tacrolimus and Kidney-Failure--Chronic

Recurrent glomerulonephritis after renal transplantation is the third most common cause of allograft loss, the most frequent of which is associated with IgA nephropathy (IgAN). This study aims to provide a systematic review of the risk factors associated with recurrent IgAN after renal transplantation. We searched English and Chinese databases, including PubMed, Embase, Web of Science, CNKI, and others, and included all case-control studies involving risk factors for recurrent IgAN after renal transplantation from the databases' establishment to March 2022. Data were analyzed using the Stata 12.0. A total of 20 case-control studies were included in the meta-analysis, with 542 patients with recurrent IgAN and 1385 patients without recurrent IgAN. The results showed that donor age (standardized mean difference [SMD] -0.13 [95% CI -0.26, -0.001]; P = 0.048), patient age at transplantation (SMD -0.41 [95% CI -0.53, -0.29]; P < 0.001), time from diagnosis to end-stage renal disease (SMD -0.42 [95% CI -0.74, -0.10]; P = 0.010), previous transplantation (odds ratio [OR] 1.73 [95% CI 1.06, 2.81]; P = 0.027), living donor (OR 1.86 [95% CI 1.34, 2.58]; P < 0.001), related donor (OR 2.64, [95% CI 1.84, 3.79]; P < 0.001), tacrolimus use (OR 0.71 [95% CI 0.52, 0.98]; P = 0.035), basiliximab use (OR 0.39 [95% CI 0.27, 0.55]; P < 0.001), proteinuria (SMD 0.42 [95% CI 0.13, 0.71]; P = 0.005) and serum IgA level (SMD 0.48 [95% CI 0.27, 0.69]; P < 0.001) were associated with recurrent IgAN after renal transplantation. In general, tacrolimus and basiliximab use were protective factors against recurrent IgAN after renal transplantation, whereas donor age, patient age at transplantation, time from diagnosis to end-stage renal disease, previous transplantation, living donor, related donor, proteinuria, and serum IgA level were risk factors for recurrent IgAN after renal transplantation. Clinical decision making should warrant further consideration of these risk factors.

Topics: Basiliximab; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Kidney Failure, Chronic; Kidney Transplantation; Proteinuria; Risk Factors; Tacrolimus

Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.. We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.. Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).. This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Topics: Adult; Azathioprine; Bone Marrow Diseases; Cyclophosphamide; Glucocorticoids; Herpes Zoster; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Neoplasms; Network Meta-Analysis; Recurrence; Tacrolimus; Treatment Outcome

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 → 3)-β-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.

Topics: Acute Kidney Injury; Administration, Inhalation; Amphotericin B; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antifungal Agents; Azithromycin; Ceftriaxone; COVID-19; Deprescriptions; Female; Glucocorticoids; Graft Rejection; Humans; Hydroxychloroquine; Hyperoxaluria, Primary; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Invasive Pulmonary Aspergillosis; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Nitriles; Oxygen Inhalation Therapy; Prednisone; Pyridines; Renal Dialysis; SARS-CoV-2; Sputum; Tacrolimus; Tomography, X-Ray Computed; Triazoles

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

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Castleman Disease; Cyclophosphamide; Doxorubicin; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lymph Nodes; Male; Mycophenolic Acid; Prednisone; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Vincristine

To avoid graft rejection during pregnancy, frequent monitoring of serum drug levels is recommended. Pregnancy induces hyperfiltration in transplanted kidneys, as in native kidneys; therefore, detection of rejection can be difficult when monitoring by serum creatinine. If rejection is suspected, ultrasonographguided graft biopsy can be done; once proven, it can be treated with pulse steroids, but data are scarce regarding other agents. Here, we present a 28-year-old pregnant female patient with resistant acute rejection but with successful pregnancy outcome. Our patient had end-stage kidney disease secondary to lupus nephropathy and underwent living-donor renal transplant in May 2013 after hemodialysis support for 1 year. She received thymoglobulin as induction therapy and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. She had normal renal graft function without proteinuria. After she received counseling, she became pregnant in February 2015. In June 2015, she presented with acute graft dysfunction with serum creatinine level of 365 μmol/L. Her abdominal ultrasonography showed mild hydronephrosis and viable fetus. She received empirical pulse steroids with partial response, and her graft biopsy showed acute T-cell-mediated rejection and negative C4d. Intravenous immunoglobulins and minipulse steroids were administered but without response. After gynecologic counseling and informed consent, she received 5 doses of thymoglobulin. She was dialysis dependent until premature vaginal labor, which resulted in birth of a viable 2-kg boy. We suggest that successful pregnancy outcomes could occur with close monitoring and daily dialysis in female kidney transplant patients with resistant rejection.

Topics: Acute Disease; Adult; Antilymphocyte Serum; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunity, Cellular; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Live Birth; Living Donors; Lupus Nephritis; Mycophenolic Acid; Prednisolone; Pregnancy; Pregnancy, Unplanned; Renal Dialysis; Risk Factors; T-Lymphocytes; Tacrolimus; Treatment Outcome

This review reports the outcomes of paediatric renal transplantation in the United Kingdom over the last 25 years. UK Transplant Registry data on 3236 paediatric renal transplants performed between 1 January 1992 and 31 December 2016 were analysed. Significant improvements in human leucocyte antigen (HLA) matching have been achieved; 84% of recipients received 000 or favourable (0 DR and 0 or 1 B) mismatched kidneys in 2016 compared with 27% in 1992. The median waiting time has increased from 126 days in 1999 to 351 days in 2016. Tacrolimus replaced ciclosporin in most immunosuppressive regimens after 2002. Renal transplant outcome has improved significantly, mainly because of a reduction in early graft loss. One-year donation after brain death renal allograft survival for those transplanted from 2012 to 2016 was 98%, compared with 72% for those transplanted from 1987 to 1991. Renal allograft survival for first kidney only transplants at 1, 5, 10, 20 and 25 years were 89%, 79%, 65%, 42% and 33% respectively. Superior survival with living donor was maintained throughout the study period with 25-year graft survival at 33% compared with 31% from deceased donor (P < 0.0001). Changes in immunosuppression regimens, improvements in HLA matching and a reduction of cold ischaemia time may in part explain the improvements in graft survival.

Topics: Adolescent; Blood Group Incompatibility; Child; Child, Preschool; Cyclosporine; Cytomegalovirus; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Practice Patterns, Physicians'; Retrospective Studies; Tacrolimus; Tissue and Organ Procurement; United Kingdom

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

Idiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome in adults and one of the leading causes of end-stage renal disease (ESRD). During recent years, the incidence of IMN has been increasing. The main treatment option for IMN is the use of immunosuppressive (IS) drugs combined with glucocorticoids (GC). However, the infection risk with different IS drug treatments has not been systematically compared. Therefore, a network meta-analysis was performed to compare the risk of infection of different IS drug treatments for IMN.. Randomized controlled trials (RCTs) that assessed the risk of infection in patients with IMN treated with different IS drugs combined with GC were included in the network meta-analysis. Risk ratios for dichotomous data with 95% confidence intervals (CI) were calculated and the data were pooled with a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated to rank the risk of infection with different interventions.. A total of 38 RCTs with 2066 participants were included for comparison of nine interventions. Tacrolimus combined with GC (TAC + GC) was associated with a significantly lower risk of infection than that with intravenous cyclophosphamide (IVCTX) + GC with a risk ratio (95% CI) of 0.52 (0.34-0.79). IVCTX + GC was associated with a significantly higher risk of infection than that with TAC + GC, cyclosporin (CSA) + GC, and oral cyclophosphamide (POCTX) + GC. A sensitivity analysis, excluding studies with a very long follow-up period, revealed minimal differences in the estimates. The SUCRA showed that CSA + GC had the lowest risk of infection (SUCRA 86.0%), and the second best treatment was POCTX + GC (SUCRA 78.6%). Conversely, IVCTX + GC (SUCRA 16.2%) had a higher risk of infection than that with the other IS drugs.. CSA + GC and POCTX+ GC were associated with a lower risk of infection than that with other IS drugs combined with GC for IMN. Combined with comparative efficacy data, these results can help patients make informed decisions about treatment options for IMN. PROSPERO registration: CRD42018104849.

Topics: China; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Risk; Tacrolimus

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has the propensity to acquire a devastating disease course. Despite the advances in therapeutics, a significant proportion of patients progress to end-stage renal disease (ESRD). Renal transplantation is being increasingly employed in this population, with gradual improvement in outcomes over the years, however, recurrence of disease requires constant surveillance and is associated with graft failure. Areas covered: A structured literature search in PubMed and Medline and abstracts of international conferences was performed to identify cases and cohorts of AAV patients who had undergone renal transplantation for ESRD. The primary objective was to describe the long-term allograft and patient survival and to reflect on current trends in transplantation in AAV and provide recommendations for the phases of pre- and post-transplantation. Expert commentary: Renal transplantation is the treatment of choice for AAV patients with ESRD. The risk of relapse is low with modern immunosuppressive regimes employing mycophenolate mofetil and tacrolimus. It is recommended that the vasculitis be in clinical remission for 12 months prior to transplantation. Although ANCA positivity is not a contraindication for renal transplantation, these patients should be monitored closely for vasculitis relapse post-transplant.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Graft Rejection; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Survival Analysis; Tacrolimus; Treatment Outcome

The prevalence of end-stage renal disease is increasing worldwide. The best treatment is kidney transplantation, although life-long immunosuppressive therapy is then mandatory. Currently, the cornerstone immunosuppressive therapy relies on tacrolimus (Tac), a calcineurin inhibitor that is nephrotoxic but whose exposition can be minimized in a delicate balance. Area covered: We addressed whether, in the setting of kidney transplantation, Tac-based therapy can be tailored to medical needs: to achieve this, we searched for suitable articles in PubMed. Expert commentary: Too over-minimization of Tac, when associated with mycophenolic acid (MPA), may cause the development of de novo donor-specific alloantibodies (DSA). However, Tac minimization, in the context of everolimus-associated therapy instead of MPA, does not increase DSA formation as demonstrated in the TRANSFORM study and, in addition, can prevent cytomegalovirus (CMV) infection/reactivation. Nonetheless, Tac therapy, regardless of its formulation (immediate or extended release) compared to cyclosporine A, increases the risk of posttransplant diabetes mellitus; this increase is not affected by steroid therapy. Tac-based immunosuppression remains the best immunosuppressive therapy in kidney-transplant recipients and can be tailored according to patients' need.

Topics: Calcineurin Inhibitors; Cyclosporine; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Tacrolimus

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

Topics: Biopsy; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Isoxazoles; JC Virus; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polymerase Chain Reaction; Polyomavirus Infections; Sirolimus; Tacrolimus; Transplantation, Homologous; Viremia

Renal transplantation and restoration of renal function are associated with significant favourable changes regarding the reproductive capacity of male patients with previous end-stage renal disease. However, there is evidence that some of the immunosuppressive agents may impair male fertility after all. Calcineurin inhibitors (CNIs), cyclosporine A and tacrolimus (FK506), which constitute the cornerstone of immunosuppression regimen following renal transplantation, have been implicated in causing an overall decline in the fertilisation capacity of male renal transplant recipients (RTRs). In this review, data from human clinical studies are collectively presented in an effort to estimate the potential adverse effects of CNIs on the masculine reproductive organs, the hormonal axis of males, the process of spermatogenesis and generally the male RTRs capacity to fertilise.

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cyclosporine; Fertility; Genitalia, Male; Gonadal Steroid Hormones; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Semen Analysis; Tacrolimus; Young Adult

End-stage renal disease is the final and irreversible stage in chronic kidney disease, leading to patient mortality, unless managed by dialysis or transplantation (the treatment of choice). This study aimed to compare a currently recommended immunosuppressive treatment, tacrolimus, against a newer treatment, belatacept, using indirect treatment comparison (ITC) techniques since no head-to-head randomized controlled trials (RCTs) comparing tacrolimus against belatacept currently exist.. ITC was employed to calculate estimates for the relative risks and mean difference of tacrolimus against belatacept. The choice of the Bucher ITC model was driven by the available data and the simple indirect treatment comparison involving three treatments was considered appropriate.. The results of the indirect analysis showed no significant differences between belatacept and tacrolimus treatments for mortality and graft loss. The acute rejection rate was significantly lower with tacrolimus (Prograf* and Advagraf (*) ) compared with belatacept (0.22 [0.13, 0.39] to 0.44 [0.20, 0.99]).. The results of this systematic review and meta-analysis suggests that tacrolimus is significantly superior to belatacept in terms of acute rejection outcomes but comparable for graft and patient survival. Further research should include a properly designed clinical trial comparing tacrolimus against belatacept directly.. These include variations in terms of clinical and design differences among the trials, weaknesses in the Bucher method and the lack of long-term clinical trial data with tacrolimus to compare with the recent long-term (7 years) belatacept trial data.

Topics: Abatacept; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Tacrolimus

End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival.. To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation.. Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost).. Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.. Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC.. The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence.. TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study.. This study is registered as PROSPERO CRD42014013544.. The National Institute for Health Research HTA programme.

Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Basiliximab; Child; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical

Uremic itch is a frequent and sometimes very tormenting symptom in patients with advanced or end-stage renal failure, with a strong negative impact on the quality of life. According to a representative study, the point prevalence of chronic itch is 25% in hemodialysis patients but may reach more than 50% in single cohorts depending on the country and dialysis efficacy. Not much is known regarding the pathogenesis of uremic itch. Besides parathyroid hormone, histamine, tryptase, and alteration of the calcium-phosphate metabolism have been suspected. More recently, derangements in the opioid system and an inflammatory condition have been investigated as suspected players in the pathogenesis of uremic itch, but remain unproven so far. Treatment of chronic itch in dialysis patients remains difficult. Besides topical application of rehydrating or immunomodulating compounds, such as γ-linolenic acid or tacrolimus treatment with nalfurafine may be helpful. Apart from that, gabapentin and pregabalin are promising drugs to alleviate uremic itch. In many cases, UVB phototherapy is effective in reducing the intensity of itch. When treating patients, one should take into account that most of the drugs available are not licensed for the treatment of itch. Therefore, a deliberate use of therapeutic options aiming for a good risk-benefit relation should be adopted. In very severe and refractory cases, patients suitable for renal transplantation might be switched to 'high urgency' status, as successful renal transplantation cures uremic pruritus in most of the cases.

Topics: Acupuncture Therapy; Amines; Analgesics, Opioid; Anticonvulsants; Calcineurin Inhibitors; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; gamma-Linolenic Acid; Humans; Kidney Failure, Chronic; Morphinans; Narcotic Antagonists; Pregabalin; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Renal Dialysis; Spiro Compounds; Tacrolimus; Ultraviolet Therapy; Uremia

End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.. To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation.. Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.. Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY.. For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled.. High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome.. Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY.. This study is registered as PROSPERO CRD42014013189.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Bayes Theorem; Cost-Benefit Analysis; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical

The etiology of tako-tsubo cardiomyopathy, defined as a transient left ventricular dysfunction in the absence of significant coronary artery stenosis, still remains unclear. This syndrome mainly occurs in postmenopausal women and is often associated with emotional stress or miscellaneous diagnostic and therapeutic procedures. Estimated prevalence of tako-tsubo cardiomyopathy is found in 1% to 2% of patients presenting with suspected acute coronary syndrome. So far there has been only one case report of tako-tsubo cardiomyopathy in a renal transplant recipient.. We describe the case of a 68-year-old woman with a history of coronary artery disease and coronary artery bypass grafting in whom unspecific transient chest pain and hypotension were observed on the first day after renal transplantation. After transplantation, the patient was anuric with pulmonary congestion and toxic tacrolimus concentrations were observed. Electrocardiogram showed sinus rhythm with left bundle branch block (LBBB) that has not been described before. Plasma cardiac necrosis markers troponin I and creatine kinase MB were mildly elevated. Echocardiography showed severe left ventricular function impairment with characteristic shape of left ventricle. Subsequent cardiac catheterization revealed the absence of angiographic evidence of acute plaque rupture within both coronary arteries and bypass grafts. During the next few days there was marked clinical improvement with resolution of LBBB and full recovery of all biochemical parameters. On discharge, full functional recovery of the left ventricle in echocardiography was observed. Postulated mechanisms of tako-tsubo cardiomyopathy include catecholamine excess, coronary artery spasm, and microvascular dysfunction. On the other hand calcineurin inhibitors are known factors causing coronary epicardial endothelial dysfunction and negatively affecting vasomotor function.. Tako-tsubo cardiomyopathy in patients after renal transplantation may be at least in part a manifestation of calcineurin inhibitor cardiotoxicity.

Topics: Aged; Calcineurin Inhibitors; Chest Pain; Delayed Graft Function; Electrocardiography; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Tacrolimus; Takotsubo Cardiomyopathy; Vasoconstriction; Ventricular Dysfunction, Left

Fertility in women with kidney failure is restored by transplantation. It requires careful planning and is only advisable in women with good kidney function, controlled blood pressure, and general good health. Immunosuppressive drugs carry risks for the fetus, but the risks of prednisone, azathioprine, cyclosporine, and tacrolimus are surprisingly low. Mycophenolate is teratogenic. The success rate for pregnancy in kidney transplant recipients is lower than in the general population with 70% to 80% of pregnancies resulting in surviving infants. Prematurity, intrauterine growth restriction, and preeclampsia are all increased. Complications are higher and outcomes are worse for women with serum creatinine levels over 1.3 mg/dL. Ten to 15% of women have a temporary or permanent decline in kidney function, particularly if prepregnancy creatinine is high. Transplant-related infections can be serious for the mother and fetus. A multidisciplinary team should coordinate care.

Topics: Anemia; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Female; Herpes Simplex; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Preconception Care; Prednisone; Pregnancy; Pregnancy Complications; Tacrolimus; Toxoplasmosis; Urinary Tract Infections

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Cardiac Tamponade; Cytokines; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Postoperative Period; Tacrolimus; Treatment Outcome; Withholding Treatment

The safety and efficacy of early steroid withdrawal or avoidance in patients receiving a kidney transplant (KT) are controversial.. We performed a systematic review and a meta-analysis of the randomized controlled studies about steroid avoidance or withdrawal after a few days in patients receiving a KT and treated with antibody induction and cyclosporine (CsA) or tacrolimus (Tac) plus mycophenolate mofetil (MMF) (nine available studies and 1934 participants).. Death and graft loss (including or excluding death with function) were similar in steroid avoidance and control patients, with no differences between CsA and Tac studies. After steroid avoidance, acute rejection was more frequent than conventional steroid use in CsA trials [risk ratios (RR) 1.59, 95% confidence intervals (95% CI) 1.01-2.49] but not when Tac was used (RR 1.06, 95% CI 0.79-1.42). Steroid avoidance was associated with less frequent new-onset diabetes mellitus, but this decrease was only evident with CsA (RR 0.54, 95% CI 0.30-0.98), whereas this difference was not significant analysing Tac studies (RR 0.75, 95% CI 0.32-1.77). Despite this trend, the corresponding interaction tests were not statistically significant (P = 0.140 and P = 0.535, for acute rejection and new-onset diabetes mellitus, respectively). Serum creatinine, creatinine clearance, mean blood pressure, serum cholesterol and serum triglycerides were similar in both groups.. Steroid avoidance or early withdrawal within the first 2 weeks is safe in KT recipients receiving induction with anti-interleukin-2 receptor antibodies or thymoglobulin and a drug regimen based on calcineurin inhibitor and MMF. However, the real benefits remain unclear.

Topics: Adrenal Cortex Hormones; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Care; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Tacrolimus; Time Factors; Transplantation Immunology; Withholding Treatment

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

Calcineurin inhibitors (CNIs), such as cyclosporin A and tacrolimus, are the cornerstone of maintenance immunosuppressive regimens in liver transplantation. CNIs prevent rejection by inhibition of calcineurin, via which lymphocyte proliferation and interleukin (IL)-2 production is prevented. Tacrolimus is now the first-choice immunosuppressant after liver transplantation, since it is associated with fewer episodes of rejection than cyclosporin A. In this review we will discuss interindividual differences, which influence tacrolimus metabolism. Because of these factors and the narrow therapeutic index of tacrolimus, monitoring of drug trough levels is necessary. Furthermore, we will discuss studies concerning conversion from the tacrolimus twice daily to tacrolimus once daily formulation in stable LT patients. Due to adverse effects of CNIs, such as chronic renal failure, hypertension, de novo malignancy and new-onset diabetes mellitus, CNI minimization strategies have been developed, which will be discussed too.

Topics: Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Drug Administration Schedule; Drug Substitution; Graft Rejection; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Tacrolimus; TOR Serine-Threonine Kinases

Barriers to successful outcomes following pediatric transplantation have shifted from ischemic reperfusion injury and rejection to more long-term complications. Of particular concern is the high prevalence of CKD owing to preexisting damage and nephrotoxicity, as well as other CV complications such as hypertension and cardiomyopathy. All of these contribute to graft loss and shortened life expectancy, thereby limiting the success story of solid-organ transplantation. Managing CKD and related CV morbidity should be integral to the care of pediatric transplant patients, and timely detection of any irregularities would increase the chances of restoring lost kidney function. GFR is still the widely accepted indicator of renal function, and nuclear medicine techniques are the gold standard measurement methods. These methods are limited by costs, radiation exposure and substrate injection, and current practice still uses the Schwartz estimate, despite its well-documented limitations. Newer endogenous markers of GFR, such as cystatin C clearance, give a more accurate measure of true GFR but have not been embraced in the management of pediatric transplant recipients. Furthermore, indirect markers (e.g., microalbuminuria and hypertension) could also aid early detection of renal damage. The effects of mainstay immunosuppressants on kidney and heart function are varied, with available data indicating favorable outcomes with tacrolimus compared with ciclosporin. There is a need for appropriately designed and powered randomized controlled trials to validate innovative concepts for tailored immunosuppression in the pediatric population. To date, very few studies have generated long-term data in pediatric renal transplant patients - results of 1-4-yr study favored tacrolimus over ciclosporin, but other immunosuppressive agents also need to be evaluated.

Topics: Cardiovascular Diseases; Chronic Disease; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Organ Transplantation; Pediatrics; Risk Factors; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Pulmonary alveolar proteinosis (PAP) has been associated with the immunosuppressant sirolimus in transplant patients. PAP is a progressive lung disease characterized by the accumulation of surfactant-like material in the lungs leading to decreased pulmonary function with shortness of breath and cough as common symptoms. We report a rare case of sirolimus-associated PAP in a kidney transplant recipient with a history of end-stage renal disease secondary to haemolytic uraemic syndrome (HUS) and review of the literature. Discontinuation of sirolimus and initiation of tacrolimus led to resolution of PAP without recurrence of HUS.

Topics: Female; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pulmonary Alveolar Proteinosis; Recurrence; Sirolimus; Tacrolimus

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Drug Administration Schedule; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Liver Transplantation; Mycophenolic Acid; 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

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 uremic pruritus is a very painful symptom suffered by chronic haemodialysis patients and is observed in 22 to 74% of the subjects. The causes of uremic pruritus have not yet been clarified. During the last 20 to 30 years it has been focused on altogether 5 different pathophysiological hypotheses: stimulating influences (e.g. calcium phosphate deposits in the epidermis), stimuli (e.g. secondary hyperparathyroidism), neuropathic injuries (e.g. disturbance of the cutaneous innervation in patients with uremic peripheral neuropathy), and central nervous changes (e.g. accumulation of endorphins in uremic patients which is associated with increasing pruritus), and immunologic conditions. The last mentioned immunological hypothesis has increasing importance, not at least based on the fact that the application of a topical calcineurin inhibitor (tacrolimus) improves the uremic pruritus. However, this fact could not be confirmed in a recent prospective placebo-controlled study from the USA. Only after kidney transplantation with a functioning transplant the uremic pruritus is stopped. That is why no causal therapy exists so far. Actually, the uremic pruritus has to be treated by topical and systemic means in a symptomatic and polypragmatic way only. Urea represents one of the most important "natural moisturizing factors" which are responsible for the hydration of the skin. It has been demonstrated that older patients have decreased urea levels within the stratum corneum of the epidermis, whereas in patients with terminal kidney insufficiency - despite dryness of the skin - as a paradox finding elevated levels of urea have been assessed in the stratum corneum. Because of this reason, the meaning of urea as part of the "natural moisturizing factors" system is not understood, until now. However, there are very promising results of clinical phase II studies showing a significant effect of topical application of 2.5% L-arginine hydrochlorid ointment - a semi-essential amino acid - on improvement of dryness and, in particular, on improvement of pruritus in haemodialysis patients.

Topics: Antipruritics; Arginine; Calcineurin Inhibitors; Capsaicin; Controlled Clinical Trials as Topic; Humans; Ichthyosis; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Ointments; Prospective Studies; Pruritus; Renal Dialysis; Skin; Tacrolimus; Urea; Uremia

Thousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO-incompatible (ABO-I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO-I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE.. The TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti-human globulin (AHG) phase before surgery. Pretransplant therapy consists of every-other-day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti-A and anti-B titers until tolerance or accommodation occurs. TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer.. Fifty-three ABO-I kidney transplants have been completed with no episodes of hyperacute antibody-mediated rejection (AMR) and only three episodes of AMR. One-year death-censored graft survival is 100 percent and patient survival is 97.6 percent.. While randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO-I renal transplantation.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Cytomegalovirus; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Plasma Exchange; Plasmapheresis; Preoperative Care; Retrospective Studies; Splenectomy; Survival Analysis; Tacrolimus

Many novel immunosuppressive agents are under active clinical investigation. In addition, creative approaches are being developed for the use of established immunosuppressive agents, with the goal of minimizing immunosuppression as early as possible posttransplantation. The hope is that these approaches will minimize the toxicity of these agents without sacrificing efficacy. Evidence suggests that the nephrotoxicity of calcineurin inhibitors can be reduced using these approaches. The introduction of newer immunosuppressive agents, including the proliferation signal inhibitors, raises the possibility that some of the long-term scourges of cardiac transplantation, including cardiac allograft vasculopathy and malignancy, can be ameliorated. Finally, costimulatory pathway inhibitors and other new immunosuppressive agents offer hope that all these goals can be accomplished with very low long-term maintenance immunosuppression.

Topics: Abatacept; Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Calcineurin Inhibitors; Cyclosporine; Everolimus; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Janus Kinase 3; Kidney Failure, Chronic; Prognosis; Protein Kinases; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

An overview of the first 4 decades of clinical kidney transplantation would characterize progress primarily in the development of new immunosuppressive agents designed to reduce the incidence and severity of acute rejection to improve short-term outcomes, but with less marked effects on long-term patient and graft survival. The new trend of immunosuppressive therapy is to facilitate long-term allograft and patient survival, and to help to maintain a good quality of life after renal transplantation. To achieve these goals, transplant physicians need to determine the immunosuppressive protocols that will best minimize risk factors associated with reduced allograft/patient survival and quality of life. Recent protocols and clinical experience with modern immunosuppression strategies, as well as the efficacy and safety of various combination protocols, will be reviewed.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cyclosporine; Daclizumab; Drug Therapy, Combination; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD). Standard protocols in use typically involve three drug groups each directed to a site in the T-cell activation or proliferation cascade which are central to the rejection process: calcineurin inhibitors (e.g. cyclosporin, tacrolimus), anti-proliferative agents (e.g. azathioprine, mycophenolate mofetil) and steroids (prednisolone). It remains unclear whether new regimens are more specific or simply more potent immunosuppressants.. To compare the effects of tacrolimus with cyclosporin as primary therapy for kidney transplant recipients.. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Renal Group's specialist register and conference proceedings were searched to identify relevant reports of randomised controlled trials (RCTs). Two reviewers assessed trials for eligibility, quality and extracted data independently.. All RCTs where tacrolimus was compared with cyclosporin for the initial treatment of kidney transplant recipients. Data were synthesised (random effects model) and results expressed as relative risk (RR), values <1 favouring tacrolimus, with 95% confidence intervals (CI). Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions.. 123 reports from 30 trials (4102 patients) were included. At six months graft loss was significantly reduced in tacrolimus-treated recipients (RR 0.56, 95% CI 0.36 to 0.86), and this effect was persistent up to three years. Meta-regression showed that this benefit diminished as higher trough levels of tacrolimus were targeted (P = 0.04), after allowing for differences in cyclosporin formulation (P = 0.97) and cyclosporin target trough level (P = 0.38). At one year, tacrolimus patients suffered less acute rejection (RR 0.69, 95% CI 0.60 to 0.79), and less steroid-resistant rejection (RR 0.49, 95% CI 0.37 to 0.64), but more insulin-requiring diabetes mellitus (RR 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia and vomiting. Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy.. Tacrolimus is superior to cyclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid 12 suffering acute rejection, two losing their graft but cause an extra five to become insulin-requiring diabetics.

Topics: Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Randomized Controlled Trials as Topic; Tacrolimus

Mycophenolate mofetil (MMF) was approved for the prevention of acute rejection following renal transplantation based on the results of three groundbreaking, large, clinical trials that demonstrated a significantly reduced risk of acute rejection in patients receiving MMF when compared with those receiving placebo or azathioprine. These three multicenter, prospective, double-blind trials performed at 55 transplant centers on three continents were the largest immunosuppressive drug trials ever attempted and the first prospective, randomized, double-blind trials ever performed in transplantation. These pivotal trials established a foundation for widespread acceptance of MMF in combination with cyclosporine and steroids as a maintenance regimen for renal transplant patients. The findings of these initial trials that led to the approval of MMF for renal transplantation, including long-term follow-up data, will be reviewed in this paper. The expanding scope of major trials of MMF, including trials in pediatric patients, combination regimens with novel induction therapies or other maintenance agents, and trials in special patient populations such as those at high immunological risk or with deteriorating kidney function, will also be discussed.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Azathioprine; Child; Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Multicenter Studies as Topic; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; Tacrolimus

The authors expounded present state of knowledge concerning immunosuppressive drugs therapy during pregnancy after kidney transplantation. Pregnancy is uncommon in women with end-stage renal disease treated with dialysis and in most cases it ends with pregnancy failure. Resuming the normal function of the ovaries after kidney transplantation substantially increases the chances of conception and successful pregnancy. The immunosuppression scheme and dosage of drugs used in pregnant women are vital to both the normal course of pregnancy and delivery of a healthy child. Considering the safety of the fetus it is acceptable to use prednisone, azathioprine, cyclosporine and tacrolimus. Due to the necessity to administer immunosuppressive drugs in relatively small doses, an important factor conditioning the normal course of pregnancy is maintaining a 1- or 2-year interval between the kidney transplantation and the conception.

Topics: Azathioprine; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant, Newborn; Kidney Failure, Chronic; Kidney Transplantation; Prednisone; Pregnancy; Pregnancy Complications; Pregnancy, High-Risk; Tacrolimus

With the improvements in short and long term graft and patient survival after renal transplantation over the last two decades Health-Related Quality of Life (HRQL) is becoming an important additional outcome parameter. Global and disease specific instruments are available to evaluate objective and subjective QOL. Among the most popular global tools is the SF-36, examples of disease specific instruments are the Kidney Transplant Questionnaire (KTQ), the Kidney Disease Questionnaire (KDQ) and the Kidney Disease-Quality of Life (KDQOL). It is generally accepted that HRQL improves dramatically after successful renal transplantation compared to patients maintained on dialysis treatment but listed for a transplant. It is less clear however which immunosuppressive regimen confers the best QOL. Only few studies compared the different regimens in terms of QOL outcomes. Although limited in number, these studies seem to favour non-cyclosporine based protocols. The main differences that could be observed between patients on cyclosporine versus tacrolimus or sirolimus therapy concern the domains of appearance and fatigue. This may be explained by two common adverse effects occurring under cyclosporine therapy, gingival hyperplasia and hair growth. Another more frequently occurring side effect under calcineurin inhibitor therapy is tremor, which may favour CNI free protocols. This hypothesis, however, has not been formally evaluated in a randomised trial using HRQL measurements.In summary HRQL is becoming more of an issue after renal transplantation. Whether a specific immunosuppressive protocol is superior to others in terms of HRQL remains to be determined.

Topics: Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Outcome Assessment, Health Care; Psychometrics; Quality of Life; Renal Dialysis; Sickness Impact Profile; Sirolimus; Surveys and Questionnaires; Tacrolimus

Chronic allograft nephropathy is one of the leading causes of long-term graft failure in kidney transplant recipients. The etiology of this condition is multifactorial, but administration of calcineurin inhibitors is often implicated. With the introduction of newer immunosuppressive agents, strategies for calcineurin inhibitor minimization, avoidance, and withdrawal have been emerging in the literature. These strategies may improve long-term kidney allograft function, but are not without risks. Results from recent clinical trials evaluating the safety and efficacy of these strategies to prevent chronic allograft nephropathy in kidney transplant recipients are summarized and reviewed. Patients who had never received a calcineurin inhibitor or who had cyclosporine withdrawn from their regimens had better kidney function than patients who received or kept receiving a calcineurin inhibitor. The impact of the improvement in kidney function on long-term graft survival remains to be determined. In addition, the benefit in renal function must be weighed against the bone marrow toxicities and/or metabolic complications associated with these regimens.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Patient Selection; Postoperative Care; Safety; Sirolimus; Tacrolimus; Transplantation, Homologous

Long-term survivors of pediatric liver and heart transplantation are at risk for progressive renal dysfunction as a result of chronic exposure to calcineuron inhibitors. This class of drugs causes alterations in renal perfusion that can result in irreversible renal injury including afferent arteriopathy, glomerulosclerosis, tubular atrophy and interstitial fibrosis. Approximately 3-6% of pediatric liver and heart recipients will develop end stage renal failure. A much larger percentage has chronic renal insufficiency and hypertension. Children with significant renal compromise in the pretransplant period and those with significantly elevated serum creatinine levels during the first post-transplant year may be at the highest risk to develop irreversible renal injury in long-term follow-up. Serum creatinine is a poor screening tool as it rises late in the course when the injury may no longer be reversible. Strategies to minimize long-term exposure to calcineuron inhibitors may reduce the prevalence of renal insufficiency in this vulnerable population.

Topics: Child; Creatinine; Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Postoperative Care; Risk Factors; Tacrolimus; Time Factors; Transplantation, Homologous

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

Kidney transplantation has seen a remarkable improvement in allograft survival rates and patient survival rates, and an equally remarkable reduction in acute rejection rates. Most attribute these changes to the introduction and widespread use of calcineurin inhibitors as part of the standard immunosuppressive regimen. Cyclosporine and tacrolimus are ideal immunosuppressive agents, much more effective and safe than the previous agents used. Especially ironic, however, for those caring for kidney transplant patients has been the finding that these breakthrough agents are toxic to the kidney and can cause hypertension. We can protect the transplanted kidney from rejection, but still damage it paradoxically by the protecting agent. Moreover, the prevalence of hypertension in transplant clinics has increased (from 40%-50% to up to 90%-100%) as these newer agents have gained widespread use. We remain uncertain of the mechanism whereby these agents cause hypertension, and therefore remain uncertain of the ideal treatment; however, the search for a mechanism has taken us from the organ level to intracellular effects of the agents. The fact that both agents cause nephrotoxicity suggests that a renal mechanism is at the heart of the hypertension.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Tacrolimus

We present a case of living, related-donor kidney transplantation during the first trimester of pregnancy. The patient received mycophenolate mofetil (MMF), tacrolimus, and prednisone throughout the entire pregnancy. This is the first reported case of use of MMF during pregnancy. The mother did well, except for mild preeclampsia and mild renal insufficiency at term. The baby girl was born prematurely at week 353/7. The only possible teratogenic effects detected included hypoplastic nails and short fifth fingers. No chromosomal abnormalities were found. The child is growing and developing normally. Although we do not recommend the use of mycophenolate mofetil during pregnancy based on this experience, it is reassuring to know that a successful outcome can be expected in mothers treated with MMF during pregnancy.

Topics: Abnormalities, Drug-Induced; Adult; Drug Therapy, Combination; Female; Fingers; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Mycophenolic Acid; Nails, Malformed; Prednisone; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; 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

Acute and chronic nephrotoxicity frequently limits the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications. The clinical aspects, pathophysiology, and relevant pharmacology of current and future immunosuppressive drugs are reviewed in this paper. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented.

Topics: Acute Kidney Injury; Animals; Cyclosporins; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polyenes; Sirolimus; Tacrolimus

Drugs used to modify the immune response in solid organ transplantation or autoimmune disease may cause dose-related nephrotoxicity. Cyclosporine, FK506, cyclosporine G, and rapamycin have all been studied experimentally and to a more limited extent in patients. This paper summarizes this literature using data from clinically relevant animal models.

Topics: Acute Kidney Injury; Animals; Cyclosporine; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Failure, Chronic; Polyenes; Sirolimus; Tacrolimus

BACKGROUND This post hoc analysis of data from the prospective OSAKA study evaluated the efficacy and safety of prolonged- and immediate-release tacrolimus in patients who received kidneys from extended-criteria (ECD) and standard-criteria (SCD) donors. MATERIAL AND METHODS Within the ECD and SCD groups, patients were randomized to one of 4 tacrolimus-based regimens (initial dose): Arm 1, immediate-release tacrolimus (0.2 mg/kg/day); Arm 2, prolonged-release tacrolimus (0.2 mg/kg/day); Arm 3, prolonged-release tacrolimus (0.3 mg/kg/day); Arm 4, prolonged-release tacrolimus (0.2 mg/kg/day) plus basiliximab. All patients received mycophenolate mofetil and bolus corticosteroids; Arms 1-3 also received tapered corticosteroids. ECDs met the definition: living/deceased donors aged ≥60 years, or 50-60 years with ≥1 other risk factor, and donation after circulatory death. Primary composite endpoint: graft loss, biopsy-confirmed acute rejection or renal dysfunction by Day 168. Outcomes were compared across treatment arms with the chi-squared or Fisher's exact test. RESULTS A total of 1198 patients were included in the analysis (ECD: n=620 [51.8%], SCD: n=578 [48.2%]). Patients with kidneys from ECDs were older versus SCDs (mean age, 55.7 vs. 44.5 years, p<0.0001). A higher proportion of patients with kidneys from ECDs versus SCDs met the primary composite endpoint (56.8% vs. 32.4%, p<0.0001). However, no statistically significant differences in clinical outcomes or the incidence of treatment-emergent adverse events were seen between treatment arms within each donor group. CONCLUSIONS Worse outcomes were experienced in patients who received kidneys from ECDs versus SCDs. Prolonged-release tacrolimus provided similar graft survival to the immediate-release formulation, with a manageable tolerability profile.

Topics: Adult; Aged; Delayed-Action Preparations; Donor Selection; Drug Administration Schedule; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome

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

De novo obese kidney transplant recipients were randomized to receive TAC-ER 0.15 mg/kg/day based on either adjusted body weight (aBW) or ideal body weight (IBW). Post-transplant patients underwent three pharmacokinetic assessments over 14 days. The primary endpoint was the difference in TAC-ER exposure (AUC0-24) in obese patients dosed using aBW compared with IBW.. A total of 20 obese renal transplant recipients were randomized to participate in the study (10 aBW and 10 IBW). Results of the primary outcome (AUC0-24) on Study Day 1, 7, and 14 were not statistically different between the two groups. There was no difference in the number of days to therapeutic trough concentration between the two dosing weights (aBW = 5.1, IBW = 4.9, days; P = 0.90).. In a population of obese renal transplant recipients, comparable trough concentrations and overall exposure in both groups indicate that IBW may be preferred, as less initial drug was needed to attain adequate exposure.

Topics: Drug Administration Schedule; Drug Liberation; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Obesity; Prognosis; Risk Factors; Tacrolimus

The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single-center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r-ATG/EVR, n = 88), or mycophenolate (r-ATG/MPS, n = 83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12 months. Secondary endpoints included treatment failure [first biopsy-proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06-0.220, P < 0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P = 0.021), graft loss (11% vs. 1%, P = 0.008), death (10% vs. 1%, P = 0.013), and treatment discontinuation (40% vs. 28%, P = 0.12) were higher in the r-ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r-ATG/EVR (31.8 ± 18.8 vs. 42.6 ± 14.9, P < 0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).

Topics: Aged; Antilymphocyte Serum; Cytomegalovirus Infections; Delayed Graft Function; Donor Selection; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Treatment Outcome

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

To evaluate the utility and safety of high-dose mizoribine combination therapy using cyclosporine and tacrolimus as calcineurin inhibitors in patients undergoing kidney transplant.. The present study enrolled 156 patients who received kidney transplants in 18 institutions between 2009 and 2013. ABO-incompatible and/or pre-sensitized recipients were excluded. Immunosuppression used cyclosporine (88) or tacrolimus (68) as a calcineurin inhibitor, and the dosage was adjusted based on blood concentrations. Mizoribine was started at 6 mg/kg/day, and the target trough level was 1-2 ng/mL. Primary efficacy end-points of this study were 2-year patient survival, 2-year graft survival and the acute rejection rate within 2 years after transplantation.. The 2-year patient and graft survival rates in the cyclosporine group were 98.9% and 94.3%, respectively, whereas those in the tacrolimus group were 100% and 98.5%, respectively, with no significant difference between groups. Rates of onset of rejection during the observation period were also equivalent, at 22.7% in the cyclosporine group and 17.6% in the tacrolimus group. Furthermore, groups showed no significant differences in transplanted renal function. No notable differences in adverse events were observed between groups.. A regimen of high-dose mizoribine in combination with calcineurin inhibitors basiliximab, and corticosteroids can provide effective immunosuppression while lowering the rate of cytomegalovirus infection in kidney transplant patients.

Topics: Adult; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Ribonucleosides; Survival Rate; Tacrolimus; Treatment Outcome

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

Topics: Anti-Bacterial Agents; Female; Follow-Up Studies; Humans; Hypersensitivity; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Macrolides; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; 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

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

This analysis compared efficacy, renal function, and histology in kidney transplant recipients receiving tacrolimus (TAC) combined with everolimus (EVR) or mycophenolate (MPS).. This was a retrospective analysis from a randomized trial in kidney transplant recipients who received a single 3 mg/kg dose of rabbit antithymocyte globulin (r-ATG), TAC, EVR, and prednisone (PRED; r-ATG/EVR, n = 85), basiliximab (BAS), TAC, EVR, and PRED (BAS/EVR, n = 102) or BAS, TAC, MPS, and PRED (BAS/MPS, n = 101). We evaluated the incidence of de novo donor-specific anti-human leukocyte antigens antibodies (DSA) and histology on protocol biopsies at 12 months, and the incidence of acute rejection, estimated glomerular filtration rate (eGFR) and proteinuria at 36 months.. At 12 months, there were no differences in de novo DSA (6.4 vs. 3.4 vs. 5.5%) or in subclinical inflammation (2.0 vs. 4.8 vs. 10.2%), interstitial fibrosis/tubular atrophy (57.1 vs. 58.5 vs. 53.8%) and C4d deposition (2.0 vs. 7.3 vs. 2.6%). At 36 months, there were no differences in the incidence of treatment failure (19.0 vs. 27.7 vs. 27.7%, p = 0.186), first biopsy-proven acute rejection (9.5 vs. 21.8 vs. 16.8%, p = 0.073), and urine protein/creatinine ratios (0.53 ± 1.05 vs. 0.62 ± 0.75 vs. 0.71 ± 1.24). eGFR was lower in the BAS/EVR compared to that in the BAS/MPS group (53.4 ± 20.9 vs. 50.8 ± 19.5 vs. 60.7 ± 21.2 mL/min/1.73 m2, p = 0.017) but comparable using a sensitive analysis (49.5 ± 23 vs. 47.5 ± 22.6 vs. 53.6 ± 27.8 mL/min/1.73 m2, p = 0.207).. In this cohort, the use of EVR and reduced TAC concentrations were associated with comparable efficacy, renal function, and histological parameters compared to the standard-of-care immunosuppressive regimen.

Topics: Adult; Allografts; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Biopsy; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Tissue Donors; Treatment Failure; Treatment Outcome; Withholding Treatment; Young Adult

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged-release tacrolimus-based immunosuppressive regimens. On Days 0-27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolonged-release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m

Topics: Adrenal Cortex Hormones; Adult; Aged; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors; Transplant Recipients; Treatment Outcome

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

Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population.. Randomized noninferiority crossover trial (noninferiority margin, -2.8mmHg).. Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m. Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout).. Average daytime (9 am to 9 pm) ambulatory SBP.. Blood pressure and laboratory parameters.. 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size, -4.2 [95% CI, -7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size, -65 [95% CI, -108 to -35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P<0.05 for both). In contrast, chlorthalidone temporarily reduced kidney function and increased both serum uric acid and glycated hemoglobin levels.. Open-label design, short follow-up, per-protocol analysis.. Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Chlorthalidone; Cross-Over Studies; Edema; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Proteinuria; Tacrolimus; Treatment Outcome

To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).. This is an open randomised controlled parallel group study.. Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.. 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).. TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.. Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Creatinine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Recurrence; Tacrolimus; Time Factors; Treatment Outcome; 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

To evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients.. Prospective safety analysis of data from a prospective, randomized, open-label, controlled study.. A total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group).. Both groups were followed for 24 months after transplantation for immunosuppressive regimen-associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs. 98%) and SAEs (27% vs. 30%). The most common AEs were gastrointestinal (70% vs. 54%, p=0.23) and infection (77% vs. 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs. 0%, p=< 0.01), sinusitis (10% vs. 0%, p=0.01), dermatitis (15% vs. 3%, p=0.03), and dyslipidemia (35% vs. 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.01, p<0.05) and skin and subcutaneous tissue (HR 2.5, 95% CI 1.1-4.1, p<0.05) AEs in the SRL/MPS group compared with the TAC/MPS group. AE-related dose reductions occurred in 18.3% of patients receiving SRL and 3.3% of patients receiving TAC. MPS dose reductions due to AEs occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC.. SRL/MPS treatment was associated with a time-dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AEs, which occurred mainly during the first 6 months after conversion from TAC/MPS. Although the treatments with SRL or TAC after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AEs.

Topics: Adult; Brazil; Calcineurin Inhibitors; Drug Eruptions; Drug Monitoring; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Severity of Illness Index; Sirolimus; Subcutaneous Tissue; Tacrolimus; TOR Serine-Threonine Kinases

High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.

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

Graft failure due to chronic rejection is greater among renal transplant patients with donor-specific antibody (DSA) than among DSA-free patients. For patients dependent on deceased donor transplantation, preoperative desensitization to eliminate DSAs may be impractical. We speculated that perioperative desensitization might eliminate preexisting DSAs and prevent de novo DSAs and improve graft outcomes. We report that brief perioperative desensitization using either intravenous immunoglobulin (IVIG) or plasmapheresis/IVIG (PP/IVIG) treatment improves clinical outcomes among patients with positive crossmatches.. Immediately following deceased donor transplantation, 235 renal recipients were assigned points for PRA and flow crossmatches (FCXM): delayed graft function (DGF) ≤ 1 point received standard therapy; 2 points received high-dose IVIG; and ≥3 points received PP/IVIG. The DSAs were serially monitored by single antigen bead luminex for 1 year. Five-year clinical outcomes were determined from the chart review.. All desensitized patients had preoperatively positive FCXM with DSA. Rejection was more common (P < .05) among desensitized than nonsensitized groups. However, overall graft survivals were similar between the groups (P = not significant) and superior to historic untreated patients (P < .05). Treatment with PP/IVIG more effectively eliminated preexisting DSAs (67% vs 33%, P < 0.05) than IVIG, but neither regimen prevented de novo formation of DSA (20%, P = not significant). Graft survival was >90% in all desensitizated patients with DSA elimination as well as PP/IVIG patients with residual DSA. In contrast, IVIG patients with persistent DSA had poorer graft survival (45%, P < .05).. Preemptive perioperative desensitization improved overall graft survival of sensitized patients compared to historic untreated patients. Plasmapheresis/IVIG had greater impact on DSA eradication and graft survival than IVIG alone.

Topics: Adult; Antibodies; Antilymphocyte Serum; Cadaver; Cohort Studies; Delayed Graft Function; Desensitization, Immunologic; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone Hemisuccinate; Middle Aged; Mycophenolic Acid; Perioperative Care; Plasmapheresis; Tacrolimus

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

Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients.. Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis.. This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus.. NCT01551212 .

Topics: Adult; Calcineurin Inhibitors; Clinical Protocols; Drug Therapy, Combination; Everolimus; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Liver Transplantation; Middle Aged; Research Design; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

New-onset diabetes after transplant (NODAT) is associated with serious morbidity and mortality. The incidence of NODAT is higher with tacrolimus (Tac) compared with cyclosporine (CsA); however, the effects of switching from Tac to CsA in NODAT have not been studied well.. This was a single-center, open-label, prospective, randomized study, including renal transplant recipients who were on Tac-based immunosuppression and developed NODAT. Those with pretransplant diabetes, hypersensitivity to CsA or Tac, severe infections, and denying consent were excluded. Subjects were randomized to either switch to CsA or to continue on Tac. Fasting and postprandial plasma glucose, fasting insulin and C-peptide levels, insulin and oral hypoglycaemic agents (OHA) use were monitored monthly for 3 months, whereas glycosylated haemoglobin (HbA1c) was checked at baseline and 3 months.. Sixty-seven subjects were randomized to switch to CsA (n = 32) or continuation of Tac (n = 35). Both groups had similar baseline characteristics. After randomization, there was significant improvement in fasting plasma glucose, fasting insulin levels, C-peptide levels, and insulin requirement in both groups, whereas HbA1c improved significantly only in the CsA group. The decline in fasting plasma glucose and insulin requirement was more significant in subjects on CsA. An equal number of subjects in each group (59.4% in CsA group and 40% in Tac group, P = ns) had resolution of NODAT. Weight gain was more significant in the CsA group; however, there was no difference in other side effects or rejection episodes.. A switch from tacrolimus to cyclosporine is a safe and effective strategy in patients with NODAT.

Topics: Adult; Cyclosporine; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; India; Kidney Failure, Chronic; Kidney Transplantation; Male; Pilot Projects; Prospective Studies; Tacrolimus

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

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

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

The once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes.. This open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m(2). The prespecified noninferiority margin was 12.5%.. The per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan-Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, -1.6%; 95% confidence interval [CI], -12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, -3.5%; 95% CI, -13.6% to 6.6%) or Arm 4 (difference, -7.1%; 95% CI, -16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m(2)) was the main determinant of composite-endpoint efficacy failure across all arms.. In patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD.

Topics: Adult; Biopsy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Treatment Outcome

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

To evaluate and compare the pharmacokinetic parameters of sublingual and oral tacrolimus in the presence and absence of a drug that interacts with tacrolimus at the intestinal level.. Prospective, randomized, open-label, parallel-group pilot study.. Large, urban, academic medical center.. Six adults with end-stage renal disease who were awaiting kidney transplantation; five completed the study.. Patients were randomized in a 1:1 ratio to receive tacrolimus plus a clotrimazole troche (a drug that interacts with tacrolimus at the intestinal level) or tacrolimus plus nystatin suspension. For the tacrolimus route of administration, patients first received sublingual tacrolimus for five doses; after a 2-day washout period, they received oral tacrolimus for five doses.. Demographic characteristics, concomitant medications, tacrolimus dosing information, and steady-state venous whole blood specimen values after tacrolimus administration were collected. Noncompartmental pharmacokinetics were calculated from the tacrolimus blood concentrations in samples collected at multiple time points after drug administration. The area under the concentration-time curve from 0-6 hours for sublingual and oral tacrolimus ranged from 27.2-66 and 32.4-76 mg·hour/L, respectively, in the tacrolimus plus clotrimazole group and from 9.3-63 and 4.9-23.2 mg·hour/L, respectively, in the tacrolimus plus nystatin group. The average maximum concentration was higher during sublingual administration than during oral administration: 16.7 versus 12.9 ng/ml in the tacrolimus plus clotrimazole group and 9.5 versus 6 ng/ml in the tacrolimus plus nystatin group.. An oral-to-sublingual tacrolimus dose conversion should be evaluated on an individual basis. A 1:1 dose conversion may be appropriate in the presence of clotrimazole, whereas a 2:1 oral-to-sublingual conversion may be appropriate when there are no concomitantly interacting drugs. These findings should be investigated further in pharmacokinetic studies conducted in solid organ transplant recipients.

Topics: Administration, Oral; Administration, Sublingual; Adult; Aged; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Pilot Projects; Prospective Studies; Tacrolimus

The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation.. Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm.. The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm.. This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded.

Topics: Adrenal Cortex Hormones; Adult; Blood Chemical Analysis; Blood Pressure Determination; Body Mass Index; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Syndrome; Middle Aged; Monitoring, Physiologic; Mycophenolic Acid; Prognosis; Reference Values; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

This multicenter, open, phase IIIb study assessed short-term efficacy, safety and dose adjustments in adult stable renal transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients receiving unchanged tacrolimus BID for ≥ 12 weeks were enrolled, and after 6-weeks, converted from tacrolimus BID to QD (morning dose) on a 1 : 1 (mg : mg) total daily dose basis, for a further 12 weeks. Primary endpoint: change in steady-state creatinine clearance between treatment phases. Secondary endpoints: biopsy-proven acute rejection (BPAR), patient and graft survival, safety. 128 patients enrolled (mean age 48.9 years; time post-transplant 48.9 months); 91 evaluated for the primary endpoint. Mean total daily dose was 0.06 mg/kg (BID) and 0.07 mg/kg (QD); 79.1% required one/no dose changes post-conversion to maintain recommended blood-trough levels; average dose increase was small (0.6-0.7 mg/day) with more dose increases in patients on the lowest tacrolimus BID doses. Renal function remained stable and non-inferiority of tacrolimus QD against tacrolimus BID was demonstrated. There were no BPAR episodes; patient and graft survival were 100%. Adverse events were few; none led to dose modifications/discontinuation. Tacrolimus BID to tacrolimus QD conversion is straightforward and does not compromise renal function in stable kidney transplant patients in the short term.

Topics: Adult; Biopsy; Delayed-Action Preparations; Europe; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Treatment Outcome

Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen.. A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD).. In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001).. Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Topics: Adult; Antibiotics, Antineoplastic; Antibodies, Anti-Idiotypic; Drug Combinations; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Prognosis; Receptors, Interleukin-2; Retrospective Studies; Survival Rate; Tacrolimus

The effects of calcineurin inhibitors on oxidative stress after renal transplant are obscure. This study sought to investigate the changes in plasma oxidative stress and lipid levels in patients receiving cyclosporine or tacrolimus before and after renal transplant for 6 months.. Twenty-one patients and 15 healthy controls were involved in our study. Twelve of the patients were treated with cyclosporine and 9 were treated with tacrolimus. Plasma malondialdehyde, nitrite/nitrate, vitamin C, vitamin E, and plasma glutathione levels, as well as total cholesterol and triglyceride levels, were evaluated before and after transplant for 6 months.. Before the transplant, patients had higher malondialdehyde and plasma glutathione levels than did healthy controls (3.76 ± 0.79 nmol/mL vs 3.21 ± 0.57 nmol/mL; P < .05, and 66.6 ± 23.2 μmol/L vs 43.3 ± 26.9 μmol/L; P < .05). In the overall group of patients, a significant increase in malondialdehyde levels was detected 3 and 6 months after transplant (3.76 ± 0.79 nmol/mL vs 4.38 ± 0.87 nmol/mL in the third month; P = .02; and 3.76 ± 0.79 nmol/mL vs 4.28 ± 0.69 nmol/mL in the sixth month; P = .04). A significant reduction in plasma glutathione levels 1 month after transplant and nitrite/nitrate levels 6 months after transplant was found. No changes in vitamin C and vitamin E levels were detected before and after transplant. After 3 and 6 months of transplant, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides when compared with tacrolimus-treated patients.. An enhancement in plasma malondialdehyde levels was found after transplant at 6-month follow-up. However, no significant change in vitamin C, vitamin E, nitrite/nitrate levels between patients and controls was recorded. Although both calcineurin inhibitors showed similar effects on oxidative stress, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides.

Topics: Adult; Antioxidants; Ascorbic Acid; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glutathione; Humans; Kidney Failure, Chronic; Kidney Transplantation; Lipids; Male; Malondialdehyde; Middle Aged; Nitrates; Nitrites; Oxidative Stress; Tacrolimus; Vitamin E; Young Adult

We investigated the safety and efficacy of Campath induction and tacrolimus (TAC) maintenance therapy compared to ATG induction with TAC +MMF + steroids in de novo kidney-pancreas transplanted patients.. 14 patients (Group A) received Campath 30 mg + methylprednisolone 500 mg before revascularization followed by TAC monotherapy, and 16 patients (Group B) ATG 8 mg/kg with TAC + MMF+ steroids (withdrawn at month 3). TAC trough levels (ng/mL) of 12-15 were aimed for in both groups until month 6 and thereafter 6-12.. 1-year patient survival was 100% in both groups; kidney and pancreas survival in Group A was 93% each. In Group B 1-year kidney and pancreas survival was 100% and 87%, respectively. A total of three pancreas grafts were lost due to thrombosis of the graft vein within the first month. The only kidney loss was due to initial non-function. All biopsy-proven acute rejections of renal transplants (n=3 in Group A, n=0 in Group B) were reversible. No acute pancreas graft rejection was demonstrated. Infectious complications, lipid metabolism and blood pressure were comparable in both groups, as were other adverse events. No tumor occurred. At 12 months 13 patients in each group were steroid-free; the mean serum creatinine level was 1.44 mg/dL in Group A and 1.33 mg/dL in Group B. All patients were exogenous insulin-free.. At one year efficacy and safety of Campath +TAC monotherapy were comparable to those of ATG + TAC + MMF + steroids in a limited number of combined kidney-pancreas transplant recipients.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Maintenance Chemotherapy; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

The aim of this study was to determine the relationship between single-nucleotide polymorphisms (SNPs) in MRP2 genes and mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients of the Symphony Pharmacogenomic substudy.. Sixty-six renal transplant recipients of eight Spanish centres were randomized into four branches of immunosuppressive regimen: low dose of cyclosporine, standard dose of cyclosporine, tacrolimus and sirolimus, all in addition to mycophenolate mofetil and steroids. Fifty-five patients were genotyped for SNPs in MRP2, C24T and C3972T. Pharmacokinetic sampling was done before MPA administration and up to 12 h post-dose at Day 7, 1 month and 3 months post-transplant. Relationships of area under the curve (AUC) of MPA and MPAG plasma sampling with the presence of MRP2 SNPs and with the immunosuppressive regimens were studied.. At steady-state conditions, MPA-reduced exposure was observed in C24T variant allele in MRP2 (CC: 68.73 ± 6.78; *T: 48.12 ± 4.90, P = 0.023); no significant differences linked to C3972T SNP were observed. Taking into account groups of treatment, lower MPA AUC in variant allele of C24T was only found under macrolides treatment with statistically significant differences at Month 3 (Tac and SRL, CC: 86.52 ± 10.98 versus *T: 41.99 ± 4.82, P = 0.001; CsA, CC: 52.31 ± 5.30 versus *T: 54.24 ± 8.30, P = 0.772); for C3972T, the same tendency was found but differences at steady state did not reach statistical significance.. Renal transplant recipients T carriers of C24T MRP2 with macrolides treatment were associated with reduced MPA AUC in steady-state conditions. Patients treated with cyclosporine lost the effect of this polymorphism.

Topics: Area Under Curve; Cyclosporine; DNA; Female; Follow-Up Studies; Genotype; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Microfilament Proteins; Middle Aged; Mycophenolic Acid; Pharmacogenetics; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Prognosis; Sirolimus; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tacrolimus

More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown.. We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group).. In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons).. Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

Topics: Adult; Case-Control Studies; Desensitization, Immunologic; Female; Histocompatibility Testing; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Renal Dialysis; Tacrolimus; Transplantation Conditioning; Transplantation Immunology

FTY720 (fingolimod), a novel immunomodulator, has demonstrated potential for prevention of acute rejection in combination with cyclosporine.. This study evaluated FTY720 2.5 mg versus mycophenolate mofetil (MMF) in a combination regimen with standard tacrolimus and corticosteroids in de novo renal transplant recipients for the composite efficacy within 6 months of transplantation.. Incidence of treated biopsy-proven acute rejection was 22.9% with FTY720 and 18.5% with MMF. Increased incidence of macular oedema, transient decrease in heart rate and low rate of infections were seen in the FTY720 arm.. FTY720 combined with tacrolimus and steroids did not show a significant therapeutic advantage over MMF for the prevention of acute rejection in de novo renal transplant recipients.

Topics: Adolescent; Adult; Aged; Cyclosporine; Drug Therapy, Combination; Female; Fingolimod Hydrochloride; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Propylene Glycols; Sphingosine; Survival Rate; Tacrolimus; Young Adult

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

Little is known about the influence of calcineurin inhibitors on advanced oxidation protein products (AOPP) and total antioxidant status (TAS) after renal transplantation.. AOPP and TAS were evaluated in transplanted patients on different calcineurin inhibitors. Thirty-five patients were treated with cyclosporine A (group A) and 33 with tacrolimus (group B).. Over 6 months, the mean levels of AOPP in group A decreased from 205.9+/-125.7 to 140.9+/-78.9 micromol/L and TAS from 1.89+/-0.30 to 1.75+/-0.27 mmol/L. In group B, the mean levels of AOPP decreased from 196.5+/-123.9 to 129.6+/-63.8 micromol/L and TAS from 1.80+/-0.39 to 1.78+/-0.23 mmol/L.. No significant differences in AOPP and TAS were found with respect to treatment. The only exception was the higher mean concentration of AOPP at month 1 in group A (p=0.026).

Topics: Adult; Aged; Antioxidants; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Oxidative Stress; Proteins; Tacrolimus

Clinical data are lacking concerning therapeutic action and systemic exposure of tacrolimus (TAC) and everolimus (EVL) in a combined regimen in renal transplantation.. A prospective randomized phase II pharmacokinetic study was conducted comparing two fixed EVL dosages (0.75 mg two times per day (BID), group A, or 1.5 mg BID, group B) in combination with standard TAC dose. Complete 12-hr pharmacokinetic curves of both drugs were performed at days 4, 14, and 42 posttransplant.. A higher TAC Cmin was observed with EVL dose of 0.75 mg BID (TAC 11.1+/-6.4 group A vs. 9.4+/-5.0 ng/mL group B, P=0.03), with equivalent TAC area under the curves (162+/-61 vs. 171+/-75). The exposure to TAC was lower in group B despite higher TAC doses were required to maintain target concentrations (day 14: 9.5 vs. 12.5 mg and day 42: 6 vs. 9 mg, P<0.05). Cmin-TAC/dose and area under the curve-TAC/dose ratios were significantly lower, from day 4 to day 42, in group B. Both groups achieved good graft function and acute rejection rate was similar (20% and 15%, respectively).. We conclude that in adult renal transplant recipients, EVL significantly decreases TAC oral bioavailability in a dose-dependent manner. Doses higher than 1.5 mg BID would be probably needed for TAC-minimization strategies because 3 mg/day is not enough to achieve levels more than 3 ng/mL during the first 2 weeks. Therapeutic drug monitoring is mandatory to adjust the dose and prevent low TAC exposure. This regimen of low EVL exposure plus standard TAC exposure avoids wound healing problems with good efficacy.

Topics: Acute Disease; Administration, Oral; Adult; Biological Availability; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Spain; Tacrolimus; Treatment Outcome; Young Adult

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard-dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 +/- 0.32 with TAC/MMF/DAC and 0.03 +/- 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04-0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05-0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy-proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Daclizumab; Growth; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Steroids; Tacrolimus

Everolimus (Evl) plus tacrolimus (Tac) in de novo renal transplantation is effective and safe. Whether the concentration of Evl affects efficacy and safety in a Tac-based regimen has not been previously reported.. To evaluate whether the concentration of Evl affects biopsy-proven acute rejection (BPAR), renal function, adverse events (AEs); and to assess for pharmacokinetic (PK) interactions.. Data were from a prospective, multicenter, open-label, randomized, exploratory 6-month study of 92 renal transplant patients treated de novo with concentration-controlled Evl (target trough levels > or =3 ng/mL) plus low-dose Tac or Evl plus standard-dose Tac; both groups received basiliximab and corticosteroids. Data were pooled across study arms to examine BPAR rates in patients with Evl trough levels less than 3 (n=26), 3 to 8 (n=62), or more than 8 ng/mL (n=4). Groups were stratified by both Evl and Tac trough levels to evaluate glomerular filtration rate and AEs. Evl and Tac PK interactions were evaluated in a subset of 14 patients.. Evl trough level of more than or equal to 3 ng/mL was associated with significantly lower rates of BPAR as compared with a trough level of less than 3 ng/mL. Glomerular filtration rate was similar at 6 months for both the low and standard Tac groups. No apparent PK interactions were observed between Evl and Tac. AEs were infrequent and did not seem to be associated with the Evl or Tac level.. Evl trough levels > or =3 ng/mL plus Tac are associated with low rates of BPAR without adversely affecting renal function. No evident PK interaction exists between Evl and Tac.

Topics: Adult; Biopsy; Cadaver; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Sirolimus; Tacrolimus; Tissue Donors

It is reported that a conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) relieves gastrointestinal (GI) symptom burden and improves health-related quality of life (HRQoL). However, it is unclear whether renal transplant recipients using tacrolimus receive the same benefit from the conversion. In this prospective, multi-center, open-label trial, patients were categorized into two groups by their GI symptom screening. Equimolar EC-MPS (n=175) was prescribed for patients with GI burdens; those with no complaints remained on MMF (n=83). Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) were evaluated at baseline and after one month. Patients and physicians completed Overall Treatment Effect (OTE) at one month. EC-MPS-converted patients had worse GSRS and GIQLI scores at baseline than MMF-continued patients (all P<0.001). Significant improvements in GSRS and GIQLI scores were observed for EC-MPS-converted patients at one month, but MMF-continued patients showed worsened GSRS scores (all P<0.05). OTE scale indicated that EC-MPS patients improved in overall GI symptoms and HRQoL more than MMF patients did (P<0.001). In tacrolimus-treated renal transplant recipients with GI burdens, a conversion from MMF to EC-MPS improves GI-related symptoms and HRQoL.

Topics: Adolescent; Adult; Aged; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Quality of Life; Surveys and Questionnaires; Tablets, Enteric-Coated; Tacrolimus

The impact of pretransplant T-cell sensitivity testing using carboxylfluorescein diacetate succinimidyl ester (CFSE)-based flow cytometry was studied in 32 patients with chronic renal failure. There was considerable interindividual variation in the inhibitory effects of cyclosporine (CSA), tacrolimus (TAC), and prednisolone (PRD) but only a small amount of interindividual variation for mycophenolic acid (MPA). Patients with high sensitivity to CSA tended to experience viral reactivation. In addition to post-transplant blood-level monitoring, pretransplant pharmacodynamics could provide useful information on optimal and safe immunosuppressive therapy.

Topics: Adult; Cell Proliferation; Cyclosporine; Female; Fluoresceins; Fluorescent Dyes; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prednisolone; Prospective Studies; Succinimides; T-Lymphocytes; Tacrolimus

Increasing long-term allograft survival is the main challenge in organ transplantation, and allograft loss due to chronic rejection has been found to correlate with episodes of early acute rejection. It is important to understand the mechanisms that maintain the donor-specific hyporesponsive state. This study prospectively evaluates immune events related to donor-specific hyporesponsiveness in the stable transplant patients on calcineurin inhibitors (CNIs).. Peripheral blood mononuclear cells of transplant recipients on CNI (n=19) were tested in mixed lymphocyte reaction (MLR) against donor and third-party peripheral blood mononuclear cells pretransplant and at 6 to 8 weeks, 14 to 18 weeks, and 6 to 8 months posttransplant. Interleukin (IL)-10 and transforming growth factor-beta were quantitated in cultures supernatants by enzyme-linked immunosorbent assay. CD4CD25 T-regulatory cells (Tregs) were enumerated using flow cytometry.. All patients showed sharp decline in anti-donor and third-party MLR response at 6 to 8 weeks posttransplant with progressive decline up to 6 to 8 months. This was accompanied by increased IL-10 levels in the supernatant at all the follow-ups. Transforming growth factor-beta level in the supernatant was significantly lower at 14 to 18 weeks. Frequency of CD4CD25 Tregs showed a significant decrease at 6 to 8 weeks posttransplant, which was sustained up to 6 to 8 months.. The study shows that the maintenance of good graft function in early posttransplant period in recipients on CNI is associated with a decrease in donor-specific and third-party MLRs. There is a decline in Treg numbers along with increased IL-10 levels. High IL-10, probably from a non-Tregs source, may have an important role in maintaining hyporesponsiveness and good graft function.

Topics: Adult; Calcineurin Inhibitors; Cell Proliferation; Cells, Cultured; Cyclosporine; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Female; Graft Survival; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Count; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Time Factors; Transforming Growth Factor beta; Transplantation Tolerance; Up-Regulation; Young Adult

The aim of this study was to evaluate the efficiency and safety of simultaneous islet and kidney transplantation in patients with type 1 diabetes and end-stage renal disease using a glucocorticoid-free immunosuppressive regimen with alemtuzumab induction.. Seven patients with type 1 diabetes and end-stage renal failure were transplanted with allogenic islets and kidneys procured from brain-dead donors. To prevent organ rejection, patients received alemtuzumab for induction immunosuppression, followed by sirolimus and tacrolimus. No glucocorticoids were given at any time.. The median duration of follow-up was 18.3 months (range 13-31). Kidney survival was 100%. Four patients became insulin independent at 1 year. The other three reduced insulin use to less than 25% of the amount required before transplantation. Serum C-peptide levels were significantly greater posttransplant in all patients, indicating continued islet function. No major procedure-related complications were observed.. Our results demonstrate that a steroid-free immunosuppressive regimen consisting of alemtuzumab, sirolimus, and tacrolimus is feasible for simultaneous islet and kidney transplantation. The question of whether this induction regimen is superior to more standard induction deserves large studies.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Diabetes Mellitus, Type 1; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Function Tests; Male; Middle Aged; Pilot Projects; Sirolimus; Tacrolimus

Clinical data are lacking concerning concomitant administration of everolimus and tacrolimus in renal transplant recipients.. In a prospective, multicenter, open-label, exploratory, randomized, 6-month study, 92 de novo renal transplant patients received everolimus, steroids, and basiliximab with low or standard tacrolimus exposure. The primary objective was to compare renal function at 6 months after transplant.. Mean 6-month serum creatinine (primary safety variable) was 112+/-31 micromol/L (1.26+/-0.35 mg/dL) and 127+/-50 micromol/L (1.44+/-0.57 mg/dL) in the low and standard tacrolimus groups, respectively, (n.s.); mean estimated GFR (Nankivell) was 75.3+/-16.6 mL/min and 72.5+/-15.2 mL/min (n.s.). Biopsy-proven acute rejection occurred in 13 patients: seven (14%) in the low tacrolimus group and six (14%) in the standard tacrolimus group, n.s. One graft was lost in the standard tacrolimus group. No patients died.. Tacrolimus exposure reduction in the presence of everolimus, steroids and basiliximab induction results in good efficacy in de novo renal transplant recipients with very well-preserved renal function. Additional studies are warranted because between-group comparisons were limited by the relatively small differences in tacrolimus exposure in the 2 arms; trough levels were toward the upper end of the low-exposure ranges and toward the bottom of the standard-exposure ranges.

Topics: Adult; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Sirolimus; Tacrolimus; Tissue Donors

To investigate the feasibility and safety of substituting tacrolimus(FK506) for cyclosporin A(CsA) on delaying the pace of renal dysfunction in patients with biopsy-proven chronic allograft nephropathy(CAN).. Seventy-three renal transplantation patients with CAN proved by allograft biopsy were collected in this study. Patients were randomly divided into 2 groups. Patients were either converted to FK506(FK506 group, n=43) or remained on their initial CsA-based immunosuppression(CsA group, n=30). The clinical data at study entry and after 12 months including blood urea nitrogen(BUN), serum creatinine(SCr), glomerular filtration rate(GFR), 24-hour urine protein excretion, serum total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL) and the side effects of calcineurin inhibitors were monitored during a follow-up of over 12 months.. Twelve months later, the level of SCr was statistically reduced and GFR levels were obviously elevated in the FK506 group as compared with CsA group [(194.8+/-42.5)micromol/L vs. (245.4+/-52.8)micromol/L and (50.14+/-3.92)mL/(min.1.73 m(2)) vs. (40.58+/-2.49)mL/(min.1.73 m2), P<0.01]. Quantity of 24-hour urine protein excretion in the FK506 group was (2.0+/-0.5)g which is significantly lower than (3.9+/-0.7)g in the CsA group(P<0.01). TC, TG, and LDL levels remained unchanged in the CsA group, while those were statistically reduced in the FK506 group respectively [(5.19+/-0.73)mmol/L vs. (6.94+/-1.37)mmol/L, (1.86+/-0.84)mmol/L vs. (3.14+/-1.38)mmol/L, (3.03+/-0.71)mmol/L vs. (3.82+/-0.89)mmol/L, P<0.01]. Tremor obviously increased (P<0.01) and hypertension obviously decreased (P<0.05) in the FK506 group compared with the CsA group.. FK506 treatment can greatly improve the proteinuria and hyperlipidemia. Conversion from CsA to FK506 is an effective and safe alternative therapy for delaying the progression of renal dysfunction induced by CAN.

Topics: Adult; Aged; Cholesterol; Creatinine; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lipoproteins, LDL; Male; Middle Aged; Tacrolimus; Treatment Outcome; Triglycerides

Cardiovascular diseases are the most important causes of death in patients with chronic renal disease (CRD). Successful renal transplantation (RTx) corrects water and electrolyte disturbances and decreases or eliminates anaemia. It favourably influences cardiac haemodynamics and reduces risk of cardiovascular events. NT-proBNP plasma concentration is one of the prognostic and risk factors in such cases, whereas echocardiography that enables evaluation of the left atrium and ventricle allows detailed analysis of haemodynamic condition of the heart.. To analyse NT-proBNP plasma concentration and selected echocardiographic parameters in patients after RTx at various time intervals after the procedure.. Seventeen patients after RTx were included in the study (age 46.5+/-16 years, 7 men and 10 women). NT-proBNP plasma level measurements and echocardiography were performed immediately before and at 3 and 6 months after RTx. Additionally, these parameters were assessed in patients receiving cyclosporine A (CsA) and tacrolimus (TAC).. NT-proBNP plasma level decreases significantly after RTx (initially 4369+/-2420, at 3 months 2056+/-576, at 6 months 1580+/-572 pg/ml). In the TAC group, a significant reduction was observed at 3 months (from 13291+/-3563 to 1845+/-1022 pg/ml). In patients treated with CsA reduction occurred at 6 months after RTx (from 9447+/-3369 to 1246+/-436 pg/ml). At six-month follow-up significant changes in ejection fraction were not found. However, a significant increase in LV mass in CsA patients was observed.. Reduction of NT-proBNP levels seems to be more the result of transplanted kidney function than of an improvement in circulation. Significant LV mass increase in CsA patients may be a result of higher blood pressure levels observed before and after RTx.

Topics: Adult; Cardiovascular Diseases; Cyclosporine; Echocardiography; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Tacrolimus; Time Factors; Ventricular Function, Left

Solid organ transplantation in human immunodeficiency virus (HIV)-infected individuals requiring concomitant use of immunosuppressants (IS) (e.g. cyclosporine [CsA], sirolimus [SrL], tacrolimus [FK]) and antiretrovirals (ARVs) (e.g. protease inhibitors [PIs] and/or nonnucleoside reverse transcriptase inhibitors [NNRTIs]) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney-liver HIV-infected subjects with end-stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2-4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV-infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.

Topics: Adult; Anti-Retroviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Pilot Projects; Sirolimus; Tacrolimus

We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen.. This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half.. At study entry tacrolimus trough level (C0) was 7.9 +/- 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 +/- 56 ng x h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 +/- 4.0 ng/mL, AUC 134 +/- 70 ng x h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 +/- 1.2 ng/mL, Cmax 10.4 +/- 5.1 ng/mL, AUC 58 +/- 20 ng x h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 +/- 1.1 ng/mL, Cmax 8.2 +/- 1.3 ng/mL, AUC 49 +/- 10 ng x h/mL.. Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.

Topics: Adrenal Cortex Hormones; Adult; Aged; Area Under Curve; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Sirolimus; 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

Single-centre and retrospective studies suggest superiority of tacrolimus over cyclosporin as cornerstone immunosuppressive therapy for simultaneous pancreas-kidney (SPK) transplantation. This open-label, multicentre trial compared the efficacy and safety of tacrolimus with cyclosporin microemulsion (ME) in diabetic patients with end-stage renal disease undergoing their first cadaveric SPK transplantation. The 3-year results are reported.. Patients were recruited from 10 centres in Europe and one centre in Israel: 103 were randomized to receive tacrolimus (initial dose: 0.2 mg/kg/day p.o.) and 102 to cyclosporin-ME (7 mg/kg/day p.o.). All patients received concomitant rabbit anti-T-cell globulin induction, mycophenolate mofetil (MMF) and short-term corticosteroids.. Fewer patients receiving tacrolimus (36.9%) than cyclosporin-ME (57.8%) were discontinued from treatment (P = 0.003). The initial episodes of biopsy-proven rejection were moderate or severe in just one out of 31 (3%) tacrolimus-treated patients compared with 11 out of 39 (28%) patients receiving cyclosporin-ME (P = 0.009). While 3-year patient and kidney survival rates were similar in the two treatment groups, pancreas survival was superior with tacrolimus (89.2 vs 72.4%; P = 0.002). Thrombosis resulted in pancreas graft loss in 10 patients receiving cyclosporin-ME and in only two treated with tacrolimus (P = 0.02). Overall adverse event frequency was similar in both groups, but MMF intolerance was more frequent with tacrolimus and hyperlipidaemia more frequent with cyclosporin-ME.. In this 3-year study, tacrolimus was more effective than cyclosporin-ME in preventing moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreas survival and reduced the risk of pancreas graft thrombosis.

Topics: Adolescent; Adult; Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Emulsions; Europe; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Israel; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Prospective Studies; Safety; Tacrolimus; Treatment Outcome

This report examines the early and late secondary effects of tacrolimus, cyclosporin microemulsion (ME), mycophenolate mofetil (MMF) and rabbit anti-thymocyte globulin (rATG) in simultaneous pancreas-kidney (SPK) recipients.. Of the 205 patients participating in the Euro-SPK 001 study, 103 were randomized to tacrolimus (0.2 mg/kg) and 102 to cyclosporin-ME (7 mg/kg). All patients received rATG for 4 days [ATG-Fresenius (ATG-F) 4 mg/kg/day or Thymoglobulin (Thymo-S) 1.25 mg/kg/day] plus MMF and short-term corticosteroids.. Thymo-S induction therapy was associated with a lower white cell count in the first 3 months than was seen with ATG-F, while ATG-F caused a lower initial nadir in platelet count. Both polyclonal preparations were well tolerated and no clinically relevant differences were observed with respect to side effects such as infections and malignancies. High cyclosporin-ME trough levels were associated with pancreas graft thrombosis, and concentrations >150 ng/ml were associated with poor renal allograft function. Treatment discontinuation was higher with cyclosporin-ME (57.8%) than with tacrolimus-based therapy (36.9%) due to more frequent toxicity, graft loss and lack of efficacy requiring a switch to tacrolimus. The main reason for withdrawal in the tacrolimus group was MMF discontinuation; MMF-related side effects resulted in more frequent dose reductions to <2 g/day and discontinuations in the tacrolimus group, and indirectly indicate a higher dose-corrected exposure to mycophenolic acid, as previously observed in kidney transplant patients.. Short-term induction therapy is effective and well tolerated in patients undergoing SPK transplantation. Tacrolimus was the preferred immunosuppressive agent, resulting in fewer cases of pancreas graft loss and drug discontinuation compared with cyclosporin-ME.

Topics: Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukocyte Count; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Time Factors; Treatment Outcome

Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice for selected diabetic patients. Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patients' health, necessitating eventual discontinuation.. This prospective study evaluated the safety and feasibility of corticosteroid withdrawal in 205 SPK transplant recipients randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporin microemulsion (ME) and MMF (n = 102).. Corticosteroid withdrawal was successful in the majority of in-study patients (66% tacrolimus, 73% cyclosporin-ME). Compared with out-of-study patients or those continuing corticosteroid therapy, in-study patients withdrawn from corticosteroids experienced fewer pancreas or kidney graft losses, fewer episodes of acute rejection and were less likely to be withdrawn from the study. Acute rejection occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection-free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in the dose of both MMF and tacrolimus.. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate the positive effects on glucose metabolism and hypertension.

Topics: Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Europe; Feasibility Studies; Follow-Up Studies; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Israel; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Safety; Tacrolimus; Time Factors; Treatment Outcome; Withholding Treatment

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

We conducted a study to assess the safety of staged, late steroid withdrawal in kidney or kidney/pancreas transplant recipients on steroids, tacrolimus, and mycophenolate mofetil (MMF).. We studied 50 patients including 33 recipients of cadaveric kidneys, eight living donor kidneys, and nine kidney-pancreas transplants. The mean time posttransplantation was 5.1 years (range 2.1 to 7.9 years). All patients were induced on prednisolone, tacrolimus, and MMF; steroids were withdrawn over 5 to 6 months. The rate of steroid reduction was altered in the face of typical steroid withdrawal symptoms (limb-girdle arthralgia/myalgia).. No rejection episodes occurred during steroid withdrawal. No patient required transplant biopsy for graft dysfunction. Six patients failed steroid withdrawal: five due to arthralgia/myalgia and one due to recurrent pulmonary sarcoidosis. The unexplained rise in serum creatinine following steroid withdrawal described in several other steroid withdrawal studies was not observed in this patient cohort. The mean serum creatinine was 137 micromol/L with deltacreatinine -6.8 micromol/y per year prior to steroid cessation versus 132 micromol/L with deltacreatinine -5.9 micromol/y in the year post-steroid cessation. There were 14 patients with posttransplant diabetes mellitus in this cohort: eight on gliclazide and six on insulin. We observed a reduction in their daily insulin/gliclazide requirements from 52 units to 41 units, and 73 mg to 65 mg, respectively. Two patients became gliclazide-independent at the time of steroid cessation.. Careful steroid withdrawal from a platform of tacrolimus and MMF is safe and not associated with a significant risk of rejection or graft dysfunction.

Topics: Adult; Creatinine; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucocorticoids; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Safety; Tacrolimus; Time Factors

To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen.. The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66).. At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3+/-0.3 vs. 1.6+/-0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (17,723 +/- 11,647 dollars TAC vs. 16,515 +/- 10,189 dollars CsA).. When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.

Topics: Adult; Antilymphocyte Serum; Costs and Cost Analysis; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Missouri; Survival Analysis; Tacrolimus

Chronic renal allograft failure (CRAF) is the leading cause of graft loss post-renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine-treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels.. Patients receiving cyclosporine-based immunosuppression who had an elevated SCr at least 3 months post-renal transplantation were enrolled. Treatment allocation was 2:1 to switch to tacrolimus or continue cyclosporine. This analysis was performed after 2 yr; patients will be followed for an additional 3 yr.. There were 186 enrolled and evaluable patients. On baseline biopsy, 90% of patients had chronic allograft nephropathy. Baseline median SCr was 2.5 mg/dL in both treatment groups. For patients with graft function at month 24, SCr had decreased to 2.3 mg/dL in the tacrolimus-treated patients and increased to 2.6 mg/dL in the cyclosporine-treated patients (p = 0.01). Acute rejection occurred in 4.8% of tacrolimus-treated patients and 5.0% of cyclosporine-treated patients during follow-up. Two-year allograft survival was comparable between groups (tacrolimus 69%, cyclosporine 67%; p = 0.70). Tacrolimus-treated patients had significantly lower cholesterol and low-density lipoprotein levels and also had fewer new-onset infections. Cardiac conditions developed in significantly fewer tacrolimus-treated patients (5.6%) than cyclosporine-treated patients (24.3%; p = 0.004). Glucose levels and the incidences of new-onset diabetes and new-onset hyperglycemia did not differ between treatment groups.. Conversion from cyclosporine to tacrolimus results in improved renal function and lipid profiles, and significantly fewer cardiovascular events with no differences in the incidence of acute rejection or new-onset hyperglycemia.

Topics: Biopsy; Creatinine; Cyclosporine; Delayed Graft Function; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Severity of Illness Index; Tacrolimus; Treatment Outcome

The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy.. This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147).. The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively.. Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Drug Administration Schedule; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Survival Analysis; Tacrolimus; Treatment Failure; Treatment Outcome

Tacrolimus (Tac) is the most frequently used base inmunosuppressant for transplantation in Spain and the United States. However, long-term data on its use in renal transplant patients are lacking. The aim of this study was to analyze the 10-year outcome of patients from our institution treated with Tac or cyclosporine (CsA) who were included in the European Multicenter Study of kidney transplantation (1993 to 1994). This trial compared the efficacy and safety of steroids + Tac + azathioprine versus steroids + CsA + azathioprine at 1 year, showing a significantly lower acute rejection rate in Tac patients, with no differences in graft or patient survival. In our long-term analysis, we included patients with a functioning graft after the first year: 15 patients on Tac and 11 on CsA. In the "intent-to-treat" (ITT) analysis, patient survival was 14/15 (93%) versus 9/11 (82%) and death noncensored graft survival was 10/15 (67%) versus 8/11 (73%) in Tac and CsA, respectively. Analyzing patients "into treatment" (TT), death/noncensored graft survival was 11/16 (69%) versus 6/9 (67%), respectively. Serum creatinine tended to be lower in Tac group (ITT 1.26 +/- 0.42 vs 1.63 +/- 1.16 mg/dL, P = NS; TT 1.23 +/- 0.4 vs 1.86 +/- 1.28 mg/dL, P = NS). However, in the TT analysis, Tac patients exhibited a significantly better creatinine clearance (89.3 +/- 40 vs 46.8 +/- 21 mL/min, P = .037) and lower systolic blood pressure (125 +/- 5 vs 140 +/- 12 mm Hg, P = .007) at 10 years. No other significant differences were observed in blood pressure, lipid profile, or glucose metabolism. Outstandingly, Tac monotherapy was the most frequently used regimen after 10 years: ITT 6/9 (67%) versus 1/8 (12.5%), P = .05, TT 7/10 (70%) versus 0/6 (0%), P = .011. Patients under Tac monotherapy exhibited an excellent graft function (serum creatinine 1.08 +/- 0.14 mg/dL) and negative proteinuria, with Tac trough levels of 7.9 +/- 1.3 ng/mL. In summary, our results suggest that Tac-based immunosuppression provides an excellent kidney function 10 years after transplantation and allows monotherapy in a high percentage of kidney transplant patients.

Topics: Adult; Creatinine; Europe; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome

Previous investigations have shown that plasma selenium concentrations are significantly lower in patients with established chronic graft nephropathy (CGN) than in healthy transplant controls. The aims of this study were to determine when in the transplant process low selenium concentrations become apparent and to explore the relationship between selenium levels and risk factors for CGN.. Plasma selenium concentrations were measured in 40 patients (20 receiving cyclosporin, 20 receiving tacrolimus) undergoing transplantation. Samples were obtained immediately before transplantation and at 3, 6 and 12 months after transplantation.. A low plasma selenium concentration was found in 30 patients at the time of transplantation but this had normalized in the majority of patients by 3 months. Plasma selenium concentrations at 3, 6 and 12 months were significantly higher than baseline values for both treatment arms, but were significantly lower at 3 months in patients who experienced either clinical acute rejection (CAR) or cytomegalovirus (CMV) infection during the preceding months.. Low plasma selenium concentrations are common at the time of transplantation but appear to normalize thereafter. The identification of low selenium levels in patients who experience CAR or CMV (two important risk factors for clinically apparent CGN) suggests that the relationship between selenium and CGN warrants further investigation.

Topics: Adolescent; Adult; Aged; Cadaver; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Peripheral Nervous System Diseases; Selenium; Tacrolimus

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

We report 6-month results of renal allograft recipients enrolled in seven Australian centers as part of a worldwide, multicenter, randomized, open-label, concentration-controlled trial comparing standard tacrolimus (sTAC) with reduced tacrolimus (rTAC) both with sirolimus (SRL) and steroids. Patients were randomized 1:1 to either rTAC (n = 33) with a target maintenance concentration of SRL of 8 to 15 ng/mL and TAC of 3 to 7 ng/mL, or sTAC (n = 31) with SRL target of 5 to 10 ng/mL and TAC of 8 to 12 ng/mL. Antibody induction was prohibited. Adult recipients of a first or second cadaveric or non-HLA-identical living donor renal graft were eligible for enrollment. Recipients with a panel-reactive antibody level of >50% and recipients of regrafts who had lost their first graft from rejection within the first 6 months were ineligible. The groups were compared for graft function, incidence of rejection, and patient and graft survival at 6 months. There were no differences in demographics. There were 30% and 29% discontinuations in the rTAC and sTAC groups mainly due to adverse events in the first month. The 6-month patient and graft survival by intention-to-treat analysis was 94% and 91% for rTAC and 100% and 97% for sTAC (P = NS), respectively. Incidence and severity of biopsy-proven acute rejection was not different between the two groups, being 21% for rTAC and 19% for sTAC. The mean serum creatinine was 121 micromol/L and 148 micromol/L for rTAC and sTAC groups (P =.09), respectively. Glomerular filtration rate (GFR) was 68 mL/min and 62 mL/min (P =.23), respectively. Adverse events, infections, and antihypertensive and antilipidemic agent usage were similar. Of interest is that the overall incidence of thrombotic microangiopathy was 14%. These results support the safety and efficacy of SRL + TAC. Reduced TAC is associated with a trend toward improved renal function.

Topics: Adult; Allergy and Immunology; Australia; Ethnicity; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Sirolimus; Tacrolimus; Transplantation, Homologous

Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present-day comparative trial of tacrolimus vs. microemulsified cyclosporine A. In this 6-month study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) or cyclosporine A (n = 271) concomitantly with azathioprine and corticosteroids. The primary endpoint was the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline, and at months 1, 3, and 6. Ten-year risk of coronary heart disease was estimated according to the Framingham risk algorithm. Tacrolimus resulted in significantly lower summary measures (time-weighted average) of serum cholesterol (p = 0.0004) and mean arterial blood pressure (p = 0.0156), but in a higher summary measure of blood glucose (p = 0.0028) than cyclosporine. The summary measure of serum triglycerides was not different between treatment groups (p = 0.368). The mean 10-year coronary artery disease risk estimate was significantly lowered in men (p = 0.0032) treated with tacrolimus, but was unchanged in women. Tacrolimus and cyclosporine A microemulsion exert a compound-specific impact on cardiovascular risk factors and appear to affect the predicted rate of cardiovascular morbidity in different manners.

Topics: Calcineurin Inhibitors; Coronary Artery Disease; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Prospective Studies; Risk Factors; Survival Analysis; Tacrolimus

Acute allograft rejection is thought to be a risk factor for chronic allograft nephropathy, the cardinal features of which are vasculopathy, interstitial fibrosis and glomerulosclerosis. Fibrosis-associated genes might act as ad interim surrogate markers for chronic allograft nephropathy. The aim of this study was to determine mRNA expression of fibrosis-associated genes in glomeruli plucked from protocol renal transplant biopsies, in patients with or without a history of acute rejection.. A consecutive series of 52 patients (31 male, 21 female) was assessed. Donor categories were cadaveric, living related or asystolic. Transplant recipients received either cyclosporin- or tacrolimus-based immunosuppression. Patients routinely underwent percutaneous needle-core renal transplant biopsy at 1 week, and 3 and 6 months. Acute rejection episodes were confirmed histologically and treated with intravenous methylprednisolone, or antithymocyte globulin if steroid resistant. Individual glomeruli were plucked and total mRNA was extracted. Fibrosis-associated genes were amplified by reverse transcriptase-polymerase chain reaction (PCR) and quantified by enzyme-linked immunosorbent assay.. The expression of both collagen type III (mean 0.42 versus 0.31 arbitrary units of PCR products corrected for a housekeeping gene) and collagen IV (mean 0.46 versus 0.42 arbitrary units) at 6 months did not differ between recipients who experienced acute rejection episodes and those who were free from rejection. There was also no significant difference between groups in terms of mRNA expression of collagen IValpha2, matrix metalloproteinase 2, tissue inhibitor of matrix metalloproteinases 1 and 2, transforming growth factor beta or tenascin.. These results suggest that acute rejection episodes do not increase the expression of fibrosis-associated genes in glomeruli from renal transplant biopsies.

Topics: Acute Disease; Adolescent; Adult; Cyclosporine; Female; Fibrosis; Gene Expression; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; RNA, Messenger; Tacrolimus; Transforming Growth Factors; Transplantation, Homologous

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

Topics: Adolescent; Adult; Azathioprine; Cyclosporine; Drug Resistance; Emulsions; Europe; Follow-Up Studies; Graft Rejection; Humans; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Safety; Tacrolimus; Time Factors

Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure.. We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Phi, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean+/-SEM. MSNA was significantly elevated in hemodialysis patients (43+/-4 bursts/min), RTX-CSA (44+/-5 bursts/min), RTX-FK (34+/-3 bursts/min), and RTX-Phi (44+/-5 bursts/min) as compared with CON (21+/-3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20+/-3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44+/-6 versus 43+/-5 bursts/min, P=NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney.. Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Hemodynamics; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Muscle, Skeletal; Nephrectomy; Renal Dialysis; Sympathetic Nervous System; Tacrolimus; Uremia

Topics: Adult; Cholesterol; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Pancreas Transplantation; Pilot Projects; Prospective Studies; Sirolimus; Tacrolimus; Time Factors

Topics: ABO Blood-Group System; Adolescent; Adult; Blood Group Incompatibility; Child; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Plasmapheresis; Survival Rate; Tacrolimus; Time Factors

Cystatin C has recently been proposed as an alternative marker of glomerular filtration rate. The diagnostic value of plasma cystatin C for the longitudinal assessment of kidney function after renal transplantation, however, has not been addressed.. Renal function was evaluated in 30 adults receiving renal transplants (46 +/- 9 years, mean +/- SD) and in 56 healthy controls (38 +/- 10 years) using cystatin C. Plasma cystatin C was determined daily starting the day of surgery and for 3 weeks after surgery by an immunonephelometric assay.. Plasma concentration significantly decreased during the first week (-44% vs -29% for creatinine). Plasma cystatin C correlated with plasma creatinine (r = 0.741; P <0.0001) and the reciprocal of the creatinine clearance estimated by the Cockcroft-Gault formula (r = 0.882; P <0.001). In all three cases of acute renal impairment, the increase in plasma cystatin C values was more prominent than that of creatinine.. Plasma cystatin C is an alternative and accurate marker of allograft function in adult transplant patients. Increased sensitivity compared with creatinine for the detection of acute reduction in glomerular filtration rate allows in some cases a more rapid diagnosis of acute rejection or treatment nephrotoxicity.

Topics: Adult; Biomarkers; Creatinine; Cystatin C; Cystatins; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Nephelometry and Turbidimetry; Postoperative Period; Prospective Studies; Renal Dialysis; Steroids; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Drug Resistance; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphocytes; Male; Middle Aged; Tacrolimus; Treatment Outcome

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

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

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Treatment Failure

Between 14 December 1989 and 17 December 1993, 43 patients undergoing kidney transplantation alone at the Children's Hospital of Pittsburgh received FK506 as the primary immunosuppressive agent. The mean recipient age was 10.2 +/- 4.8 years (range 0.7-17.4 years), with 7 (16%) children under 5 years of age and 2 (5%) under 2 years of age. Fifteen (35%) children underwent retransplantation, and 5 (12%) had a panel-reactive antibody level greater than 40%. Twenty-two (51%) transplants were with cadaveric donors and 21 (49%) were with living donors. The mean follow-up was 25 +/- 14 months; there were no deaths; 1- and 3-year actuarial graft survival was 98% and 85%. The mean serum creatinine and blood urea nitrogen were 1.2 +/- 0.6 mg/dl and 26 +/- 11 mg/dl; the calculated creatinine clearance was 75 +/- 23 ml/min per 1.73 m2. Twenty-four (62%) patients have been successfully withdrawn from steroids and 24 (62%) require no anti-hypertensive medication. Improved growth was seen, particularly in pre-adolescent children off steroids. Between 28 July 1990 and 2 December 1993, 24 children were referred for rescue therapy with FK506, 14.6 +/- 16.4 months (range 1.1-53.2 months) after transplantation. Nineteen (79%) were referred because of resistant rejection; 4 (17%) were referred because of proteinuria; 1 (4%) was switched because of steroid-related obesity. There were no deaths; 1- and 2-year graft survival was 75% and 68%; 17 (71%) patients were successfully rescued, including 1 of 2 patients who arrived on dialysis; 4 (24%) of the successfully rescued patients were weaned off steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Antilymphocyte Serum; Child; Child, Preschool; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Survival Analysis; Tacrolimus

Topics: Adult; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Survival Rate; Tacrolimus; Time Factors

The authors examined the safety and pharmacokinetics of FK506, a new hepatically metabolized immunosuppressant, after single-dose intravenous (i.v.) infusion (20 micrograms.kg(-1) x 4 hours-1) and oral (80 micrograms/kg) administration in six nondialysis patients, aged 27 to 53 years, with chronic renal failure awaiting transplantation. A two-period, randomized, crossover study protocol was used with blood samples drawn for 72 hours after each dose and a washout period of 4 days. Whole-blood FK506 levels were determined using a standard, two-step, nonspecific enzyme immunoassay. There were no significant changes in vital signs, EKG, or complete laboratory test battery for any patient during the entire study period. No side effects were noted after i.v. or oral FK506 dosing. Mean +/- SD distribution half life was 0.9 +/- 0.2 hours, elimination half life (t1/2 beta) 33 +/- 8 hours, total body clearance (CL) 2.4 +/- 1.1 L/hour, and bioavailability 14 +/- 12%. There was no significant correlation between serum creatinine (Cr) and CL (r = 0.36) or between Cr and t1/2 beta (r = -0.30). It was found that FK506 is incompletely and erratically absorbed after oral administration and is rapidly distributed outside the blood compartment after IV dosing. An extended sampling period seems necessary to accurately characterize the slow elimination phase of FK506.

Topics: Administration, Oral; Adult; Cross-Over Studies; Female; Half-Life; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus

To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians.. Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit.. No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD = 5.00 compared with 3.25 L/h/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p = .07 and p = .08).. There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

Topics: Australia; Bayes Theorem; Cytochrome P-450 CYP3A; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Biological; Mycophenolic Acid; Native Hawaiian or Other Pacific Islander; Prospective Studies; Tacrolimus; Transplant Recipients; White People

BACKGROUND Pure red cell aplasia (PRCA) is an uncommon cause of anemia in end-stage kidney disease (ESKD). It is attributed to recombinant human erythropoietin (rHuEPO) administration. Although immunosuppression is the mainstay therapy, its effectiveness varies from 30% to 70%. PRCA in ESKD has been reported to improve following kidney transplantation. CASE REPORT A 46-year-old woman with ESKD secondary to lupus nephritis was treated for uremia at our center. She developed severe anemia. Bone marrow aspiration and biopsy revealed a reduction of erythroid precursors, consistent with PRCA. Because she had no sibling's blood group matched with her, ABO-incompatible kidney transplantation was an option for treatment. She underwent a desensitization protocol consisting of rituximab 375 mg/m2, tacrolimus, mycophenolate mofetil, and prednisolone 4 weeks before surgery, in addition to 3 sessions of double-filtration plasmapheresis (DFPP) every other day followed by intravenous immunoglobulin (IVIG) and 1 session of specific immunoadsorption (Glycosorb® B column) at pre-transplant day -1. She also received low-dose rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) (total 2.0 mg/kg). Maintenance therapy included tacrolimus, mycophenolate mofetil, and prednisolone. Allograft function normalized a few days after transplantation and her Hb gradually increased. CONCLUSIONS We report a rare case of PRCA in a patient with ESKD undergoing ABO-incompatible kidney transplantation. The outcome was satisfactory, with complete correction of anemia and kidney function.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Red-Cell Aplasia, Pure; Renal Dialysis; Tacrolimus; Thailand

Topics: Carcinoma, Hepatocellular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma, Primary Effusion; Male; Middle Aged; Pleural Effusion; Stomach Ulcer; Tacrolimus

Coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality worldwide in both the general population and kidney transplant recipients. Acute kidney injury is a known complication of COVID-19 and appears to most commonly manifest as acute tubular injury on renal biopsy. Coagulopathy associated with COVID-19 is a known but poorly understood complication that has been reported to cause thrombotic microangiopathy on rare occasions in native kidneys of patients with COVID-19. Here, we report the first case of biopsy-proven thrombotic microangiopathy in a kidney transplant recipient with COVID-19 who developed acute pancreatitis and clinical features of microangiopathic hemolytic anemia. The patient recovered with supportive care alone.

Topics: COVID-19; Creatinine; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreatitis; Platelet Count; SARS-CoV-2; Tacrolimus; Thrombotic Microangiopathies; Transplantation, Homologous

Kidney transplant recipients (KTR) are considered high-risk for morbidity and mortality from coronavirus disease 2019 (COVID-19). However, some studies did not show worse outcomes compared to non-transplant patients and there is little data about immunosuppressant drug levels and secondary infections in KTR with COVID-19. Herein, we describe our single-center experience with COVID-19 in KTR.. We captured KTR diagnosed with COVID-19 between March 1, 2020 and May 18, 2020. After exclusion of KTR on hemodialysis and off immunosuppression, we compared the clinical course of COVID-19 between hospitalized KTR and non-transplant patients, matched by age and sex (controls).. Eleven KTR were hospitalized and matched with 44 controls. One KTR and 4 controls died (case fatality rate: 9.1%). There were no significant differences in length of stay or clinical outcomes between KTR and controls. Tacrolimus or sirolimus levels were >10 ng/mL in 6 out of 9 KTR (67%). Bacterial infections were more frequent in KTR (36.3%), compared with controls (6.8%, P = .02).. In our small case series, unlike earlier reports from the pandemic epicenters, the clinical outcomes of KTR with COVID-19 were comparable to those of non-transplant patients. Calcineurin or mammalian target of rapamycin inhibitor (mTOR) levels were high. Bacterial infections were more common in KTR, compared with controls.

Topics: Adult; Aged; Antiviral Agents; Case-Control Studies; COVID-19; COVID-19 Drug Treatment; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Length of Stay; Male; Middle Aged; Pandemics; SARS-CoV-2; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis.

Topics: Administration, Intravenous; Adult; Anaphylaxis; Blood Pressure; Castor Oil; Graft Rejection; Hemodynamics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Piperacillin; Tacrolimus

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.

Topics: Adult; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Retrospective Studies; Tacrolimus

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

Topics: Caliciviridae Infections; Diabetes Mellitus, Type 1; Diagnosis, Differential; Diarrhea; Disease Progression; Drug Tapering; Feces; Fluid Therapy; Gastroenteritis; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Sapovirus; Tacrolimus

Kidney transplant (KTx) recipients with IgAN as primary disease, were compared with recipients with other causes of renal failure, in terms of long-term outcomes.. Ninety-nine KTx recipients with end-stage kidney disease (ESKD) due to IgAN, were retrospectively compared to; i/ a matched case-control group of patients with non-glomerular causes of ESKD, and ii/ four control groups with ESKD due to glomerular diseases; 44 patients with primary focal segmental glomerulosclerosis (FSGS), 19 with idiopathic membranous nephropathy (IMN), 22 with lupus nephritis (LN) and 21 with pauci-immune glomerulonephritis (PIGN).. At end of the observation period, graft function and survival, were similar between KTx recipients with IgAN and all other groups, but the rate of disease recurrence in the graft differed significantly across groups. The rate of IgAN recurrence in the graft was 23.2%, compared to 59.1% (p<0.0001) in the FSGS group, 42.1% (p = 0.17) in the IMN group, and 0% in the LN and PIGN groups (p = 0.01). IgAN recipients, who were maintained with a regimen containing tacrolimus, experienced recurrence less frequently, compared to those maintained with cyclosporine (p = 0.01). Graft loss attributed to recurrence was significantly higher in patients with FSGS versus all others.. Recipients with IgAN as primary disease, experienced outcomes comparable to those of recipients with other causes of ESKD. The rate of IgAN recurrence in the graft was significantly lower than the rate of FSGS recurrence, but higher than the one recorded in recipients with LN or PIGN. Tacrolimus, as part of the KTx maintenance therapy, was associated with lower rates of IgAN recurrence in the graft, compared to the rate cyclosporine.

Topics: Adult; Cyclosporine; Female; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome

Azathioprine (AZA), methotrexate, or rituximab is used for the maintenance therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Although the efficacy of tacrolimus (TAC) in various autoimmune diseases has been demonstrated, there have been few reports on the efficacy of TAC in AAV. We investigated the efficacy of TAC as maintenance therapy for AAV and compared its efficacy with that of AZA.We retrospectively analyzed the medical records of 81 patients with AAV who received cyclophosphamide as induction therapy and AZA or TAC as maintenance therapy. All-cause death, relapse, and progression to end-stage renal disease (ESRD) were analyzed.Among 81 patients with AAV, 69 patients received AZA alone, 6 patients received TAC alone, and 6 patients received TAC after AZA for maintenance therapy. Overall, 11 patients (13.6%) died, 30 patients (37.0%) experienced relapse, and 16 patients (19.8%) progressed to ESRD during a median of 33.8 months. No significant differences were observed in cumulative patients', relapse-free, and ESRD-free survival rates between patients administered AZA alone and TAC alone. There were no significant differences in the cumulative patients' and relapse-free survival rate between patients who received AZA alone and TAC after AZA. However, the cumulative ESRD-free survival rate was lower in patients who received TAC after AZA than in those who received AZA alone (P = .027).Patients who received TAC as maintenance therapy showed a higher incidence of ESRD than those who received AZA; however, this might be attributed to the lack of efficacy of AZA rather than the low ESRD prevention effect of TAC.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Azathioprine; Cyclophosphamide; Disease Progression; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus

Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS).. We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate).. Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041).. C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.

Topics: Adult; Aged; Allografts; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Assessment; Tacrolimus

Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8 kg/m

Topics: Female; Gastrectomy; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Laparoscopy; Male; Middle Aged; Mycophenolic Acid; Obesity, Morbid; Prospective Studies; Tacrolimus

Dendritic cells (DCs) have a major role in the initiation of an immune response and Immunoglobulin-like transcript 3&4 (ILT3&ILT4) are inhibitory receptors that induce tolerance in DCs. Recent studies show that immunosuppressive agents affect frequency of DCs. Herein, we compared the effect of mycophenolate mofetil (MMF) and sirolimus (SRL) in tacrolimus (TAC)-based immunosuppression on DC subsets frequency and ILT3/ILT4 gene expression in kidney transplant recipients. We enrolled 24 adult transplant recipients who received MMF/TAC (n = 14) or SRL/TAC (n = 10). Peripheral blood samples were obtained from recipients, 24-48 h before transplantation and 4 months after transplantation. The frequency of DC subsets was analyzed by flow cytometry and gene expression of ILT3/ILT4 were estimated by real-time PCR. Our results showed that MMF vs. SRL treated recipient showed an increase in pDC % with increased in the expression of ILT3/ILT4 which is in favor of better allograft survival; However, for confirming the results of this preliminary study, a cohort study with larger sample size is necessary.

Topics: Adult; Blood Cell Count; Cohort Studies; Dendritic Cells; Female; Gene Expression; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Membrane Glycoproteins; Middle Aged; Mycophenolic Acid; Receptors, Immunologic; Sirolimus; Tacrolimus; Transplant Recipients; Transplantation Conditioning; Young Adult

Topics: Aged; Betacoronavirus; Cobicistat; Colchicine; Coronavirus Infections; COVID-19; Cytokines; Darunavir; Drug Combinations; Female; Humans; Hydroxychloroquine; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lopinavir; Male; Middle Aged; Mycophenolic Acid; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Tacrolimus; Transplant Recipients; Treatment Outcome

The clinical manifestation of COVID-19 can vary from an asymptomatic course to ARDS requiring invasive mechanical ventilation and extracorporeal membrane oxygenation. A kidney transplanted patient infected with SARS CoV-2 infection showed a mild disease despite immune suppression. It is possible that Immunosuppression can "be protective" as the cytokine storm is an important factor in the disease story. Despite the good outcome reported in the present case report, is remains of vital importance the solid organ transplant patients use precautions in order to avoid the infection.

Topics: Betacoronavirus; Ceftriaxone; Coronavirus Infections; COVID-19; Cytokines; Glomerulonephritis, IGA; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pandemics; Pneumonia, Viral; SARS-CoV-2; Tacrolimus; Treatment Outcome

This study aims to assess outcomes of interleukin-2 (IL-2) receptor blocker induction therapy on allograft and patients' outcomes in standard risk recipients in the tacrolimus era, analysing data form the British Renal Transplant Registry.. The study population involved all standard-risk renal transplant patients from 2000 till 2015 who were registered in the UK transplant registry and followed up till May 2018. Standard risk transplants were defined as patients with <2DR mismatch, calculated reaction frequency <20%, live donors or donors after brain death and patients with no previous renal transplantation transplant. We used inverse probability weights to adjust different covariates between the groups. Cox regression analysis for adjusted data and treatment effects model were used to assess outcomes.. In all, 3,597 renal transplant patients were included in the study. Two groups were identified; induction group (n = 2,858) which included patients who received IL-2 receptor blocker induction therapy and the no-induction group (n = 739). There was no significant difference between both groups in terms of estimated glomerular filtration rate (eGFR) rate at 1-year post-transplant (correlation co-efficient = 1.224, 95% CI ranges from -0.347 to 2.796). Average eGFR was 59.922 mL/min/1.73 m2 in the induction group (SD 29.171) and 64.557 mL/min/1.73 m2 in the no-induction groups (SD 46.763). There was no significant difference between both groups regarding graft survival at 5 years post-transplant (hazard ratio [HR] 0.944, 95% CI ranges from 0.599 to 1.485, p = 0.804), patient survival at 5 years post-transplant (HR 0.809, 95% CI ranges from 0.477 to1.372, p = 0.433).. In the standard risk renal transplant population, the IL2 receptor blocker induction regimen does not affect eGFR at 1 year or renal and graft outcomes at 5 years.

Topics: Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Receptors, Interleukin-2; Registries; Retrospective Studies; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome; United Kingdom

During the novel coronavirus pandemic, organ transplant recipients represent a frail susceptible category due to long-term immunosuppressive therapy. For this reason, clinical manifestations may differ from general population and different treatment approaches may be needed. We present the case of a 36-year-old kidney-transplanted woman affected by Senior-Loken syndrome diagnosed with COVID-19 pneumonia after a contact with her positive mother. Initial symptoms were fatigue, dry cough, and coryza; she never had fever nor oxygen supplementation. Hydroxychloroquine and lopinavir/ritonavir were started, and the antiviral drug was replaced with darunavir/cobicistat after 2 days for diarrhea. Immunosuppressant levels were closely monitored, and we observed very high tacrolimus trough levels despite initial dose reduction. The patient was left with steroid therapy alone. The peculiarity of clinical presentation and the management difficulties represent the flagship of our case report. We stress the need for guidelines in transplant recipients with COVID-19 infection with particular regard to the management of therapy.

Topics: Adult; Antiviral Agents; Betacoronavirus; C-Reactive Protein; Ciliopathies; Cobicistat; Common Cold; Coronavirus Infections; Cough; COVID-19; COVID-19 Drug Treatment; Cytochrome P-450 CYP3A Inhibitors; Darunavir; Deprescriptions; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Fatigue; Female; Glucocorticoids; Graft Rejection; Humans; Hydroxychloroquine; Immunocompromised Host; Immunosuppressive Agents; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Kidney Diseases, Cystic; Kidney Failure, Chronic; Kidney Transplantation; Leber Congenital Amaurosis; Lopinavir; Methylprednisolone; Optic Atrophies, Hereditary; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Severity of Illness Index; Tacrolimus

Coronavirus Disease 2019 (COVID-19) is currently a pandemic with a mortality rate of 1%-6% in the general population. However, the mortality rate seems to be significantly higher in elderly patients, especially those hospitalized with comorbidities, such as hypertension, diabetes, or coronary artery diseases. Because viral diseases may have atypical presentations in immunosuppressed patients, the course of the disease in the transplant patient population is unknown. Hence, the management of these patients with COVID-19 is an area of interest, and a unique approach is warranted. Here, we report the clinical features and our treatment approach for a kidney transplant patient with a diagnosis of COVID-19. We believe that screening protocols for SARS-Cov-2 should be re-evaluated in patients with solid-organ transplants.

Topics: Adult; Antiviral Agents; Betacoronavirus; Coronavirus Infections; Cough; COVID-19; COVID-19 Drug Treatment; Disease Management; Female; Fever; Glucocorticoids; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Oseltamivir; Pandemics; Pneumonia, Viral; Prednisone; SARS-CoV-2; Severity of Illness Index; Tacrolimus

The fatality of novel coronavirus disease 2019 (COVID-19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID-19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36-year-old man who underwent KT 3 years ago. He was diagnosed with COVID-19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID-19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug-to-drug interaction. The second case was developed in a 56-year-old man without any symptoms. He received a second KT from an ABO-incompatible donor 8 years ago. He was diagnosed with COVID-19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors.

Topics: Adult; Antiviral Agents; Azithromycin; Betacoronavirus; Calcineurin Inhibitors; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Humans; Hydroxychloroquine; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lopinavir; Male; Middle Aged; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Tacrolimus; Transplant Recipients

Several PK studies have shown that most pediatric patients may require higher doses on a mg/kg basis compared to adults to attain similar therapeutic trough concentrations. The aim of this study was to compare the efficacy and safety of three times daily to twice a day dosing of tacrolimus in pediatric kidney transplant recipients at a major tertiary care transplant center.. Retrospective, single-center, and comparative cohort study. All pediatric kidney transplant recipients received either tacrolimus BID (group 1) or tacrolimus TID (group 2).. A total of 87 patients were included in this study; 48 patients received BID tacrolimus (group 1), and 39 patients received TID tacrolimus (group 2). The percentage of patients who achieved therapeutic trough concentrations in group 2 did not significantly differ from those in group 1 at day 7 (84.62% TID vs 83.33% BID; P = .42). The median time to reach therapeutic trough concentrations was three days in group 1 compared to four days in group 2.. No significant difference was observed between tacrolimus BID and TID dosing in the time to reach therapeutic trough concentration or in the proportion of patients achieving therapeutic trough concentrations at day 7.

Topics: Adolescent; Child; Child, Preschool; Data Collection; Drug Administration Schedule; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Pediatrics; Retrospective Studies; 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

Topics: Anti-Infective Agents; Azithromycin; Betacoronavirus; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Testing; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Oxygen Inhalation Therapy; Pandemics; Pneumonia, Viral; Prednisolone; SARS-CoV-2; Tacrolimus; Treatment Outcome

Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for the increased risk of gastrointestinal complications in kidney transplant recipients. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. This study evaluated the incidence of post-transplant gastrointestinal complications during screening colonoscopy. Kidney transplant recipients undergoing a colonoscopy for any reasons in the period 2014-2018 were included. Among the 134 patients completing the colonoscopy, 74 patients (56%) had an abnormal finding: an adenoma was found in 25 patients (18.6%), while 19 patients (14.1%) had colitis. Mycophenolic acid/related colitis was the most common colitis (6%), while 7 patients (5.2%) developed a

Topics: Adenoma; Age Distribution; Aged; Anemia; Colitis; Colonoscopy; Colorectal Neoplasms; Diarrhea; Diverticulosis, Colonic; Early Detection of Cancer; Female; Gastrointestinal Hemorrhage; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Topics: Adult; Anti-Bacterial Agents; Drug Interactions; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Tigecycline; Urinary Tract Infections

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

An improved understanding of the impact of clinical surrogates on disparities in African-American (AA) kidney transplantation (KTX) is needed. We conducted a 10-year retrospective longitudinal cohort study of electronically abstracted clinical data assessing the impact of surrogates on disparities in KTX. Clinical surrogates were assessed by posttransplant year (1, 2, 3 or 4) and defined as acute rejection (Banff ≥1A), mean SBP >140 mmHg, tacrolimus variability (CV) >40%, mean glucose >160 mg/dl and mean hemoglobin <10 g/dl. We utilized landmark methodology to minimize immortal time bias and logistic and survival regression to assess outcomes; 1610 KTX were assessed (54.2% AAs), with 1000, 468, 368 and 303 included in the year 1, 2, 3 and 4 complete case analyses, respectively. AAs had significantly higher odds of developing a clinical surrogate, which increased in posttransplant years three and four [OR year 1 1.99 (1.38-2.88), year 2 1.77 (1.20-2.62), year 3 2.35 (1.49-3.71), year 4 2.85 (1.72-4.70)]. Adjusting for the five clinical surrogates in survival models explained a significant portion of the higher risks of graft loss in AAs in post-transplant years three and four. Results suggest focusing efforts on improving late clinical surrogate management within AAs may help mitigate racial disparities in KTX.

Topics: Adult; Aged; Black or African American; Female; Graft Rejection; Graft Survival; Health Status Disparities; Healthcare Disparities; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors; Transplant Recipients; Treatment Outcome

Topics: Adult; Cations; Delayed Graft Function; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Graft Rejection; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Safety; Polymers; Tacrolimus; Transplant Recipients; Treatment Outcome

The number of simultaneous liver-kidney transplantations (SLKTs) and use of induction therapy for SLKT have increased recently, without much published evidence, especially in the context of maintenance immunosuppression containing tacrolimus (TAC) and mycophenolic acid (MPA). We queried the Organ Procurement and Transplant Network registry for SLKT recipients maintained on TAC/MPA at discharge in the United States for 2002-2016. The cohort was divided into 3 groups on the basis of induction type: rabbit antithymocyte globulin (r-ATG; n = 831), interleukin 2 receptor antagonist (IL2RA; n = 1558), and no induction (n = 2333). Primary outcomes were posttransplant all-cause mortality and acute rejection rates in kidney and liver allografts at 12 months. Survival rates were analyzed by the Kaplan-Meier method. A propensity score analysis was used to control potential selection bias. Multivariate inverse probability weighted Cox proportional hazard and logistic regression models were used to estimate the hazard ratios (HRs) and odds ratios. Among SLKT recipients, survival estimates at 3 years were lower for recipients receiving r-ATG (P = 0.05). Compared with no induction, the multivariate analyses showed an increased mortality risk with r-ATG (HR, 1.29; 95% confidence interval [CI], 1.10-1.52; P = 0.002) and no difference in acute liver or kidney rejection rates at 12 months across all induction categories. No difference in outcomes was noted with IL2RA induction over the no induction category. In conclusion, there appears to be no survival benefit nor reduction in rejection rates for SLKT recipients who receive induction therapy, and r-ATG appears to increase mortality risk compared with no induction.

Topics: Adult; Aged; Antilymphocyte Serum; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Severity of Illness Index; Survival Rate; Tacrolimus; United States

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

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10

Topics: Cytochrome P-450 CYP3A; Ethnicity; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Prospective Studies; Tacrolimus

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

The aims of the present study were to describe the experiences of kidney transplant patients attending a young adult clinic or a regular adult clinic, to explore similarities and differences between the groups, and to conduct an evaluation of the clinical and psychosocial outcomes of the young adult clinic, by comparing these outcomes to those of the regular adult clinic. A mixed-methods design combining qualitative and quantitative data was used. Empirically validated questionnaires measuring self-determination theory variables, quality of life, and adherence were distributed to all consenting patients attending the YAC (n = 17) and RAC (n = 16). Semi-structured interviews were conducted with a subsample of the first (n = 10) and second group (n = 8), and analyzed using thematic analysis. Clinical outcomes were retrieved from medical records. Descriptive, correlational, and comparative analyses were performed. We found clinically significant differences on tacrolimus blood levels variability, self-reported adherence, and physical quality of life. Small and medium effect sizes were detected. No statistical differences were found. Statistically significant correlations were found between self-determination theory variables and both physical quality of life and different measures of adherence. Four themes characterized patients' experiences: resilience; relational needs and the therapeutic alliance; quest for balance; and quest for normalcy. The young adult clinic seems to meet its initial objectives and to make a difference particularly in the early period post-transition, but over time what matters most for patients is therapeutic alliance. Mental health issues need to be better addressed, and special attention should be paid to youths transplanted in an adult setting.

Topics: Adolescent; Adult; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Patient Compliance; Postoperative Period; Qualitative Research; Quality of Life; Self Report; Social Support; Surveys and Questionnaires; Tacrolimus; Transition to Adult Care; Treatment Outcome; Young Adult

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.

Topics: Adult; Age Factors; Aged; Delayed-Action Preparations; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Tissue Donors; Transplant Recipients

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

Topics: Calcineurin Inhibitors; Graft Rejection; Humans; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Pseudohypoaldosteronism; Severity of Illness Index; Tacrolimus

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

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

Bardet-Biedl Syndrome (BBS) is a rare multi-systemic disease with autosomal recessive transmission. BBS was at first considered to be homogeneous as for its genetics, but subsequent studies have shown an extensive gene variability. Currently, 21 genes (BBS1-21) present on different chromosomes have been mapped: these genes are responsible for BBS phenotypes and they show a great heterogeneity of mutations.The most common genes are BBS1 (locus 11q13) and BBS10.We show here the case of a 50 year old patient with BBS. Medical History: retinitis pigmentosa at 4 years of age evolved to complete blindness, generalized epilepsy crises, poly-syndactyly, left-hand malformation. In April 1986 developed an epileptic episode: on that occasion Chronic Kidney Failure (CKF) diagnosis and starting of haemodialysis. In 1989, hospitalization for epileptic seizures. In 2009 the patient underwent kidney transplantation from deceased donor. Immunosuppressive initial protocol: Basiliximab, Azathioprine, Tacrolimus, Steroid, and Tacrolimus, Azathioprine, Steroid at hospital discharge. Post-operative care complicated by respiratory failure with mechanical ventilation assistance. During hospitalization, the neurological picture remained stable. At hospital discharge Creatinine 1.8 mg/dl. Subsequently, immunosuppressant were gradually tapered until monotherapy with Tacrolimus. At present the patient's conditions appear to be good, renal function has remained substantially stable with Creatinine between 1.4-1.5 mg/dl and glomerular filtration rate (GFR) estimated at 39-42 mL/min/1.73 m ² according to MDRD study Equation. This case shows the possibility to successfully manage a BBS-affected uremic patient, despite the complexity of the pathology and the aggravating factor of extreme rarity in diagnostic pathway.

Topics: Bardet-Biedl Syndrome; Creatinine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Phenotype; Tacrolimus

Kidney transplantation (KT) is the replacement therapy of choice in patients with end-stage renal disease (ESRD). Here we show a cohort of kidney transplant recipients from the period of May 1994 to May 2016 in 2 2nd-level private hospitals from the city of Toluca in the state of Mexico.. We checked the clinical files of all the patients that received KT in the period of study.. We report 25 KT: 23 performed in Sanatorio Toluca and 2 in Sanatorio Florencia; 16 (64%) male and 9 (26%) female; mean age 36.03 ± 15.9 years (range, 10-66); 19 (76%) hemodialysis and 9 (24%) continuous ambulatory peritoneal dialysis before KT; ESRD etiology unknown in 16 (64%), diabetes in 5 (20%), IgA nephropathy in 2 (8%), and other in 2 (8%); living donors in 13 (52%) and deceased donors in 12 (48%); blood group 0+ in 18 (72%), A+ in 5 (20%), and B+ in 2 (8%); 21 (84%) with 0 and 4 (16%) with 1 HLA mismatch; and delayed graft function in 8 (32%), of which 7 were from deceased donors and 1 from a living donor. All 25 (100%) had a functional kidney at 1 year of follow-up. Immunosuppression regime consisted of multitarget maintenance therapy in all 25 (100%): cyclosporine in 18 (72%) and tacrolimus in 7 (28%). We used only methylprednisolone (MTP) as induction therapy. There were only 2 cases (8%) of acute rejection during the 1st 6 months of follow-up, and both responded to treatment with MTP.. KT is the treatment of choice for patients with ESRD. The obtained results using only an MTP induction regime are satisfactory, with graft and patient survivals of 100% in the 1st year of follow-up.

Topics: Adolescent; Adult; Aged; Child; Cyclosporine; Female; Hospitals, Private; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mexico; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein-signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.

Topics: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator; Bone Morphogenetic Protein Receptors, Type I; Cell Line; Disease Progression; Gene Knockdown Techniques; Humans; Kidney; Kidney Failure, Chronic; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pyrrolidines; Signal Transduction; Tacrolimus; Tacrolimus Binding Protein 1A; YY1 Transcription Factor

This work investigated, in two large cohorts of French renal transplants treated with tacrolimus, the influence of donor and recipient ABCB1, CYP3A4, and CYP3A5 genotypes on the risk of allograft loss. A discovery and a replication population of 330 and 369 adult renal transplant patients, each from a different transplantation center and all receiving a tacrolimus-based immunosuppressive regimen, were retrospectively genotyped. The influence of genetic factors and other known risk factors on allograft loss was investigated using multivariate Cox proportional hazard analyses. The existence of previous transplantations (per unit HR = 1.89 [1.10-3.26] P = .0216) and the donor ABCB1 c.1199GA/AA genotype (GA/AAvs GG: HR = 3.22 [1.14-9.09], P = .0288) were associated with an increased risk of allograft loss in the discovery cohort and with graft loss due to humoral rejection in the replication cohort (per unit HR = 2.26 [1.34-3.81], P = .00229; GA/AAvs GG HR = 3.42 [1.28-9.16], P = .0142). Genotyping the donor for the ABCB1 c.1199 G>A (exon 11, rs2229109) allele may be of interest before prescribing tacrolimus to the recipient, although this polymorphism is rather rare and its effect may be limited to certain mechanisms of graft loss.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B; Child; Child, Preschool; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Genetic Association Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Tissue Donors; Transplant Recipients; Young Adult

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 use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.

Topics: Biological Availability; Cost-Benefit Analysis; Delayed-Action Preparations; 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; Multicenter Studies as Topic; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Tacrolimus

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Neutropenia; Prognosis; Tacrolimus

Topics: Adult; Amyloidosis; Basiliximab; Biopsy; Familial Mediterranean Fever; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Interleukin-1; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome; Young Adult

BK virus (BKV) infection has become one of the main complications in renal transplant recipients (RTRs) with the arrival of newer potent immunosuppressive agents. However, reports on the epidemiology of BKV infection and risk factors in Chinese population after renal transplantation are scarce.. From June 2015 to July 2016, living-donor renal transplant recipients (LDRTRs) who routinely received the quantitative BKV DNA testing of urine and plasma samples using quantitative real-time polymerase chain reaction (PCR) for the first time after transplantation were selected, while dialysis patients and healthy living donors during that period served as controls. Potential variables were compared and analyzed using logistic regression model multivariate analysis to assess the BKV infection related factors in LDRTRs.. Among the 52 LDRTRs identified, BKV DNA was detected in 16 urine samples (30.8%), significantly higher than that of dialysis patients (6.3%) and healthy living donors (4.2%) (p < .001). Nevertheless, no statistically significant difference wax noted between the latter two groups in urine samples (p = .842). Meanwhile, BKV DNA detection in blood samples was all negative in the three groups. Univariate analysis shown tacrolimus (Tac) trough level and lymphocyte percentage were associated with BKV infection in LDRTRs. Multivariate regression analysis also showed Tac trough level (HR, 1.644; p = .03), lymphocyte percentage (HR, 0.878; p = .026) were associated with BKV infection in LDRTRs.. In Chinese population, the incidence of BKV infection increased significantly after living-donor renal transplantation. Significantly increased Tac trough level and decreased lymphocyte percentage might be the risk factors for BKV infection in LDRTRs.

Topics: Adult; BK Virus; China; DNA, Viral; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Logistic Models; Male; Middle Aged; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Risk Factors; Tacrolimus; Transplant Recipients; Viral Load; Young Adult

Solid organ transplant patients are well established to be at risk of herpes simplex virus and varicella zoster virus infection and reactivation. We present a case of a 41-year-old woman with a history of pancreas and renal transplant who presented with what appeared to be disseminated herpes simplex virus or varicella zoster virus induced rash, but who was ultimately diagnosed and treated as linear IgA bullous dermatosis. This case alerts physicians to other non-infectious dermatoses as a cause of vesiculobullous rash in solid organ transplant patients.

Topics: Adult; Dermatitis Herpetiformis; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Linear IgA Bullous Dermatosis; Pancreas Transplantation; Prednisone; Skin; Tacrolimus

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

Successful simultaneous pancreas and kidney transplantation (SPK) or pancreas transplantation alone (PTA) restores glycemic control. Diabetes and impaired kidney function are common side effects of immunosuppressive therapy. This study addresses glucometabolic parameters and kidney function during the first year.. We examined 67 patients with functioning grafts (SPK n = 30, PTA n = 37) transplanted between September 2011 and November 2016 who underwent repeated oral glucose tolerance tests (OGTTs) 8 and 52 weeks after transplantation. Another 19 patients lost their graft the first year post-transplant and 28 patients did not undergo repeated OGTTs and could not be studied. All patients received ATG induction therapy plus tacrolimus, mycophenolate and prednisolone. Glomerular filtration rate was measured before and 8 and 52 weeks after transplantation by serum clearance methods.. From week 8 to 52 after transplantation, mean fasting glucose decreased (SPK: 5.4 ± 0.7 to 5.1 ± 0.8 mmol/L, PTA: 5.4 ± 0.6 to 5.2 ± 0.7 mmol/L; both P < 0.05), and also 120-min post-OGTT glucose (SPK: 6.9 ± 2.9 to 5.7 ± 2.2 mmol/L; P = 0.07, PTA: 6.5 ± 1.7 to 5.7 ± 1.2 mmol/L; P < 0.05). Fasting C-peptide levels also decreased (SPK: 1500 ± 573 to 1078 ± 357 pmol/L, PTA: 1210 ± 487 to 1021 ± 434 pmol/L, both P < 0.005). Measured GFR decreased from enlistment to 8 weeks post transplant in PTA patients (94 ± 22 to 78 ± 19 mL/min/1.73 m2; P < 0.005), but did not deteriorate from week 8 to week 52 (SPK: 55.0 ± 15.1 vs 59.7 ± 11.3 ml/min/1.73 m²; P = 0.19, PTA: 76 ± 19 vs 77 ± 19 mL/min/1.73 m²; P = 0.74).. Glycemic control and kidney function remain preserved in recipients with functioning SPK and PTA grafts 1 year after transplantation.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Prospective Studies; Tacrolimus

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

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.

Topics: Adult; Antibiotics, Antitubercular; Brain Stem; DNA; Early Diagnosis; Female; Humans; Immunosuppressive Agents; JC Virus; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Mycophenolic Acid; Tacrolimus

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

The CYP3A metric 4β-hydroxycholesterol (4βOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4βOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n = 79). The goal of the current study was determine whether these findings could be validated in a substantially larger cohort.. In a retrospective analysis of 279 renal recipients, tacrolimus trough concentrations (C0), daily dose, haematocrit and other relevant covariates were registered every day for the first 14 days after transplantation. 4βOHC and cholesterol were quantified on plasma collected immediately pretransplant using liquid chromatography tandem-mass spectrometry. Patients were genotyped for CYP3A5*1 and CYP3A4*22.. The CYP3A metric 4βOHC cannot be used to predict tacrolimus dose requirements in the first days after transplantation.

Topics: Adult; Age Factors; Aged; Biological Variation, Population; Biomarkers, Pharmacological; Cytochrome P-450 CYP3A; Female; Genotype; Glomerular Filtration Rate; Graft Rejection; Hematocrit; Humans; Hydroxycholesterols; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Postoperative Period; Preoperative Period; Retrospective Studies; Tacrolimus

Topics: Adolescent; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Resonance Imaging; Male; Posterior Leukoencephalopathy Syndrome; Tacrolimus

Renal transplantation is the definitive treatment for end stage renal disease. Patients subjected to transplantation require lifelong immunosuppression and are prone to several gastrointestinal disorders. Dyspepsia is a common disorder in these patients. The objective of this study was to determine factors leading to dyspepsia in renal (kidney) transplant recipients.. It was a cross sectional study conducted at department of hepatogastroenterology and transplant sciences, SIUT Karachi, from 1-6-15 to 1-12-15 for six months. All renal transplanted patients having dyspeptic symptoms for more than 6 weeks. EGD was performed, biopsy specimens obtained from antrum and duodenum, these were sent for histopathological examination. Frequency and percentages were obtained for categorical variables, mean ± SD was calculated for continuous variables. Chi square test was used for categorical variable and student t-test for continuous variables.. Ninety patients were included in the study out of which 64 (71.1%) were males, mean age was 35.82 ± 10.04 years (range: 18-65 years). Gastritis (non. Gastritis is the most common factor accountable for this symptoms, followed by duodenitis and

Topics: Adolescent; Adult; Aged; Cross-Sectional Studies; Duodenitis; Dyspepsia; Female; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pakistan; Risk Factors; Tacrolimus; Young Adult

Topics: Adult; Biological Availability; Graft Rejection; HLA-B27 Antigen; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Spondylarthropathies; T-Lymphocytes; Tacrolimus; Treatment Outcome

Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile; however, higher incidence of acute rejection and posttransplant lymphoproliferative disorder are the shortcomings of this agent. In this study, ASP2409, a new cytotoxic T-lymphocyte associated protein 4-immunoglobulin possessing 14-fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys. ASP2409 monotherapy dose-dependently prolonged renal allograft survival. Low-dose ASP2409 in combination with a subtherapeutic dose of tacrolimus showed much longer median survival time than monotherapy. Similar allograft survival results were observed in regimens based on high-dose ASP2409, belatacept, and therapeutic-dose tacrolimus. The results of renal allograft histopathology with high-dose ASP2409-based regimens were not inferior to the belatacept-based regimen. Moreover, higher frequencies of FoxP3-positive regulatory T cells in renal allografts were observed in ASP2409- and belatacept-based regimens compared with tacrolimus-based regimens. No serious side effects related to ASP2409 administration were found during the study. These data suggest that ASP2409 is a promising candidate for calcineurin inhibitor-sparing or -avoidance regimens.

Topics: Abatacept; Animals; B7-2 Antigen; Drug Therapy, Combination; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Immunoconjugates; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Macaca fascicularis; Male; T-Lymphocytes, Cytotoxic; Tacrolimus; Transplantation, Homologous

Topics: Area Under Curve; Calcineurin Inhibitors; Drug Administration Schedule; Drug Monitoring; Gastrectomy; Gastric Absorption; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Treatment Outcome

Condyloma acuminata (CA) are warty lesions caused by human papilloma virus (HPV) that generally affect the external genitalia and mucocutaneous junctions. Involvement of the urinary tract is rare, and involvement of the urinary bladder is thought to be due to immunosuppression. A 30-year-old woman was diagnosed with urethral CA 12 months after renal transplantation. She underwent transurethral resection (TUR) of the urethral lesions. During the operation, multiple sessile warty lesions were found incidentally inside the bladder and were also removed by TUR. The patient's postoperative course was uneventful. Pathological examination confirmed that the lesions were CA. Multiplex real-time polymerase chain reaction was performed to confirm the HPV genotype and revealed type 45 HPV DNA. CA of the urethra are uncommon, and bladder involvement is extremely rare. This case is the first reported, to our knowledge, to involve HPV type 45 in bladder condyloma. TUR may be the preferred option for the management of CA in the urinary bladder.

Topics: Adult; Condylomata Acuminata; Cystoscopy; Diabetes Mellitus, Type 1; Female; Genotype; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Papillomaviridae; Prednisolone; Real-Time Polymerase Chain Reaction; Tacrolimus; Transplant Recipients; Urethra; Urinary Bladder

Topics: Alagille Syndrome; Choroidal Neovascularization; Corneal Dystrophies, Hereditary; Female; Humans; Kidney Failure, Chronic; Liver Transplantation; Night Blindness; Photoreceptor Cells, Vertebrate; Renal Dialysis; Retinal Pigment Epithelium; Tacrolimus; Tomography, Optical Coherence; Vitamin A; Vitamin D; Young Adult

Kidney transplantation (KT) of human immunodeficiency virus (HIV)-positive patients has transformed the management of end-stage kidney disease in this population. Although favourable outcomes have been reported, patients experience high rates of acute allograft rejection (AR). We examined factors associated with AR in the first year after KT, with particular emphasis on the choice of calcineurin inhibitor (CNI) immunosuppressive therapy.. We conducted a national observational cohort study of HIV/KT in the United Kingdom. Patients were included if HIV positive at KT, transplanted in the United Kingdom between January 2005 and December 2013, and did not experience primary graft failure. Kaplan-Meier methods were used to estimate host/graft survival and cumulative incidence of biopsy proven AR. Logrank tests were used to compare survival, and Cox proportional hazard models to examine factors associated with AR.. Our study analyzed the incidence of AR in the first year after KT in 78 HIV-positive patients of whom 31 initiated cyclosporin (CsA) and 47 tacrolimus (Tac) based immunosuppression. AR was observed in 28 patients (36%) after a median of 2.6 (interquartile range, 0.5-5.9) months. The cumulative incidence of AR at 1 year was 58% and 21% among patients on CsA and Tac, respectively (P =0.003). Choice of CNI was the only factor significantly associated with AR (hazard ratio for Tac vs CsA 0.25 [95% confidence interval, 0.11-0.57], P = 0.001). Subtherapeutic CNI concentrations were common in the first 12 weeks after KT.. Our data suggest that Tac may be the preferred CNI for use in KT in people living with HIV.

Topics: Acute Disease; Aged; Allografts; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; HIV Infections; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Selection; Proportional Hazards Models; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome; United Kingdom

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

Transplantation is now lifesaving therapy for patients with end-stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor-recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplantation and pharmacological mobilization, resulting in a chimeric, repopulated organ. We now confirm these findings in a well-characterized large animal preclinical model. Here, we show that AMD3100 and FK506 mobilization of endogenous stem cells immediately post kidney transplantation combined with repeat therapy at 1, 2, and 3 months led to drug-free long-term survival in maximally immunologically mismatched swine. Three long-term recipients have stable chimeric transplants, preserved antidonor skin graft responses, and normal serum creatinine levels despite withdrawal of all medication for 3 years.

Topics: Allografts; Animals; Anti-HIV Agents; Benzylamines; Calcineurin Inhibitors; Cyclams; Graft Rejection; Graft Survival; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Kidney Failure, Chronic; Kidney Transplantation; Peripheral Blood Stem Cell Transplantation; Skin Transplantation; Swine; Swine, Miniature; Tacrolimus; Transplantation Chimera; Transplantation Tolerance

Transplant tolerance allowing the elimination of lifelong immunosuppression has been the goal of research for 60 years. The induction of mixed chimerism has shown promise and has been extended successfully to large animals and to the clinic; however, it remains cumbersome and requires heavy early immunosuppression. In this study, we reported that four injections of AMD3100, a CXCR4 antagonist, plus eight injections of low-dose FK506 (0.05 mg/kg per day) in the first week after kidney transplantation extended survival, but death from renal failure occurred at 30-90 days. Repeating the same course of AMD3100 and FK506 at 1, 2 and 3 mo after transplant resulted in 92% allograft acceptance (n = 12) at 7 mo, normal kidney function and histology with no further treatment. Transplant acceptance was associated with the influx of host stem cells, resulting in a hybrid kidney and a modulated host immune response. Confirmation of these results could initiate a paradigm shift in posttransplant therapy.

Topics: Allografts; Animals; Animals, Genetically Modified; Anti-HIV Agents; Benzylamines; Calcineurin Inhibitors; Cyclams; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Peripheral Blood Stem Cell Transplantation; Rats; Rats, Inbred Lew; Tacrolimus; Transplantation Chimera; Transplantation Tolerance

Optimal tacrolimus exposure in transplant recipients is not well established. The results from the Symphony study indicated that low-target tacrolimus (trough concentrations 3-7 µg/L) in de novo standard risk renal transplant recipients should be appropriate. The aim of this study was to evaluate real-life outcomes when applying a similar strategy in a clinical setting.. A single-centre analysis was conducted in standard risk renal transplant recipients receiving low-target tacrolimus, mycophenolate mofetil, glucocorticoids and basiliximab induction. One-year estimated glomerular filtration rate (eGFR, Cockcroft-Gault), one-year biopsy-proven acute rejection rate and graft- and patient survival up to 3 years post-transplant were compared with the outcomes in the Symphony study.. From 1 January 2009 to 31 March 2013, we included 406 patients. One year after transplantation, the mean ± SD eGFR was 76.8 ± 28.3 mL/min (Symphony: 65.4 ± 27.0 mL/min, P < 0.001). Biopsy-proven acute rejections were seen in 14.5% of the patients (Symphony: 12.3%, P = 0.35). Kaplan-Meier estimates [95% confidence interval] of three-year death-censored graft- and patient survival were 96.6% [94.2-99.0%] (Symphony: 93%) and 95.0% [92.6-97.3%] (Symphony: 95%), respectively.. Low-target tacrolimus-based immunosuppression is safe and effective also in a standard clinical setting in de novo standard risk renal transplant recipients.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Biopsy; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glomerular Filtration Rate; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Norway; Outcome and Process Assessment, Health Care; Recombinant Fusion Proteins; Retrospective Studies; Risk Adjustment; Survival Analysis; Tacrolimus

Topics: Amyloidosis; Azathioprine; Creatinine; Female; Fibrinogen; Gene Expression; Genes, Dominant; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Middle Aged; Mutation; Proteinuria; Tacrolimus; Treatment Outcome

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.

Topics: 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; Male; Middle Aged; Pharmacogenetics; Prognosis; Prospective Studies; Risk Factors; Tacrolimus; Tissue Distribution

Although monitoring the intracellular concentration of immunosuppressive agents may be a promising approach to individualizing the therapy after organ transplantation, additional studies on this issue are needed prior to its clinical approval. We investigated the relationship between intracellular and whole blood concentrations of tacrolimus (IC-TAC and WB-TAC, respectively), the factors affecting this relationship, and the risk of rejection based upon IC-TAC in stable kidney recipients. Both IC-TAC and WB-TAC were measured simultaneously in 213 kidney recipients with stable graft function using LC-MS/MS. The tacrolimus ratio was defined as IC-TAC per WB-TAC. The genetic polymorphism of ABCB1 gene and flow cytometric analyses were conducted to probe the correlation between tacrolimus concentrations and the immunoreactivity status as a potential risk of rejection, respectively. The correlation between IC-TAC and WB-TAC was relatively linear (r = 0.67; P<0.001). The factors affecting the tacrolimus ratio were sex, hematocrit, and the transplant duration, as follows: a high tacrolimus ratio was noted in female patients, patients with a low hematocrit, and patients with a short transplant period. However, the tacrolimus ratio did not reflect the prior clinical outcomes (e.g., rejection) or the genetic polymorphism of ABCB1. After stimulation with phorbol-12-myristate 13-acetate and ionomycin, the proportion of T cells producing interferon-gamma or interleukin-2 was higher in the low-IC-TAC group than in the high-IC-TAC group. Further studies are required to evaluate the value of the intracellular tacrolimus concentrations in several clinical settings, such as rejection, infection, and drug toxicity.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B; Chromatography, Liquid; Female; Graft Survival; Humans; Intracellular Space; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Monitoring, Physiologic; Polymorphism, Genetic; Tacrolimus; Tandem Mass Spectrometry; Tissue Donors; Transplant Recipients

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

Hypomagnesemia is a frequent finding in kidney transplant patients and plays a causal role in insulin resistance and diabetes. The aim of this study was to investigate whether the pretransplant magnesium (Mg) level is a risk factor for the development of new-onset diabetes after kidney transplantation (NODAT) and the presence of relationship between pretransplant hypomagnesemia and the development period of NODAT.. Four hundred and nineteen nondiabetic renal transplant recipients were evaluated retrospectively. The patients were divided into NODAT and non-NODAT groups. The time of diagnosis of patients with NODAT was divided into 0 to 3, 3 to 6, 6 to 12 months, and after 12 months. Patients' characteristics and pretransplant Mg levels in NODAT were compared with non-NODAT, and it was investigated whether pretransplant hypomagnesemia was a risk factor for the development of NODAT.. Totally 70 (16.6%) patients (36 female [F], mean age 51.7 ± 8.2 years) were diagnosed with NODAT. Three hundred and forty-nine patients (115 F, mean age 43.2 ± 12.5 years) did not have NODAT. Pretransplant mean Mg level was 1.97 ± 0.40 mg/dL in patients with NODAT, while it was 2.5 ± 0.45 mg/dL in non-NODAT patients (P < .001). Serum Mg level was found to be similar in subgroups according to the development period of NODAT (P = .07). When patients were stratified according to quartiles of Mg level, the frequency of NODAT was significantly higher in patients in the lower quartile (Mg < 2.1 mg/dL; P < .001). Older age, high body mass index, and low pretransplant serum Mg levels were established as risk factors for developing NODAT. According to the quartile of Mg level, the risk of developing NODAT was highest in the lowest quartile.. Pretransplant hypomagnesemia is an independent risk factor of NODAT. Therefore, it is necessary to closely monitor the Mg levels in the posttransplant period.

Topics: Adult; Age Factors; Body Mass Index; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Magnesium; Male; Middle Aged; Mycophenolic Acid; Overweight; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Water-Electrolyte Imbalance

The performance of belatacept in a real clinical setting has not been reported. A retrospective cohort study was conducted using registry data comparing 1-year clinical outcomes between belatacept- and tacrolimus-treated adult kidney transplant recipients (KTRs) from January 6, 2011, through January 12, 2014. Of 50 244 total patients, 417 received belatacept plus tacrolimus, 458 received belatacept alone, and 49 369 received tacrolimus alone at discharge. In the overall study cohort, belatacept alone was associated with a higher risk of 1-year acute rejection, with the highest rates associated with non-lymphocyte-depleting induction (adjusted hazard ratio 2.65, 95% confidence interval 1.90-3.70, p < 0.0001). There was no significant difference in rejection rates between belatacept plus tacrolimus and tacrolimus alone. In KTRs who met inclusion criteria for the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), 1-year kidney function was higher with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (mean estimated GFR 65.6, 60.4 and 54.3 mL/min per 1.73 m

Topics: Abatacept; Adult; 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; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

Obesity has been reported as risk factor for reduced posttransplant graft and patient survival and increased delayed graft function (DGF).. The purpose of this work is to analyze the effect of body mass index (BMI) on defined transplant outcomes in patients transplanted under defined guidelines in a kidney transplant program.. Review of a prospectively collected database in renal transplant recipients receiving rabbit antithymocyte globulin induction, mycophenolate mofetil, tacrolimus, and early corticosteroid withdrawal between 2001 and 2011.. This review was conducted in a single abdominal transplant program in the United States.. Primary outcome was death-censored graft survival categorized by posttransplant body mass groups. Secondary outcomes included DGF as well as patient survival.. Four hundred sixty seven patients were identified. No difference was observed in graft survival or DGF between BMI groups. One-year, death-censored graft survival and patient survival rates ranged from 97.5% to 100% and 96.6% to 100%, respectively. Delayed graft function was uncommon across all BMI groups, ranging from 5.3% to 9.1%, with the lowest incidence in patients with a BMI ≥ 35 kg/m(2). Biopsy-proven acute rejection rates at 1 year were similar across all groups (10.1%-14%) as were estimated glomerular filtration rates were at 1, 3, and 5 years.. Our results do not show an effect of BMI on posttransplant outcomes, suggesting that relaxation of BMI criteria may be warranted for recipient selection.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Body Mass Index; Comorbidity; Databases, Factual; Delayed Graft Function; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Obesity; Overweight; Retrospective Studies; Survival Rate; Tacrolimus; Thinness; Treatment Outcome

Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by rapid progression to end-stage renal disease (ESRD). We evaluated the clinicopathological spectrum of cFSGS and compared its clinical behavior to steroid and tacrolimus (TAC)-resistant noncollapsing focal segmental glomerulosclerosis (FSGS). All patients (>14 years) diagnosed with cFSGS were enrolled in the study. Staining for differentiated podocyte markers such as WT 1, PAX and KI67 were performed in all patients. The outcome and histological features of cFSGS was compared with a prospectively followed cohort of steroid and TAC-resistant noncollapsing FSGS. The study included 22 cFSGS patients and 19 cases of steroid and TAC-resistant FSGS. Complete remission, partial remission, steroid resistance, progression to ESRD and death were observed in 13.6%, 4.5%, 27.3%, 36.4% and 18.2% patients, respectively. Patients with cFSGS had higher serum creatinine and more advanced tubulointerstitial changes compared to resistant FSGS. Twenty-six percent of therapy resistant noncollapsing FSGS progressed to ESRD after two years of stopping TAC. However, there was no difference in progression to ESRD between cFSGS and therapy-resistant noncollapsing FSGS at the end of two years. Glomerular collapse in the setting of FSGS is poorly responsive to treatment and has a high rate of progression to ESRD. The long-term prognosis of cFSGS and steroid and TAC-resistant FSGS are similar.

Topics: Adolescent; Adult; Creatinine; Disease Progression; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Podocytes; Prognosis; Prospective Studies; Remission Induction; Steroids; Tacrolimus; Young Adult

The aim of this study was to evaluate the association between cancer occurrence and risk of graft failure in kidney transplant recipients. From November 1998 to November 2013, 672 adult patients received their first kidney transplant from a deceased donor and had a minimum follow-up of 6 months. During a median follow-up of 4.7 years (3523 patient-years), 47 patients developed a nonmelanoma skin cancer (NMSC) and 40 a noncutaneous malignancy (NCM). A total of 59 graft failures were observed. The failure rate was 6 per 100 patient-year (pt-yr) after NCM versus 1.5 per 100 pt-yr in patients without NCM. In a time-dependent multivariable model, the occurrence of NCM appeared to be associated with failure (HR = 3.27; 95% CI = 1.44-7.44). The effect of NCM on the cause-specific graft failure was different (P = 0.002) when considering events due to chronic rejection (HR = 0.55) versus other causes (HR = 15.59). The reduction of the immunosuppression after NCM was not associated with a greater risk of graft failure. In conclusion, our data suggest that post-transplant NCM may be a strong risk factor for graft failure, particularly for causes other than chronic rejection.

Topics: Adult; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Neoplasms; Prospective Studies; Retrospective Studies; Risk; Tacrolimus; Time Factors

We assessed the effect of hepatitis C seropositivity on the percentage of various T-cells in living donor renal transplant recipients (LDRTRs) and their association with intercurrent infections post renal transplantation (post-Tx).. One hundred and thirty-three matching LDRTRs [A (seronegative) (68 patients) and B (seropositive) (65 patients) by ELISA] were studied prospectively 10 days, 6 months and 12 months post-Tx for intercurrent infections, acute rejection and T-cell% by flow cytometry.. CD4(+), CD8(+), CD4/CD8 were significantly higher 10 days post-Tx in Group B compared to Group A, p < 0.001. A significant increase in CD8% was seen 6-month post-Tx among Group B compared to Group A. No difference was detected between groups in (CD4(+), CD8(+), CD4/CD8, CD3-CD16/65(+)%), rate and severity of intercurrent infection, rate of acute rejection, 12 months post-Tx. A significantly higher rate of severe infections particularly urinary tract infections (UTI) was noted in Group B compared to Group A the first 3 months post-Tx particularly in those who received the combination of antithymocyte globulin (ATG) or basiliximab, tacrolimus, steroids, mycophenolate mofetil (MMF). CD4(+)% correlated negatively with intercurrent infections in Group B 6 months post-Tx.. HCV(+) patients are more prone to intercurrent infections the first 3 months post-Tx. Infection rate correlates positively with pre-transplant HCV seropositivity and immunosuppressive regimen.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Basiliximab; CD4-CD8 Ratio; Child; Egypt; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Regression Analysis; T-Lymphocytes; Tacrolimus; Urinary Tract Infections; Young Adult

Topics: Adult; Brain; Brain Diseases; Cerebrovascular Circulation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Resonance Imaging; Male; Tacrolimus; Tomography, Emission-Computed, Single-Photon

Immune-checkpoint inhibitors have been approved for the treatment of metastatic melanoma based on several phase III trials. Patients after organ transplantation and patients with impaired renal function were excluded from these studies. Recently, allograft rejections were reported in organ transplant recipients receiving PD-1 blocking antibodies.. Four patients with metastatic melanoma and impaired kidney function (baseline serum creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of which one was a kidney-transplant recipient receiving immunosuppressive therapy with tacrolimus and prednisolone. The patient was initially treated with the anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk of allograft rejection. Upon disease progression, therapy was switched to the anti-PD-1 antibody nivolumab. The other three patients were treated with nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab.. The patients received a median of six doses (range 3-21) of anti-PD-1 antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable throughout the course of checkpoint blockade. In the kidney transplant recipient, neither ipilimumab nor nivolumab led to an allograft rejection. Responses to anti-PD-1 treatment were divergent with two patients showing disease progression, one achieving a mixed response and one experiencing a complete response.. These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; CTLA-4 Antigen; Graft Rejection; Humans; Immunosuppressive Agents; Ipilimumab; Kidney Failure, Chronic; Kidney Transplantation; Male; Melanoma; Middle Aged; Nivolumab; Patient Safety; Prednisolone; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus

Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long‑term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK‑52E, were cultured either with oxidized low‑density lipoprotein (ox‑LDL), FK506, ox‑LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin‑like ox‑LDL receptor‑1 (LOX‑1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis‑associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague‑Dawley rats were divided randomly into four groups, which included a high‑fat group, FK506 group, high‑fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox‑LDL, ROS, and the expression levels of transforming growth factor (TGF)‑β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX‑1 markedly reduced the levels of TGF‑β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation.

Topics: Allografts; Animals; Connective Tissue Growth Factor; Disease Models, Animal; Dyslipidemias; Fibrosis; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lipid Metabolism; Lipoproteins, LDL; Mice; Rats; Reactive Oxygen Species; Scavenger Receptors, Class E; Tacrolimus; Transforming Growth Factor beta1

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Topics: ABO Blood-Group System; Acute Disease; Adult; Cystic Fibrosis; Disease-Free Survival; Female; Graft Rejection; HLA Antigens; Humans; Isoantigens; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Lung Transplantation; Middle Aged; Mothers; Mycophenolic Acid; Plasmapheresis; Prednisolone; Sepsis; Tacrolimus; Withholding Treatment

Topics: Adult; Biopsy; Delayed Graft Function; Female; Humans; Hypophosphatemia; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Phosphates; Tacrolimus; Treatment Outcome

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

Pretransplant removal of antiblood group ABO antibodies is the cornerstone of all current ABO-incompatible (ABOi) transplantation programmes. In our protocol, plasmapheresis (PP) is performed with a plasmafilter followed by immunoadsorption (IA) of anti-ABO antibodies. The bleeding complications of this technique are not known. We analysed the data of all 65 consecutive ABOi kidney transplantations between March 2006 and October 2013 and compared these with matched 130 ABO-compatible (ABOc) kidney transplantations. Cases differed from controls in the pre-operative regimen, which included IA-PP and rituximab, tacrolimus, mycophenolate mofetil, prednisone and immunoglobulines. Data on platelet count, blood loss and red blood cell (EC) transfusions during 48 h postoperatively were collected. ABOi patients received EC transfusions more frequently than controls (29% vs. 12%, P = 0.005). Intra-operative blood loss was higher (544 vs. 355 ml, P < 0.005) and they experienced more major bleeding (≥3 EC within 24 h, 15% vs. 2%, P < 0.0005). Platelet count decreased by 28% after the pre-operative IA. In a multivariate model, only the number of pre-operative IAs was associated with the number of ECs given (OR per IA 1.9, P < 0.05). ABOi kidney transplant recipients have a high postoperative bleeding risk, correlating with the number of pre-operative IA sessions performed.

Topics: ABO Blood-Group System; Antibodies; Antibodies, Monoclonal, Murine-Derived; Antigens; Blood Group Incompatibility; Case-Control Studies; Cohort Studies; Erythrocyte Transfusion; Female; Hemorrhage; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Platelet Count; Prednisone; Rituximab; Tacrolimus

Sudden cardiac deaths due to arrhythmias are thought to be an important cause of mortality in patients with renal transplants. Exposure to immunosuppressive drugs may lead to QT or PR interval abnormalities which may consequently cause arrhythmias. Our study investigated the long term impact of four different immunosuppressive drugs on PR and corrected QT intervals (QTc) in renal transplant patients. The study population consisted of 98 kidney transplant recipients. Study patients were receiving immunosuppressive management with tacrolimus, cyclosporine A, everolimus or azathioprine according to the local protocols. QTc and PR intervals obtained from the most recent post-transplant electrocardiograms were compared with the pre-transplant intervals dated before the transplantation procedure.. Post-transplant QTc intervals had prolonged significantly in comparison to the pre-transplant QTc intervals in all groups. However, there were no significant differences between the immunosuppressive agents with regard to post-transplant QTc interval prolongation (p > 0.05). There were no significant differences between the groups with regard to the pre and post-transplant PR interval changes (p > 0.05).. QT interval prolongation, a marker of risk for arrhythmias and sudden death, is highly prevalent among kidney transplant patients receiving different classes of immunosuppressive drugs.

Topics: Adult; Arrhythmias, Cardiac; Azathioprine; Cyclosporine; Death, Sudden, Cardiac; Disease Progression; Electrocardiography; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; 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

Long-term survival of renal allografts has improved over the last 20 years. However, less is known about current expectations for long-term allograft function as determined by estimated glomerular filtration rate (eGFR). The aim of this study was to investigate factors which affect graft function at 5 years' post-renal transplantation. The statistically significant factors were then used to construct a predictive model for expected eGFR at five years' post-transplant.. We retrospectively reviewed all adult patients who received a renal transplant in the Republic of Ireland between 1990 and 2004. Data collected included era of transplantation (1990-1994, 1995-1999, 2000-2004), donor and recipient age and gender, number of human leucocyte antigen mismatches, cold ischemia time (CIT), number of prior renal transplants, immunosuppressive regimen used and acute rejection episodes. Estimated GFR was calculated at 5 years after transplantation from patient data using the Modified Diet in Renal Disease (MDRD) equation. Consecutive sampling was used to divide the study population into two equal unbiased groups of 489 patients. The first group (derivation cohort) was used to construct a predictive model for eGFR five years' post-transplantation, the second (validation cohort) to test this model.. Nine hundred and seventy eight patients were analyzed. The median age at transplantation was 43 years (range 18-78) and 620 (63.4%) were male. One hundred and seventy five patients (17.9%) had received a prior renal transplant. Improved eGFR at five years' post-transplantation was associated with tacrolimus-based combination immunosuppression, younger donor age, male recipient, absence of cytomegalovirus disease and absence of acute rejection episodes as independently significant factors (p < 0.05). The predictive model developed using these factors showed good correlation between predicted and actual median eGFR at five years. The model explained 20% of eGFR variability. The validation model findings were consistent with the derivation model (21% variability of eGFR explained by model using same covariates on new data).. The predictive model we have developed shows good correlation between predicted and actual median eGFR at five years' post-transplant. Applications of this model include comparison of current and future therapy options such as new immunosuppressive regimens.

Topics: Adult; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Ireland; Kidney Failure, Chronic; Kidney Transplantation; Male; Prognosis; Retrospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Time

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

We report a 16-yr-old female who developed AN within a month after renal transplantation and its resolution after switching from tacrolimus to cyclosporine. Her initial maintenance immunosuppressive regimen after renal transplantation consisted of tacrolimus, mycophenolate, and steroid. She had 7 kg weight loss within the first month of transplant with subsequent 10, 12, 17, and 19 kg loss after three, five, seven, and nine months of transplant, respectively. Besides weight loss and disturbances in body image, the patient developed alopecia, bradycardia, and persistent secondary amenorrhea. Upon switching to cyclosporine from tacrolimus nine months after transplant, she started regaining weight with 5 kg gain within two months and 10 kg after four months. She restarted her menstrual cycle, alopecia and bradycardia resolved, and her body image disturbance improved. Here, we describe a very unusual neuropsychiatric side effect of tacrolimus and its resolution with another calcineurin inhibitor, cyclosporine, in an adolescent renal transplant recipient.

Topics: Adolescent; Anorexia Nervosa; Body Weight; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Tacrolimus; Transplant Recipients; Treatment Outcome

OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. Moreover, regimens containing cyclosporine were more cost-effective [corrected].

Topics: Adult; Cohort Studies; Cost Savings; Cost-Benefit Analysis; Cyclosporine; Drug Administration Schedule; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Quality-Adjusted Life Years; Tacrolimus

Data on transplantation survival is widely available for developed countries where cadaveric transplantation is the dominant transplantation type. We aimed to assess patient and graft survival and to determine the possible factors affecting graft survival in a developing country where kidney transplantations were mainly performed from living donors.. We retrospectively analyzed data from 427 adult kidney transplantations performed at our center from January 1990 to November 2010. We collected data from patient files, including characteristics of the recipients and donors, transplantation-related factors, post-transplantation features, causes of graft loss, and patient death. The Kaplan-Meier method was used to analyze survival, and Cox regression analysis was used to evaluate the effects of multiple factors on graft survival.. Most of the recipients (82.6%) received their organs from living donors. One-year and 5-year graft survival rates were 87.5% and 78.3%, respectively, where the 5-year graft survival rates were 87.1% for living donors and 74.8% for cadaveric donors. The 1-year and 5-year patient survival rates were 90.9% and 88.9%, respectively. Univariate analysis showed that predictors for better graft survival were serum creatinine levels <1.5 mg/dL at 1 month after transplantation, proteinuria <500 mg/d at 1 year after transplantation, use of tacrolimus and mycophenolic acid derivative-based immunosuppression at baseline, living-donor transplantation, and transplantations performed in the years 2000-2010.. We report data on kidney transplantation in an emerging country where living-donor transplantation constitutes a large proportion of kidney transplant activities. Modern immunosuppressive medications help to achieve a better survival. Our 5-year results are similar to those of developed countries.

Topics: Adult; Aged; Creatinine; Developing Countries; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Tertiary Care Centers; Turkey

Management of mental health issues in the post-transplant setting can be difficult given the potential for medication related neurotoxicity. The lack of established guidelines in this area further compounds this difficulty. The current report details the course of patient with stable bipolar affective disorder prior to renal transplantation, who developed de novo psychosis post-transplantation as an adverse effect of her tacrolimus therapy. The patient was unable to take her usual oral immunosuppressants due to the severity of her psychosis and she eventually required alemtuzumab parenterally as rescue therapy from rejection. This case highlights the diagnostic and therapeutic challenges when dealing with transplant recipients with significant psychosis.

Topics: Administration, Oral; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antipsychotic Agents; Bipolar Disorder; Drug Interactions; Drug Substitution; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Psychoses, Substance-Induced; Severity of Illness Index; Sirolimus; Tacrolimus; Treatment Outcome

The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the Annual Kidney Week Meeting of the American Society of Nephrology. Once again, the conference hall was overflowing with audience members and eager quiz participants. Topics covered by the expert discussants included electrolyte and acid-base disorders, glomerular disease, ESRD/dialysis, and transplantation. Complex cases representing each of these categories along with single best answer questions were prepared and submitted by the panel of experts. Before the meeting, program directors of United States nephrology training programs and nephrology fellows answered the questions through an internet-based questionnaire. During the live session, members of the audience tested their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They compared their answers in real time using audience response devices with the answers of the nephrology fellows and training program directors. The correct and incorrect answers were then discussed after the audience responses and the results of the questionnaire were displayed. As always, the audience, lecturers, and moderators enjoyed this educational session. This article recapitulates the session and reproduces its educational value for the readers of CJASN. Enjoy the clinical cases and expert discussions.

Topics: Anemia; Calcineurin Inhibitors; Female; Humans; Hypertension, Renal; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nephritis; Nephrology; Neuroimaging; Parvoviridae Infections; Parvovirus B19, Human; Posterior Leukoencephalopathy Syndrome; Radiography; Surveys and Questionnaires; Tacrolimus

We evaluated the relationship of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) levels with graft function in kidney transplantation patients receiving tacrolimus-based immunosuppression during the early post-transplantation period.. There were 112 patients who underwent kidney transplantation from live donors between May 2011 and May 2013. Eight patients had at least 1 of the exclusion criteria, and the remaining 104 patients were included in the study. The recipients underwent evaluation for biochemical markers, complete blood count, and creatinine and cytokine (IL-10, TGF-β) levels during the pretransplantation and post-transplantation 6 months.. The creatinine level was negatively correlated with IL-10 and positively correlated with TGF-β levels in both the pretransplantation and early post-transplantation period.. Low serum TGF-β and high IL-10 levels at post-transplantation month 6 might have a positive effect on graft survival in living donor kidney recipients on tacrolimus-based immunosuppressive treatment.

Topics: Adult; Biomarkers; Creatinine; Cytokines; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-10; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Tacrolimus; Transforming Growth Factor beta

The Collaborative Brazilian Pediatric Renal Transplant Registry started in 2004 as a multicenter initiative aiming to analyze, report, and share the results of pediatric kidney transplantation in Brazil. Data from all pediatric kidney transplants performed between January 2004 and December 2013 were recorded electronically and periodically updated. All patients under 18 years old from the participating centers were enrolled. Demographic data, etiology of chronic kidney disease, and patient and graft survival were analyzed. From a total of 2443 pediatric kidney transplants performed in Brazil during the study period, we report data from 1751 pediatric renal transplants performed in 13 centers enrolled in the collaborative study. Median age at transplantation was 12.4 years, and most of recipients were male (56%). The most common underlying renal etiologies were obstructive uropathy (31%) and glomerulopathy (26%).. According to donor source, 1155 (66%) of transplants were performed with deceased donors (DD). Initial immunosuppression consisted mainly of tacrolimus, mycophenolate, steroids, and induction therapy with anti-IL-2R antibodies.. One-year graft survival (death-censored) was 93% and 90% (log rank test, P < .01), respectively, for living donor (LD) and DD. Graft losses (15%) were most frequently caused by vascular thrombosis, chronic allograft nephropathy, death with functioning kidney, acute rejection, and recurrent renal disease. Recipients of DD had 2.02 (95% confidence interval: 1.14-3.59) times the hazard of graft loss compared with those of LD (P = .015). Patient survival rates at 1 and 5 years were 98% and 97% for LD and 97% and 93% for DD, respectively. The mortality rate was 3.8%, mainly as the result of infection and cardiovascular disease.. The results of this collaborative pediatric transplant study are comparable to international registries. Our effort has been able to maintain an exchange of information, both among the participating centers and with other international registries.

Topics: Adolescent; Adrenal Cortex Hormones; Brazil; Child; Child, Preschool; Cooperative Behavior; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Proportional Hazards Models; Recurrence; Registries; Renal Insufficiency, Chronic; Survival Rate; Tacrolimus; Tissue Donors

New-onset diabetes after transplantation (NODAT) is a common metabolic complication. Most conventional immunosuppressive medications, especially steroids and tacrolimus, are responsible for its development. NODAT may rarely be associated with severe, life-threating complications in kidney transplantation recipients.. A 44-year-old man was admitted to our polyclinic for a routine post kidney transplantation visit. He reported polyuria, polydipsia, and general weakness. The patient had undergone preemptive, living-related kidney transplantation 5 weeks previously. Immunosuppressive treatment comprised tacrolimus, prednisolone, and mycophenolate mofetil. Physical examination revealed no abnormalities except signs of mild dehydration. Although he had no history of diabetes before kidney transplantation and his serum fasting glucose levels were within the reference range at the follow-up visits, his laboratory tests revealed high serum glucose and creatinine levels, ketosis, and metabolic acidosis. Our diagnosis was NODAT with diabetic ketoacidosis and prerenal azotemia. Initial treatment comprised intravenous saline and insulin infusion and subsequently involved intensive subcutaneous insulin administration. Despite the intensive insulin therapy and reduction of the tacrolimus dose, sufficient glucose regulation was not achieved. Tacrolimus was switched to everolimus on day 6 of hospitalization. The patient's insulin requirement gradually decreased to one-half of the primary dose over the following several days, and he was discharged on day 10 with successful serum glucose regulation. Although the diabetogenic potential of sirolimus is similar to that of tacrolimus, the impact of everolimus on glucose metabolism remains unclear.. We have reported a life-threating metabolic complication associated with tacrolimus and successful treatment of NODAT by switching from tacrolimus to everolimus.

Topics: Adult; Diabetic Ketoacidosis; Everolimus; Humans; Immunosuppressive Agents; Insulin; Kidney Failure, Chronic; Kidney Transplantation; Male; Risk Factors; 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

Tacrolimus pharmacokinetics prediction by CYP3A5 genotyping is not available in many Asian resource-limited settings. Therefore, an alternative technique is needed to estimate the dose of tacrolimus perioperatively. The 12-hour level after the first dose (C12-0) is an alternative technique for estimating the dose of tacrolimus. This simple and inexpensive calculation technique can be used by any transplantation center.. A prospective study on a cohort of 57 incident post-kidney transplant recipients was conducted. The whole-blood tacrolimus trough level (C12-0) was measured at 12 hours after the first dose (0.1 mg/kg) of orally administered tacrolimus during transplantation. Concomitant medications with CYP3A5 inhibitors/inducers were not allowed. Genotyping for CYP3A5 expression was carried out by reverse transcription polymerase chain reaction. The dosages and trough levels of tacrolimus at postoperative day 7 and postoperative months 1 to 3 were measured and analyzed for the dose requirements for therapeutic levels (mg/kg/d).. The doses of tacrolimus were widely diverse, ranging from 0.049 to 0.260 mg/kg/d and 0.031 to 0.298 mg/kg/d at day 7 and months 1 to 3, respectively. There were 9, 28, and 20 patients (15.8%, 49.1%, and 35.1%) with CYP3A5 *1/*1, *1/*3, and *3/*3, respectively. The CYP3A5 genotypes were significantly correlated with the target tacrolimus dose at day 7 (r(2) = 0.307) and the stable dose at months 1 to 3 (r(2) = 0.337). The C12-0 level also was significantly correlated with the dose of tacrolimus at day 7 (r(2) = 0.546) and the stable dose at months 1 to 3 (r(2) = 0.406).. There were strong correlations between the C12-0 level and the tacrolimus doses during the perioperative period at day 7 and the stable period at 1 to 3 months. Countries with limited resources for genotype testing can use the C12-0 level as an alternative to estimate the tacrolimus dose.

Topics: Adult; Asian People; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Genotype; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus

Selective interleukin-2 receptor (IL2R) blockade is one option to decrease acute rejection rates in kidney transplant recipients. However, there are little data on the impact of basiliximab in a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and low-dose steroids). Thus, this analysis aims at investigating the impact of basiliximab induction on rejection rates and immediate graft function following kidney transplantation.. Basiliximab was introduced in our center according to our center's policy in the beginning of 2011. Patients who received basiliximab (n = 83) were compared with patients without induction therapy (n = 65) transplanted before the introduction of IL2R antibody induction.. The use of basiliximab as induction therapy decreased the incidence of biopsy-proven acute rejection (BPAR) within the 1st year after transplantation (21.5% vs 14.5%; P = .283). Overall rejection episodes (including BPAR and borderline rejection) were significantly reduced in patients with basiliximab compared with patients without (41.5% vs 24.1%; P = .033). However, graft function (incidence of delayed graft function, primary nonfunction, slow graft function, and serum creatinine decline) and overall outcome (patient and graft survivals) were similar in both groups.. We found a favorable impact of basiliximab induction therapy on early acute rejection rate. The impact on long-term outcome must be addressed in further randomized controlled trials.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus

Bronchiectasis is characterized by abnormal, permanent and irreversible dilatation of the bronchi, usually responsible for daily symptoms and frequent respiratory complications. Many causes have been identified, but only limited data are available concerning the association between bronchiectasis and renal transplantation.. We conducted a retrospective multicenter study of cases of bronchiectasis diagnosed after renal transplantation in 14 renal transplantation departments (French SPIESSER group). Demographic, clinical, laboratory and CT scan data were collected.. Forty-six patients were included (mean age 58.2 years, 52.2 % men). Autosomal dominant polycystic kidney disease (32.6 %) was the main underlying renal disease. Chronic cough and sputum (50.0 %) were the major symptoms leading to chest CT scan. Mean duration of symptoms before diagnosis was 1.5 years [0-12.1 years]. Microorganisms were identified in 22 patients, predominantly Haemophilus influenzae. Hypogammaglobulinemia was observed in 46.9 % patients. Bronchiectasis was usually extensive (84.8 %). The total bronchiectasis score was 7.4 ± 5.5 with a significant gradient from apex to bases. Many patients remained symptomatic (43.5 %) and/or presented recurrent respiratory tract infections (37.0 %) during follow-up. Six deaths (13 %) occurred during follow-up, but none were attributable to bronchiectasis.. These results highlight that the diagnosis of bronchiectasis should be considered in patients with de novo respiratory symptoms after renal transplantation. Further studies are needed to more clearly understand the mechanisms underlying bronchiectasis in this setting.

Topics: Adult; Agammaglobulinemia; Aged; Aged, 80 and over; Azathioprine; Bronchiectasis; Chronic Disease; Cough; Cyclosporine; Everolimus; Female; Forced Expiratory Volume; Graft Rejection; Haemophilus Infections; Haemophilus influenzae; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polycystic Kidney, Autosomal Dominant; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Vital Capacity; Young Adult

Kidney transplant recipients may develop new-onset diabetes after transplantation (NODAT) and transplant-associated hyperglycemia (TAH) (NODAT or new-onset impaired glucose tolerance-IGT). We studied 251 consecutive renal transplant South Asian recipients for incidence of NODAT and its risk factors between June 2004 and January 2009. Pre-transplant glucose tolerance test (GTT) identified non-diabetics (n = 102, IGT-24, NGT-78) for analysis. Baseline immunosuppression along with either cyclosporine (CsA) (n = 70) or tacrolimus (Tac) (n = 32) was given. Patients underwent GTT 20 days (mean) post-transplant to identify NODAT, normal (N) or IGT. TAH was observed in 40.2% of the patients (40% in CsA and 40.6% in Tac) (P = 0.5). NODAT developed in 13.7% of the patients (12.9% in CsA and 15.6% in Tac) (P = 0.5). Overall, Hepatitis C (P = 0.007), human leukocyte antigen (HLA) B52 (P = 0.03) and lack of HLA A28 (A68/69) (P = 0.03) were associated with TAH. In the Tac group, higher Day 1 dosage (P <0.001), HLA A1 (P = 0.04), B13 (P = 0.03) and lack of DR2 (P = 0.004) increased the risk of TAH. In the CsA group, HLA A10 (P = 0.03), failure of triglyceride (P = 0.001) or low-density lipoprotein (LDL) (P = 0.03) to lower or high-density lipoprotein to rise (P = 0.001), and higher post-transplant LDL (P <0.001) and cholesterol levels (P = 0.02) were associated with NODAT or TAH. Post-transplant fasting plasma glucose on Day 1 had sensitivity-54.5%, specificity-50.1%, positive predictive value-18.1% and negative predictive value-84.8% for detecting NODAT. In conclusion, there is a genetic predisposition to NODAT and TAH in South Asia as seen by the HLA associations, and a predisposition exists to the individual diabetogenic effects of Tac and CsA based on HLA type. This could lead to more careful selection of calcineurin inhibitors based on HLA types in the South Asian population.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Female; Genetic Predisposition to Disease; Graft Rejection; HLA Antigens; Humans; Hyperglycemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus

Tacrolimus-induced cardiomyopathy (TICM) is a rare but serious adverse effect of tacrolimus, which has been described primarily in pediatric non-renal transplant recipients. We describe a case of TICM in an adult renal transplant recipient that resulted in allograft dysfunction and multiple hospital admissions for heart failure exacerbation. Prompt and complete reversal of TICM occurred after tacrolimus discontinuation. Although tacrolimus-induced cardiomyopathy is reversible, availability of alternative immunosuppressants is limited, particularly in the setting of renal dysfunction. Available studies and patient-specific factors must be considered when determining an alternative maintenance immunosuppression regimen. We chose to use belatacept as alternative immunosuppression in this patient with TICM. Over the next 3 years, the patient remained free of hospital admissions and acute rejection, and demonstrated superior renal allograft function than was observed before her first heart failure admission. We believe that belatacept is an acceptable alternative to tacrolimus therapy for resolution of TICM.

Topics: Cardiomyopathies; Diagnosis, Differential; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Tacrolimus; Ultrasonography

Topics: Acidosis; Adult; Fludrocortisone; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Treatment Outcome

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

Topics: Adolescent; Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Maintenance Chemotherapy; Male; Mycophenolic Acid; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

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

Goal tacrolimus concentrations for the prevention of rejection in sensitized renal transplant recipients are not well established.. We evaluated the association between discharge tacrolimus trough concentration and the incidence of biopsy-proven acute rejection (BPAR) in 216 moderately sensitized renal transplant recipients (negative flow crossmatch and positive donor-specific antibodies) treated with tacrolimus.. At transplant, the mean±standard deviation (SD) peak panel-reactive antibody was 60±33 and median donor-specific antibody level was a mean fluorescence intensity of 710 (interquartile range, 328-1202). The mean±SD tacrolimus trough concentration at discharge (median postoperative day, 5; interquartile range, 4-7) was 7.6±3.7 ng/dL. Patients were divided into two groups based on a discharge tacrolimus trough concentration of 8 ng/mL. Baseline characteristics were similar between groups. Thirty-four (28.6%) of the 119 patients with a tacrolimus trough concentration less than 8 ng/mL and 19 (19.6%) of 97 patients with concentrations of 8 ng/mL or greater experienced BPAR during a median follow-up of 14±4.7 months (P=0.04). Adjusting for age, race, donor status, and peak panel-reactive antibody, a discharge tacrolimus trough concentration less than 8 ng/mL was significantly associated with a higher risk of BPAR (hazard ratio, 1.84; 95% confidence interval, 1.04-3.25; P=0.04). Serum creatinine, cytomegalovirus, BK viremia, or BK nephropathy at 1 year did not differ between groups.. In a patient population predisposed to BPAR, discharge tacrolimus trough concentration less than 8 ng/mL was associated with a nearly two times greater risk of BPAR.

Topics: Biopsy; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus; Treatment Outcome

MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events.

Topics: Adult; Dose-Response Relationship, Drug; 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; Prognosis; Prospective Studies; Risk Factors; Tablets, Enteric-Coated; Tacrolimus

Kidney transplantation increases the chances for pregnancy and live birth for women with end-stage kidney disease. The aims of this study were to describe the outcomes of pregnancies in women with a kidney transplant and to evaluate the impact on anti-human leucocyte antigen (HLA) alloimmunization.. We analysed 61 pregnancies that occurred in 46 patients after having excluded 10 miscarriages during the first trimester and 10 other pregnancies from which important data were missing. Anti-HLA antibodies were screened using the Luminex assay.. Overall, the live birth rate was 83% (94% after exclusion of miscarriages during the first trimester). Pre-eclampsia and gestational diabetes occurred in 26 and 21% of cases, respectively. The use of tacrolimus was an independent predictive factor for gestational diabetes. Twenty-four newborns (42%) were premature (<37 weeks). The median birth weight was 2720 (1040-3730) g. Nine newborns (15%) had low birth weights (<2.5 kg). At least one severe complication occurred in 56% of pregnancies. A high glomerular-filtration rate (GFR) before pregnancy was the sole independent protective factor that avoided a severe complication. Death-censored kidney-allograft survival was 80.4% at 6 years. De novo donor-specific anti-HLA antibodies were detected after only 5.9% of pregnancies: for two women, the father had the same HLA antigens as those from the deceased organ donor. The determination of the HLA of the father before pregnancy can better inform the woman about the possible impact of pregnancy on her kidney-allograft function.. Despite many complications, the outcomes for pregnancy and kidney allografts are good. The risk of anti-HLA alloimmunization was low.

Topics: Adolescent; Adult; Female; Glomerular Filtration Barrier; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Infant, Newborn; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus; Transplantation, Homologous; Young Adult

Recent efforts have been made to identify genetic markers of CYP3A4 enzymatic activity within genes encoding for regulatory elements. The aim of the current study was to investigate the impact of polymorphism of PPARA and POR genes on tacrolimus (TAC) dose-adjusted trough concentration and risk of new-onset diabetes after transplantation (NODAT). A total of 241 White kidney transplant patients were genotyped for three functional single nucleotide polymorphisms: rs1057868 (*28) in POR, rs4253728:G>A, and rs4823613:A>G in PPARA. No significant genotype-dependent differences in TAC dose-adjusted trough concentration were observed for either POR or PPARA variants. No significant differences in the incidence of NODAT were observed between patients stratified by PPARA and POR genotypes. The frequency of NODAT among PPARA rs4253728 AA homozygotes (42%) was higher compared with heterozygotes (22%) and GG homozygotes (19%), but the difference was not significant. Testing TAC-medicated renal transplant recipients for POR and PPARA variants seems to have limited clinical application.

Topics: Adolescent; Adult; Aged; Alleles; Cytochrome P-450 Enzyme System; Diabetes Complications; Diabetes Mellitus; Female; Genotype; Heterozygote; Homozygote; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Pharmacogenetics; Polymorphism, Genetic; PPAR alpha; Risk Factors; Tacrolimus

There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients.. This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors.. 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients.. AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Topics: Adult; Aged; BK Virus; Black or African American; Cardiovascular Diseases; Cohort Studies; Dyslipidemias; Female; Graft Rejection; Graft Survival; Health Status Disparities; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Medicare; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; United States

Calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF) and steroid is mainly used as immunosuppressive therapy after the living-donor liver transplantation (LDLT). However, the nephrotoxicity caused by CNI remains a critical problem for patients with chronic renal failure, especially on early postoperative period. A 62-year-old woman with decompensated liver cirrhosis secondary to hepatitis B (Child-Pugh C, MELD score 11 points) and chronic renal failure due to diabetic nephropathy (Cr 1.56 mg/dl, GFR 27 ml/min/1.73 m2) experienced LDLT. During the reconstruction of hepatic vein, the supra-and infra-hepatic vena cava was totally clamped. The estimated right lobe liver graft volume was 540 g, representing 51.3% of the standard liver volume of the recipient. Because of the perioperative renal dysfunction due to diabetic nephropathy and the total clamping the vena cava which induced the congestion kidney, MMF (1500 mg/day) and steroid (250 mg/day converted into predonisolone) were mainly introduced as an immunosuppressive therapy after LDLT. The low-dose CNI, tacrolimus also induced the nephrotoxicity and was given for only a short time. Finally, according to the postoperative renal function, the low-dose CNI, cyclosporin (50 mg/day) was able to be added to the introduced immunosuppressive therapy. After having left the hospital, MMF (1500 mg/day), steroid (20 mg/day converted into predonisolone) and cyclosporin (75 mg/day) continued to be given as the immunosuppressive therapy and neither acute graft rejection nor drug-induced renal dysfunction was occurred. This is a case report of introducing with mainly MMF and steroid as an immunosuppressive therapy after LDLT for a patient with perioperative renal dysfunction.

Topics: Cyclosporine; Diabetic Nephropathies; Female; Hepatitis B; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

Tacrolimus (Tac) is a core immunosuppressive drug in human organ transplantation. In feline kidney transplantation, however, the cost of Tac therapy is a significant obstacle. Clarithromycin (CLM) increases the blood trough level of Tac, effectively reducing the Tac dosage in human transplant patients. The interaction between CLM and Tac in cats has not been reported. In this study, the effect of multiple CLM dosing on the pharmacokinetics of Tac in three healthy cats was investigated. The treatments included Tac at 0.3 mg/kg and Tac at 0.3 mg/kg + multiple-dose CLM at 10 mg/kg. Co-administration of CLM and Tac resulted in significant increases in the oral bioavailability of Tac. These preliminary findings suggest that administration of multiple doses of CLM may decrease the required Tac dosage in Tac-based immunosuppressive therapy used as an alternative to the classic cyclosporine-based protocol for feline renal transplantation.

Topics: Animals; Biological Availability; Cat Diseases; Cats; Clarithromycin; Dose-Response Relationship, Drug; Drug Synergism; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus

Tacrolimus is a CYP3A4 inhibitor and can alter colchicine metabolism. In this study, we aimed to evaluate plasma colchicine levels in different stages of kidney disease as well as in kidney transplant (KTx) recipients using tacrolimus.. This study included six familial Mediterranean fever (FMF) patients with normal glomerular filtration rate (GFR) as controls, three patients with low GFR, six FMF patients on hemodialysis (HD), and six FMF patients who were KTx recipients using tacrolimus. After a three-d washout period, plasma colchicine levels were measured at 0 (pre-dose), one, two, four, eight, and 24 h post-dose of 1 mg oral colchicine. Area under the curve 0-24 h (AUC0-24 ) and maximum concentration (Cmax ) were evaluated and compared between the groups.. Colchicine AUC0-24 was six-fold higher in HD (p < 0.001) and three-fold higher in KTx recipients (p < 0.001) when compared to the control. The low GFR group had mildly higher AUC0-24 than the control group. Cmax levels were also higher in HD (p = 0.011) and KTx recipient (p = 0.06) groups and mildly elevated in low GFR patients in comparison with controls.. Colchicine AUC0-24 and Cmax were significantly increased in HD patients and KTx recipients using tacrolimus. Therefore, dose adjustments are needed to avoid toxicity in both circumstances.

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

Topics: Adolescent; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Patient Satisfaction; Retrospective Studies; Surveys and Questionnaires; Tacrolimus; Treatment Outcome

Belatacept is a novel immunosuppressive agent that may be used as an alternative to calcineurin inhibitors (CNI) in immunosuppression (IS) regimens. We report two cases of pancreas transplant that were switched from tacrolimus (TAC) to belatacept. Case 1: 38-year-old female with pancreas transplant alone maintained on TAC-based IS regimen whose serum creatinine (SCr) slowly deteriorated from 0.6 mg/dL at baseline to 2.2 mg/dL, 16 months posttransplant. A native kidney biopsy performed showed CNI toxicity. The patient was started on belatacept and TAC was eliminated. Case 2: 49-year-old female with simultaneous pancreas-kidney transplant, maintained on TAC-based regimen where the SCr worsened over an initial 3-month period from a baseline of 1.0 to 3.0 mg/dL. Belatacept was started and TAC was lowered. Due to persistent graft dysfunction and kidney transplant biopsy still showing changes consistent with CNI toxicity, the TAC was then discontinued. At >1 year postbelatacept and off TAC follow-up, kidney function as measured by SCr remains stable at 1.0±0.2 mg/dL in both recipients. Neither patient developed rejection following the switch, and pancreas allograft function remains stable in both recipients.

Topics: Abatacept; Adult; Disease Progression; Female; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Failure, Chronic; Middle Aged; Pancreas Transplantation; Tacrolimus

Calcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Dietary fish oil may minimize nephrotoxicity caused by long-term use of calcineurin inhibitors. The purpose of the present study was to evaluate the effects of omega-3 fatty acids on calcineurin inhibitor nephrotoxicity in rats that had normal kidney function or chronic kidney failure.. Rats that had normal kidney function or chronic renal failure that was induced by mass reduction surgery were treated with tacrolimus without or with fish oil, fish oil alone, or olive oil. Kidney function and histology were evaluated after 14 days.. Mean body weight loss, serum creatinine, change in serum creatinine, and rate of decrease in creatinine clearance were greater in normal rats that received than did not receive tacrolimus. Tacrolimus nephrotoxicity was greater in rats that had chronic renal failure than normal kidney function, but the mean change in serum creatinine was significantly lower in rats with chronic renal failure that were treated with tacrolimus and fish oil than tacrolimus alone. Fish oil supplementation was associated with fewer abnormal histopathologic lesions in the kidneys of tacrolimustreated rats that had normal kidney function or chronic renal failure (not signifant).. Fish oil may be protective against the development of kidney dysfunction and histopathologic changes in rats treated with tacrolimus.

Topics: Animals; Biomarkers; Calcineurin Inhibitors; Creatinine; Cytoprotection; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Proteinuria; Rats, Wistar; Tacrolimus; Time Factors

Topics: Adolescent; Antibodies, Monoclonal; Basiliximab; Body Weight; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Treatment Outcome

Advanced kidney disease is usually considered an absolute contraindication for lung transplantation due to the difficult management of these patients in the post-operative period. Combined lung-kidney transplantation, however, could offer an opportunity for selected patients with renal and pulmonary dysfunction. This study summarizes the long-term success of a double transplantation in a 38-year-old male patient with cystic fibrosis who presented respiratory and kidney failure. After a complicated post-operative period, the patient currently lives completely independently 46 months after the operation and he enjoys excellent pulmonary and renal function.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Basiliximab; Coinfection; Cystic Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Transplantation; Male; Mycophenolic Acid; Pneumonia; Prednisone; Recombinant Fusion Proteins; Recovery of Function; Renal Dialysis; Respiratory Insufficiency; Tacrolimus

Dysregulation of complement activation is the most common cause of the atypical haemolytic uraemic syndrome (aHUS). Many patients with aHUS develop end-stage renal disease and consider kidney transplantation. However, the recurrence rate after transplantation ranges from 45-90% in patients with known abnormalities in circulating complement proteins. It was recently proposed that patients with aHUS should be treated prophylactically with plasma exchange or eculizumab to prevent recurrence after transplantation.. A case series describing the successful outcome of kidney transplantation without prophylactic therapy in four adult patients with aHUS and a high risk of disease recurrence. Patients received a living donor kidney and immunosuppression consisting of basiliximab induction, low-dose tacrolimus, prednisone and mycophenolate mofetil. Patients received a statin, and were targeted to a low blood pressure preferably using blockers of the renin-angiotensin system.. After a follow-up of 16-21 months, none of the patients developed recurrent aHUS. Also, no rejection was observed.. Kidney transplantation in adult patients with aHUS can be successful without prophylactic eculizumab, using a protocol that minimises cold ischaemia time, reduces the risk of rejection and provides endothelial protection. Our data suggest that in patients with aHUS, controlled trials are needed to demonstrate the optimal strategy.

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Basiliximab; Cold Ischemia; Drug Therapy, Combination; Female; Hemolytic-Uremic Syndrome; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recombinant Fusion Proteins; Secondary Prevention; Tacrolimus; Young Adult

Continuous systolic blood pressure (SBP) and interbeat intervals (IBI) recordings reveal sequences of consecutive beats in which SBP and heart rate change in opposite direction, representing negative feedback baroreflex mechanisms, as well as sequences in which SBP and heart rate change in the same direction (non-baroreflex), believed to represent feedforward control mechanisms. The present study was undertaken to assess the relationship between baroreflex and non-baroreflex sequences in end stage renal insufficiency.. Continuous beat-to-beat SBP and IBI monitoring was performed in patients on chronic hemodialysis (HD, n=72), in age-matched patients after renal transplantation (TX, n=41) and healthy (control) individuals (C, n=34). The proportion of baroreflex and nonbaroreflex episodes and the b coefficients (the regression line slope of SBP-IBI correlation) were determined using a newly developed 1 minute sliding window method, the classical sequence technique and the "Z" coefficient method. Analysis using the 1 minute sliding window showed an increased proportion of baroreflex episodes in controls and HD, and predominance of nonbaroreflex episodes in TX. An increased proportion of nonbaroreflex episodes in TX patients relative to HD was also revealed by the "Z" method. Baroreflex and nonbaroreflex b coefficients obtained by all methods were markedly decreased in HD. This alteration was reversed at least partly in TX. In HD, both baroreflex and nonbaroreflex b coefficients were inversely correlated to age and CRP levels; in TX, the nonbaroreflex b coefficient was influenced by the type of calcineurin inhibitor.. Renal status affects the contribution of baroreflex and nonbaroreflex mechanisms and the strength of SBP-IBI relationship. The predominant contribution of nonbaroreflex mechanisms in TX may be suggestive of enhanced central sympathetic control. Our data may be relevant for understanding of the pathogenesis and selection of appropriate treatment of post-transplant hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Baroreflex; Blood Pressure; Calcineurin; Calcineurin Inhibitors; Female; Heart Rate; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Risk Factors; Tacrolimus; Time Factors; Vasomotor System

The porphyrias are a group of disorders of the heme biosynthesis pathway that may present with acute life-threatening attacks, commonly exacerbated by a wide variety of medications. Many newer immunosuppressive medications, which are in use following kidney transplantation, have not been fully explored in acute porphyrias.. A 53-year-old woman received a kidney from a deceased donor, after being on hemodialysis for 4 years. Hereditary coproporphyria was diagnosed at age 19 years. We administered tacrolimus, mycophenolate mofetil and steroid immunosuppression. In the immediate post-transplant periods she displayed abdominal pain and transient uroporphyrin elevation in parallel with slightly elevated (15 ng/mL) tacrolimus concentrations. As the target tacrolimus level was achieved, these findings disappeared.. Tacrolimus, mycophenolate- mofetil, and steroid therapy for hereditery coproporphyri was safe, in the long term.

Topics: Abdominal Pain; Coproporphyria, Hereditary; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Risk Factors; Tacrolimus; Treatment Outcome

ABO-incompatible renal transplantation (ABOi-RTx) following preconditioning with immunoadsorption (IA) and rituximab is a promising approach to facilitate living-related RTx. However, clinical experience is limited in pediatric patients.. Three patients underwent living-related ABOi-RTx in our center. Preoperative IA was performed six, ten and 11 times in patient one, two and three, respectively, to achieve isoagglutinin titers of ≤1:8 on the day of transplantation; rituximab was administered once. The immunosuppressive regimen further comprised tacrolimus, mycophenolate, methylprednisolone and basiliximab; immunoglobulin G (IgG) was infused on the day of ABOi-RTx.. All three patients achieved normal renal function within 2-6 days post-RTx. Major postoperative bleeding occurred in two patients, with one requiring repeated blood transfusions and the other a surgical revision 4 h after RTx, despite local citrate anticoagulation use during the preoperative IA procedures in the latter patient. A pyelonephritis-associated increase of the isoagglutinin IgG/IgM titers to 1:64/1:128 led to a biopsy-proven acute humoral rejection in the third patient, which was treated successfully with plasma exchange and methylprednisolone pulses. The estimated glomerular filtration rate at 18, 8 and 23 months post-RTx was 96, 52 and 74 ml/min/1.73 m(2), respectively.. ABOi-RTx can successfully be performed in pediatric patients after preconditioning with quadruple immunosuppression, rituximab and IA. Caution is required regarding bleeding complications, which are most likely due to the unspecific binding of coagulation factors during repeated IA.

Topics: ABO Blood-Group System; Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Anticoagulants; Basiliximab; Blood Group Incompatibility; Child, Preschool; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Heparin; Humans; Immunoglobulin G; Immunoglobulin M; Immunosorbent Techniques; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Methylprednisolone; Mycophenolic Acid; Postoperative Hemorrhage; Pyelonephritis; Recombinant Fusion Proteins; Rituximab; Tacrolimus; Young Adult

Kidney transplantation in HIV-infected patients is associated with a higher rate of graft rejection as well as an increased toxicity of the immunosuppressive therapy. Specifically, the use of the calcineurin inhibitor tacrolimus is problematic because of a narrow therapeutic range, a high interindividual variability of trough levels, and multiple interactions with combination antiretroviral therapy (cART). Our objective was to establish the optimal individual immunosuppressive dose for the time after kidney transplantation. We administered a temporary course of immunosuppressive therapy in three HIV-infected patients with end-stage renal disease (ESRD) after wait-listing and prior to transplantation for deceased donor kidney transplantation. Starting with a tacrolimus dose of 1 mg twice daily, the dose was titrated to reach a tacrolimus trough level of 8-12 ng/ml. HIV had been diagnosed 7-14 years prior. All patients had no detectable HIV-1 RNA while on cART. All three patients had been on chronic dialysis for 4, 7, and 10 years. In two patients, the intended tacrolimus trough levels of 8-12 ng/ml were achieved within a month. The required tacrolimus dose ranged from 0.5 mg thrice weekly to 10 mg daily. In one case, ventricular tachycardia occurred, so the immunosuppressive therapy was switched to cyclosporine A. So far, two patients have been transplanted successfully. In summary, dose-finding of immunosuppressive therapy with tacrolimus in patients on cART before renal transplantation is feasible and appears useful to minimize immunosuppressive therapy-related complications in the post-transplantation period.

Topics: Adult; Anti-Retroviral Agents; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Graft Survival; HIV Infections; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Safety; Preoperative Care; Risk Assessment; Sampling Studies; Tacrolimus; Treatment Outcome

Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored.. A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure.. No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC's reported in HIV-negative recipients, when similar trough levels were targeted.. In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.

Topics: Adult; AIDS-Associated Nephropathy; Area Under Curve; Biotransformation; Computer Simulation; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Enzyme Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Models, Biological; Pilot Projects; Ritonavir; Tacrolimus

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Diabetes Mellitus; Forehead; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Kidney Failure, Chronic; Lasers, Solid-State; Lichen Planus; Low-Level Light Therapy; Male; Middle Aged; Sulfonylurea Compounds; Tacrolimus; Treatment Outcome

Topics: Blood Pressure; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Sensitivity and Specificity; Signal Transduction; Sodium Chloride Symporters; Tacrolimus

Gastrointestinal (GI) complications may affect up to 64% of kidney transplant recipients, with a higher incidence of symptoms in patients receiving tacrolimus-based immunosuppression. Tacrolimus extended release once-daily (OD) formulation offers the benefit of OD administration over standard tacrolimus, with a similar rate of GI complications when compared with the standard tacrolimus. We hypothesized that patients with tacrolimus-based immunosuppressive regimen with posttransplant gastrointestinal symptoms may benefit from a conversion to a tacrolimus OD regimen.. In this pilot study, 27 kidney transplant recipients with tacrolimus-related GI complications were converted to a tacrolimus OD regimen (group 1). This group was compared with a historical cohort of 30 patients on standard tacrolimus therapy with GI symptoms (group 2). Patients were followed up for 1 year after initial enrollment.. Patients in group 1 reported a significant improvement in GI symptoms, as expressed by the change in the Gastrointestinal Symptom Rating Scale scores (1.7±0.3 vs. 1.2±0.2, P<0.001) and GI-specific health-related quality of life scores (87±26.3 vs. 97±24.6, P<0.05). After comparing changes in Gastrointestinal Symptom Rating Scale total scores and subscale scores at 12 months, patients in Group 1 scored better than patients in Group 2 in total scores (-0.5 vs. -0.12, P<0.0001), abdominal pain (P<0.001), diarrhea (P<0.001), and reflux (P=0.013).. Preliminary results from this study demonstrate that kidney transplant recipients experiencing tacrolimus-induced GI symptoms may benefit from a conversion to a tacrolimus OD regimen.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Quality of Life; Tacrolimus; Treatment Outcome

This study reports initial results of the development of the SIAM, a non-adherence risk assessment system for tacrolimus and sirolimus for the pediatric kidney transplant population. Forty-eight youths between 10 and 25 yr of age diagnosed with chronic kidney disease or a kidney transplant used an electronic pill bottle (EM; time stamps each bottle opening) to dispense their medication for at least 30 days or until their next clinic appointment. Youth also completed a self-report adherence measure, and standard deviations were calculated for the last four medication serum trough levels obtained for each patient. Estimation models were developed for each medication (i.e., SIAM(TACRO) and SIAM(SIRO) ) to assign weights to these clinically available adherence measures (self-report and trough levels) for the calculation of a non-adherence risk composite score. SIAM(TACRO) models included both self-report and tacrolimus trough levels and significantly predicted EM. For sirolimus, the model predictive of adherence as measured by EM consisted of the standard deviation of sirolimus trough levels only (SIAM(SIRO) ). Non-adherence risk can be effectively assessed using clinically available assessment tools. However, the best methods for using self-report and trough levels to predict non-adherence likely differ based on the medication for which adherence is being assessed.

Topics: Adolescent; Adult; Child; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Linear Models; Logistic Models; Male; Medication Adherence; Nephrotic Syndrome; Risk Assessment; Self Report; Sirolimus; Tacrolimus; Young Adult

To present our experience with simultaneous living donor liver and kidney (SLK) transplantation from two different living donors.. We performed five SLK transplantations from two different living donors from November 2006 to December 2010. Four patients were males and one, female. Their age range was 47 to 66 years (mean, 55 years). The primary liver diseases included hepatitis B virus (n=2), alcoholic liver cirrhosis (n=2), cryptogenic liver disease (n=1), and hepatitis C virus with hepatocellular carcinoma (n=1). All five patients had chronic renal failure: four were on hemodialysis (H/D) and one on chronic ambulatory peritoneal dialysis for 1 to 20 years. Liver implantation was performed first, followed by kidney transplantation. The liver and kidney teams worked closely to shorten the ischemia time.. All surgical procedures were performed uneventfully and all recipients and donors survived the operations. Good liver graft function was noted in all five patients. The patient with both anti-T- and anti-B-cell positive crossmatch tests developed hyperacute rejection of the kidney graft requiring its immediate removal. This patient was maintained on regular H/D afterward. The other four patients displayed good renal function. No evidence of severe acute rejection was noted during the follow-up period (range, 9-55 months) among patients treated with tacrolimus-based immunosuppression.. We suggest that SLK transplantation be performed with organs from two different instead of a single live donor.

Topics: Aged; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver Diseases; Liver Transplantation; Living Donors; Male; Middle Aged; Reoperation; Retrospective Studies; Tacrolimus; Taiwan; Time Factors; Treatment Outcome

Recipients after liver transplantation. (OLT) often experience renal dysfunction. Acute kidney injury (AKI) and chronic kidney disease (CKD) after OLT occur among 20% to 50% and 30% to 90% of recipients, respectively; 2% to 5% of them deteriorate into end-stage renal disease each year. Since the predictable factors for CKD have not been well identified. We sought to investigate the incidence and predictors of CKD at 5 years after OLT.. Between August 2002 and December 2005, we enrolled 77 patients who underwent adult living donor OLT with over 2 years of follow-up. The strategies to prevent renal dysfunction included induction with basiliximab to delay the use of tacrolimus: addition of mycophenolate mofetil to reduce the tacrolimus dosage; avoidance of the calcineurin inhibitor using sirolimus or administration of an angiotensin II receptor antagonist. The clinical variables were reviewed for analysis.. The mean follow-up was 76 ± 14 months. The incidence of AKI (over 50% increase level of creatinine) was 29%. Ten (13.0%) patients developed CKD (creatinine > 2 mg/dL). One (1.3%) subject developed end-stage renal disease requiring hemodialysis. Upon multivariate analysis the development of CKD was significantly associated with the posttransplant 4-week creatinine level: 0.92 ± 0.23 versus 1.37 ± 0.93 mg/dL (P = .008).. The 4-week creatinine value was predictive of the occurence of CKD over 5 years after OLT.

Topics: Acute Kidney Injury; Adult; Angiotensin Receptor Antagonists; Antibodies, Monoclonal; Basiliximab; Creatinine; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Basiliximab is a recently developed immunosuppressive agent for the prevention of acute allograft rejection in renal transplant recipients. The combination use of basiliximab and a calcineurin inhibitor was suggested to be more effective in comparison to immunosuppressive therapy using calcineurin inhibitor without basiliximab. Cyclosporine has been generally administered with basiliximab for renal transplant recipients. However, in cases of tacrolimus-based immunosuppressive regimen, the clinical efficacy and safety of combined use of tacrolimus and basiliximab remains to be elucidated. This study evaluated the tacrolimus pharmacological efficacy using a lymphocyte immunosuppressant sensitivity test (LIST) with MTT assay procedures in 16 cases of renal transplant recipients treated by tacrolimus without basiliximab and in 13 cases treated by tacrolimus in combination with basiliximab. The rate of acute rejection episodes in the recipients treated with tacrolimus plus basiliximab was 1/13 (7.7%), whereas the rate in the recipients treated with tacrolimus without basiliximab was 6/16 (37.5%). The recipients were divided into two groups according to their peripheral blood mononuclear cell (PBMC) sensitivity to tacrolimus [i.e., including a tacrolimus high sensitivity group (IC(50) <1.0 ng/ml) and a low sensitivity group (IC(50) >1.0 ng/ml). In the recipients treated with tacrolimus without basiliximab, the rate of acute rejection episodes in the tacrolimus high sensitivity group was 1/10 (10.0%), which was significantly lower than the rate in the low sensitivity group of 5/6 (83.3%; p = 0.008). The incidence of cytomegalovirus infection was not significantly different between the tacrolimus high and the low sensitivity groups of the recipients treated with tacrolimus with and without basiliximab. Therefore, in the case of selected tacrolimus-based immunosuppressive therapy for renal transplant recipients, the tacrolimus pharmacological efficacy should be evaluated using LIST at a time just before the transplant procedure in order to accurately predict allograft rejection. The data also suggested that low tacrolimus sensitivity recipients should be treated with tacrolimus-based immunosuppressive therapy in combination with basiliximab.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Calcineurin; Calcineurin Inhibitors; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Recombinant Fusion Proteins; 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

Desensitization protocols reduce donor-specific anti-HLA antibodies (DSA) and enable renal transplantation in patients with a positive complement-dependent cytotoxic cross-match (CDC-CXM). The effect of this treatment on protective antibody and immunoglobulin levels is unknown. Thirteen patients with end-stage renal disease, DSA and positive CDC-CXM underwent desensitization. Sera collected pre- and post-transplantation were analysed for anti-tetanus and anti-pneumococcal antibodies, total immunoglobulin (Ig) levels and IgG subclasses and were compared to healthy controls and contemporaneous renal transplant recipients treated with standard immunosuppression alone. Ten patients developed negative CDC-CXM and enzyme-linked immunosorbent assay (ELISA) and underwent successful transplantation. Eight recipients achieved good graft function without antibody-mediated or late rejection, BK virus or cytomegalovirus infection. One patient had primary non-function due to recurrent oxalosis, and one patient with immediate graft function died from septicaemia. Seven recipients required post-operative transfusion and three developed septicaemia. DSA remained negative by ELISA at 12 months, but were detectable by Luminex(®) . Anti-tetanus and anti-pneumococcal antibodies, total Ig and IgG subclasses were below the normal range but comparable to levels in renal transplant recipients who had not undergone desensitization. Desensitization protocols effectively reduce DSA and allow successful transplantation. Post-operative bleeding and short-term infectious risk is increased. Protective antibody and serum immunoglobulin levels are relatively preserved.

Topics: Adult; Aged; Antibodies; Antibodies, Bacterial; Antibodies, Monoclonal; Basiliximab; Desensitization, Immunologic; Female; HLA Antigens; Humans; Immunoglobulin G; Immunologic Memory; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Streptococcus pneumoniae; Tacrolimus; Tetanus; Tissue Donors

Topics: Cardiovascular Diseases; Child; Clinical Trials as Topic; Congresses as Topic; Humans; Kidney Failure, Chronic; Kidney Transplantation; Pediatrics; Risk Factors; Tacrolimus; Transplantation; Treatment Outcome

Topics: Acute Kidney Injury; Azathioprine; Biopsy; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pain, Postoperative; Tacrolimus

Chronic kidney disease (CKD) is common in liver transplant recipients receiving calcineurin inhibitors.. The goals of this case-control study were to identify risk factors associated with CKD and its effect on mortality in 294 liver transplant recipients receiving calcineurin inhibition with tacrolimus.. Hepatitis C virus (HCV) was the most common indication (42%) for transplantation. CKD 4 and 5 (estimated glomerular filtration rate (eGFR) of <=29 ml/min/1.73 m2) developed in 10.8% of recipients during a mean follow-up of 52 months. The incidence density of CKD was 2.56 per 100 patient-years. End-stage renal disease developed in 2.7%. By univariate analysis, CKD patients were older (mean±sd, 57±10 vs. 51±11, p<0.05) with hypertension (56 vs. 32%, p<0.05), had lower preoperative hematocrit (31±6 vs. 34±5, p<0.05), alanine aminotransferase (median (95% confidence limit) 46 (34–80) vs. 68 (56–77), <0.05) and eGFR (56±28 vs. 91±35 ml/ min/1.73 m2, p<0.05), had higher preoperative prothrombin time (16.1 (14.6–17.2) vs. 14.8 (14.5–15.1) seconds, p<0.05), and required more perioperative renal replacement therapy (RRT) (41% vs. 6.5%, p<0.05) compared to controls. Perioperative need for RRT (hazard ratio (95% CI) 2.72 (1.05–7.03)) and lower preoperative eGFR: 60–89 (4.08 (1.23–13.5)), 30–59 (4.26 (1.18–15.36)), and<=29 (5.91 ((1.28–27.19)) vs. eGFR>=90 ml/min/1.73 m2 were independently associated with development of CKD adjusting for important covariates. The development of CKD (2.36 (1.22–4.59)) was independently associated with late mortality with an attributable risk of 12.8%.. Data demonstrate that CKD is an important clinical event associated with increased risk for death after primary liver transplantation.

Topics: Adult; Aged; Calcineurin Inhibitors; Case-Control Studies; Chi-Square Distribution; Chronic Disease; Drug Therapy, Combination; Florida; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Renal Replacement Therapy; Retrospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Time Factors

Topics: Adult; Area Under Curve; CD4 Lymphocyte Count; Drug Interactions; Graft Rejection; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Patient Selection; Tacrolimus

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

New-onset diabetes after transplantation may be associated with the use of tacrolimus (Tac) causing impaired insulin release or reduced insulin sensitivity. Such effects have not been studied in renal transplant recipients receiving traditional twice-daily tacrolimus (TacBID) and then compared to the new once-daily prolonged release formulation of tacrolimus (TacOD).. We performed a prospective crossover study of 20 stable non-diabetic renal transplant recipients. All patients underwent one hyperglycaemic clamp on TacBID (3.8 ± 2.2 mg/day) and a new clamp 4-6 weeks after a 1:1 mg/day switch to TacOD (4.0 ± 2.8 mg/day).. Tac trough concentrations decreased from 6.6 ± 2.9 to 5.4 ± 1.4 μg/mL (P = 0.037) and Tac max from 21.3 ± 8.4 to 15.2 ± 3.5 μg/L (P = 0.001). Tac AUC(0-24) was reduced from 265 ± 112 to 218 ± 47 μg × h/L (P = 0.12). The hyperglycaemic clamp did not detect any change in insulin sensitivity index after conversion [0.26 ± 0.21 versus 0.26 ± 0.25 μmol/min/kg/(pmol/L insulin), P = 0.99] nor any change in first (334 ± 274 versus 353 ± 248 μIU × min/mL, P = 0.41) or second phase insulin secretion (224 ± 155 versus 263 ± 210 μIU × min/mL/mmol glucose, P = 0.60) on TacBID versus TacOD.. Conversion from standard TacBID to TacOD on a 1:1 mg basis is safe. In spite of a reduced Tac exposure, there was no change in insulin release or sensitivity in renal transplant recipients.

Topics: Adult; Aged; Blood Glucose; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hyperglycemia; Immunosuppressive Agents; Insulin Resistance; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prognosis; Prospective Studies; Tacrolimus; Tissue Distribution

De novo thrombotic microangiopathy(TMA) is most commonly triggered by calcineurin inhibitors (CNI) and the prognosis is less severe than with recurrent TMA. However, it is difficult to distinguish de novo TMA from CNI toxicity and acute antibody-mediated rejection(AMR) soon after renal transplantation. We present a case of tacrolimus-associated TMA soon after ABO blood type incompatible renal transplantation that was difficult to differentiate from acute AMR. On day 9 his urine output decreased dramatically and the Scr level increased. His anti-blood type A antibody titer increased to ×16 postopratively and the tacrolimus trough level was higher than in our immunosuppressive regimen. Although we gave priority to anti-AMR treatment, adequate dose adjustment of tacrolimus after tacrolimus nephrotoxicity was diagnosed from graft biopsy could correct allograft dysfunction.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prognosis; Tacrolimus; Thrombotic Microangiopathies

A 33-year-old woman with a history of chronic transplant dysfunction because of repeated bouts of haemolytic uraemic syndrome (HUS) was considered for a second transplant. Extensive genetic investigation of the complement system was executed to rule out known mutations prone to development of HUS. This case illustrates the importance of genetic screening in patients with recurrent HUS.

Topics: Adult; Atypical Hemolytic Uremic Syndrome; Complement Factor H; Disease Progression; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Plasma Exchange; Reoperation; Tacrolimus; Unrelated Donors

Chronic kidney disease (CKD) is a common complication after lung transplantation (LTx). Smoking is a risk factor for many diseases, including CKD. Smoking cessation for >6 months is required for LTx enlistment. However, the impact of smoking history on CKD development after LTx remains unclear. We investigated the effect of former smoking on CKD and mortality after LTx. CKD was based on glomerular filtration rate (GFR) ((125) I-iothalamate measurements). GFR was measured before and repeatedly after LTx. One hundred thirty-four patients never smoked and 192 patients previously smoked for a median of 17.5 pack years. At 5 years after LTx, overall cumulative incidences of CKD-III, CKD-IV and death were 68.5%, 16.3% and 34.6%, respectively. Compared to never smokers, former smokers had a higher risk for CKD-III (hazard ratio [HR] 95% confidence interval [95%CI]= 1.69 [1.27-2.24]) and IV (HR = 1.90 [1.11-3.27]), but not for mortality (HR = 0.99 [0.71-1.38]). Adjustment for potential confounders did not change results. Thus, despite cessation, smoking history remained a risk factor for CKD in LTx recipients. Considering the increasing acceptance for LTx of older recipients with lower baseline renal function and an extensive smoking history, our data suggest that the problem of post-LTx CKD may increase in the future.

Topics: Adult; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Lung Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Smoking; Smoking Cessation; Tacrolimus

Immunosuppressive treatment following renal transplantation includes induction therapy during the initial period when the risk of rejection is higher. Depleting anti-lymphocyte antibodies are indicated mostly in patients who developped anti-HLA antibodies and following a second graft. Anti-IL2 receptor antibodies may be used in non-responders. After the first month, maintenance therapy mostly consists in the association of several immunosuppressants, mainly corticosteroids, an antimetabolic agent (azathioprine or mycophenolate mofetil) and a calcineurin inhibitor (cyclosporine or tacrolimus). Side effects associated with these treatments led to the development of new immunosuppressive protocols, with the reduction or withdrawal of corticosteroids treatment due to its deleterious effects on statural growth, and decreased doses of anti-calcineurin agents to reduce their nephrotoxic effect. These therapeutic options are possible in patients at low immunological risk.

Topics: Antimetabolites; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Evidence-Based Medicine; Glucocorticoids; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Mycophenolic Acid; Postoperative Care; Tacrolimus; Treatment Outcome

The immunosuppressive medications that have contributed greatly to the success of liver transplantation are also associated with posttransplant renal dysfunction. We reviewed measured glomerular filtration rate (GFR) data from patients who underwent transplantation more than 10 years ago to assess whether results from specific time points can predict renal failure.. The GFR data were obtained at initial evaluation (IE), at month 3, and at years 1, 2, 5, 10, and 15. Two groupings were compared, one based on GFR at IE and the other at month 3. Patients were further stratified into three GFR (mL/min/1.73 m2) groups: G1, GFR more than 80; G2, GFR 60 to 80; and G3, GFR less than 60.. A total of 592 liver transplant recipients met the inclusion criteria; 114 had paired GFR data from IE to year 15. Analysis of paired and censored data based on IE GFR showed that 62.2% of G3 patients developed renal failure by year 5; another 6.7% did so by year 10 (P=0.027). The month 3 GFR data showed that 56.3% of G3 patients developed renal failure by year 5; another 15.6% did so by year 10. Surprisingly, 37.0% of G2 patients experienced renal failure by year 5; another 11.1% did so by year 10 (P=0.0024).. The month 3 data indicate a slow but steady decline in GFR over years. The lower the initial GFR is after transplant, the sooner renal failure develops. Patients with GFR less than 60 mL/min per 1.73 m2 at month 3 have a higher risk of renal failure; however, those who avoid renal failure seem to maintain renal function long term.

Topics: Azathioprine; Cyclosporine; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Mycophenolic Acid; Patient Selection; Predictive Value of Tests; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Failure

In our Universitary Hospital of Canarias we iniciated in May 2008 a induction therapy protocol for sensitized patients receiving cadaveric renal graft using intravenous immunoglobulins, plasmapheresis and rituximab plus immunosuppression with prednisone, tacrolimus and mycophenolate mofetil. We present the results of four patients. Everyone had anti-HLA antibodies rate (PRA by CDC) more than 75%, were on a waiting list during 4 to 17 years and follow-up time was 10-14 months after transplantation. Patient and graft survival in this period was 100%. Only one patient suffered a humoral acute rejection and another one cellular rejection, in both cases reversible with treatment. During the first year, no evidence of de novo donor-specific antibodies was detected. All patients had significantly reduced the CD19+ cells percentage after infusion of rituximab. Neurological symptoms suggestive of progressive multifocal leukoencephalopathy or serious viral infections after transplantation have not been observed. Additionally, no immediate side effects were observed after administration of medication. In summary, induction therapy by combining immunoglobulin, plasmapheresis and rituximab in hypersensitive patients allows the realization of deceased kidney transplantation with good results in the short and medium-term without serious side effects. It remains to know whether this success will continue in the long term.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cadaver; Combined Modality Therapy; Female; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunization; Immunoglobulins, Intravenous; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Prednisone; Premedication; Reoperation; Rituximab; Tacrolimus; Tissue Donors

Infection occurs frequently in the organ transplant recipients during the post-transplant period because of immunosuppression. Therefore, prophylactic antimicrobial agents are often used. The azole antifungals, widely prescribed prophylactically, are known to have many drug-drug interactions. This report presents a case of drug-drug interaction between voriconazole and tacrolimus in a kidney transplant recipient. Voriconazole treatment led to a dramatic increase in tacrolimus concentration that required its discontinuation in spite of the manufacturer's guidelines that recommend a reduction of tacrolimus dosage by one-third. The present drug-drug interaction can be attributed to a strong inhibitory effect on cytochrome P450-3A4 activity by voriconazole. When voriconazole and tacrolimus are coadministered, close monitoring of tacrolimus blood levels is recommended as the rule-of-thumb reduction of tacrolimus dose by one-third may not be satisfactory.

Topics: Adult; Antifungal Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Pyrimidines; Tacrolimus; Treatment Outcome; Triazoles; Voriconazole

Accurate measurement of whole-blood tacrolimus concentration is essential for achieving therapeutic immunosuppression and minimizing toxicity in renal transplant recipients. Falsely elevated or decreased values may trigger unnecessary dose adjustments. We identified a falsely elevated whole-blood tacrolimus immunoassay result in a renal transplant patient. Twelve hours after the patient received his first dose, the blood concentration was 24.4 ng/mL using the Siemens Dimension RxL immunoassay. Immunoabsorption studies showed that the cause of the interference was an endogenous antibody present in the patient's plasma that recognized a unique epitope present on the antibody-enzyme (beta-galactosidase) conjugate used in the Siemens tacrolimus immunoassay but not on the antibody or beta-galactosidase alone. This report adds to the growing knowledge base of endogenous antibody interferences in diagnostic immunoassays. To our knowledge, this is the first such report of a falsely elevated tacrolimus concentration due to recognition of an epitope present only on the monoclonal antibody-enzyme conjugate.

Topics: Adult; Antibodies; Binding, Competitive; Humans; Immunoassay; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Technology, Pharmaceutical

Tacrolimus is an immunosuppressive medication in the class of calcineurin inhibitors that acts by inhibiting T-cell and interleukin-2 activity, and is commonly used after allogeneic organ transplant. We present a patient who used tacrolimus after cadaveric kidney transplant and experienced blurry vision. Ocular examination and patient's course subsequently revealed aqueous tear deficiency as a dose-dependent adverse effect of oral tacrolimus.

Topics: Dry Eye Syndromes; Glomerulonephritis, IGA; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lacrimal Apparatus Diseases; Male; Middle Aged; Ophthalmic Solutions; Tacrolimus; Vision Disorders; Visual Acuity

Simultaneous heart and kidney transplantation (SHKT) has become an accepted therapeutic option for patients with end-stage heart failure associated with end-stage renal disease. The immunosuppressive therapy is usually based upon a heart transplantation protocol using a calcineurin inhibitor (CNI). Sirolimus (SRL) is a potent nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Its use has recently been reported to show less nephrotoxicity among both heart and kidney transplants. However, the data for the SHKT are limited. We retrospectively examined the causes of 5 patients who received combined SRL-CNI immunosuppressive therapy with reduced CNI doses from 2003 to 2009. There was no mortality during follow-up. Two of the 3 patients who received a conversion regimen recovered renal function. One who suffered severe proteinuria after transplantation proceeded to hemodialysis at 3 years after conversion. Both of the patients who received the combined regimen de novo remained stable regarding their renal function. Cardiac function was stable in these patients; there was neither allograft rejection nor allograft coronary vasculopathy. We observed that patients without dyslipidemia or hyperuricemia before SHKT were less likely to develop these disorders under the combined regimen. Early medical intervention after close follow-up of lipid and uric acid values by dose adjustments resulted in a stable status of our patients.

Topics: Adolescent; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Heart Failure; Heart Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Sirolimus; Tacrolimus; Young Adult

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Coronary Artery Bypass; Diabetic Nephropathies; Drug Interactions; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Long QT Syndrome; Male; Tacrolimus; Treatment Outcome

We describe the longitudinal follow-up of calcineurin activity and its clinical relevance in 4 de novo living-donor kidney transplant recipients treated with cyclosporine (n=1) or tacrolimus (n=3). The calcineurin activity in peripheral blood mononuclear cells was measured in combination with therapeutic drug monitoring during hospitalization. Serial blood samplings were performed after the oral administration of each drug to evaluate the temporal pharmacokinetic and pharmacodynamic profiles. Significant changes in enzyme activity were evaluated in relation to clinical outcomes. A nadir of calcineurin activity occurred at the maximum blood drug concentration within 4 h post-dose in most cases. Unlike cyclosporine, tacrolimus partially suppressed calcineurin activity throughout the dosing interval compared to the pre-dose level (cyclosporine, 62-67% inhibition; tacrolimus, 13-35% inhibition). Notably, calcineurin activity rapidly increased a few days before the onset of acute rejection in 2 patients, 1 receiving cyclosporine and 1 receiving tacrolimus, despite the achievement of therapeutic trough blood concentrations. These preliminary findings indicate that therapeutic monitoring of calcineurin activity in addition to the measurement of blood drug concentrations may be helpful to evaluate the pharmacodynamic effects of cyclosporine and tacrolimus early after renal transplantation.

Topics: ABO Blood-Group System; Adult; Blood; Creatinine; Cyclosporine; Drug Monitoring; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes, Mononuclear; Living Donors; Male; Middle Aged; Phosphoric Monoester Hydrolases; Tacrolimus

Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.

Topics: Adult; Cyclosporine; Female; Graft Rejection; Graft Survival; HIV Infections; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Paris; Retrospective Studies; Tacrolimus

We report the successful allotransplantation of cryopreserved parathyroid tissue to reverse hypocalcemia in a kidney transplant recipient. A 36-year-old male received a second deceased donor kidney transplant, and 6 weeks later developed severe bilateral leg numbness and weakness, inability to walk, acute pain in the left knee and wrist tetany. His total calcium was 2.6 mg/dL and parathormone level 5 pg/mL (normal 10-60 pg/mL). He underwent allotransplantation of parathyroid tissue cryopreserved for 8 months into his left brachioradialis muscle. Immunosuppression included tacrolimus (target C(0) 10-12 ng/mL), mycophenolate mofetil and steroids. Within 2 weeks, the left knee pain, leg weakness and numbness resolved, and by 1 month he could walk normally. After a peak at month 2, his parathyroid hormone (PTH) level fell to <10 pg/mL; therefore at month 3 he received a second parathyroid transplant from the same donor. Eight months later (11 months after initial graft) he has a total calcium of 9.3 mg/dL, PTH level 15 pg/mL and is clinically asymptomatic. The amount of parathyroid tissue needed to render a patient normocalcemic is not known. In our case, the need for second transplant suggests that the amount of tissue transferred for an allograft may need to be substantially greater than for an autograft.

Topics: Adult; Cryopreservation; Drug Therapy, Combination; Glomerulonephritis; Glucocorticoids; Humans; Hypocalcemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Muscle, Skeletal; Mycophenolic Acid; Parathyroid Glands; Prednisone; Reoperation; Severity of Illness Index; Tacrolimus; Transplantation, Heterotopic; Transplantation, Homologous

Kidney transplantation is the optimal treatment for many patients with end-stage renal disease (ESRD). Due to shortage of donor kidneys in Denmark, there is a need to expand the possibilities for donation. At the Odense University Hospital (OUH), we have introduced ABO-incompatible kidney transplantation. We used antigenspecific immunoadsorptions to remove blood group antibodies and anti-CD20 antibody (rituximab) to inhibit the antibody production. The aim of introducing the ABO-incompatible kidney transplantation at the OUH was to increase the rate of living donor kidney transplantation without increasing rejection or mortality rates.. Retrospective evaluation. Eleven patients received ABO-incompatible kidney transplantation. The patients were followed for 3-26 months.. One patient had an antibody-mediated rejection, one patient suffered T-cell-mediated rejection, and one patient died of myocardial infarction with a functioning graft on the third post-operative day. Both rejections were treated effectively. Among the patients, the average serum creatinine level was 128 micromol/l.. The rejection and mortality rates for ABO-incompatible kidney transplantation at the OUH are similar to the results from ABO-compatible kidney transplantations performed at the OUH and at other hospitals.

Topics: ABO Blood-Group System; Adult; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Blood Group Incompatibility; Creatinine; Denmark; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Rituximab; Tacrolimus

The prevalence of psychiatric disorders in dialyzed patients is estimated around 5-20% of the cases. This explains the high use of antidepressant drugs in these patients. We present the case of a 68-year-old woman with a history of renal failure, with chronic hemodialysis and a depressive syndrome in treatment with Mirtazapine. In November 2008, the patient received a renal graft. An immunosuppressant treatment was started with Basiliximab, Tacrolimus, Mycophenolate Mofetil, and corticosteroids. The patient did not present renal immediate renal function. Four days after the transplant, the treatment with Mirtazapine was re-applied, with an asymptomatic hypotension after 2 hours, and without surgical complications. Tacrolimus blood levels were higher than 15 ng/ml. In our opinion, hypotension was a consequence of the interaction Mirtazapine-Tacrolimus in a patient without immediate renal function. This situation has not been described in the literature before, and hypotension could have had negative consequences in the evolution of the graft.

Topics: Aged; Antidepressive Agents, Tricyclic; Blood Pressure; Depressive Disorder; Drug Interactions; Female; Humans; Hypotension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mianserin; Mirtazapine; Tacrolimus

A 53-year-old man who underwent successful kidney transplantation for stage 5 chronic kidney disease presented to our clinic with intermittent painless gross hematuria. Urachal adenocarcinoma, stage III A by Sheldon system, was diagnosed after serial histopathologic and radiological studies. The patient was treated with extended partial cystectomy, en bloc resection of urachus and umbilicus, pelvic lymphadenectomy, and ileocystoplasty. There were no complications seen in this patient. Neither urachal adenocarcinoma recurrence, metastasis, nor de novo uroileal cancer developed during 48-month follow-up. His reconstructed bladder functioned efficiently, without compromising the transplanted kidney function. Our case demonstrated that conservative surgery and augmentation ileocystoplasty could be offered to kidney transplant recipients with localized urachal carcinoma.

Topics: Adenocarcinoma; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Mycophenolic Acid; Neoplasm Staging; Prednisolone; Tacrolimus; Urachus

It has been reported that low-dose of tacrolimus (Tac) is advantageous for the long-term allograft function and survival when compared with standard-dose of tacrolimus. However, the underlying mechanism is not known and remains to be elucidated. CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) play a key role in the induction and maintenance of transplantation tolerance. We studied whether low-dose of Tac would favor the induction of donor-specific Tregs. We found that in all transplant recipients treated with low-dose of Tac (target trough level of 3 to 7 ng/ml), CD4(+)CD25(+)FoxP3(+) Tregs were induced and expanded in the periphery and accumulated in the allograft after transplantation, and they retained their suppressive efficacy in vitro. When studied in vitro, we found that high concentration of Tac significantly decreased the induction of FoxP3 expression in mixed lymphocyte reactions (MLR) when compared with low concentration of Tac. Taken together, these data imply that in solid-organ transplantation the minimization of Tac might be beneficial and favors the induction of donor-specific Tregs maintaining transplantation tolerance to alloantigen.

Topics: Adult; CD4 Antigens; Cell Movement; Cell Proliferation; Female; Forkhead Transcription Factors; Graft Rejection; Humans; Immunosuppression Therapy; Interleukin-2 Receptor alpha Subunit; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Prospective Studies; T-Lymphocytes, Regulatory; Tacrolimus

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Daclizumab; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

A patient with human immunodeficiency virus infection and end-stage renal disease received a renal transplant. At the time of surgery, the patient was on quadruple antiretroviral therapy (lamivudine, zidovudine, and amprenavir/ritonavir). Immunosuppression was initiated with basiliximab, corticosteroid, mycophenolate mofetil, and a single 0.5 mg dose of tacrolimus. In the following days, an increase in tacrolimus concentration was observed with a peak of 37 ng/mL. Tacrolimus half-life was 6.5 days and tacrolimus maintenance dose was 0.5 mg every 4 days. Eleven months later, the patient had developed Kaposi sarcoma. Tacrolimus was replaced by sirolimus (first dose 1 mg), and the patient was stabilized with 1.5 mg of sirolimus once a week. Increased tacrolimus half-life and increased dose interval of sirolimus and tacrolimus were due to CYP3A4/5 and/or P-glycoprotein inhibition by protease inhibitors. Close monitoring is required in the management of tacrolimus and sirolimus dosing regimens when combined with ritonavir boosted HIV-1 protease inhibitors.

Topics: Drug Interactions; Half-Life; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Tacrolimus

The in vitro response of peripheral blood mononuclear cells (PBMCs) to the suppressive effects of calcineurin inhibitors is known to correlate with the clinical efficacy of drugs used in renal transplantations. The present study was conducted to examine the differences of PBMC responses to calcineurin inhibitors between chronic renal failure (CRF) patients awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. The study included 99 CRF patients awaiting renal transplantation and 27 cirrhosis patients awaiting liver transplantation. Twenty milliliters of venous blood was taken 1-7 days before transplantation. The in vitro drug concentrations giving 50% inhibition of PBMC blastogenesis stimulated with concanavalin A (IC(50)s) were calculated. The suppressive effects of tacrolimus against PBMC blastogenesis were more than 10-100 times stronger than those of cyclosporine. The median IC(50) value for cyclosporine against the CRF PBMCs was not significantly different from the median IC(50) value against the cirrhosis PBMCs. In contrast, tacrolimus sensitivity in cirrhosis PBMCs is approximately seven times higher than that in CRF PBMCs. The median IC(50) value for tacrolimus against cirrhosis PBMCs was significantly lower and therefore the effect was stronger in comparison to the CRF PBMCs (p < 0.001). These data suggest that the PBMCs of cirrhosis patients, in comparison to those of CRF patients, are highly sensitive to the suppressive effect of tacrolimus. However, PBMC sensitivity to cyclosporine was not significantly different between the CRF and cirrhosis patients. These observations raise the possibility that treatment with tacrolimus, rather than cyclosporine, may therefore be a better choice to reduce the risks of allograft rejection in liver transplantation.

Topics: Aged; Calcineurin; Calcineurin Inhibitors; Concanavalin A; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver Cirrhosis; Liver Transplantation; Lymphocyte Activation; Male; Middle Aged; Tacrolimus

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

We performed this study to investigate the trend and characteristics of various immunosuppressive regimens as well as their efficacy and safety for long-term survival of Chinese pediatric renal allograft recipients.. Thirty-four patients who underwent kidney transplantation between January 1985 and July 2002 had >/=5 years follow up. We retrospectively reviewed the baseline characteristics, patient and kidney survival rates, renal function, immunosuppressive regimens, drug levels, and adverse effects of immunosuppressive medications.. The 1-, 3-, and 5-year recipient versus graft survival rates were 100% and 97.1%; 91.2% and 88.2%; 85.3% and 82.4%, respectively. The proportions of patients treated with cyclosporine- or tacrolimus-based immunosuppressive regimen at these times were 48.5%/51.5%; 60.0%/40.0%; and 53.6/46.4%. There were no significant differences in the dosages and drug levels after 1 year (P > .05). The proportions of azathioprine versus mycophenolate mofetil adjunctive therapy were 21.3/78.8%; 23.3%/70%; and 32.1%/60.7%, respectively. Forty percent of the surviving recipients developed complications, including hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, liver dysfunction, herpes zoster, diabetes mellitus or cataracts.. Cyclosporine or tacrolimus, plus mycophenolate mofetil or azathioprine, and prednisone triple therapies showed promising long-term results with similar efficacy and safety in pediatric renal recipients. Periodic drug level monitoring is required to facilitate individualization of immunosuppressive regimens. Drug doses and levels differed markedly from non-Chinese patients because of the ethnic discrepancy.

Topics: Adolescent; Child; China; Cyclosporine; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Renal Replacement Therapy; Survivors; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

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

Bortezomib can be used to successfully treat acute kidney injury in the renal transplant allograft due to light chain cast nephropathy from recurrent multiple myeloma.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Biopsy; Bone Marrow; Boronic Acids; Bortezomib; Female; Humans; Immunoglobulin kappa-Chains; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Multiple Myeloma; Mycophenolic Acid; Protease Inhibitors; Pyrazines; Recurrence; Syndecan-1; Tacrolimus

In the setting of kidney transplantation, cinacalcet has been given, mainly, once daily, but also twice daily. The aims of this prospective study were to assess the acute pharmacodynamic effect of cinacalcet administrated once or twice daily to kidney transplant patients with normal renal function and persisting hypercalcaemia due to hyperparathyroidism and to evaluate 1-year efficacy and tolerance of cinacalcet given at a dose of 30 mg b.i.d.. Eleven patients, who received a transplant 6 (6-59) months previously, were included in the study. A first kinetic was done after administration of 60 mg of cinacalcet at 8 a.m. After a washout period of 1 week, the second kinetic was performed with cinacalcet given at 30 mg b.i.d within a 12-h period.. During both kinetics, serum calcium (sCa), ionized calcium (sCa(2+)), albumin-corrected Ca and parathyroid hormone (PTH) levels decreased significantly. At 24 h after the second kinetic, sCa(2+) was significantly lower. After 1 year of cinacalcet treatment, given at the dose of 30 mg b.i.d., there was a significant decrease in sCa, sCa(2+), PTH levels and calcium x phosphorus (Ph) product. In contrast, Ph levels increased significantly. There was no significant change in renal function.. Once- or twice-daily acute administration of cinacalcet to kidney-transplant patients has similar efficacy. One-year administration of cinacalcet, given as two daily doses, is safe and efficient.

Topics: Adult; Aged; Calcium; Cinacalcet; Cyclosporine; Dose-Response Relationship, Drug; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Phosphorus; Prospective Studies; Tacrolimus

The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) help prevent allograft rejection but are associated with nephrotoxicity. Cytochrome P450 2C8 (CYP2C8) and CYP2J2 are polymorphic enzymes expressed in the kidney that metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, promoting kidney homeostasis. This study examined the association between CNI-induced nephrotoxicity in liver transplant patients and CYP2C8 and CYP2J2 polymorphisms.. Liver transplantation patients receiving CNIs for at least 3 years were genotyped for CYP2C8*3, CYP2C8*4, CYP2C8 Haplotypes B and C, and CYP2J2*7 and evaluated for nephrotoxicity (serum creatinine > or = 1.6 mg/dl) 3-year post-transplantation. CYP2C8 proteins were also engineered in E. coli and their activity towards AA and inhibition by CNIs was investigated in vitro.. The risk of kidney disease post-transplantation was positively associated with CYP2C8*3 genotype. Odds ratios for all participants carrying at least one CYP2C8*3 allele were significant [odds ratio=2.38 (1.19-4.78)]. Stratification by CNI indicated a significant association between CYP2C8*3 and nephrotoxicity among patients receiving Tac but not CsA. The risk of renal dysfunction was not significantly influenced by CYP2C8*4, CYP2J2*7, or CYP2C8 haplotype B genotypes although inheritance of haplotype C seems to be protective. In vitro, the gene products of CYP2C8*3 and CYP2C8*4 were deficient in AA epoxidation, retaining 26 and 18% of wild-type activity, respectively. Circulating plasma concentrations of CsA and Tac inhibited CYP2C8 wild-type in vitro epoxidation of AA by 17 and 35%, respectively.. Inheritance of CYP2C8*3 is associated with a higher risk of developing renal toxicity in patients treated chronically with CNIs, and especially Tac, possibly by reducing formation of kidney protecting vasodilatory epoxyeicosatrienoic acids.

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acid; Aryl Hydrocarbon Hydroxylases; Calcineurin Inhibitors; Cyclosporine; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Demography; Female; Genetic Predisposition to Disease; Genotype; Humans; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Kinetics; Male; Middle Aged; Tacrolimus; United States

This retrospective study was done to assess the efficacy and safety of immunosuppression conversion on progression of chronic allograft nephropathy.. One hundred seventy-four cyclosporine-treated renal transplant recipients were studied. Patients were included if they had biopsy-proven chronic allograft nephropathy (mild to moderate) with a serum creatinine level of 300 micromol/L or less. The treatments groups were (1) mycofenolate mofetil and reduced-dosage cyclosporine (group MMF/CsA; n=132) and (2) azathioprine and reduced-dosage tacrolimus (group Aza/Tac; n=42). Patient records were checked for graft function, survival, and comorbidities after conversion.. Mean follow-up before conversion was 52.2 -/+ 31.1 and 47.9 -/+ 27.4 month in groups MMF/CsA and Aza/Tac, respectively. There was a significant deterioration of graft function in group Aza/Tac after 5 years (P < .05). Ten-year actuarial graft survival in group MMF/CsA was 38%; in group Aza/Tac it was 19% (P = .04). Nine patients started dialysis within 12 months. Tacrolimus-treated patients had a lower insignificant incidence of hyperlipidemia (P = .05) but a significantly higher incidence of diabetes mellitus (P = .04). There were no significant changes or differences in blood pressure between the groups.. Our results suggest that in patientswith chronic allograft nephropathy and deteriorating allograft function, cyclosporine minimization and addition of mycofenolate mofetil achieve favorable effects in retarding the decline of graft function. Further prospective studies with larger cohorts are needed for validation.

Topics: Adult; Azathioprine; Cohort Studies; Cyclosporine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Histocompatibility Testing; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Reoperation; Reproducibility of Results; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

This retrospective study was conducted to assess the efficacy and safety of immunosuppression conversion on progression of chronic allograft nephropathy (CAN).. One hundred-seventy four cyclosporin (CsA)-treated renal transplant recipients were studied. Patients were included if they had a biopsy-proven CAN (mild to moderate) with serum creatinine < or =3.5 mg/dL. Patients were treated with either: (A) MMF/reduced dose CsA [MMF for azathioprine (Aza)] (n=132); (B) Aza/Tac for CsA (n=42). Patient records were checked for graft function and survival, co-morbidities after conversion.. Mean follow-up before conversion was 52.2+/-31.1 and 47.9+/-27.4 month in-group A and B, respectively. There was a significant deterioration of graft function in-group B after 5-years (P<0.5). Ten-year actuarial graft survival was 38% in-group A and 19% in-group B (P=0.04). Nine patients started dialysis within 12 months. Tacrolimus-treated patients had a lower insignificant incidence of hyperlipidemia (P=0.05), but a significantly higher incidence of diabetes mellitus (P=0.04).There was no significant change or difference in blood pressure between groups.. Our results suggest that in patients with CAN and deteriorating allograft function, CsA minimization and addition of MMF achieved favorable efficacies in retarding the decline of graft function. Further prospective studies with larger cohorts are needed for validation.

Topics: Adult; Azathioprine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Hyperlipidemias; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Hyperlipidemia following successful renal transplantation is a frequent and persistent complication. Several immunosuppressive agents including cyclosporine A (CyA), corticosteroids, and tacrolimus appear to have a significant pathogenetic role. The aim of this study is to investigate the differential effects of different immunosuppressive agents on lipids in renal transplant patients.. Two groups of renal transplant recipients, each treated with a different combination of immunosuppressive agents, were studied: Group A (n = 13), cyclosporine A, mycophenolate mofetil (MMF), steroids, and basiliximab; Group B (n = 13), tacrolimus, MMF, steroids, and daclizumab). Plasma lipids [cholesterol (CHOL), low-density lipoprotein (LDL)-CHOL, high-density lipoprotein (HDL)-CHOL, and triglycerides (TG)] were examined before transplantation and 1 and 6 months posttransplantation.. The patients treated with cyclosporine A-MMF showed a significant increase in mean cholesterol and mean LDL-cholesterol values at the 1-month posttransplantation follow-up compared with pretransplant levels (CHOL: 208.9 +/- 47.4 vs. 268.7 +/- 42.2 mg/dl, P = 0.004; LDL: 118.4 +/- 49.9 vs. 198.7 +/- 40.7 mg/dl, P = 0.002; pretransplant vs. 1 month, respectively). At 6 months, LDL-cholesterol levels were significantly elevated compared with pretransplant levels (LDL: 118.4 +/- 49.9 vs. 148.3 +/- 48.5 mg/dl, P = 0.034), whereas there was no significant change in the cholesterol level during the same period. In cyclosporine A-MMF-treated patients, plasma triglyceride levels were reduced at the 1- and 6-month follow-up (TG: 293.9 +/- 59.2 vs. 182.9 +/- 48.7 mg/dl, P = 0.03; 293.9 +/- 59.2 vs. 178.6 +/- 74.2 mg/dl, +/- = 0.023; pretransplant vs. 1 and 6 months, respectively). Patients receiving combined therapy with tacrolimus-MMF showed no significant changes in LDL-CHOL levels during the trial. Cholesterol levels at 6 months posttransplantation were significantly lower than the pretransplant measurements (CHOL: 182.9 +/- 44.4 vs. 162.3 +/- 37.2 mg/dl, P = 0.024; pretransplant vs. 6 months). A significant reduction in triglyceride level was documented at the 1-month follow-up followed by a subsequent decrease within 6 months (TG: 228.5 +/- 61.6 vs. 147.6 +/- 51.5 mg/dl, P = 0.005; TG: 228.5 +/- 61.6 vs. 130.4 +/- 54.7 mg/dl, P = 0.011; pretransplant vs. 1 and 6 months, respectively).. In posttransplant patients with stable renal function cyclosporine therapy is associated with increased cholesterol and LDL-cholesterol levels. Hyperlipidemia is less pronounced in patients given tacrolimus. Tacrolimus appears to an immunosuppressant agent with fewer and less severe adverse effects on lipid metabolism.

Topics: Adult; Cholesterol, LDL; Creatinine; Cyclosporine; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

Topics: Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Mental Disorders; Middle Aged; Posterior Leukoencephalopathy Syndrome; Tacrolimus

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.

Topics: Arthritis, Rheumatoid; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Tacrolimus

Many cases of patients with chronic renal failure (CRF) on hemodialysis are known to be infected with Staphylococcus aureus (S. aureus) from the sites of blood vessel puncture for hemodialysis and the custody of the vascular access catheter. S. aureus produces superantigens, such as toxic shock syndrome toxin-1 (TSST-1), which may influence the sensitivity of peripheral-blood mononuclear cells (PBMCs) to immunosuppressive drugs after they are received postrenal transplantation.. We examined the drug-sensitivities of PBMCs stimulated with TSST-1 in 18 CRF patients on hemodialysis. PBMCs were isolated from venous blood before hemodialysis, and were cultured in the presence of concanavalin A (ConA) or TSST-1 and serial concentrations of the drugs. In vitro drug concentrations giving 50% inhibition (IC(50)) of PBMC blastogenesis were calculated. INF-gamma and IL-4 in supernatants of cultured PBMCs were measured with ELISA.. The median (range) IC(50) values (ng/ml) for four drugs; tacrolimus, cyclosporine, methylprednisolone, and prednisolone, evaluated in ConA-stimulated PBMCs of CRF patients were 0.04 ng/ml (0.03-0.21), 3.0 (0.1-15.1), 3.0 (1-104), and 16.2 (5.9-35.4), respectively. The values for the four drugs evaluated in TSST-1-stimulated PBMCs were 0.22 (0.08-0.36), 18.9 (5.1-38.2), 328.3 (1.9-1000), and 150.9 (94.7-880), respectively, which were significantly higher than those evaluated in the ConA-stimulated PBMCs (p=0.003-0.023). Amounts of INF-gamma and IL-4 produced from cells were not significantly different between the ConA-or TSST-1-stimulated PBMCs in the presence or absence of immunosuppressive drugs.. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in CRF patients after renal transplantation. Furthermore, INF-gamma and IL-4 related pathways appear not to play major roles in the TSST-1-induced attenuation of the drug sensitivities.

Topics: Aged; Bacterial Toxins; Calcineurin; Cells, Cultured; Cyclosporine; Dose-Response Relationship, Drug; Enterotoxins; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Inhibitory Concentration 50; Interferon-gamma; Interleukin-4; Kidney Failure, Chronic; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Methylprednisolone; Microbial Sensitivity Tests; Prednisolone; Renal Dialysis; Staphylococcal Infections; Superantigens; Tacrolimus

The prevalence of subclinical rejection is lower in patients receiving tacrolimus than in patients treated with cyclosporine. However, it is not known whether this difference is related to the modulation of a specific cell immunophenotype. We perform a two case-one control study in patients treated with tacrolimus (n=44) or cyclosporine (n=22) with a protocol biopsy performed at 4 to 6 months. Immunophenotype of infiltrating cells was evaluated with monoclonal antibodies directed against CD45 (all leukocytes), CD3 (T lymphocytes), CD68 (monocytes/macrophages), and CD20 (B lymphocytes) and expressed as interstitial positive cells/mm(2). The number of interstitial CD45 (290+/-209 vs. 696+/-560; P<0.01), CD3 (121+/-84 vs. 208+/-104; P<0.01), and CD68 (155+/-232 vs. 242+/-280; P<0.05) but not CD20 (137+/-119 vs. 197+/-154) positive cells was lower in tacrolimus-treated patients. T lymphocytes and macrophages interstitial infiltration was reduced in tacrolimus treated patients evaluated with protocol biopsies in comparison to cyclosporine-treated patients.

Topics: Adult; Antigens, CD; Biopsy; Cyclosporine; Female; Humans; Immunophenotyping; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Transplantation, Homologous

Because of its narrow therapeutic index, monitoring of drug exposure is recommended for tacrolimus (T). Limited data are available on kinetics of T in children after transplantation. Our study investigated the correlation between T trough and the area under the time-concentration curve (AUC) in pediatric renal transplant recipients and investigated the effect of steroids. Data on T troughs and two h and four h post-dose concentrations over the first post-transplant year in 20 transplant recipients from August 2001 to June 2005 were analyzed. Patients were analyzed in two groups based on their use of steroids. Although the overall correlation between the troughs and AUC was good (r = 0.85, Pearson test), during the first month the correlation was poor in the cohort receiving steroids (r = 0.5) compared with those on a steroid minimization regimen (r = 0.9). In 85% of patients there was a discrepancy between the trough and AUC leading to errors in dose adjustment. In conclusion, although the overall correlation between T trough and AUC is good, it is suboptimal in the first post-transplant month in children receiving steroids. Because of large variation in exposure, we recommend AUC monitoring for T. Prospective studies are needed to determine the impact of more accurate monitoring of T exposure on outcomes.

Topics: Child; Drug Monitoring; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Period; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

The impact of CYP3A and MDR1 gene single-nucleotide polymorphisms on long-term tacrolimus disposition and drug-related toxicity has not been assessed. A study was performed in 95 genotyped recipients by measuring (12 and 4 h) concentration-time curves on day 7; 3, 6 months; 1, 2, 3, 4, and 5 years after transplantation. In contrast to recipients carrying the CYP3A4*1/CYP3A5*1 or CYP3A4*1B/CYP3A5*1 genotypes, dose-corrected tacrolimus exposure almost doubled over 5 years in patients with the CYP3A4*1/ CYP3A5*3 genotype (AUC(0-12 h): from 41.7+/-18.7 to 80+/-39.2 ng h/ml/mg; P<0.05), whereas apparent oral steady-state clearance and dose requirements significantly decreased accordingly. The CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes were significantly more frequently associated with the development of biopsy-proven tacrolimus-related nephrotoxicity than the CYP3A4*1/ CYP3A5*3 genotype (37.5 vs 11.2%; P=0.03 and 42.8 vs 11.2%; P=0.02). The lack of a time-related increase in dose-corrected tacrolimus exposure observed with the CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes is associated with tacrolimus-related nephrotoxicity, possibly as a result of higher concentrations of toxic metabolites.

Topics: Adult; Aged; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biopsy; Confounding Factors, Epidemiologic; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Genotype; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Tacrolimus; Time Factors

A pilot study was performed on eight consecutive renal-transplant (RT) patients presenting with acute humoral rejection (AHR) to assess the efficacy of monoclonal anti-B cell antibodies, such as rituximab (375 mg/m weekly) for 3 to 5 consecutive weeks, in addition to plasma exchange (PE), steroids, mycophenolate mofetil, and tacrolimus. AHR was associated with increased serum creatinine, the appearance of donor-specific alloantibodies (DSA), and the presence of C4d in a transplant biopsy. After a follow-up of 10 months (range 7-23), patient and graft survivals were 100% and 75%, respectively. Renal function improved in six cases in which serum creatinine decreased from 297+/-140 to 156+/-53 micromol/L (P=0.015); graft loss occurred in two cases; and four patients had infectious complications. At last follow-up, DSA had disappeared or decreased in four cases. Rituximab therapy, in addition to PE, might be of benefit for RT patients presenting with AHR.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibody Formation; Creatine; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Infections; Isoantibodies; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Plasma Exchange; Rituximab; Steroids; Tacrolimus; Tissue Donors; Treatment Outcome

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

Topics: Adult; Heart Failure; Heart Transplantation; Humans; Israel; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Treatment Outcome

In 16 patients (7 males, 9 females), aged 47.2 +/- 15.9 years, blood serum concentrations of osteocalcin, beta-crosslaps, parathormone, calcium, phosphate, creatinine and urea were determined before renal transplantation and 3 and 6 months following the procedure. Three as well as six months following renal transplantation significant decrease in blood serum concentration of osteocalcin and beta-crosslaps are found. A significant positive correlation between osteocalcin and beta-crosslaps concentration was found in each investigated period. Six-months observation revealed only partial correction of bone metabolism following renal transplantation.

Topics: Adult; Biomarkers; Bone and Bones; Bone Resorption; Collagen; Creatinine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Osteocalcin; Osteogenesis; Peptide Fragments; Tacrolimus

Chronic renal failure (CRF) is a major cause of morbidity and mortality after orthotopic liver transplantation (OLTX) and is predominantly caused by calcineurin inhibitors (CI)-induced nephrotoxicity. The activation of the renin angiotensin system (RAS) has been implicated in the pathogenesis of chronic nephrotoxicity from CI.. We retrospectively investigated the genes coding for components of the RAS (ACE gene, Angiotensin II receptor 1 gene, Angiotensinogen gene) in 233 liver transplant recipients receiving Cyclosporine (CsA) or Tacrolimus (Tac) as maintenance immunosuppressant. All patients with serum creatinine (sCr) <1.0 mg/dL (n=143) before orthotopic liver transplantation (OLTX) were included in the final analysis. Patients were than categorized into two groups based upon their most recent postliver transplant sCr level: Group 1 (n=83) with sCr <1.5 mg/dL (mean 1.1+/-0.2) and group 2 (n=60) with sCr > or =1.5 mg/dL (mean 2.5+/-1.3). ACE D/D genotype was found in 57% of patients with sCr > or =1.5 mg/dL compared to 20% of patients with sCr <1.5 mg/dL (P<0.0001). Our analysis strongly suggests that liver transplant patients with ACE gene D/D genotype are at a significant higher risk of developing CI-induced chronic nephrotoxicity.

Topics: Angiotensinogen; Calcineurin Inhibitors; Cyclosporine; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Risk Factors; Tacrolimus

The aims of our trial were to study the pharmacokinetics of tacrolimus in paediatric kidney transplant recipients. The study comprised 25 patients (median age 13 years, range 2-20 years) followed for 12 months; five pharmacokinetics profiles (within the first and second week and after 1 month, 6 months and 12 months) were obtained. Patients were divided into two groups: six children<6 years old and 19 older children. Tacrolimus was given at an initial dose of 0.15 mg/kg twice a day. Blood samples were drawn before and 1 h, 2 h, 3 h, 4 h, 6 h, 9 h and 12 h after drug administration. Patient and kidney survival rates were 100% at 1 year. At 6 months and 12 months creatinine clearance was 68.5+/-16.3 ml/min per 1.73 m2 and 64.0+/-15.2 ml/min per 1.73 m2 body surface area, respectively. Tacrolimus trough levels were 7.8+/-1.9 ng/ml and 7.3+/-2.5 ng/ml. The area under the concentration-time curve for 0 h to 12 h (AUC0-12) normalised to a dose of 0.15 mg/kg, increased with time from the kidney transplantation and stabilised after the 6th month post-transplantation. During the first month after transplantation the normalised tacrolimus concentration-time profiles were significantly greater in the older children (P<0.05); the actual doses were significantly greater in the younger children (P<0.05). In conclusion, initial doses of 0.15 mg/kg twice a day orally are safe and guarantee a satisfactory degree of immunosuppression, with our therapeutic regimen. Children<6 years old need to start with a 50% higher tacrolimus dose to achieve the same pharmacokinetic and immunosuppressive results.

Topics: Adolescent; Adult; Age Factors; Area Under Curve; Child; Child, Preschool; Drug Monitoring; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Prospective Studies; Survival Analysis; 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

Topics: Adult; Complement C4b; Diagnosis, Differential; Female; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Peptide Fragments; Purpura, Thrombotic Thrombocytopenic; Tacrolimus; Transplantation, Homologous

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

Subclinical rejection (SCR) causes chronic allograft damage, which may be prevented by antirejection therapy.. A pilot study of the effect of routine treatment of SCR was performed in 88 recipients of either a kidney (n=59) or combined kidney-pancreas transplant (n=29) undergoing protocol biopsy (PBX) surveillance at 1 and 3 months, using calcineurin inhibitors, mycophenolate mofetil, and corticosteroid therapy.. SCR was seen in 46.6% (41/88 patients), as 30 borderline and 11 acute SCR. From 279 transplant biopsies, the prevalence of SCR was 25% (22/88) at 1 month, 10.2% (9/88) at 3 months, and 8.3% (2/24) at 12 months PBX. Treatment included bolus intravenous or oral corticosteroids (n=20) and augmented immunosuppression, either by conversion to tacrolimus (n=6) or increased doses of maintenance therapy (n=14), whereas OKT3 was used in one case of subclinical vascular rejection. Borderline episodes were not treated in 12 patients. In biopsies taken to assess therapeutic response, persistent SCR was present in 46.1% (6/13). Treatment of SCR at 1 month was followed by lower acute Banff sum scores at 3 months PBX (P<0.01-0.0001). Early chronic damage was already present in the 1 month PBX, associated with SCR (P<0.0005 versus without SCR), although by 3 months these differences were lost. Rates of opportunistic infections and BK nephropathy were not increased by SCR treatment.. Early chronic allograft damage was associated with SCR and therapy appeared to ameliorate further immune-mediated injury, although the efficacy of corticosteroids alone may be inadequate. A controlled trial of therapy for SCR is warranted.

Topics: Adult; Aged; Biopsy; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Muromonab-CD3; Pancreas Transplantation; Pulse Therapy, Drug; Tacrolimus

The serious shortage of cadaveric organs has prompted the development of ABO-incompatible live donor renal transplantation. We report our experience of the initial two live donor ABO incompatible renal transplants at our hospital. The first patient was a 55-year-old type A female who received a kidney from her AB type husband. The second patient was a 27-year-old type O male who received renal transplantation from his type A father. Preconditioning immunosuppressive therapy in the two patients with tacrolimus, mycophenolate mofetil and methylprednisolone was started 7 days before transplantation. During the period of preconditioning, double filtration plasmapheresis (DFPP) was employed to remove anti-A and -B antibodies. Laparoscopic splenectomy and renal transplantation were performed after the anti-donor ABO antibodies were reduced to a titer of 1:4. Rituximab, a humanized monoclonal anti-CD20 antibody, was administered to the second patient due to a rebound in the anti-A antibody titer during the preconditioning period. Under a tacrolimus-based immunosuppressive regimen, both patients recovered very well without any evidence of rejection. Serum creatinine levels were 1.0 and 1.4 mg/dL at 6 and 3 months after transplantation, respectively. These cases illustrate that with new immunosuppressive agents, DFPP and splenectomy, ABO-incompatible renal transplantation can be successfully conducted in end-stage renal disease patients whose only available live donors are blood group incompatible.

Topics: ABO Blood-Group System; Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Blood Group Incompatibility; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Rituximab; Splenectomy; Tacrolimus; Tissue and Organ Procurement; Transplantation Conditioning; Transplantation Immunology

Cyclosporine is used routinely for prophylaxis for renal allograft rejection. In experimental animal studies, cyclosporine had been shown to inhibit smooth muscle cell proliferation during the arterial response to injury. We investigated whether systemic immunosuppression may inhibit in-stent restenosis in renal transplant patients undergoing coronary stenting.. From 1993 to 2003, 33 renal transplant patients with 45 coronary lesions and 37 dialysis patients with 52 lesions underwent coronary stenting using bare metal stents at our center. We followed all patients clinically for a mean period of 37 +/- 31 months and 40 patients angiographically at 14 +/- 15 months after coronary intervention. Cyclosporine was combined with corticosteroids in 32 patients and one patient received tacrolimus instead of cyclosporine.. The baseline clinical and angiographical characteristics were similar and the success rate of the procedure was 100% in both groups. In renal transplant group, the mean dose of cyclosporine was 192.5 +/- 68 mg/day and the blood cyclosporine level at the time of procedure was 152.9 +/- 51.5 ng/mL. The rate of in-stent restenosis was 7.1% in renal transplant group and 57.1% in dialysis group (P < 0.0001). The mean late loss was 0.47 +/- 0.57 mm in renal transplant group when compared with 1.51 +/- 1.09 mm in dialysis group (P = 0.004). The overall rate of major adverse cardiac events (MACEs) was 6.1% in renal transplant group and 35.1% in dialysis group (P < 0.0001).. Renal transplant patients receiving combined immunosuppressive agents showed markedly low rates of in-stent restenosis and MACE after coronary revascularization with stent. We consider that this result may be related to the ability of combined immunosuppressive therapy to inhibit inflammatory reaction and vascular smooth muscle cell proliferation induced by coronary stenting.

Topics: Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Cyclosporins; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prosthesis Failure; Retrospective Studies; Stents; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Red-Cell Aplasia, Pure; Tacrolimus

Topics: Adult; Cyclosporine; Hirsutism; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Nephritis, Hereditary; Renal Dialysis; Somatoform Disorders; Tacrolimus

Tacrolimus (Tac), developed in 1990, has been applied as an immunosuppressive agent for liver, heart, and kidney transplantation and is known to have more powerful immunosuppressive effects than cyclosporine (CyA). To evaluate the efficacy of Tac in cadaveric kidney transplants from non-heart beating donors, we present the long-term outcome of patients receiving kidneys with ischemic damage, and compared it with that of CyA. Between July 1990 and December 2000, 55 patients with end-stage renal disease received kidneys from non-heart beating donors (Maastrichy category 3) and were treated with Tac and steroid immunosuppressive therapy. During the same period, we also performed 137 non-heart beating cadaveric renal transplants treated with CyA-based immunosuppressive therapy. The patient survival rate was 98% at 1 yr and 96% at 3-10 yr in the Tac group, and 97% at 1-3 yr, 93% at 5 yr and 85% at 10 yr in the CyA group. The graft survival rate was 91% at 1 yr, 80% at 3 yr, 63% at 5 yr and 34% at 10 yr in the Tac group, and 88% at 1 yr, 75% at 3 yr, 63% at 5 yr and 49% at 10 yr in the CyA group. There was no significant difference in either patient or graft survival rates between the two groups. Acute early rejection in the Tac group was less than that in the CyA group but acute tubular necrosis was the same in both groups. This indicates that Tac is available for cadaveric kidney transplants from non-heart beating donors. In conclusion, Tac is available as an immunosuppressive agent even for kidney transplants from non-heart beating donors.

Topics: Adult; Cadaver; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Ischemia; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Longitudinal Studies; Male; Methylprednisolone; Survival Rate; Tacrolimus; Tissue and Organ Harvesting; Tissue Donors; Treatment Outcome

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

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

To report the occurrence of a potential tacrolimus elevation in a renal transplant recipient after adding metronidazole to the medication regimen.. A 24-year-old white man status post living-related renal transplant who had been stabilized on tacrolimus 4 mg twice daily (trough concentrations 7-10 ng/mL) for 2 months and prednisone 20 mg daily presented to the clinic with severe diarrhea. Stool cultures were positive for Clostridium difficile, and therapy with metronidazole 500 mg 4 times daily was initiated. Between days 4 and 14 of metronidazole therapy, the patient's tacrolimus trough concentration and serum creatinine level increased to maximum levels of 26.3 ng/mL and 3.3 mg/dL (baseline 1.6-1.8 mg/dL), respectively. Tacrolimus was withheld for one dose and then decreased to 1 mg twice daily. Two days after metronidazole discontinuation, tacrolimus trough concentrations dropped to 9.4 ng/mL and serum creatinine to 2.3 mg/dL, warranting a tacrolimus dose increase to 3 mg daily.. As of April 15, 2005, one other case has been reported documenting an elevation in tacrolimus concentrations with the addition of metronidazole. The possible mechanism may be related to metronidazole's weak inhibition of CYP3A4 and, possibly, P-glycoprotein. According to the Naranjo probability scale, metronidazole was the probable cause of this adverse reaction.. Coadministration of tacrolimus with metronidazole may result in elevated tacrolimus concentrations, possibly leading to tacrolimus toxicity. Practitioners should be aware of this potential interaction and closely monitor tacrolimus concentrations and renal function.

Topics: Adult; Creatinine; Drug Interactions; Drug Therapy, Combination; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Metronidazole; Tacrolimus; Treatment Outcome

Forty-two ESRD patients underwent renal transplantation using basiliximab (mean age: 30.6 +/- 18.6 years at transplantation; male: 50%; ESRD duration: 51.6 +/- 13.0 months) between February, 2000 and July, 2003. All patients had a protocol biopsy on the day of transplant, on discharge from the hospital (35.5 +/- 13.2 days), and at 1 year after transplant. The immunosuppression included a calcineurin inhibitor, basiliximab, mycophenolate mofetil (MMF), and methylprednisolone. While 16 patients used tacrolimus (FK group: 29.4 +/- 16.6 years old), 26 patients used cyclosporine (CsA group: 31.4 +/- 20.1 years old). Protocol biopsies were graded according to the Banff 97 classification. The incidence of acute rejection episodes within 1 year was greater in the CsA (15%) than the FK group (6%). Serum creatinine at hospital discharge was similar (CsA: 1.01 +/- 0.59 mg/dL, FK: 0.97 +/- 0.49, p = .18); however creatinine at 1 year differed significantly (CyA: 1.22 +/- 0.88 mg/dL, FK: 0.92 +/- 0.39, P = .03). There was a trend toward an increase in the score of interstitial inflammations in the CsA group, while it remained constant in the FK cohort (P = .05 at 1 year between the two groups). Other pathologic scores (t, ci, ct, cv, ah) did not differ between the groups at 1 year. Although there were no differences in the demographics between the two groups, there were several trends toward better renal function in the FK group.

Topics: Antibodies, Monoclonal; Basiliximab; Biopsy; Creatinine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus

Switching from calcineurin inhibitors (CNIs) to sirolimus might improve renal function in chronic renal transplant patients.. In a prospective study, we assessed long-term efficacy and safety parameters in 43 renal transplant recipients who were switched from a CNI (cyclosporin A, 65%; and tacrolimus, 35%) to sirolimus for either chronic allograft dysfunction (n = 38) or recurrent cutaneous cancers (n = 5). A kidney biopsy was done in 79% of patients prior to conversion, and showed either chronic allograft nephropathy (n = 26) or CNI nephrotoxicity (n = 7). Conversion was either abrupt or progressive, with CNI withdrawal over 3 weeks. All patients also received steroids with or without mycophenolate mofetil or azathioprin. Patient data were recorded at baseline (D0), at 1 (D30) and 6 months (D180), and at 1, 1.5 and 2 years post-conversion.. After a mean post-conversion follow-up of 27+/-1.5 months, 58% of the patients were still on sirolimus. The survival of intent to treat patients and grafts was 95.3 and 93%, respectively. Overall, there was significant improvement in renal function, creatinine clearance increasing from 49.4+/-14.9 to 53+/-16.3 ml/min at D30 (P = 0.01), and to 54.7+/-20 ml/min at D180 (P = 0.01). Thereafter, creatinine clearance was not different from baseline, i.e. 54.7+/-21.7, 52.8+/-20 and 51.7+/-20.3 ml/min at years 1, 1.5 and 2, respectively. We divided the patients into two groups: responders (n = 29), those with an increase in creatinine clearance at 6 months post-conversion compared with D0, and non-responders (n = 14), those with a decrease in creatinine clearance at 6 months post-conversion compared with D0. In univariate analysis, factors predictive of response included proteinuria at D0 and the magnitudes of the differences between D30 and D0 for serum creatinine and lactate dehydrogenase. The conversion was associated with (i) significant decreases in serum calcium, phosphorus and uric acid, and in haemoglobin levels; (ii) significant increases in serum alkaline phosphatase, total cholesterol, parathyroid hormone, and the number of patients on statin and recombinant erythropoietin therapies; and (iii) the appearance of de novo proteinuria of >1 g/day in 28% of patients (P < 0.0009), which was >2 g/day in 12% of the entire cohort. Kidney biopsies in 17 patients 2 years after conversion showed the same Banff scores as observed at baseline. We identified three independent predictive factors for a renal response to the switch: absence of proteinuria, presence of antihypertensive therapy at D0 and serum lactate dehydrogenase level at D30.. Conversion from CNIs to sirolimus in renal transplant patients with chronic allograft nephropathy was associated with improved renal function; however, 33% of the patients developed overt proteinuria.

Topics: Biopsy; Calcineurin Inhibitors; Chronic Disease; Creatinine; Cyclosporine; Drug Therapy, Combination; Enzyme Inhibitors; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

In adult renal recipients, coadministration of tacrolimus (TAC) and sirolimus (SIR) results in reduced exposure to TAC at SIR doses of 2 mg/day. Eight pediatric renal recipients (median age at transplant 2.0 years, range: 1.2-12.9 years) were converted to TAC- and SIR-based immunosuppression as a rescue therapy. All patients had biopsy-proven chronic allograft nephropathy. TAC levels were measured using a commercially available EMIT assay and SIR levels with a newly developed assay based on the LC-MS MS technology. SIR was started at 0.13+/-0.05 mg/kg/day (3.51+/-1.26 mg/m2/day) in two divided doses. TAC was given at 0.14+/-0.09 mg/kg/day, resulting in a trough level of 6.3+/-2.5 ng/mL. After the addition of SIR, the median dose required to keep TAC blood trough concentrations within the target range increased by 71.2% (range: 21.9-245.4%), dose-normalized TAC exposure (AUC) decreased to 67.1% and the dose-normalized C(max), a surrogate for absorption rate, to 53.8% (both geometric means) while terminal half-life (t1/2), a pharmacokinetic parameter characterizing systemic elimination, remained unchanged (p<0.93). Adding SIR to TAC-based immunosuppression in young pediatric renal transplant recipients results in a significant decrease of TAC exposure. TAC trough levels should be monitored frequently.

Topics: Adolescent; Child; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation, Homologous

In end-stage cardiomyopathy where concomitant chronic renal failure is a contraindication for cardiac transplantation (HTx), simultaneous heart and kidney transplantation (HKTx) may be the only feasible therapeutic option. Due to the increased donor shortage, the clinical outcome of combined HKTx patients on tacrolimus-based immunosuppression was assessed and compared with a group of HTx patients.. Three hundred forty-nine HTxs, including 13 (4%) combined HKTxs, were performed since 1995. Two hundred twenty-one HTx and all HKTx recipients received tacrolimus-based immunosuppression. Acute rejection episodes (AREs), infections, renal function and clinical outcome were evaluated. Pre-operative renal diagnoses for HKTx patients included cystic nephropathy (n = 4), glomerulonephritis (n = 4), cytostatica-induced nephropathy (n = 1), chronic rejection after renal transplant (n = 1), reflux nephropathy (n = 2) and chronic calcineurin-inhibitor -induced nephropathy after HTx (n = 1). Twelve patients (92%) were on hemodialysis pre-operatively, 1 underwent implantation of a left ventricular assist device (LVAD) before HKTx.. After 4.7 +/- 2 years, 92% of HKTx compared with 85% of HTx patients had survived (p = 0.42). Acute cardiac rejection episodes were more frequent in HTx than in HKTx patients (0.04 +/- 0.09 vs 0.02 +/- 0.04 ARE/100 patient-days; p = 0.07). Incidence of infection was comparable (0.3 +/- 0.2 vs 0.5 +/- 0.4 infection/100 patient-days). Freedom from transplant vasculopathy was 100% in the HKTx group compared with 71% in the HTx group after 4 years (p = 0.04).. Tacrolimus-based immunosuppression yields promising long-term results in HKTx and HTx. The incidence of transplant vasculopathy seems to be lower after HKTx than after HTx. If these results are secondary to a protective effect of tacrolimus-induced tolerance or of tolerance-associated co-transplantation they will need to be investigated in prospective multicenter trials.

Topics: Cardiomyopathy, Dilated; Comorbidity; Coronary Disease; Creatinine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Chronic kidney disease (CKD) is associated with increased cardiovascular events. The relationships between the markers of inflammation and endothelial dysfunction were investigated both before and after living donor kidney transplantation.. Twenty-seven renal transplant patients were studied. Eleven patients (six male, five female) were on cyclosporine A, whereas 16 patients (nine male, seven female) were treated with tacrolimus based regimes. Twenty-seven subjects (12 males, 15 females) were studied as controls. Plasma adiponectin, high sensitive C reactive protein (hsCRP), Asymetric dimethyl arginine (ADMA) levels were studied before transplantation and on days 1, 3, 7, 14, and 28. The brachial artery flow mediated dilatation (FMD) was studied before transplantation and on the 28th day.. Serum hsCRP and ADMA levels decreased significantly from the first posttransplantation day on each measurement (P<0.001 for all) while the decrement of plasma adiponectin started in the third day (P<0.001 for all). The FMD was lower in the patients than the control group (P<0.001) and improved significantly in the 28th day of transplantation (P<0.001).. The results indicate that ADMA is associated with FMD in CKD both before and after kidney transplantation. Endothelial functions improve at the very beginning of the posttransplantation period with accompanying reduction in ADMA and hsCRP levels.

Topics: Adult; Arginine; Biomarkers; Blood Glucose; Blood Pressure; C-Reactive Protein; Cohort Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lipids; Living Donors; Male; Prospective Studies; Tacrolimus; Treatment Outcome

This study was designed to examine the hypothesis that the nephrotoxicities caused by cyclosporin and tacrolimus might differ in respect of sodium and potassium handling.. 125 patients were studied retrospectively for the first 90 days after renal transplantation. Eighty were treated initially with cyclosporin and 45 with tacrolimus.. A serum sodium level of <135 mmol/l was present for 542/5171 (10.5%) days under tacrolimus treatment compared with 377/5486 (6.9%) days under cyclosporin treatment (P < 0.0001). Severe hyponatraemia, below 120 mmol/l, was also more prevalent under tacrolimus than cyclosporin treatment, P < 0.025. Nine patients, all receiving tacrolimus, were treated with fludrocortisone for fluid depletion and/or hyponatraemia. Serum potassium levels were higher in tacrolimus-treated patients (P < 0.0001), and subjects with hyponatraemia were more likely to experience hyperkalaemia (P < 0.0001).. Hyponatraemia and hyperkalaemia were more frequent in tacrolimus-treated subjects. Taken together with previous work showing that hyperuricaemia is more frequent with cyclosporin treatment, and hypomagnesaemia with tacrolimus treatment, these findings are consistent with qualitative differences between the nephrotoxicities of cyclosporin and tacrolimus.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperkalemia; Hyponatremia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Care; Prevalence; Probability; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tacrolimus; Transplantation Immunology; Treatment Outcome

We report two renal transplant patients who experienced onset of severe bilateral knee pain 1 and 3 months after transplantation, respectively, while on tacrolimus therapy. Tacrolimus, like cyclosporine A, is an immunosuppressive agent that inactivates the enzyme calcineurin phosphatase. A bone pain syndrome was reported in 1989 in organ transplant recipients treated with cyclosporine A. Our cases suggest that tacrolimus may induce the same syndrome. Technetium 99m bone scanning shows increased uptake in the affected areas, and magnetic resonance imaging changes are consistent with bone marrow edema. The tacrolimus dosage need not be reduced unless trough levels are too high. The symptoms resolve completely within a few months. Imaging studies should be done to rule out avascular necrosis. The pathophysiology of this syndrome is discussed. Since tacrolimus was introduced recently, similar cases should be published.

Topics: Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Knee; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Pain Measurement; Radionuclide Imaging; Risk Assessment; Syndrome; Tacrolimus; Technetium

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Prevalence; Retrospective Studies; Sex Distribution; Tacrolimus

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

Tacrolimus-induced toxicity is considered a dose-related side effect largely due to a direct action of this potent calcineurin inhibitor on its targets including the kidney and the pancreas. This paper describes a case of tacrolimus systemic toxicity that appeared in a pediatric kidney transplant recipient who received a low drug dose. The kidney biopsy was a crucial aid toward the correct diagnosis, which reversed upon conversion to cyclosporine-based immunosuppression. A review of the literature suggests a chance of systemic toxicity even when the patient is maintained on therapeutic levels of tacrolimus. Because idiosyncratic reactions to the drug have not yet been postulated, we conclude that this suspicion may be addressed by a safe conversion to cyclosporine in pediatric patients.

Topics: Adolescent; Cyclosporine; Emulsions; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Kidney Tubules; Male; Microscopy, Electron; Tacrolimus; 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

We report a diabetic renal transplant recipient who experienced an episode of acute allograft rejection in the 6th month posttransplant when there was an attempt at steroid withdrawal. The acute rejection was steroid resistant. Furthermore calcineurin inhibitor nephrotoxicity was exacerbated by rescue therapy with tacrolimus conversion. The allograft dysfunction ultimately stabilized upon institution of sirolimus and minimization of tacrolimus.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Diabetic Nephropathies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Reoperation; Sirolimus; 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

The occurrence of a post-renal transplant syndrome of lower limbs joint pain has been reported extensively over the last decade. Clinical examination of the symptomatic joints is often unremarkable and magnetic resonance imaging reveals abnormalities of the bone marrow suggestive of edema and/or hemorrhage. The main striking features of this syndrome are the spontaneous resolution of the symptoms within a few weeks as well as of the marrow abnormalities. This syndrome has been attributed to cyclosporine, given in the immunosuppression regimen or to epiphyseal impactions. We here document the occurrence of this syndrome in 5 kidney graft recipients given a tacrolimus-based immunosuppression.

Topics: Adult; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Knee Joint; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Syndrome; Tacrolimus

This study investigated the effect of St John's wort (SJW) extract on the pharmacokinetics of the immunosuppressants tacrolimus (TAC) and mycophenolic acid (MPA).. Ten stable renal transplant patients received 600 mg SJW extract for 14 days in addition to their regular regimen of TAC and mycophenolate mofetil.. Dose-corrected AUC((0-12)) of TAC decreased significantly from 180 ng/ml/h at baseline to 75.9 ng/ml/h after 2 weeks of SJW treatment. To maintain therapeutic TAC concentrations, dose adjustments from a median 4.5 mg/day at baseline to 8.0 mg/day under SJW treatment were required. Two weeks after discontinuation of SJW, TAC doses were reduced to a median of 6.5 mg/day. MPA pharmacokinetics remained unaffected by comedication with hypericum extract.. Administration of SJW extract to patients receiving TAC treatment can result in a serious drug interaction leading to markedly reduced TAC blood concentrations associated with the risk of organ rejection.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hypericum; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Probability; Prospective Studies; Sampling Studies; Statistics, Nonparametric; Tacrolimus; Transplantation Immunology; 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

In recent years an increasing number of cases with polyomavirus (PV)-nephropathy after renal transplantation were reported from several transplant centres. New, highly potent immunosuppressive drugs like tacrolimus or mycophenolate mofetil were accused as risk factors for this increase. However, data about the incidence of PV-nephropathy in correlation to different immunosuppressive therapy concepts are lacking.. All renal transplant biopsies performed at Hannover Medical School between 1999 and 2001 (n=1276) were immunohistochemically screened for the presence of PV-specific proteins. The results were correlated to the different immunosuppressive therapy protocols and patients with PV-nephropathy were compared with a matched control group.. PV-nephropathy was found in <1% of all investigated allograft biopsies (11/1276) and in approximately 1% of all patients (7/638), respectively. All patients being immunohistochemically positive for PV-specific proteins also showed the typical morphological changes of PV-nephropathy. Four out of seven patients with PV-nephropathy were under triple immunosuppression comprising tacrolimus and mycophenolate mofetil. Under this immunosuppressive therapy protocol an eight times higher incidence and a 13 times higher risk (multivariate odds ratio 12.7) of PV-nephropathy was observed in our patients compared with the control group.. PV-nephropathy is a rare but serious complication after renal transplantation. A small group of patients under intensive immunosuppression comprising tacrolimus in combination with mycophenolate mofetil has a significantly increased risk of acquiring this deleterious complication.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus; Polyomavirus Infections; Prospective Studies; Risk Factors; Tacrolimus; Tumor Virus Infections

Withdrawal of corticosteroids from the immunosuppressive regimens of kidney transplant recipients has been associated with an increased risk of acute and chronic allograft rejection. Previous studies indicate that the risk of rejection is particularly high in African Americans.. We prospectively enrolled 44 African American kidney transplant recipients to participate in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids. No patient received antibody induction therapy. Prednisone was withdrawn from eligible patients free of acute rejection beginning as early as 3 months posttransplant, and followed for a minimum of 9 months posttransplant. Patients were followed for acute rejection and for changes in blood pressure, body weight, and serum creatinine concentrations before and after withdrawal of steroids.. Thirty of 44 patients (68%) were weaned off of prednisone. Follow-up after withdrawal of prednisone ranged from 3 to 26 months (mean, 14.3+/-7.7 months). Two of 30 patients (6.7%) developed acute rejection. At last follow-up, 27 of 30 patients (90%) remain steroid-free. Steroid withdrawal was associated with significant reductions in blood pressure.. Use of sirolimus and tacrolimus, without the use of induction antibody therapy, allows withdrawal of prednisone as early as 3 months posttransplant with low rates of subsequent acute rejection in African American kidney transplant recipients. Withdrawal of prednisone was associated with lower blood pressures and the need for fewer antihypertensive medications.

Topics: Adrenal Cortex Hormones; Adult; Aged; Black or African American; Diabetic Nephropathies; Drug Administration Schedule; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Ohio; Retrospective Studies; Sirolimus; Tacrolimus

This multicenter study was retrospectively evaluated for the predictive factors affecting the long-term graft survival of a kidney transplant from a non-heart-beating donor (NHBD).. A total of 706 patients received transplants from NHBD in 11 centers between 1986 and 2000 and the results were entered into the analysis. The patients were treated with cyclosporine- or tacrolimus-based immunosuppressive therapy. Graft survival was calculated by the Kaplan-Meier method. Factors selected for univariate analysis were donor age, and acute early and acute late rejection. Hypertension (HT), hyperlipidemia (HL), and diabetes mellitus were also analyzed in 638 recipients whose graft survived for more than 1 yr.. In the cases using NHBD, graft survival for 1, 5, and 10 yr was 87, 69, and 53%, respectively. Donor age of over 55 yr, acute early and late rejection, post-transplant HT and diabetes at the first post-operative year were shown to be significantly harmful on long-term graft survival. For longer graft survival in NHBD kidney transplantations, reducing acute rejection, and controlling blood pressure and sugar are crucial.

Topics: Age Factors; Cadaver; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Tissue Donors

In 1983, the launch of cyclosporin was a significant clinical advance for organ transplant recipients. Subsequent drug research led to further advances with the introduction of cyclosporin microemulsion (cyclosporin ME) and tacrolimus. This paper presents the results from a long-term model comparing the clinical and economic outcomes associated with cyclosporin ME and tacrolimus immunosuppression for the prevention of graft rejection following renal transplantation.. A model was developed to project the costs and outcomes over a 10-year period following transplantation. The model was based on the results of a prospective, randomised study of 179 renal transplantation recipients receiving either cyclosporin ME or tacrolimus, which was conducted by the Welsh Transplantation Research Group (median follow-up: 2.7 years).. The short-term costs and outcomes were the averages from the actual head-to-head trial data. From this, the long-term costs and outcomes were extrapolated based on the rate of change in patient and graft survival at 3, 5 and 10 years post transplant, as reported in the 1995 United Kingdom Transplant Support Service Authority Renal Transplant Audit. PERSPECTIVE AND YEAR OF COST DATA: The analysis was conducted from the perspective of a UK transplant unit. Costs were at 1999 prices (pounds sterling 1 = dollars US 1.42 = Euro 1.5) and costs and outcomes were discounted at 6% and 1.5%, respectively.. The model estimated that 10 years after transplantation, the proportion of patients surviving was 56% of the cyclosporin ME cohort and 64% of the tacrolimus cohort. The cumulative cost of maintenance therapy at 10 years was pounds sterling 23204 per patient maintained on cyclosporin ME versus pounds sterling 23803 per patient on tacrolimus. The cost per survivor at 10 years was pounds sterling 37000 (tacrolimus) versus pounds sterling 41000 (cyclosporin ME) and the cost per patient with a functioning graft was pounds sterling 39000 versus pounds sterling 45000. A Monte Carlo simulation of the model (10000 simulations) gave an average cost at 10 years of pounds sterling 23279 (SD pounds sterling 3457) for cyclosporin ME and pounds sterling 22841 (SD pounds sterling 3590) for tacrolimus. A (second order) probabilistic sensitivity analysis was also performed. The average cost at 10 years from a simulated cohort of 1000 was pounds sterling 23473 (SD pounds sterling 2154) for cyclosporin ME and pounds sterling 24087 (SD pounds sterling 2025) for tacrolimus.. Renal transplant recipients maintained on tacrolimus have better short- and long-term outcomes than patients maintained on cyclosporin ME. The long-term use of tacrolimus is a more cost-effective solution in terms of the number of survivors, patients with a functioning graft and rejection-free patients.

Topics: Adult; Cost Savings; Cost-Benefit Analysis; Cyclosporine; Drug Administration Schedule; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Models, Economic; Prospective Studies; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

A 59-year-old man inadvertently received a 10-fold increase in his twice-daily oral dose of tacrolimus 1 mg that resulted in trough blood levels above 90 ng/ml for over a week. The patient had end-stage renal disease secondary to diabetes mellitus and had received a kidney transplant from his daughter 3 months earlier. Despite the numerous adverse effects commonly reported with tacrolimus, such as mild nephrotoxicity, nausea, tremors, and elevated liver enzyme levels, our patient's acute but prolonged overdose resulted in minimal signs and symptoms of toxicity. Nevertheless, education regarding the importance of accurate dosing, close monitoring, potential drug interactions, and the various capsule colors should be provided to all patients who receive tacrolimus, as well as their physicians, nurses, and pharmacists, in order to prevent as many errors as possible.

Topics: Diabetic Nephropathies; Drug Labeling; Drug Overdose; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Education as Topic; Tacrolimus

Topics: Cadaver; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Arrest; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nephrectomy; Survival Rate; Tacrolimus; Time Factors; Tissue and Organ Harvesting; Tissue Donors; Treatment Outcome

Topics: Adult; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Antilymphocyte Serum; Azathioprine; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Prednisone; Tacrolimus; Time Factors; Treatment Failure; Treatment Outcome

Plasma endothelin (ET)-1 concentrations have been shown to be elevated in patients receiving calcineurin-inhibitors (CI). We investigated urinary and plasma ET-1 (uET-1, pET-1), BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble endothelin-converting enzyme (ECE) concentrations in 381 adult caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. Blood and urine probes were always drawn immediately before morning dosage of immunosuppressants. Mean of urinary protein excretion (meanProt) and mean of serum creatinine (meanCrea) were calculated from all available measurements in the most recent year. uET-1 and uBigET-1 were adjusted for urinary protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Patients (n=310) were on a cyclosporine A or FK506 (CI-group) based immunosuppression protocol, and 71 patients were immunosuppressed without use of CI (nonCI group). Time since transplantation was similar in both groups (mean+/-S.D.; CI-group: 7.55+/-2.50; nonCI-group: 7.74+/-3.06 years, P=0.240) as well as meanCrea (mean+/-S.D.; CI-group: 1.97+/-1.34; nonCI-group: 1.77+/-1.29 mg/dl, P=0.326). pET-1 was significantly higher in the CI-group, compared with nonCI (mean+/-S.D.; 0.87+/-1.4 versus 0.56+/-0.76 fmol/ml, P=0.011). pBigET-1 was similar (mean+/-S.D.; 0.85+/-1.41 versus 0.70+/-1.21 fmol/ml, P=0.33). ECE concentrations were higher in the CI group (mean+/-S.D.; 14.30+/-18.02 versus 9.23+/-7.42 ng/ml, P=0.001). uET-1/meanProt and uBigET-1/meanProt concentration were similar in the CI-group compared with the nonCI-group (mean+/-S.D.; uET-1/meanProt: 15+/-24 versus 21+/-40 pmol/g, P=0.139; uBigET-1/meanProt: 34+/-55 versus 19+/-23pmol/g, P=0.248). pET-1 elevation in patients receiving CI might be more likely to be due to elevated conversion of pBig-ET-1 by more ECE, and not to higher concentrations of pBigET-1.

Topics: Adult; Aspartic Acid Endopeptidases; Calcineurin Inhibitors; Cyclosporine; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Inhibitors; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Metalloendopeptidases; Protein Precursors; Tacrolimus; Transplantation, Homologous

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

Topics: Adult; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Odorants; Tacrolimus

Topics: Acute Disease; Anti-Bacterial Agents; Drug Interactions; Female; Fusidic Acid; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Rhabdomyolysis; Simvastatin; Tacrolimus; Treatment Failure

A successful immunosuppression regimen for combined kidney and pancreas transplants is tacrolimus, mycophenolate mofetil, and prednisone. However, not all patients tolerate these immunosuppressants especially tacrolimus.. To evaluate the efficacy of cyclosporine as a rescue agent for tacrolimus toxicity in combined kidney and pancreas transplants.. Retrospective.. Single center.. Thirty-five combined kidney and pancreas transplants were performed between July 1994 and January 1999. All patients were insulin dependent diabetics with end-stage renal disease. Twenty-eight (mean age: 36 years and 57% female) were available with at least 12 month follow-up.. Conversion to cyclosporine following renal (biopsy proven) or pancreatic dysfunction.. Toxicity, rejection rate, and patient/transplant organ survival.. Nineteen transplant recipients (68%) were continuously maintained on tacrolimus while nine (32%) required conversion to cyclosporine 75 +/- 20 days post-transplant. Reasons for conversion included: hyperglycemia (n=2), hemolytic-uremic syndrome (n=1), and severe tacrolimus nephrotoxicity (n=6). By 12 months post-transplant, the 19 patients maintained on tacrolimus had 5 rejections (26%). Three of the 9 patients (33%) converted to cyclosporine had an acute rejection prior to conversion. Seven of these 9 patients (78%; P=0.017 vs. patients maintained on tacrolimus) had rejections an average of 25 +/- 4 days post-conversion. Four of the 7 patients had no previous rejections prior to conversion. In spite of increased rejections, the 1- and 2-year patient/graft survivals were unchanged by converting.. Converting to cyclosporine from tacrolimus was associated with an increased risk of acute rejection especially within the first 30 days post conversion.

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Drug Tolerance; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Pancreas Transplantation; Retrospective Studies; Salvage Therapy; Survival Rate; 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: 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: Adolescent; Brain; Brain Edema; Cerebral Infarction; Dementia, Vascular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Resonance Imaging; Male; Postoperative Complications; Tacrolimus

Acute intermittent porphyria results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis and is commonly exacerbated by a wide variety of medications. When referred a patient with acute intermittent porphyria for a renal transplant, only steroids and azathioprine were discovered as safe in patients with acute intermittent porphyria. The administration of many newer immunosuppressive medications, including calcineurin inhibitors, has not been documented in acute intermittent porphyria. Actually, cyclosporine is presently considered contraindicated in acute intermittent porphyria. To determine if calcineurin inhibitors would be tolerated in acute intermittent porphyria, cyclosporine and tacrolimus were administered pretransplant and were documented not to exacerbate acute intermittent porphyria. A successful renal transplant was then performed using tacrolimus. This is the first reported patient with documented acute intermittent porphyria to tolerate safely several of the newer immunosuppressive medications, including tacrolimus, mycophenolate, and rabbit antithymocytic globulin following renal transplantation. This patient's pretransplant evaluation also suggested that cyclosporine may be safe for some patients with acute intermittent porphyria.

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Porphyria, Acute Intermittent; Tacrolimus

End-stage renal failure after successful liver transplantation (LTx) has been described in up to 5% of patients. Kidney transplantation (KTx) has been the treatment of choice in these cases. However, in recipients infected with hepatitis C virus (HCV), the augmentation of immunosuppression after KTx may result in an increased viral load. This, in turn, may adversely affect the liver allograft.. The present study retrospectively examined the outcome in 17 patients (3 females and 14 males, mean age 51.1+/-11.3 years) who received KTx after LTx. The mean interval from LTx to KTx was 57.6+/-32.1 months. The mean follow-up was 41.7+/-20.5 months after KTx, and 99.6+/-37.7 months after LTx. Sixteen of the 17 patients received tacrolimus-based immunosuppression at the time of KTx.. During the follow-up period, one patient underwent combined liver and kidney retransplantation 3.7 years after KTx and 12.7 years after LTx. She subsequently died secondary to primary nonfunction. Four other patients died, two of lung cancer, one of pancreatitis/sepsis, and one of severe depression leading to noncompliance. A total of 29 episodes of biopsy-proven acute renal allograft rejection (1.7 episodes/ patient) were encountered and treated with steroids. Seven patients experienced a rise in liver function tests during the period of increased steroid dosage. Four patients received no treatment, and their liver function returned to baseline. The remaining three were treated with interferon. Overall 1- and 3-year actuarial patient and liver allograft survival was 88% and 71% (after renal transplantation); corresponding 1- and 3-year actuarial graft survival was 88% and 61%. Twelve patients are alive with normal liver function. One patient is on dialysis, because of renal allograft loss to noncompliance.. In this series, LTx recipients with HCV infection were able to undergo KTx with a reasonable degree of success. KTx should be offered for end-stage renal failure after LTx, even in the presence of HCV infection, to individuals with stable liver function and no signs of liver failure.

Topics: Adult; Biopsy; Female; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immune Tolerance; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Transplantation; Male; Middle Aged; Quality of Life; Survival Rate; Tacrolimus; Virus Replication

A woman on daclizumab developed thrombotic microangiopathy secondary to cyclosporine after a living-unrelated kidney transplant. Despite cyclosporine discontinuation, hemolysis persisted. The second dose of daclizumab was postponed 24 h, and after a maximum of two sessions of plasmapheresis (to avoid further modifications in daclizumab schedule) with plasma exchange, daclizumab was administered. Plasma infusions were prescribed until D-dimer and fibrinogen-degradation products normalized; thereafter, FK-506 was started without recurrence of the hemolytic picture and renal function restored. This observation suggests that in patients on daclizumab who develop thrombotic microangiopathy secondary to immunosuppressants, if discontinuation of the offending drug is unsuccessful, plasmapheresis with plasma exchange can be performed when the lowest levels of daclizumab exist, followed by daclizumab infusion. Plasma prescription must be continued thereafter until D-dimer and figrinogen-degradation products normalize. However, if hemolysis persists when daclizumab levels are high, plasma infusions are useful and plasmapheresis avoided. FK-506 administration did not result in recurrence of hemolysis during daclizumab induction.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers; Blood Component Transfusion; Cyclosporine; Daclizumab; Drug Therapy, Combination; Female; Fibrin Fibrinogen Degradation Products; Hemolysis; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Microcirculation; Middle Aged; Plasmapheresis; Polycystic Kidney Diseases; Tacrolimus; Thrombosis

Topics: Adult; Aged; Area Under Curve; Cadaver; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Metabolic Clearance Rate; Middle Aged; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

Topics: Cyclosporine; Electrocardiography; Heart Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Tacrolimus

Neurological complications post transplant have been described with the use of calcineurin inhibitors. Although tacrolimus may be a better immunosuppressant than cyclosporine, its neurological side effects may be worse. Two children, living-related kidney transplant recipients, were treated with antibody induction, mycophenolate mofetil, prednisone, and tacrolimus. Soon after transplant, they each developed an encephalopathy, which when visualized by magnetic resonance imaging showed that it affected both white and grey matter of the brain. Although the encephalopathy was associated with the use of tacrolimus, there was a complete neurological recovery without cessation of the drug.

Topics: Adolescent; Brain Diseases; Child; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Resonance Imaging; Male; Tacrolimus

The calcineurin inhibitors cyclosporine and tacrolimus are both known to be nephrotoxic. Their use in orthotopic liver transplantation (OLTX) has dramatically improved success rates. Recently, however, we have had an increase of patients who are presenting after OLTX with end-stage renal disease (ESRD). This retrospective study examines the incidence and treatment of ESRD and chronic renal failure (CRF) in OLTX patients.. Patients receiving an OLTX only from June 1985 through December of 1994 who survived 6 months postoperatively were studied (n=834). Our prospectively collected database was the source of information. Patients were divided into three groups: Controls, no CRF or ESRD, n=748; CRF, sustained serum creatinine >2.5 mg/dl, n=41; and ESRD, n=45. Groups were compared for preoperative laboratory variables, diagnosis, postoperative variables, survival, type of ESRD therapy, and survival from onset of ESRD.. At 13 years after OLTX, the incidence of severe renal dysfunction was 18.1% (CRF 8.6% and ESRD 9.5%). Compared with control patients, CRF and ESRD patients had higher preoperative serum creatinine levels, a greater percentage of patients with hepatorenal syndrome, higher percentage requirement for dialysis in the first 3 months postoperatively, and a higher 1-year serum creatinine. Multivariate stepwise logistic regression analysis using preoperative and postoperative variables identified that an increase of serum creatinine compared with average at 1 year, 3 months, and 4 weeks postoperatively were independent risk factors for the development of CRF or ESRD with odds ratios of 2.6, 2.2, and 1.6, respectively. Overall survival from the time of OLTX was not significantly different among groups, but by year 13, the survival of the patients who had ESRD was only 28.2% compared with 54.6% in the control group. Patients developing ESRD had a 6-year survival after onset of ESRD of 27% for the patients receiving hemodialysis versus 71.4% for the patients developing ESRD who subsequently received kidney transplants.. Patients who are more than 10 years post-OLTX have CRF and ESRD at a high rate. The development of ESRD decreases survival, particularly in those patients treated with dialysis only. Patients who develop ESRD have a higher preoperative and 1-year serum creatinine and are more likely to have hepatorenal syndrome. However, an increase of serum creatinine at various times postoperatively is more predictive of the development of CRF or ESRD. New strategies for long-term immunosuppression may be needed to decrease this complication.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Hepatorenal Syndrome; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

Hemolytic uremic syndrome (HUS) is a rare complication in solid organ transplantation. It can be associated with severe hypertension. Several risk factors have been identified including immunosuppressive drugs such as cyclosporin A and, more recently, tacrolimus.. Here we report a case of tacrolimus-induced HUS in a 61-yr-old woman after liver transplantation. Hypertension, microangiopathic anemia and end-stage renal failure occurred 2 yr after liver transplantation.. At admission, she had malignant hypertension with a severe hypertensive retinopathy, renal failure (creatininemia: 800 micromol/L) and microangiopathic anemia (Hb: 7.3 g/dL, a low platelet count and elevated lactate dehydrogenase). At renal biopsy, histologic findings were ischemic and sclerotic glomeruli with hyaline thrombi, severe mesangiolysis and interstitial fibrosis.. Despite steroid treatment, antihypertensive agents and fresh frozen plasma therapy, end-stage renal failure was observed and chronic hemodialysis treatment was required.

Topics: Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Liver Transplantation; Middle Aged; Tacrolimus

Topics: Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Nephrotic Syndrome; Postoperative Complications; Tacrolimus

Topics: Antigens, CD; Azathioprine; Cell Differentiation; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes; Mycophenolic Acid; 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

The development of thrombotic microangiopathy (TMA) associated with the use of cyclosporine has been well documented. Treatments have included discontinuation or reduction of cyclosporine dose with or without concurrent plasma exchange, plasma infusion, anticoagulation, and intravenous immunoglobulin G infusion. However, for recipients of organ transplantation, removing the inciting agent is not without the attendant risk of precipitating acute rejection and graft loss. The last decade has seen the emergence of tacrolimus as a potent immunosuppressive agent with mechanisms of action virtually identical to those of cyclosporine. As a result, switching to tacrolimus has been reported to be a viable therapeutic option in the setting of cyclosporine-induced TMA. With the more widespread application of tacrolimus in organ transplantation, tacrolimus-associated TMA has also been recognized. However, literature regarding the incidence of the recurrence of TMA in patients exposed sequentially to cyclosporine and tacrolimus is limited. We report a case of a living donor renal transplant recipient who developed cyclosporine-induced TMA that responded to the withdrawal of cyclosporine in conjunction with plasmapheresis and fresh frozen plasma replacement therapy. Introduction of tacrolimus as an alternative immunosuppressive agent resulted in the recurrence of TMA and the subsequent loss of the renal allograft. Patients who are switched from cyclosporine to tacrolimus or vice versa should be closely monitored for the signs and symptoms of recurrent TMA.

Topics: Adult; Colon; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Microcirculation; Tacrolimus; Thrombosis

Topics: Adult; Azathioprine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Recurrence; Retrospective Studies; Ribonucleosides; Survival Rate; Tacrolimus; Time Factors

A striped pattern of fibrosis has been described in the kidneys of patients undergoing long-term cyclosporine or tacrolimus therapy. This lesion is frequently misconstrued as being specific for drug toxicity.. We performed clinicopathologic correlation on 18 patients with striped fibrosis identified by reviewing 61 biopsies from kidney transplant recipients maintained with tacrolimus.. Acute rejection was identified in 14 of 18 patients, chronic rejection in 9 of 18 patients, potential diabetic microvascular injury in 8 of 18, and pre-existing donor disease in 2 of 18. In only one patient could striped fibrosis be ascribed primarily to tacrolimus. Striped fibrosis could also be demonstrated in 6 of 10 late allograft biopsy specimens from patients maintained with only azathioprine, and 8 of 10 native biopsies from patients with advanced diabetes mellitus.. Multiple insults contribute to the pathogenesis of striped fibrosis in the kidney. This lesion can be attributed entirely to chronic drug toxicity in only a minority of allografts.

Topics: Adult; Biopsy; Diabetic Nephropathies; Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Medulla; Kidney Transplantation; Middle Aged; Tacrolimus; Transplantation, Homologous

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

Nephrotoxicity is a frequently encountered adverse effect of calcineurin inhibitors (cyclosporine and tacrolimus)-combined immunosuppressive regimens.. We have compared the glomerular filtration rate in 14 patients who underwent lung transplantation, before and after replacement of azathioprine by mycophenolate mofetil and reduction of associated calcineurin inhibitors doses.. After a mean follow-up of 16+/-4 months with the modified immunosuppressive regimen, the mean glomerular filtration rate increased by 20% with no change in lung function.. By its strong immunosuppressive effect, mycophenolate mofetil allows the decrease of associated calcineurin inhibitor doses, with subsequent improvement of renal function without jeopardizing the transplanted lung.

Topics: Calcineurin Inhibitors; Cyclosporine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lung Transplantation; Mycophenolic Acid; Tacrolimus

Association between lymphocyte-sensitivity to immunosuppressants in transplant recipients in vitro and clinical outcomes has been demonstrated. In general, renal transplant recipients are treated with a combination of immunosuppressants such as either glucocorticoid/cyclosporin A (CsA) or glucocorticoid/tacrolimus (FK506) but the pharmacological complementarity of these drugs is still controversial. We examined relationships between the lymphocyte-sensitivities to these immunosuppressants.. We examined lymphocyte-sensitivities to prednisolone (PSL), CsA, and FK506 in vitro in a total of 190 chronic renal failure (CRF) patients and 140 healthy subjects. The lymphocyte-sensitivity was evaluated from the IC50 value against mitogen-stimulated lymphocyte-blastogenesis in vitro.. Statistically significant correlations of the IC50 values in CRF patients between the following pairs of drugs were observed: PSL and CsA (P<0.0001; n=129, r=0.419), PSL and FK506 (P<0.001; n=54, r=0. 441), and CsA and FK506 (P<0.0001; n=45, r=0.608). Similar correlations were also observed in lymphocytes from healthy subjects. The population of CRF patients who exhibited high IC50 values (low sensitivities) to PSL and FK506 was significantly larger than that of healthy subjects (P<0.05).. Patients who showed low lymphocyte-sensitivity to either of the drugs also may exhibit low sensitivity to the others, and thus they may have a high risk of unsatisfactory outcome under combination therapy after renal transplantation. To overcome this risk, the selection of immunosuppressants is recommended to be restricted according to individual lymphocyte-sensitivities to these drugs in vitro, or alternatively, by addition of other drugs with different mechanisms for immunosuppression.

Topics: Adult; Aged; Anti-Inflammatory Agents; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; In Vitro Techniques; Interleukin-2; Kidney Failure, Chronic; Leukocytes, Mononuclear; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Prednisolone; Tacrolimus

To evaluate the prevalence of colonization with vancomycin-resistant enterococcus (VRE) in end-stage renal failure (ESRF), we screened the intestinal flora from 338 pediatric ESRF patients treated in 13 pediatric nephrology units in mid-Europe. Eighty-one patients were undergoing hemodialysis, 66 were undergoing chronic peritoneal dialysis, and 191 were transplant recipients. A total of 363 enterococcal strains were recovered from 232 patients. Twenty-seven enterococcal strains from 24 patients (7.1%) had reduced susceptibility to vancomycin (minimal inhibitory concentration [MIC], >4 microg/mL). Although two patients (0.6%) carried enterococci with high-level resistance to vancomycin (MIC, >32 microg/mL; i.e., VRE), strains of enterococcus with reduced susceptibility to vancomycin (ERSV) were recovered from the other 22 subjects. Past use of vancomycin (P = .05) and tacrolimus therapy (P = .011) were independent risk factors for ERSV or VRE carriage. Enterococcal infections occurred with a similar frequency among enterococcal carriers and noncarriers; no infections with VRE or ERSV were reported. In conclusion, the prevalence of ERSV carriage and the rate of VRE colonization among mid-European children and adolescents with ESRF currently are moderate and low, respectively.

Topics: Adolescent; Adult; Carrier State; Child; Child, Preschool; Enterococcus; Humans; Infant; Kidney Failure, Chronic; Prevalence; Risk Factors; Tacrolimus; Vancomycin Resistance

The aim of this study was to report the results of 50 transplantations of kidney and pancreas performed in the same surgical centre for chronic renal insufficiency of patients with insulino-dependent diabetes.. From 1989 to 1999, 50 pancreatic transplantations were consecutively performed, 48 combined with a kidney transplantation and two in patients having a functioning kidney graft. The whole pancreas was transplanted in the right iliac fossa through an extraperitoneal approach with duodeno-vesical bypass of exocrine secretion. The kidney was transplanted in the left iliac fossa through a different extraperitoneal approach. Immunosuppression protocol included Azathioprine replaced by Mycophenolate Mofetil since 1996, associated with corticotherapy and Ciclosporine replaced by FK 506 since 1997. Recipients were 32 women and 18 men (mean age: 37 +/- 5 years) treated by insulinotherapy since 23 +/- 6 years and receiving 35 +/- 10 insulin units per day. Peptide C was 0.33 +/- 0.35 mg/mL and serum creatinin 726 +/- 260 mumol/L.. One patient died on d10 from pulmonary artery thrombosis due to unknown drepanocytosis. The most frequent postoperative complications were leakage of duodeno-vesical anastomosis (n = 9) decreasing in frequency with experience, reoperated with preservation of the pancreatic graft in all cases and venous thrombosis of the pancreatic graft (n = 5) with a definitive loss of function. Secondary deaths occurred at 24, 36, 48, 50, 72 months with functioning grafts in two patients. With a mean 5-year follow-up, 44 patients were alive (88% of the whole series), 34 of them with two functional grafts (68% of the whole series) Sixteen pancreas grafts were lost: three by death of the patients, eight from surgical complications, four by rejection and one by transplantectomy of a functional graft.. Combined kidney and pancreas transplantation is now very efficient in the treatment of diabetic renal insufficiency. Total pancreas transplantation through an extraperitoneal approach seems to be the safest method. A very strict selection of both donors and recipients is necessary.

Topics: Adult; Azathioprine; Combined Modality Therapy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Survival Analysis; Tacrolimus; Treatment Outcome

Kidney transplantation has become a reasonable treatment option for selected patients aged 60 years or older, and a number of different immunosuppressive drug protocols have been described. This article concerns 230 recipients who were aged 60 years or older and who were undergoing kidney-only transplantation at the University of Pittsburgh between January 1990 and April 1997. All recipients were treated with a tacrolimus-based immunosuppression regimen. The median follow-up was 31.5 months (range, 1-86). The 1-, 3-, and 5-year actuarial patient survival rates were 90%, 83%, and 76%, respectively. There were 42 (19%) deaths, cardiovascular disease (50%) and infection (38%) being the main causes. Death with a functioning kidney occurred in 28 (67%) patients. The 1-, 3-, and 5-year actuarial graft survival rates were 84%, 74%, and 64%, respectively. The delayed graft function rate was 33%. Rejection was seen in 57 (25%) elderly patients. The mean serum creatinine was 2.6 +/- 2.7 mg/dL and the serum urea nitrogen was 35 +/- 22 mg/dL. The mean tacrolimus level was 8.5 +/- 3.8 ng/mL. These results suggest that renal transplantation in older recipients under tacrolimus-based immunosuppression is associated with reasonable outcomes, and can be offered to appropriately selected patients.

Topics: Actuarial Analysis; Age Factors; Aged; Aged, 80 and over; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

Analysis of the SPK program at the University of Pittsburgh has led to a number of observations: 1. Under tacrolimus-based immunosuppression, without antibody induction, it has been possible to achieve (a) One- and 3-year actuarial patient survival rates of 98% and 95% (b) One- and 3-year actuarial kidney survival rates of 95% and 87% (c) One- and 3-year actuarial pancreas survival rates of 86% and 80% 2. Steroid withdrawal has been achieved in over half of the successfully transplanted recipients, with excellent outcomes and a low rate (4.7%) of subsequent rejection. 3. Bone marrow augmentation has been associated with (a) less rejection (b) less pancreatic graft loss to rejection (c) an increased ability to withdraw steroids 4. Rejection has been associated with a rising serum lipase. 5. Renal allograft rejection in SPK patients with elevated serum lipase levels has been seen in the setting of normal renal function. 6. Enteric drainage has been associated with a reasonably low complication rate. 7. SPK transplantation is a successful therapeutic option in selected type I diabetics with end-stage renal disease.

Topics: Adult; Bone Marrow Transplantation; Cause of Death; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Graft Rejection; Graft Survival; Hospitals, University; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Pennsylvania; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Methylprednisolone has been found to be significantly more suppressive than prednisolone (the pharmacologically active metabolite of prednisone) of mitogen-stimulated human lymphocyte proliferation. In this study, peripheral blood mononuclear cells (PBMC) from end stage renal disease patients were cultured with phytohemagglutinin (PHA) alone and with methylprednisolone and prednisolone individually, as well as each glucocorticoid (10(-7) mol/L) in combination with 300 ng/ml cyclosporine, 10 ng/ml tacrolimus, 25 microg/ml pentoxifylline, and 10(-7) mol/L mycophenolic acid. Under each experimental condition, the mean +/- SD % inhibition of PHA-stimulated 3H-thymidine incorporation was significantly greater with methylprednisolone than with prednisolone: methylprednisolone 55 +/- 17 versus prednisolone 28 +/- 14, p < 0.001; methylprednisolone + cyclosporine 76 +/- 18 versus prednisolone + cyclosporine 52 +/- 18, p < 0.001; methylprednisolone + tacrolimus 74 +/- 18 versus prednisolone + tacrolimus 50 +/- 20, p = 0.001; methylprednisolone + mycophenolic acid 69 +/- 14 versus prednisolone + mycophenolic acid 46 +/- 15, p < 0.001. These results confirm and extend previous observations and suggest that methylprednisolone might be more effective than prednisone in treatment protocols used to suppress allograft rejection.

Topics: Cells, Cultured; Cyclosporine; Drug Combinations; Enzyme Inhibitors; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphocytes; Methylprednisolone; Mycophenolic Acid; Pentoxifylline; Prednisolone; Tacrolimus

Topics: Adult; Delivery, Obstetric; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infant, Newborn; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Period; Pregnancy; Recurrence; Tacrolimus

Topics: Adolescent; Adult; Aged; Diabetes Mellitus; Diabetic Nephropathies; Ethnicity; Female; Follow-Up Studies; Graft Rejection; Hispanic or Latino; Humans; Immunosuppressive Agents; Indians, North American; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Muromonab-CD3; New Mexico; Survival Rate; Tacrolimus

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Tacrolimus

Topics: Administration, Oral; Adult; Biological Availability; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fasting; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Postprandial Period; Premedication; 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

To evaluate the effectiveness of renal transplantation in systemic lupus erythematosus (SLE).. A total of 97 SLE patients who underwent renal transplantation between January 1984 and September 1996 were selected for study and were matched with a group of non-SLE controls (1 control for each SLE patient) who also received transplants during that period. SLE patients and controls were matched on 6 covariates: age, sex, race, type of allograft (cadaveric versus living-related), number of previous transplants, and year of transplantation. All study subjects received either cyclosporine or FK-506/tacrolimus as part of their immunosuppressive regimen. In a rigorous medical records review, the status of each allograft and the cause of each graft loss was determined. Using a stratified Cox proportional hazards model, the transplantation outcomes of the SLE patients were compared with those of the controls. The effects of 9 individual variables on transplantation outcomes were also examined, and the statistically significant variables were compared in a stratified, multivariate Cox proportional hazards model.. The control group included patients with 20 different causes of end-stage renal disease (ESRD). The mean followup times for the SLE patients and controls were 323 weeks and 320 weeks, respectively. During the followup period, 52 SLE patients and 37 controls lost their allografts. The 1-, 2-, 5-, and 10-year allograft survival probabilities for the 2 groups (SLE versus controls) were as follows: 81.7% versus 88.2% (1-year); 74.7% versus 84.4% (2-year); 45.9% versus 75.0% (5-year); and 18.5% versus 34.8% (10-year). In the multivariate model, the relative hazard of allograft loss associated with SLE as the cause of ESRD was 2.1 (95% confidence interval 1.06-4.06, P = 0.0328). The total number of HLA mismatches, smoking status, and delayed allograft function were also associated with allograft loss in the multivariate model.. Compared with matched controls, renal transplant patients with SLE had inferior transplantation outcomes, with more than twice the risk of allograft loss.

Topics: Adult; Antirheumatic Agents; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Multivariate Analysis; Probability; Proportional Hazards Models; Survival Analysis; Tacrolimus; Treatment Outcome

Topics: Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prednisolone; Reoperation; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Organ Preservation; Pancreas; Pancreas Transplantation; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Topics: Acidosis, Renal Tubular; Adult; Azathioprine; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Prednisolone; Tacrolimus; Transplantation, Homologous

Topics: Adult; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Proteinuria; Tacrolimus

We describe a case of de novo membranous glomerulopathy in the renal allograft of a diabetic patient, treated with the newer immunosuppressive agent FK 506. Twenty-two months later this patient developed nephrotic range proteinuria.

Topics: Basement Membrane; Cyclosporine; Diabetic Nephropathies; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Male; Microscopy, Fluorescence; Middle Aged; Tacrolimus; Treatment Outcome

Renal transplantation is a treatment option that should be considered for the elderly (> or = 60 years old) with end-stage renal disease. Little is known regarding the use of tacrolimus (as induction and maintenance immunosuppression) in this age group. We report the outcome of kidney transplantation in 21 patients aged 60 years or more with tacrolimus. During the past few years in kidney transplant maintenance immunosuppressive regimens, we have revised our standard general protocol from cyclosporine to tacrolimus-based therapy for maintenance immunosuppression and for rescue therapy. We also introduced mycophenolate (RS-61443) while we have continued to use ATGAM/OKT3 as induction regimen in the immediate postoperative period. We treated these renal recipients with tacrolimus and steroids in combination with azathioprine or mycophenolate mofetil without antibody induction. This was well tolerated and not associated with a higher rate of rejection (20%) whereas the potential toxicity of antilymphocyte preparations was avoided.

Topics: Administration, Oral; Age Factors; Aged; Azathioprine; Cadaver; Cyclosporine; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus; Treatment Outcome

Topics: Adult; Alopecia; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus

Three cases of insulin-requiring diabetes mellitus associated with tacrolimus (FK506) therapy in pediatric renal transplant patients are presented. New-onset diabetes mellitus has been reported with tacrolimus therapy post liver and kidney transplants in up to 12% of adult patients, but is thought to be rare in pediatrics. Although insulin requirement with tacrolimus therapy has been occasionally reported in adolescent patients post liver transplant, only a single case in a pediatric kidney transplant recipient has been previously documented. These cases illustrate the significant diabetogenic effect of tacrolimus in pediatric renal transplant patients. As the use of tacrolimus becomes more prevalent in pediatric kidney transplantation, pediatric nephrologists should be aware of this potential complication.

Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 1; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus

Hepatitis C virus (HCV) is the predominant cause of posttransplant non-A, non-B hepatitis among renal allograft recipients. Prior studies evaluating the impact of HCV in kidney transplantation have been retrospective in design and based largely on changes in serum transaminases. We studied a group of HCV-infected end-stage renal disease patients prospectively with pretransplant liver biopsies and close virologic and biochemical follow-up posttransplant. Fourteen patients have been followed a mean of 11.6 +/- 5.6 months posttransplant (range, 5-21 months). Six had changes of chronic hepatitis on pretransplant liver biopsy while 8 showed only mild histologic abnormalities. Circulating viral titers increased several-fold over baseline levels during posttransplant follow-up. Viral replication was particularly enhanced immediately following a course of antilymphocyte therapy. Although all patients showed a 2-3 fold increase in alanine aminotransferase (ALT) following transplantation, there were no association noted between pretransplant liver histology, the use of FK506 and/or cyclosporine-based immunosuppression, and the magnitude of ALT change posttransplant. The only clinical outcome found to differ significantly was a higher incidence of cytomegalovirus infection among patients with chronic hepatitis. All patients are alive with functioning grafts. There have been no episodes of fulmiinant or subfulminant liver failure. We conclude that HCV-infected patients can be safely transplanted with excellent short-term follow-up. Continued monitoring with sequential liver biopsies will be needed to define the long-term course of HCV infection in an immuno-suppressed population.

Topics: Adult; Biopsy; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome

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

We describe a patient who received a living related kidney transplant that worked very well initially but developed oliguria and renal failure within 1 week and required dialysis. Clinical and hemological changes, as well as renal biopsy, confirmed the diagnosis of cyclosporin-induced hemolytic uremic syndrome. The patient did not respond to antirejection therapy or plasma exchange but did respond to the withdrawal of cyclosporin A and the commencement of FK 506.

Topics: Adult; Cyclosporine; Female; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Kidney Failure, Chronic; Kidney Transplantation; Tacrolimus

Topics: Anti-Bacterial Agents; Diabetes Complications; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Risk Factors; Tacrolimus

The experimental immunosuppressive drug FK 506 was given to 36 renal transplant recipients, many of whom were highly sensitized. Ten were undergoing kidney retransplantation, 10 also underwent liver transplantation at an earlier time (6 patients) or concomitantly (4 patients), and 2 patients received a third organ (heart or pancreas) in addition to a liver and kidney. With follow-ups of 4 to 13 months, all but 2 of the 36 patients are alive, 29 (81%) are dialysis free, and most have good renal function. Twenty of the 29 dialysis-free patients are receiving no or low-dose (2.5 to 5.0 mg/d) prednisone therapy. Only one kidney was lost to cellular rejection. However, patients who had antidonor cytotoxic antibodies in current or historical serum samples had a high rate (3 of 9) of irreversible humoral rejection. A low incidence of posttransplant hypertension was noteworthy. Hirsutism and gingival hyperplasia were not observed. Serum cholesterol levels in patients who took FK 506 were unexpectedly low, and the effect on the level of uric acid was minimal. The side effects of FK 506 therapy include nephrotoxicity, neurotoxicity, and potential induction of a diabetic state. These are similar to the side effects of cyclosporine use, but probably less severe. The seeming safety, efficacy, and relative freedom from side effects of FK 506 encourage further trials in kidney transplantation.

Topics: Adult; Anti-Bacterial Agents; Child; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Tissue Donors