efficacy of antithymocyte globulin or alemtuzumab preconditioning, steroid avoidance and reduced calcineurin inhibitor (CNI) immunosuppression in 34 children undergoing renal transplantation.. ATG (n=8) or alemtuzumab (n=26) were infused at the time of transplantation. This was followed by low-dose twice a day tacrolimus monotherapy with consolidation to once daily dosing by 6 months and once every other day dosing by 12 months. Follow-up ranged from 0.5-2.9 years (mean 1.33 years), with a minimum of 6 months.. Both ATG and alemtuzumab were well tolerated. Lymphopenia occurred routinely and resolved after 3-6 months. Acute cellular rejection occurred in 9%; it was related to medical nonadherence in two patients and resulted in one graft loss at 1.5 years. Important adverse events included transient neutropenia in 10 children (none with serious infection), and autoimmune hemolytic anemia in two (resolved with a steroid course in both and conversion to sirolimus in one). Estimated glomerular filtration rate (e-GFR) was stable and averaged 88 mL/min/1.73 m2 at latest follow-up. Fifteen preadolescents had a greater increase in height Z-score at 1 year (1.3 vs. 0.5, P=0.001), and a higher e-GFR (94.8+/-21 vs. 76.6+/-20 ml/min/1.73 m2, P<0.05), when compared to case-matched historical controls who were weaned off steroids by 6 months after transplantation and received twice daily tacrolimus monotherapy.. This simple regimen appears safe, has a low risk for acute cellular rejection or other adverse effects, and is associated with excellent growth and renal function. Such a regimen may also improve compliance and limit CNI nephrotoxicity.

Topics: Adolescent; Alemtuzumab; Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Child; Child, Preschool; Creatinine; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infant; Intraoperative Care; Kidney Diseases; Kidney Transplantation; Lymphocyte Depletion; Postoperative Complications; Tacrolimus; Transplantation Conditioning; Treatment Outcome

The clinical picture in pyoderma gangrenosum varies but a typical medical history with resistance to antimicrobial treatment and worsening or first manifestation of disease because of surgical procedures are indications of this diagnosis. We describe the course of a woman patient who had a pyoderma gangrenosum for more than 1.5 years. After confirming the diagnosis an immunomodulating therapy was initiated until complete remission of the ulcers. Differential diagnosis and different clinicopathologic forms of pyoderma gangrenosum are discussed and an overview of the association with internal diseases is provided.

Topics: Aged; Biopsy; Cyclosporine; Diagnosis, Differential; Drug Therapy, Combination; Female; Hip Fractures; Humans; Methylprednisolone; Postoperative Complications; Pyoderma Gangrenosum; Skin; Surgical Wound Infection; Tacrolimus

To summarize the diagnosis and treatment of acute rejection after lung transplantation and to discuss optimized immunosuppressive therapy.. Between November 2002 and June 2006, 16 patients underwent operations on lung transplantation, 7 cases on single-lung transplantation and 9 cases on bilateral-lung transplantation. Immunosuppressive therapy was new triple drug maintenance regimen including tacrolimus (Tac), mycophenolate mofetil (MMF) and steroids, and (or) daclizumab.. Eight cases in new triple drug maintenance regimen with daclizumab. There is no acute rejection in 6 months. Except 2 of the 8 cases died of early post-lung transplantation sever pulmonary edema and dysfunction, 3 of the rest 6 cases underwent acute rejection incident about 21.4% (3/14).. In this group the new triple drug maintenance regimen including tacrolimus (Tac), mycophenolate mofetil (MMF) and steroids, and (or) daclizumab acquired beneficial effect in preventing acute rejection after lung transplantation.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Tacrolimus; Treatment Outcome

To evaluate the outcome of pediatric patients who underwent liver transplantation between Oct. 2002 and May 2005 in the Pediatric Hospital.. Eight cases aged from 4 to 67 months who underwent liver transplantation were analyzed retrospectively. Four of the patients were boys and 4 girls, whose body weight at the time of liver transplantation was 6-19 kg. The underlying diseases were biliary atresia, congenital cholestasis, drug-induced cholestatic cirrhosis and cryptogenic cirrhosis. These patients had been followed up for blood routine examinations, liver and renal function, serum electrolytes and blood concentration of tacrolimus for 16 to 43 months after liver transplantation. Results of serological studies for viral etiology, liver biopsy, growth and mental development were also recorded.. One-year survival rate was 75.0% with the longest survival time being 43 months after transplantation. One patient died from renal failure due to postoperative bleeding 24 hours after the surgery and another case died of variceal hemorrhage 8 months after transplantation. Posttransplantation complications included acute cellular rejection, viral infection and hypoalbuminemia. Viral infections included cytomegalovirus infection in 3 cases, Epstein-Barr virus infection in 1 and hepatitis B virus infection in 1. Surgical complications of portal vein thrombosis and stenosis of inferior vena cava and hepatic vein occurred in 2 cases respectively. Side effects of tacrolimus including hypertension, renal damage, liver damage and diarrhea were observed. Significant growth-retardation was not often seen. A self-reported high quality of life was common.. Close follow-up and management of patients after liver transplantation may significantly increase the survival rate and improve quality of life in children with end-stage liver diseases.

Topics: Biliary Atresia; Child; Child, Preschool; Constriction, Pathologic; Female; Graft Rejection; Hepatitis B; Herpesvirus 4, Human; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Pediatrics; Postoperative Complications; Survival Rate; Tacrolimus; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

The purpose of this study was to ascertain the prognosis of patients with hepatorenal syndrome (HS) prior to orthotopic liver transplantation (OLT) by comparisons with a group of selected patients with normal renal function (NRF) pretransplantation who developed acute renal failure (ARF) in the early postoperative period.. Fifty-two OLT cases developed ARF in the early postoperative period between March 1999 and October 2004; 17 cases experienced HS prior to OLT. ARF was defined as serum creatinine level (Cr) >1.5 mg/dL or a creatinine clearance (CrCl) <50 mL/min. The immunosuppressive therapy was the same in both groups: low doses of tacrolimus were prescribed to reach trough levels of 5 ng/mL in the first week after OLT, where patients were administered monoclonal antibodies and corticosteroids.. No differences were observed between the groups for gender, age or APACHE II Score in the first 24 hours after OLT. Patients with HS pretransplantation showed higher Cr and urea (U) levels than the other group (Cr: 2.1 +/- 0.8 HS vs 0.9 +/- 0.2, P = .000; U: 93.6 +/- 51.9 HS vs 42.1 +/- 19.3, P = .001). The ICU days of stay were similar (12.8 +/- 0.5 HS vs 19.7 +/- 15.2, P = .053). At the end of 1 year follow-up after OLT there were no differences in mortality (35% HS vs 26%), need for renal replacement therapy (23% HS vs 34%), infection (59% HS vs 51%), or rejection (6% HS vs 29%, P = .06).. Patients with HS prior to OLT showed a similar prognosis to a group of selected patients with NRF pretransplantation, but developed ARF in the early postoperative period which was treated with monoclonal antibodies and low doses of tacrolimus.

Topics: Acute Kidney Injury; APACHE; Creatinine; Female; Hepatorenal Syndrome; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Postoperative Complications; Postoperative Period; Retrospective Studies; Tacrolimus; Urea

Bronchiolitis obliterans syndrome (BOS) continues to be the main factor limiting the long-term survival of lung transplant recipients. The objective of this study was to prospectively assess the impact of conversion from cyclosporine (CsA) to tacrolimus on lung function in patients who developed BOS while receiving CsA-based immunosuppressive therapy. A total of 79 patients with BOS were included in the study. Sixty percent of patients had stage II or III BOS according to the International Society for Heart and Lung Transplantation criteria. Mean time from transplantation was 30.4 +/- 21.9 months and all patients were on CsA therapy at enrollment in the study, with mean trough levels of 232.75 +/- 98.26 ng/mL. After conversion, tacrolimus trough levels were 11.0 +/- 3.6 ng/mL at 3 months and 9.0 +/- 3.4 ng/mL at 12 months. Sixteen deaths occurred during the first year postconversion, 56% of which were due to respiratory failure. Comparison of forced expiratory volume in 1 second (FEV(1)) preconversion versus postconversion showed a change in the slope of the FEV(1)-time curve. The slope of the preconversion curve was -0.44 versus a zero slope, whereas the slope of the postconversion curve was 0.005, with a statistically significant difference between both slopes. This change in slopes, which was also seen in FEV(1%), suggests that lung function loss closed after conversion from CsA to tacrolimus supporting this therapeutic strategy in lung transplant recipients with BOS treated with CsA.

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Female; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Respiratory Function Tests; Retrospective Studies; Tacrolimus; Tissue Donors

HC and HU predispose healthy children to develop hematuria and nephrolithiasis. The natural history of HC and HU has not been studied in renal transplant recipients who may be at greater risk of complications. Our study investigated the prevalence of HC and HU after Tx and determined independent predictors of urinary calcium and uric acid excretion. Twenty-five pediatric transplant patients were studied between one and 12 months after Tx. Demographic data and measurements of the random Uca/cr and uric acid excretion were collected. Multivariable regression analyses were used. The median age of the patients was 10.6 yr. The prevalence of HC and HU was 20% each at one month. At 12 months, 20% had HC and 13% had HU. There were no predictors for HC; for HU, the only predictor was systolic hypertension (p = 0.03). Our data demonstrate a high prevalence of HU and HC in pediatric renal Tx recipients. The long-term clinical implication of these metabolic abnormalities remains to be elucidated in prospective trials.

Topics: Adolescent; Adult; Biomarkers; Calcium; Child; Child, Preschool; Female; Hematuria; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Nephrolithiasis; Postoperative Complications; Tacrolimus; Uric Acid

Incisional hernias occur in up to 17% of patients after liver transplantation. Laparoscopic ventral hernia repair is associated with fewer wound complications and a decreased incidence of recurrence when compared to open hernia repair in nontransplant patients. This is a retrospective review of 13 patients who underwent laparoscopic incisional hernia repair (LAP group) after liver transplantation compared to 14 patients who had open repairs (OP group; all but one with mesh). Primary immunosuppression in both groups at the time of transplantation was tacrolimus, but more patients in the LAP group were on sirolimus at the time of hernia, while more patients in the OP group were on prednisone at the time of hernia repair. All operations were completed with a laparoscopic approach; there were no conversions to open. Length of stay differed significantly between the 2 groups, with a mean of 5.4 days for the LAP group compared to 2.7 days in the OP group (0.0059). Complications occurred in 2 (15%) of the patients in the LAP group and 5 (36%) in the OP group. One patient in the LAP group required mesh removal to exclude causes of recurrent ascites, and 1 in the OP group for mesh infection. One (7.6%) of the patients in the LAP group developed a recurrence, compared to 29% (4) of the OP group (P =0.3259). In conclusion, laparoscopic incisional hernia repair is safe in patients after liver transplantation, with a low risk of infection or recurrence.

Topics: Aged; Female; Graft Rejection; Hernia, Ventral; Humans; Immunosuppressive Agents; Laparoscopy; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Recurrence; Retrospective Studies; Sirolimus; Surgical Mesh; Surgical Wound Infection; Tacrolimus

Sirolimus (SRL) has become an option in kidney transplantation, especially among patients who develop chronic allograft nephropathy (CAN). This study sought to evaluate the safety and efficacy of SRL in 103 kidney recipients of mean age 40 years, including 78 recipients of organs from deceased donors. The major reason for conversion was calcineurin inhibitor (CNI) nephrotoxicity (42.3%) followed by CAN (35.4%). A preconversion kidney biopsy was performed in 89 patients with CAN diagnosed in 51. Mean time to conversion was 40.5 months. The new therapy was: SRL/mycophenolate mofetil (MMF)/prednisone (Pred) in 79 patients; SRL/tacrolimus (TAC)/Pred in 15; and other SRL combinations in 9. The target SRL trough level was 5.0 to 8.0 ng/mL. To evaluate the impact of conversion on renal function, we compared the proteinuria and inverse serum creatinine at 3 months before conversion, at conversion, and at 1, 3, 6, 12, and 24 months postconversion. The overall mean follow-up time was 13.2 months. The analysis showed significant improvement in renal function at month 1 postconversion (P<.05) with stabilization thereafter. The SRL/MMF combination frequently induced anemia and/or leukopenia (n=23). Infections included pneumonia (n=10), herpes zoster (n=7), herpes simplex (n=3), cytomegalovirus (n=2), histoplasmosis (n=2), tuberculosis (n=2), and neurocryptococcosis (n=1). Reasons for SRL discontinuation were myelotoxicity (n=4), infection (n=3), nephrotoxicity (n=3), gastrointestinal intolerance (n=3), myopathy (n=1), pneumonitis (n=1), hyperlipidemia (n=1), and other reasons (n=3). Graft loss occurred in 29 patients due to CAN (n=21) followed by death (cardiovascular, n=2; infectious, n=2), acute rejection (n=3), and infection following immunosuppression withdrawal (n=1). We concluded that SRL represented an option but reducing associated immunosuppression should strongly be considered to minimize the frequent side effects, especially infections.

Topics: Azathioprine; Drug Therapy, Combination; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P<.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr>1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.

Topics: Creatinine; Cyclosporine; Drug Administration Schedule; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Treatment Outcome

Tacrolimus is used widely for immunosuppression following transplantation. It has rarely been linked to the development of peripheral neuropathy. However, one study also reported improvement in peripheral neuropathy after tacrolimus use. We have reported herein two patients who developed chronic sensorimotor polyneuropathy after tacrolimus use following renal transplantation. One patient had an unusual presentation with bilateral facial and extremity weakness and a relapsing course. The other patient presented with focal sensory symptoms in one hand. Electrophysiological studies confirmed widespread, predominantly demyelinating or axonal polyneuropathy. We concluded that patients on tacrolimus should be carefully monitored for symptoms suggestive of peripheral neuropathy.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neural Conduction; Peripheral Nervous System Diseases; Polyneuropathies; Postoperative Complications; Tacrolimus

Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti-viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus-based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine-based immunosuppression (n = 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus-based therapy (n = 59, P = 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose-dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon-based therapy and should be studied in a prospective randomized trial.

Topics: Adult; Cyclosporine; Follow-Up Studies; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; In Vitro Techniques; Liver Failure; Liver Transplantation; Middle Aged; Postoperative Complications; Retrospective Studies; Secondary Prevention; Tacrolimus; Treatment Outcome

Pelger-Huët anomaly is a congenital or acquired abnormality of neutrophil nuclear segmentation. The acquired form may be a result of a clonal myeloid malignancy, such as myelodysplastic syndrome, or may be a secondary nonclonal change related to a variety of underlying causes, including infections and medications. We report a case of a 56-year-old man who developed acquired Pelger-Huët anomaly following liver transplantation while on the immunosuppressive agents tacrolimus and mycophenolate mofetil. These medications have been reported in association with this abnormality, but usually as a single agent or in combination with other drugs. In our case, the Pelger-Huët anomaly may be the result of the combination of these 2 drugs or mycophenolate alone with subsequent desensitization because resolution of the abnormality occurred after a reduction in mycophenolate mofetil dose, and the abnormality did not recur when mycophenolate mofetil was increased to a dose previously associated with Pelger-Huët anomaly during the time that tacrolimus was discontinued.

Topics: Desensitization, Immunologic; Drug Therapy, Combination; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutrophils; Pelger-Huet Anomaly; Postoperative Complications; Recovery of Function; Tacrolimus

To determine whether pancreatic islet transplantation can control diabetes and prevent severe life-threatening hypoglycaemia.. A single-arm observation study of six patients undergoing islet transplantation. All patients had had type 1 diabetes mellitus for over 5 years and documented episodes of repeated severe hypoglycaemia. Islets were isolated from donor pancreases digested by Liberase. Separated islets were infused into the recipient's liver via the portal vein. Patients were immunosuppressed with daclizumab, sirolimus and tacrolimus. The transplants were performed at Westmead Hospital, NSW, between October 2002 and February 2005.. Normal blood glucose control without administration of exogenous insulin; demonstration of islet function and abolition of hypoglycaemia.. Five of the patients received two islet infusions, and the sixth was withdrawn after one infusion following a portal vein thrombosis. Three patients became insulin-independent, with excellent glycaemic control. Two had islet function with circulating C-peptide, improved glycaemic control, reduced insulin requirement and abolition of severe hypoglycaemia. However, over a 2-year period, graft function deteriorated. Recipients who were initially insulin free remained C-peptide positive but required supplemental insulin. Complications included one postoperative bleed, two portal vein thromboses (which resolved completely), presumed recurrence of tuberculosis in one patient, and deterioration in renal function in one patient.. Islet transplantation is effective at improving glycaemic control and hypoglycaemia unawareness in the short to medium term. However, problems with long-term safety of immunosuppression, islet-induced thrombosis and early detection of loss of islet function remain to be addressed.

Topics: Adult; Age Factors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Australia; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Survival; Humans; Hypoglycemia; Immunoglobulin G; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Among 71 patients, 19 (26.7%) experienced tacrolimus-related complications including 15 neurologic reactions and four problems with nephrotoxicity. Seven of these patients received grafts from cadaveric donors and 12 from living donors. Nine patients were children. The cohort included 5 female and 14 male subjects of mean age 26 +/- 20 (min 6, max 65) years. The common indications for the liver transplantation were cholestatic and metabolic diseases in pediatric patients, and viral hepatitis in adult patients. Blood tacrolimus levels were within the normal range. All patients with neurologic complications received antiepileptic therapy and drug conversion to rapamycin in 4 cases and to cyclosporine (CsA) in 11 cases. Six cases with Wilson disease and all cases with tyrosinemia experienced neurologic complications, which reversed in all but one case. In four cases with nephrotoxicity, we switched to rapamycin. Renal function improved in all cases. Patients with Wilson disease and tyrosinemia were more susceptible to the neurologic side effects of tacrolimus. In these cases we recommend the use of drugs with fewer neurologic side effects. Tacrolimus also has nephrotoxic effects, which can be reversed by converting to rapamycin.

Topics: Cyclosporine; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Nervous System Diseases; Postoperative Complications; Psychotic Disorders; Retrospective Studies; Risk Factors; Tacrolimus

Several factors may contribute to post-transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus-based immunosuppression following liver transplantation and all of them suffered from previous steroid-resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid-resistant graft rejection, even if given in therapeutic doses.

Topics: Adolescent; Child; Cholestasis; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver; Liver Transplantation; Postoperative Complications; Pruritus; Retrospective Studies; Tacrolimus

HIV infection has experienced dramatic improvement in morbidity and mortality with the highly active antiretroviral therapy (HAART). This prompted a reevaluation of organ-solid transplantation as a treatment option for HIV-infected patients. Some trials in the United States have shown that one- and 2-year graft and patient survival is comparable to HIV-negative transplant population. In Europe the experience is still scarce. The aim of this study is to analyse the outcome and the clinical characteristics of HIV-infected patients who received kidney transplantation in Spain in the HAART era. Ten patients were transplanted in our country since 2001. Only one patient was black. The main cause of end-stage renal disease reported was glomerulonephritis. Six of the recipients were coinfected by hepatitis C virus. Inclusion criteria included undetectable HIV viral load and CD4 counts greater than 200/pL. Immunosuppression consisted of steroids, tacrolimus and mycophenolate mofetil, with antibody induction in 4 cases. The median and mean follow-up was 11 and 16.3+/-15.6 (3-46) months, respectively. One recipient lost his graft because of early renal venous thrombosis. The remaining patients are functioning graft with mean serum creatinina level of 1.5 +/- 0.5 mg/dl. Biopsy-proven acute rejection was diagnosed in 4 recipients and was reversed in all cases with antirejection treatment. The plasma HIV RNA levels have remained controlled and CD4 counts have been stable in excess of 200 cell/microL. None of patients have developed AIDS complications. Recipients receiving protease inhibitor-based HAART regimens required significant dosing modification to maintain appropriate tacrolimus levels. Our results show that renal transplantation can be a safe and effective treatment in select HIV-infected patients. Like other series, the acute rejection rate was higher than in non-HIV recipients. The reasons of this rejection incidence remain unknown.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Interactions; Female; Follow-Up Studies; Graft Rejection; HIV Infections; HIV Protease Inhibitors; Humans; Kidney Failure, Chronic; Kidney Transplantation; Life Expectancy; Male; Middle Aged; Postoperative Complications; RNA, Viral; Spain; Survival Analysis; Tacrolimus; Treatment Outcome; Viral Load

The infectious disease is one of the most important complications related to the organ transplantation. Patients using immunosuppressive agents often present atypical tuberculosis and the treatment of such case is far more difficult in some cases due to the liver damage and/or the drug interaction. We report a case of pulmonary tuberculosis in a patient of 60-year-old man using tacrolimus after an orthotopic liver transplantation. He had liver transplanted orthotopically for the long-term history of chronic hepatitis B and subsequent liver failure on January 28, 2004. An abnormal shadow was first detected on his chest X-ray film on October, 2004. He was admitted to our hospital after the smear of the gastric juice showed some acid-fast bacilli and tubercle bacilli were confirmed by polymerase chain reaction (PCR). Tuberculin skin test was positive (erythema 10 x 10) and the computed tomography (CT) scan of his chest revealed a nodular opacity with some smaller nodules scattered around in the right upper lobe. We started four anti-tuberculous drugs other than pyrazinamide (PZA) and rifampicin (RFP), which included isoniazid (INH), ethambutol (EB), streptomycin (SM), levofloxacin (LVFX). The liver enzyme was transiently elevated (AST 123 IU/I, ALT 103 IU/I) but improved after desensitization against INH. The blood concentration of tacrolimus preserved between 5 and 7 ng/ml and there was no need to change the dosage.

Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Tuberculosis, Pulmonary

Infection is a common cause of morbidity and mortality in kidney transplant recipients. The incidence of esophageal and urogenital candidiasis in kidney and kidney-pancreas transplant recipients has not been well documented. Azoles are safe, effective agents to treat esophageal candidiasis. However, resistance to azoles is now becoming common. This study reports the use of caspofungin for the treatment of azole-resistant esophageal and urogenital candidiasis in kidney transplant recipients.. The incidence of esophageal and urogenital candidiasis was evaluated among 140 kidney transplantations and four combined kidney-pancreas transplants performed over a 2-year period.. Twenty-two patients (15.7%) presented with esophageal candidiasis, while seven patients (5%) showed urogenital candidiasis. Thirteen patients with esophageal candidiasis (59%) and four patients (57%) with urogenital candidiasis did not improve after a week of azole treatment. A regimen of caspofungin was started in these patients, who tolerated the treatment. Urogenital candidiasis recurred in two patients 2 and 3 months after the treatment. One patient with esophageal candidiasis did not improve with caspofungin and was switched to amphotericin B therapy. There were no other recurrences of candidiasis among patients treated with caspofungin for a median follow-up of 8 months.. Renal transplant patients remain at high risk for fungal infections. Although the number of patients was limited, the results of this study indicated that caspofungin is an effective, well-tolerated alternative for difficult-to-treat, azole-resistant candida infections in kidney and pancreas transplant recipients. The high costs of the drug limit the use of caspofungin as first-line antifungal therapy, reserving its use to recipients who had undergone unsuccessful azole therapy.

Topics: Adult; Aged; Antifungal Agents; Candidiasis; Candidiasis, Vulvovaginal; Caspofungin; Cyclosporine; Echinocandins; Esophageal Diseases; Female; Fluconazole; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lipopeptides; Middle Aged; Peptides, Cyclic; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

This study was performed to investigate the clinical and pathologic features of C4d-positive steroid-resistant acute rejection (AR) at different phases after renal transplantation. Fifty-six kidney allograft recipients with C4d-positive AR were divided into three groups, very early rejection (VER, occurring < or =14 days following transplantation, n=28), early rejection (ER, occurring 15-180 days following transplantation, n=5), and late rejection (LR, occurring >180 days following transplantation, n=23). Clinical and pathological features were evaluated. Significantly more patients in the ER and LR groups were associated with a reduction or withdrawal of immunosuppressants. More patients in the ER and LR groups experienced a significant (>3 g/l) decrease in serum albumin (80% ER, 91.3% LR, 7.1% VER, P<0.001) and a decrease in hemoglobin (>1 g/dl) (80, 100 vs 17.9%, P<0.001). Most VER patients reported a fever and had very rapid graft dysfunction requiring dialysis. Significantly more patients (87%) had interstitial fibrosis and tubular atrophy in the LR group compared with the other groups and 13% had transplant glomerulopathy. Most cases of VER were reversed with tacrolimus and mycophenolate mofetil treatment, with or without immunoadsorption, with a 1-year survival rate of 96.4%, compared with only 60 and 52.2% in the ER and LR groups. In conclusion, C4d-positive steroid-resistant AR at different time points is associated with unique clinico-histopathological manifestations requiring distinct treatment strategies. Late episodes are usually associated with significantly reduced serum albumin and hemoglobin levels and a poorer outcome. A more specialized treatment protocol should be established for these patients.

Topics: Acute Disease; Adult; CD4-Positive T-Lymphocytes; Female; Graft Rejection; Graft Survival; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Serum Albumin; Tacrolimus; Time Factors

The aim of our study was to determine the prevalence and predictive factors for post-transplant anemia (PTA) at 6 (M6) and 12 (M12) months after orthotopic liver-transplant (OLT) in a cohort of 97 consecutive patients.. Anemia was defined at M6 and M12 according to the World Health Organization criteria, i.e., a hemoglobin level of <12 g/dL for women and <13 g/dL for men. Immunosuppression relied on tacrolimus and steroids with or without mycophenolate mofetil.. Anemia was present in 64.5%, 50%, and 52.8% of patients before OLT and at M6 and M12, respectively. Of the anemic patients, 33% (M6) and 30.3% (M12) received recombinant erythropoietin therapy. In multivariate analysis, the independent predictive factors for anemia at M6 were mean corpuscular volume (<85 fl) at day 7, daily steroid dosage (<0.3 mg/kg), serum creatinine (>130 micromol/L), and hemoglobin level (<11 g/dL) 1 month after OLT (M1). Independent predictive factors for anemia at M12 were daily steroid dosage at M1 (<0.3 mg/kg), hematocrit at M1 (<33%), red blood cell count at M6 (<3.75 T/L), daily dosage at M1 of cyclosporine and tacrolimus, and OLT for causes other than alcohol abuse.. Anemia is highly prevalent within the first year post-OLT. This deserves further investigation and appropriate treatment.

Topics: Adult; Anemia; Creatinine; Cyclosporine; Erythrocyte Count; Erythropoietin; Female; Graft Rejection; Hemoglobins; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression.. We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure.. Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive.. Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.

Topics: Aged; Antibodies; Antigens, CD20; Cyclosporine; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Viral Load

Cardiovascular disease is the main cause of death after renal transplantation. There are few trials evaluating the efficacy of prevention strategies in renal transplant patients on major adverse cardiac events (MACE) and cardiovascular mortality. However, there is general agreement that active prevention strategies can significantly decrease cardiovascular mortality after renal transplantation. Here, we present the case of a 52-year-old male patient who received a first kidney transplant in 1993. He showed a small fixed perfusion defect on thallium scintigraphy before transplant. He was admitted at 13 months due to an antero-lateral myocardial infarction that was complicated with ventricular fibrillation. Despite anti-coagulation with acenocumarol, treatment with statins and angiotensin II receptor blocking agents and an excellent preservation of renal function, the patient presented with a second episode of myocardial infarction at 9 years post-transplant. This case report is discussed in order to highlight the way in which attitudes have been modified in the past decade in order to systematically pursue an early diagnosis of pre-existing coronary artery disease, aggressively treat MACE and actively decrease cardiovascular risk in transplant patients, using all available efficacious treatments as well as individualizing immunosuppression to prolong not only graft but also patient survival.

Topics: Acenocoumarol; Amiodarone; Angioplasty; Calcineurin Inhibitors; Carbazoles; Carvedilol; Cyclosporine; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Immunosuppressive Agents; Indoles; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Nitroglycerin; Postoperative Complications; Pravastatin; Prednisone; Propanolamines; Risk Factors; Tacrolimus; Treatment Outcome

Topics: Child; Cholangitis, Sclerosing; Escherichia coli Infections; Esophageal and Gastric Varices; Female; Gastritis; Gastrointestinal Hemorrhage; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Postoperative Complications; Tacrolimus

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.

Topics: Adolescent; Biliary Atresia; Bone Density; Bone Diseases; Calcineurin Inhibitors; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Information Services; Kidney Failure, Chronic; Length of Stay; Liver Failure, Acute; Liver Transplantation; Male; Ohio; Postoperative Complications; Quality of Life; Risk Factors; Tacrolimus; Treatment Outcome

Neuropsychiatric complications are an important source of morbidity following orthotopic liver transplantation. Etiology of liver disease and type of immunosuppression are possible related factors. The aim of this study was to describe the prevalence of neuropsychiatric complications after liver transplantation, the role of immunosuppression, and the association between these and specific liver diseases such as hepatitis C. One hundred twenty-eight patients with liver transplants were studied. Tacrolimus was the primary immunosuppressant in 101 patients and cyclosporine in 27 patients. Seventy-five complications in 49 patients (38.2%) were reported. In 43 patients, the etiology was associated with immunosuppression: 36 on tacrolimus and 7 on cyclosporine (P = 0.34). Seventeen and four-tenths percent of patients with hepatitis C and 4.6% of patients without hepatitis C developed depression (P = 0.02). There is no difference between types of primary immunosuppression and neuropsychiatric complications. There is a significantly greater incidence of depression in patients transplanted for hepatitis C.

Topics: Adult; Aged; Cyclosporine; Depressive Disorder; Female; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Liver Diseases; Liver Transplantation; Male; Medical Records; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tennessee

Hyperuricemia is common after renal and cardiac transplantations, but it is rarely reported after liver transplantations. The aim of this study is to determine the frequency of hyperuricemia in children following orthotopic liver transplantation and the effects of calcineurin inhibitors tacrolimus and cyclosporine) on blood uric acid levels. Between September 1997 to January 2004, 76 liver transplantations were performed in 70 children (male/female; 39/31) at Ege University, Organ Transplantation Center (37 deceased donation and 39 live donors). Patients who had been transplanted within the last three months and patients who died within six months after liver transplantation were excluded from the study. Finally 59 patients were included in this study. Uric acid levels were measured before transplantation and after transplantation within six months intervals for two yr. In these series 17 cases had increased uric acid levels after liver transplantation (28.8%). Serum uric acid levels in both groups (tacrolimus or cyclosporine) were detected to be significantly higher than initial values at 12th months (p < 0.05). Hyperuricemia developed in eight patients receiving cyclosporine (eight of 11; 72%) whereas nine patients receiving tacrolimus developed hyperuricemia (nine of 48; 18%). However, the rate of having high uric acid levels was significantly higher in cyclosporine group compared tacrolimus group (p = 0.001, OR: 11.5, CI 95% 2.5-52.4). Uric acid levels were also significantly higher in cyclosporine group in 12th and 18th months (respectively, p = 0.003 and p = 0.003). Serum creatinine levels at 12th, 18th and 24th months were significantly higher in cyclosporine group than tacrolimus group (respectively, p = 0.009, p = 0.04 and p = 0.02). Hyperuricemia is a common complication after liver transplantation in children. Cyclosporine may cause hyperuricemia more often in respect to tacrolimus and this may be related to the impairment of renal functions. Complications developing because of hyperuricemia such as gout disease or renal calculi are quite rare in children.

Topics: Adolescent; Chi-Square Distribution; Child; Child, Preschool; Creatinine; Cyclosporine; Female; Humans; Hyperuricemia; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Postoperative Complications; Tacrolimus; Treatment Outcome; Uric Acid

The immunosuppressant FK506 has been reported to increase the rate of peripheral nerve regeneration in nerve crush injury and nerve allograft models. The purpose of this study was to determine whether low doses of FK506 and mycophenolate mofetil had a neuroregenerative effect in revascularized peripheral nerve allografts in a rat hind limb transplantation model.. Wistar Furth rat recipients received limbs from syngeneic Wistar Furth donors (group 1, n = 4) or from allogeneic August X Copenhagen Irish rat donors (group 2, n = 6). Wistar Furth recipients received limbs from August X Copenhagen Irish donors and were treated with FK506/mycophenolate mofetil for 5 months (group 3, n = 7). At the end of the follow-up period, histomorphometric analysis of sciatic and tibial nerves from transplanted and intact hind limbs was conducted. Sciatic and tibial nerves were examined at the level of coaptation and near the neuromuscular junction, respectively.. Transplanted limbs in groups 1 and 3 completed the study without rejection, while the limbs in group 2 were rejected within a few days. Sciatic and tibial nerve analysis in groups 1 and 3 limbs showed myelinated axons of various diameters but in significantly fewer numbers than in nontransplanted contralateral nerves. The number and size of myelinated axons of transplanted nerves at corresponding levels were not significantly different between syngeneic and allogeneic (FK506/mycophenolate mofetil-treated) transplants.. The authors conclude that long-term neuroregeneration of revascularized peripheral nerves using low-dose FK506/mycophenolate mofetil was similar to that of syngeneic transplants. The occurrence of acute rejection episodes with low-dose FK506/mycophenolate mofetil did not appear to benefit nor impair neuroregeneration.

Topics: Anastomosis, Surgical; Animals; Axons; Contracture; Drug Evaluation, Preclinical; Drug Therapy, Combination; Femoral Nerve; Foot Deformities, Acquired; Graft Rejection; Hindlimb; Immunosuppressive Agents; Male; Microsurgery; Mycophenolic Acid; Myelin Sheath; Nerve Regeneration; Postoperative Complications; Rats; Rats, Inbred Strains; Rats, Inbred WF; Sciatic Nerve; Suture Techniques; Tacrolimus; Transplantation, Homologous

Lipid abnormalities including increased total cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) have been frequently reported in renal transplantation and could be involved in the high frequency of cardiovascular diseases in this population.. Two hundred ninety-five patients were transplanted between January 1995 and October 2000 in our center. Two hundred two patients were included in this study. Seventy-six patients received tacrolimus (Tac), and 126 patients cyclosporine (CsA). Lipid parameters were assessed the day of transplantation and 1 year posttransplantation.. Serum lipids were similar between the two groups at D0. At M12, TC and LDL-C were significantly higher in the CsA group (6.14 +/- 1.37 vs 5.28 +/- 1.32 mmol/L; P < .05 and 3.98 +/- 1.05 vs 3.26 +/- 1.03 mmol/L; P < .05 CsA vs Tac, respectively). TG were comparable in both groups (1.86 +/- 1.07 vs 1.62 +/- 0.92 mmol/L; P = .55; CsA vs Tac). Incidence of de novo hypercholesterolemia was significantly higher in the CsA group (28 vs 8%) whereas incidence of hyperTG was similar in both groups. Prevalence of LDL-C was significantly higher in the CsA group (65% vs 31%; P < .001), whereas there was no difference in high density lipoprotein (HDL)-C levels.. Mean serum lipid levels and incidence and prevalence of hyperTC, especially LDL-C, was significantly higher in patients receiving CsA when compared with Tac. TG and HDL-C levels were similar. Although the study was retrospective, our results confirm that CsA increases lipid levels, whereas Tac does not.. Lipid disorders are frequently observed in renal transplant recipients. CsA, but not Tac, significantly increases incidence and prevalence of high TC and LDL-C.

Topics: Adult; Body Mass Index; Cholesterol; Cyclosporine; Dyslipidemias; Hemoglobins; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipids; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Tacrolimus; Triglycerides

Immunosuppressive therapy is frequently associated with dyslipidemia, which is involved in cardiovascular morbidity and mortality in transplant patients. Beyond classical factors, such as low-density lipoprotein (LDL) cholesterol (LDL-C), qualitative abnormalities of lipoproteins, such as presence of the atherogenic factor, small dense LDL, may be of interest for a cardiovascular risk assessment. This study was designed to explore LDL size in renal transplant recipients in relation to quantitative lipid parameters and apolipoprotein (apo) CIII polymorphism.. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, apoA1, apoB, apoCIII, and LDL size were measured in 62 patients of mean age 45 +/- 13 years including 71% men at 2 +/- 0.5 years after renal transplantation. Thirty-two patients received cyclosporine (CsA), while 30 received tacrolimus (FK). ApoCIII Sstl genotype was determined by restriction fragment length polymorphism.. The CsA group exhibited higher TC (P = .001), LDL-C (P = .004), non-HDL-C (P = .009), HDL-C (P = .03), apoB (P = .008), and apoCIII (P = .002) levels than the FK group. However, LDL-C (CsA: 3.7 +/- 1.2, FK: 3.0 +/- 0.6 mmol/L) and triglyceride levels (CsA: 1.55 mmol/L, FK: 1.37 mmol/L) were near the normal range in both groups. Allelic frequency of the sparse A2 allele associated with hypertriglyceridemia was 6%, similar to the general population. LDL size, which was comparable in the CsA and FK groups (25.87 +/- 0.89 vs 25.75 +/- 0.62 nm, respectively), inversely correlated with TG/HDL ratio (P = 10(-4)). Prevalence of small dense LDL (defined as <25.5 nm) was 26% in the CsA group and 33% in the FK group.. After LDL-C goal has been achieved, LDL size modulation may be taken into account in order to prevent cardiovascular complications.

Topics: Adult; Apolipoprotein C-III; Apolipoproteins B; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, LDL; Male; Middle Aged; Postoperative Complications; Tacrolimus; Triglycerides

We evaluated the relevance of human cytomegalovirus (HCMV) monitoring with quantitative real-time polymerase chain reaction in 42 consecutive HCMV positive liver transplant patients, and we analyzed the factors that determined the treatment of the first episode of HCMV DNAemia. No patients received anti-HCMV prophylaxis. HCMV infection monitoring was assessed every 2 weeks until day 90 and thereafter at every 3 to 4 weeks until day 180. HCMV infection was detected among 27 patients (64%, ie, 92/380 samples). Of these, 12 had their first HCMV DNAemia treated with IV gancyclovir (group I), whereas the other 15 patients were not treated (group II). Immunosuppressive treatment was not modified in cases of HCMV DNAemia. The median time between transplantation to the first CMV DNAemia was 37 days in group I and 52 days in group II (NS). Median HCMV viral load, whatever the treatment group and whatever the time of DNAemia, was 3 log copies/mL (0.48 to 5.80). Median HCMV viral load of the first positive DNAemia was 3.45 log copies/mL (1.69 to 5.80) in group I and 2.70 log copies/mL (1.15 to 3.94) in group II (P = .01). Even though liver enzymes were increased in almost all patients presenting with HCMV infection, comparison of liver-enzyme levels and hematological parameters between the two groups at first HCMV viremia showed that alkaline phosphatase levels were significantly higher (P = .0011) and hemoglobin levels were significantly lower in group I patients (P = .0443). The only factor that predicted treatment for the first episode of HCMV DNAemia was an alkaline phosphatase level >150 UI/mL at the time of the first HCMV reactivation [odds ratio 20 (1.96 to 203.3); P = .01].

Topics: Adrenal Cortex Hormones; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Polymerase Chain Reaction; Postoperative Complications; Retrospective Studies; RNA, Viral; Tacrolimus; Viral Load; Viremia

There are few data directly comparing the effects of two-hour postingestion monitored cyclosporine (C2-CsA) vs. trough-monitored tacrolimus (C0-Tac) on renal function and cardiovascular risk factors.. We studied 378 (202 C2-CsA vs. 176 C0-Tac) incident kidney transplant recipients in Toronto, Canada, from August 1, 2000 and December 31, 2003. Outcomes included changes in estimated glomerular filtration rate (eGFR at 1 and 6 months by modification of diet in renal disease four-variable equation), mean arterial pressure (MAP), total cholesterol (TC), and new-onset diabetes mellitus (NODM) at six months posttransplant. The independent effect of treatment/monitoring strategies on continuous outcomes and time-to-NODM was modeled using linear and Cox regression, respectively.. Mean eGFR was 59.5 vs. 62.9 ml/min at one month and 50.6 vs. 61.2 ml/min at six months for C2-CsA vs. C0-Tac, respectively. Multiple linear regression revealed the slope of eGFR to be 0.93 ml/min/month lower in C2-CsA patients. This was equivalent to an adjusted average eGFR difference of 4.64 ml/min between months one and six posttransplant. There was no significant difference in average MAP and TC. In a stepwise multivariable Cox model and a propensity score analysis, there was no significant association between the type of treatment/monitoring strategy and time-to-NODM.. There was a greater decline in eGFR for patients on C2-CsA (vs. C0-Tac) between one and six months posttransplant. However, MAP, TC, and the risk of NODM were comparable in both treatment/monitoring groups. The long-term impact of short-term reductions in eGFR as a function of the type of treatment/monitoring strategy requires further study.

Topics: Adolescent; Adult; Cardiovascular Diseases; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Patient Selection; Postoperative Complications; Risk Factors; Tacrolimus

Sarcoidosis is a granulomatous disease of unknown etiology and is only rarely seen in infants and children. We present the case of a 9-year-old boy who developed sarcoidosis with multi-organ involvement 9 years after cardiac transplantation for Shone complex. The patient was on immunosuppressive therapy with tacrolimus and mycophenolate mofetil. He presented with severe respiratory distress due to marked mediastinal lymphadenopathy and bilateral pulmonary infiltrates in association with fatigue, low-grade fever, hepatosplenomegaly and generalized lymphadenopathy. Lymph node histology showed non-caseating epitheloid cell granulomas and giant cells. Initialization of therapy with prednisolone resulted in prompt clinical recovery and resolution of all symptoms except for the development of mild pulmonary fibrosis. Tapering of the steroids led to recurrence of mediastinal lymphadenopathy 5 months after the initial disease, which responded to an increase in steroid dose. The clinical course, the medical management, and the possible role of immunosuppression in the etiology of the disease are discussed.

Topics: Child; Dose-Response Relationship, Drug; Glucocorticoids; Heart Transplantation; Humans; Immunosuppressive Agents; Lymph Nodes; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Radiography, Thoracic; Recurrence; Retreatment; Sarcoidosis; Tacrolimus; Tomography, X-Ray Computed

To investigate the incidence and risk factors of late-onset acute rejection (LAR) and to clarify the effectiveness of our immunosuppressive regime consisting of life-long administration of tacrolimus and steroids.. Adult living donor liver transplantation recipients (n=204) who survived more than 6 mo after living donor liver transplantation were enrolled. Immunosuppression was achieved using tacrolimus and methylprednisolone. When adverse effects of tacrolimus were detected, the patient was switched to cyclosporine. Six months after transplantation, tacrolimus or cyclosporine was carefully maintained at a therapeutic level. The methylprednisolone dosage was maintained at 0.05 mg/kg per day by oral administration. Acute rejections that occurred more than 6 mo after the operation were defined as late-onset. The median follow-up period was 34 mo.. LAR was observed in 15 cases (7%) and no chronic rejection was observed. The incidence of hyperlipidemia, chronic renal failure, new-onset post-transplantation diabetes, and deep fungal infection were 13%, 2%, 24%, and 17%, respectively. Conversion from tacrolimus to cyclosporine was required in 38 patients (19%). Multivariate analysis revealed that a cyclosporine-based regimen was significantly associated with LAR.. Both LAR and drug-induced adverse events happen at a low incidence, supporting the safety and efficacy of the present immunosuppression regimen for living donor liver transplantation.

Topics: Adolescent; Adult; Aged; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

At present, there is some controversy about the impact of diabetes mellitus on heart transplant patients. The effect of the disease on mortality and on other complications, such as infection or rejection, is unclear. The objective of this study was to investigate these factors in our heart transplant patients.. We studied 365 consecutive patients who underwent heart transplantation between November 1987 and May 2003. We divided them in three groups according to whether they had pretransplantation diabetes (group 1), de novo diabetes (group 2), or no diabetes (group 3). Baseline variables and the development of complications were recorded, and findings were analyzed using Student's t test, chi squared test, and Kaplan-Meier survival analysis.. There was no difference in the 1-year or 5-year survival rate between the groups (P=.24 and P=.32, respectively). Patients with pretransplantation and de novo diabetes were older (54.6 years vs 54.9 years vs 50.6 years, P=.04), had a higher prevalence of hypertension (48% vs 36% vs 23%, P=.001), and had more frequently been treated with tacrolimus (10% vs 12% vs 4%, P=.04) or steroids (92% vs 86% vs 70%, P=.001). The incidence of rejection during follow-up was greater in these two groups (64% vs 70% vs 45%, P=.001).. Neither pretransplantation diabetes nor de novo diabetes had a negative impact on survival in our heart transplant patients. The disease's presence was associated with treatment with steroids and tacrolimus. In these patients it would be preferable to individualize immunosuppressive therapy.

Topics: Adrenal Cortex Hormones; Age Factors; Chi-Square Distribution; Data Interpretation, Statistical; Diabetes Complications; Diabetes Mellitus; Female; Follow-Up Studies; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Postoperative Complications; Prevalence; Risk Factors; Survival Analysis; Tacrolimus; Time Factors

Relative adrenal insufficiency is now a well-known clinical condition that occurs in critically ill patients particularly with septic complication. However, this pathology has long been unrecognized until recently in liver transplantation patients, for whom postoperative immunosuppressive therapies almost always comprise corticosteroids. We report an obvious case of relative adrenal insufficiency manifested by severe multiple organ dysfunction in a recipient after living donor liver transplantation (LDLT). A 38-year-old woman with multiple hepatocellular carcinoma developed refractory liver failure 2 months after the completion of the dual treatment; namely a cytoreductive right hepatectomy for bulky main tumors followed by 2 courses of percutaneous isolated hepatic perfusion for residual tumors in the remnant liver. She underwent a right-lobe LDLT, and postoperative immunosuppression was initiated with a low-dose tacrolimus monotherapy without corticosteroid because of a severe septic condition before transplantation. Postoperatively, she developed progressive hyperbilirubinemia, renal dysfunction, and coagulopathy. As the corticotropin stimulation test suggested the relative adrenal insufficiency, corticosteroid was commenced 40 days after LDLT. Thereafter, multiple organ dysfunction resolved dramatically and promptly. The patient is presently alive and well with completely normalized liver function 45 months after LDLT.

Topics: Adrenal Insufficiency; Adult; Carcinoma, Hepatocellular; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Methylprednisolone; Multiple Organ Failure; Postoperative Complications; Radiography, Abdominal; Tacrolimus; Tomography, Spiral Computed

Matched sibling donor (MSD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA); however, only about 33% of patients will have an HLA-identical sibling. Alternative donor (AD) transplants may be an option for these patients, but such therapies have been associated with greater incidence of graft failure and graft-versus-host disease (GVHD). We retrospectively analyzed 36 pediatric patients who received 38 bone marrow or peripheral blood stem cell transplants (15 MSD and 23 AD) for SAA at our institution from April 1997 to October 2005. Nineteen AD recipients received reduced intensity conditioning with cyclophosphamide, low-dose total body irradiation, and antithymocyte globulin (ATG) or Campath. The 4-year overall survival for MSD recipients was 93% versus 89% for AD recipients treated with reduced intensity conditioning regimens at a median follow-up of 52 months (range, 6-99 months). No patient receiving Campath, compared with 3 of 9 patients receiving ATG, developed extensive, chronic GVHD. We conclude that, for children with SAA, AD transplantation is as effective as MSD transplantation. Further, compared with ATG, preparatory regimens containing Campath may be associated with a lower incidence of extensive, chronic GHVD.

Topics: Adolescent; Alemtuzumab; Anemia, Aplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Bone Marrow Transplantation; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Graft vs Host Disease; Histocompatibility; Humans; Immunosuppressive Agents; Infant; Infections; Kaplan-Meier Estimate; Male; Methotrexate; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Retrospective Studies; Siblings; Survival Analysis; T-Lymphocyte Subsets; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Calcium-oxalate crystal deposition in kidney transplant biopsy specimen led us to investigate the impact of calcineurin inhibitor treatment on urinary excretion of lithogenic and stone inhibitory substances in 53 children after successful kidney transplantation (KTx) receiving cyclosporine A (CsA) or tacrolimus. We compared the values obtained with those of 12 patients with recurrent nephrotic syndrome under CsA and of 6 patients with Rasmussen encephalitis (RE) under tacrolimus therapy. Renal ultrasound examinations were repeatedly performed. Hypocitraturia was found in 69% of patients, with KTx patients having a significantly lower urinary citrate excretion than those receiving calcineurin inhibitors for other reasons. Secondly, we found hyperoxaluria in 35% of patients, again especially in those after KTx. No significant difference in urinary substances was seen comparing CsA with tacrolimus treatment. Urolithiasis was found in one and calcium-oxalate crystal deposition in biopsy specimen of three KTx patients. Calcineurin inhibitor treatment can lead to significant hypocitraturia, especially in patients after KTx receiving the highest dose of medication. Hyperoxaluria is primarily the result of a removal of significant body oxalate stores, deposited during dialysis, but may not be suspected as a specific side effect of calcineurin inhibitor therapy. Both findings can increase the risk for urolithiasis or nephrocalcinosis.

Topics: Adolescent; Adult; Calcineurin Inhibitors; Calcium Oxalate; Child; Citric Acid; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Nephrocalcinosis; Postoperative Complications; Risk Factors; Tacrolimus; Urinary Calculi

Topics: Antilymphocyte Serum; Brain Neoplasms; Cytomegalovirus Retinitis; Epstein-Barr Virus Infections; Female; Ganciclovir; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisolone; Radiography; RNA, Viral; Tacrolimus; Transplantation, Homologous

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.

Topics: Adult; Aged; Biopsy; Diabetes Mellitus; Female; Glomerulonephritis, IGA; Graft Survival; Hepatitis; Humans; Hydroxyethyl Starch Derivatives; Hypertension; Immunosuppressive Agents; Interferon-alpha; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Risk; Tacrolimus; Time Factors

Increased risk of cardiovascular disease contributes significantly to the higher rate of mortality seen in kidney transplant patients compared to the general population. New-onset diabetes mellitus (NODM) is a major risk factor for cardiovascular disease, as well as being associated with significantly increased graft loss and higher health care costs compared to the nondiabetic transplant population. Evidence from large-scale analyses of registry databases has shown that the calcineurin inhibitor, tacrolimus, is associated with approximately a 50% increase in the risk of NODM compared to the microemulsion formulation of cyclosporine (CsA); but to date, little robust evidence is available from clinical trials. The DIRECT (Diabetes Incidence after REnal transplantation: Neoral C2 monitoring versus Tacrolimus) study will be the first prospective trial to compare directly the impact of tacrolimus and CsA microemulsion on glucose metabolism in kidney transplant recipients. DIRECT is a 6-month, parallel-group, open-label, randomized trial for which approximately 700 patients will be recruited at around 70 transplant centers worldwide. Patients will be randomized to tacrolimus or CsA microemulsion (using C2 monitoring), with mycophenolate mofetil or enteric-coated mycophenolic acid, steroids, and basiliximab. Primary endpoints are: (a) a composite of NODM or impaired fasting glucose among patients who are nondiabetic at time of transplantation; and (b) combined incidence of biopsy-proven acute rejection, graft loss, or death with CsA microemulsion C2 monitoring compared to tacrolimus trough monitoring . Full results are expected in 2006, with interim results available by the end of 2004, and will be awaited with interest by the transplant community.

Topics: Adult; Aged; Cyclosporine; Diabetes Mellitus; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multicenter Studies as Topic; Postoperative Complications; Randomized Controlled Trials as Topic; Research Design; Survival Rate; Tacrolimus

After allogenic transplantations, a dramatic increase in the development of arteriosclerotic plaques can be observed, which might be due to metabolic alterations, changes in the transplant organ, or the immunosuppression regimen. Many studies have demonstrated beneficial effects of tacrolimus compared with cyclosporine with regard to these conditions. These results have suggested that conversion to tacrolimus from cyclosporine is advantageous. Our study investigated whether patients with deteriorating renal function profit from this conversion. Thirty renal transplant patients were studied retrospectively, using data recorded from 3 years before to 3 years after conversion from cyclosporine to tacrolimus. While renal function (GFR) deteriorated progressively under cyclosporine, it stabilized and even improved under tacrolimus (creatinine: DeltaCyc = +1.4 mg/d; DeltaTac = -0.7 mg/dL; GFR: DeltaCyc = -35 mL/min; DeltaTac = 14 mL/min). In addition, uric acid levels (7.0 mg/dL vs 6.4 mg/dL, P < .05) and cholesterol levels (258 mg/dL vs 225 mg/dL, P < .05) were both significantly lower under tacrolimus. Conversion from cyclosporine to tacrolimus is recommended for kidney transplant patients in whom there has been a progressive fall in renal function. It leads to stabilization or even improvement of transplant function and a reduction in cardiovascular risk factors.

Topics: Adult; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Cyclosporine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipids; Postoperative Complications; Retrospective Studies; Risk Assessment; Tacrolimus

In a single-center prospective randomized controlled study, the impact of calcineurin inhibitor (CNI) reduction or withdrawal on the pharmacokinetics of mycophenolic acid (MPA) was studied in a group of renal transplant recipients with impaired renal function. Mycophenolate mofetil (MMF) was added to a baseline regimen of prednisolone and CNI. Afterwards the patients were randomized into "CNI withdrawal" and "CNI continuation" groups. The dosage of CNIs, cyclosporine or tacrolimus, was gradually reduced and withdrawn within 6 weeks from patients in the withdrawal group. The continuation group was maintained on therapy with CNI, MMF, and steroids. These regimens were maintained until the ninth month. In contrast to the withdrawal of tacrolimus, which has no significant effect on MPA pharmacokinetics, cyclosporine withdrawal was associated with a significant increase in the trough levels and areas under the curve of MPA. Serum creatinine and urine albumine levels stabilized on average after CNI withdrawal in this population. The results are consistent with the hypothesis that cyclosporine attenuates the enterohepatic recirculation of MPA. The withdrawal of CNI has a positive effect on renal function in chronic allograft dysfunction.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Cyclosporine; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Postoperative Complications; Randomized Controlled Trials as Topic; Tacrolimus

Tacrolimus was approved in Japan in April 1996 for the prevention of allograft rejection in patients receiving kidney transplants. There has been a concern that immunosuppressive therapy may be associated with cardiovascular and metabolic complications, including hyperlipidemia, hypertension, and posttransplant diabetes mellitus. A multicenter (59 institutions) study was conducted in Japan in patients who underwent renal transplantation and received tacrolimus immunosuppression. Patients were followed for >5 years, from April 1996 to December 2002. Of the 1569 patients enrolled, 1542 were evaluated. In this analysis, graft survival rate and medication usage patterns of antihyperlipidemics, antihypertensives, insulin, and oral hypoglycemics were observed for >5 years in patients receiving tacrolimus immunosuppression. The graft survival rates of patients requiring antihyperlipidemic therapy and experiencing acute rejection were significantly lower compared with all other patients (P < .05). The risk of graft rejection was significantly greater in patients with cardiovascular complications requiring antihyperlipidemics or antihypertensives. Graft survival was significantly lower in patients with acute rejection and antihyperlipidemic therapy than in other patients.

Topics: Follow-Up Studies; Graft Survival; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Japan; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Safety; Tacrolimus; Time Factors

In Japan, the number of kidney transplants for the patients with diabetic nephropathy is limited because of an extreme organ shortage and poor patient and graft survival rates. We analyzed the 5-year outcomes in kidney transplant recipients treated with tacrolimus with (group 1; n = 53) and without a diagnosis of diabetic nephropathy (group 2; n = 1432). We also investigated outcomes in patients who received simultaneous pancreas and kidney transplants since 2000 (group 3; n = 15). Patients in group 1 were older than those in group 2, with a shorter duration of pretransplant dialysis (P = .0001). Five-year patient survival rates in groups 1 and 2 were 89.7% and 97.9%, respectively (P = .13), and 5-year graft survival rates were 89.6% and 94.8%, respectively (P = .44). The incidence of acute rejection within 3 months of transplantation was 28.3% in group 1 and 29.2% in group 2 (P = .98). Tacrolimus-based induction therapy was used in 13 of the 15 group 3 cases. Both kidney and pancreas grafts are surviving to date in all but one of the group 3 patients; one patient had the pancreas removed due to venous thrombosis at 7 days. It was concluded that tacrolimus-based therapy resulted in excellent 5-year outcomes in patients who had kidney transplantation because of diabetic nephropathy, despite the higher risks associated with this condition. Tacrolimus was also beneficial in association with simultaneous pancreas and kidney transplantation. These data encourage us to perform kidney transplantation in patients with diabetic nephropathy.

Topics: Adult; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Japan; Kidney Transplantation; Postoperative Complications; Renal Replacement Therapy; Retrospective Studies; Survival Analysis; Tacrolimus

The safety and efficacy of tacrolimus (Tac)-based immunosuppressive treatments were studied in 115 pediatric renal transplant recipients (mean follow-up period, approximately 20 months). The acute rejection rate was 22.7% 6 months after transplantation and the steroid-resistant acute rejection rate was 6.4%. The 5-year patient and graft survival rates were 98.6% and 95.9%, respectively. Major adverse effects included infection, ie, cytomegalovirus (CMV) antigenemia (41.7%), renal dysfunction (29.6%), and impaired glucose tolerance (20.9%). The incidences of these adverse events were significantly decreased among patients who had undergone transplantation after March 2000 (n = 43), namely, 30.2%, 18.6%, and 11.6%, respectively.

Topics: Adult; Cadaver; Female; Follow-Up Studies; Glucose Intolerance; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Japan; Kidney Transplantation; Living Donors; Male; Nervous System Diseases; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

Recent clinical trials have documented the short-term safety of steroid avoidance (SA) in kidney transplant recipients. Since July 2003, we have used a SA immunosuppression protocol for low-risk kidney transplant recipients. Eligibility criteria are age > or = 18, primary transplant (living or deceased donor), and tacrolimus started by postoperative day 3. Recipients were excluded if peak/current PRA was >50%/20%, or if they had a positive flow crossmatch, or if they had the recent use of corticosteroids (<6 months). All recipients received induction with rabbit anti-thymocyte globulin, total dose 6 mg/kg, or basiliximab. Recipients received 5 daily doses of corticosteroid and mycophenolate mofetil 1 gm twice daily starting on the day of transplantation. Tacrolimus was started when the serum creatinine level decreased by 20%, or by postoperative day 3. The goal for trough tacrolimus levels was 10-15 ng/mL for the first month, 8-12 ng/mL for months 2-3, and 5-10 ng/mL after month 3. Protocol biopsies (bx) were performed at reperfusion, 1 month, 4 months, and 12 months. Ninety-four kidney transplantations were performed during the study period. Sixty-seven recipients (71%) were eligible and enrolled in SA. Characteristics of the 67 SA recipients: mean age, 53 years (range, 26-70); 41% female; 67% Caucasian; 24% Hispanic; 15% African American; and 5% Native American. Also, 77% received a living donor kidney. The mean follow-up was 180 days (range, 10-360). At last follow-up, 91% remained steroid-free. Biopsy-proven acute rejection (BPAR) occurred in 5 recipients (7.5%). Three recipients (4.5%) had clinical BPAR and 2 had subclinical. One recipient died with pneumonia 4 months following transplantation. Posttransplantation diabetes mellitus (PTDM) occurred in 2 (5%) of 38 recipients. In the initial 41 recipients, 27 had protocol bx at 1 month and 13 at 4 months available for analysis. Chronic allograft nephropathy (CAN) was present on protocol bx in 48% at 1 month and 69% at 4 month. Actuarial (Kaplan-Meier method) patient and graft survival rates at 351 days were 97.8% and 96.8%, respectively. SA with anti-thymocyte globulin induction in low-immunologic risk kidney transplant recipients is safe and is associated with a low risk of BPAR. The incidence of PTDM appears to be lower.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Transplantation, Homologous

Posttransplantation diabetes mellitus (PTDM) is a complication arising mostly during the first 6 months after kidney transplantation. Considering the serious outcomes of chronic hyperglycemia in kidney transplant patients, the recognition of factors that contribute to the onset of PTDM is of particular relevance. A retrospective analysis was performed to document the incidence of and the risk factors for diabetes mellitus occurring in the first year after kidney transplantation among 177 adult patients, without previously known diabetes transplanted between January 1998 and December 2000. PTDM, defined as fasting plasma glucose > or = 126 mg/dL confirmed by repeat testing on a different day, occurred in 48 (27.12%) patients of whom 36 showed transient changes during the first year after transplantation. Univariate analysis identified variables to be associated with the onset of PTDM: older recipient age (P = .05), male gender (P = .03), family history of diabetes (P = .04), advanced donor age (P = .008), absence of induction immunosuppression (P = .04), use of tacrolimus (vs cyclosporine; P = .01), one or more than one (steroid-treated) acute rejection episode(s) (P = .000001), cytomegalovirus infection (P = .02), and use of beta-blockers or diuretics (P = .05). By multivariate analysis, five factors were independently associated with the onset of PTDM: two episodes of rejection (odds ratio = 42.69, P = .000025), one episode of rejection (5.01, P = .007), older recipient age (1.06, P = .017), family history of diabetes (7.24, P = .011), and weight at transplantation (1.03, P = .048). Tacrolimus treatment remained of borderline significance (2.77, P = .05). In addition to traditional risk factors predisposing to the development of type 2 diabetes in the general population, episodes of acute rejection significantly influence the incidence of PTDM.

Topics: Adult; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Patient Selection; Postoperative Complications; Retrospective Studies; Tacrolimus

The incidence of new-onset posttransplant diabetes mellitus (PTDM) is increased in renal transplant patients treated with tacrolimus.. We retrospectively analyzed fasting plasma glucose and HbA1c levels as well as the dose of glucose-lowering agents in 34 renal transplant patients converted from tacrolimus to cyclosporine (CsA) for PTDM. Diabetes was defined according to current guidelines as repeated fasting plasma glucose (FPG) levels > or =126 mg/dL.. At conversion, 11 patients received insulin, 5 received oral agents, and 18 had no glucose-lowering therapy. Fasting plasma glucose levels decreased from 146 +/- 64 mg/dL at conversion to 111 +/- 26 mg/dL at 3 months and 104 +/- 21 mg/dL at 12 months (P < .001). HbA1c levels decreased from 6.8 +/- 0.8% at conversion to 6.0 +/- 0.6% at 12 months (P = .001). Insulin was stopped in 3, the dose reduced in 7, and remained stable in 1 of the patients. The average daily insulin dose among these patients was reduced from 31 +/- 17 units at conversion to 13 +/- 12 units at 12 months (P < .05). There was no significant change in the number of patients treated with oral glucose-lowering agents. Diabetes reversed (fasting plasma glucose < or = 125 mg/dL without glucose-lowering therapy) in 44% (95% confidence interval, 23% to 64%) of patients during the first year after conversion (P < .001). Graft function, blood pressure, and lipid levels remained stable after conversion but the proportion of patients receiving lipid-lowering therapy increased from 18% to 49% (P < .01).. Conversion from tacrolimus to CsA for PTDM was associated with a marked improvement in glucose metabolism and frequent reversal of diabetes.

Topics: Blood Glucose; Cyclosporine; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Incidence; Insulin; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Retrospective Studies; Tacrolimus

Posttransplant diabetes mellitus (PTDM) is an important complication in a tacrolimus (TAC)-based immunosuppressive regimen. The present study investigated the incidence, clinical risk factors, TAC pharmacokinetics (PK), and genomic polymorphisms related to TAC-PK or diabetes mellitus (DM) under the TAC-based immunosuppressive protocol.. Seventy-one nondiabetic renal allograft recipients transplanted from February 1998 to March 2004 were studied. Patients with over 6.5 mg/dL of hemoglobin A1c on sequential blood samples or requiring insulin or oral antidiabetic agents around 6 months after transplantation were diagnosed as having PTDM.. Six months after transplantation, 10 recipients (14.1%) developed PTDM. The positive risk factors were age (P = .003) and body mass index (P = .035). There were no significant differences in gender distribution, pretransplant dialysis period, dialysis modality, acute rejection rate, total steroid doses, TAC-PK, or its related genomic polymorphisms between the two groups. In the DM-related polymorphisms, the frequency of PTDM was significant higher in patients with the VDR TaqI tt or Tt genotype than in those with the TT genotype (P = .013). After a multivariate analysis, age over 50 years (P = .007, odds ratio 8.92) and the presence of VDR TaqI t allele (P = .043, odds ratio 6.71) were correlated with the development of PTDM.. The incidence of PTDM in our series was 14.1%. Age over 50 years was a risk factor. The presence of VDR TaqI t allele might be a risk for PTDM. An association between TAC-PK and development of PTDM was not observed.

Topics: Body Mass Index; Diabetes Mellitus; Female; Genome, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Polymorphism, Genetic; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

The main rheological properties of red blood cells (RBC) are deformability and aggregability. Deformability is one of the most important factors of RBC flow in high-shear rate areas, especially in the microcirculation. Aggregability of erythrocytes can impair circulation in low-shear rate areas. Both deformability and aggregability of RBC are abnormal in patients with renal insufficiency and after kidney transplantation. Cyclosporine (CsA) and less frequently tacrolimus (Tc) may cause hyperlipidemia and hypertension. Dobiasova et al proposed the term Atherogenic Index of Plasma (AIP), defined as a log (TG/HDL-C). Subjects with high AIP have and higher risk of cardiovascular complications due to atherosclerosis. Hence the aim of this study was to compare aggregability and deformability of RBC from kidney transplant recipients on CsA or Tc-based immunosuppression with healthy volunteers and subjects with dyslipidemia (control groups). Both control and transplant recipient groups were arbitrarily divided by value of AIP as < or = 0 (AIP-) or >0 (AIP+). Deformability and aggregability of erythrocytes were measured using Rheodyn SSD and Myrenne Aggregometer, respectively.. We observed a significant increase in aggregation index at stasis in CsA-treated patients and an increased deformability in Tc-treated patients with negative AIP. Deterioration of hemorheological properties of RBC in kidney transplant recipients was confined to an increased aggregability in CsA-treated patients regardless of AIP value. An increased deformability of RBC in Tc-treated patients with normal lipid profiles may suggest a positive effect of Tc on mechanical properties of RBC.

Topics: Adult; Arteriosclerosis; Creatinine; Cyclosporine; Erythrocytes; Female; Hematocrit; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Postoperative Complications; Rheology; Risk Factors; Tacrolimus

Dietary salt is an important contributor to hypertension in the general population. While its role in cyclosporine-induced hypertension is minimal, its role in tacrolimus-based immunosuppression has not been defined. We measured the 24-hour urine sodium excretion as an estimate of intake in a group of stable renal transplant recipients on tacrolimus (N = 143) who had serum creatinine fluctuations <20% during the preceding 3 months. Average clinic-measured blood pressure (BP) from before and after the 24-hour urine collection was computed. Patients with recent changes in antihypertensive medications were excluded. Average systolic BP was 126 +/- 14 and diastolic BP 76 +/- 7 mm Hg. Urine sodium was 162.6 +/- 70 mmol/d (range 50 to 351), and the sodium/creatinine ratio was 15.4 +/- 6.4. There was no correlation between urine sodium excretion and either systolic or diastolic BP (R = 0.07 and R = 0.05, P = NS) or the sodium/creatinine and systolic/diastolic BP (R = 0.13, R = 0.11, P = NS). By multiple linear regression only weight and urine protein were independently associated with both systolic BP (P < .0001 for each) and diastolic BP (P < .05 for each). In conclusion, there is no appreciable influence of dietary salt intake on BP under tacrolimus-based immunosuppression. Restricting dietary salt intake in these patients cannot be recommended at the current time.

Topics: Analysis of Variance; Blood Pressure; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sodium; Sodium Chloride, Dietary; Tacrolimus

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

Topics: Adult; Calcineurin Inhibitors; Deafness; Follow-Up Studies; Hearing Aids; Hearing Loss; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Surveys and Questionnaires; Tacrolimus; Time Factors

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV.

Topics: Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Recurrence; Registries; Survival Analysis; Tacrolimus; Treatment Outcome

Early steroid discontinuation (ESD) has been associated with a lower incidence of post-transplant diabetes mellitus (PTDM). We retrospectively reviewed the incidence of PTDM in relation to racial groups in kidney transplant recipients treated with ESD. Between January 2002 and September 2003, 125 consecutive primary adult kidney transplants were performed. Group A (n = 91) had steroids discontinued on postoperative day 6 and maintenance immunosuppression of Tacrolimus and mycophenolate mofetil. Group B (n = 34), received the same immunosuppression but was maintained on steroids indefinitely. Induction consisted of thymoglobulin in African-Americans; all others received Simulect. At 1 yr, patient/graft survival, serum creatinine and rate of acute rejection were similar in both groups. The incidence of PTDM was significantly lower in group A (7%) compared with group B (26%, p = 0.0209). The incidence of PTDM in group A was limited to Hispanic patients with a family history of diabetes mellitus. African-Americans and Caucasians in group A did not experience PTDM (p = 0.005 compared with African-American in group B). Our steroid free protocol nearly eliminated the incidence of PTDM in African-Americans and Caucasians, but was still associated with significant rate of PTDM in Hispanic recipients. Alternative immunosuppression may benefit this population.

Topics: Adult; Diabetes Mellitus; Female; Graft Survival; Hispanic or Latino; Humans; Immunosuppression Therapy; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Steroids; Tacrolimus

Previous studies suggest the association of recipient hepatitis C seropositivity (HCV+) and use of tacrolimus (TAC) with post-transplant diabetes mellitus (PTDM) may differ by manifestations of type I or type II diabetes, but this has not been assessed in the era of current immunosuppression.. We performed a retrospective cohort study of 10,342 Medicare primary renal transplantation recipients without evidence of diabetes at the time of listing in the United States Renal Data System between January 1, 1998 and July 31, 2000, followed until December 31, 2000. Outcomes were hospitalizations for a primary diagnosis of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS). Cox regression analysis was used to calculate adjusted hazard ratios (AHR) for time to DKA or HHS, stratified by diabetes status at the time of transplant.. In Cox regression analysis, use of TAC at discharge was independently associated with shorter time to DKA (AHR, 1.88; 95% CI, 1.05-3.37, p=0.034) but not HHS. In contrast, recipient HCV+ was independently associated with shorter time to HHS (AHR, 3.90; 1.59-9.60, p=.003), but not DKA. There was no interaction between TAC and HCV+ for either outcome.. These results confirm earlier findings that TAC and HCV+ may mediate the risk of PTDM through different mechanisms, even in the modern era.

Topics: Diabetes Mellitus; Female; Graft Rejection; Hepatitis C; Hospitalization; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; United States

Up to date, 24 hands/thumbs have been transplanted in 18 patients. We herein report on cytomegalovirus (CMV) infection, disease, and the adopted treatment.. Immunosuppression consisted of tacrolimus-based triple-drug therapy with antithymocyte globuline or CD25-receptor antagonist induction. Donor/recipient CMV match was negative/negative (n=8), negative/positive (n=3), positive/positive (n=3), positive/negative (n=3) and unknown in one case. Six patients (three +/-, two +/+, and one -/+) received gancyclovir i.v. followed by oral gancyclovir or valgancyclovir for prophylaxis.. Patient and graft survival at a mean follow-up of 42.9 months were 100% and 91%, respectively. Of all patients tested for CMV, 45.5% developed CMV infection or disease. Two patients that were given a CMV-positive graft showed very high viral loads (550 and 1200/200000 leukocytes) after transplantation. Gancyclovir treatment failed to permanently control CMV in 80% of the patients experiencing CMV infection. Those patients requiring more toxic second-line therapies (foscarnet/cidofovir) suffered from side effects such as nephrotoxicity, nausea, vomiting, and diarrhea.. CMV infection/disease complicated the postoperative course after composite tissue allograft (CTA) transplantation in five of nine recipients challenged with the virus. The close time correlation suggests an association between virus replication and rejection in some cases. CMV represents the major infectious threat in CTA transplantation. Therefore, CMV-mismatch should be avoided and prophylaxis with valgancyclovir and anti-CMV hyperimmunoglobulin should be mandatory.

Topics: Adolescent; Adult; Antibodies, Viral; Antigens, Viral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Therapy, Combination; Follow-Up Studies; Ganciclovir; Glucocorticoids; Graft Rejection; Graft Survival; Hand Injuries; Hand Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tissue Donors

Acute overdose of tacrolimus appears to cause no or minimal adverse clinical consequences. We encountered a pediatric case who underwent liver transplantation associated with hepatic artery thrombosis (HAT), which recurred following acute tacrolimus overdose. A 10-month-old girl underwent living-related liver transplantation because of biliary atresia. To reconstruct the hepatic artery, the right gastroepiploic artery of the donor was interposed between the right hepatic artery of the recipient (2.5 mm in diameter) and the left hepatic graft artery (1 mm in diameter) under microscopy. On postoperative day 4, Doppler ultrasonography showed a remarkable reduction in hepatic arterial flow, which was consistent with HAT. The patient underwent immediate hepatic arteriography and balloon angioplasty. The stenotic sites were dilated by the procedure. Tacrolimus was infused intravenously after transplantation and the infusion rate was adjusted to achieve a target concentration of 18-22 ng/mL, which remained stable until the morning of day 6. An unexpectedly high blood concentration of tacrolimus (57.4 ng/mL) was detected at 6:00 PM on day 6, and tacrolimus was discontinued at 9:00 PM; however, the tacrolimus level reached 119.5 ng/mL at 0:00 h on day 7. While the concentration decreased to 55.2 ng/mL on the morning of day 7, the hepatic arterial flow could not be observed by Doppler ultrasonography. Emergent hepatic arteriography showed stenosis of the artery at the proximal site of the anastomosis. Balloon angioplasty was again performed and the stenotic site was successfully dilated. High level of tacrolimus exposure to the hepatic artery with injured endothelium by preceding angioplasty may have been related to the recurrence of HAT in the present case.

Topics: Blood Urea Nitrogen; Child; Cholangitis; Creatinine; Drainage; Drug Monitoring; Drug Overdose; Female; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intravenous; Liver Transplantation; Postoperative Complications; Recurrence; Tacrolimus; Thrombosis; Treatment Outcome; Ultrasonography

The effectiveness of the novel immunosuppressive agent FK778 and of tacrolimus to prevent the development of obliterative airway disease (OAD) was investigated in an animal model.. Tracheae from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with FK778 (5 or 20 mg/kg), tacrolimus (1 or 4 mg/kg) or combination regimens at varying doses (5 + 1 mg/kg, 10 + 2 mg/kg or 20 + 4 mg/kg). Grafts were harvested and processed for histologic and immunohistochemical evaluation. Lymphocyte surface antigen expression was quantified and in vitro smooth muscle cell (SMC) proliferation assays were performed.. In untreated recipients, very large amounts of infiltrating CD4+, CD8+ and ED1+ mononuclear cells were observed in the peritracheal region with epithelial loss and complete luminal obliteration. Granulation tissue consisted of alpha-actin-positive cells and collagen-rich fibrosis. FK778 and tacrolimus as well as combination regimens of both agents dose-dependently inhibited peritracheal infiltration and luminal obliteration. Only tacrolimus-treated recipients showed preserved luminal epithelial coverage with airway goblet cells, whereas, in animals that received FK778, no epithelium was found. Both agents equally suppressed in vivo lymphocyte CD25 expression. Only FK778-treated animals were completely free of adverse drug side effects. FK778 but not tacrolimus showed potent anti-proliferative effects on SMC in vitro.. Although both agents proved effective to prevent OAD development, histology revealed major differences. The anti-proliferative potency of FK778 on SMC may be an important mechanism of action. Combination regimens showed favorable drug interaction and allowed dose reduction of both agents to achieve maximal immunosuppressive efficacy.

Topics: Actins; Alkynes; Animals; Bronchiolitis Obliterans; Disease Models, Animal; Granulation Tissue; Immunosuppressive Agents; Isoxazoles; Lymphocyte Activation; Nitriles; Postoperative Complications; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Trachea

Immunosuppressive drugs given to solid organ transplant recipients may be responsible for cosmetic side effects which can endanger patient compliance. Cyclosporine is associated with hirsutism whereas tacrolimus has been associated with rare cases of alopecia. Since 1998, we have included tacrolimus within the immunosuppressive regimen following kidney-pancreas transplantation. The aim of this study was to evaluate the incidence of alopecia in this population and possible risk factors.. Between January 1, 1995 and October 31, 2003, 59 consecutive simultaneous kidney-pancreas (SPK) transplants were performed in 58 recipients (27 females and 31 males). The immunosuppressive regimen comprised corticosteroids, calcineurin inhibitor (cyclosporine, n=11; or tacrolimus, n=40) and a purine inhibitor (azathioprine or mycophenolate mofetil).. Clinically significant alopecia occurred in 13 patients (28.9%) receiving tacrolimus versus none receiving cyclosporine (P<0.001). Of those who experienced alopecia, 11 were female and two were male (P=0.02). The mean delay between transplantation and alopecia was 422 days (range 100-1,567). Other causes of alopecia were excluded. Treatment of alopecia with topic minoxidil was successful in all cases but one, which required conversion from tacrolimus to cyclosporine.. Alopecia is a frequent complication in women receiving tacrolimus therapy following SPK transplantation. Its pathogenesis is unknown. This cosmetic complication must be discussed with patients before transplantation to minimize the risk of noncompliance.

Topics: Alopecia; Antilymphocyte Serum; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphocyte Count; Male; Pancreas Transplantation; Postoperative Complications; Retrospective Studies; Sex Characteristics; Tacrolimus

The occurrence of an oesophageal squamous cell carcinoma following liver transplantation is very infrequent. Such an event has been related to a history of alcohol-induced cirrhosis, as in other squamous cell tumours of the oropharynx. We report the case of a 64-year-old male patient diagnosed as having oesophageal squamous cell carcinoma six years after having had a liver transplant due to alcohol-induced cirrhosis. The tumour was treated surgically and consisted of an Ivor-Lewis oesophagectomy. The patient is disease-free 17 months after surgery. A review of the cases reported in the literature indicated treatment with chemotherapy and radiation therapy, and with excision in some cases. Generally, despite aggressive treatment the prognosis is poor.

Topics: Alcoholism; Carcinoma, Squamous Cell; Cardia; Deglutition Disorders; Esophageal Neoplasms; Esophageal Stenosis; Esophagectomy; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Neoplasms, Multiple Primary; Postoperative Complications; Remission Induction; Stomach Neoplasms; Tacrolimus

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.

Topics: Adult; Body Mass Index; Diabetes Mellitus; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tissue Donors; Weight Gain

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation; Postoperative Complications; Tacrolimus

De novo hepatitis B was diagnosed in a 47-year-old man 15 months after liver transplantation for end-stage alcoholic cirrhosis. Serum antibodies to hepatitis B core antigen (anti-HBc) were negative, and remained undetectable over 20 months of follow-up. The possible causes of negative serum anti-HBc despite of active hepatitis B virus infection are reviewed. Immunosuppression may underlie this phenomenon in similar cases.

Topics: Antibody Formation; DNA, Viral; False Negative Reactions; Follow-Up Studies; Graft Rejection; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Antigens; Hepatitis B virus; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Tacrolimus; Viremia

In pediatric solid organ transplantation, the Epstein-Barr virus (EBV)-related lymphoproliferative disorders (PTLD) still play a major role in post-transplant morbidity and mortality. The aim of the study was to determine the incidence of PTLD in pediatric patients with liver transplant who receive low-dose immunosuppression protocols.. All pediatric patients (n = 269) received a dual immunosuppression therapy consisting of cyclosporine A (initial trough levels, 170-200 microg/L; trough levels for maintenance immunosuppression after 1 year, 80-100 microg/L) and prednisolone (starting dose, 60 mg/m2). Steroids were reduced to 30 mg/m2 after 1 week, followed by a weekly tapering to 5 mg/m2. Seventy-seven of 269 patients were switched to tacrolimus therapy. The authors evaluated the significance of EBV-DNA monitoring by quantitative polymerase chain reaction in identifying patients at risk for PTLD.. Patient survival was 90.3%; graft survival was 85.9%. Eight patients lost their grafts because of chronic rejection. The incidence of PTLD was low (0.7%), although a significant EBV viral load was found in 42.4% of the patients. One third of the patients with a viral load of 3,000 genomes/10(5) cells or greater had clinical signs of EBV infection.. The authors conclude that low-dose immunosuppressive protocols significantly reduce the incidence of PTLD. In patients treated with that regimen, the monitoring of EBV viral load seems not to be helpful. It can be assumed that low-dose immunosuppression does not suppress EBV-specific cytotoxic CD8+ T cells, thus allowing the host to control EBV infection without the risk of PTLD. Our low-dose immunosuppression protocol did not increase the risk of chronic rejection.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; DNA, Viral; Epstein-Barr Virus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Viral Load

Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients.. Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue.. Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003.. RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Topics: Adult; Aged; Azathioprine; Bronchi; Bronchiolitis Obliterans; Cell Division; Cells, Cultured; Cyclosporine; Everolimus; Female; Fibroblasts; Humans; Immunosuppressive Agents; Infections; Lung Diseases; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

Topics: Adolescent; Adult; Anemia, Aplastic; Antilymphocyte Serum; Child; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Postoperative Complications; Prednisone; Tacrolimus

A retrospective study involving 13 institutions was performed to assess the efficacy of conversion from cyclosporine (INN: ciclosporin) to tacrolimus.. Data from 244 patients were analyzed. Indications for conversion were recurrent-ongoing rejection (n = 110) and stage 1 to 3 bronchiolitis obliterans syndrome (n = 134).. The incidence of acute rejection decreased significantly within 3 months after versus before the switch from cyclosporine to tacrolimus (P <.01). For patients with recurrent-ongoing rejection, the forced expiratory volume in 1 second decreased by 1.96% of predicted value per month (P =.08 vs zero slope) before and increased by 0.34% of predicted value per month (P =.32 vs zero slope) after conversion (P <.06). For patients with stage 1 to 3 bronchiolitis obliterans syndrome, a significant reduction of rejection episodes was observed (P <.01). In single transplant recipients a decrease of the forced expiratory volume in 1 second averaged 2.25% of predicted value per month (P <.01 vs zero slope) before and 0.29% of predicted value per month after conversion. Corresponding values for bilateral transplant recipients were 3.7% of predicted value per month (P <.01 vs zero slope) and 0.9% of predicted value per month (P = 0.04 vs zero slope), respectively. No significant difference in the incidence of infections within 3 months before and after conversion was observed.. Conversion from cyclosporine to tacrolimus after lung transplantation is associated with reversal of recurrent-ongoing rejection. Conversion for bronchiolitis obliterans syndrome allows short-term stabilization of lung function in most patients.

Topics: Acute Disease; Adult; Australia; Azathioprine; Bronchiolitis Obliterans; Canada; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Incidence; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Tacrolimus and mycophenolate mofetil are effective drugs characterized by specific toxicity profiles that may compromise their long-term use in renal transplant recipients. Clinicians, therefore, need reliable drug monitoring tools for relating efficacy and toxicity to drug exposure. Study design We conducted a prospective 12-month pharmacokinetic study of tacrolimus and mycophenolic acid in 100 de novo recipients. The aim was to examine whether tacrolimus and mycophenolic acid exposure parameters (predose trough blood concentration [C(0)], area under the concentration curve from 0 to 12 hours [AUC(0-12)], maximum blood or plasma concentration [C(max)], and dose) would reflect clinical efficacy and toxicity at different time points after transplantation (7 days, 6 weeks, and 3, 6, and 12 months).. Initially, after grafting, the tacrolimus AUC(0-12) was higher in recipients with infection (P =.01 on day 7, P =.02 at week 6), whereas the mycophenolic acid AUC(0-12) was not different. There was no difference in tacrolimus exposure between patients who had arterial hypertension or hyperlipidemia and those who did not. Patients with tacrolimus nephrotoxicity received a higher drug dose (P =.03) and had higher drug clearance (P =.02). From 3 months, recipients with anemia or leukopenia had higher mycophenolic acid AUC(0-12) (anemia, P =.03 at month 3 and P =.01 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year) and C(0) (anemia, P =.001 at month 3 and P =.001 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year). Finally, for recipients who did not simultaneously have a target tacrolimus AUC(0-12) of 150 ng x h/mL and a mycophenolic acid AUC(0-12) of 45 mg x h/L by day 7, the incidence of acute rejection tended to be higher (26.3%) compared with patients who reached both target values (7.7%) (P =.07).. Pharmacokinetic exposure parameters of tacrolimus and mycophenolic acid are related to specific drug-induced side effects in a time-dependent fashion. In addition, this study has provided a conceptual basis for defining a combined target therapeutic window for tacrolimus and mycophenolic acid based on sparse AUC(0-12) measurements.

Topics: Area Under Curve; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Drug Therapy, Combination; Female; Germany; Graft Rejection; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Serum Albumin; Tacrolimus; Triglycerides

A prospective, pilot trial was started to evaluate the effect of a sirolimus-based immunosuppressive regimen on acute and chronic rejection in de novo lung transplant patients. Primary lung transplant (LTx) recipients received a sirolimus- and tacrolimus-based immunosuppressive therapy immediately after transplantation. Both immunosuppressants were administered with trough level adjusted, while steroid administration was minimized. Four patients were enrolled (2 single-lung transplants, 1 double-lung transplant, 1 heart-lung transplant) in the study. Mean ischemia time was 387 +/- 92 minutes. Acute rejection (at least Grade A1 ISHLT) was detected in 1 patient. Incidence of infection was 0.6 infection per 100 patient-days (3 Aspergillus infections). Until hospital discharge mean sirolimus trough level was 6.2 +/- 1.2 ng/ml. Depending upon mean sirolimus trough levels of each patient, severe wound-healing complications were seen in 3 patients, resulting in bronchial airway dehiscence in 2 patients with lethal outcome in 1 patient. As a result of these complications, we revised the study design after inclusion of only 4 patients: Sirolimus administration is now started after completion of bronchial wound-healing. Sirolimus-based immunosuppressive therapy administered immediately after lung transplantation seems to be associated with severe wound-healing complications of the bronchial anastomosis.

Topics: Adrenal Cortex Hormones; Adult; Bronchial Diseases; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prospective Studies; Sirolimus; Tacrolimus; Wound Healing

Among the numeruos adverse side effects of tacrolimus (TAC), de novo thrombotic microangiopathy stands out as an infrecuente but severe complication. Renal dysfunction is the only alteration that should lead to suspicion of thrombotic microangiopathy, because the clinical features of intravascular hemolysis are not always found. The definitive diagnosis can usually be made with kidney biopsy. Patientes with TAC induced thrombotic microangiopathy usually promptly recover after treatment withdrawal or reduction in the dose of TAC and a short course of plasma therapy, but the risk of rejection increases. Switching from TAC to cyclosporine has also been tried with resolution of the hemolysis but thrombotic microangiopathy has been noted with both and this condition may later recur. We present a 29-year-old man who received a kidney-pancreas transplant for end-stage diabetic nephropathy. After initial induction with basiliximab, the immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil. Twenty four days posttransplantation his renal function declined with a peak creatine level of 2.35 mg/dl. Laboratory studies showed thrombocytopenia and features of intravascular hemolysis. TAC associated hemolytic uremic syndrome was suspected and drug was immediately stopped and converted to sirolimus. Also he was treated with plasma infusion. The allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection. Our experience demostrate that switching from tacrolimus to sirolimus could be an adecuate strategy for patients who develop FK506-associated de novo thrombotic microangiopathy without increase risk of acute rejection.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Duodenostomy; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Jejunostomy; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Mycophenolic Acid; Pancreas Transplantation; Pancreatic Fistula; Plasma; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Although drugs used in renal transplant recipients such as steroids, cyclosporine, and particularly, tacrolimus have diabetogenic potential, diabetic ketoacidosis is uncommon. There are few data concerning the long-term follow-up of these patients. Diabetic ketoacidosis occurred in a renal transplant recipient following de novo development associated with tacrolimus.

Topics: Adult; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Postoperative Complications; Tacrolimus; Treatment Outcome

New-onset diabetes mellitus after transplantation (NODAT) is a severe complication of kidney transplantation (KTx) with negative effects upon patient and graft survival. Several risk factors for NODAT have been described; however, the search for an early predictive marker is ongoing. It has recently been demonstrated that high concentrations of adiponectin (APN), which is an adipocyte-derived peptide with antiinflammatory and insulin-sensitizing properties, protect against future development of type 2 diabetes in healthy individuals. The purpose of this report was to study pretransplant insulin resistance and analyze pretransplant serum leptin and APN levels as independent risk factors for the development of NODAT.. A total of 68 KTx patients were studied [mean age, 48 +/- 11 years; 70% males; body mass index (BMI), 25 +/- 3 kg/m]; 31 KTx patients with NODAT and 37 KTx patients without NODAT (non-NODAT) with similar age, sex, BMI, immunosuppression, and posttransplant time were studied. All patients received prednisone and calcineurin inhibitors (75% tacrolimus and 25% cyclosporine A), and 76% of patients received mycophenolate mofetil. Family history of diabetes mellitus was recorded. Pretransplant homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated from fasting plasma glucose and insulin. Pretransplant serum leptin and APN levels were determined by radioimmunoassay.. NODAT patients showed higher pretransplant plasma insulin concentrations [NODAT, 13.4 (11-22.7) microIU/mL; non-NODAT, 10.05 (7.45-18.4) microIU/mL; P=0.049], HOMA-IR index [NODAT, 4.18 (2.49-5.75); non-NODAT, 2.63 (1.52-4.68); P=0.043], and lower pretransplant serum APN concentration [NODAT, 8.78 (7.2-11.38) microg/mL; non-NODAT, 11.4 (8.56-15.27) microg/mL, P=0.012]. Inverse correlations between APN and BMI (r=-0.33; P=0.014) and APN and HOMA-IR index (r=-0.39; P=0.002) and between APN and NODAT (r=-0.31; P=0.011) were observed. Multiple logistic regression analysis showed the patients with lower pretransplant APN concentrations to be those at greater risk of developing NODAT [Odds Ratio=0.832 (0.71-0.96); P=0.01].. Pretransplant serum APN concentration is an independent predictive factor for NODAT development in kidney-transplanted patients.

Topics: Adiponectin; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Kidney Transplantation; Leptin; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Proteins; Risk Factors; Tacrolimus

Induction therapy with thymoglobuline significantly decreases the risk of acute rejection, particularly in high immunological risk patients, in combined transplantations and in pediatric renal transplantation. After the introduction of cyclosporin in the 1980's and the recognition of its potential nephrotoxicity, induction therapy with delayed introduction of cyclosporin (sequential protocols) have became very popular in many transplant centers and are now used even in low-immunological risk patients. The aim of the present study was to assess the recovery of renal function in low-immunological risk patients receiving a sequential protocol versus those receiving a calcineurin inhibitor at day 1. Among patients receiving their first transplant in our center between January 1999 and June 2000, we selected 72 recipients with no immunological risk and no risk of delayed graft function (DGF). 35 patients (group I) have received a sequential protocol whereas 37 patients (group II) have received a calcineurin inhibitor (Neoral or prograf) at day 1. We analysed creatinine reduction ratio, 24-hour creatinine excretion on post-transplant day 2, and serum creatinine and creatinine clearance at day 15, 30, 45, 60 and 90 post-transplant. There was no difference between groups concerning demographic, immunological or surgical parameters. The percentage of patients with immediate graft function was similar between the two groups (10 versus 9). The number of patients requiring dialysis in the first post-transplant week was also similar (8/35 versus 6/37). The day serum creatinine reached 200 micromol/l was 15 +/- 11 versus 14 +/- 12 in groups I and II respectively. Serum creatinine and creatinine clearance were similar at all time intervals. CMV disease was significantly higher in the group 1 (42% versus 18.5%; p < 0.005). Our data suggest that in patients with low immunological risk and low-risk of DGF, introduction of calcineurin inhibitors as early as the post-transplant day 1 is not deleterious for renal function recovery. These data should be confirmed by a prospective randomised trial.

Topics: Adult; Antilymphocyte Serum; Child; Creatinine; Cyclosporine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Treatment Outcome

This study was designed to test the hypothesis that heterotopic heart transplant (HHT) patients have lower blood pressure than orthotopic cardiac transplant (OCT) patients because their native heart is involved in blood pressure homeostasis.. Hypertension occurs more frequently after OCT than after liver or lung transplantation, suggesting that transplantation of the heart itself contributes to post-transplant hypertension.. Blood pressure and related measurements in 233 OCT and 38 HHT patients were studied retrospectively post-transplant.. Systolic blood pressure (SBP) was persistently lower among HHT patients (means 121 vs. 137, 126 vs. 137, 125 vs. 139, and 128 vs. 143 mm Hg at month 3 and years 1, 3, and 5 respectively, p < 0.005). Left ventricular and aortic systolic pressures were also lower (130 vs. 143 mm Hg, p = 0.01 and 129 vs. 142 mm Hg, p = 0.01). Multivariable analysis with age, gender, body mass index, creatinine, steroids, cyclosporine, use of antihypertensive medication, donor left ventricular ejection fraction, donor weight, and type of transplant as covariables showed HHT to be independently associated with a lower SBP at each time point (beta-coefficients -16.2, -12.1, -13.3, and -14.2 mm Hg, p < 0.01). The adjusted hazard ratio for the development of systolic hypertension among HHT compared with OCT patients was 0.59 (95% confidence interval 0.39 to 0.91, p = 0.017).. Heterotopic heart transplant patients had lower SBP than OCT patients, consistent with the hypothesis that the native heart continues to contribute to blood pressure homeostasis.

Topics: Adolescent; Adult; Aged; Aorta; Blood Pressure; Female; Heart Transplantation; Heart Ventricles; Humans; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Retrospective Studies; Risk Reduction Behavior; Systole; Tacrolimus; Time Factors; Transplantation, Heterotopic; Treatment Outcome

Standard treatment for autoimmune hemolytic anemia (AIHA) due to warm antibodies includes combinations of glucocorticoids, immunosuppressive drugs (mainly azathioprine) and splenectomy. Patients who are refractory or intolerant to these therapies constitute an important therapeutic challenge. Rituximab, an anti-CD20 chimeric monoclonal antibody, can effectively deplete B-cells and is commonly used in B-cell non-Hodgkin lymphoma. In addition, it is being increasingly used in autoimmune disorders, such as idiopathic thrombocytopenic purpura, AIHA, systemic lupus erythematosus or vasculitis. We report a case of warm AIHA associated to primary antiphospholipid syndrome (APS). The patient was refractory to high-dose corticosteroids. Splenectomy was discarded in view of the high risk of thrombotic and/or hemorrhagic perioperative complications, due to the presence of APS. After treatment with four weekly doses of rituximab the patients had a rapid and sustained response which allowed progressive tapering of prednisone dose to 5 mg/d. In addition, IgM anticardiolipin titres decreased from > 600 MPL to < 100 MPL. Thirteen further cases of warm AIHA in adults treated with rituximab have been reviewed, showing excellent tolerance and high response rates. Rituximab may be considered prior to splenectomy in patients with refractory AIHA and high risk of complications following splenectomy.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antiphospholipid Syndrome; Contraindications; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Methylprednisolone; Middle Aged; Postoperative Complications; Prednisone; Remission Induction; Rituximab; Splenectomy; Stroke; Tacrolimus; Vasculitis

Topics: Adult; Brain Edema; Cerebral Hemorrhage; Fatal Outcome; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertension; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Myelin Sheath; Postoperative Complications; Seizures; Tacrolimus

Cardiac allograft vasculopathy (CAV), a disorder characterized by rapid development and progression of obliterative vasculopathy in the transplanted heart, continues to be a major cause of graft failure in long-surviving human transplants. The mechanisms and histopathologic processes of CAV remain unknown. Previous animal studies have shown that inhibition of matrix metalloproteinase (MMP) prevents migration and proliferation of smooth muscle cells in CAV. In this study, we hypothesized that MMPs may be expressed in and may play an important role in CAV.. An F344-to-WKAH rat heterotopic heart transplantation model was used. Tacrolimus was administered intramuscularly 14 days after transplantation to prevent acute rejection and to allow the development of CAV. We divided the animals into 2 groups according to post-operative treatment: an ONO group received an MMP inhibitor (ONO-4817) daily by oral gavage for 14 days after transplantation (n = 6), and a control (n = 6) group received no treatment. Grafts were harvested 60 days after treatment.. Immunohistochemical staining revealed that MMP-2 and tissue inhibitors of metalloproteinase-2 (TIMP-2) were expressed more strongly in the neointima and media of the control CAV animals than in the ONO-CAV animals. The animals given ONO-4817 exhibited a significant decrease in the percentage of affected vessels, in the percentage of intimal proliferation, in the intima-to-media ratio, and in the expression of MMP-2 and TIMP-2.. These results suggest that MMP-2 and TIMP-2 play an important role in the development of CAV and that the use of an MMP inhibitor (ONO-4817) may prevent neointimal proliferation in patients with CAV.

Topics: Animals; Coronary Disease; Coronary Vessels; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Phenyl Ethers; Postoperative Complications; Rats; Rats, Inbred F344; Rats, Inbred Strains; Tacrolimus; Tissue Inhibitor of Metalloproteinase-2; Transplantation, Homologous

Recombinant adeno-associated virus vector (rAAV) is a promising vehicle for gene delivery, but few reports have documented its application in solid organ transplantation. In a rat orthotopic liver transplantation model, we investigated the efficacy of rAAV-mediated human cytotoxic T-lymphocyte-associated antigen 4 and immunoglobulin G (hCTLA4Ig) gene transfer to induce long-term allograft survival.. Dark Agouti and Lewis rats were used as donors and recipients, respectively, in six experimental groups: (a) syngeneic control, (b) no treatment, (c) rAAV-green fluorescent protein, (d) rAAV-hCTLA4Ig, (e) low-dose FK506 for 7 days, and (f) rAAV-hCTLA4Ig and low-dose FK506 for 7 days.. The liver allografts were rejected within 10 days when no treatment was given or rAAV-green fluorescent protein was delivered. rAAV-hCTLA4Ig transduction slightly prolonged the survival time to 11 days. Long-term survival was achieved using the combined treatment of rAAV-hCTLA4Ig and low-dose FK506, whereas grafts were rejected on day 33 in the low-dose FK506 group. A sustained hCTLA4 level in plasma was detected in the combined treatment group from day 5 to day 180. On postoperative day 5, combined treatment significantly decreased the interleukin-2 and interferon-gamma protein levels in the grafts and the number of infiltrating B, T, CD25+, CD4+, CD8+, and NK cells.. This study shows that rAAV-hCTLA4Ig gene transfer combined with low-dose FK506 can achieve long-term liver allograft survival.

Topics: Abatacept; Adenoviridae; Animals; Combined Modality Therapy; Cytokines; Genetic Vectors; Graft Rejection; Graft Survival; Immunoconjugates; Immunophenotyping; Immunosuppressive Agents; Liver Transplantation; Male; Postoperative Complications; Rats; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous

Topics: Family; Hepatectomy; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Living Donors; Postoperative Complications; Tacrolimus; Tissue and Organ Harvesting

Topics: Adult; Child; Cyclosporine; Drug Therapy, Combination; Graft Survival; Heart Arrest; Histocompatibility Testing; HLA-DR Antigens; Humans; Immunosuppressive Agents; Ischemia; Kidney; Kidney Transplantation; Middle Aged; Organ Preservation; Postoperative Complications; Renal Dialysis; Tacrolimus; Time Factors; Tissue Donors

Topics: Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Adult; Biopsy; Female; Gastric Mucosa; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymph Nodes; Mycophenolic Acid; Postoperative Complications; Sarcoma, Kaposi; Tacrolimus

Topics: Adult; Diabetes Mellitus; Dose-Response Relationship, Drug; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphocele; Male; Middle Aged; Postoperative Complications; Tacrolimus

Topics: Adult; Bilirubin; Cholesterol; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Function Tests; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Barium; Cyclosporine; Diabetic Nephropathies; Drug Therapy, Combination; Enema; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pneumatosis Cystoides Intestinalis; Postoperative Complications; Tacrolimus

Topics: Agglutinins; Anemia, Hemolytic; Autoantibodies; Biliary Atresia; Child; Cryoglobulins; Cyclosporine; Drug Therapy, Combination; Family; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Methylprednisolone; Postoperative Complications; Tacrolimus; Treatment Outcome

Topics: Adult; Ceftriaxone; Epilepsies, Myoclonic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Postoperative Complications; Risk Assessment; Tacrolimus; Tomography, X-Ray Computed; Transplantation Immunology; Treatment Outcome

Topics: Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Retrospective Studies; Tacrolimus

Topics: Adrenal Cortex Hormones; Cholesterol; Cyclosporine; Follow-Up Studies; Heart Transplantation; Humans; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Immunosuppression Therapy; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Diuresis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors

The incidence of posttransplantation diabetes mellitus (PTDM) has been reported to vary according to different study populations or different definitions. In this study, using American Diabetes Association criteria, the incidence and clinical characteristics of PTDM in Korean renal allograft recipients undergoing tacrolimus-based immunosuppression were examined.. A total of 21 patients taking tacrolimus as primary immunosuppressant were recruited and tested with a serial 75-g oral glucose tolerance test at 0, 1, 3, and 6 months after renal transplantation.. The cumulative incidence of PTDM was 52.4% at 1 month and 57.1% at 3 and 6 months. The baseline characteristics of the PTDM group were old age (especially >40 years), a high BMI, a high fasting glucose level, a high plasma insulin level, and increased insulin resistance. Among these parameters, old age was the only independent risk factor. The insulin secretory capacity in the PTDM group was maximally suppressed 3 months after transplantation. Thereafter, it was gradually restored along with dose reduction of tacrolimus.. Routine screening for PTDM is necessary in patients over 40 years of age who are undergoing a relatively higher dose tacrolimus therapy during the early course of postrenal transplantation.

Topics: Adult; C-Peptide; Cholesterol; Diabetes Mellitus; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incidence; Insulin; Kidney Transplantation; Male; Postoperative Complications; Societies, Medical; Tacrolimus; Time Factors; Triglycerides; United States

Our objective was to investigate brain MR imaging findings and the utility of diffusion-weighted (DW) imaging in organ transplant patients who developed neurologic symptoms during tacrolimus therapy. Brain MR studies, including DW imaging, were prospectively performed in 14 organ transplant patients receiving tacrolimus who developed neurologic complications. In each patient who had abnormalities on the initial MR study, a follow-up MR study was performed 1 month later. Apparent diffusion coefficient (ADC) values on the initial MR study were correlated with reversibility of the lesions. Of the 14 patients, 5 (35.7%) had white matter abnormalities, 1 (7.1%) had putaminal hemorrhage, and 8 (57.1%) had normal findings on initial MR images. Among the 5 patients with white matter abnormalities, 4 patients (80.0%) showed higher than normal ADC values on initial MR images, and all showed complete resolution on follow-up images. The remaining 1 patient (20.0%) showed lower than normal ADC value and showed incomplete resolution with cortical laminar necrosis. Diffusion-weighted imaging may be useful in predicting the outcomes of the lesions of tacrolimus-induced neurotoxicity.

Topics: Adult; Brain; Brain Mapping; Child; Child, Preschool; Diffusion Magnetic Resonance Imaging; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Japan; Male; Middle Aged; Neurotoxicity Syndromes; Organ Transplantation; Postoperative Complications; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Failure

Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation.. A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals.. BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A.. Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Topics: Adult; Aged; Alkaline Phosphatase; Biomarkers; Bone Density; Bone Resorption; Cholestasis; Collagen; Collagen Type I; Cyclosporine; Female; Femur Neck; Follow-Up Studies; Forearm; Fractures, Bone; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Longitudinal Studies; Lumbar Vertebrae; Male; Middle Aged; Norway; Osteocalcin; Osteoporosis; Peptide Fragments; Peptides; Postoperative Complications; Survival Analysis; Tacrolimus; Treatment Outcome; Waiting Lists

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G(1)-S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10-15 ng/mL) with low dose CsA (target trough concentration, 50-100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

Topics: Blood Pressure; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Reoperation; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Time Factors

The diagnosis and treatment of diarrhea in liver transplant recipients often pose a challenge owing to the variety of infectious and non-infectious causes. However, diagnosis is principally focused on ruling out an infectious etiology. Tacrolimus, an immunosuppressive agent generally used after liver transplantation, is absorbed mainly from the duodenum through the upper jejunum. It can be assumed that metabolism of the drug will be influenced by diarrhea.. Four liver transplant recipients who developed an episode of acute gastroenteritis. Infectious etiology was confirmed; trough tacrolimus levels were measured before, during and after gastroenteritis.. All patients presented a two- to three-fold increase in blood tacrolimus levels after the onset of gastroenteritis.. Until the role played by the intestine in the metabolism of tacrolimus is fully understood, it is prudent to recommend early dose reduction of tacrolimus and careful monitoring of trough levels during diarrheal disorders of any nature in pediatric liver-transplanted patients.

Topics: Acute Disease; Child, Preschool; Diarrhea; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Intestinal Mucosa; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients.. The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii.. A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections.. We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Topics: Adolescent; Adult; Aged; Bronchi; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus; Surgical Wound Dehiscence; Tacrolimus

We combined alemtuzumab (Campath-1H, Berlex Laboratories, Montville, NJ) and tacrolimus (Tac) immunosuppression for intestinal and multivisceral transplantation.. A total of 21 adult patients received 24 grafts: 14 intestinal, nine multivisceral, and one liver-intestinal graft. Alemtuzumab was administered perioperatively in four doses with low-dose Tac (levels 10-15 ng/dL) and no maintenance steroids. Tac was substituted with sirolimus in case of Tac-related complications. Suspected or mild rejections were treated with steroids. Moderate rejections were treated with steroids or OKT3. Severe rejections were treated with OKT3.. Of the 16 patients that were followed up for an average of 9 months, 12 are alive with functioning grafts. Two patients experienced severe rejection, three experienced moderate rejection episodes, and seven experienced mild acute rejection episodes. Four patients never developed acute rejection. Infectious complications included a cytomegalovirus enteritis and four fungal infections (related to central venous access).. The combination of alemtuzumab and Tac therapy without steroid use seems to efficiently prevent acute rejection in a significant number of patients without causing frequent opportunistic infections.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Intestines; Liver Transplantation; Postoperative Complications; Prospective Studies; Tacrolimus

In a retrospective study we analyzed the incidence and characteristics of de novo tumors developing in renal transplant recipients treated in our center. The 5% incidence de novo tumors developing among patients treated with azathioprine and prednisolone (n = 241) was similar to the 5.4% incidence of de novo tumors developing among patients treated with calcineurin-based immunosuppression (n = 1918). The most common malignancies among our patients were basal cell (21.7%) and squamous cell (13.9%) carcinomas of the skin, followed by urogenital (10.4%) and lung malformations (9.6%). A high incidence of Kaposi's sarcoma (9.6%; half cutaneous and half visceral) and a lower than expected incidence of posttransplant lymphoproliferative disorder (PTLD; 3.5%) was found. Among patients developing de novo tumors, the incidence of death with a functioning graft was higher than among recipients without tumors. Moreover, the incidence of tumor-related death was high among the de novo tumor recipients. Among our recipients, the most aggressive tumors were Kaposi's sarcoma, lung tumors, lymphomas, and gastrointestinal tumors, which occurred relatively early after transplantation and were the cause of death in most cases. Compared to tumor registry data, we found an inverse basal-to-squamous cell carcinoma ratio, a lower incidence of PTLD, and a higher incidence of Kaposi's sarcoma.

Topics: Azathioprine; Cyclosporine; Female; Humans; Hungary; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Prednisolone; Retrospective Studies; Risk Factors; Tacrolimus

Seemingly conflicting results have been reported on the prevalence and severity of inflammatory bowel disease after liver transplantation. Regimens with different combinations of drugs can be used for immunosuppression after transplantation.. To study retrospectively the prevalence of inflammatory bowel disease after liver transplantation, and the possible relationship with maintenance immunosuppressive regimens.. All 78 patients with end-stage primary sclerosing cholangitis (48 patients) or autoimmune cirrhosis (30 patients), transplanted between 1979 and July 2001, and with a follow-up of at least 1 year, were eligible for this study. In addition to patient and transplant characteristics, data on inflammatory bowel disease and immunosuppression before and after transplantation were collected. The Kaplan-Meier method was used for survival analysis. Possible risk factors for inflammatory bowel disease after transplantation were analysed by Cox univariate and multivariate regression.. The median follow-up after transplantation was 7.2 years (range, 1.1-22.3 years). Nine of 25 patients with pre-transplant inflammatory bowel disease experienced flare-ups after transplantation. Six of 53 patients without pre-transplant inflammatory bowel disease developed de novo inflammatory bowel disease after transplantation. The cumulative risks (standard errors in parentheses) for inflammatory bowel disease were 6% (3%), 12% (4%) and 20% (5%) at 1, 3 and 5 years after transplantation, respectively. The inflammatory bowel disease-free survival was significantly higher in patients not receiving tacrolimus vs. those receiving tacrolimus, in patients receiving azathioprine vs. those not receiving azathioprine and in patients taking the regimen prednisolone-azathioprine-ciclosporin A vs. those taking tacrolimus-prednisolone. Pre-transplant inflammatory bowel disease and the use of tacrolimus were found to be independent predictors for inflammatory bowel disease after transplantation.. The prevalence of inflammatory bowel disease after liver transplantation is affected by the immunosuppression used. Azathioprine seems to have a protective effect and tacrolimus a promoting effect.

Topics: Adolescent; Adult; Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Risk Factors; Tacrolimus

Tacrolimus is a potent calcineurin inhibitor that was introduced to heart transplantation in the early 1990s. The side-effect profile of tacrolimus is more favorable than that of cyclosporine and some reports have suggested an advantage of tacrolimus in the treatment of rejection. The present study was undertaken to determine whether a late conversion to tacrolimus affords these benefits to heart transplant recipients.. Charts from 109 patients who underwent conversion from cyclosporine to tacrolimus for recurrent rejection or adverse effects were retrospectively reviewed.. During the year after conversion to tacrolimus, there was a significant decrease in treated rejection episodes. Conversion to tacrolimus rapidly resulted in an improved lipid profile. Two years after conversion blood pressure was significantly reduced. Apart from rejection, these benefits were found mainly among individuals converted to tacrolimus within 1 year of heart transplantation.. Conversion from cyclosporine to tacrolimus is safe and results in a more favorable risk factor profile. However, most of the benefits are seen in individuals converted within 1 year of transplantation.

Topics: Adult; Biomarkers; Blood Glucose; Blood Pressure; California; Cholesterol; Creatinine; Cyclosporine; Diastole; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Ischemia; Postoperative Care; Postoperative Complications; Recurrence; Steroids; Survival Analysis; Systole; Tacrolimus; Time Factors; Treatment Outcome

A 24 year old woman presented with a sudden excruciating headache mimicking an acute vascular event. She had undergone a lung transplantation because of cystic fibrosis and was receiving maintenance treatment with tacrolimus and prednisone. Ancillary investigation excluded vascular causes. Magnetic resonance imaging demonstrated hyperintense lesions in the infratentorial and parieto-occipital regions consistent with posterior leucencephalopathy syndrome. Both her clinical condition improved and the lesions disappeared completely after withdrawal of tacrolimus, suggesting that her condition could be explained by a tacrolimus encephalopathy.

Topics: Acute Disease; Adult; Brain; Brain Diseases; Cyclosporine; Cystic Fibrosis; Diagnosis, Differential; Drug Therapy, Combination; Female; Headache; Humans; Image Enhancement; Immunosuppressive Agents; Lung Transplantation; Magnetic Resonance Imaging; Neurologic Examination; Postoperative Complications; Prednisone; Recurrence; Tacrolimus

Neurotoxicity is a well-known side effect of tacrolimus-based immunosuppression after liver transplantation. Until now, only 31 cases of immunosuppression-associated leukoencephalopathy in liver transplant recipients reported in the literature are related to tacrolimus therapy. We report a patient who developed a posterior leukoencephalopathy syndrome, secondary to tacrolimus-based immunosuppression, after living donor liver transplantation. The special features of this case are the sudden and late onset of neurologic symptoms, a persistent comatose state, and increased signal intensity in follow-up MRI.

Topics: Coma; Female; Humans; Immunosuppressive Agents; Leukoencephalopathy, Progressive Multifocal; Liver Transplantation; Living Donors; Magnetic Resonance Imaging; Middle Aged; Postoperative Complications; Tacrolimus

Recent reports have demonstrated the efficacy of interleukin-2-receptor blockers in lowering the incidence of early acute rejection. The present study aimed to test the hypothesis that the use of daclizumab induction (DAC) plus low-dose tacrolimus, mycophenolate mofetil, and steroid diminishes the incidence of delayed graft function (DGF) in renal transplants from non-heart-beating donors (NHBD).. We compared the incidence of DGF and rejection in 185 renal transplants from NHBD treated as follows: Group-I: quadruple sequential therapy with antithymocyte globulin, cyclosporine, azathioprine, and steroids (n=22); Group-II: cyclosporine (8 mg/kg/d) plus azathioprine plus steroid (n=26); Group-III: low-dose cyclosporine (5 mg/kg/d) plus mycophenolate mofetil plus steroid (n=68); Group-IV: low-dose tacrolimus (0.1 mg/kg/d) plus mycophenolate mofetil plus steroid (n=17); and Group-V: DAC plus low-dose tacrolimus plus mycophenolate mofetil plus steroid (n=43).. The incidences of DGF were 72.7% in Group-I, 73.1% in Group-II, 69.1% in Group-III, 76.5% in Group-IV, and 44.2% in Group-V. Acute rejection was higher in Group-IV.. The combination of DAC, low-dose tacrolimus, mycophenolate mofetil, and steroids is effective in lowering the incidence of DSF in NHBD kidney transplant recipients without any increase in acute rejection.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cytomegalovirus Infections; Daclizumab; Drug Therapy, Combination; Graft Rejection; Graft Survival; Heart Arrest; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Tissue Donors

Calcineurin inhibitors (CIs) contribute to cardiovascular risk (CR) in renal transplant (RT) patients. However, the CR profile in RT patients without preexistent diabetes is not well known. We compared CR factors in 191 nondiabetic RT recipients with functioning grafts beyond 1 year, receivingly either CsA (Neoral; n=100) or tacrolimus (Tac; n= 91). Clinical data and pretransplant CR profiles were similar in both groups. There were no differences in acute rejection episodes and graft survival rates during follow-up. The overall proportions of posttransplant diabetes (9% versus 6%), and of hypertension (73% vs 63%) were similar in both groups. Hyperlipidemia was more frequent in the CsA group (58% vs 31%; P=.0001). The cholesterol levels in the CsA group showed at 3 months (232+/-47 vs 202+/-42 m/dL; P=.0001), 6 months (232+/-49 vs 205+/-41 mg/dL; P=.0001), and 12 months (217+/-50 vs 202+/-40 mg/dL; P=.028), despite receiving a greater proportion of lipid-lowering drugs (49% vs 15%; P=.0001). Logistic regression analysis showed that CsA was an independent predictor of posttransplant hyperlipidemia (OR: 5.8, CI 95%; 3.3-10.7; P=.0001) as were age, female gender, pretransplant dyslipidemia, and body mass index (BMI). Interestingly, an interaction was observed between pretransplant BMI and CIs: Among pretransplant normal weight patients (BMI <25 kg/m2), CsA produced a greater incidence of hyperlipidemia than tacrolimus (58% vs 23%; P=.0001) while not among patients who were overweight (BMI >25 kg/m2: pretransplant 58% vs 42%; P=.341). In conclusion, CsA confers a higher risk of hyperlipidemia after RT in nondiabetic patients, particularly those with normal pretransplant weight.

Topics: Adult; Body Mass Index; Cardiovascular Diseases; Cholesterol; Cyclosporine; Diabetes Mellitus; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Renal Replacement Therapy; Risk Factors; Tacrolimus

Tacrolimus (FK) is being increasingly used as an alternative to cyclosporine (CyA) in heart transplantation (HTx). It is believed to engender slightly more powerful protection against acute rejection. However, the increased immunosuppression could result in an excess of infectious complications.. Our study compared the incidence of major infections (MInf), defined as life-threatening infectious episodes requiring admission and intravenous (IV) antimicrobial therapy, among a series of HTx recipients treated with either FK (n=30) or CyA (n=84).. A total of 21 patients received FK in an elective protocol and 9 patients initially treated with CyA were converted to FK. Tacrolimus was combined with azathioprine and prednisone in 21 cases, and with mycophenolate mofetil and steroids in 8 recipients. After a follow-up between 6 and 37 months, 11 patients (37%) in the FK group developed 13 episodes of MInf, most (85%) occurring during the first posttransplant year. Conversely, CyA patients (n=84), a group with similar characteristics and follow-up, showed a MInf incidence of 12% (P<.05). Among the FK group, the most common site of MInf was pulmonary (69%). A variety of opportunistic agents caused MInf in 54% of cases, whereas the remaining ones were attributed to nosocomial bacteria. There were three deaths (27% of all MInf), all in azathioprine-treated patients with initial FK therapy.. Tacrolimus therapy seems to be associated with an increased incidence of severe infections in HTx recipients. We recommend aggressive diagnostic and therapeutic approaches for patients on FK who develop signs or symptoms of infection in the first year after HTx.

Topics: Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Infections; Male; Middle Aged; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus

Topics: Child; Child, Preschool; Cyclosporine; Cytochrome P-450 Enzyme System; Diarrhea; Drug Monitoring; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Postoperative Complications; Tacrolimus

The choice of initial immunosuppressive therapy (IST) following solid organ transplant remains a source of some controversy. Cyclosporine A (CsA) has been the basis of most IST protocols over the past two decades but has recently been supplanted in many centers by the use of tacrolimus (TAC)-based protocols. Renal allograft recipients in London may receive either CsA or TAC based IST, along with prednisone and azathioprine or (since 1999) mycophenolate mofetil (MMF). The decision is based on criteria such as age, gender, diabetic status, and lipid levels, which are felt to be impacted by the delivery of CsA or TAC based IST. The present analysis focuses on the results of BP and renal function in renal transplant patients receiving CsA or TAC based initial therapy during the period January 1, 1996 to June 30, 2002. Patients receiving TAC based IST were significantly younger than those receiving CsA (44 +/- 13.9 vs 50.5 +/- 12.3 years; P < .004). Mean arterial pressure (MAP) was lower in the TAC patients at 1 month (97.8 +/- 13.1 vs 103.2 +/- 11.8 mm Hg; P = .035), but became equivalent to CsA-treated patients for the balance of the follow-up period of up to 60 m. Serum creatinine was not significantly different between groups at any time during up to 60 months of follow-up. Based on these results, it seems apparent that the choice of calcineurin inhibitor may not influence renal function or blood pressure in long-term renal allograft survivors.

Topics: Adult; Blood Pressure; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

The use of antilymphocyte antibodies for induction therapy or for treatment for rejection has been associated with an increased risk of posttransplant lymphoproliferative disorder (PTLD). The authors investigated the incidence of PTLD after monoclonal antilymphocyte, polyclonal antilymphocyte, interleukin (IL)-2 receptor antibody, or no induction therapy in primary kidney transplant recipients.. A multivariate Cox analysis of 38,519 primary kidney transplants from January 1, 1997, to December 31, 2000, was performed to compare the incidence of PTLD, graft survival, and patient survival among the induction groups.. The actual incidence of PTLD was 0.85% in 2,713 recipients with monoclonal, 0.81% in 4,343 with polyclonal, 0.50% in 7,800 with IL-2, and 0.51% in 23,663 recipients with no induction therapy (P=0.02). The Cox model indicated that as compared with no induction, the increased risk of PTLD was 72% with monoclonal (P=0.03), 29% with polyclonal (P=0.27), and 14% with IL-2 induction (P=0.52). IL-2 receptor antibody was associated with a 17% reduced risk of graft loss (P=0.002) and a 21% reduced risk of mortality (P=0.005) compared with no induction. Monoclonal and polyclonal induction therapies were not associated with a reduced risk of graft loss or mortality. Mycophenolate mofetil discharge maintenance immunosuppression was associated with a significantly reduced risk of PTLD and graft loss compared with azathioprine.. Among induction therapies, IL-2 receptor antibody induction was associated with the smallest risk of PTLD and improved graft and patient survival. Monoclonal or polyclonal induction was not associated with improved graft or patient survival, and monoclonal induction was associated with an increased risk of PTLD.

Topics: Adolescent; Adult; Antilymphocyte Serum; Child; Cyclosporine; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Interleukin-2; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Survival Analysis; Tacrolimus

Topics: Angioedema; Child; Food Hypersensitivity; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Tacrolimus

Topics: Biopsy; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Liver Transplantation; Necrosis; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Adrenal Cortex Hormones; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Liver Transplantation; Living Donors; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Azathioprine; Blood Glucose; Blood Pressure; Cholesterol; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Monitoring, Physiologic; Postoperative Complications; Retrospective Studies; Safety; Tacrolimus

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Creatinine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Function Tests; Liver Failure, Acute; Liver Transplantation; Middle Aged; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus

Topics: Adolescent; Adult; Aged; Body Weight; Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Transplantation, Homologous

Topics: Adult; Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Cyclosporine; Cytomegalovirus Infections; Female; Humans; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Medical Records; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppression Therapy; Japan; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Safety; Survivors; Tacrolimus; Time Factors; Treatment Outcome

Topics: Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Living Donors; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Aged; Diabetes Mellitus; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adolescent; Adult; Aged; Azathioprine; Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Acute Disease; Adult; Aged; Biopsy; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Treatment Failure

Topics: Adult; Diabetes Mellitus; Female; Glucose Intolerance; Glucose Tolerance Test; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Sex Characteristics; Tacrolimus

Topics: ABO Blood-Group System; Blood Group Incompatibility; Cyclosporine; Humans; Incidence; Kidney Transplantation; Microcirculation; Postoperative Complications; Prospective Studies; Tacrolimus; Thrombosis

Topics: ABO Blood-Group System; Adult; Blood Group Incompatibility; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Adult; Biopsy, Needle; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adolescent; Adult; Blood Pressure; Cardiovascular Diseases; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger; Tacrolimus; Transcription, Genetic; Transforming Growth Factor beta; Transplantation, Homologous

Topics: Adult; Cohort Studies; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Regression Analysis; Renal Insufficiency; Tacrolimus

Topics: Cyclosporine; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Multivariate Analysis; Pancreas Transplantation; Postoperative Complications; Survival Rate; T-Lymphocytes; Tacrolimus; Treatment Failure; Treatment Outcome

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Child; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus

Topics: Adolescent; Age Distribution; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

Heart and/or lung transplantation are life-saving treatments for end-stage cardiopulmonary disease; however, chronic renal failure may develop. The impact of thoracic organ transplant on renal function in infants and children is not well characterized. This retrospective cohort study evaluated renal function following thoracic organ transplantation in 46 children (32 heart, 9 lung, 5 heart-lung; median age 4.1 years) with at least 12 months of follow-up. Glomerular filtration rate (GFR, ml/min/1.73 m2) was estimated by the Schwartz formula throughout and each GFR estimate was converted to per cent normal for age (GFR%). Changes in renal function following transplantation were analyzed using longitudinal mixed-effects linear regression models. GFR% decreased following thoracic organ transplantation (p <0.001). Younger age at transplant was associated with a greater decline in GFR% (p <0.01). The decline in GFR% persisted after adjustment for nutritional status with body mass index or weight-for-length z-scores. The prevalence of renal insufficiency (GFR% <75) increased from 22% at transplant to 55% and 85% at 1 and 5 years post transplant, respectively, while 15% had a GFR% <50 at 5 years post transplantation. Higher tacrolimus trough levels over the first 6 months correlated with a lower GFR% (p <0.01). Renal function declined significantly following thoracic organ transplantation.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Cyclosporine; Female; Follow-Up Studies; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppression Therapy; Kidney Function Tests; Lung Transplantation; Male; Postoperative Complications; Reference Values; Retrospective Studies; Tacrolimus; Time Factors

Topics: Calcium Channel Blockers; Gynecomastia; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Time Factors

Infection due to cytomegalovirus (CMV) is the most frequent opportunistic infection following renal transplantation (RT). It is usually asymptomatic. Cytomegalovirus disease causes fever leucopenia, thrombocytopenia and slightly elevated transaminases. The development of severe invasive forms is uncommon nowadays with post-transplantation monitoring, prophylactic regimens in high-risk patients and early treatment with ganciclovir. We report two renal transplant recipients who presented with severe gastrointestinal bleeding as the first manifestation of CMV disease at 9 and 14 weeks after transplantation. In both patients repeated post-transplantation pp65 antigenemia monitoring was negative. One patient developed hypovolemic shock due to severe rectal bleeding; an atypical bleeding ulcer was detected in the ileocecal valve. The other patient presented with upper gastrointestinal hemorrhage from a bleeding duodenal ulcer. Histological and immunohistochemical study confirmed the diagnosis. Both patients were elderly and on triple therapy with tacrolimus, mycophenolate and prednisone. We discuss the role of mycophenolate and the new immunosuppressant agents as factors favoring a state of enhanced immunosuppression, which may facilitate the onset of severe atypical forms of CMV disease.

Topics: Aged; Cytomegalovirus; Cytomegalovirus Infections; Disease Susceptibility; Duodenal Ulcer; Gastrointestinal Hemorrhage; Humans; Ileal Diseases; Ileocecal Valve; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Postoperative Complications; Prednisone; Shock; Tacrolimus; Ulcer

Alloimmune hemolytic anemia is a rare complication following allogeneic organ transplantation. Despite that some other drugs have also been reported, in the majority of cases this complication has been associated with cyclosporine therapy. We here present a case of severe alloimmune hemolytic anemia due to ABO minor incompatibility after renal transplantation in a patient treated with tacrolimus.

Topics: ABO Blood-Group System; Adult; Anemia, Hemolytic; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Tacrolimus

Post-transplant complications are common among patients receiving immunosuppressive medications, including pain syndromes. Recently, a pain syndrome, calcineurin-inhibitor induced pain syndrome (CIPS) has been described. To our knowledge, this article is the second report of tacrolimus-associated CIPS, and the first report in the pediatric setting.

Topics: Adolescent; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Neuralgia; Postoperative Complications; Syndrome; Tacrolimus

Topics: Antibodies, Monoclonal; Basiliximab; Child; Creatinine; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus

Topics: Adolescent; Adult; Aged; Cadaver; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Nervous System Diseases; Postoperative Complications; Retrospective Studies; Seizures; Tacrolimus; Tissue Donors

We describe a renal transplant recipient, with overimmunosuppression induced by the interaction of tacrolimus and fluconazole, who developed two severe diseases produced by two different viruses of the herpes group (cytomegalovirus [CMV] disease and posttransplant lymphoproliferative [PTLD] disease EBV-related). Detection of Epstein-Barr virus (EBV) DNA in the blood preceded the histological diagnosis of PTLD. Both diseases improved after changes in the immunosuppressive regime and treatment with ganciclovir. Because CMV infection is a risk factor in developing PTLD, and the clinical and endoscopic manifestations of both diseases could be become confused, PTLD should be excluded in EBV seronegative patients that develop CMV disease. The detection of the EBV genome in blood could help in the early diagnosis of PTLD in these patients.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Fluconazole; Ganciclovir; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppression Therapy; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Tacrolimus

Acute cellular rejection, though mostly encountered during the first 3 months after liver transplant, may occur later on. Clinical features and outcome of children experiencing late cellular rejection (LCR) have not been described to date.. A total of 20 children who developed acute rejection 6 months or more after liver transplant were studied for history of early rejection, levels of immunosuppression, causes of low immunosuppression, viral infections, signs of autoimmunity, and HLA mismatch. All liver biopsies were reviewed. Fifteen patients with no history of LCR were randomly selected as controls.. Of 20 children 5 were appropriately immunosuppressed, although 15 were not. Causes of low immunosuppression were: unknown (seven), poor compliance (three), posttransplant lymphoproliferative disease, (two), hepatocellular carcinoma recurrence (one), tuberculosis (one), gastroenteritis (one). Of 20 patients early rejection occurred in 13 and cytomegalovirus infection in 5. At last follow-up 10 children have persistent graft dysfunction, of whom 5 have progressed to de novo autoimmune hepatitis, 2 to chronic rejection, one has persistent graft dysfunction with recurrent cytomegalovirus activation, one has hepatic artery thrombosis and one is likely to have persistent poor compliance. None of the 15 controls developed de novo autoimmune hepatitis or any other form of persistent graft dysfunction at the time of last follow-up.. Late cellular rejection in children is usually due to low or decreased immunosuppression and is associated with long-term complications. Prompt intervention to correct inadequate immunosuppression and careful follow-up of the other patients to identify other treatable conditions is essential.

Topics: Antibodies, Viral; Biopsy; Child; Cyclosporine; Cytomegalovirus Infections; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunoglobulin M; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti-graft rejection and autoimmune disease therapy, is limited by their hepato- and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti-CYP reactivity in 16% of children on CyA for anti-graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8.5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti-cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.

Topics: Adolescent; Adult; Antibody Specificity; Aryl Hydrocarbon Hydroxylases; Autoantibodies; Autoantigens; Azathioprine; Blotting, Western; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclosporine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Therapy, Combination; Epitopes; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Isoenzymes; Kidney Diseases; Kidney Transplantation; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Mixed Function Oxygenases; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Tacrolimus

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Cyclosporine; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Renal Replacement Therapy; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors; Treatment Failure

Topics: Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphocytes; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Tissue Donors

Topics: Antibodies; Antilymphocyte Serum; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Liver Transplantation; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Creatinine; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Patient Selection; Postoperative Complications; Tacrolimus; Time Factors; White People

Topics: Bronchiolitis Obliterans; Drug Therapy, Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.

Topics: Adult; Diabetes Complications; Diabetes Mellitus; Female; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Logistic Models; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Marrow Transplantation; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diarrhea; Dogs; Immunosuppression Therapy; Immunosuppressive Agents; Intestine, Small; Mixed Function Oxygenases; Models, Animal; Postoperative Complications; Tacrolimus; Time Factors; Transplantation, Autologous

Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection and a defect of EBV specific cellular immunity is supposed to be the basis of PTLD. However, EBV load is so far the only marker proposed to evaluate PTLD risk, and no study has investigated the role of specific anti-EBV T lymphocytes (EBV-TL).. We therefore prospectively measured the EBV-TL by enzyme-linked immunospot (elispot) assay, in correlation to EBV load by real-time quantitative PCR and lymphoproliferation occurrence in 45 liver transplanted children.. EBV load at the time of primary infection was high in all patients irrespective to subsequent emergence of PTLD. Seven patients developed PTLD, all of them following primary EBV infection. All seven had low EBV-TL (<2/mm3) associated with high viral load (>25,000 copies/microg DNA). Both parameters can be combined in a 100% positive predictive index. Healing from lymphoma was characterized by rapid EBV-TL increase concomitant to decreasing viral load. EBV-TL follow-up helped to adapt immunomodulation. No patient had PTLD whenever EBV-TL were above 2/mm3.. We conclude that high viral load is systematic in patients who underwent primary EBV infection and is indicative of the PTLD risk only if there is low concomitant cellular immune response. Healing from PTLD requires modulation of immunosuppression, and appearance of EBV-TL.

Topics: Adolescent; Child; Child, Preschool; DNA, Viral; Epstein-Barr Virus Infections; Follow-Up Studies; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Predictive Value of Tests; T-Lymphocytes; Tacrolimus; Viral Load

Topics: Adolescent; Brain; Brain Edema; Cerebral Infarction; Dementia, Vascular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Resonance Imaging; Male; Postoperative Complications; Tacrolimus

Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation.. 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records.. In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose-dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1.71 [1.1-2.7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1.97 [1.2-3.2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6.07 [1.7-21.7]) in the liver group.. The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Fractures, Spontaneous; Germany; Heart Transplantation; Humans; Immunosuppressive Agents; Likelihood Functions; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Osteoporosis; Postoperative Care; Postoperative Complications; Proportional Hazards Models; Radiography; Risk Factors; Spinal Fractures; Tacrolimus

The purpose of this study was to compare the effects of Cyclosporine A (CyA) and FK506 on bone mass and mineral metabolism in liver transplantation (LT) patients. A prospective study was performed on 18 male patients who underwent LT treated with CyA, and 7 LT patients who received FK506. Bone mineral density (BMD) of the lumbar spine and proximal femur (DPX-L) was measured before and at 6, 12, and 24 months after transplantation. Moreover, intact parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) levels were determined at the same time. The cumulative dose of glucocorticoids was calculated in all patients. At 6 months, lumbar BMD decreased 5.2 +/- 1.2% (P = 0.0005) and 2.9 +/- 2.1% (p = ns) in CyA and FK506 groups, respectively. Lumbar BMD reached baseline values at 1 year in the FK506 group and 2 years after LT in the CyA group. Moreover, significant intergroup differences in femoral neck BMD changes after 2 years of transplant were observed (CyA: -5.2 +/- 1.97 versus FK506: +1.55 +/- 2.2%; P = 0.039). In the first year posttransplant both groups showed a marked increase in PTH and 25OHD levels. The mean cumulative dose of glucocorticoids was higher in the CyA group (CyA group 11.06 +/- 0.46 g versus FK 506 group 6.71 +/- 0.42 g; P < 0.001), and multiple linear regression analysis showed a negative correlation between BMD changes at the lumbar spine and mean cumulative dose of glucocorticoids (P = 0.022). In conclusion, our data suggest that after liver transplantation treatment with FK506 shows a more favorable long-term effect on bone mass evolution than CyA therapy. These differences seem to be associated with the lower dose of glucocorticoids used in the FK506 group.

Topics: Absorptiometry, Photon; Azathioprine; Bone Density; Cyclosporine; Drug Therapy, Combination; Femur Neck; Humans; Immunosuppressive Agents; Liver Transplantation; Lumbar Vertebrae; Male; Osteoporosis; Parathyroid Hormone; Postoperative Complications; Prednisone; Prospective Studies; Tacrolimus; Vitamin D

Although some previous studies have indicated the possibility of immunosuppression withdrawal in clinical liver transplantation, the mechanism of graft acceptance is not clear. The aim of this study is to elucidate the alloreactivity against the donor and intragraft cytokine profiles in living donor liver transplant (LDLT) recipients with graft acceptance. In October 1999, we had 23 patients who survived without immunosuppression after LDLT with a median drug-free period of 25 months (range: 3-69 months). They consisted of six patients who were electively weaned by an elective weaning protocol and 17 either forcibly or accidentally weaned patients due to various causes but mainly due to infection. We evaluated the alloreactivity against the donor in these patients by a mixed lymphocyte reaction and intragraft cytokine profiles by real-time reverse transcriptase-polymerase chain reaction. The development of donor-specific hyporeactivity was observed in the patients with graft acceptance. The cytokine pattern in the supernatant of the culture medium revealed a down regulation of T helper (Th) 1 cytokine INF gamma against the donor while no significant difference was seen in Th2 cytokine IL-10. Regarding the intragraft cytokine profiles, we could find no amplification of Thl cytokines (IL-2, INF y) and IL-4 while some of the patients revealed a gene expression of IL-10 with no significant difference from that of the normal, untransplanted liver specimen. In addition, no difference was observed in any other cytokines (IL-1beta, IL-8, IL-15, TNFalpha) compared with those of the normal controls. We propose that the down regulation of Th1 cytokine is one possible mechanism of graft acceptance in LDLT recipients.

Topics: Administration, Oral; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cytokines; Drug Therapy, Combination; Female; Gene Expression Profiling; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Infant, Newborn; Infections; Injections, Intravenous; Interferon-gamma; Interleukins; Liver; Liver Transplantation; Lymphocyte Culture Test, Mixed; Male; Postoperative Complications; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Th1 Cells; Tissue Donors; Tumor Necrosis Factor-alpha

Topics: Diarrhea; Drug Monitoring; Gastroenteritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Postoperative Complications; Rotavirus Infections; Tacrolimus; Transplantation

Rotavirus (RV) is the most common cause of diarrheal illness in children. We report three solid-organ-transplanted patients in whom RV infection caused increased trough levels of the immunosuppressive macrolide tacrolimus (TAC) by mechanisms that are still under investigation. The virus was detected for longer in the feces of these patients than in infants not receiving immunosuppressive therapy. In association with short-term monitoring of blood trough levels of TAC, the dosage should be reduced early if symptoms of an acute gastroenteritis are present.

Topics: Adult; Child; Diarrhea; Drug Monitoring; Feces; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Postoperative Complications; Rotavirus Infections; Tacrolimus; Transplantation

Topics: Administration, Oral; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Postoperative Complications; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adolescent; Adult; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Middle Aged; Paris; Postoperative Complications; Tacrolimus; Time Factors; Transplantation Immunology

As the survival of renal transplant patients has increased, so has their risk of significant morbidity. Immunosuppressive drugs can exacerbate preexisting conditions and promote development of new disease. Effective long-term care of transplant recipients requires an understanding of how these drugs affect clinical evaluations and treatments.

Topics: Anti-Inflammatory Agents; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Prednisone; Risk Factors; Tacrolimus

Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal.. An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls.. Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months.. Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Topics: Adolescent; Adult; Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biopsy; Child; Cohort Studies; Daclizumab; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infections; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Steroids; Survival Analysis; Tacrolimus

Cases of so-called autoimmune hepatitis (AH) have been reported after liver transplantation. Our aim was to evaluate the incidence in a series of 471 pediatric liver transplant recipients.. Between 1984 and 1998, 471 children had orthotopic liver transplantation (OLT). Children are followed up on a regular basis, with full clinical, biochemical, and histologic evaluation at 6 months, 1, 2, 5, 7, and 10 years after OLT. Children with unexplained abnormal liver tests were screened for autoimmune markers (total gamma-globulins, smooth muscle antibodies [SMA], liver kidney microsome antibodies [LKM], antinuclear factor [ANA]). From January of 1998 until December of 1998, autoimmune markers were prospectively searched in all children admitted for regular posttransplant follow-up (n = 118).. Eleven of 471 children (2.35%) were found with autoimmune hepatitis, 9 retrospectively and 2 prospectively. None had previous autoimmune liver disease. Patients had a history of steroid-dependent hepatitis. Histology showed variable degree of portal and lobular inflammation, piecemeal necrosis, and bridging collapse. Mean (+/-SDS) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities at diagnosis were 173+/-145 and 196+/-157 IU/L, respectively (nl<32). Median gamma-globulin levels reached 1365 mg/dl versus 931 mg/dl in controls (P<0.05). Nine had ANA (titer 1/80 up to 1/10,000), 1 SMA (1/320), and 2 LKM1 antibodies (1/1280). Patients did not respond to increasing charge of cyclosporine (n=10) or tacrolimus (n=1). Eleven received steroids (prednisolone: 2 mg/kg per day, then tapered) and azathioprine (1.5 to 2.5 mg/kg per day). All patients normalized within 3 months (mean AST/ALT levels of 26+/-8 and 30+/-9 IU/L). Three had mild to moderate relapse with increase of ALT thereafter. Gamma-globulins decreased to 1190 mg/dl (ns). Amongst the 116 remaining prospectively evaluated patients, 85 had normal evaluation, despite low titers of autoantibodies in 15 (SMA< or =1/40, ANA 1/80). Thirty-one patients had graft dysfunction, related to well-explained posttransplant causes, among which 7 had similar low levels of autoantibodies.. A total of 2.35% of our transplant children present evidence of immune hepatitis after transplantation. Patients do not respond to increasing cyclosporine or tacrolimus levels and require steroid and azathioprine. In view of this specific treatment, systematic screening for "autoimmune" markers is advised in children with liver transplant.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Azathioprine; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Male; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus

Mesial temporal lobe epilepsy (MTLE) developed in a boy receiving FK506 (tacrolimus) after liver transplantation. He had no history of convulsions. At the age of 7, he underwent liver transplantation 13 days after he developed the abdominal form (fulminant hepatitis) of Wilson's disease. On postoperative day 18, he had a generalized tonic seizure (duration 20 min.) with loss of consciousness. FK506 was discontinued under the suspicion of FK506-induced encephalopathy. His symptoms resolved within a few days. FK506 was readministered at 3 months after transplantation. Ten months later, he developed complex partial seizures characterized by right tonic posturing with oral automatism. EEG revealed sporadic spikes in the anterior temporal region. MRI and SPECT showed bilateral (left side dominant) hippocampal lesion, which suggested the diagnosis of MTLE. Since seizures became refractory to medical treatment with progressive worsening of memory functions, FK506 was discontinued again at 36 months after readministration. Six months later, his memory improved remarkably, but there were no changes in seizure frequency and in MRI and SPECT findings. Our findings indicate that FK506 might damage the hippocampus, thereby causing MTLE. Additional case reports, however, will be required to elucidate this new FK506-related neurological complication.

Topics: Child; Epilepsy, Temporal Lobe; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

Hypertrophic cardiomyopathy (HCM) has been reported in pediatric transplant patients receiving tacrolimus. It is unclear whether tacrolimus is associated with HCM in adult transplant recipients.. To determine the prevalence of HCM in noncardlac adult transplant patients receiving tacrolimus.. A retrospective analysis of nonheart transplant recipients who received tacrolimus at our institution from January 1982 to April 1996 was conducted. Patients with left-ventricular hypertrophy (LVH) defined as a posterior or septal wall thickness > or = 1.3 cm by echocardiography (ECHO) were independently evaluated.. There were 3609 patients who met entry criteria including 2257 liver, 1333 kidney, and 19 other organ transplants. Of the 502 patients who had undergone ECHOs after transplantation, 171 had LVH. The etiology of LVH was categorized as valvular disease (36%), hypertensive disease (29%), ischemic heart disease (17%), or multifactonal (15%). There were six patients in whom, after detailed chart review, no underlying cause of LVH was evident. Five of these patients had HCM, representing an overall prevalence of 0.1% in the entire group of tacrolimus-treated patients, and 1% in patients referred for ECHO.. The prevalence of HCM in our tacrolimus-treated adult transplant population is similar to that reported in general population studies. These data suggest that tacrolimus is not a risk factor for HCM in adult transplant recipients.

Topics: Adult; Cardiomyopathy, Hypertrophic; Echocardiography; Female; Graft Rejection; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Prevalence; Retrospective Studies; Tacrolimus

To improve long-term outcome after renal transplantation, attention should be placed on the tailored use of immunosuppressive regimens that have a more favorable impact on the immunological and nonimmunological risk profiles of an individual recipient. Tacrolimus is widely used for maintenance and rejection immunosuppression in solid organ transplantation, and compared with cyclosporine, its use in renal transplantation is associated with a reduced incidence and severity of acute rejection and a more positive effect on known cardiovascular risk factors. Recent experience with tacrolimus-based therapy has demonstrated an improved lipid profile and lower arterial blood pressure, with less requirement for lipid-lowering and antihypertensive medication compared with cyclosporine, without significantly increasing the risk of long-term insulin-dependent posttransplant diabetes mellitus. The advantageous effects of tacrolimus on both immunological and nonimmunological risk factors offer potential benefits for long-term graft function and survival.

Topics: Cardiovascular Diseases; Child; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Ohio; Postoperative Complications; Risk Factors; Tacrolimus

Risk factors for the development of posttransplant lymphoproliferative disease (PTLD), a major cause of morbidity and mortality after pediatric liver transplantation, are primary Epstein-Barr virus (EBV) infection and intensity of immunosuppression. The authors assessed monitoring of EBV replication and preemptive immunosuppression reduction in pediatric liver transplant recipients.. The authors prospectively followed monthly EBV-quantitative competitive polymerase chain reaction to measure EBV replication in 23 patients who underwent liver transplant between July 1997 and November 1998. Preemptive immunosuppression reduction was instituted for significant EBV replication. Patients were followed up for at least 1 year and divided in two groups for analysis (group 1, pretransplant seronegative for EBV [13 patients]; group 2, seropositive for EBV [10 patients]).. In group 1, 9 of 13 patients had positive polymerase chain reaction results at a mean time of 22.4 weeks after transplantation. All but one of these patients were asymptomatic. In seven of nine patients, preemptive immunosuppression reduction was undertaken without development of PTLD or rejection. In two of nine patients, immunosuppression could not be continuously reduced, and both patients experienced low-grade and medically responsive PTLD. In no patient in group 2 did an EBV-positive viral load or PTLD develop.. Prospective longitudinal measurement of EBV by quantitative competitive polymerase chain reaction permits early detection of asymptomatic viral replication. Subsequent preemptive reduction of immunosuppression may prevent the progression to PTLD.

Topics: Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Epstein-Barr Virus Infections; Fatal Outcome; Female; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphoproliferative Disorders; Male; Organ Transplantation; Polymerase Chain Reaction; Postoperative Complications; Prospective Studies; Risk Factors; Tacrolimus; Viral Load

Topics: Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leg; Middle Aged; Postoperative Complications; Retreatment; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

The introduction of potent new immunosuppressive agents may allow simultaneous kidney-pancreas transplantation to be performed without antilymphocyte induction.. We analyzed 30 simultaneous kidney-pancreas transplantations receiving tacrolimus, mycophenolate mofetil, and steroids without without antilymphocyte induction. Eighteen patients underwent pancreas transplantation with portal-enteric (P-E) drainage and the remaining 12 had systemic bladder (S-B) drainage. Target 12 hr trough tacrolimus levels for the first 3 months after simultaneous kidney-pancreas transplantation were 15-20 ng/ml. The oral mycophenolate mofetil dose was 2-3 g/day begun immediately posttransplant in two to four divided doses. Steroids were tapered according to protocol.. All patients experienced immediate function of both kidney and pancreas grafts. One-year actuarial patient, kidney, and pancreas graft survival rates are 93, 93, and 90%, respectively. Nine patients (30%) had a total of 13 rejection episodes (12 biopsy proven) including 4 within 2 weeks, 6 between 2 weeks and 3 months, and 3 beyond 3 months after simultaneous kidney-pancreas transplantation. Three rejection episodes were treated with steroids alone and 10 were treated with antilymphocyte therapy (5 OKT3 and 5 ATGAM). A total of seven patients (23%) received antilymphocyte therapy. Three patients (10%) had more than one rejection episode. Two pancreas grafts (7%) and one kidney graft (3%) were lost from rejection. Four patients (13%) developed cytomegalovirus infection, but none had tissue-invasive cytomegalovirus. At present, 22 surviving patients (81%) remain on triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone with excellent dual graft function.. Tacrolimus, mycophenolate mofetil, and prednisone immunosuppression without without antilymphocyte induction is safe and effective after simultaneous kidney-pancreas transplantation.

Topics: Adult; Antilymphocyte Serum; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Kidney Transplantation; Length of Stay; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Postoperative Care; Postoperative Complications; Prednisone; Survival Analysis; Tacrolimus

Neurological complications after orthotopic liver transplantation (OLTX) have remained a major concern in a small proportion of patients. The etiology of these complications is often thought to be multifactorial: the influence of calcineurin inhibitors is occasionally thought to play an important role. When neurotoxicity occurs after OLTX under tacrolimus, it is usually a minor complication and responds readily to a reduction in the dosage of or a temporary withdrawal of tacrolimus. However, neurotoxic complications occasionally do not respond to this conventional process. Neoral is a microemulsion formulation of cyclosporine. It has more consistent pharmacokinetic parameters and improved bioavailability when compared with conventional cyclosporine. The aim of the present report was to evaluate the role of Neoral in OLTX recipients with neurotoxic complication who failed to respond to a reduction in the dosage of tacrolimus.. Between August 1995 and November 1997, 330 adults (age >18 years) received primary OLTX under tacrolimus-based immunosuppression (mean age 52.6+/-11.4 years). There were 190 men and 140 women. Twenty-three (7%) patients (mean age 53.2+/-11.8 years; 17 men, 6 women) were converted to Neoral (mean 35+/-41 days after OLTX). These patients were followed until June 1998 (mean follow-up 22.7+/-7.8 months).. Four (17.4%) patients died during the follow-up period, and two patients underwent retransplantation. Neurological symptoms improved in all patients who survived. Adequate trough concentrations were achieved in all patients with p.o. Neoral. Nine (39%) patients experienced rejection episodes after conversion. Six (26.1%) patients were converted back to tacrolimus because of ongoing rejection (n=3), retransplantation (n=2), or persistent nausea and vomiting (n=1) without recurrence of the original neurological complication.. Neurological complications after OLTX disorders that occur under tacrolimus and that fail to respond to a reduction in the dosage can be treated safely by conversion to Neoral. However, the rate of rejection is up to 39%, and patients can often be converted back to tacrolimus without recurrence of the original neurological complication.

Topics: Adult; Aged; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Postoperative Complications; Reoperation; Retreatment; Tacrolimus; Tomography, X-Ray Computed

Topics: Adult; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Reoperation; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Tacrolimus

Topics: Adult; Drug Therapy, Combination; Family; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Spouses; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Apolipoproteins B; Cholesterol; Cholesterol, LDL; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Postoperative Complications; Prospective Studies; Tacrolimus; Time Factors; Triglycerides

To evaluate the impact of acute and chronic liver disease and single immunosuppression (cyclosporine A [CSA] or FK506) on insulin sensitivity and glucose effectiveness in liver-grafted patients, we performed a frequently sampled intravenous glucose tolerance test (FSIGTT) in nondiabetic patients after orthotopic liver transplantation (OLT) with acute liver failure ([ALF] group, n = 9, with CSA therapy), in patients after OLT with chronic liver disease (CSA group, n = 8; FK506 group, n = 8), and in 9 healthy control subjects. Insulin sensitivity and glucose effectiveness were determined by analyzing glucose and insulin data from the FSIGTT with Bergman's minimal model technique for glucose. The intravenous glucose tolerance index ([KG] ie, the slope of the regression of the logarithm of blood glucose concentration) was not different between the ALF group (2.17 +/- 0.16 min(-1)) and controls (2.29 +/- 0.13 min(-1)), but was lower (P < .05) in both groups with chronic liver disease (CSA group, 1.46 +/- 0.1; FK506 group, 1.61 +/- 0.11 min(-1)) compared with the ALF group (P < .05). A positive relation for the KG and glucose effectiveness was found in all liver-grafted patients and controls. Insulin sensitivity was not different between all liver-grafted patients and controls. The body mass index (BMI) was the overall determinant of insulin sensitivity in all groups. Single immunosuppressive therapy does not impair insulin sensitivity in liver-grafted patients. The lower glucose effectiveness in liver-grafted patients with chronic liver disease but not in patients after ALF points to a defect in the regulation of glucose-mediated glucose uptake in peripheral tissue.

Topics: Adult; Blood Glucose; Cholesterol; Cyclosporine; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Insulin; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Male; Models, Biological; Postoperative Complications; Reference Values; Tacrolimus; Triglycerides

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.

Topics: Adult; Calcineurin; Cyclosporine; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Topics: Anti-Bacterial Agents; Chloramphenicol; Drug Interactions; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Urinary Tract Infections

Topics: Acute Disease; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Phenobarbital; Postoperative Complications; Renal Dialysis; Tacrolimus

Topics: Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Nephrotic Syndrome; Postoperative Complications; Tacrolimus

Topics: Adolescent; Adult; Antibodies, Viral; Antigens, Viral; Child; Child, Preschool; Cyclosporine; Female; Herpesvirus 4, Human; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Monitoring, Physiologic; Postoperative Complications; Tacrolimus

In this study, we investigated the relationship between excretion of urinary nitrate as a stable end-product of nitric oxide (NO) metabolism and hepatic allograft rejection. In experimental rat models, hepatic allograft rejection was associated with increased nitrate excretion with a peak on postoperative day 5. The severity of the hepatic allograft rejection was dependent on the increased urinary nitrate excretion. No significant increase in urinary nitrate excretion was observed in cases in which effective immunosuppression was achieved. Inducible nitric oxide synthase mRNA expression was upregulated parallel to interferon-gamma gene expression in the graft-infiltrating mononuclear cells and spleen cells from the recipients. In clinical cases, urinary nitrate excretion increased parallel to increased serum cytosolic enzymes that accompanied rejection. These results suggest that urinary nitrate excretion is a useful indicator for the surveillance of graft rejection and the monitoring of therapeutic effects of antirejection treatments.

Topics: Animals; Child; Disease Models, Animal; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Muromonab-CD3; Nitrates; Postoperative Complications; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ischemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Radiography; Splanchnic Circulation; Tacrolimus

Topics: Adult; Child; Cytomegalovirus Infections; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Intestines; Postoperative Complications; Retrospective Studies; Stomach; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous; Viscera

A 25-year-old woman with severe aplastic anemia received allogeneic bone marrow transplantation from an HLA-identical sibling. Pretransplant conditioning comprised 3.6 Gy of total body irradiation and 200 mg/kg cyclophosphamide. Cyclosporine (CSP) and methotrexate were administered to prevent graft-versus-host disease (GVHD). The patient complained of severe headache soon after CSP administration on day-1. On day 3, convulsion developed and she lost consciousness for 15 min. CT and MRI demonstrated low density areas and high signals, respectively, in the frontal and parietooccipital lobes and splenium of the corpus callosum, suggesting brain edema probably induced by CSP. After immediate withdrawal of CSP, glycerol and prednisolone were instituted, and the patient's condition improved. Thereafter, she developed grade II acute GVHD. This was treated with tacrolimus, which produced no adverse effects including central nervous system (CNS) toxicity. This case illustrates that careful management of CNS disorders induced by CSP can be important in patients undergoing allogeneic bone marrow transplantation.

Topics: Adult; Bone Marrow Transplantation; Brain Diseases; Cyclosporine; Female; Graft vs Host Disease; Humans; Postoperative Complications; Tacrolimus; Transplantation, Homologous

Despite new advances in transplantation, complete venous thrombosis (VT) of the pancreas after simultaneous pancreas kidney (SPK) transplantation usually results in graft loss. Data are limited regarding the outcome and treatment of partial VT of the pancreas allograft. From July 1994 to December 1999, 126 patients with IDDM/end-stage renal disease underwent SPK with systemic bladder drainage at the University of Miami. We retrospectively reviewed our experience regarding the outcome and treatment options of partial VT of the pancreas allografts. From July 1994 to April 1997, partial VT was not seen in the first 66 SPK patients induced with anti-CD3 rnAb and oral or intravenous (i.v.) tacrolimus (TAC) in the operating room. From May 1997 to June 1999, 14 (29%) out of 48 patients had VT. These cases were identified following the i.v. use of TAC with anti-IL-2R antibody-induction therapy (7/15) or without (7/33). Partial thrombosis of the splenic vein (PTSV) was documented in 10 patients, 2 had complete thrombosis of the splenic vein (CTSV), 1 had partial thrombosis of the superior mesenteric vein (PTSMV), and 1 patient had PTSV and PTSMV. These were identified incidentally during routine color Doppler ultrasonography (CDU). None of these SPK recipients demonstrates a change in clinical parameters. The first 8 patients were systemically heparinized, followed by oral anticoagulation, except 1 patient with CTSV. He progressed to complete thrombosis of the pancreas allograft and was treated with percutaneous thrombectomy and urokinase infusion, followed by heparinization and oral anticoagulation. One patient required exploration for bleeding. In an attempt to reduce the morbidity of heparinization, we treated the next 6 patients with PTSV with aspirin followed by serial CDU. All 14 patients had preservation of the endocrine and exocrine pancreatic functions. CDU showed resolution with recanalization of the thrombosed vein(s). From July 1999 to December 1999, 12 SPK recipients were administered TAC orally with or without induction therapy with anti-IL-2R antibody. So far, in this group, VT has not been identified. In summary, a total of 14 out of 126 patients (11%) had isolated VT with a mean follow-up of 36.4 months. Based on our experience, we suggest that extensive VT after pancreas transplantation, including splenic and superior mesenteric VT, be treated with heparin and subsequent oral anticoagulation for 3 months. For more limited, partial splenic VT, asp

Topics: Adult; Anticoagulants; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Heparin; Humans; Immunosuppressive Agents; Kidney Transplantation; Mesenteric Vascular Occlusion; Mesenteric Veins; Pancreas Transplantation; Platelet Aggregation Inhibitors; Postoperative Complications; Receptors, Interleukin-2; Retrospective Studies; Risk Factors; Splenic Vein; Tacrolimus; Time Factors; Transplantation, Homologous; Venous Thrombosis

Successful small bowel transplantation requires effective immunosuppression that preserves intestinal function but avoids opportunistic infection. This study aims to evaluate FK506 as a single immunosuppressant in different pretreatment regimens in a rat high responder strain combination.. Lewis --> DA rat heterotopic small bowel transplantation was performed. Studied groups were (1) untreated control, n = 12; (2) FK-1, n = 8; (3) FK-3, n = 8. FK506 (2 mg/kg/d, intramuscularly) was given to the recipients for 1 day (FK-1) and 3 days (FK-3) before small bowel transplantation, followed by 2 weeks of subtherapeutic treatment (0.3 mg/kg/d, intramuscularly) after small bowel transplantation. Syngeneic small bowel transplantation also was performed (n = 8). FK blood levels, maltose absorption test, histology, and bacteriology were performed at different postoperative days.. Allograft survival was prolonged significantly with FK pretreatment, being more so in FK-3 group (FK-1, 22.2 +/- 1.5 d; FK-3, 40.7 +/- 14.1 d; control, 6.6 +/- 0.8 d; P< .01). In the first postoperative week, FK blood level was significantly higher in FK-3 group (19.8 +/- 1.5 ng/mL) than in FK-1 group (5.0 +/- 0.4 ng/mL; P < .05). There was no evidence of systemic infection in either FK-treated group. For maltose absorption, control allograft was abnormal on day 7 correlating to severely damaged intestinal architecture. In contrast, FK-treated allografts showed well-protected intestinal structure and normal absorption on days 7 and 21.. High FK506 blood levels in the first postoperative week, achieved with FK pretreatment, prolonged intestinal allograft survival and preserved intestinal structure and function without allowing systemic infection.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Intestinal Diseases; Intestine, Small; Male; Postoperative Complications; Postoperative Period; Preoperative Care; Probability; Rats; Rats, Inbred Lew; Sensitivity and Specificity; Tacrolimus; Tissue Transplantation; Transplantation Immunology; Transplantation, Homologous; Treatment Outcome

Because of the donor shortage, there are concerns for liver transplantation in patients with alcoholic cirrhosis. We therefore analyzed patients transplanted for alcoholic cirrhosis at our center with respect to patient and graft survival, recurrence of disease, and postoperative complications. Out of 1000 liver transplantations performed in 911 patients, 167 patients were transplanted for alcoholic cirrhosis; 91 patients received CsA- and 76 patients FK506-based immunosuppression. Recurrence was diagnosed by patient's or relative's declaration, blood alcohol determination, and delirium. Diagnosis and treatment of acute and chronic rejection was performed as previously described. One- (96.8% versus 91.3%) and 9-year patient survival (83.3% versus 80%) compared well with other indications. Five of 15 patients died due to disease recurrence. Recurrence of disease was significantly related to the duration of alcohol abstinence prior to transplantation. In patients who were abstinent for less than 6 months (17.1%), recurrence rate was 65%, including four of the five patients who died of recurrence. Recurrence rate decreased to 11.8%, when abstinence time was 6-12 months and to 5.5%, when the abstinence times was > 2 years. Next to duration of abstinence, alcohol relapse was significantly related to sex, social environment, and psychological stability. The incidence of acute rejection compared well with other indications (38.1%); CsA: 40.1% versus 33.3% in FK506 patients. In all, 18.2% of CsA patients experienced steroid-resistant rejection compared with 2.6% of FK506 patients. Seven patients (7.6%) in the CsA group and one patient (1.3%) in the FK506 group developed chronic rejection. A total of 57.1% developed infections; 5.7% were life-threatening. CMV infections were observed in 14.3% (versus 25% for other indications). New onset of insulin-dependent diabetes was observed in 8.6% and hypertension in 32.4%. In conclusion, alcoholic cirrhosis is a good indication for liver transplantation with respect to graft and patient survival and development of postoperative complications. FK506 therapy was favourable to CsA treatment. Patient selection is a major issue and established criteria should be strictly adhered to. Patients with alcohol abstinence times shorter than 6 months should be excluded, since recurrence and death due to recurrence was markedly increased in this group of patients.

Topics: Adult; Alcoholism; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus; Temperance; Time Factors

Although the introduction of FK506 and MMF has markedly improved patient and graft outcome after pancreas transplantation, this procedure is still associated with a high surgical complication rate. The aim of the following study was to retrospectively analyze a series of 40 consecutive pancreas transplants with enteric drainage with regard to intraabdominal infection (IAI). Between March 1997 and December 1998 a total of 40 whole pancreas transplants were performed. Prophylactic immunosuppression consisted of an intraoperative single shot ATG (Thymoglobulin), FK506, MMF, and prednisone. The mean observation period was 14.6 (5-26) months. Overall incidence of IAI was 27.5% (n = 11) leading to pancreatectomy in 5 patients (12.5%). In the remaining 6 patients the graft could be rescued by necrosectomy and radical drainage of the abscess (5 patients) or percutaneous drainage (1 patient). Pancreatectomy or local infection did not alter kidney graft function in the 11 patients with simultaneous pancreas kidney transplantation. In 10 patients no evidence for leakage at the site of enteric anastomosis was present, one duodenal leak occurred due to ischemia. IAI in the early postoperative period was the predominat risk factor for graft loss. An early and invasive diagnostic approach is recommended to maximize the chance of graft rescue.

Topics: Adult; Antilymphocyte Serum; Female; Graft Survival; Humans; Immunosuppressive Agents; Infections; Intestines; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Pancreatectomy; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Azathioprine; Cholesterol; Cholesterol, HDL; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Immunosuppressive Agents; Incidence; Japan; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Retrospective Studies; Ribonucleosides; Risk Factors; Tacrolimus; Triglycerides

Topics: Acidosis, Renal Tubular; Bicarbonates; Biliary Atresia; Bilirubin; Child, Preschool; Creatinine; Electrolytes; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Living Donors; Postoperative Complications; Tacrolimus

Topics: Adult; Blood Glucose; Diabetes Mellitus; Drug Monitoring; Female; Humans; Hyperglycemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Retrospective Studies; Tacrolimus

Topics: Adult; Apolipoprotein C-III; Apolipoproteins A; Apolipoproteins B; Apolipoproteins C; Azathioprine; Calcineurin Inhibitors; Cholesterol; Cyclosporine; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Postoperative Complications; Reference Values; Sirolimus; Tacrolimus; Triglycerides

Hemolytic-uremic syndrome (HUS) is a well-recognized complication of cyclosporine (CyA) therapy. Transplant recipients with this complication are frequently switched to tacrolimus, although this drug has also been implicated. We report a case of a renal transplant recipient who developed severe graft dysfunction due to biopsy-proven HUS after receiving CyA. Renal function and hemolytic parameters improved with discontinuation of the drug, but they deteriorated again after commencement of tacrolimus 15 days later. A second transplant biopsy demonstrated fresh lesions diagnostic of HUS. Hemolytic parameters resolved with discontinuation of tacrolimus. This is the first report of metachronous HUS being caused in a renal transplant by both CyA and tacrolimus. We therefore believe that caution should be exercised when using tacrolimus as rescue therapy in patients with CyA-induced HUS.

Topics: Biopsy; Cyclosporine; Endothelium, Vascular; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Interleukin-2; Kidney; Kidney Transplantation; Middle Aged; Phosphoric Monoester Hydrolases; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Recurrence; Tacrolimus

Diabetes mellitus (DM) is a well-recognized complication of immunosuppressive therapy in the post-transplant (Tx) period. The DM encountered in the setting of tacrolimus therapy has been managed in the past by tacrolimus dose reduction and a rapid corticosteroid taper; frequently insulin therapy is also required to maintain normoglycemia. However, the dose reduction of immunosuppressive agents has often resulted in acute allograft rejection. We are reporting our experience in managing three pediatric renal Tx recipients who developed DM in the post-Tx period while on triple immunosuppressive therapy including tacrolimus and corticosteroids. All of our patients were managed by substitution of tacrolimus with conventional doses of neoral while maintaining their usual corticosteroid dose. All three patients had resolution of hyperglycemia and none experienced acute rejection. Tacrolimus was then successfully reinitiated 4.6 months later; at last follow-up, all of our patients have good allograft function and have maintained a normal blood sugar. In conclusion, we feel that conversion of patients from tacrolimus to neoral should be attempted as a safer alternative to tacrolimus dose reduction, for managing post-Tx DM in tacrolimus treated patients.

Topics: Adrenal Cortex Hormones; Azathioprine; Child; Cyclosporine; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus

Posttransplant lymphoproliferative disorder (PTLD) is a potentially lethal complication in the pediatric transplant patient secondary to Epstein-Barr virus (EBV) infection and potent immunosuppression. PTLD may develop in up to 10% of pediatric transplant recipients with mortality rates up to 80%. The authors report their experience with the diagnosis and efficacy of aggressive sequential management of PTLD in five patients under age 5 years.. A review of 75 pediatric liver transplant recipients on FK-506-based immunosuppression identified five biopsy-proven cases of PTLD and one probable case (8%). The probable case was a teenager, 6 months posttransplant in Spain, with mediastinal masses. No treatment or diagnosis was sought, and the patient died. The other five cases were managed with sequential therapy on an "intent-to-treat" basis with initial withdrawal of immunosuppression. If the disease progressed, patients were treated with four courses of intravenous cyclophosphamide, vincristine, Adriamycin, and intrathecal methotrexate and ara-C.. Five children were anti-EBV titer negative at the time of transplant. Three of five received EBV-positive donor organs and two children received EBV-negative livers. Monoclonal PTLD developed between 2 and 31 months posttransplant (mean, 15.7 months). With onset of PTLD (four B cell lymphoma, one B cell leukemia) all patients had tapering or withdrawal of immunosuppression and initiation of highdose acyclovir. Two of five patients had complete remission and resumed immunosuppression. Two patients progressed and required chemotherapy. One patient with initial response relapsed 4 months later with B cell leukemia and required chemotherapy. All five patients are alive 10 to 38 months postdiagnosis (mean, 29 months). Three patients had rejection requiring resumption of FK-506 therapy. Two patients are maintained on low-dose alternate-day prednisone and no FK-506. All patients have normal liver function. Central nervous system lymphoma developed in one child with significant neurological sequelae.. PTLD can develop in pediatric liver transplant recipients. Early withdrawal of immunosuppression and aggressive chemotherapy enabled us to achieve 100% patient and graft survival.

Topics: Algorithms; Antigens, Viral; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

Poor linear growth after pediatric orthotopic liver transplantation (OLT) is a well-described phenomenon. We have undertaken a bivariate and multivariate analysis of multiple factors that might effect postOLT growth in all children who underwent transplantation at a single center, with survival > 1 year and adequate follow-up.. Standardized height score (Z score) and height deficit (centimeters below the 50th percentile) were computed for each patient over time. The variables assessed were (i) age at OLT, (ii) gender, (iii) pretransplantation diagnosis, (iv) Z score and height deficit at OLT, (v) tacrolimus versus cyclosporine as primary immunosuppressive therapy, (vi) retransplantation, (vii) graft disease, (viii) chronic illness, (ix) posttransplant lymphoproliferative disease, (x) intractable rejection, and (xi) prednisone withdrawal.. A total of 236 children met the inclusion criteria, with a mean follow-up of 3.8+/-1.9 years. For the population as a whole, the baseline Z score was -1.72 (fourth percentile) with a significant improvement to - 1.37 (ninth percentile) at 2 years, but with no additional gain at 5 years (Z score -1.4). The baseline height deficit was -6.4 cm, with no improvement at 2 years (-6.52 cm), and was significantly worse at 5 years (-7.87 cm). In the bivariate analysis, the most important variables affecting growth were age at OLT, Z score at OLT, and diagnosis. In general, children <2 years with biliary atresia and those with the most growth delay at OLT showed the best posttransplantation growth. In the multivariate analysis, 18 factors were considered, of which 9 were significant. These were (i) Z score at baseline, (ii) follow-up time, (iii) age at OLT, (iv) diagnosis of tumor, (v) diagnosis of fulminant hepatic failure, (vi) retransplantation, (vii) graft disease, (viii) posttransplant lymphoproliferative disease, and (ix) stoppage of prednisone. Multivariate models using these nine variables accounted for 84% of the variation in standardized height.. In general, children after OLT show some potential for catch-up growth but do not achieve normal height compared with their age and sex-matched peers. A multivariate analysis was necessary to investigate the interdependent effects of the many variables that can affect growth after OLT. The most important detrimental affects were older age at time of OLT, Z scores greater than -2.0 at OLT, fulminant hepatic failure, tumor, and postOLT complications causing graft dysfunction.

Topics: Adolescent; Age Factors; Body Height; Child; Child, Preschool; Cyclosporine; Female; Follow-Up Studies; Growth; Hospital Records; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Postoperative Complications; Reoperation; Retrospective Studies; Sex Factors; Survival Analysis; Tacrolimus; Time Factors

The introduction of tacrolimus has shown decreased rates of acute and steroid-resistant rejection after liver transplantation (LTx). The aim of the present study is to examine the long-term efficacy and safety of tacrolimus in primary liver transplant recipients. The first 121 consecutive adults (aged >16 years) who underwent primary LTx at a single center from August 1989 to February 1990 were followed up until August 1997. The mean follow-up was 93.2 +/- 1.2 months (range, 90.5 to 96.5 months). Patient survival, graft survival, rate of rejection, and adverse events were examined. The actual 7-year patient survival rate was 67.8%, and the graft survival rate was 63.6%. Infections, recurrence of disease, de novo malignancies, and cardiovascular events constituted the main causes of graft loss and death in the long term. Graft loss related to acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most rejections were steroid responsive. Approximately 70% of the patients received only tacrolimus after 1 year. Four patients developed end-stage renal disease, and 2 patients underwent kidney transplantation. Hyperkalemia and hypertension were observed in one third of the patients. New-onset insulin-dependent diabetes mellitus was observed in 9% and 13% of the patients at the 1-year and 7-year follow-up, respectively. Seven patients developed de novo malignancies, including two skin malignancies. Six patients developed posttransplantation lymphoproliferative disorder during the entire follow-up period. Actual patient and graft survival at 7 years was excellent, and few adverse events developed after the first year. Graft loss from acute or chronic rejection was rare under tacrolimus, and approximately 70% of the patients were steroid free on tacrolimus monotherapy after the first year after LTx.

Topics: Adult; Aged; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; Postoperative Complications; Reoperation; Survival Analysis; Tacrolimus

Tacrolimus has been used as a primary immunosuppressive agent in adult and pediatric renal transplant recipients, with reasonable outcomes. Methods. Between December 14, 1989 and December 31, 1996, 82 pediatric renal transplantations alone were performed under tacrolimus-based immunosuppression without induction anti-lymphocyte antibody therapy. Patients undergoing concomitant or prior liver and/or intestinal transplantation were not included in the analysis. The mean recipient age was 10.6+/-5.2 years (range: 0.7-17.9). Eighteen (22%) cases were repeat transplantations, and 6 (7%) were in patients with panel-reactive antibody levels over 40%. Thirty-four (41%) cases were with living donors, and 48 (59%) were with cadaveric donors. The mean donor age was 27.3+/-14.6 years (range: 0.7-50), and the mean cold ischemia time in the cadaveric cases was 26.5+/-8.8 hr. The mean number of HLA matches and mismatches was 2.8+/-1.2 and 2.9+/-1.3; there were five (6%) O-Ag mismatches. The mean follow-up was 4.0+/-0.2 years.. The 1- and 4-year actuarial patient survival was 99% and 94%. The 1- and 4-year actuarial graft survival was 98% and 84%. The mean serum creatinine was 1.1+/-0.5 mg/dl, and the corresponding calculated creatinine clearance was 88+/-25 ml/min/1.73 m2. A total of 66% of successfully transplanted patients were withdrawn from prednisone. In children who were withdrawn from steroids, the mean standard deviation height scores (Z-score) at the time of transplantation and at 1 and 4 years were -2.3+/-2.0, -1.7+/-1.0, and +0.36+/-1.5. Eighty-six percent of successfully transplanted patients were not taking anti-hypertensive medications. The incidence of acute rejection was 44%; between December 1989 and December 1993, it was 63%, and between January 1994 and December 1996, it was 23% (P=0.0003). The incidence of steroid-resistant rejection was 5%. The incidence of delayed graft function was 5%, and 2% of patients required dialysis within 1 week of transplantation. The incidence of cytomegalovirus was 13%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 12%. The incidence of early Epstein-Barr virus-related posttransplant lymphoproliferative disorder (PTLD) was 9%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 4%. All of the early PTLD cases were treated successfully with temporary cessation of immunosuppression and institution of antiviral therapy, without patient or graft loss.. These data demonstrate the short- and medium-term efficacy of tacrolimus-based immunosuppression in pediatric renal transplant recipients, with reasonable patient and graft survival, routine achievement of steroid and anti-hypertensive medication withdrawal, gratifying increases in growth, and, with further experience, a decreasing incidence of both rejection and PTLD.

Topics: Actuarial Analysis; Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Child; Child, Preschool; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Tacrolimus; Tissue Donors

A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.

Topics: Animals; Aorta, Thoracic; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Disease Models, Animal; Hypertension; Hypertrophy, Left Ventricular; Ligation; Male; Postoperative Complications; Random Allocation; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Tacrolimus

Newer surgical techniques and immunosuppressive therapies have resulted in paediatric liver transplantation being available for most children with end-stage liver disease and has resulted in a greater than 80% 5-year survival rate. The most common indications for paediatric liver transplantation are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approximately 75% of children with acute hepatic failure, the cause is unknown. Timing of liver transplantation not only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numerous types of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, have reduced the mortality of children who are waiting for liver transplantation. However, the mortality and morbidity before and after liver transplantation remain high for children who have fulminant hepatic failure or are less than 5 months of age at the time of transplantation. The principle medical complications after liver transplantation are rejection and infection. Although use of newer immunosuppressive regimens has reduced the rate of rejection, Epstein-Barr virus infection with associated lymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

Topics: Adolescent; Adult; Age Factors; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Hepatic Encephalopathy; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

Advances in surgical techniques, postoperative care, and experience have led to improved outcome in heart transplant patients. Specifically, the use of corticosteroid-free immunosuppression has reduced the risk of infection. The use of pravastatin early after transplantation has led to a decrease in clinically severe rejection episodes, improvement in survival, and reduction in transplant coronary artery disease. Reduction in natural-killer-cell cytotoxicity in the pravastatin-treated patients suggests an adjunct immunosuppressive effect of pravastatin in those patients on CyA-based immunosuppression. Quality of life has also improved in the heart transplant recipient with cardiac rehabilitation demonstrating a beneficial role in the improvement of exercise capacity. Newer immunosuppressive agents and strategies continue to demonstrate benefit in improving survival and the quality of life of the heart transplant recipient.

Topics: Acute Kidney Injury; Antibodies, Monoclonal; Denervation; Graft Rejection; Heart; Heart Transplantation; Humans; Immunosuppression Therapy; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Quality of Life; Sirolimus; Tacrolimus; Ventricular Dysfunction, Right

To summarize the long-term efficacy and safety of tacrolimus in orthotopic liver transplant (OLT) recipients, as well as to examine the factors that influence long-term morbidity and mortality rates.. Tacrolimus (FK506, Prograf) was introduced as primary immunosuppression for primary liver transplantation in 1989; many subsequent trials have verified the association of tacrolimus with decreased rates of acute rejection and steroid-resistant rejection after OLT. Cumulative experience with tacrolimus has also defined its short- and intermediate-term toxicity.. One thousand consecutive patients undergoing primary OLT at a single center from August 1989 to December 1992, under tacrolimus immunosuppression, were followed until January 1999. Patients were categorized by age. Mean follow-up was 93.4+/-11 months after OLT. Patient survival, graft survival (with corresponding causes of death and retransplantation), and rejection rates (and corresponding doses of immunosuppression) were examined as efficacy parameters. Hypertension, renal function, incidence of malignancies, incidence of diabetes, and other toxicities were examined as safety parameters.. Actual 6-year overall patient survival rate was 68.1% and graft survival rate was 62.5%, with significant differences in the patterns of survival among the different age groups. After the first post-OLT year, infection, recurrence of disease, de novo malignancies, and cardiovascular events were the main causes of graft loss and death during the long-term follow-up. Graft loss related to either acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most were steroid-responsive. Approximately 70% of the patients were receiving tacrolimus monotherapy beyond year 1; at the latest follow-up, 74.2% were maintained on tacrolimus alone. In 6.1% of the survivors, end-stage renal disease developed during the follow-up period, requiring either dialysis or kidney transplantation. Hyperkalemia and hypertension was observed in approximately one third of the patients. Insulin-dependent diabetes mellitus (including patients who had diabetes before the transplant) was observed in 14% in year 1, dropping to 11% in year 7. In 82 patients, de novo malignancies developed; in 41 patients, lymphoproliferative disorders developed during the entire follow-up period.. Long-term patient and graft survival rates are excellent under tacrolimus immunosuppression. Pediatric patients have a better long-term outcome than adults, in part because of the limited recurrence of the original disease, which was the most common cause of late graft loss (other than patient death, most commonly the result of late de novo malignancies and cardiovascular events). Graft loss from late rejection was rare.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus

Topics: Adult; Aged; Antifungal Agents; Candidiasis; Drug Interactions; Erythromycin; Female; Humans; Immunosuppressive Agents; Ketoconazole; Kidney Transplantation; Male; Phenytoin; Postoperative Complications; Rifampin; Tacrolimus

Topics: Adult; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Cyclosporine; Data Collection; Drug Therapy, Combination; Europe; Hepatitis B; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Renal Insufficiency; Tacrolimus

Topics: Adolescent; Adult; Aged; Child; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; London; Middle Aged; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

An activated coagulation system has been implicated as a potential initiating or inciting factor in the development and progression of cardiac allograft vasculopathy (CAV).. By performing ex vivo perfusion studies of blood thrombogenicity under constant rheologic conditions and with a constant substrate, we sought to determine the relative effects on the coagulation system of FK506 vs cyclosporine in patients who have undergone cardiac transplantation.. Compared with cyclosporine, FK506 significantly decreased the propensity to form thrombus; this suggests that FK506 may have a favorable impact on the development of CAV.

Topics: Blood Coagulation; Cyclosporine; Female; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Tacrolimus; Thrombosis

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

Topics: Adolescent; Adult; Age Distribution; Aged; Antibodies, Viral; Antiviral Agents; Child; Child, Preschool; Ganciclovir; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Middle Aged; Postoperative Complications; Survival Analysis; Tacrolimus; Tissue Donors

We describe two children with intestinal failure due to short or absent small bowel who underwent isolated liver transplantation for liver disease related to parenteral nutrition. Both received reduced-size liver grafts whilst awaiting a suitable small bowel donor. Immunosuppressive therapy was based on oral tacrolimus and intravenous steroids. Therapeutic levels of tacrolimus were achieved at low dosage of 0.14-0.28 mg/kg per day. Median and mean blood tacrolimus levels were 9.9 and 13.7 ng/ml (range 4.9-42.3 ng/ml) in case 1 and 5.8 and 7.2 ng/ml (range 1-30 ng/ml) in case 2 before small bowel transplantation, respectively. Following small bowel transplantation, levels were 17.1 and 20.1 ng/ml (range 9.2-30 ng/ml), with oral doses of 0.54-1.35 mg/kg per day. Both children died of adenovirus pneumonia, with functioning grafts. Our experience demonstrates that effective levels of immunosuppression can be achieved by oral administration of tacrolimus in children with short or absent small bowel.

Topics: Adenoviridae Infections; Administration, Oral; Child, Preschool; Colon; Cyclosporine; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Absorption; Intestinal Atresia; Intestine, Small; Liver Failure; Liver Transplantation; Male; Parenteral Nutrition; Pneumonia, Viral; Postoperative Complications; Short Bowel Syndrome; Tacrolimus

Topics: Child, Preschool; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Postoperative Complications; RNA, Viral; Tacrolimus

In this study, we compare cholesterol levels during the first year after renal transplantation in FK506 (Prograf)- and cyclosporine-treated patients matched for cumulative first-year steroid dose and hypercholesterolemia risk factors. All patients had pretransplant cholesterol levels < 200 mg/dl. At 3 months posttransplant, 68% of the cyclosporine-treated patients had at least one cholesterol level greater than 200 mg/dl compared with 30% of the FK506-treated patients (P < 0.05). At the end of the year, 26% of FK506- and 67% of cyclosporine-treated patients remained hypercholesterolemic (P < 0.05). We conclude that cyclosporine has inherently more effect on cholesterol levels than FK506 during the first year after kidney transplantation.

Topics: Adult; Age Factors; Cholesterol; Cyclosporine; Diabetes Mellitus, Type 1; Female; Furosemide; Humans; Hypercholesterolemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sex Factors; Tacrolimus

One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression.. Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years).. Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07).. Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.

Topics: Adult; Aged; Analysis of Variance; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Military Personnel; Morbidity; Multivariate Analysis; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; United States

Topics: Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Pancreas Transplantation; Postoperative Complications; Risk Factors; Tacrolimus

Topics: Dermatomycoses; Granuloma; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Topics: Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Sarcoma, Kaposi; Saudi Arabia; Tacrolimus

Chronic rejection or transplant-associated coronary artery disease (TxCAD) is the most serious complication after human cardiac transplantation. Previous studies, using Western blotting, have shown formation of antibodies against endothelial antigens of 56 and 58 kDa, which are associated with early TxCAD. These antigens were later identified as being vimentin and its breakdown products. The aims of the present study were to devise a robust assay for detection of anti-vimentin antibodies and to compare antibody formation in patients taking different immunosuppressive drugs.. 106 sequential serum samples from 19 patients taking tacrolimus and 68 sera from 12 patients taking cyclosporine were examined by enzyme-linked immunosorbent assay (ELISA) for anti-vimentin antibodies and Western blotting for reactivity against bands at 56/58 kDa. Serum samples were taken before transplantation and at 1, 3, 6, 9, and 12 months.. The vimentin ELISA produced significantly higher numbers of positive episodes per patient (3.92+/-1.08) compared with use of Western blotting (2.54+/-0.52). Serum from patients taking tacrolimus contained significantly less antibodies measured by ELISA (15.8%) or Western blotting (6.5%) than sera from patients taking cyclosporine (46.8% for ELISA; P=0.001 and 21% by Western blotting, P=0.01). Intravascular ultrasound performed on six patients at 12 months showed a correlation between anti-vimentin antibody formation and detection of early coronary disease.. The results demonstrate first, that differences in antibody profiles produced by different immunosuppressive drugs, and second, that detection of anti-vimentin antibodies may be a noninvasive method of detecting disease activity in transplanted vessels.

Topics: Antibodies; Blotting, Western; Coronary Disease; Cyclosporine; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Postoperative Complications; Postoperative Period; Tacrolimus; Vimentin

The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient.. An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation.. Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicol. Chloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

Topics: Adolescent; Anti-Bacterial Agents; Bacterial Infections; Chloramphenicol; Dose-Response Relationship, Drug; Drug Interactions; Enterococcus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Peritonitis; Postoperative Complications; Tacrolimus

Topics: Animals; CDC2-CDC28 Kinases; Coronary Artery Disease; Coronary Vessels; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Endothelins; Genetic Therapy; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Oligonucleotides, Antisense; Postoperative Complications; Protein Serine-Threonine Kinases; Tacrolimus; Transfection

Topics: Adult; Antilymphocyte Serum; Azathioprine; Drug Therapy, Combination; Graft Rejection; Heart Function Tests; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Muromonab-CD3; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Administration, Oral; Adult; Azathioprine; Communicable Diseases; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Methylprednisolone; Muromonab-CD3; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Child; Child, Preschool; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Methylprednisolone; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Age Factors; Aged; Child; Creatinine; Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Infant; Liver Transplantation; Postoperative Complications; Prednisone; Survival Rate; Tacrolimus; Time Factors

Topics: Cyclosporine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Cyclosporine; Follow-Up Studies; Humans; Hypercholesterolemia; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Survivors; Tacrolimus; Time Factors

Topics: Biological Availability; Bronchiolitis Obliterans; Cyclosporine; Cystic Fibrosis; Follow-Up Studies; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adolescent; Child; Child, Preschool; Colon; Communicable Diseases; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Transplantation, Homologous

Bacterial infections complicate the course of up to 80% of pediatric liver transplant recipients, and in some cases, neutropenia, surgical complications and/or antibiotic resistance prevent successful control of sepsis. The aim of the present study was to evaluate the safety and efficacy of granulocyte macrophage colony stimulating factors (GM-CSF) in treating neutropenia following pediatric orthotopic liver transplantation.. Among a cohort of 430 pediatric orthotopic liver transplantation recipients, 13 children (12 months to 15 years, median 2 years, 10 males) received 15 courses of GM-CSF, 5 microg x kg(-1) x d(-1) subcutaneously, during their post-transplant course. In nine cases, the initial neutrophil count was below 1000/mm3. Ten patients were infected. Three received GM-CSF for severe sepsis without neutropenia. The mean duration of treatment was 16.3 days (range 4-49).. In all but one neutropenic patient the neutrophil count increased above 1500/mm3 and the mean neutrophil count increased from 1392+/-1912/mm3 (range 130-7170, median 640) to 4508+/-2459/mm3 (range 350-9630, median 4390) (p<0.01). Only one neutropenic patient (FK506 related) failed to respond to treatment. No rejection episode was induced by treatment, no side effects were noted, and patients with sepsis were cured.. In these patients, GM-CSF was safe, it achieved a significant increase in neutrophilic count, and was beneficial in patients with severe bacterial infections. This compound may prevent infectious complications in neutropenic patients and may benefit patients with severe sepsis with or without neutropenia.

Topics: Adolescent; Child; Child, Preschool; Graft Rejection; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Incidence; Infant; Leukocyte Count; Liver Transplantation; Neutropenia; Postoperative Complications; Sepsis; Survival Rate; Tacrolimus

Liver transplant recipients are at risk of chronic renal disease, principally as a result of nephrotoxicity of the commonly used immunosuppressive agents cyclosporine and tacrolimus. We have investigated the incidence of chronic renal failure and its risk factors in our transplant population, which was treated predominantly with cyclosporine.. A single-center retrospective study was done of 883 consecutive adult patients receiving a first liver transplant between 1982 and 1996. Potential risk factors for the development of chronic renal failure were recorded, including serial measurements of cyclosporine therapy and renal function.. Severe chronic renal failure (serum creatinine level >250 microM/L for at least 6 months) developed in 25 patients, representing 4% of patients surviving 1 year or more. Twelve of these patients developed end-stage renal failure and mortality was 44%. The predominant cause of renal failure was cyclosporine nephrotoxicity. Serum creatinine as early as 3 months after surgery was strongly associated with the eventual development of severe chronic renal failure (P=0.001), and this group could be further subdivided into two groups with differing risk factors. The first group had early (<1 year) renal dysfunction, with older age (P=0.03), cytomegalovirus infection (P=0.03), need for perioperative renal replacement therapy (P=0.06), and regrafting (P=0.06) as risk factors for eventual renal failure; the second group had late-onset (>1 year) renal dysfunction, with cyclosporine levels at 1 month after surgery (P=0.007) and daily and cumulative cyclosporine dosage at 5 years (P=0.01 for both) as risk factors.. With improved survival of liver transplant recipients, chronic renal failure has become an important cause of morbidity and is associated with a high mortality. Many patients at risk of severe chronic renal failure may be identified at an early stage. Treatment regimens that avoid or prevent cyclosporine-induced nephrotoxicity are urgently required for this population.

Topics: Adolescent; Adult; Aged; Cyclosporine; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

Recent advances, first and foremost the development of new immunosuppressive agents, have markedly improved the outcome of intestinal transplantation, which is a treatment option for patients with serious intestinal diseases who have become dependent on total parenteral nutrition. The first small bowel transplantation in Sweden was performed at Huddinge Hospital in 1997, in the adult patient with intestinal pseudo-obstruction. The article reports the course of this patient and an update of international progress in intestinal transplantation.

Topics: Abdominal Pain; Adult; Fatal Outcome; Female; Graft Rejection; History, 20th Century; Humans; Immunosuppressive Agents; Intestinal Mucosa; Intestinal Obstruction; Intestine, Small; Middle Aged; Postoperative Complications; Tacrolimus

Topics: Antigens, CD; CD4-CD8 Ratio; Cyclosporine; Follow-Up Studies; Hepatitis B; HLA-DR Antigens; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Lymphocyte Subsets; Postoperative Complications; Recurrence; Retrospective Studies; Tacrolimus; Time Factors

Delayed graft function is a common and severe complication after cadaveric kidney transplantation. Besides a more complicated postoperative course, DGF can worsen the overall graft survival. In particular, DGF enhances the nephrotoxicity of mainstream immunosuppressants cyclosporine and FK506. This study evaluates a new therapeutical approach to the treatment of DGF related nephrotoxicity, based on the administration of IGF-I.. Sixty inbred Lewis rats underwent a bilateral clamping of the renal pedicles (20') as standard damage. The animals were stratified in six groups, according to the postoperative treatment. Group 1 served as control and received only the standard ischemic injury. Cyclosporine and FK506 were added in groups 3 and 5. Groups 2, 4 and 6 had the same treatment of groups 1, 3, 5 respectively, plus the administration of IGF-I. Blood samples were drawn daily to evaluate creatinine and BUN for 7 days.. The rats treated with IGF-I had significantly better values compared to the respective controls (2-way ANOVA, p < 0.05).. In conclusion, IGF-I improves the nephrotoxicity of mainstream immunosuppressants in this model. Its use is potentially beneficial for transplantation.

Topics: Animals; Cyclosporine; Immunosuppressive Agents; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Kidney Transplantation; Male; Postoperative Complications; Rats; Rats, Inbred Lew; Tacrolimus

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Renal Insufficiency; Tacrolimus

Posttransplant lymphoproliferative disease (PTLD) after pediatric liver transplantation has been associated with high mortality rates.. The present study examined 282 consecutive pediatric liver transplant recipients from October 1989 to June 1996 who received primary tacrolimus immunosuppression. The aim was to determine the incidence of PTLD, management strategies, and patient outcome.. The incidence of PTLD was 13% (361282) with a mean age of 5.5+/-0.7 years (range 0.6 to 15) at diagnosis. The average time from transplantation to PTLD was 10.1+/-2.1 months. Initial treatment of PTLD consisted of reduction (3 patients) or discontinuation (33 patients) of tacrolimus and initiation of antiviral therapy (intravenous ganciclovir, 14 patients; intravenous acyclovir, 22 patients; or both, 5 patients). Alpha-interferon was used in four patients (two successfully). One patient also received gamma-interferon, chemotherapy, and radiation for a central nervous system lesion. Chemotherapy was also used in one patient with Burkitt's, whereas one patient with a pulmonary lesion received additional radiation therapy. Three patients received supportive surgery for gastrointestinal involvement, and one patient had a splenectomy for hemolysis. Overall mortality was 22% (8/36) with 5 (14%) PTLD-related deaths (disseminated disease, 4 patients; bowel perforation, 1 patient). Of 31 survivors, 23 had acute rejection at a median time of 24 days after PTLD, with 2 patients developing chronic rejection. One patient required retransplantation. Present immunosuppression consists of tacrolimus monotherapy in 14 patients, tacrolimus/prednisone in 8 patients, and none in 6 patients.. In summary, PTLD can be successfully treated with reduction of immunosuppression and administration of antiviral agents in most patients. The management of rejection after PTLD requires reassessment of disease status and judicious reintroduction of immunosuppression therapy.

Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Cohort Studies; Epstein-Barr Virus Infections; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Intestines; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Prednisone; Reoperation; Splenectomy; Survival Analysis; Tacrolimus; Treatment Outcome

A case of tacrolimus (FK 506)-induced hemolytic uremic syndrome is reported. The direct implication of tacrolimus, an alternative immunosuppressant to cyclosporine, was strongly supported by the recurrence of the syndrome after a second exposure to the treatment.

Topics: Cardiomyopathy, Dilated; Graft Rejection; Heart Transplantation; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Recurrence; Tacrolimus

Topics: ABO Blood-Group System; Adult; Blood Group Incompatibility; Cadaver; Cyclosporine; Female; Graft Survival; Heart Arrest; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Nephrectomy; Organ Preservation; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Tissue Donors

Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Muromonab-CD3; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Dehydration; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Function Tests; Kidney Transplantation; Male; Pancreas Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Adult; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies; Safety; Tacrolimus

The orthotopic liver transplantation (OLT) program of the University of Liège was initiated in 1986. Between 1986 and December 1998, 150 adult OLT have been performed in our institution, including 18 liver retransplantations, 1 combined heart and liver transplantation and 3 combined liver and kidney transplantations. The aim of this study was to report the last 3 years of our experience. From January 1996 to November 1998, we performed 50 OLT on 49 patients. Three were retransplantations and two were combined liver and kidney transplantations. Fourty-three patients were transplanted for chronic liver disease and 6 for acute or subacute hepatopathy. Mean waiting time on the list was 4 weeks. Immunosuppression was based on triple therapy (cyclosporin A/tacrolimus, steroids, azathioprine), with steroid and azathioprine withdrawal in most of the patients after 3 months. In the chronic liver disease group, operative (< 30 days) survival was 95% (peroperative myocardial infarction in 2 patients). In the acute liver disease group, postoperative survival was 66%. No perioperative death occurred in 1997 and 1998. Actuarial one year survival was 87%. In our experience, OLT has become a safe procedure.

Topics: Actuarial Analysis; Acute Disease; Adrenal Cortex Hormones; Adult; Azathioprine; Belgium; Chronic Disease; Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Transplantation; Myocardial Infarction; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus; Time Factors; Waiting Lists

The immunosuppression required to prevent rejection of intestinal transplants causes a high rate of infection and lymphoma. It is crucial that immunomodulatory strategies be developed to facilitate intestinal engraftment.. We prospectively examined the effect of unpurified donor-specific bone marrow transfusions (DSBMTs) on rejection, infection, graft-versus-host disease (GVHD), and survival after intestinal transplantations in 44 Yorkshire Landrace pigs. Four groups that differed according to presence or abscence of treatment with FK506 and DSBMT were analyzed.. In nonimmunosuppressed pigs, DSBMTs had no effect on survival (8 days versus 9 days in controls; p = 0.9). In FK506 pigs, DSBMTs tended to reduce survival (21 days versus 37 days in FK506 controls; p = 0.1); no difference was seen between two bone marrow dosages 5 x 10(7) or 5 x 10(8) bone marrow cells/kg. No difference in the incidence of death caused by rejection was seen between DSBMTs and controls, but there was a marked tendency toward more deaths caused by rejection in DSBMTs + FK506 versus FK506-only pigs (p = 0.09). Daily stomal assessment showed a higher rate of moderate and severe interstitial rejection in DSBMT + FK506 versus FK506-only pigs; DSBMT was also associated with increased vascular rejection. Finally, groupwise comparison showed an order of susceptibility to lethal GVHD and infection as follows: DSBMT + FK506 > FK506 > DSBMT > controls.. Rather than promoting engraftment, DSBMT can sensitize recipients and cause rejection after intestinal transplantation. It aggravates the risks of generalized GVHD and infection and tends to reduce graft and recipient survival. Before being applied clinically, DSBMT needs to be refined to increase its tolerogenic potential without causing GVHD.

Topics: Animals; Bone Marrow Transplantation; Graft Rejection; Graft vs Host Disease; Immunosuppressive Agents; Infections; Intestines; Postoperative Complications; Survival Analysis; Swine; Tacrolimus; Time Factors; Tissue Donors

Immunosuppression has been sporadically discontinued by noncompliant liver allograft recipients for whom an additional 4 1/2 years of follow-up is provided. These anecdotal observations prompted a previously reported prospective drug withdrawal program in 59 liver recipients. This prospective series has been increased to 95 patients whose weaning was begun between June 1992 and March 1996, 8.4+/-4.4 (SD) years after liver replacement. A further 4 1/2 years follow-up was obtained of the 5 self-weaned patients. The prospectively weaned recipients (93 livers; 2 liver/kidney) had undergone transplantation under immunosuppression based on azathioprine (AZA, through 1979), cyclosporine (CsA, 1980-1989), or tacrolimus (TAC, 1989-1994). In patients on CsA or TAC based cocktails, the adjunct drugs were weaned first in the early part of the trial. Since 1994, the T cell-directed drugs were weaned first. Three of the 5 original self-weaned recipients remain well after drug-free intervals of 14 to 17 years. A fourth patient died in a vehicular accident after 11 years off immunosuppression, and the fifth patient underwent retransplantation because of hepatitis C infection after 9 drug-free years; their allografts had no histopathologic evidence of rejection. Eighteen (19%) of the 95 patients in the prospective series have been drug free for from 10 months to 4.8 years. In the total group, 18 (19%) have had biopsy proved acute rejection; 7 (7%) had a presumed acute rejection without biopsy; 37 (39%) are still weaning; and 12 (13%, all well) were withdrawn from the protocol at reduced immunosuppression because of noncompliance (n=8), recurrent PBC (n=2), pregnancy (n=1), and renal failure necessitating kidney transplantation (n=1). No patients were formally diagnosed with chronic rejection, but 3 (3%) were placed back on preexisting immunosuppression or switched from cyclosporine (CsA) to tacrolimus (TAC) because of histopathologic evidence of duct injury. Two patients with normal liver function died during the trial, both from complications of prior chronic immunosuppression. No grafts suffered permanent functional impairment and only one patient developed temporary jaundice. Long surviving liver transplant recipients are systematically overimmunosuppressed. Consequently, drug weaning, whether incomplete or complete, is an important management strategy providing it is done slowly under careful physician surveillance. Complete weaning from CsA-based regimens has been di

Topics: Adult; Analysis of Variance; Azathioprine; Child; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Liver Transplantation; Postoperative Complications; Prednisone; Pregnancy; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Proteinuria; Tacrolimus

A 40-year-old Asian man, 6 months post renal transplant and receiving tacrolimus therapy, presented to the emergency department with a complaint of sudden-onset left eye pain with blurred vision, headache on the left side, and nausea and vomiting. On being admitted, the patient was intubated for respiratory depression, and erythromycin was initiated for suspected atypical pneumonia. Tacrolimus concentrations (whole blood) drawn on the 3rd day of hospitalization were reported to be > 60.0 ng/ml. Before hospitalization, tacrolimus concentrations were reported to be 9.8 ng/ml on a maintenance dose of 7 mg twice daily. Six days after discontinuation of erythromycin and a decrease in tacrolimus dose, the concentration decreased to 11.5 ng/ml and the original dose of tacrolimus was restarted. It is recommended that concurrent administration of erythromycin and tacrolimus be avoided. However, if concomitant therapy is necessary, tacrolimus concentrations, serum creatinine, blood urea nitrogen, and urine output should be monitored.

Topics: Adult; Anti-Bacterial Agents; Drug Interactions; Erythromycin; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pneumonia; Postoperative Complications; Tacrolimus

Tacrolimus has a negative effect on the pancreatic beta islet cell, and both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid organ transplant recipients.. To determine the association between tacrolimus and new-onset diabetes mellitus in childhood, we reviewed data on 78 pediatric heart and heart-lung/lung recipients receiving tacrolimus-based immunosuppression. Trough tacrolimus levels, fasting and random blood glucose levels, and corticosteroid requirements were reviewed. Diabetes was defined as glucose intolerance requiring long-term insulin treatment more than 30 days after transplantation.. No patient had diabetes before introduction of tacrolimus. In heart-lung/lung recipients, 12 of 28 (43%) had development of diabetes at a median follow-up of 7 months (range 1 to 39). In this group diabetes developed in three of eight (38%) patients with cystic fibrosis and nine of 20 (45%) without (p = NS). In contrast, only two of 50 (4%) heart transplant recipients had development of diabetes. Of the 14 patients with diabetes, 10 had development of diabetes during augmentation of immunosuppression with pulsed corticosteroids. Tacrolimus trough levels were significantly lower in heart compared with heart-lung/lung transplant recipients (9.4 +/- 3.3 versus 15.3 +/- 0.9 ng/ml) (p < 0.01), and at latest follow-up significantly fewer heart transplant recipients were treated with maintenance corticosteroids (28% versus 75%; p < 0.01). In the heart-lung/lung group, no significant difference in tacrolimus levels was found between patients with and without diabetes, nor was there a significant difference in the average corticosteroid dose or number of pulses of corticosteroids per patient.. New-onset diabetes mellitus is rare in pediatric heart transplant recipients receiving tacrolimus-based immunosuppression, but it occurs with a high incidence after pediatric heart-lung/lung transplantation and usually develops during pulsed corticosteroid therapy. However, it is currently not possible to predict which heart-lung/ lung transplant recipients will have development of this serious complication.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cystic Fibrosis; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucose Tolerance Test; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Infant; Islets of Langerhans; Lung Transplantation; Male; Postoperative Complications; Risk Factors; Tacrolimus

Exclusion of occult diseases in the donor organ and prevention of infectious disease transmission are minimal requirements in organ transplantation. We report here a case of hepatic graft tuberculosis, which was most likely transmitted by the graft from the living-related donor. The course of the recipient included tuberculosis, rejection, and other infections, which led to vanishing bile duct syndrome. Due to various infections and tuberculosis, as well as a strong interaction between rifampicin and tacrolimus, the patient died of pneumonia on day 273 after transplantation. This case emphasizes the importance of care in the selection of a living-related donor for liver transplantation.

Topics: Adult; Drug Interactions; Fatal Outcome; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Function Tests; Liver Transplantation; Living Donors; Mothers; Postoperative Complications; Rifampin; Tacrolimus; Tuberculosis

Atypical Epstein-Barr virus (EBV) infection developed in a patient under intermittent administration of FK506 (one dose in 10 days) after living-related liver transplantation. The clinical course was similar to severe chronic active EBV infection syndrome (SCAEBV), which is characterized by extremely high titers of antibody to EBV antigens. The clinical symptoms improved without graft rejection even after the cessation of FK506; however, the titers of antibody to EBV antigens remained at high levels. It was considered that: (i) even intermittent use of FK506 could influence the immune response, which then induced atypical EBV infection similar to SCAEBV; and (ii) the impaired immune response, especially to EBV antigens, remained after complete cessation of FK506.

Topics: Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Polymerase Chain Reaction; Postoperative Complications; Receptors, IgE; Serologic Tests; Tacrolimus

Chronic lung allograft rejection manifested by sustained declines in lung function is the most common cause of late death after lung transplantation. Numerous strategies have shown variable results. We sought to evaluate the effect of FK506 (tacrolimus) on bronchiolitis obliterans syndrome (BOS) after lung transplantation.. A single-center open study was conducted of 15 patients whose treatment was converted to tacrolimus from cyclosporine. Of the 15, 12 patients had BOS characterized by sustained loses in lung function while receiving cyclosporine. Rate of decline of forced expiratory volume in 1 second (FEV1) for the 12 patients was calculated before and after administration of tacrolimus. Biochemical changes before and after conversion were compared for the entire group.. Median monthly rate of decline in FEV1 was significantly reduced after administration of tacrolimus (5.3% vs 1.1%; p = 0.002). Forced vital capacity did not change significantly. No subjects experienced at least a 10% improvement in FEV1. At least a 10% further decline in FEV1 was noted in five subjects, and seven subjects had no change (i.e., within 10% of baseline). A minor nonsignificant increase in creatinine occurred after administration of tacrolimus. Blood cell count, electrolytes, and liver enzymes remained unchanged. The median change in fasting blood glucose was +0.7 mmol/L (p = 0.02).. Although tacrolimus does not reverse changes in FEV1 with BOS, in this nonrandomized study it seemed to be associated with a decrease in the rate of decline in lung function and no significant sustained toxicity. Further studies are necessary to substantiate this observation.

Topics: Adult; Bronchiolitis Obliterans; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Spirometry; Tacrolimus; Treatment Outcome

Topics: Florida; Follow-Up Studies; Graft Rejection; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus

In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) "rescue" immunosuppression were assessed. Recipients were 22+/-18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDX fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The "rescue" regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) "Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts" as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The deltaFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05).. The deltaFEV1/month slopes were -0.0687+/-0.0221 and +0.0300+/-0.033 L/mo (mean+/-SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage IIIb died of hypercapnic respiratory failure at 6 and 8 months after conversion.. The deltaFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT "Staging of OB Syndrome" may have significant clinical implications vis-à-vis prognosis and potential therapies.

Topics: Bronchiolitis Obliterans; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Prevalence; Societies, Medical; Tacrolimus; Treatment Outcome

Graft arteriopathy limits the long-term survival of allograft recipients. Cardiac allografts in mice develop graft coronary arteriopathy similar to that observed in clinical chronic rejection in human beings. We found that antiintercellular adhesion molecule-1 (ICAM-1) and antilymphocyte function-associated antigen-1 (LFA-1) monoclonal antibodies (mAbs) induce immunologic tolerance to mice with cardiac allografts.. To evaluate the effects of short-term administration of anti-ICAM-1 plus anti-LFA-1 mAbs in preventing graft arteriopathy, we treated C3H/He mice that received cardiac allografts from BALB/c mice with anti-ICAM-1 plus anti-LFA-1 mAbs for the first 5 days after transplantation. For control studies, FK506 was administered daily to other allograft recipients. Allografts were harvested on day 60. Immunohistochemical analysis was used to detect the expression of ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and in situ reverse transcriptase polymerase chain reaction was performed to detect platelet-derived growth factor (PDGF)-B mRNA expression in the graft arteries.. Allografts from mice that received FK506 treatment daily showed significant neointimal thickening with increased expression of ICAM-1, VCAM-1, and PDGF-B mRNA, whereas there was almost no intimal thickening and ICAM-1, VCAM-1, and PDGF-B mRNA expression in the mice that received anti-ICAM-1 plus anti-LFA-1 mAbs.. Short-term blockade of ICAM-1 and LFA-1 adhesion not only induces immunologic tolerance to cardiac allografts but also prevents graft arteriopathy.

Topics: Animals; Antibodies, Monoclonal; Coronary Artery Disease; Graft Rejection; Heart Transplantation; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Platelet-Derived Growth Factor; Postoperative Complications; RNA, Messenger; Tacrolimus; Transplantation, Heterotopic

Bile acids are synthesized and secreted by the liver. During liver failure and hepatic dysfunction, a marked reduction of bile acid synthesis has been shown. The purpose of this study was to determine whether the biliary bile acid pattern was affected by preservation injury and rejection and whether it was a reliable marker for graft function in pediatric liver recipients after liver transplantation.. We prospectively measured the biliary bile acid pattern in 126 serial bile samples obtained from 15 consecutive pediatric liver recipients by reversed phase high pressure liquid chromatography and correlated our results with clinical findings: preservation injury, no rejection, rejection, or infection.. There was a significant change of the bile acid pattern during the first 3 days after transplant. Total biliary bile acids, cholic acid (CA), and CA/chenodeoxycholic acid (CDCA) ratio increased in 12 of 15 patients with mild preservation injury. These changes of the bile acid pattern were markedly delayed in patients with severe preservation injury. During 16 rejection episodes, total biliary bile acid, CA, and CA/CDCA ratio decreased significantly, but returned to normal after successful treatment of rejection. Bacterial infection, observed in nine children, and cyclosporine toxicity, observed in three children, seemed to have no affect on the biliary bile acids.. Liver cell damage as a result of preservation injury or rejection leads to a reduction of biliary CA, resulting in a decrease of total biliary bile acids and the CA/CDCA ratio in pediatric liver recipients. This might be caused by a diminished secretion of bile acids and by a decreased synthesis of bile acids.

Topics: Adolescent; Bile Acids and Salts; Child; Child, Preschool; Cholic Acid; Cholic Acids; Chromatography, High Pressure Liquid; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Ischemia; Liver; Liver Transplantation; Male; Postoperative Complications; Prospective Studies; Tacrolimus

Small bowel transplantation has become a life-saving procedure for selected adults and children with intestinal failure who are intolerant to parental nutrition. There are few pediatric data available on the results of this procedure. In this article we review the background of intestinal transplantation, present the results from the University of Western Ontario in London, Ontario and the University of Miami in Miami, Florida, and discuss some future directions. The majority of successful transplants are fully functional, and these children are able to assume a normal diet.

Topics: Child; Child, Preschool; Cytomegalovirus Infections; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Intestine, Small; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Tacrolimus (formerly known as FK506) is a macrolide immunosuppressant that has been used to prevent rejection of solid organ allografts. Acute hemolytic anemia is one of the side effects associated with tacrolimus therapy, and two mechanisms have been described to account for acute hemolytic anemia in patients receiving tacrolimus: drug-induced hemolysis and alloimmune hemolysis resulting from donor lymphocytes derived from the allograft (passenger lymphocyte syndrome). We report a case of a liver transplant recipient who developed fatal autoimmune hemolytic anemia while under treatment with tacrolimus for allograft rejection, and in whom postmortem examination revealed a clinically unsuspected posttransplant lymphoproliferative disorder. This case implicates autoimmune hemolytic anemia as a novel mechanism of acute hemolysis in patients treated with tacrolimus and further suggests that acute hemolytic anemia in this group of patients may herald an occult lymphoproliferative disorder.

Topics: Anemia, Hemolytic, Autoimmune; Child; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Tacrolimus

The authors report on experience with liver transplantation for infants younger than 1 year of age.. Over the last 15 years, orthotopic liver transplant has become the only lifesaving procedure available for infants with end-stage liver disease. Many transplant centers initially required infants to reach a specific weight or age to minimize morbidity and mortality. Size-appropriate infant donors also were uncommon. As a result, many children, in the first few years of life, died of their disease. The availability of reduced-size cadaveric and living-related liver transplants has offered the ability to transplant the young infant with liver failure.. The authors instituted a program to aggressively transplant infants with liver failure in the first year of life using both cadaveric and living-related liver donors.. Between June 1991 and January 1995, 13 infants were transplanted for rapidly progressive liver failure. Infant age ranged from 4 to 11 months (mean, 7.5 months). The cause of liver failure included biliary atresia (11), alpha 1-antitrypsin deficiency (1), and liver failure secondary to echovirus 7 (1). The United Network for Organ Sharing status at the time of transplant ranged from status 4, intensive care unit bound (4 patients); status 3, hospitalized (4 patients); or status 2, failing at home (5 patients). Six patients (46%) received cadaveric whole organ (2) or segmental transplants (4). Seven patients (54%) received left lateral segment living-related transplants from parental donors. After operation, patients received cyclosporine or FK506-based immunosuppression. Three patients (23%) required four retransplants (two cadaveric for primary nonfunction; one living-related for graft thrombosis in the face of fungal infection and bile leak). Postoperative complications included primary nonfunction (15%), rejection (85%), graft vascular thrombosis (15%, two of three revascularized successfully), bacterial and fungal infections (77%), and viral infections (46%). Epstein-Barr virus-associated lymphoproliferative developed in two patients (15%). Intestinal perforation requiring reoperation developed in two patients (15%). Bile leaks requiring reoperation or transhepatic stinting or both developed in three patients (23%). Two patients died in the perioperative period (< 1 month) from a combination of primary nonfunction or graft thrombosis and sepsis. Overall survival was 85%, ranging from 11.0 months to 4.5 years.. Orthotopic liver transplantation in infants younger than 1 year of age poses significant challenges from technical and infectious complications. Despite these barriers, overall patient survival is comparable to that of older children and adults.

Topics: Biliary Atresia; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Topics: Adolescent; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Tolerance Test; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors

Topics: Animals; Drug Therapy, Combination; Graft Survival; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Macaca; Methotrexate; Papio; Pneumonia; Pneumothorax; Postoperative Complications; Splenectomy; Surgical Wound Infection; Tacrolimus; Transplantation, Heterologous

Topics: Actuarial Analysis; Age Factors; Antihypertensive Agents; Blood Pressure; Cyclosporine; Female; Follow-Up Studies; Graft Survival; Humans; Hypertension; Incidence; Kidney Transplantation; Male; Postoperative Complications; Risk Factors; Sex Factors; Tacrolimus; Time Factors

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

Topics: Adolescent; Child; Child, Preschool; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Muromonab-CD3; Postoperative Complications; Reoperation; Risk Factors; Salvage Therapy; Survival Analysis; Tacrolimus; Treatment Outcome; Tumor Virus Infections

The incidence and potential risk factors of Pneumocystis carinii pneumonia (PCP) in our population of renal transplant recipients were analyzed retrospectively. Of 1427 patients who received transplants between January 1986 and June 1994, 1192 were evaluated. Four different immunosuppressive regimens were applied: (1) cyclosporine (CsA) + prednisolone (Pred), (2) CsA + azathioprine (Aza, 2 mg/kg/day) + Pred, (3) CsA + Aza + antithymocyte globulin, and (4) (after December 1, 1993, European multicenter trial) FK506 + Aza (1 mg/kg/day) + Pred. No prophylaxis against PCP was performed. Before December 1, 1993, three PCPs in 494 patients on protocol 2 or 3 occurred (0.6%). Afterward, seven PCPs in 77 patients occurred (9%): three in 38 patients on protocol 2 (7.8%) and four in 28 patients on protocol 4 (14.3%). Comparing patients with PCP on CsA and FK506, the mean Aza dose was 2.40 and 1.32 mg/kg/day, five and two patients received additional steroids, antibody treatment was used in three and no patients, and CMV infections occurred in five and two patients, respectively. The incidence of PCP with a moderate CsA-based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors. Despite a general increase of PCP, its incidence was highest in patients on FK506 with fewer immunosuppressive cofactors. Thus, prophylaxis against PCP after renal transplantation should be performed, if not in every renal transplant recipient, at least in case of treatment with additional steroids, antibodies, or FK506.

Topics: Adult; Female; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Pneumonia, Pneumocystis; Postoperative Complications; Retrospective Studies; Tacrolimus

In immunocompromised HIV-infected and transplanted patients, there is a risk of developing Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) and lymphomas. EBV has previously been detected by the polymerase chain reaction (PCR) in cerebrospinal fluid from all AIDS patients with EBV-associated cerebral lymphomas. We therefore thought it would be of interest to determine whether transplant patients with extracerebral EBV-associated LPD have detectable EBV genomes in serum. Nested PCR (nPCR) showed that 58% (18/31) of liver transplant (LTX) patients had EBV DNA in 17% (21/125) of serum samples obtained within the first 3 months after LTX. In 39% (7/18) of the patients, the first EBV nPCR-positive sample was found within 2 weeks post-LTX. Basic immunosuppression with cyclosporin A or FK506 did not seem to influence the frequency of detectable EBV genomes in serum. In contrast, positive EBV nPCR correlated to secondary OKT3 treatment for severe acute rejection (P = 0.009). EBV-associated malignant lymphoma developed in three patients 2-6 months post-LTX. In all of them, EBV DNA was amplifiable within 12-14 days after LTX. The EBV antibody titers were not directly related to detectable EBV DNA in serum. We conclude that monitoring of LTX patients receiving increased immunosuppression by nPCR for EBV DNA in serum may help in the early identification of those at risk of developing EBV-associated LPD.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antigens, Viral; Child; Child, Preschool; Cyclosporine; DNA, Viral; Female; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Infant; Infections; Liver Transplantation; Lymphoma, B-Cell; Male; Middle Aged; Muromonab-CD3; Polymerase Chain Reaction; Postoperative Complications; Postoperative Period; Survival Rate; Tacrolimus; Tumor Virus Infections; Viral Proteins; Viremia; Virus Activation

Topics: Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Ischemia; Kidney; Kidney Transplantation; Middle Aged; Muromonab-CD3; Postoperative Complications; Tacrolimus

The effects of low dose FK506 therapy (0.1 mg/ kg/day x 1 day) on graft survivals were analyzed, and the feasibility of splenectomy was assessed. ACI strain liver grafts were orthotopically implanted into LEW male rat recipients. In the control group, the survival period was 10.4 +/- 1.4 days. In the group treated with splenectomy, the survival period was 13.4 +/- 2.0 days. In the groups with low dose FK506 therapy, the survival periods were 22.7 +/- 6.7 and 39.7 +/- 6.3 days with or without splenectomy, respectively. Rats in the group with average dose FK506 (1.0 mg/kg/day x 7 days) survived more than 100 days. In summary, the effect of low dose FK506 therapy was relatively limited. Splenectomy by itself was marginally effective; however, this effect was enhanced when combined with low dose FK506 therapy.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Graft Rejection; Graft Survival; Immunosuppressive Agents; Jaundice; Liver Transplantation; Male; Postoperative Complications; Rats; Splenectomy; Tacrolimus

Topics: Animals; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Postoperative Complications; Steroids; Swine; Tacrolimus; Transplantation, Homologous

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Infant; Intestine, Small; Male; Peritonitis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Adult; Central Nervous System Diseases; Cerebrospinal Fluid; Electroencephalography; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Postoperative Complications; Tacrolimus; Transplantation

Topics: Adolescent; Adult; Cyclosporine; Female; Follow-Up Studies; Hepatolenticular Degeneration; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Nervous System Diseases; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Antibiotics, Antitubercular; Drug Interactions; Ethambutol; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Isoniazid; Liver Transplantation; Living Donors; Mycobacterium tuberculosis; Postoperative Complications; Rifampin; Streptomycin; Tacrolimus; Tuberculosis

Topics: Biopsy; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Carcinoma, Hepatocellular; Cyclosporine; Graft Rejection; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Postoperative Complications; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus

Topics: Carcinoma, Hepatocellular; Cyclosporine; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma; Neoplasms; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Reported side-effects of tacrolimus, a potent immunosuppressive agent, have not included cardiotoxicity. We describe 5 consecutive paediatric transplant recipients (3 small bowel with or without liver and 2 liver) who received tacrolimus. 2 developed congestive heart failure and hypertrophic obstructive cardiomyopathy which resolved after changing to cyclosporin. In the other 3 patients the cardiomyopathy regressed or improved with a lower dose of tacrolimus or after stopping the drug.

Topics: Blood Pressure; Cardiomyopathy, Hypertrophic; Child, Preschool; Colon; Echocardiography; Female; Heart Failure; Humans; Infant; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

Topics: Antibodies, Viral; Cytomegalovirus Infections; Follow-Up Studies; Ganciclovir; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Kidney Transplantation; Liver Transplantation; Methylprednisolone; Postoperative Complications; Tacrolimus; Time Factors

Hypertension is common after orthotopic liver transplantation and may be due, in part, to cyclosporin A-induced renal dysfunction and/or enhanced proximal tubular sodium reabsorption. To determine whether enhanced proximal tubular sodium reabsorption is central to the development of posttransplant hypertension, measurements of renal hemodynamics and fractional clearances of lithium and sodium were compared 1 month after orthotopic liver transplantation in previously normotensive patients receiving either cyclosporin A (N = 24) or FK506 (N = 18), an immunosuppressive agent that is structurally unlike cyclosporin A and that has a lower reported incidence of hypertension. Median prednisone doses were 20 and 13 mg/day in the cyclosporin A and FK506 groups, respectively (P < 0.05). At 1 month, mean arterial blood pressure was higher in the cyclosporin A versus the FK506 group: 108 +/- 2 versus 95 +/- 3 mm Hg (P < 0.05). GFR, RBF, and renal vascular resistance were not different between the two groups: 59 +/- 4 and 53 +/- 5 mL/min per 1.73 m2, 439 +/- 28 and 440 +/- 41 mL/min per 1.73 m2, and 22,429 +/- 1,822 and 22,977 +/- 3,506 dyne s/cm5 per 1.73 m2, respectively. Fractional lithium excretion was similar in the cyclosporin A and FK506 groups: 19.9 +/- 2.2 and 19.4 +/- 2.0% (P = not significant) although both values were lower than those of normal controls (25.5 +/- 1.1%) (P < 0.05). Fractional sodium excretion was 2.7 +/- 0.3 and 2.3 +/- 0.4% in the cyclosporin A and FK506 groups, respectively (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Case-Control Studies; Cyclosporine; Electrolytes; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Circulation; Sodium; Tacrolimus

Topics: Adolescent; Humans; Liver Transplantation; Male; Postoperative Complications; Rubella; Tacrolimus

Topics: Adult; Bacterial Infections; Female; Follow-Up Studies; Graft Rejection; Humans; Intestine, Small; Male; Middle Aged; Mycoses; Postoperative Complications; Prednisone; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors; Virus Diseases

Outcome after renal transplantation in children has been variable. We undertook a retrospective study of our experience over the past five years.. From January 1, 1988, to October 15, 1992, 60 renal transplantations were performed upon 59 children at the Children's Hospital of Pittsburgh. Twenty-eight (47 percent) of the kidneys were from cadaveric donors, and 32 (53 percent) were from living donors. The recipients ranged in age from 0.8 to 17.4 years, with a mean of 9.8 +/- 4.8 years. Forty-six (77 percent) recipients were undergoing a first transplant, while 14 (23 percent) received a second or third transplant. Eight (13 percent) of the patients were sensitized, with a panel reactive antibody of more than 40 percent. Eleven of the 14 patients undergoing retransplantation and seven of the eight patients who were sensitized received kidneys from cadaveric donors. Thirty-three (55 percent) patients received cyclosporine-based immunosuppression, and 27 (45 percent) received FK506 as the primary immunosuppressive agent.. The median follow-up period was 36 months, with a range of six to 63 months. The one- and four-year actuarial patient survival rate was 100 and 98 percent. The one- and four-year actuarial graft survival rate was 98 and 83 percent. For living donor recipients, the one- and four-year actuarial patient survival rate was 100 and 100 percent; for cadaveric recipients, it was 100 and 96 percent. Corresponding one- and four-year actuarial graft survival rates were 100 and 95 percent for the living donor recipients and 96 and 69 percent for the cadaveric recipients. Patients on cyclosporine had a one- and four-year patient survival rate of 100 and 97 percent, and patients on FK506 had a one- and three-year patient survival rate of 100 and 100 percent. Corresponding one- and four-year actuarial graft survival rates were 100 and 85 percent in the cyclosporine group, while one- and three-year actuarial graft survival rates were 96 and 84 percent in the FK506 group. The mean serum creatinine level was 1.24 +/- 0.64 mg per dL; the blood urea nitrogen level was 26 +/- 13 mg per dL. The incidence of rejection was 47 percent; 75 percent of the rejections were steroid-responsive. The incidence of cytomegalovirus was 10 percent. The incidence of post-transplant lymphoproliferative disorder was 8 percent. None of the patients on cyclosporine were able to be taken off prednisone; 56 percent of the patients receiving FK506 were taken off prednisone successfully. Early growth and development data suggest that the patients receiving FK506 off prednisone had significant gains in growth.. These results support the idea that renal transplantation is a successful therapy for end-stage renal disease in children. They also illustrate the potential benefits of a new immunosuppressive agent, FK506.

Topics: Adolescent; Child; Child, Preschool; Humans; Immunosuppression Therapy; Infant; Kidney Failure, Chronic; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

This prospective study characterizes the incidence, etiology, timing, risk factors, and outcome of the infectious complications after 88 consecutive liver transplantations in 79 patients receiving tacrolimus (FK506) as primary immunosuppression with a median follow-up of 880 days. Infections occurred in 59% (47/79) of the patients, and 39% had major infections. Of the major infections, 55% were bacterial, 22% were viral, and 22% were fungal. Bacteremia accounted for 30% of major bacterial infections. Sixty percent of bacteremias occurring within the first 3 months were catheter related, while 75% of those occurring more than 3 months after transplant were of a biliary source. Patients with recurrent hepatitis C virus hepatitis and patients requiring dialysis after transplant had a significantly higher rate of infections as compared with other patients. Overall mortality was 18%, and 29% of all deaths were associated with infection. Only invasive aspergillosis was associated with infectious mortality. Our data suggest that the potent immunosuppressive agent FK506 is not associated with a higher incidence of infectious complications as compared with previous studies using CsA.

Topics: Adult; Aged; Bacterial Infections; Female; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Infections; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Prospective Studies; Risk Factors; Survival Rate; Tacrolimus; Treatment Outcome; Virus Diseases

Topics: Administration, Oral; Biopsy; Cholestasis; Cyclosporine; Humans; Immunosuppression Therapy; Intestinal Absorption; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Graft rejection remains a major problem in liver transplantation. The frequency of acute rejection is of the order of 50%. The first episode usually occurs around the 7th day. The diagnosis, suggested by clinical signs and biochemical abnormalities, is confirmed by histology. Three fundamental histological lesions are usually observed: portal infiltrate, biliary lesions and endothelitis. Chronic liver rejection is characterised by progressive reduction in the number of interlobular bile ducts. It affects 5 to 15% of transplant recipients, is refractory or poorly responsive to current immunosuppressant treatments and usually requires retransplantation. Prophylactic immunosuppression usually consists of a triple combination of cyclosporin-azathioprine-corticosteroids. FK 506 has been recently proposed. Corticosteroids inhibit the synthesis of interleukin 1 and reduce the synthesis of mediators of inflammation. Azathioprine is an antimetabolite which inhibits T lymphocyte cell division. Cyclosporin decreases lymphokine secretion. FK 506 can be used to treat acute rejection resistant to other immunosuppressants and may prevent chronic rejection. Cyclosporin is started at low doses and gradually increased until the desired serum concentration is obtained. Regular monitoring of serum cyclosporin levels is essential to reduce the adverse effects of this drug. The doses of corticosteroids are gradually decreased to achieve a maintenance dose (10-30 mg/day). Azathioprine is commenced postoperatively (0.5 to 1.5 mg/kg/day). In the long term, azathioprine should be suspended and the dosage of corticosteroids should be reduced. The initial treatment of rejection consists of bolus injections of corticosteroids: 10 to 15 mg/kg/day of i.v. methylprednisolone for 2 or 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adrenal Cortex Hormones; Azathioprine; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Liver Transplantation; Postoperative Complications; Tacrolimus; Transplantation, Homologous

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Cyclosporine; Drug Administration Schedule; Graft Rejection; Graft Survival; Hepatitis B; Hepatitis B Surface Antigens; Humans; Immunosuppression Therapy; Liver Failure; Liver Transplantation; Postoperative Complications; Prednisolone; Receptors, Interleukin-2; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

To study the neurological sequelae in liver transplanted recipients, 25 patients were followed up between 5 and 30 months after transplantation and another 14 patients were seen before and after transplantation. Physical examination took special note of tremor and polyneuropathy; additionally, patients estimated concentration and memory, tremor, paraesthesias and sleep disturbances on a self-rating scale. Tremor was reported to be preexistent in 50% of the later FK 506 and cyclosporin group and only temporarily rose afterwards. Twenty-eight percent complained of tremor and 20% said that it interfered mildly with daily activity. Only 2 of 39 patients showed new signs of polyneuropathy. Concentration and memory improved significantly after transplantation. In the second group of patients, MRI, EEG, lumbar puncture and neuropsychological tests were done just before and routinely after transplantation, revealing numerous preexisting neurological deficits with only singular changes afterwards.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Nervous System Diseases; Neurologic Examination; Physical Examination; Postoperative Complications; Tacrolimus; Time Factors

Topics: Azathioprine; Biopsy; Creatinine; Cyclosporine; Graft Rejection; Humans; Kidney Transplantation; Nephrotic Syndrome; Pilot Projects; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Transplantation, Homologous

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14%) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67%. In children with congenital heart disease (> 6 months of age) the perioperative (30 day) mortality was 66% before mid-1988 (n = 10) and 0% since mid-1988 (n = 11). The late mortality (> 30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66% (n = 14) and 7% since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82% in children with congenital heart disease and 90% in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82% at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60% at 3 and 6 months after transplantation versus 20% and 12%, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83%) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4% in the FK 506 group versus 70% in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression.

Topics: Adolescent; Cardiomyopathies; Child; Child, Preschool; Cyclosporine; Extracorporeal Membrane Oxygenation; Female; Graft Rejection; Heart Defects, Congenital; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Infections; Kidney; Lymphoproliferative Disorders; Male; Postoperative Complications; Tacrolimus

During the time 1989 to 1992 we collected PAP smears of 58 women before and several times after a liver transplantation. Five of the patients (= 8.6%) showed a suspicious PAP smear, although pre-transplantation they had a normal cervical cytology. Histological one woman even had a higher grade dysplasia. 30 women received FK 506 after the liver transplantation, 28 patients Cyclosporin A as long-term medication. Likewise kidney and liver transplanted women have a higher risk to be affected by a cervical neoplasia. A acceleration of malignant growth seems to be likely. The influence on the cervical cells of both immunosuppressive drugs Cyclosporin A (Sandimmun) and FK 506 seem to be similar. It should be recommended to perform a close-meshed cervical cytology control when following -up the female liver transplant recipients.

Topics: Adolescent; Adult; Aged; Cervix Uteri; Cyclosporine; Female; Follow-Up Studies; Humans; Liver Transplantation; Middle Aged; Neoplasm Staging; Papanicolaou Test; Postoperative Complications; Precancerous Conditions; Risk Factors; Smoking; Tacrolimus; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears

Intestinal transplantation, solitary (n = 3) or in combination with the liver (n = 7), was performed in 10 pediatric patients with intestinal failure. The liver was only replaced if there was liver failure and portal hypertension. Immunosuppression was based on FK 506. Two patients died, one of graft-versus-host disease and one of lymphoproliferative disease. One patient as still in the intensive care unit 1 month posttransplantation due to perioperative complications. The function of the intestinal grafts in the remaining patients is normal. All nutrition and medications including immunosuppression are being administered enterally. This series indicates that small bowel transplantation, alone or in combination with the liver, is feasible in pediatric patients.

Topics: Child; Child, Preschool; Female; Graft Rejection; Humans; Immunosuppression Therapy; Infant; Intestine, Small; Liver Transplantation; Male; Parenteral Nutrition, Total; Postoperative Complications; Tacrolimus

Thirty-seven primary renal transplant patients were enrolled in the early phase II study on kidney transplantation. All grafts survived during the follow-up period. However, 10 of the 37 patients were changed from FK 506 to conventional drugs, and 3 were treated concomitantly with azathioprine (AZA) or mizoribine (MZR) in the 3-month period of observation. After 3 months posttransplantation, an additional 10 patients were treated continuously with AZA or MZR. In addition, 3 were converted from FK 506 to conventional drugs. No additional conversion was observed after 4 months. Trough level monitoring was effective enough to regulate the FK 506 dosage. Nephrotoxicity and hyperglycemia were associated with a high trough level of FK 506 (whole blood, > 20 ng/ml).

Topics: Azathioprine; Cadaver; Creatinine; Drug Therapy, Combination; Follow-Up Studies; Histocompatibility Testing; Humans; Immunosuppressive Agents; Isoantibodies; Japan; Kidney Transplantation; Living Donors; Postoperative Complications; Prednisolone; Tacrolimus; Time Factors; Tissue Donors

The authors performed 20 liver transplantations from living related donors between June 1990 and July 1991. The 20 pediatric patients (14 biliary atresia, two Budd-Chiari syndrome, one liver cirrhosis after hepatitis C viral infection (HCV hepatitis), 1 progressive intrahepatic cholestasis, 1 liver cirrhosis, 1 protoporphyria) were transplanted with 11 left lobes, eight left lateral segments, and one right lobe. The choice of donors was restricted to the parents of the recipients. The immunosuppressive treatment consisted of FK 506 and steroids. Seventeen recipients are alive, 15 of whom are well and at home. Two recipients, who underwent emergency transplantation, died of postoperative complications. Another recipient died of accidental asphyxia at 6 months after the transplantation. All 20 donors had uneventful postoperative courses and were able to resume their normal social lives. The arterial ketone body ratio (AKBR) increased to above 1.0 within 2 days after the transplantation in all cases. Relatively mild rejection episodes were encountered in only two cases transplanted with ABO-compatible grafts, and these were treated successfully with steroids and FK 506.

Topics: Adolescent; Biliary Atresia; Child; Child, Preschool; Female; Graft Rejection; Humans; Infant; Liver Diseases; Liver Transplantation; Male; Methylprednisolone; Parents; Postoperative Complications; Survival Rate; Tacrolimus; Tissue Donors

Topics: Antibody Specificity; Antilymphocyte Serum; Cyclosporine; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Life Tables; Liver Transplantation; Postoperative Complications; T-Lymphocytes; Tacrolimus; Tissue Donors

Topics: Adult; Akathisia, Drug-Induced; Anxiety Disorders; Humans; Kidney Transplantation; Male; Postoperative Complications; Psychomotor Agitation; Substance-Related Disorders; Tacrolimus

Topics: Adult; Child; Female; Gastrointestinal Motility; Graft Rejection; Humans; Intestine, Small; Male; Postoperative Complications; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Anti-Bacterial Agents; Communicable Diseases; Cyclosporins; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus; Time Factors

Liver grafting is now established as the optimal treatment for patients with end-stage parenchymal liver disease. Twenty-three years of experience at a single center is presented. The 1-year actuarial patient survival rate for all cases transplanted in Cambridge has now risen from 10% in 1968 to 1970 to 80% in 1990 to 1991. Increasing numbers of patients are being referred for transplantation with an ever-increasing range of indications being developed. Many inborn errors of metabolism can now be cured by liver grafting. There is still, however, considerable scope for improvement in many areas of patient treatment from operative and postoperative care to long-term immunosuppressive management. Much remains to be done to minimize early sepsis- and rejection-related deaths and late immunosuppression-related morbidity.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Azathioprine; Child; Child, Preschool; Cross-Cultural Comparison; Cyclosporine; England; Female; Follow-Up Studies; Graft Survival; Hepatic Encephalopathy; Humans; Immunosuppression Therapy; Infant; Infant, Newborn; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus; Tissue Donors

Topics: Anti-Bacterial Agents; Communicable Diseases; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Prospective Studies; Tacrolimus; Wound Infection

Topics: Animals; Anti-Bacterial Agents; Body Weight; Dogs; Duodenum; Graft Rejection; Immunosuppressive Agents; Injections, Intramuscular; Injections, Intravenous; Pancreas Transplantation; Postoperative Complications; Tacrolimus; Thrombosis; Transplantation, Homologous

Topics: Adult; Amino Acid Isomerases; Anti-Bacterial Agents; Aphasia; Carrier Proteins; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Peptidylprolyl Isomerase; Postoperative Complications; Tacrolimus

Topics: Animals; Foot; Hindlimb; Immunosuppressive Agents; Knee Joint; Lymphocyte Culture Test, Mixed; Male; Postoperative Complications; Pyridines; Rats; Rats, Inbred Lew; Skin Transplantation; Tacrolimus

Topics: Animals; Aqueous Humor; Conjunctiva; Cornea; Corneal Transplantation; Graft Rejection; Immunosuppressive Agents; Microinjections; Postoperative Complications; Pyridines; Rabbits; Reoperation; Tacrolimus

The effect of the new immunosuppressive agent FK-506 on rat limb allograft was investigated across the BN-to-F344 histocompatibility barrier. A 14-day course of FK-treatment at doses of 1 mg/kg per day or more, begun on the day of operation, significantly increased the period of graft survival. Additional studies demonstrated that single treatment with FK only on the day of operation prolonged the graft survival in a dose-dependent manner. These results stress the profound immunosuppressive effect of FK and suggest the possible future application of composite tissue allograft in humans.

Topics: Animals; Drug Administration Schedule; Female; Graft Survival; Graft vs Host Disease; Hindlimb; Immunosuppressive Agents; Injections, Intramuscular; Postoperative Complications; Pyridines; Rats; Rats, Inbred BN; Rats, Inbred F344; Skin Transplantation; Tacrolimus

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis; Vomiting

Topics: Administration, Oral; Animals; Dogs; Drug Evaluation, Preclinical; Female; Graft Rejection; Heart; Immunosuppressive Agents; Injections, Intramuscular; Intestines; Kidney; Kidney Transplantation; Liver; Myocardium; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Hyperglycemia; Immunosuppressive Agents; Kidney; Kidney Transplantation; Papio; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis

The immunosuppressive activities of a newly discovered macrolide extracted from Streptomyces tsukubaensis, FK506, were examined using 38 renal allografts in the beagle dog. The median survival time was 15.5 days in dogs without treatment, 61 days with a dose of 0.08 mg/kg/day and 176 days with a dose of 0.16 mg/kg/day of intramuscularly administered FK506. Prolongation of survival was statistically significant when compared with controls (P = 0.02, 0.0044, respectively). None of 6 recipient dogs receiving the agent at a dose of 0.16 mg/kg/day encountered rejection during the treatment course. Three of them survived over 200 days. Oral administration of FK506 at a dose of 0.32 mg/kg/day did not prolong the median survival time (20.5 days) compared with the placebo treated control (16.5 days), but oral treatment with 1.0 mg/kg/day resulted in all of the recipient dogs surviving over 130 days. Histological studies of 7 kidney graft biopsy specimens of the dogs surviving over 3 months revealed no cell infiltration or only some degree of reversible interstitial cell infiltration, but vascular and glomerular changes were not observed in any of the specimens. Irregularity of nuclear shape and cytoplasmic vacuolation of the pars recta of the proximal tubules were observed in one dog each. Liver biopsy specimens showed no consistent evidence of hepatocellular damage. Three dogs died of intussusception 2-3 weeks posttransplant. The dogs treated intramuscularly with 0.32 mg/kg/day suffered from anorexia. Two dogs receiving oral treatment at a dose of 1.0 mg/kg developed papilloma of the skin around day 60, but the tumors disappeared by day 120. We conclude that FK506 is a powerful immunosuppressant in the dog with tolerable side effects.

Topics: Administration, Oral; Animals; Anorexia; Dogs; Drug Evaluation, Preclinical; Female; Graft Survival; Immunosuppressive Agents; Injections, Intramuscular; Intussusception; Kidney; Kidney Transplantation; Liver; Postoperative Complications; Pyridines; Tacrolimus; Transplantation, Homologous