tacrolimus and Renal-Insufficiency

TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome.. Both patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly.. In both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients' laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis.. In case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy.. This report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome.

Topics: Adolescent; Aged; Bone Marrow; Calcineurin Inhibitors; Cardiomyopathies; Castleman Disease; Cyclosporine; Edema; Female; Fever; Fibrosis; Glucocorticoids; Hepatomegaly; Humans; Interleukin-6; Male; Primary Myelofibrosis; Renal Insufficiency; Splenomegaly; Syndrome; Tacrolimus; Thrombocytopenia; Treatment Outcome

The use of immunodepressants in the medical practice provided tens of thousands of favourable outcomes of the liver, kidney or heart transplantation and significant success in the treatment of a number of autoimmune diseases. Calcineurine inhibitors (cyclosporine A and tacrolimus) provoke a number of adverse reactions. Among them nephrotoxicity is clinically most dangerous. Complex estimation of the immunological and biochemical indices in the treatment with calcineurine inhibitors is an important precondition for increasing the efficacy of immunodepressive therapy and decreasing the frequency and level of the adverse reactions.

Topics: Cadherins; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Gene Expression Regulation; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Lymphotoxin-alpha; Organ Transplantation; Renal Insufficiency; Tacrolimus

Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings.

Topics: Abatacept; Calcineurin Inhibitors; Everolimus; Humans; Immunoconjugates; Immunosuppression Therapy; Liver Transplantation; Mycophenolic Acid; Precision Medicine; Pyrroles; Quinazolines; Renal Insufficiency; Risk Factors; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin inhibitor everolimus (Zortress®, Certican®) was recently approved in the USA and a number of EU countries for use in combination with a reduced dosage of tacrolimus and corticosteroids for the prophylaxis of organ rejection in adult liver transplant recipients. Compared with standard-exposure tacrolimus, early use of everolimus plus a reduced dosage of tacrolimus did not compromise efficacy in liver transplant recipients. In addition, significantly better renal function with everolimus plus reduced-exposure tacrolimus than with standard-exposure tacrolimus was seen from 6 weeks post-transplant onwards. Everolimus plus reduced-exposure tacrolimus has an acceptable tolerability profile in liver transplant recipients.

Topics: Adrenal Cortex Hormones; Adult; Allografts; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Renal Insufficiency; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Renal dysfunction is a critical issue for liver transplant candidates and recipients. Acute nephrotoxicity and chronic nephrotoxicity, however, are the compromises for the potent immunosuppression provided by calcineurin inhibitors (CNIs). To maintain the graft and patient survival afforded by CNIs while minimizing renal dysfunction in liver transplant patients, the reduction, delay, or elimination of CNIs in immunosuppression regimens is being implemented more frequently by clinicians. The void left by standard-dose CNIs is being filled by nonnephrotoxic immunosuppressants such as mycophenolates and mammalian target of rapamycin inhibitors. The results of studies of renal-sparing regimens in liver transplant recipients have been inconsistent, and this may be explained upon a closer examination of several study-related factors, including the study design and the duration of follow-up.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Drug Administration Schedule; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Liver Failure; Liver Transplantation; Mycophenolic Acid; Renal Insufficiency; Tacrolimus; TOR Serine-Threonine Kinases

Renal replacement therapies which consist of renal transplantation and dialysis are the only treatment options for patients with terminal renal failure. These therapies have changed the outcome from being fatal to being a chronic disease. Kidney transplantation involves the use of immunosuppressive agents to prevent rejection. Currently, several immunosuppressive agents have shown efficacy, safety, and different costs.. The aim was to evaluate the cost-effectiveness of early conversion from tacrolimus to mammalian target of rapamycin inhibitors sirolimus or everolimus versus continuous treatment with tacrolimus among renal transplantat patients in Colombia.. We performed systematic literature review to extract data for clinical effectiveness and safety of tacrolimus replacement schemes for immunosuppressive therapy in renal transplantation in adults. A Markov model in TreeAge was developed, simulating the patient's natural history with renal transplantation. The perspective of the Colombian Health System was used, including only direct costs. The cost-effectiveness ratio and incremental cost-effectiveness ratio were estimated. Deterministic and probabilistic sensitivity analyses were performed. A 5% discount rate was applied in costs and health results.. Results for the replacement of tacrolimus to sirolimus are provided. The cost per year of additional life gained for sirolimus was Col$2,441,171.43; the cost for avoided loss was Col$4,014,152.84. The acceptability curve shows that a strategy with sirolimus is the most cost-effective one.. This study suggested that the sirolimus strategy is cost-effective in Colombia for patients with renal transplantation using as threshold less than three times the gross domestic product (GDP) per capita of Colombia per life of years gained.

Topics: Clinical Trials as Topic; Colombia; Cost-Benefit Analysis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Markov Chains; Registries; Renal Insufficiency; Sirolimus; Tacrolimus; Treatment Outcome

The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation.. In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes.. Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Renal Insufficiency; Tacrolimus

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols. As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (<50 mL/h urine output) or rising serum creatinine levels. There are a variety of postulated causes for calcineurin inhibitor-associated early renal insufficiency including direct calcineurin inhibitor-mediated renal arteriolar vasoconstriction, increased levels of endothelin-1 (a potent vasoconstrictor), as well as decreased nitric oxide production and alterations in the kidney's ability to adjust to changes in serum tonicity. Once early renal insufficiency occurs, no single treatment has been shown to be effective. Approaches discussed in this paper include reduction in calcineurin inhibitor dosages, as well as various drugs to promote increased renal perfusion such as misoprostol and dopamine. In addition, the paper emphasizes the importance of ruling out other causes of renal insufficiency in the early postoperative period, including volume depletion, depressed cardiac output, and mechanical obstruction to urine flow. Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal in

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Renal Insufficiency; Risk Factors; Tacrolimus; Time Factors

Topics: Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency; Sirolimus; Tacrolimus

Topics: Cyclosporine; Drug Monitoring; Humans; Immunosuppressive Agents; Kidney; Organ Transplantation; Renal Insufficiency; Tacrolimus

It has been known for some time that a variety of liver diseases affect kidney function, but renal dysfunction associated with orthotopic liver transplantation has received scant attention. Although the mechanisms mediating these abnormalities are incompletely defined, advances in the understanding of renal pathophysiology after liver transplantation have made it possible to develop new treatment strategies. Aggressive and early intervention to diagnose and treat renal complications associated with liver transplantation should be the goal for transplant centres.

Topics: Chronic Disease; Cyclosporine; Hepatitis C; Hepatorenal Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Liver Transplantation; Prostaglandins; Renal Dialysis; Renal Insufficiency; Tacrolimus

Topics: Cyclosporine; Follow-Up Studies; Humans; Hypertension; Immunosuppression Therapy; Liver Cirrhosis; Liver Transplantation; Renal Insufficiency; Tacrolimus; Time Factors

Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years.. Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio).. Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80).. Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.

Topics: Aged; Area Under Curve; Cross-Over Studies; Drugs, Generic; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymorphism, Genetic; Prospective Studies; Renal Insufficiency; Tacrolimus; Therapeutic Equivalency; Transplant Recipients

Early after renal transplantation, it is often challenging to achieve and maintain tacrolimus concentrations within the target range. Computerized dose individualization using population pharmacokinetic models may be helpful. The objective of this study was to prospectively evaluate the target concentration achievement of tacrolimus using computerized dosing compared with conventional dosing performed by experienced transplant physicians.. A single-center, prospective study was conducted. Renal transplant recipients were randomized to receive either computerized or conventional tacrolimus dosing during the first 8 weeks after transplantation. The median proportion of tacrolimus trough concentrations within the target range was compared between the groups. Standard risk (target, 3-7 μg/L) and high-risk (8-12 μg/L) recipients were analyzed separately.. Eighty renal transplant recipients were randomized, and 78 were included in the analysis (computerized dosing (n = 39): 32 standard risk/7 high-risk, conventional dosing (n = 39): 35 standard risk/4 high-risk). A total of 1711 tacrolimus whole blood concentrations were evaluated. The proportion of concentrations per patient within the target range was significantly higher with computerized dosing than with conventional dosing, both in standard risk patients (medians, 90% [95% confidence interval {95% CI}, 84-95%] vs 78% [95% CI, 76-82%], respectively, P < 0.001) and in high-risk patients (medians, 77% [95% CI, 71-80%] vs 59% [95% CI, 40-74%], respectively, P = 0.04).. Computerized dose individualization improves target concentration achievement of tacrolimus after renal transplantation. The computer software is applicable as a clinical dosing tool to optimize tacrolimus exposure and may potentially improve long-term outcome.

Topics: Adult; Aged; Aged, 80 and over; Computer Simulation; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Theoretical; Prospective Studies; Renal Insufficiency; Risk Factors; Software; Tacrolimus; Treatment Outcome

Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD).. Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m(2)/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m(2) leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m(2) leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated.. Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m(2), AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease.. A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m(2) seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.

Topics: Adenosine Deaminase Inhibitors; Adult; Antibodies, Monoclonal; Area Under Curve; Blood Transfusion, Autologous; Creatinine; Cyclosporine; Drug Resistance; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infliximab; Lymphocyte Transfusion; Male; Methotrexate; Methylprednisolone; Middle Aged; Pentostatin; Renal Insufficiency; Stem Cell Transplantation; Tacrolimus; Young Adult

Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention-to-treat population there were no differences in eGFR (66.2 ± 25.3 vs. 70.7 ± 25.1, p = 0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-to-creatinine ratio (0.36 ± 0.69 vs. 0.15 ± 0.53, p = 0.03) and higher incidence of treated acute rejection between months 3-24 (13.4% vs. 4.7%, p = 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months.

Topics: Adult; Biopsy; Creatinine; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Renal Insufficiency; Sirolimus; Tacrolimus; Treatment Outcome

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.

Topics: Adrenal Cortex Hormones; Adult; Black or African American; Body Mass Index; Double-Blind Method; Female; Humans; Hyperkalemia; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Renal Insufficiency; Tacrolimus

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

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

Immunosuppressive regimens have lowered the rate of kidney rejection, but with increasing immunodeficiency-related complications. New cytomegalovirus (CMV) prophylaxis also has become available. The impact of these 2 developments on CMV diseases has not been well evaluated. We conducted a randomized trial comparing a drug regimen common in the 1980s, cyclosporin A (CsA) with azathioprine (Aza), with a drug combination used most today, tacrolimus (Tac) with mycophenolate mofetil (MMF), and we analyzed CMV risk factors in kidney transplant patients.. The 300 patients included in the trial underwent the same universal prophylaxis and preemptive therapy. CMV events and risk factors were prospectively recorded.. With preventive and preemptive strategies combined for 3 months, CMV replication was detected in 32.6% and CMV disease in 18.1% of patients. Multivariate analysis on risk factors for CMV disease were CMV donor (D)/recipient (R) matching and first month renal function (risk ratio [95% confidence interval]: 1.02 [1.01; 1.04]; P=0.011), but not the immunosuppressive regimen (P=0.35). The D+/R- combination increased the risk of CMV disease by a factor of 9 (P<0.0001) when compared with D-/R- status, and a factor of 3.5 (P<0.0001) when compared with all CMV-positive recipients. Despite the 50% rate of CMV disease in the D+/R- group, no asymptomatic CMV replication was detected with the preemptive strategy.. With modern immunosuppression, a sequential quadritherapy with Tac/MMF, and a 3-month CMV prevention strategy, the risk for CMV disease remains close to that with CsA/Aza. A CMV-negative recipient transplanted from a CMV-positive donor (D+/R-) remains a major risk factor, calling for better CMV prophylaxis or matching in negative recipients. Preemptive strategy thus appeared inefficient for this high-risk group. Transplant recipients with altered renal function should also be considered at risk.

Topics: Adult; Antiviral Agents; Azathioprine; Chemoprevention; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Ganciclovir; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Renal Insufficiency; Risk Factors; Tacrolimus; Treatment Outcome

In an effort to mitigate progression of IF/TA associated with chronic renal allograft injury, we hypothesize that adjuvant immunosuppression with sirolimus (SRL) will delay progression compared with MMF. Subjects 5-17 yr old, >1-yr post-transplant with mild or moderate IF/TA (Banff criteria) and tacrolimus dose minimization were randomized to continue MMF or convert to SRL and followed for two yr. For the entire cohort (n = 20), there was significant progression of %GGS, ci, ct, cv, and ah scores over the follow-up period (p < 0.05). There was no difference in rates of progression of Banff scores, %GGS, or % IF over two yr between the two groups, though power was low. Both groups exhibited similar rates of eGFR decline (MMF: -12.3 vs. SRL: -11.8 mL/min/1.73 m²/yr), which was correlated with ct score (p < 0.05). The SRL group had more episodes of acute allograft dysfunction and oral ulcers. Proteinuria at 24 months was significantly increased in the SRL group (6/9 subjects) but was not correlated with eGFR or %GGS. We conclude that neither MMF nor SRL, combined with low-dose tacrolimus, was effective at mitigating progressive histological changes or functional decline associated with chronic renal allograft injury.

Topics: Adolescent; Child; Child, Preschool; Chronic Disease; Cohort Studies; Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Renal Insufficiency; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Low-dose calcineurin inhibitors (CNIs) in combination with a fixed dose (2 g/d) of mycophenolate mofetil (MMF) are a strategy to minimize exposure to cyclosporine (CSA) or tacrolimus (TAC) and thus reduce CNI-related side effects. This study compared the pharmacokinetics (PK) of mycophenolic acid (MPA) and its glucuronide metabolites in stable adult liver transplant recipients with moderately impaired renal function converted from a standard to a low-dose CNI regimen in combination with a fixed dose of MMF. Full 12-hour PK profiles of MPA, free MPA, the aryl glucuronide (MPAG), and the acyl glucuronide (AcMPAG) were obtained from 30 stable liver transplant patients on low-dose CNI (CSA, n = 12; TAC, n = 18) therapy at least 3 months after initiation of low-dose therapy. Predose CSA and TAC concentrations (quantified by liquid chromatography-tandem mass spectrometry) ranged from 17 to 35 and 1.1 to 3.7 microg/L, respectively. The PK variables for MPA, MPAG, AcMPAG, and free MPA displayed wide interindividual variability. Of note was the observation that there were no significant differences in the exposure to MPA, MPAG, and free MPA between the CSA and TAC groups. MPA area under the concentration-time curves (AUCs) ranged from 31.8 to 102.1 (median: 52.9) mg.h(-1).L(-1) in the CSA group and from 22.9 to 144.8 (median: 55.9) mg.h(-1).L(-1) in the TAC group. The AcMPAG AUC on patients under low-dose CSA therapy was higher than that observed under patients on low-dose TAC therapy, although this did not quite reach statistical significance (P = 0.057). Patients receiving CSA had a significantly higher AcMPAG Cmax but not AcMPAG AUC, suggesting that only peak CSA concentrations on a low-dose CSA regimen are sufficient to impair the biliary excretion of AcMPAG. In summary, the influence of CSA on the exposure to MPA was attenuated in stable adult liver transplant recipients on a low-dose CNI therapy in combination with a fixed dose of MMF as compared with patients on a standard CNI therapy. Dose adjustment according to drug concentration measurements is recommended to optimize dosing of MMF and to maintain adequate immunosuppression in patients converted to low-dose CNI therapy.

Topics: Adult; Aged; Area Under Curve; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Glucuronides; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

This pilot study was designed to evaluate the safety and efficacy of converting from a calcineurin inhibitor (CI) to a sirolimus (SRL)-based regimen in established renal transplant recipients with moderate renal insufficiency. Sixty renal transplant recipients on CI-based immuno-suppression with a serum creatinine (SCr) between 159 and 265 microM (1.8 and 3.0 mg/dL) and a glomerular filtration rate (GFR) between 30 and 70 mL/min were enrolled. SRL dosing was dependent upon concomitant immunosuppressive therapy. The mean patient age was 45 yr and the mean time from transplant to study enrollment was 60.8 months (range: 7-198). The median SCr was 168 microM (1.9 mg/dL) and the median GFR was 51 mL/min. Twelve months after conversion the patient and graft survival rates were 96.7% and 95%, respectively. The incidence of biopsy-proven acute rejection was 3.3% (two cases reported, Banff grades IA and IB). The median SCr and median creatinine clearance were 168 microM (1.9 mg/dL) and 53 mL/min, respectively. Hyperlipidemia, diarrhea, peripheral edema, rash, and anemia were the most commonly reported adverse events. Patients with moderate renal insufficiency can be converted from CI to SRL-based therapy and maintain renal function over a 1-yr period.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Renal Insufficiency; Sirolimus; Survival Analysis; Tacrolimus; Treatment Outcome

Seventy-nine patients with cyclosporine- and prednisone-dependent myasthenia gravis (MG) after thymectomy received tacrolimus for a mean of 2.5 +/- 0.8 years. Prednisone was withdrawn in all but two patients. Anti-acetylcholine antibodies and MG score for disease severity decreased significantly and muscular strength increased by 39%. Complete stable remission was achieved in 5% of patients and pharmacologic remission in 87.3%. All patients resumed full activities of daily living.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Ataxia; Autoantibodies; Cyclosporine; Dizziness; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Muscle Weakness; Myasthenia Gravis; Prednisone; Prospective Studies; Receptors, Cholinergic; Remission Induction; Renal Insufficiency; Tacrolimus; Thymectomy; Time; Treatment Outcome

Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low-dose tacrolimus (target trough level 4-8 ng/mL, starting day 4-6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end-points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m(2); P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m(2); P = 0.038). In conclusion, delayed low-dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post-liver transplantation without the cost of increased acute rejection.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Dose-Response Relationship, Drug; Female; Hepatic Insufficiency; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Tacrolimus; Treatment Outcome

Mycophenolate mofetil (MMF) has no known nephrotoxicity. This report examines the outcome in patients who received MMF for renal impairment on tacrolimus-based immunosuppression. From 1995 to 1996, twelve liver transplantation (LTx) patients (mean age 54.6 years) with serum creatinine >1.8 mg/dl were included in the study. MMF was introduced and tacrolimus dose was reduced by 30-50%. Each patient was followed for 6 years. Renal function showed improvement in seven patients, deterioration in four, and no change in one patient. Overall mean serum creatinine decreased from 2.5 to 1.9 mg/dl at 6 months but increased to 2.2 mg/dl at 18 to 24 months. After that, renal function remained stable for 72 months. Iothalamate clearance showed 18.5% improvement at 1 year. Three patients developed renal failure. Six patients died in the follow-up period. Addition of MMF with reduced tacrolimus dose resulted in sustained improvement in renal function in 58% of patients.

Topics: Adult; Aged; Aging; Creatine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Organ Size; Renal Insufficiency; Sex Characteristics; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Although used for more than 20 years, optimal dosing strategies of most immunosuppressants have never been determined. Tacrolimus, one of the newer agents used in solid-organ transplantation, is gaining increasing popularity because of its ability to reverse refractory rejection in cyclosporine-treated patients and its favorable side-effect profile. As with many other immunosuppressive agents, absorption and metabolism vary between individuals, which complicates dosing.. We hypothesized that a 1-mg dose of tacrolimus may be used to gauge each patient's metabolism. A novel dosing scheme was evaluated to establish the safety and efficacy of this approach. Outcomes were incidence of renal insufficiency and treatment efficacy as assessed by the rejection grade on the first endomyocardial biopsy.. The risk of renal insufficiency was low, with only a 3% rise in creatinine at 7 days posttransplant. The risk of renal insufficiency was highest during the first 3 days of tacrolimus therapy, and the change in tacrolimus level during this time was identified as the single best predictor of renal insufficiency. From days 4 to 7, the rise in tacrolimus level had much less influence on renal function. Ninety-two percent of patients had a low- or intermediate-grade first cardiac biopsy.. It was shown that this conservative initial dosing approach, which guarantees renal safety, is not associated with an increased risk of allograft rejection. We conclude that administration of tacrolimus via a tailored protocol soon after transplantation ensures a safe and effective means of immunosuppression.

Topics: Adult; Aged; Algorithms; Biopsy; Cohort Studies; Creatinine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Myocardium; Predictive Value of Tests; Renal Insufficiency; Tacrolimus

Chronic renal failure is a major cause of morbidity and mortality after orthotopic liver transplantation. We did a randomised controlled trial of mycophenolate mofetil monotherapy in liver transplant patients who developed renal failure associated with calcineurin-inhibitor (ciclosporin or tacrolimus) immunosuppressive therapy. Although renal failure improved when the calcineurin-inhibitor dose was reduced and ultimately stopped, the trial was stopped when three of five patients on monotherapy developed organ rejection requiring a second transplantation.

Topics: Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Liver Transplantation; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

FK506 has been proven effective for prevention and treatment of liver allograft rejection. Herein, we compare FK506-based immunosuppression with an effective quadruple immunosuppressive regimen, including cyclosporine and antithymocyte globulin. The results of a single center participating in the European multicenter FK506 study are reported, including immunosuppressive efficacy as well as toxicity. One-year patient and graft survival was 96.7% and 90.0% for the CsA group and 90.2% and 88.5% for the FK506 group, which is not statistically different. The incidence and severity of acute rejection episodes during the first postoperative year was similar in both treatment groups with 34.4% and 33.3% for the FK506 and CsA treatment group, respectively. Immunosuppressive potency was better for the FK506 group compared with the CsA group according to the incidence of chronic rejection. Furthermore, 5 patients (8.3%) required conversion to FK506 for immunological reasons, i.e., refractory acute or chronic rejection. The incidence of moderate and severe neurotoxicity during the early postoperative period was higher in the FK506 group (21.3%) compared with the CsA group (11.7%), while the incidence of renal insufficiency and acute renal failure was similar (18.0% and 18.3% for the FK506 and CsA treatment groups, respectively). The incidence of CMV infection was significantly higher under treatment with CsA (25.0%) than with FK506 (6.6%) (P < or = 0.05), while the incidence of pneumonia (13.1% and 13.3%), cholangitis (29.5% and 26.7%), and urinary tract infection (39.3% and 28.3% for the FK506 and CsA treatment groups, respectively) was similar in both treatment groups. However, infection was more serious in some cases treated with FK506, and evolved as the main cause of death in the FK506 treatment group. Therefore, caution should be paid to over immunosuppression and toxicity in FK506-treated patients. Regarding the monitoring of FK506, FK506 plasma level failed to be a reliable indicator, and therefore we recommend measurement of whole blood FK506 levels. Our data indicate that immunosuppressive potency of FK506 is greater than that of CsA, especially concerning the incidence of chronic rejection.

Topics: Adolescent; Adult; Aged; Cyclosporine; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Opportunistic Infections; Renal Insufficiency; Survival Analysis; Tacrolimus; Transplantation, Homologous

We examined the occurrence of renal complications and hypertension in 540 primary liver recipients entered into the European liver trial comparing primary FK 506 to a cyclosporin A based immunosuppression regimen (CBIR). No difference in serious renal impairment or mean creatinine levels was observed with similar rates of "kidney failure" (FK 506 9.4% vs. CBIR 7.3%) and dialysis requirements (FK 506 12% vs. CBIR 11%). "Abnormal kidney function", a less serious parameter of renal impairment, was reported in 89 recipients (33%) in the FK 506 group versus 58 (21%) in the CBIR group (P < 0.01). Development of this complication was associated with elevated intravenous FK 506 dosing schedules, with the mean cumulative dose 43% higher than treated patients with unaffected kidney function. In a later cohort of patients where intravenous dosing was lower, no significant difference in renal complications was detectable. The 6-month prevalence rate of systemic arterial hypertension was noted to be lower in the FK 506-treated patients compared to the CBIR group [33 (17.2%) vs. 47 (25.7%)].

Topics: Adolescent; Adult; Aged; Azathioprine; Cohort Studies; Creatinine; Cyclosporine; Drug Therapy, Combination; Europe; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prednisolone; Renal Insufficiency; Tacrolimus

Nephrotoxicity represents a serious side-effect of immunosuppression following orthotopic liver transplantation. In order to preserve the therapeutic potential of cyclosporin (CsA) and FK 506 in human liver transplantation and to differentiate the nephrotoxic action of either drug in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 randomly assigned to CsA- and 61 to FK 506-based immunosuppression. Early postoperative renal insufficiency (between POD0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (36.7%) and FK 506 (42.6%). Early postoperative acute renal failure (ARF; SCr > 3 mg/dl) occurred in 18.3%, regardless of the immunosuppressive management. Approximately 50% of patients with ARF required hemodialysis (CsA: 11.7%; and FK 506: 8.3%). Mean onset of hemodialysis in CsA-treated patients was POD1 and in FK 506-treated patients, POD6, which demonstrated a different time course of drug-specific nephrotoxicity of CsA and FK 506 in early ARF. All patients with early postoperative ARF requiring hemodialysis survived more than 1 year (100% survival). New onset of late ARF (between POD30 and 365), however, occurred in 6.5% under FK 506 and in 1.7% under CsA immunosuppression due to severe infections with the multiple organ failure syndrome. This observation was consistent with the assumption of over-immunosuppression rather than a primary nephrotoxic effect. Mortality of patients with late ARF requiring hemodialysis was 100%. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK 506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity. These preliminary results demonstrated a similar outcome in terms of early and late nephrotoxicity, but longer follow-up will delineate its overall efficacy and toxicity in humans.

Topics: Creatinine; Cyclosporine; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Period; Renal Dialysis; Renal Insufficiency; Survival Rate; Tacrolimus; Time Factors

Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress.. In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2'-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1).. CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF-1 treatment abolished the effects of CTLA4-Ig.. CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

Topics: Abatacept; Animals; Apoptosis; Apoptosis Regulatory Proteins; CTLA-4 Antigen; Forkhead Box Protein O3; Humans; Insulin-Like Growth Factor I; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Renal Insufficiency; Signal Transduction; Tacrolimus

Currently, clinicians often delay initiation of tacrolimus after orthotopic heart transplantation (OHT) to help mitigate nephrotoxicity. This study aimed to determine if there is an association between the time-to-therapeutic range (TTT) of tacrolimus, early renal dysfunction, and acute cellular rejection (ACR) after OHT.. This was a retrospective, single center study with adult patients who underwent OHT from July 2013 to April 2020. Logistic regression analysis was utilized to examine the association of TTT with new renal dysfunction after tacrolimus initiation post-OHT.. In a study of 317 patients, the unadjusted analysis showed patients who developed new renal dysfunction after tacrolimus initiation had a numerically shorter TTT (9.5 vs. 11.0 days, P = .065), and were more likely to have supratherapeutic tacrolimus levels (56% vs. 39.2%, P = .010). When adjusted for established risk factors for renal dysfunction, TTT was significantly associated with new renal dysfunction (OR .95; 95% CI [.90, .99], P = .03). There was no association between TTT and the incidence of ACR (11.1 vs. 10.8 days, P = .64).. When adjusting for known risk factors, a shorter TTT was associated with new renal dysfunction. Supratherapeutic tacrolimus levels were also associated with new renal dysfunction. There was no association between TTT and ACR in the setting of high use basiliximab induction.

Topics: Adult; Basiliximab; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Renal Insufficiency; Retrospective Studies; Tacrolimus

Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical.. This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis.. The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A.. For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

Topics: Allografts; Antiviral Agents; Creatinine; Fanconi Anemia; Fanconi Syndrome; Humans; Kidney Transplantation; Kidney Tubules, Proximal; Renal Insufficiency; Retrospective Studies; Scoliosis; Tacrolimus

Mycophenolate (mycophenolate mofetil [MMF]; mycophenolate sodium [MPS]) and tacrolimus (FK-506) are commonly and concomitantly used to prevent rejection in organ transplant. Mycophenolate-induced hepatotoxicity causing the reduced FK-506 metabolism with nephrotoxicity may be less appreciated, leading to inappropriate management. We describe a new living donor kidney recipient receiving pretransplant and post-transplant immunosuppressants including oral mycophenolate (MMF 1 g daily) and tacrolimus (FK-506 4-8 mg daily) who developed progressive liver dysfunction (up to 10-fold increase) despite the reduced FK-506 dosage (6 mg daily). A thorough investigation including infection, inflammation, and autoimmune hepatitis were unremarkable. With a withdrawal of MMF, his liver function improved, but persistently higher trough serum FK-506 level (12-15 ng/mL) and increased serum creatinine were notable. Moreover, the reintroduction of MPS with the reduced FK-506 dosage (4 mg daily) worsened liver function along with FK-506 nephrotoxicity (serum creatinine from 1.4-2.4 mg/dL). The replacement of MPS with mammalian target of rapamycin inhibitor not only resolved liver injury but also normalized serum FK-506 level and kidney function. Mycophenolate should be kept in mind as a cause of drug-induced hepatotoxicity that can reduce tacrolimus metabolism, leading to FK-506 nephrotoxicity and acute kidney injury in organ transplant.

Topics: Chemical and Drug Induced Liver Injury; Creatinine; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

Acute calcineurin inhibitor (CNI) nephrotoxicity is a common complication associated with CNI exposure. However, it can be difficult to diagnose. Herein, we report a case of acute CNI nephrotoxicity after heart transplant that was visualized using kidney Doppler ultrasonography.. A 38-year-old female patient underwent heart transplant 5 years after the use of left ventricular assist device support because of advanced heart failure due to ischemic cardiomyopathy. Corticosteroids, tacrolimus, and mycophenolate mofetil were administered as immunosuppressive regimens postoperatively. The patient gradually developed kidney dysfunction despite a favorable perioperative clinical course and hemodynamics. Serum creatinine increased to 1.89 mg/dL on postoperative day (POD) 9, and the kidney Doppler ultrasonography examination showed severely reduced blood flow in the renal and renal segmental arteries, indicating acute CNI nephrotoxicity due to vasoconstriction of the renal arterioles. After the cessation of tacrolimus, kidney function returned to baseline levels within 2 days, and the kidney Doppler ultrasonography examination on POD 19 revealed a significant increase in blood flow in the renal and renal segmental arteries. Basiliximab followed by everolimus were administered as alternative immunosuppressants. No organic stenosis of the renal artery was detected on the kidney magnetic resonance angiography, and the patient was discharged on POD 51, without any other adverse events, including rejection.. Although CNIs are widely used after heart transplant, acute nephrotoxicity should always be considered. After heart transplant, a kidney Doppler ultrasonography should be performed routinely and promptly if there are any clinical manifestations related to kidney function.

Topics: Adult; Calcineurin Inhibitors; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Mycophenolic Acid; Renal Insufficiency; Tacrolimus; Ultrasonography, Doppler

Little is known regarding optimal tacrolimus (TAC) trough levels after 1 year post-transplant in stable kidney transplant recipients (KTRs) who have not experienced renal or cardiovascular outcomes. This study aimed to investigate the effect of 1-year post-transplant TAC trough levels on long-term renal and cardiovascular outcomes and opportunistic infections in stable KTRs.. KTRs receiving TAC with mycophenolate-based immunosuppression who did not experience renal or cardiovascular outcomes within 1 year post-transplant were enrolled from a multicenter observational cohort study. Renal outcome was defined as a composite of biopsy-proven acute rejection, interstitial fibrosis and tubular atrophy, and death-censored graft loss. Cardiovascular outcome was defined as a composite of de novo cardiomegaly, left ventricular hypertrophy, and cardiovascular events. Opportunistic infections were defined as the occurrence of BK virus or cytomegalovirus infections.. A total of 603 eligible KTRs were divided into the low-level TAC (LL-TAC) and high-level TAC (HL-TAC) groups based on a median TAC level of 5.9 ng/mL (range 1.3-14.3) at 1 year post-transplant. The HL-TAC group had significantly higher TAC trough levels at 2, 3, 4, and 5 years compared with the levels of the LL-TAC group. During the mean follow-up of 63.7 ± 13.0 months, there were 121 renal outcomes and 224 cardiovascular outcomes. In multivariate Cox regression analysis, LL-TAC and HL-TAC were not independent risk factors for renal and cardiovascular outcomes, respectively. No significant differences in the development of opportunistic infections and de novo donor-specific anti-human leukocyte antigen antibodies and renal allograft function were observed between the two groups.. TAC trough levels after 1 year post-transplant remained at a similar level until the fifth year after kidney transplantation and were not directly associated with long-term outcomes in stable Korean KTRs who did not experience renal or cardiovascular outcomes. Therefore, in Asian KTRs with a stable clinical course, TAC trough levels higher than approximately 6 ng/mL might not be required after a year of kidney transplantation.

Topics: Adult; Cardiovascular Diseases; Cohort Studies; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Opportunistic Infections; Polyomavirus Infections; Renal Insufficiency; Republic of Korea; Tacrolimus

What is the central question of this study? Does immunosuppression restore the baroreflex control of renal sympathetic nerve activity (RSNA) in an animal model of kidney injury? What is the main finding and its importance? Tacrolimus, a calcineurin inhibitor, restored the high- and low-pressure baroreflex control of RSNA following cisplatin-induced renal injury.. Cisplatin administration causes depression of renal haemodynamic and excretory function and is associated with renal sympatho-excitation and loss of baroreflex regulation of renal sympathetic nerve activity (RSNA). This study investigated whether administration of the immunosuppressant tacrolimus in this cisplatin-mediated renal injury model could restore, or the acute intra-renal infusion of tumour necrosis factor α (TNF-α) could blunt, the high- or low-pressure baroreflex control of RSNA. Groups of control and cisplatin-treated (5 mg kg

Topics: Animals; Baroreflex; Blood Pressure; Cisplatin; Heart Rate; Hemodynamics; Kidney; Male; Rats; Rats, Wistar; Renal Insufficiency; Sympathetic Nervous System; Tacrolimus

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

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

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Animals; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Cullin Proteins; Gene Expression Regulation; Germ-Line Mutation; Humans; Hyperkalemia; Hypertension; Kidney; Kidney Tubules, Distal; Mice; Microfilament Proteins; Multiprotein Complexes; Phosphorylation; Protein Serine-Threonine Kinases; Renal Insufficiency; T-Lymphocytes; Tacrolimus; Ubiquitination

Pulmonary alveolar echinococcosis is a rare but potentially severe condition.. We report the case of a 50-year-old woman suffering from pulmonary alveolar echinococcosis who had had a renal transplant for polycystic liver and kidney disease. A lung opacity was identified radiologically in May 2013. Both broncho-alveolar lavage and bronchial biopsy were uninformative. In January 2014, a follow up CT-scan showed the opacity to be enlarging. A surgical biopsy revealed a giant cell epithelioid granuloma with caseous necrosis suggesting a diagnosis of pulmonary tuberculosis. Antituberculous treatment was started but cultures remained negative. A histological revue was therefore requested in March 2014. This suggested bronchocentric granulmatosis, possibly associated with echinococcosis. This hypothesis was finally confirmed serologically. Treatment for alveolar echinococcosis was begun in June 2014 after consultation with the national reference centre for parasitology.. Outside endemic areas and in the absence of hepatic involvement pulmonary alveolar echinococcosis can be difficult to diagnose. This case report focuses on the diagnostic criteria and treatment.

Topics: Echinococcosis; Echinococcosis, Hepatic; Echinococcosis, Pulmonary; Female; Granuloma; Humans; Immunocompromised Host; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Radiography, Thoracic; Renal Insufficiency; Tacrolimus

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

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

Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Logistic Models; Male; Matched-Pair Analysis; Mycophenolic Acid; Prednisolone; Renal Insufficiency; Retrospective Studies; Tacrolimus; Treatment Outcome

Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities.. Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens, and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data.. One thousand four hundred eleven recipients were included (54.4% AA) with 39 521 concentrations used to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs versus non-AAs (39.9 ± 19.8 % vs 34.8 ± 15.8% P < 0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (adjusted hazard ratio, 1.20, 1.13-1.28; P < 0.001) and the risk of graft loss by 30% (adjusted hazard ratio, 1.30, 1.23-1.37; P < 0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss.. These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients.

Topics: Adolescent; Adult; Black or African American; Drug Administration Schedule; Electronic Health Records; Female; Graft Rejection; Graft Survival; Healthcare Disparities; Humans; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Renal Insufficiency; Risk Factors; Tacrolimus; Time Factors; United States; Young Adult

High intrapatient variability (IPV) in tacrolimus trough levels has been shown to be associated with higher rates of renal transplant failure. There is no consensus on what level of IPV constitutes a risk of graft loss. The establishment of such a threshold could help to guide clinicians in identifying at-risk patients to receive targeted interventions to improve IPV and thus outcomes.. A multicentre Transplant Audit Collaborative has been established to conduct a retrospective study examining tacrolimus IPV and renal transplant outcomes. Patients in receipt of a renal transplant at participating centres between 2009 and 2014 and fulfilling the inclusion criteria will be included in the study. The aim is to recruit a minimum of 1600 patients with follow-up spanning at least 2 years in order to determine a threshold IPV above which a renal transplant recipient would be considered at increased risk of graft loss. The study also aims to determine any national or regional trends in IPV and any demographic associations.. Consent will not be sought from patients whose data are used in this study as no additional procedures or information will be required from participants beyond that which would normally take place as part of clinical care. The study will be registered locally in each participating centre in line with local research and development protocols. It is anticipated that the results of this audit will be disseminated locally, in participating NHS Trusts, through national and international meetings and publications in peer-reviewed journals.

Topics: Adult; Drug Monitoring; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Practice Guidelines as Topic; Renal Insufficiency; Reproducibility of Results; Retrospective Studies; Tacrolimus; Time Factors; Transplant Recipients; Treatment Outcome; United Kingdom

Although tacrolimus (TAC) can induce remission in children with refractory inflammatory bowel disease (IBD) or autoimmune gastroenteropathy (AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use.. This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort.. Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate (eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC.. TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC.

Topics: Autoimmune Diseases; Biopsy; Child; Crohn Disease; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Kidney; Maintenance Chemotherapy; Male; Renal Insufficiency; Retrospective Studies; Tacrolimus; Treatment Outcome

We assessed the relations between MPA, free MPA (fMPA) and MPA glucuronide (MPAG) pharmacokinetics and the clinical condition of renal transplant recipients treated with EC-MPS and tacrolimus (Tac) in the first post-transplant year. In 18 adult patients blood samples were collected up to 12 h after EC-MPS oral administration. EC-MPS metabolites' plasma concentrations were determined using validated HPLC methods. All patients reached MPA area under the time-concentration curve (AUC0-12) above 30 µg h/mL. Most of the MPA, fMPA and all MPAG concentrations correlated significantly with respective AUC0-12 values. Some fMPA and all MPAG pharmacokinetic parameters correlated negatively with creatinine clearance and positively with creatinine concentration, whereas no such correlation was observed for MPA. Lower hemoglobin concentrations were observed in patients with higher MPA or fMPA C 0. The significant correlations between MPA C 3 as well as MPA C 4 and MPA AUC0-4 and MPA AUC0-12 may be of importance in further studies including larger number of patients in regard to establishing LSS. In patients treated with EC-MPS and Tac, monitoring MPA C 0 may be important, as too high MPA C 0 may contribute to anemia onset. In EC-MPS treated patients, MPAG concentration is related to renal function as MPAG pharmacokinetics were higher in patients with renal impairment.

Topics: Adult; Aged; Area Under Curve; Creatinine; Drug Therapy, Combination; Female; Glucuronides; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post-transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re-initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post-transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re-initiation of cysteamine therapy in cystinosis patients post-transplant should be considered.

Topics: Adolescent; Child; Corneal Diseases; Cysteamine; Cystinosis; Drug Administration Schedule; Fanconi Syndrome; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inpatients; Kidney Transplantation; Male; Postoperative Period; Renal Insufficiency; Tacrolimus; Treatment Outcome

Although de novo DSA are associated with inferior graft survival, there are no effective strategies to prevent their formation. Underexposure to MPA (prodrug: MMF) also contributes to rejection rates early after transplantation, but the effect of this phenomenon on the formation of DSA long-term post-transplantation is unknown. Data are expressed as mean (standard deviation). All available data from 32 renal transplant recipients (age at transplantation 7.5 [4.5] yr) on tacrolimus and MPA immunosuppression with an average follow-up of 9.4 (s.d. 4.6) yr were analyzed. DSA were measured using the Luminex assay (>500 MFI was considered DSA-positive). Tacrolimus and MPA levels were measured with the Abbot Tacro II and EMIT assay, respectively. Among 1964 MPA and 3462 tacrolimus trough levels, the average MPA trough level was 3.2 (1.5) mg/L and the average tacrolimus level was 6.7 (2.8) ng/mL. At last follow-up, only 5/32 patients had undetectable DSA, with 5/32 having no class I antibodies and 6/32 having no class II antibodies. DSA formation was associated with a lower minimum MPA trough level (0.27 [0.23] vs. 0.47 [0.18] mg) and cystatin C eGFR (48 [21] vs. 70 [23] mL/min/1.73 m(2)) for class I DSA formers. The average eGFR of patients without class I DSA was 70 (23) mL/min/1.73 m(2), whereas the average eGFR of patients with class I DSA was 48 (21) mL/min/1.73 m(2) (p = 0.0071). MPA trough levels <1.3 mg/L long-term post-transplantation are associated with the formation of DSA. The association between the formation of DSA and minimum MPA exposure may support a strategy for preventing the formation of DSA.

Topics: Anthropometry; Antibodies; Antibody Formation; Area Under Curve; Child; Cohort Studies; Cystatin C; Drug Monitoring; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency; Tacrolimus; Tissue Donors; Transplant Recipients; Treatment Outcome

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

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

A steroid-free protocol for ABO-compatible renal transplantation has been used at our center since 1983. To minimize the adverse effects of steroids, we also developed a steroid sparing protocol for ABO-incompatible renal transplantation in 2008. The present study is a report of our results. A retrospective review of the first 50 ABO-incompatible renal transplantations performed at a single university center. If no immunological events occurred in the post-transplant period, prednisolone tapering was initiated approximately 3 months after transplantation. Forty-three patients completed prednisolone tapering after 289 ± 58 days. Three patients died during follow-up, and four patients lost graft function. None of these adverse events were rejection related. Eleven patients experienced rejections; seven were on prednisolone and four were after weaning from prednisolone. All patients responded well to antirejection treatment. Overall, 1-year rejection rate was 19%. One- and 3-year graft survival was 94% and 91%, respectively. One-year post-transplant median serum creatinine was 123 μmol/L. We found acceptable rejection rates, graft survival, and creatinine levels in patients undergoing ABO-incompatible renal transplantations with a steroid sparing protocol. However, a longer follow-up of a lager cohort is needed before firm conclusions can be made.

Topics: ABO Blood-Group System; Adult; Aged; Antibodies; Biopsy; Blood Group Incompatibility; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prednisolone; Renal Insufficiency; Retrospective Studies; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF's possible protective effect. Our results showed that MMF (at 50 mg kg(-1) body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg(-1) b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process.

Topics: Animals; Biomarkers; Calcineurin Inhibitors; Chemical and Drug Induced Liver Injury; DNA Damage; Dose-Response Relationship, Drug; Enzyme Inhibitors; Immunosuppressive Agents; IMP Dehydrogenase; Kidney; Liver; Male; Mycophenolic Acid; Oxidative Stress; Protective Agents; Protein Carbonylation; Random Allocation; Rats, Wistar; Renal Insufficiency; Tacrolimus

Kidney failure after lung transplantation is a risk factor for chronic kidney disease. Calcineurin inhibitors are immunosuppressants which play a major role in terms of postoperative kidney failure after lung transplantation. We report our preliminary experience with the anti-interleukin-2 monoclonal antibody Basiliximab utilized as a "calcineurin inhibitor-free window" in the setting of early postoperative kidney failure after lung transplantation. Between 2012 and 2015 nine lung transplant patients who developed kidney failure for more than 14 days were included. Basiliximab was administrated in three doses (Day 0, 4, and 20) whilst Tacrolimus was discontinued or reduced to maintain a serum level between 2 and 4 ng/mL. Baseline glomerular filtration rate pre transplant was normal for all patients. Seven patients completely recovered from kidney failure (67%, mean eGFR pre and post Basiliximab: 42.3 mL/min/1.73 m(2) and 69 mL/min/1.73 m(2)) and were switched back on Tacrolimus. Only one of these patients still needs ongoing renal replacement therapy. Two patients showed no recovery from kidney failure and did not survive. Basiliximab might be a safe and feasible therapeutical option in patients which are affected by calcineurin inhibitor-related kidney failure in the early post lung transplant period. Further studies are necessary to confirm our preliminary results.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Lung Transplantation; Male; Middle Aged; Recombinant Fusion Proteins; Renal Insufficiency; Tacrolimus

Minimizing IS to reduce side effects without compromising long-term renal transplant survival is the goal of all IS protocols. We conducted a retrospective study of pediatric renal transplants performed August 1988 to July 2008 and treated with two-drug maintenance therapy by one of three protocols: prednisone/cyclosporine without induction (SB) or with daclizumab induction (SBI), or tacrolimus/mycophenolate with daclizumab induction (SF). Kaplan-Meier survival curves were used to determine graft and patient survival at one, three, five, and 10 yr. Associations between graft survival and patient/transplant characteristics were determined using log-rank test and CPH model adjusting for treatment group. About 208 patients were included in the analysis (96 SB, 97 SBI, 15 SF; 148 DD, 60 LD, 37 pre-emptive). Overall graft and patient survival at one, three, five, and 10 yr were similar to the previously published results of pediatric renal transplants in similar years treated predominantly with three-drug maintenance therapy (https://web.emmes.com/study/ped/annlrept/2010). Only biopsy-proven TG was significantly associated with worse graft survival (HR 11.5, 95% CI: 3.4, 38.7). Malignancy rate was low (2.4%) with little PTLD (0.5%). Few opportunistic or other infections occurred (<5% patients). Minimizing IS to a two-drug maintenance regimen had no adverse effect on long-term transplant outcome and had low malignancy and infection rates.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Biopsy; Child; Cyclosporine; Daclizumab; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Multivariate Analysis; Mycophenolic Acid; Prednisone; Proportional Hazards Models; Renal Insufficiency; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

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

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

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

Klotho is highly expressed in the kidney, is present in the circulation and urine, and has protective effects against various renal injuries. We examined whether reduced Klotho expression affects tacrolimus (Tac)-induced renal injury in an experimental model of chronic Tac nephropathy.. First, we evaluated the association between the Tac dose and Klotho expression by giving different doses of Tac (0.25, 0.5, and 1 mg/kg) to wild-type (WT) mice for 4 weeks. Second, we compared Klotho levels, renal function, fibrosis, and apoptosis between WT mice and Klotho heterozygous (HT) mice in an experimental model of chronic Tac nephropathy. Third, we examined whether the oxidative stress and signaling pathway are involved in the protection by Klotho against Tac-induced renal injury.. Klotho levels in renal tissue and urine were reduced in a dose-dependent manner in Tac-treated WT mice. Tac-treated HT mice showed lower levels of Klotho in the renal cortex and urine, and higher serum creatinine level, fibrosis, and apoptosis compared with WT mice. Treatment of Tac to WT mice increased markers of oxidative stress such as phosphatidylinositol 3-kinase (PI3K)-Akt and Forkhead box protein O (FoxO) 3a phosphorylation but decreased FoxO1 dephosphorylation. These effects were greater in HT mice. HT mice exhibited a much lower level of manganese superoxide dismutase level and higher level of Bim, target genes of FoxOs, compared with the levels in WT mice.. Reduced Klotho expression aggravates Tac-induced renal injury via the PI3K-Akt-FoxO pathway.

Topics: Animals; Forkhead Transcription Factors; Glucuronidase; Klotho Proteins; Male; Mice; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Renal Insufficiency; Tacrolimus

Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.

Topics: Adolescent; Adult; Aged; Biopsy; Creatinine; Female; Graft Rejection; Humans; Immunoassay; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Proportional Hazards Models; Renal Insufficiency; Reproducibility of Results; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

We examined integrated national transplant registry, pharmacy fill, and medical claims data for Medicare-insured kidney transplant recipients in 2000-2011 (n = 45 164) from the United States Renal Data System to assess the efficacy and safety endpoints associated with seven early (first 90 days) immunosuppression (ISx) regimens. Risks of clinical complications over 3 years according to IS regimens were assessed with multivariate regression analysis, including the adjustment for covariates and propensity for receipt of a nonreference ISx regimen. Compared with the reference ISx (thymoglobulin induction with tacrolimus, mycophenolate, and prednisone maintenance), sirolimus-based ISx was associated with significantly higher three-year risks of pneumonia (adjusted hazard ratio, aHR 1.45; P < 0.0001), sepsis (aHR 1.40; P < 0.0001), diabetes (aHR 1.21; P < 0.0001), acute rejection (AR; adjusted odds ratio, aOR 1.33; P < 0.0001), graft failure (aHR 1.78; P < 0.0001), and patient death (aHR 1.40; P < 0.0001), but reduced skin cancer risk (aHR 0.71; P < 0.001). Cyclosporine-based IS was associated with increased risks of pneumonia (aHR 1.17; P < 0.001), sepsis (aHR 1.16; P < 0.001), AR (aOR 1.43; P < 0.001), and graft failure (aHR 1.39; P < 0.001), but less diabetes (aHR 0.83; P < 0.001). Steroid-free ISx was associated with the reduced risk of pneumonia (aHR 0.89; P = 0.002), sepsis (aHR 0.80; P < 0.001), and diabetes (aHR 0.77; P < 0.001), but higher graft failure (aHR 1.35; P < 0.001). Impacts of ISx over time warrant further study to better guide ISx tailoring to balance the efficacy and morbidity.

Topics: Adolescent; Adult; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Pneumonia; Renal Insufficiency; Risk; Sepsis; Sirolimus; Tacrolimus; United States; Young Adult

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

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

We describe an observational, retrospective study that included patients who underwent a liver transplantation (LT) for hepatocellular carcinoma (HCC) in our center between 2004 and 2012.. Clinical variables were recorded for donors and recipients as diagnosis and treatment, immunosuppressive therapy, toxicity, graft dysfunction, recurrence, and exitus. Fifty-eight patients were analyzed. The mean age was 57 ± 8 years. The viral etiology of HCC was 50% (n = 29), alcoholic 26% (n = 15), and others, 24% (n = 14). Regarding initial immunosuppressive strategy (IS), 51 patients (87.9%) were treated with standard regimen with corticosteroids (CS) and tacrolimus (TA), compared with 7 patients with impaired renal function (12.1%) who underwent a delayed therapy with calcineurin inhibitors (CNI) + mycophenolate mophetil (MMF) + CS. Concomitant use of anti-CD25 monoclonal antibodies was less than 10%. Regarding maintenance, 43 patients (74.1%) were treated with MMF + CNI versus 15 treated only with TA (25.9%).. Recurrence of HCC was approximately 12%: 7 patients (2 hepatic only, 5 also extra-hepatic). Exitus was established in 19 patients (32.75%); only 3 patients (5.17%) were attributable to HCC. Bivariate studies were conducted according to the initial IS (standard regimen versus delayed therapy) and maintenance therapy (MMF + TA versus TA alone), with no differences in any of them in recurrence, treatment toxicity, graft rejection, and dysfunction.. In our experience with the IS, we found no differences in the development of recurrent disease, treatment toxicity, development of graft dysfunction, or rejection. We believe that individualized immunosuppressive therapy in these patients is safe and effective.

Topics: Adrenal Cortex Hormones; Aged; Antibodies, Monoclonal; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Female; Graft Rejection; Graft Survival; Hospitals, University; Humans; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Renal Insufficiency; Retrospective Studies; Tacrolimus

Topics: Aged; Antithrombins; Atrial Fibrillation; Conjunctival Diseases; Dabigatran; Drug Interactions; Drug Substitution; Eye Hemorrhage; Female; Humans; Immunosuppressive Agents; International Normalized Ratio; Liver Transplantation; Renal Insufficiency; Tacrolimus; Treatment Outcome

A 63-year-old Japanese woman with a 30-year history of systemic lupus erythematosus developed macrohematuria and massive proteinuria after seroconversion of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy indicated focal proliferative lupus nephritis (class III A/C) with a fibrous crescent formation. Methylprednisolone pulse therapy (500 mg, 3 successive days) was administered because of progressive proteinuria. Steroid therapy did not suppress the progressive proteinuria; therefore, tacrolimus was added as an alternative immunosuppressive therapy, resulting in the improvement of proteinuria and renal impairment. This case report suggests that MPO-ANCA might play a pathogenic role in the exacerbation of immune-complex-type lupus nephritis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Coloring Agents; Disease Progression; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Peroxidase; Proteinuria; Renal Insufficiency; Tacrolimus; Treatment Outcome

Calcineurin-inhibitor (CNI)-induced nephrotoxicity frequently complicates transplantation. African-Americans are at a greater risk of renal failure than the general population. We investigated whether race was an effect modifier of the relationship between CNI exposure and kidney function after nonrenal solid organ transplantation.. This is a retrospective cohort study of 1609 patients who underwent initial nonrenal solid organ transplantation between January 2000 and June 2012. A central repository administrative database was queried electronically for demographics, comorbidities, and serial levels of tacrolimus, cyclosporine, and serum creatinine. Predictors of interest were total drug exposure of tacrolimus and cyclosporine (area under the concentration-time curve) and self-reported race. The outcome of interest was cumulative change in estimated glomerular filtration rate (GFR).. There were 1109 patients treated with tacrolimus (271 African-Americans) and 500 patients treated with cyclosporine (113 African Americans). A decline in GFR over time was seen with total tacrolimus exposure (-1.3 mL/min/1.73 m(2) for every 5 ng/mL·year increase in tacrolimus) and total cyclosporine exposure (-1.1 mL/min/1.73 m(2) for every 50 ng/mL·year increase in cyclosporine). However, total CNI exposure effect on estimated GFR changes did not vary by race (P interaction was 0.9 for tacrolimus and 0.6 for cyclosporine).. Total CNI exposure is associated with worsening kidney function among patients with nonrenal solid organ transplantation. However, African-American patients are not more vulnerable to chronic CNI-induced nephrotoxicity when compared to white patients.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Incidence; Kidney Function Tests; Male; Middle Aged; Organ Transplantation; Racial Groups; Renal Insufficiency; Retrospective Studies; Survival Rate; Tacrolimus; United States

GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid-sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty-eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m² at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long-term follow-up.

Topics: Antibiotics, Antineoplastic; Biopsy; Child; Child, Preschool; Cohort Studies; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency; Steroids; Tacrolimus

Long-term graft survival and function has not kept pace with short-term success in kidney transplant (Tx) recipients. LAR ≥6 months post-Tx may contribute to lack of improvement; risk factors for LAR are not well known. Of 64 Tx recipients followed over six yr, 23 (35.9%) had LAR (LAR group) and 41 had no LAR (no LAR group). Of all variables, significant risk factors for LAR included DGF, (43.4% LAR vs. 14.6% in no LAR group, p = 0.0096); de novo DSA (65.2% vs. 26.8%, p = 0.003); mean COV% of TAC (41.8% vs. 34.6%, p = 0.03); and non-adherence (34.8% vs. 7.3%, p = 0.0043). DGF and DSA remained statistically significant (p = 0.002 and 0.003, respectively); COV% TAC had borderline significance (p = 0.057), and non-adherence was not significant on multivariate regression analysis. Patients with LAR had inferior graft survival and function, whereas graft function was stable in the no LAR group over a mean follow-up of 31.2 months. Patients with de novo DSA and DGF should be considered at risk of LAR; an early diagnosis and treatment of LAR may improve graft survival and function.

Topics: Adolescent; Child; Female; Graft Rejection; Graft Survival; Humans; Incidence; Kidney Transplantation; Male; Multivariate Analysis; Patient Compliance; Renal Insufficiency; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

Kidney transplantation is currently the best treatment for end-stage renal disease, both in terms of mortality benefit and quality of life (QOL). Elderly patients are a rapidly growing subset of the kidney transplant waiting list. While it is clear that elderly individuals have a mortality benefit from kidney transplant, it is less clear how to make sure these individuals benefit from optimal QOL following transplant. Several studies demonstrate superiority of some immunosuppressive regimens over others in the QOL domain. Tacrolimus has been shown to be associated with better QOL than cyclosporine (ciclosporin), as has corticosteroid-free immunosuppressive regimens. Similarly, patients on drug regimens, which tend to lessen the side effects, report better QOL. However, these studies are observational or cross-sectional and not focused exclusively on the elderly patient. More studies are needed to determine optimal immunosuppression regimens for elderly individuals. Additionally, further studies on determinants of QOL in elderly kidney transplant recipients are also needed.

Topics: Aged; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Quality of Life; Renal Insufficiency; Research Design; Tacrolimus

Topics: Biopsy; Bipolar Disorder; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Kidney Transplantation; Lithium; Middle Aged; Nephritis, Interstitial; Renal Insufficiency; Risk; Risperidone; Tacrolimus; Treatment Outcome; Valproic Acid

There exists a major concern regarding toxic effects of immunosuppressive medication on the kidney graft during post-transplant care, with observed variation in individual susceptibility to adverse drug effects amongst patients. To date, there has been no possibility to identify susceptible patients prospectively. This study analyzes medical data which includes time series of measures of renal function and trough levels of immunosuppressive drug Tacrolimus, with the main aim of identifying patients susceptible to drug toxicity. We evaluate a plethora of time-series distance measures, determining their appropriateness to the domain based on two criteria: (1) preserving the expected correlations between distances, and (2) ability to detect the expected patterns of interaction between immunosuppressive drug levels and renal function. Besides identifying the most suitable time-series distance measures, we observed that the majority of patients do not exhibit an association between impaired graft function and higher Tacrolimus dosing. On the other hand, the minority of patients determined most sensitive to varying Tacrolimus levels showed a strong tendency to prefer low Tacrolimus dosing.

Topics: Adolescent; Adult; Aged; Child; Creatinine; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Models, Statistical; Renal Insufficiency; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Non-adherence is common in adolescent and young adult kidney transplant recipients, leading to adverse graft outcomes. The aim of this study was to determine whether adherence to immunosuppressant medications changes during transition from a pediatric to an adult program within the same transplant center. Adherence was assessed for a period of two yr before and two yr after the transfer. Subtherapeutic trough levels of serum tacrolimus and level variability were used as measures of adherence. Twenty-five patients were transitioned between 1996 and 2011 at the median age of 22.3 [IQR 21.6-23.0] yr. Young adults 21-25 yr of age (n = 26) and non-transitioned adolescents 17-21 yr of age (currently followed in the program, n = 24 and those that lost their grafts prior to the transfer, 22) formed the comparison groups. In the transitioned group, adherence prior to the transfer was not significantly different from the adherence after the transfer (p = 0.53). The rate of non-adherence in the group of non-transitioned adolescents who lost their grafts (68%) was significantly higher than in the transitioned group (32%, p = 0.01). In the group of young adults, adherence was not significantly different from the transitioned group (p = 0.27). Thus, transition was not associated with differences in medication adherence in this single-center study. Large-scale studies are needed to evaluate the national data on medication adherence after transfer.

Topics: Adolescent; Adult; Blood Pressure; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Medication Adherence; Pediatrics; Renal Insufficiency; Retrospective Studies; Tacrolimus; Transition to Adult Care; Transplant Recipients; Treatment Outcome; Urban Population; Young Adult

Topics: Antibodies, Monoclonal; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Glomerulonephritis, IGA; HIV Seronegativity; Humans; Immunosuppression Therapy; Inflammation; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Renal Dialysis; Renal Insufficiency; Sinusitis; Tacrolimus; Valganciclovir

BK virus nephropathy and cellular rejection are common causes of allograft dysfunction in renal transplant recipients. The two can be difficult to distinguish on allograft biopsy and can be present simultaneously. Management of the patient with coexistent BK infection and rejection is complicated by the conflicting ideals of decreasing immunosuppression to treat the former and increasing immunosuppression to treat the latter. The authors present the case of a 57-year-old renal transplant recipient who underwent allograft biopsy 8 weeks post-transplant for evaluation of increased serum creatinine in the setting of BK viremia (BKV). Biopsy revealed Banff classification 1b acute cellular rejection, with insufficient evidence to diagnose BK virus-associated nephropathy. The patient was administered intravenous immune globulin (IVIG), with no other changes in immunosuppressive therapy. Plasma and urine BK increased exponentially following IVIG administration, and allograft function further deteriorated. Repeat biopsy showed overt BK viral nephropathy, and BKV and creatinine decreased only after reduction in immunosuppression and initiation of leflunomide. Although case series have suggested a potential role for IVIG in the setting of BK infection, further study is needed to define the safety and efficacy of this approach.

Topics: BK Virus; Fatal Outcome; Female; Graft Rejection; Humans; Immunity, Cellular; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Renal Insufficiency; Tacrolimus; Tumor Virus Infections; Viremia

A reliable biomarker to differentiate high-risk recipients who will experience a decrease in allograft function after glucocorticoid withdrawal has not been established in renal transplantation. We examined the clinical significance of peripheral blood lymphocyte sensitivity to glucocorticoids in vitro for the differentiation of the high-risk patients after glucocorticoid reduction/withdrawal in renal transplant recipients.. The study included 44 renal transplant recipients with stable allograft function. Peripheral lymphocyte responses to suppressive effects of cortisol, methylprednisolone, cyclosporine, and tacrolimus in mitogen assay procedures in vitro were examined. Clinical outcome after glucocorticoid reduction/withdrawal was retrospectively compared between recipients with lymphocytes normally sensitive to the drugs and those with hyposensitivity. The receiver-operating characteristic (ROC) curve analysis was undertaken for setting the cutoff IC50 values of the drugs against the T cell mitogen-induced lymphocyte proliferation to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal.. The median (range) IC50 value for cortisol in the recipients who showed decreased renal function due to glucocorticoid withdrawal was 10,000 (570.9-72,279.3) ng/mL (n = 9), which was significantly higher than the value of 351.6 (2.0-10,000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 35) (P < 0.001). Similarly, the median (range) IC50 value for methylprednisolone in the recipients who showed decreased renal function after glucocorticoid withdrawal was 69.1 (21.5-1442.7) ng/mL (n = 9), which was significantly higher than the value of 13.8 (0.7-1000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 30) (P < 0.003). In contrast, there was no significant difference in the median IC50 values of cyclosporine and tacrolimus between the 2 recipient subgroups. The ROC curve analyses for the IC50 values of the immunosuppressive drugs estimated the cutoff value of cortisol and methylprednisolone to be 3580.0 and 21.5 ng/mL, respectively. The ROC AUCs for cortisol and methylprednisolone were 0.83 and 0.84, respectively. According to the cutoff IC50 value, the incidence of decreased allograft function in the low cortisol sensitivity (IC50 >3580.0 ng/mL) subgroup was 7 of 13 patients, which was significantly higher than that of the higher sensitivity subgroup of 2 of 31 (P = 0.0012). A similar case was observed using the cutoff IC50 value of methylprednisolone (P = 0.0012), whereas recipient grouping according to the cutoff IC50 values of cyclosporine and tacrolimus failed to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal.. Glucocorticoid pharmacodynamics in lymphocytes of individual patient origin is a reliable biomarker for differentiation of renal transplant recipients who will experience a safe reduction/withdrawal of glucocorticoid.

Topics: Adult; Allografts; Area Under Curve; Biomarkers; Cell Proliferation; Cells, Cultured; Cyclosporine; Female; Glucocorticoids; Humans; Hydrocortisone; Immunosuppressive Agents; Inhibitory Concentration 50; Kidney; Kidney Transplantation; Lymphocytes; Male; Methylprednisolone; Middle Aged; Renal Insufficiency; Retrospective Studies; Risk Assessment; ROC Curve; Tacrolimus; Withholding Treatment

The development of de novo renal cell carcinoma (RCC) in a transplanted kidney is a rare condition. Currently, this is the second case report of a 41-year-old man in whom carcinoma of a renal allograft was detected by contrast-enhanced ultrasound (CEUS). An abdominal CT scan was not conclusive enough to differentiate between septal enhancement of a cyst and a low vascularized tumor. CEUS confirmed a solid, homogeneously enhancing but hypoechoic and hypovascular lesion compared to the surrounding kidney parenchyma without septal enhancement. Therefore, the patient underwent nephron-sparing surgery (NSS), affirming papillary RCC type 2. Graft function remained unchanged postoperatively; 12 months after NSS, no local recurrence or distant metastasis was described. CEUS seems to be a minimally invasive and efficient imaging option if other diagnostic tools cannot clearly exclude RCC, with the advantage of wide-ranging use, especially in cases of impaired renal function.

Topics: Adult; Carcinoma, Renal Cell; Contrast Media; Everolimus; Humans; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Male; Neoplasm Metastasis; Nephrons; Postoperative Period; Recurrence; Renal Insufficiency; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Ultrasonography

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient's risk management strategies.

Topics: Adult; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Renal Insufficiency; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study.. The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%), with a higher prevalence observed in male patients (68.18%). The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1±9.32 days and the mean Model for End-stage Liver Disease score was 26.18±4.28. There were five cases of acute cellular rejection (11.37%) and 16 cases of infection (36.37%). The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (p<0.05). Patients with infections had a higher serum level of Tacrolimus (p = 0.012). The dose and presence of rejection were significantly different (p = 0.048) and the mean glomerular filtration rate was impaired in patients who underwent rejection compared with patients who did not undergo rejection (p = 0.0084).. Blood Tacrolimus levels greater than 10 ng/ml were correlated with impaired renal function. Doses greater than 0.15 mg/kg/day were associated with the prevention of acute cellular rejection but predisposed patients to infectious disease.

Topics: Adult; Aged; Creatinine; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Length of Stay; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Statistics, Nonparametric; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Assessment of renal function 12 months after liver transplantation (LT) predicts chronic renal failure on long-term follow up.. To evaluate pre- and post- LT factors associated with development of renal dysfunction (RD) in cirrhotic patients.. Between June 2005 and June 2010, 104 cirrhotic patients were selected from 268 consecutively transplanted adult patients. RD was defined as a calculated glomerular filtration rate (cGFR) < 50 ml/min/1.73m2 by modification of diet in renal disease (MDRD), 12 months after LT.. Baseline pre-LT creatinine was 1.0 ± 0.7 mg/dL and cGFR was 64 ± 32.8 mL/min. At 12 month follow up, creatinine was 1.3 ± 0.6 mg/dL and cGFR was 47 ± 18 mL/min. The prevalence of RD was 55%. Variables related to RD on univariate analysis were age (P = 0.007), pre-L T GFR (P = 0.012) and 7th day post-L T GFR (P = 0.003). Risk factors associated with RD on multivariate stepwise regression analysis were patient age [Odds ratio (OR) 1.04 (95% confidence interval (CI) 0.99- 1.09, P = 0.06)] and 7 day post-LT GFR [OR 0.97 (95% CI 0.96-0.99, P = 0.013)]. ROC curve analysis for 7th day post-LT GFR was 0.71 (95% CI 0.61-0.81).. The 7th day post-LT GFR in cirrhotic patients may be a useful clinical tool to identify which patients might benefit from earlier nephroprotective immunosuppression.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Period; Renal Insufficiency; Retrospective Studies; Risk Assessment; Sensitivity and Specificity; Tacrolimus; Time Factors

Topics: Graft Survival; Humans; Liver Transplantation; Randomized Controlled Trials as Topic; Renal Insufficiency; Tacrolimus

Topics: Dose-Response Relationship, Drug; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Randomized Controlled Trials as Topic; Renal Insufficiency; Tacrolimus

Overimmunosuppression is a widely recognized risk factor for BK virus (BKV) infection, particularly with the combination of tacrolimus, mycophenolate mofetil (MMF), and steroids. Nevertheless, the exact impact of exposure to tacrolimus and MMF is not well understood.. We examined 240 kidney recipients between 2006 and 2008. BKV was monitored every 2 months in the urine or blood. A kidney biopsy was performed when viremia exceeded 10 copies/mL.. Ninety-five (40%) patients had sustained viruria, 48 (20%) sustained viremia, and 17 (7%) biopsy-proven polyomavirus-associated nephropathy. The mean time-to-occurrence was 7.6, 7.9, and 9.7 months for viruria, viremia, and polyomavirus-associated nephropathy. Risk factors associated with BKV infection in univariate analyses were retransplantation, panel-reactive antibody more than 0%, cytomegalovirus D+/R-, cold ischemia time, delayed graft function, induction with antithymocyte globulins, acute rejection before month 3 (M3), tacrolimus trough levels more than 10 ng/mL, and M3 AUC0-12 hr more than 50 hr mg/L. Multivariate analyses showed that cytomegalovirus D+/R- (adjusted hazard ratio [AHR], 2.03; P=0.05), acute rejection (AHR, 5.4; P<0.001), and mycophenolic acid AUC0-12 hr more than 50 hr mg/L (AHR, 3.6; P=0.001) were risk factors for BKV.. This study identified a link between a state of increased immunosuppression and BKV infection, especially in patients with higher MMF exposure and elevated tacrolimus trough levels at M3.

Topics: Adolescent; Adult; Aged; Area Under Curve; Biopsy; BK Virus; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Renal Insufficiency; Risk Factors; Steroids; Tacrolimus; Viremia; Young Adult

Most calcineurin inhibitor (CNI)-based protocols reduce blood trough goals approximately 2-3 months post-transplant in clinically stable kidney transplant recipients. The CNI target trough level to prevent rejection, after reduction, is unknown. Using a multivariate Cox proportional hazards model, we determined the association of time-varying tacrolimus (TAC) trough levels with acute rejection (AR) occurring in the first 6 months post-transplant, but specifically we assessed this association after 3 months. A total of 1930 patients received TAC-based immunosuppression prior to AR in a prospective study. Of the 151 (7.8%) who developed AR, 47 developed AR after 3 months post-transplant. In an adjusted time-varying multivariate model, each 1 ng/ml decrease in TAC trough levels was associated with a 7.2% increased risk of AR [hazards ratio (HR) = 1.07, 95% confidence interval (CI) (1.01, 1.14) P = 0.03] in the first 6 months. There was an additional 23% increased risk of AR with each 1 ng/ml decrease in the TAC trough levels in months 3-6 [HR = 1.23, 95% CI (1.06, 1.43) P = 0.008]. In conclusion, lower TAC trough levels were significantly associated with increased risk of AR in the first 6 months post-transplant with additional risk of AR between months 3 and 6 post-transplant. The timing and practice of TAC dose reduction should be personalized based on the individual's risk factors.

Topics: Adult; Age Factors; Calcineurin Inhibitors; Clinical Trials as Topic; Cohort Studies; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Pancreas Transplantation; Proportional Hazards Models; Prospective Studies; Renal Insufficiency; Reproducibility of Results; Risk Factors; Tacrolimus

ALA induction in transplantation has been shown to reduce the need for maintenance immunosuppression. We report the outcome of 25 pediatric renal transplants between 2007 and 2010 using ALA induction followed by tacrolimus maintenance monotherapy. Patient ages were 1-19 yr (mean 14 ± 4.1 yr). Time of follow-up was 7-51 months (mean 26 ± 13 months). Tacrolimus monotherapy was maintained in 48% of patients, and glucocorticoids were avoided in 80% of recipients. Mean plasma creatinine and GFR at one yr post-transplant were 0.88 ± 0.3 mg/dL and 104.4 ± 25 mL/min/1.73m(2) , respectively. One, two, and three-yr actuarial patient and graft survival rates were 100%. The incidence of early AR (<12 months after transplantation) was 12%, while the incidence of late AR (after 12 months) was 16%. Forty-four percent of the recipients recovered normal, baseline renal function after an episode of AR, and 44% had persistent renal dysfunction (plasma creatinine 1.0-1.8 mg/dL). One graft was lost four yr after transplantation due to medication non-compliance. Four (16%) patients developed BK or CMV infection. In our experience, ALA induction with tacrolimus monotherapy resulted in excellent short- and mid-term patient and graft survival in low-immunologic risk pediatric renal transplant recipients.

Topics: Adolescent; Alemtuzumab; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Creatinine; Delayed Graft Function; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Renal Insufficiency; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Hearing impairment is a frequent problem that can easily influence the quality of life for the individual. It may affect one's social and academic life. Knowledge regarding hearing impairment after renal transplant is sparse. It has been suggested that renal transplant improves hearing function. Potential ototoxic side effects may be related to immunosuppression with calcineurin inhibitors. In pediatric renal transplanted patients, we do not have enough information about this subject. We report 2 cases that developed sudden hearing loss after a renal transplant that was associated with high serum levels of tacrolimus.. Two renal transplanted children (a 15-year-old boy and a 17-year-old girl), in the fourth year of their follow-up after transplant, developed symptomatic bilateral sudden hearing loss. There was a marked hearing impairment for the higher frequencies between 4000 and 8000 Hz in pure-tone audiometry evaluation. Also, a decrease of speech understanding was found, but the patients were not conscious of this problem. Hearing loss in these patients was not associated with any known risk factors such as chronic renal disease, ototoxic drugs, or acoustic trauma. Sudden hearing loss occurred under high serum levels of tacrolimus, and after dosage correction of tacrolimus pure-tone audiometry ruled out hearing loss progression for each patient.. Awareness of this potential complication of tacrolimus may be helpful for early recognition and treatment.

Topics: Adolescent; Dose-Response Relationship, Drug; Female; Hearing Aids; Hearing Loss, Sudden; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Quality of Life; Renal Insufficiency; Tacrolimus

CKD is a frequent long-term complication after SBTx. CNIs are a well-known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC-based maintenance immunosuppression. Median follow-up was seven yr (3-21). A renal biopsy was performed in 14 patients, 1-18 yr post-SBTx. A reduced GFR was observed in 17 children (63%) during the follow-up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post-transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow-up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infant; Intestinal Diseases; Intestine, Small; Male; Renal Insufficiency; Risk Factors; Tacrolimus; Transplantation; Treatment Outcome

Topics: Aged; Fatal Outcome; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Nervous System Diseases; Renal Dialysis; Renal Insufficiency; Survival Analysis; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

We report successful kidney transplantation in a 10-yr-old boy with aHUS and heterozygous factor H mutation using the terminal complement inhibitor eculizumab to avoid recurrence of aHUS in the renal graft. Vaccination against meningococcus C (Men C) is essential in patients with dysfunction of the complement system, as induced by eculizumab. In our patient, we report waning SBA titers but maintenance of protective SBA titers (≥1:8) after kidney transplantation under immunosuppressive therapy with mycophenolate mofetil, tacrolimus, steroids, and eculizumab over a 27-month observational period. Our case illustrates that a humoral immune response to conjugate Men C vaccination may be mounted and maintained despite chronic renal disease, kidney transplantation, immunosuppressive drugs, and immunomodulatory therapy with eculizumab. However, it remains unclear whether serologically defined protective SBA titers mediate true protection from invasive meningococcal disease in an immunocompromised patient, particularly under treatment with a complement inhibitor. Thus, close monitoring of SBA titers seems mandatory in this patient.

Topics: Antibodies; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Child; Complement Factor H; Complement Inactivating Agents; Hemolytic-Uremic Syndrome; Heterozygote; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Meningococcal Infections; Meningococcal Vaccines; Mutation; Mycophenolic Acid; Neisseria meningitidis; Peritoneal Dialysis; Recurrence; Renal Insufficiency; Steroids; Tacrolimus; Time Factors

There is very little information in the literature on the treatment and prognosis of primary focal segmental glomerulosclerosis (FSGS) among children in Pakistan. This is a review of 94 children (≤16 years) with a diagnosis of primary FSGS who presented to the Sindh Institute of Urology and Transplantation between 1995 and 2008. The clinical records and original renal biopsy reports were reviewed to determine demographic, clinical, laboratory and pathologic features. Renal biopsies were studied by light microscopy, immunofluoroscence and electron microscopy. Thera-peutic regimens and response to therapy were analyzed. Majority of the children (60, 63.8%) had steroid-dependant nephrotic syndrome (SDNS) and 33 (35%) had steroid-resistant nephrotic syndrome (SRNS). Cyclosphosphamide was used in SDNS, and this produced complete remission (CR) in 25/36 (69.4%), partial response (PR) in 4/36 (11%) and no response in 7/36 (19.4%) cases. Cyclosporine was used in SRNS and some SDNS children, and showed a CR in 30 (52.6%), PR in 20 (35%) and no response in seven (12.2%) cases. Tacrolimus was used in seven (7.44%) children. CR was obtained in two (28.5%) and PR in five (71.4%) cases. Renal insufficiency developed in 12 (12.7%) children. Results from this study show that majority of the children with primary FSGS at our center could achieve high rates of sustained remission with second- and third-line immunosuppressive therapies with fairly good prognosis.

Topics: Adolescent; Age Factors; Biopsy; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Disease Progression; Female; Fluorescent Antibody Technique; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infant; Kidney Glomerulus; Male; Microscopy, Electron; Nephrotic Syndrome; Pakistan; Remission Induction; Renal Insufficiency; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

High intra-patient variability in TCL exposure is a risk factor for allograft loss and late acute rejection. We hypothesized that a higher intra-patient variability leads to a faster decline in GFR in pediatric renal transplant patients and that adolescents have a higher intra-patient variability due to poorer adherence. We included 69 children aged 3.5-18 yr who had undergone renal transplantation between April 1996 and May 2009 in two pediatric nephrology centers in the Netherlands. We analyzed TCL trough concentrations over a period of one yr and calculated TCL trough concentrations variability using VC. We investigated the correlation between the TCL trough concentrations variability and the decline in estimated GFR over four yr. The median intra-patient variability in TCL concentrations was 30.1% (range 8.6-77.6) and the mean GFR slope -3.8 mL/min/1.73 m(2) /yr. The VC correlated neither with the GFR slope, nor with the patients' age. However, children with late acute rejection had higher VC (p = 0.045). We were unable to provide evidence that a high variability in TCL exposure leads to a faster decline in renal function, although children with late acute rejection have a higher variability in TCL exposure. Adolescents do not have a higher intra-patient variability in TCL trough concentrations than younger children.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney; Kidney Transplantation; Male; Patient Compliance; Renal Insufficiency; Reproducibility of Results; Tacrolimus; Treatment Outcome

The use of proliferation signal inhibitors (PSIs) for calcineurin-inhibitor (CNI) minimization or conversion protocols has been promoted for heart transplantation (HT) in the contexts of renal insufficiency, cardiac allograft vasculopathy (CAV), or malignancy. We evaluated our experience with conversion of patients from a CNI-based to a PSI-based immunosuppressive regimen. We focused on improvement in renal function.. This prospective follow-up included 96 HT patients converted to a PSI-based regimen from 2001 to 2010. We evaluated changes in creatinine clearance (CrCl) prior to at 1 year and at the end of follow-up after conversion.. Ninety-six patients including 86% men showed a mean age of 62 ± 8 years. They were converted to a PSI-based regimen at 6.3 ± 4 years post-HT due to the following causes: CNI toxicity (45%), CAV (16%), cancer (16%), CNI toxicity + CAV (17%), or CNI toxicity + cancer (6%). CNI withdrawal was achieved in 77 cases (80%) and minimization in 19 (20%). Everolimus was used in 54 (56%) and sirolimus in 42 (44%) cases. Median follow-up time was 3.8 years. PSI discontinuation due to side effects was common (38%). There were 43 deaths mainly due to cancer and CAV. CrCl improved albeit not significantly in the withdrawal group from a median of 51 mL/min preconversion to 59 mL/min at the last follow-up (P = .12). In the minimization group, median CrCl worsened from a median of 61 mL/min preconversion to 51 mL/min at the last follow-up (P = .001). In the 58 cases (61%) of CNI nephrotoxicity, median CrCl improved from a median of 41 mL/min preconversion to 49 mL/min at the last follow-up (P = .04).. Despite high rates of discontinuation of PSIs during long-term follow-up, the conversion regimen seemed to be useful to diminish CNI-related renal insufficiency especially with CNI withdrawal.

Topics: Aged; Biomarkers; Calcineurin Inhibitors; Cause of Death; Creatinine; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Prospective Studies; Recovery of Function; Renal Insufficiency; Signal Transduction; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

To investigate the differences in the pharmacokinetics of Prograf and the prolonged release formulation Advagraf and to develop a Bayesian estimator to estimate tacrolimus inter-dose area under the curve (AUC) in renal transplant patients receiving either Prograf or Advagraf.. Tacrolimus concentration-time profiles were collected, in adult renal transplant recipients, at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation from 32 Prograf treated patients, and one profile was collected from 41 Advagraf patients more than 12 months post-transplantation. Population pharmacokinetic (popPK) parameters were estimated using nonmem. In a second step, the popPK model was used to develop a single Bayesian estimator for the two tacrolimus formulations.. A two-compartment model with Erlang absorption (n= 3) and first-order elimination best described the data. In Advagraf patients, a bimodal distribution was observed for the absorption rate constant (K(tr) ): one group with a K(tr) similar to that of Prograf treated patients and the other group with a slower absorption. A mixture model for K(tr) was tested to describe this bimodal distribution. However, the data were best described by the nonmixture model including covariates (cytochrome P450 3A5, haematocrit and drug formulation). Using this model and tacrolimus concentrations measured at 0, 1 and 3h post-dose, the Bayesian estimator could estimate tacrolimus AUC accurately (bias = 0.1%) and with good precision (8.6%).. The single Bayesian estimator developed yields good predictive performance for estimation of individual tacrolimus inter-dose AUC in Prograf and Advagraf treated patients and is suitable for clinical practice.

Topics: Adolescent; Adult; Aged; Area Under Curve; Bayes Theorem; Cytochrome P-450 Enzyme System; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genotype; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Biological; Polymorphism, Single Nucleotide; Renal Insufficiency; Tacrolimus; Young Adult

Stiffness and cytokine in blood levels show 24-h rhythms in rheumatoid arthritis (RA) patients. We previously revealed that higher therapeutic effects were obtained in RA patients and RA model animals when the dosing time of methotrexate was chosen according to the 24-h rhythms to cytokine. In this study, we examined whether a dosing time-dependency of the therapeutic effect of tacrolimus (TAC) could be detected in collagen-induced arthritis (CIA) and MRL/lpr mice. To measure the levels of cytokines and serum amyloid A (SAA), blood was collected from CIA mice at different times. TAC was administered at two different dosing times based on these findings and its effects on arthritis and toxicity were examined. Plasma tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and SAA concentrations showed obvious 24-h rhythms with higher levels during the light phase and lower levels during the dark phase after RA crisis. The arthritis score and leukocyte counts were significantly lower in the group treated at 2 h after the light was turned on (HALO) than in the control and 14 HALO-treated groups. Our findings suggest that choosing an optimal dosing time could lead to the effective treatment of RA by TAC.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Collagen Type II; Drug Chronotherapy; Immunosuppressive Agents; Interleukin-6; Leukocyte Count; Leukocytosis; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Inbred MRL lpr; Renal Insufficiency; Serum Amyloid A Protein; Severity of Illness Index; Tacrolimus; Tumor Necrosis Factor-alpha

In Brazil, the National Health System (SUS) is responsible for almost all renal transplants. SUS protocols recommend using cyclosporine, in association with azathioprine and corticosteroids, to maintain the immunosuppression that is essential for successful renal transplant. Alternatively, cyclosporine can be replaced by tacrolimus.. To evaluate the effectiveness of therapeutic schema involving cyclosporine or tacrolimus after renal transplant during a 60-month follow-up period.. A historical cohort study, from 2000 to 2004, was conducted using 5686 patients who underwent renal transplant and received cyclosporine or tacrolimus. Uni - and multivariate analyses were performed using the Cox model to examine factors associated with progression to treatment failure.. Most of the patients were male, aged 38 years or older, for whom the most frequent primary diagnosis of chronic renal failure (CRF) was glomerulonephritis/nephritis. Higher risk of treatment failure was associated with: therapeutic regimen (tacrolimus, HR 1.38, 95% CI 1.14 to 1.67), patient age at transplantation (additional year, HR 1.01, 95% CI 1.00 to 1.02), donor type (deceased, HR 1.60, 95% CI 1.35 to 1.89), median time of dialysis prior to transplantation (>24 mo, HR 1.29, 95% CI 1.09 to 1.52), and primary CRF diagnosis (diabetes, HR 1.54, 95% CI 1.09 to 2.17).. The risk of treatment failure of patients receiving tacrolimus was observed to be 1.38 times that of those receiving cyclosporine, after adjusting the model for possible confounding factors such as patient sex, patient age, graft origin, prior time of dialysis, and cause of CRF. Our results were obtained from an observational study, and further studies are necessary to evaluate whether compliance with SUS clinical protocols could result in more effective care for renal transplant recipients.

Topics: Adolescent; Adult; Aged; Brazil; Child; Child, Preschool; Cohort Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Tacrolimus; Young Adult

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.

Topics: Biomarkers, Pharmacological; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus, Type 2; Drug Discovery; Genotype; Humans; Hypertension; Immunosuppressive Agents; Polymorphism, Genetic; Precision Medicine; Renal Insufficiency; Risk Factors; Tacrolimus

Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log¹⁰ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.

Topics: Adult; Aged; Cidofovir; Cytosine; Female; Humans; Isoxazoles; Kidney Diseases; Leflunomide; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Organophosphonates; Polyomavirus Infections; Prednisone; Renal Insufficiency; Tacrolimus; TOR Serine-Threonine Kinases

Topics: Calcineurin Inhibitors; Cyclosporine; Everolimus; Humans; Liver Transplantation; Renal Insufficiency; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; France; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Linear Models; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Retrospective Studies; Risk Assessment; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Tacrolimus (TAC) pharmacokinetics are characterized by a very high variability that complicates its therapeutic use. The aims of this study were: 1) to identify and model the effect of demographic, clinical, and genetic factors and time of drug administration on TAC pharmacokinetic variability; and 2) to assess the influence of the analytical method by modeling the TAC blood concentrations measured simultaneously by microparticle enzyme immune assay (MEIA) and liquid chromatography-tandem mass spectroscopy. Data from 19 renal transplant candidates were analyzed. A total of 266 blood samples were analyzed for TAC by both techniques. Linear regression and Bland and Altman analyses were performed to compare TAC blood concentrations obtained with MEIA and liquid chromatography-tandem mass spectroscopy. A population pharmacokinetic analysis was performed. As expected, blood concentrations obtained by MEIA were higher than those obtained by liquid chromatography-tandem mass spectroscopy. A two-compartment model with first-order absorption and elimination best fit TAC blood concentrations. An exponential model was used to describe the interindividual and interoccasion variability and a mixed model was retained for the residual variability. A supplementary proportional term was necessary for the residual error in case of TAC blood concentrations determined by MEIA. The following covariates were retained in the final model: time of drug administration on the absorption rate constant and CYP3A5 and ABCB1 genotypes on the TAC apparent clearance. All parameter estimates had reliable values. The final model was found to be stable and generated parameters with good precision. The validation of the final model by bootstrapping (2000 bootstraps), case deletion diagnostics, crossvalidation, and visual predictive check (1000 simulated subjects) gave satisfactory results. This is the first population pharmacokinetic study confirming the chronopharmacokinetics of TAC and showing an effect of ABCB1 genotype and analytical method on TAC pharmacokinetics. These results may be helpful for TAC dose individualization.

Topics: Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bayes Theorem; Chemistry Techniques, Analytical; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Demography; Drug Administration Schedule; Drug Monitoring; Female; Genotype; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Male; Microspheres; Middle Aged; Models, Biological; Renal Insufficiency; Tacrolimus; Tandem Mass Spectrometry

Sirolimus is a potent immunosuppressive drug that has been shown to decrease the incidence of rejection post renal transplantation. Dyslipidemia is a well recognized side effect of sirolimus therapy, which may have an impact on patient survival and post-transplant cardiac morbidity and mortality. It is unknown whether sirolimus-induced dyslipidemia is aggravated by concomitant use of tacrolimus which may also affect lipid profile. To compare sirolimus induced dyslipidemia in tacrolimus based vs. tacrolimus free regimens in renal transplant recipients.. Patients who received sirolimus post kidney transplantation for at least nine sequential months were included in our retrospective study. Forty-eight renal transplant recipients were divided into 2 groups based on the immunosuppressive regimen; Group 1 received prednisone, sirolimus and mycophenolate mofetil, while Group 2 received prednisone, sirolimus, mycophanolate mofetil and tacrolimus. Lipid profile was assessed pre-transplantation and at one, three, six and nine months post sirolimus therapy.. Both groups showed significant but comparable elevation in total cholesterol, LDL-C and triglycerides with sirolimus therapy. The elevation was evident starting from the first month of sirolimus administration and remained to the ninth month at the end of the follow up period. At first month, mean triglycerides was 2.68 and 2.6 mmol/L (P>0.1) and mean total cholesterol was 6.3 and 5.7 mmol/L in group 1 and 2 (P>0.1); respectively. By the ninth month, triglycerides level was 2.6 and 3.9 mmol/L (P>0.1) while mean total cholesterol level was 6.2 and 6.1 mmol/L (P>0.1) in group 1 and 2 respectively. Lipid-lowering agents and total steroids dose were similar in both groups.. Hypercholesterolemia and hypertriglyceridemia secondary to sirolimus therapy is independent from concomitant tacrolimus use. Lipid-profile should be monitored in all renal transplant recipients receiving sirolimus as early as first month regardless of the immunosuppressive regimen used.

Topics: Adult; Cohort Studies; Drug Therapy, Combination; Dyslipidemias; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus

Survival for heart transplantation (HTx) patients is limited by nephrotoxicity of the calcineurin inhibitors cyclosporine and tacrolimus. To determine whether genetic factors are involved in the development of renal dysfunction under immunosuppressive therapy, we screened various genes for sequence variations.. In a case-control study we analyzed in parallel polymorphisms within the transforming growth factor-beta1 gene (TGF-beta1; L10P, R25P), the multidrug resistance gene MDR 1 (A893T/S) and the CYP3A5 gene (CYP3A5*1/*3 allele). In total, we included 53 cardiac allograft recipients with renal insufficiency (serum creatinine >or=1.8 mg/dl and glomerular filtration rate <50 ml/min/1.73 m(2)) and 53 patients with normal renal function as controls. The controls were matched with patients for age, gender and post-HTx time. The polymorphisms were assessed by denaturing high-performance liquid chromatography (dHPLC) and direct sequencing. We performed univariate and multivariate logistic regression analysis to assess the association between different gene variants and renal dysfunction.. No significant (p > 0.05) relationship was found between the polymorphisms investigated and the susceptibility of renal insufficiency under immunosuppressive therapy.. Our data do not justify genotyping of the investigated single nucleotide polymorphisms (SNPs) to assess the development of renal dysfunction post-HTx.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Cyclosporine; Cytochrome P-450 CYP3A; Female; Genotype; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Renal Insufficiency; Tacrolimus; Transforming Growth Factor beta1

While providing potent immunosuppression for liver transplant recipients, calcineurin inhibitors (CNI) exhibit nephrotoxicity as a major side effect. The purpose of this study was to evaluate the safety and efficacy of conversion from CNI to sirolimus (SRL) among liver transplant recipients with CNI-induced chronic nephrotoxicity.. Between January 2004 and June 2005, we performed conversion in 16 recipients after a median period of 8.5 months after liver transplantation. The indication for conversion was CNI-related nephrotoxicity with a serum creatinine (sCr) value >132.6 umol/L. Renal function was measured before and after conversion to SRL. Clinical and laboratory data related to the clinical course of the patients were recorded to investigate the safety and efficacy of conversion.. Sixteen patients were converted to SRL after developing nephrotoxicity. Their renal function improved gradually after conversion. The levels of sCr decreased significantly within the first 30 days (164.1 +/- 12.48 micromol/L to 130.1 +/- 5.573 micromol/L), and over the next 60 days after conversion (97.86 +/- 11.69 micromol/L to 90.7 +/- 8.95 micromol/L) (P < .01). Similarly, the mean glomerular filtration rate (GFR) increased significantly during the same period. Four recipients experienced hypercholesterolemia, 1 with ankle edema, and 1 with acute rejection. The median follow-up was 2.4 years. No patient discontinued SRL due to side effects. No patient needed dialysis or kidney transplantation during the study period.. SRL is a safe, effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant recipients with CNI-induced chronic nephrotoxicity.

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Safety; Sirolimus; Tacrolimus

Calcineurin inhibitors (CNI) cyclosporine (Csa) and tacrolimus (Tac) are now first intention immunosuppressive drugs in renal transplantation. However, although these treatments are effective for preventing allograft rejection, they are nephrotoxic: they can cause chronic renal dysfunction and degradation of renal graft function [Nankivell BJ, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003 Dec 11;349(24):2326-33]. In view of these undesirable effects, several strategies have been developed to minimize or even avoid their use. These strategies are reviewed and discussed in this paper.

Topics: Antibodies, Monoclonal; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Recombinant Fusion Proteins; Renal Insufficiency; Tacrolimus

Uremia has been implicated in increased oxidative stress (OS) and decreased monocyte HLA-DR expression in chronic kidney disease (CKD) patients. Thus, one would expect normalization of these parameters after successful kidney transplant (KTx). Our aim was to describe patterns of OS and HLA-DR expression after KTx and to explore the effect of renal function and different immunosuppression regimens. 30 KTx patients (20 male; 48 +/- 11 years) were enrolled and compared with 20 healthy controls. We measured advanced oxidation protein products (AOPP) and the percentage of monocytes expressing HLA-DR (%DR+) before (preKTx) and after KTx (on days 2, 30, 90, 180 and after 1 year). Compared to controls, patients had a higher preKTx AOPP (152.6 vs. 69.3 micromol/l; p < 0.001). AOPP decreased at 48 h after KTx, achieving values similar to controls. Thereafter, it increased again and remained significantly higher compared to controls, returning to preKTx levels at 90 days. Prior to KTx there was a trend for lower %DR+ in KTx patients compared to controls (96 vs. 98%; NS). Following KTx, patients had a lower %DR+ in the 1st month; then it gradually returned to preKTx levels during the 1st year; at no time did it reach a value similar to controls. Cyclosporine (CyA)-treated patients had a significantly higher AOPP (161.5 vs. 99.5 micromol/l; p = 0.03) and a lower %DR+ (91.7 vs. 96.4; p < 0.05) at 30 days than patients on tacrolimus (FK). Patients on mycophenolate mofetil (MMF) showed a low AOPP (106.9 vs. 168.1 micromol/l; p = 0.05) and a high %DR+ (96.7 vs. 88.2%; p = 0.001) than those on everolimus. After 3 months, CyA-treated patients had a non-significant increase in AOPP levels, whereas those on FK showed a decrease (p < 0.05) as did those treated with MMF (p < 0.05). Successful KTx reduced but did not normalize AOPP, suggesting ongoing OS, perhaps due to persistent mild renal dysfunction and the effects of immunosuppression. HLA-DR expression remained low after KTx, which may be a possible contributing factor to infectious complications after transplantation. Immunosuppressive agents appear to have diverse effects on OS and HLA-DR expression.

Topics: Adult; Cyclosporine; Female; HLA-DR Antigens; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Function Tests; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Monocytes; Mycophenolic Acid; Oxidative Stress; Prospective Studies; Renal Insufficiency; Tacrolimus

Renal dysfunction is one of the most significant complications after liver transplant. It is attributed mainly to nephrotoxicity caused by calcineurin inhibitors. We evaluated the renal functioning in liver transplant recipients alive for at least 6 months after liver transplant.. One hundred seventy patients (108 male [63.5%], 62 female [36.5%]; mean age, 31.4 +/- 13.3 years; age range, 13-61 years) were included in this study. Patients who had undergone a liver transplant between 1994 and 2006 at the Organ Transplantation Center of the Shiraz University of Medical Sciences in Shiraz, Iran, and had been alive for at least 6 months after surgery were included. Data were collected regarding age, sex, body mass index, underlying liver disease, graft type, immunosuppressive medications, serum creatinine levels, and glomerular filtration rate before, 1, and 6 months after liver transplant. Renal dysfunction was defined as a serum creatinine level above 132.6 micromol/L or a glomerular filtration rate less than 60 mL/min/1.73 m2, based on our reference range. Glomerular filtration rate was calculated using the Schwartz formula (glomerular filtration rate mL/min/1.73 m2 = K x Ht (cm) / Cr mg/dL). Data were analyzed with SPSS software.. The mean follow-up was 25.9 +/- 23.5 months (range, 6-156 months). The main indications for liver transplant were cryptogenic cirrhosis (n=42), hepatitis B infection (n=34), autoimmune cirrhosis (n=30), Wilson's disease (n=21), and primary sclerosing cholangitis (n=18). The mean pretransplant glomerular filtration rate was 93.7 +/- 35.6 mL/min/1.73 m2. The mean glomerular filtration rates in the first and sixth months after liver transplant were 81.6 +/- 29.3 mL/min/1.73 m2 and 83.6 +/- 32.9 mL/min/1.73 m2. Sex, body mass index, type of immunosuppressive medication, and underlying liver disease were not predictors of renal dysfunction (P > .05). Posttransplant renal dysfunction was significantly more common in older patients (ie, those aged 38.8 years and older) (P = .0001) and those with a family history of renal disease (P < .05).. Renal dysfunction may be a significant problem for patients after liver transplant, and early detection of renal dysfunction in patients after liver transplant is important. Of all the risk factors studied here, only older age and family history of renal disease were correlated with development of renal dysfunction after liver transplant.

Topics: Adolescent; Adult; Body Mass Index; Creatinine; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Renal Insufficiency; Risk Factors; Tacrolimus

The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype.. Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5*3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program.. CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A5*1 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17-1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A5*3/*3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan-Meier method, was significantly associated with the recipient's but not donor's CYP3A5 genotype (*1/*1 and *1/*3 vs. *3/*3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81).. These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.

Topics: Administration, Oral; Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Drug Resistance; Enterocytes; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Living Donors; Male; Metabolic Clearance Rate; Middle Aged; Pharmacogenetics; Renal Insufficiency; Tacrolimus

Tacrolimus dosage in pediatric RTRs is empirically based on weight. There is evidence that adolescents are at greater risk of toxicity than young children on this dosing regimen. We investigated the rate of tacrolimus overexposure within the first three wk post-transplantation in pediatric RTRs receiving tacrolimus 0.15 mg/kg twice daily. Of 63 RTRs studied, 41 (65.1%) experienced a tacrolimus level above the therapeutic range (supratherapeutic), the majority (48.8%) on days two to four post-transplant. Patients with supratherapeutic levels were older (14.2 vs. 9.9 yr, p = 0.016), taller (146.7 vs. 126.5 cm, p = 0.029), larger (1.36 vs. 1.01 m(2), p = 0.039) and heavier (44.1 vs. 29.3 kg, p = 0.043) and by day 12 were receiving much lower tacrolimus doses than those without supratherapeutic levels (0.425 vs. 0.198 mg/kg/day, p = 0.0002). Supratherapeutic levels were more common among white (British) children than other ethnic groups (74 vs. 45%, p = 0.02). There were no observed differences in rates of patient or graft survival, or acute rejection during the three-yr study period. Adolescent patients appear to be at greater risk of excessive tacrolimus dosing on a standard regimen. We therefore outline a regimen restricting tacrolimus dosage given to larger/older patients, but emphasize the need for a prospective randomized trial to define optimal dosing.

Topics: Administration, Oral; Adolescent; Area Under Curve; Body Size; Child; Child, Preschool; Female; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Renal Insufficiency; Tacrolimus

Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. This study aimed to determine whether sirolimus is effective and safe in treating renal insufficiency related to tacrolimus after liver transplantation.. Tacrolimus for primary immunosuppression was used in 16 patients after liver transplantation. Patients with a creatinine level higher than 132.6 micromol/L were eligible for conversion to sirolimus. Simultaneously, the dose of tacrolimus was decreased to half. Blood urea nitrogen, creatinine, tacrolimus level, liver function and rejection episodes were monitored dynamically.. All patients showed improvement of renal function after conversion to sirolimus. Blood creatinine level was reduced from 146.8+/-92.4 to 105.3+/-71.3 micromol/L (P<0.05). One patient had an acute rejection episode that was successfully treated with pulsed corticosteroids and low-dose tacrolimus. The side-effects of sirolimus included hyperlipidemia (4 patients) and leukocytopenia (2).. Sirolimus can be safely used in liver transplant recipients suffering from tacrolimus-related renal insufficiency.

Topics: Adult; Calcineurin; Creatinine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Tacrolimus

The diagnosis of acute rejection (AR) relies on biopsy (Bx), with all the noninvasive tests failing to show satisfactory predictive value. Nitric oxide (NO) has been shown to play a role in AR. The aim of this study is to analyze the relationship between NO and (1) biopsy-proven allograft rejection and (2) other reasons of allograft dysfunction.. Fifty consecutive renal allograft recipients ages 23-72 yrs who were transplanted were prospectively recruited. Blood samples were collected for 3 months. Endogenous serum nitrate (SNO(3)) levels were measured with Griess reagent in 1178 samples. Biopsies were performed as clinically indicated. Tacrolimus levels, urinary cultures, and renal function tests were done as per unit protocol.. Fifty recipients (mean+/-SD age 45.2+/-2.18 yrs, 24 men and 6 women) underwent 68 biopsies. Forty-five Bx (66.2%) showed AR in 19 recipients (mean age 47+/-8) and 23 (33.8%) Bx in 13 recipients (mean age 43+/-12) showed no AR. SNO(3) in AR was (73+/-8.89 micromol/L) compared with negative Bx (45+/-4.5 micromol/L; P<0.05). There was also a significant difference in SNO(3) during AR and other causes of allograft dysfunction; delayed graft function (54+/-7.8 micromol/L), urinary tract infection (44+/-2.9 micromol/L), tacrolimus toxicity (51+/-2.86 micromol/L), and increase in serum creatinine (44+/-2.36 micromol/L).. There is a significant increase of serum nitrate with episodes of acute rejection compared with other causes of renal dysfunction. SNO(3) can therefore aid in the diagnosis of acute rejection.

Topics: Acute Disease; Adult; Biomarkers; Biopsy; Creatine; Female; Graft Rejection; Graft Survival; Health; Humans; Kidney Transplantation; Male; Middle Aged; Nitrates; Nitric Oxide; Pituitary Hormones; Renal Insufficiency; Tacrolimus

This case report describes the successful treatment of severe plaque psoriasis with etanercept in a patient who underwent a liver transplant. It also addresses the concerns that arise in the treatment of chronic inflammatory dermatologic disease accompanied by multiple organ disorders.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 1; Etanercept; Graft Rejection; Humans; Immunocompromised Host; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Psoriasis; Receptors, Tumor Necrosis Factor; Renal Insufficiency; Sirolimus; Tacrolimus

Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.. We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy.. In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added.. Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Topics: Aniline Compounds; BK Virus; Blood; Cells, Cultured; Creatinine; Crotonates; Female; Humans; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Kidney; Kidney Transplantation; Leflunomide; Male; Middle Aged; Nitriles; Polyomavirus Infections; Renal Insufficiency; Tacrolimus; Toluidines; Urine; Virus Replication

To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients.. Thirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT.. The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable.. The conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.

Topics: Adaptor Proteins, Signal Transducing; Adult; Calcineurin; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phosphoproteins; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation; Transplantation, Homologous

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

While most BK virus infections are asymptomatic, immunosuppression has been associated with BK virus reactivation and impaired graft function or ureteric ulceration in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. Oncogenicity is also postulated and this is the first report of a child with a carcinoma of the donor renal pelvis following BK virus allograft nephropathy. Removal of the primary tumor and cessation of immunosuppression led to regression of secondary tumors and a return to health.

Topics: Adenocarcinoma; BK Virus; Child; Genetic Diseases, X-Linked; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Neoplasms; Kidney Transplantation; Male; Polyomavirus Infections; Renal Insufficiency; Tacrolimus; Tumor Virus Infections

Topics: Alendronate; Bone Density; Bone Resorption; Calcitriol; Creatinine; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Prednisone; Renal Insufficiency; Tacrolimus

Although renal insufficiency following liver transplantation is not infrequent, only limited reports describe the incidence and progression of the kidney disease.. This single-centre retrospective analysis after successful liver transplantation between January 1985 and March 2002 defined the baseline serum creatinine at 50 days after liver transplantation to represent the renal function. The primary end-point was an increase of serum creatinine by more than 50% above the baseline.. Long-term data were available for 162 patients (84 women, 78 men) who received 167 liver transplants. The median serum creatinine level at 50 days after liver transplantation was 1.0 mg/dL (range 0.5-3.5 mg/dL). The median serum creatinine increased to 1.2 mg/dL (0.4-9.8 mg/dL) at the end of follow-up. Six patients (4%) experienced end-stage renal failure. Forty-one patients (25%) showed a 50% increase in the serum creatinine. Kaplan-Meier analysis revealed that 43% and 48% of patients had a deterioration of renal function at 10 and 15 years after liver transplantation, respectively. Patients at risk showed an increase of serum creatinine by 0.25 mg/dL/y. Only the recipient age was an independent risk factor for deterioration of renal function.. Although there is a high risk for the impairment of renal function after liver transplantation, progression of renal disease is slow and rarely results in end-stage renal failure within 10-15 years. However, patients at risk should be identified early to prevent further decline in renal function.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Child; Creatinine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Risk Factors; Tacrolimus

Topics: Adult; Cohort Studies; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Predictive Value of Tests; Regression Analysis; Renal Insufficiency; Tacrolimus

Chronic nephrotoxicity is one of the most serious side-effects of calcineurin inhibitor treatment and a factor in mortality and morbidity after liver transplantation. In our transplant centre, among patients who underwent a liver transplantation between January 1989 and December 2000, 14 liver graft recipients (6.86%) developed de novo severe renal dysfunction as defined by a serum creatinine concentration above 200 micromol/L. Renal biopsy was performed in nine cases and evidenced histological lesions compatible with chronic nephrotoxicity related to calcineurin inhibitor treatment. For nine patients, we report the results of a prospective non-randomized study consisting of cyclosporine or tacrolimus withdrawal associated with administration of mycophenolate mofetil or azathioprine. Despite this therapeutic modification, we did not observe a significant renal function improvement but on the other hand, there was no graft rejection.

Topics: Adolescent; Adult; Aged; Azathioprine; Calcineurin Inhibitors; Child; Creatinine; Female; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

Several studies have shown that calcineurin may play a critical role in the signalling of cardiac hypertrophy in various experimental models.. To elucidate whether calcineurin is involved in cardiac hypertrophy due to energy metabolic disorder by using the juvenile visceral steatosis (JVS) mouse, which is a murine model of systemic carnitine deficiency.. Cardiac hypertrophy in JVS mice (C3H strain) progresses gradually after birth and is present until eight weeks of age. In this study, calcineurin activity in JVS mice increased significantly at four weeks of age (the developing stage of cardiac hypertrophy) compared with age-matched control mice. Treatment with calcineurin inhibitor FK506 (0.5 or 1.0 mg/kg/day) from the age of four to eight weeks attenuated cardiac hypertrophy without beneficially affecting cardiac function. Gene expression, accompanied by cardiac hypertrophy, was also suppressed by the FK506 treatment.. The activation of calcineurin is involved in the development of cardiac hypertrophy in the JVS mouse, and calcineurin inhibition may be useful for reducing cardiac hypertrophy.

Topics: Animals; Blood Pressure; Cachexia; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Hypertension; Infections; Metabolism, Inborn Errors; Mice; Mice, Inbred C3H; Myocardium; Reference Values; Renal Insufficiency; Tacrolimus

Daclizumab is a monoclonal antibody directed against the alpha chain of the interleukin 2 receptor. We review our experience with the use of daclizumab in liver transplant recipients.. Thirty-two patients were given daclizumab as induction therapy in the setting of hepatic transplantation. Seven of these patients were enrolled in a pilot study to determine the efficacy of daclizumab in conjunction with corticosteroids and mycophenolate mofetil without the initial use of calcineurin inhibitors (CI). The remaining 25 patients received daclizumab, mycophenolate mofetil, and steroids, with the institution of CI generally within the first postoperative week. The majority of these patients (n = 17) had some degree of renal insufficiency.. The pilot study was halted after the first seven patients were enrolled because of an unacceptably high rate of rejection (7/7 = 100%). The patients outside of this pilot study, however, had a much lower rate of rejection (36%). The incidence and severity of rejection correlated with the delay in institution of CI. The described dosing schedule resulted in subtherapeutic daclizumab levels in liver transplant recipients.. Daclizumab used in liver transplant recipients without any CI was ineffective and can potentially lead to steroid-resistant rejection. The dosing regimen used in renal transplant recipients is most likely insufficient for liver transplant patients. However, daclizumab can be used safely in patients with preexisting or postoperative renal dysfunction in conjunction with low doses of CI given within the first week postoperatively.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Child; Daclizumab; Dose-Response Relationship, Drug; Female; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Renal Insufficiency; Tacrolimus

The aim of this study is to evaluate the hemodynamics and pregnancy outcome of women with prior orthotopic liver transplantation. Hemodynamic measurements by Doppler technique were performed on pregnant subjects with prior orthotopic liver transplantation. Maternal characteristics, renal function, pregnancy complications, delivery indications, delivery mode, and neonatal outcomes were evaluated. Six pregnancies occurred in 5 women after orthotopic liver transplantation at the University of Washington Medical Center (Seattle, WA) between 1991 and 1999. Four of the 6 pregnancies were complicated by chronic hypertension, fetal growth restriction, and preterm delivery. Two pregnancies had worsening hypertension characterized by vasoconstriction in the second trimester despite antihypertensive therapy. These 2 subjects were administered cyclosporine for maintenance immunosuppression and had greater mean arterial pressures preconception and in the first trimester than the other subjects. One of these pregnancies resulted in fetal demise at 25 weeks' gestation. The other subject was delivered at 28 weeks' gestation for nonreassuring fetal status and superimposed preeclampsia. All pregnancies were complicated by renal insufficiency; however, the 2 subjects with poor obstetric outcome had preconception serum creatinine levels greater than 1.5 mg/dL and creatinine clearances less than 40 mL/min. Pregnancies complicated by second-trimester vasoconstriction and moderate renal insufficiency are at risk for preeclamspia, fetal growth restriction, and fetal demise. Good obstetric outcome can occur in women with mild renal insufficiency and well-controlled chronic hypertension. Improved hypertensive control preconception may decrease the risk for preeclampsia and poor obstetric outcome.

Topics: Adolescent; Adult; Cesarean Section; Creatinine; Female; Hemodynamics; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Renal Insufficiency; Tacrolimus

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.

Topics: Cyclosporine; Disease Progression; Drug Therapy, Combination; Hepatitis C; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Prognosis; Recurrence; Renal Insufficiency; Risk Factors; Sepsis; Tacrolimus; Treatment Outcome

Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.

Topics: Antigens, CD; Bone Marrow Transplantation; Child; Child, Preschool; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant, Newborn; Kidney Transplantation; Lymphopenia; Male; Osteochondrodysplasias; Pedigree; Renal Insufficiency; Tacrolimus

The effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in rats. Experimental renal dysfunction was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)) into rats. The blood concentration of tacrolimus was measured after intravenous and intra-intestinal administration of the drug. The blood concentration of tacrolimus after intravenous administration (1 mg kg(-1)) was slightly increased (up to 1.3 fold) by induction of renal dysfunction. In contrast, the peak tacrolimus concentration after intra-intestinal administration (1 mg kg(-1) or 3 mg kg(-1)) in rats with renal failure was about 2-fold higher than that in normal controls. The bioavailability was increased by about 35% in rats with impaired renal function as compared with normal controls. These results suggested that the bioavailability of tacrolimus, which is mainly metabolized in the liver and intestine after oral administration, is also influenced by renal function.

Topics: Alanine Transaminase; Animals; Area Under Curve; Aspartate Aminotransferases; Biological Availability; Blood Urea Nitrogen; Cisplatin; Creatinine; Immunosuppressive Agents; Infusions, Intravenous; Intestinal Absorption; Male; Metabolic Clearance Rate; Rats; Rats, Wistar; Renal Insufficiency; Tacrolimus

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Renal Insufficiency; Tacrolimus; Vasomotor System

The management of liver transplant recipients with renal function impairment remains controversial because cyclosporine withdrawal from triple immunosuppression regimens may be followed by graft rejection. A nonnephrotoxic and powerful immunosuppressant such as mycophenolate mofetil (MMF) could allow a reduction of cyclosporine dosage or its withdrawal and an improvement in renal function in these patients. Eleven patients with serum creatinine levels greater than 1.5 mg/dL, normal graft function, and a rejection-free period of at least 1 year started MMF at a dose of 2000 mg/d (reduced in case of adverse events) while cyclosporine dosage was slowly reduced. At last follow-up (63 +/- 5 weeks), 7 patients remained free of cyclosporine (6 of those patients are also free of steroids), 2 patients reduced their cyclosporine dose, and 2 patients developed mild acute rejection that responded to a switch to tacrolimus therapy. Serum creatinine and urea levels in the 7 patients free of cyclosporine decreased from 2.22 +/- 0.13 to 1.90 +/- 0.19 mg/dL (P =.05) and 0.95 +/- 0.10 to 0.60 +/- 0.10 g/L (P <.001), respectively. Creatinine clearance increased from 38.16 +/- 5.60 to 47.01 +/- 6. 76 mL/min (P =.005). Control of arterial hypertension also improved. Tolerance to MMF was good, but 6 patients required dose reductions, mainly because of asymptomatic anemia. In conclusion, in liver transplant recipients with stable graft function, MMF may allow cyclosporine dose reduction or discontinuation, thus improving renal function and the control of arterial hypertension. This change of treatment must be carefully monitored because of the frequent need for MMF dose reduction and the risk for rejection.

Topics: Aged; Azathioprine; Biopsy; Blood Pressure; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Lipids; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Renal Insufficiency; Retrospective Studies; Tacrolimus; Treatment Outcome; Urea

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Cyclosporine; Data Collection; Drug Therapy, Combination; Europe; Hepatitis B; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Renal Insufficiency; Tacrolimus

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Renal Insufficiency; Tacrolimus

Successful use of cyclosporine in organ transplant can be associated with unwanted side-effects that can affect graft function. We report three kidney transplant recipients in whom severe migraine headache occurred as a side-effect of cyclosporine therapy. This endangered graft survival in all three and eventually led to loss of graft in two.

Topics: Adult; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Migraine Disorders; Renal Insufficiency; Reoperation; Tacrolimus; Vomiting

We conducted a study to evaluate the efficacy of the combination of tacrolimus and short-course methotrexate for the prevention of acute GVHD in patients with hematologic malignancies. Patients received preparative regimens specific for their disease category. Twenty-six out of 28 received HLA-identical sibling transplants and the two remaining patients received one-antigen mismatched transplants from a family member. With a median follow-up of 14 months, the Kaplan-Meier estimate of event-free survival was 50 +/- 9%. The probability of grade II-IV GVHD was 15 +/- 7%. Four patients developed GVHD: two had grade II and one each developed grade III and IV GVHD. Administration of methotrexate was associated with severe mucositis and there was no correlation between the distribution of the GVHD grade and the cumulative dose of methotrexate given. Thirteen patients have died; nine from transplant-related complications and four from relapse. The major toxicity of tacrolimus was renal. Nine out of 28 patients (32%) developed renal dysfunction attributed to tacrolimus. The combination of tacrolimus and methotrexate is an effective regimen for GVHD prophylaxis but associated with significant renal and mucosal toxicity. Further studies of tacrolimus as a single agent or in combination with either steroids or with a lower dose of methotrexate or with other antiproliferative drugs to modify the adverse events may improve the therapeutic index of this useful and promising agent.

Topics: Acute Disease; Adult; Bone Marrow Transplantation; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Prognosis; Recurrence; Renal Insufficiency; Tacrolimus; Transplantation, Homologous