tacrolimus and Renal-Insufficiency--Chronic

Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the

Topics: Azathioprine; Cyclosporine; Humans; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Genetic; Prednisolone; Renal Insufficiency, Chronic; Tacrolimus; Treatment Outcome

Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) μ-opioid receptor antagonists and κ-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as μ-opioid-receptor-antagonists (i.e., naltrexone) or κ-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP.

Topics: Acupuncture Therapy; Amines; Anti-Inflammatory Agents; Calcium Channel Blockers; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; gamma-Linolenic Acid; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Pentoxifylline; Phototherapy; Pregabalin; Pruritus; Receptors, Opioid, kappa; Renal Insufficiency, Chronic; Spiro Compounds; Tacrolimus; Thalidomide; Uremia

There is no doubt that acute calcineurin inhibitor (CNI) nephrotoxicity exists; however, chronic CNI nephrotoxicity is questionable at best.. We reviewed the literature to identify original articles related to the use of CNIs in renal and nonrenal solid organ transplantation in order to examine the available evidence about their chronic nephrotoxicity and contribution to graft failure.. Early clinical experience and animal studies support the evidence of CNI nephrotoxicity. These findings evolved into the dogma that CNI nephrotoxicity is the major cause of late renal allograft failure. However, in transplanted kidneys the specific role of chronic CNI nephrotoxicity has been questioned. The emerging literature clearly highlights the lack of solid evidence for the role of CNIs as the sole and major injurious agents that cause chronic renal dysfunction and subsequent graft failure. Most of the evidence available to date is against complete CNI avoidance, and minimization appears to be a more viable strategy. It is becoming increasingly clear that the typical pathological lesions linked to chronic CNI use are highly nonspecific, and most of the chronic changes that have been attributed to chronic CNI nephrotoxicity are the consequences of previously unrecognized immunologic injuries. One needs to keep in mind that the potential risk of side effects of CNI use should be balanced against the risk of rejection.. More research should focus on addressing the true causes of chronic graft dysfunction rather than focusing on the overexaggerated contribution of CNIs to late graft loss.

Topics: Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Renal Insufficiency, Chronic; Tacrolimus; Transplantation; Transplantation Immunology

The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.

Topics: Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Liver Transplantation; Renal Insufficiency, Chronic; Sirolimus; Tacrolimus

Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research.. The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Topics: Child; Drug Therapy, Combination; Everolimus; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency, Chronic; Tacrolimus

Prevention of rejection after renal transplantation requires treatment with immunosuppressive drugs. Data on their in vivo effects on T- and B-cell phenotype and function are limited.. In a randomized double-blind placebo-controlled study to prevent renal allograft rejection, patients were treated with tacrolimus, mycophenolate mofetil (MMF), steroids, and a single dose of rituximab or placebo during transplant surgery. In a subset of patients, we analyzed the number and phenotype of peripheral T and B cells by multiparameter flow cytometry before transplantation, and at 3, 6, 12, and 24 months after transplantation.. In patients treated with tacrolimus/MMF/steroids the proportion of central memory CD4+ and CD8+ T cells was higher at 3 months post-transplant compared to pre-transplant levels. In addition, the ratio between the percentage of central memory CD4+ and CD4+ regulatory T cells was significantly higher up to 24 months post-transplant compared to pre-transplant levels. Interestingly, treatment with tacrolimus/MMF/steroids resulted in a shift toward a more memory-like B-cell phenotype post-transplant. Addition of a single dose of rituximab resulted in a long-lasting B-cell depletion. At 12 months post-transplant, the small fraction of repopulated B cells consisted of a high percentage of transitional B cells. Rituximab treatment had no effect on the T-cell phenotype and function post-transplant.. Renal transplant recipients treated with tacrolimus/MMF/steroids show an altered memory T and B-cell compartment post-transplant. Additional B-cell depletion by rituximab leads to a relative increase of transitional and memory-like B cells, without affecting T-cell phenotype and function.. ClinicalTrials.gov NCT00565331.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Double-Blind Method; Drug Therapy, Combination; Flow Cytometry; Graft Rejection; Graft Survival; Humans; Immunologic Memory; Immunophenotyping; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Phenotype; Renal Insufficiency, Chronic; Rituximab; Steroids; Tacrolimus

Chronic kidney disease (CKD) is a frequent complication after liver transplantation (LT) and is associated with increased mortality. Strategies to reduce calcineurin inhibitor (CNI) dose or conversion to either mycophenolate mofetil and/or rapamycin resulted in variable results and side-effect profiles.. We evaluated the effectiveness of CNI conversion to long-term anti-CD25 monoclonal antibody (mAb)-based immunosuppression in 15 adult LT patients with CKD at 7.6±4 years posttransplant (intervention group). Three patients had been previously switched to rapamycin, and 12 patients were on CNI. The control group included 15 LT patients on CNI with stable renal function over a similar posttransplant follow-up period.. Anti-CD25 mAb were given over a period of 26±15 months (range, 2-51 months) and were well tolerated. The slope of calculated creatinine clearance was -0.66 mL/min/month over 6 months before conversion and -0.05 mL/min/month after conversion to anti-CD25 mAb (P=0.16 and P=0.86 vs. controls). Three acute rejection episodes occurred in the intervention group. Acute rejection was reversible in two patients. However, one patient died of chronic rejection 1 year after having been switched to tacrolimus. Anti-CD25 mAb were replaced with either CNI or rapamycin in six patients (acute rejection [n=2], progression to end-stage renal disease [n=2], poor venous status [n=1], increased liver enzymes [n=1]).. The use of long-term anti-CD25 mAb therapy as a replacement to CNI and rapamycin-based immunosuppression may be feasible. It is crucial that rejection surveillance is intensified. A randomized controlled trial is required to confirm the benefits of this strategy.

Topics: Aged; Antibodies, Monoclonal; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Interleukin-2 Receptor alpha Subunit; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation; Treatment Outcome

Chronic kidney disease (CKD) is a progressive and irreversible complication in lung transplant patients who have received long-term treatment with tacrolimus. This study aimed to verify long-term tacrolimus exposure values in CKD progression.. We retrospectively analyzed the clinical data of adult lung transplant recipients performed at our center between 2012 and October 2015. Patients who completed the 5-year follow-up period were enrolled in this study. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m. Eighty patients were analyzed. Compared with baseline (109 ± 38.1 mL/min/1.73 m2), the average eGFR values of our patients gradually decreased during the fifth-year post transplantation (46.5%, 58.3 ± 28.3 mL/min/1.73 m2), and the decline in eGFR values was particularly pronounced in the first year (31.2%, 74.6 ± 28.91 mL/min/1.73 m2). Moreover, 10 (12.7%), 21 (26.9%), 24 (31.2%), 28 (41.2%), and 48 (60%) patients had eGFR <60 mL/min/1.73 m. eGFR constantly decreased and the incidence of CKD increased during the 5-year follow-up period after LT. The tacrolimus dose had a significant negative correlation with eGFR at 6 months after LT. Meanwhile, whole-blood tacrolimus trough concentrations were not correlated with eGFR decline. When possible, lower dosing within 1 year after LT can reduce potential nephrotoxic side effects.

Topics: Adult; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Liver Transplantation; Lung Transplantation; Renal Insufficiency, Chronic; Retrospective Studies; Tacrolimus

The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC.. We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months.. Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016).. We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment.

Topics: Acute Kidney Injury; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Male; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

Chronic kidney disease (CKD) is common following liver transplantation (LT). We aimed to investigate the frequency, risk factors, and impact of CKD on cardiovascular disease (CVD), graft, and patient survival. We analyzed 752 patients who received LT at the University of Alberta. Development of CKD was defined as eGFR <60 ml/min for greater than 3 months, intrinsic renal disease or presence of end-stage renal disease requiring renal replacement therapy. 240 patients were female (32%), and mean age at LT was 53 ± 11 years. CKD was diagnosed in 448 (60%) patients. On multivariable analysis, age (OR 1.3; P = 0.01), female sex (OR 3.3; P < 0.001), baseline eGFR (OR 0.83; P < 0.001), MELD (OR 1.03; P = 0.01), de novo metabolic syndrome (OR 2.3; P = 0.001), and acute kidney injury (OR 3.5; P < 0.001) were associated with CKD. A higher tacrolimus concentration to dose ratio was protective for CKD (OR 0.69; P < 0.001). CKD was associated with post-transplant CVD (26% vs. 16% P < 0.001), reduced graft (HR 1.4; P = 0.02), and patient survival (HR 1.3; P = 0.03). CKD is a frequent complication following LT and is associated with an increased risk of CVD and reduced graft and patient survival.

Topics: Adult; Cardiovascular Diseases; Female; Glomerular Filtration Rate; Humans; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Tacrolimus

Renal failure is predictive of mortality in the early postliver-transplantation period and calcineurin inhibitors toxicity is a main challenge. Our aim is to assess the impact of longitudinal tacrolimus exposure (TLE) and other variables on chronic kidney disease (CKD)-free 1-year-survival.. Retrospective data of consecutive patients transplanted between 2011 and 2016 and treated with tacrolimus were collected. TLE and all relevant pre- and post-liver transplantation (LT) predictive factors of CKD were tested and included in a time-to-event model. CKD was defined by repeated estimated glomerular filtration rate (eGFR) values below 60 mL/min/1.73m2 at least for the last 3 months before M12 post-LT.. Data from 180 patients were analyzed. CKD-free survival was 74.5% and was not associated with TLE. Pre-LT acute kidney injury (AKI) and eGFR at 1-month post-LT (eGFRM1) <60 mL/min/1.73m2 were significant predictors of CKD. By distinguishing 2 situations within AKI (ie, with or without hepatorenal syndrome [HRS]), only HRS-AKI remained associated to CKD. HRS-AKI and eGFRM1 <60 mL/min/1.73m2 increased the risk of CKD (hazard ratio, 2.5; 95% confidence interval, 1.2-4.9; hazard ratio, 4.8; 95% confidence interval, 2.6-8.8, respectively).. In our study, TLE, unlike HRS-AKI and eGFRM1, was not predictive of CKD-free survival at 1-year post-LT. Our results once again question the reversibility of HRS-AKI.

Topics: Acute Kidney Injury; Adult; Aged; Disease-Free Survival; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Time Factors

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Myoclonus; Renal Insufficiency, Chronic; Tacrolimus

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

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

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

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

The antioxidant function of Klotho is well-documented as a regulatory factor implicated in countering the aging process. This study investigated whether ginseng upregulates Klotho and its antiaging signaling in a setting of calcineurin inhibitor-induced oxidative stress. Although tacrolimus treatment reduced Klotho level in the serum and kidney, ginseng treatment was found to reverse the levels. Tacrolimus-induced oxidative stress was reduced by ginseng treatment, with functional and histological improvements. Effect of ginseng on Klotho-induced manganese superoxide dismutase signaling pathway during tacrolimus treatment in mice revealed that ginseng suppressed phosphatidylinositol 3-kinase/serine-threonine kinase Akt-mediated phosphorylation of forkhead box protein O3a and promoted the binding of forkhead box protein O3a to manganese superoxide dismutase promoter. In the mitochondria, ginseng reduced mitochondrial reactive oxygen species production, mitochondrial membrane potential, and oxygen consumption rate, whereas blocking phosphatidylinositol 3-kinase activity with LY294002 enhanced them. These findings together suggested that ginseng attenuated tacrolimus-induced oxidative stress via signaling between Klotho and the phosphatidylinositol 3-kinase/serine-threonine kinase Akt/forkhead box protein O3a-related antioxidant pathway.

Topics: Aging; Animals; Antioxidants; Calcineurin Inhibitors; Cell Line; Disease Models, Animal; Forkhead Box Protein O3; Glucuronidase; Humans; Kidney; Klotho Proteins; Male; Mice; Mice, Inbred BALB C; Mitochondria; Panax; Phytotherapy; Renal Insufficiency, Chronic; Signal Transduction; Superoxide Dismutase; Tacrolimus

Chronic nephrotoxicity with potentially irreversible lesions is a major concern regarding calcineurin inhibitor (CNI) treatment in children with severe forms of idiopathic nephrotic syndrome (INS).. We retrospectively included all children on CNI for steroid-dependent INS with a duration of CNI treatment of more than 1 year. Only patients in whom CNI could not be replaced by mycophenolate mofetil were included. All included patients underwent a kidney biopsy. All results were expressed as median and range. Twenty-one children (6 girls) were included. Age at disease onset was 49 (29-66) months and treatment duration on CNI was 30 (20-45) months. Age at kidney biopsy was 108 (78-170) months. Number of relapses was 7 (3-9) since disease onset. Serum creatinine level was transiently and moderately increased in two patients. Kidney biopsy revealed minimal change disease in 20/21 patients and focal segmental glomerulosclerosis in 1/21. Evidence for chronic CNI nephrotoxicity was found in one patient revealed by arteriolar hyalinosis and fibrosis in 50% of glomeruli.. CNI-induced chronic nephrotoxicity was infrequent. In patients who require long-term and/or high-dose CNI treatment, kidney biopsies might be useful to exclude chronic CNI-induced lesions.

Topics: Child, Preschool; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Renal Insufficiency, Chronic; Retrospective Studies; Tacrolimus

Tacrolimus minimization is usually restricted to patients with pretransplant renal impairment, and this strategy could result into worse renal outcomes after liver transplantation (LT).. A consecutive cohort of 455 LT patients receiving tacrolimus-based immunosuppression was studied (2008-2013). Cumulative exposure to tacrolimus was calculated as the area under curve of trough concentrations (AUCtc). Patients were stratified as tacrolimus minimization, conventional, or high exposure, according to the thresholds based in the COMMIT consensus. Estimated glomerular filtration rates (eGFR) were assessed by the Modification of Diet in Renal Disease formula (MDRD-4) up to 5 years after LT.. Seventy patients (15.4%) had pretransplant eGFR < 60 mL/min, which was associated with increased mortality rates, particularly within the first 5 years post-LT (31.4% versus 17.5%; Breslow P = 0.010). After LT, there was an abrupt eGFR decline within the first 3 months (median 18.6 mL/min; P < 0.001), further decreasing up to 12 months (additional 3 mL/min), without any improvement thereafter. According to AUCtc, 33.7% of patients received tacrolimus minimization, 44.8% conventional exposure, and 21.5% high exposure. Conventional/high exposure to tacrolimus resulted in a more pronounced eGFR decline within the first 3 months when compared with minimization (23.3 mL/min versus 9.5 mL/min; P < 0.001). This gap was even higher in patients with initially preserved renal function. Tacrolimus AUCtc was an independent predictor of eGFR decline within the first 3 months after controlling for potential confounders.. AUCtc is a surrogate of cumulative exposure to tacrolimus and may be helpful for routine dose adjustments. Tacrolimus minimization should be universally attempted after LT to preserve renal function.

Topics: Disease Progression; Dose-Response Relationship, Drug; End Stage Liver Disease; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prognosis; Renal Insufficiency, Chronic; Retrospective Studies; Spain; Survival Rate; Tacrolimus; United Kingdom

Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

Topics: Adult; Bayes Theorem; Cohort Studies; Drug Dosage Calculations; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Linear Models; Machine Learning; Male; Middle Aged; Multivariate Analysis; Precision Medicine; Renal Insufficiency, Chronic; Tacrolimus; Transplant Recipients

The aim of this study was to evaluate risk factors affecting graft and patient survival after transplantation from deceased donors.. We retrospectively analyzed the outcomes of 186 transplantations from deceased donors performed at our center between 2006 and 2014. The recipients were divided into two groups: Group I (141 recipients without graft loss) and Group II (45 recipients with graft loss). Kaplan-Meier, log-rank test, and Cox proportional hazard regressions were used.. The characteristics of both groups were similar except renal resistive index at the last follow-ups. When graft survival and mortality at the first, third, and fifth years were analyzed, tacrolimus (Tac)-based regimens were superior to cyclosporine (CsA)-based regimens (P < .001). Risk factors associated with graft survival at the first year included cardiac cause of death (versus cerebrovascular accident [CVA]; hazard ratio [HR], 6.36; 95% confidence interval [CI], 1.84-22.05; P = .004), older transplant age (HR, 1.05; 95% CI, 1.02-1.08; P < .001), and high serum creatinine level at 6 months post-transplantation (HR, 1.74; 95% CI, 1.48-2.03; P < .001), whereas younger donor age decreased risk (HR, 0.97; 95% CI, 0.95-1.00; P = .019). Also, the Tac-based regimen had a 3.63-fold (95% CI, 1.47-8.97; P = .005) lower risk factor than the CsA-based regimen, and 2.93-fold (95% CI, 1.13-7.63; P = .027) than other regimens without calcineurin inhibitors. When graft survival at 3 years was analyzed, diabetes mellitus was lower than idiopathic causes and pyelonephritis (P = .035). In Cox regression analysis at year 3, older transplantation age (HR, 1.20; 95% CI, 1.04-1.39; P = .014) and serum creatinine level at month 6 post-transplantation (HR, 1.65; 95% CI, 1.42-1.90; P < .001) were significant risk factors for graft survival. Hemodialysis (HD) plus peritoneal dialysis (PD) treatment was 2.22-fold (95% CI, 1.08-4.58; P = .03) risk factor than only HD before transplantation. When graft survival and mortality at year 5 were analyzed, diabetes mellitus was lower compared with all other diseases. In Cox regression analysis at year 5, younger donor age (HR, 0.73; 95% CI, 0.62-0.86; P < .001) was protective for graft survival, whereas older transplantation age (HR, 1.40; 95% CI, 1.20-1.64; P < .001) and serum creatinine level at month 6 of post-transplantation (HR, 1.39; 95% CI, 1.19-1.61; P < .001) were significant risk factors. PD increased 3.32 (95% CI, 1.28-8.61; P = .014) times the risk than HD. In Cox regression analysis at year 1, cardiac cause of death (versus CVA; HR, 5.28; 95% CI, 1.37-20.31; P = .016), CsA-based regimen (versus Tac; HR, 4.95; 95% CI, 1.78-13.78; P = .002), HD plus PD treatment (versus alone HD; HR, 3.26; 95% CI, 1.28-8.30; P = .013), older transplantation age (HR, 1.08; 95% CI, 1.04-1.11; P < .001), serum creatinine level at month 6 post-transplantation (HR, 1.34; 95% CI, 1.11-1.62; P = .003), and low HLA mismatches (HR, 1.67; 95% CI 1.01-2.7. Death of donor with cardiac cause, CsA-based immunosuppressive regimen, donor age, serum creatinine level at month 6 post-transplantation, and renal replacement therapy before transplantation affected mortality and graft survival in deceased donors.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Developing Countries; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Renal Replacement Therapy; Retrospective Studies; Risk Factors; Tacrolimus; Tissue Donors; Transplant Recipients; Treatment Outcome; Young Adult

Developmental changes (ontogeny) of drug disposition of Mycophenolate mofetil (MMF) have been understudied.. The charts of 37 pediatric renal transplant recipients (median age 7.3 years, median follow-up 7.8 (IQR 6.6, 14.3 years) who had regular mycophenolic acid (MPA) trough level monitoring in combination with tacrolimus (n = 31) or sirolimus (n = 6) therapy were analyzed retrospectively for their dose-normalized MPA exposure, steroid dose, albumin, hematocrit, and cystatin C estimated glomerular filtration rate (eGFR). Using appropriate univariate and multivariate methods, we determined whether MPA exposure was age dependent when controlling for the confounders.. Dose-normalized MPA trough levels could be calculated in 2,128 (median 45/patient) instances. Spearman rank correlation analysis revealed that age correlated with dose-normalized MPA trough level for both body weight and body surface area, as well as serum albumin, hematocrit, steroid dose, and eGFR. In the multivariate analysis, serum albumin and steroid dose were not significant, and hematocrit only being significant when the youngest group of patients < 6 years of age was compared. eGFR was the most important confounder, but age dependency remained significant when controlling for all confounders.. Small children are at a significantly greater risk for low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA.

Topics: Adolescent; Adult; Age Factors; Child; Child Development; Child, Preschool; Drug Monitoring; Drug Therapy, Combination; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Tacrolimus; Young Adult

Data on renal allograft outcome in sensitized children are scarce. We report the clinical courses of four children who received desensitization therapy prior to renal transplantation in our institution.. Between 2009 and 2011, four pediatric patients with stage 5 chronic kidney disease received desensitization therapy due to: (1) positive donor-specific antibodies (DSA) and/or crossmatches with potential living donors, (2) more than three positive crossmatches with deceased donors or (3) high calculated panel-reactive antibody of >80 %. Desensitization with rituximab, intravenous immunoglobulin and bortezomib was performed in all patients. Induction therapy included combinations of plasmapheresis and/or alemtuzumab or anti-thymocyte globulin. Standard post-transplant medications included tacrolimus, mycophenolate mofetil and prednisolone.. Post-transplant screening revealed DSA in three patients. Biopsy showed no evidence of rejection at 1 month in two patients, one of whom developed chronic active antibody-mediated rejection 4.5 years later. One patient developed borderline acute cellular rejection at 1 month, but the serum creatinine level was stable and DSA disappeared without treatment 1 month later, with stable long-term allograft function at 3 years. Estimated or measured glomerular filtration rate of the patients ranged between 30 and 75 ml/min/1.73 m(2) after 1 to 4.5 years.. The four sensitized patients reported here who received desensitization therapy had successful renal transplants with a low risk of immediate post-transplant rejection. Overall, long-term allograft functions and complications from immunosuppression were encouraging.

Topics: Adolescent; Bortezomib; Child; Child, Preschool; Desensitization, Immunologic; Female; Glomerular Filtration Rate; Graft Rejection; Histocompatibility Testing; HLA Antigens; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Plasmapheresis; Renal Insufficiency, Chronic; Rituximab; Tacrolimus

Cyclosporine and tacrolimus are well established immunosuppressants; however little is known about long term survival rates. The project aim was to compare 10-year graft survival and associated factors among kidney transplant patients within the Brazilian Public Health System (SUS) prescribed either immunosuppressant.. Analyze a national cohort of kidney transplant recipients within SUS. Graft loss defined by death or dialysis for more than three months. Kaplan-Meier method used to estimate cumulative probabilities of survival. Cox proportional hazards model used to evaluate factors associated with progression to graft loss.. 13,811 patients were included, 5,887 used cyclosporine and 7,924 tacrolimus. A higher risk of graft loss was associated with tacrolimus, a deceased donor, additional years of age, median period of dialysis greater than 47 months, diagnosis of diabetes as the primary cause of chronic kidney disease and transplantation between 2005 and 2009.. Among other factors, tacrolimus-based regimens were associated with worse graft survival.

Topics: Adolescent; Adult; Age Factors; Aged; Brazil; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Young Adult

New-onset diabetes mellitus after transplantation (NODAT) is a serious and frequent complication of solid organ transplantations. NODAT leads to 2-3 times higher cardiovascular morbidity and mortality. Visceral obesity is a key factor for diabetes mellitus type 2 and metabolic syndrome development, and is an independent risk factor for cardiovascular diseases.. The series consisted of 167 patients after primary kidney transplantation from a dead donor (64 patients had developed NODAT), average age of the series was 46.1±11.6 years. We retrospectively examined waist circumference, body mass index, and weight gain in the 12th month after transplantation. We examined average level of triglycerides, cholesterol, and immunosuppression throughout the 12 monitored months.. Patients with NODAT were significantly older (P=0.004) and had greater waist circumference (P<0.0001) and higher average sirolimus level (P=0.0262). We identified the following independent risk factors for NODAT by using multivariate analysis: age at the time of transplantation above 50 years (HR=2.5038, [95% CI: 1.7179 to 3.6492], P<0.0001), waist circumference in men greater than 94 cm (HR=1.9492, [95% CI: 1.1697 to 3.2480], P=0.0104) and in women greater than 80 cm (HR=4.5018, [95% CI: 1.8669 to 10.8553], P=0.009). By using correlation coefficient we have proved that greater waist circumference was related to higher incidence of NODAT (r=0.1935, [95% CI: 0.01156 to 0.3630], P=0.0374). Graft survival (death censored) 12 months after kidney transplantation was 97.1% in the control group and 95.3% in the NODAT group (P=0.5381). Patient survival 12 months after kidney transplantation in the control group was 98.1% and in the NODAT group it was 96.9% (P=0.6113).. We identified waist circumference as an independent risk factor for NODAT in our analysis.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Waist Circumference

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

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

Accumulating evidence shows that a gut-released hormone, the glucagon-like peptide-1 (GLP-1), has not only a glucose-lowering effect but also a renoprotective effect against kidney injury. In this study, we investigated whether a dipeptidyl peptidase (DPP) IV inhibitor has a protective effect against tacrolimus-induced renal injury. Rats were treated with tacrolimus (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. MK0626 treatment attenuated tacrolimus-induced renal dysfunction, tubulointerstitial fibrosis, and arteriolopathy. Moreover, these improvements were accompanied by a reduction in oxidative stress and apoptosis. MK0626 treatment increased the blood level of GLP-1 and the level of its receptor in tissue sections but did not alter the levels of other DPP IV substrates, such as neuropeptide Y and the stromal cell-derived factor-1. These data suggest that DPP IV inhibition has an important role in the renoprotection against tacrolimus-induced nephrotoxicity via antioxidative and antiapoptotic effects and preservation of the GLP-1 system.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Calcineurin Inhibitors; Diet, Sodium-Restricted; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Immunosuppressive Agents; Kidney; Male; Oxidative Stress; Random Allocation; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tacrolimus; Triazoles

Kidney transplantation is the best treatment option in chronic kidney disease patients. Despite the new potent immunosuppressants, the long-term graft survival has not significantly improved. This is a rather complex issue with interrelationship between pretransplant donor-recipient variables, recipient post-transplant perioperative non/immunological factors, the combination/dose of maintenance immunosuppression and the general noncompliance of the patient. The recipients with an increased immunological risk should be maintained on triple therapy with steroids, preferably tacrolimus (Tac) or cyclosporine (CsA) plus mycophenolate mofetil (MMF). Eventual calcineurin inhibitor (CNI) minimization should be coupled with either protocol biopsies or frequent biochemistry monitoring including periodical assessment of anti-human leukocyte antigen and donor-specific antibodies. Recipients with standard immunological risks may be considered for as low as possible triple immunosuppression (steroids, Tac/CsA, MMF) after a period of 6 - 12 months. In cases of CNI minimization, a modification with a higher dose of the other two drugs in the triple therapy combination might be considered. The nonadherence to the prescribed maintenance therapy should be regularly checked-up. In conclusion, antibody induction, MMF, steroids and low-dose Tac/CsA should be the mainstream therapy in majority of patients. The short- and mid-term encouraging results for CNI minimization/withdrawal seem to correspond to recent findings of chronic antibody-mediated rejection, and long-term results need further evaluation.

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

Tacrolimus is an important immunosuppressant administered to patients following liver transplantation (LT), with a recommended trough concentration of 8 to 11 ng/mL to prevent allograft rejection. We retrospectively examined our data to identify the tacrolimus trough concentration that combined efficacy with minimal adverse effects.. The case records of LT recipients, who were nondiabetic, nonhypertensive, and with normal renal parameters prior to LT were retrospectively examined for acute cellular rejection (ACR) episodes and three major adverse effects of tacrolimus, i.e. neurotoxicity, nephrotoxicity, and new onset diabetes mellitus (NODM).. Thirty-two LT recipients fulfilled the criteria for the study. The mean (±SD) tacrolimus level for the 290 troughs (after 10 days) was 8.5 ± 3.8 ng/mL. At 10 days, 1 month, 3 months, and 6 months, the trough values were 7.3 ± 2.9, 9.7 ± 3.4, 7.9 ± 3.3, and 7.6 ± 2.6 ng/mL, respectively. The mean time taken for stabilization of the blood pressure and biochemical parameters was 7 ± 2 days. Overall, a trough window with the least adverse effect was 7 to 7.9 ng/mL. Neurotoxicity was least in the trough range 5 to <8 ng/mL. Symptoms included headache in four, tremors in three, seizure in one, confusion and psychosis in two, and combination in three. Nephrotoxicity was least in trough 8 to <11 ng/mL. One patient progressed to chronic kidney disease at 6 months. NODM was present in 11 % to 18 % across the various trough range, including the extremes (mean trough level, 8.4 ± 4.4 ng/dL). At 6 months, five recipients were on treatment for NODM. Three recipients developed ACR, two within the first month and one at 7 weeks. The trough levels were 8.5, 9, 15.2 ng/mL, respectively. All recovered with three pulse doses of methylprednisolone.. Tacrolimus concentration of 5 to <8 ng/mL was associated with least overall toxicity, neurotoxicity, and ACR.

Topics: Adolescent; Adult; Aged; Confusion; Dose-Response Relationship, Drug; Drug Monitoring; Female; Graft Rejection; Headache; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Psychotic Disorders; Renal Insufficiency, Chronic; Retrospective Studies; Seizures; Tacrolimus; Tremor; Young Adult

Chronic kidney disease (CKD) after liver transplantation (LT) is a major clinical problem that appears to be associated with nongenetic as well as genetic determinants. Calcineurin inhibitor (CNI) use is considered to play a major role in the development of CKD after LT. We studied the influence of single-nucleotide polymorphisms (SNPs) in the genes of the donor and recipient CNI-metabolizing enzyme CYP3A5 and the CNI-transporting ABCB1 on the development of CKD after LT.. Tacrolimus (Tac) predose concentrations at different time-points after transplantation and the CYP3A5 6986A>G and ABCB1 3435C>T SNPs were determined in 125 LT recipients and their respective donors to study the influence of Tac predose levels and genetics on the development of CKD.. After a median follow-up of 5.7±2.9 years, CKD developed in 47 patients (36%). The Tac predose levels were not correlated with the development of CKD. Neither did we find a correlation between the investigated SNPs in either donor or recipient ABCB1 and CYP3A5 genes (or combinations thereof) and the development of CKD. These genetic variations did not relate to Tac predose blood concentrations in our study.. An individual's risk of developing CKD after LT is not associated with genetic variation in either recipient or donor CYP3A5 or ABCB1 genotype status.

Topics: Adult; ATP Binding Cassette Transporter 1; Calcineurin Inhibitors; Cytochrome P-450 CYP3A; Drug Dosage Calculations; Female; Genetic Association Studies; Graft Rejection; Humans; Liver Transplantation; Living Donors; Male; Middle Aged; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Retrospective Studies; Tacrolimus

To determine whether low-dose tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is a safe approach to decrease the incidence of chronic kidney disease (CKD) in liver transplantation (LT) recipients.. We analyzed the medical records of 689 patients who underwent LT between March 1999 and December 2012 in a single Chinese center. Immunosuppression was initiated with a calcineurin inhibitor (TAC or CSA) and prednisone with or without MMF. CKD is defined by the glomerular filtration rate (GFR), estimated by an abbreviated Modification of Diet in Renal Disease formula, < 60 mL/min per 1.73 m(2) for at least 3 consecutive months after LT. Individuals with TAC trough concentrations ≤ 8 ng/mL at 3 mo after LT were defined as the low-dose group. The incidence of CKD within 5 years was compared between the TAC group and the CSA group, as well as between four subgroups (low-dose and high-dose TAC groups with or without MMF).. No difference regarding the occurrence of pre-LT renal dysfunction or that of post-LT rejection was found between the TAC and CSA groups or between the four subgroups. With a definition of GFR < 60 mL/min per 1.73 m(2), the overall incidence of CKD was significantly higher in the CSA group than in the TAC group. The incidence of CKD in the low-dose TAC + MMF group (7.7%) was significantly lower than that observed in the low-dose TAC group (15.9%), high-dose TAC group (24.6%) and high-dose TAC + MMF group (18.5%). The cumulative 1-, 3- and 5-year incidence rates of CKD were 12.7%, 14.5% and 16.7%, respectively. The cumulative 5-year survival rates were 61.7% and 82.2% in patients with or without CKD, respectively.. In LT patients, the choice of immunosuppressive therapy appears to affect renal function and patient survival.

Topics: Adult; Calcineurin Inhibitors; China; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Incidence; Kidney; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

The efficacy in renal protection of Everolimus (Evr)-based regimens compared to standard dosages of Tacrolimus (Tac) has recently become known. The purpose of this study was to retrospectively compare the renal function in the first year after LT, with a case-control approach, in patients treated with Tac monotherapy at sub-standard dose vs. an immunosuppressive regimen with Tac and Evr.. Following a 2: 1 case-control approach, 37 patients with an immunosuppression regimen based on Tac only (Tac Group) were retrospectively compared with 74 patients utilizing a combination of Evr and Tac (Evr-Tac Group), based on the following preoperative parameters: sex, age, MELD score (±3), and pre-LT chronic kidney disease (CKD) stage.. After a mean follow-up of 82.8 ± 24 vs. 42.4 ± 16.6 months (p < 0.001), overall survival in 1, 3, and 5 years was 97.3, 91.9, and 86.5% vs. 95.9, 81.1, and 69.5% (p = 0.10) for the Tac Group vs. the Evr-Tac Group, respectively. The trend of the estimated glomerular filtration rate (e-GFR) during the first year post-LT was similar between the 2 study groups (80.1 ± 21 vs. 73.3 ± 16 mL/min/1.73 m^2, for the Tac Group vs. the Evr-Tac Group, respectively, p = 0.23). The incidence of acute rejection histologically proven was 32.4% vs. 20% (p = 0.71) for the Tac Group vs. the Tac-Evr Group, respectively. The rate of CKD was also similar in the 2 study groups.. The early combination of Evr and Tac is an efficient immunosuppressant regimen and provided similar renal function at 1 year post-LT, compared to a minimization of the monotherapy dose of Tac. The combination therapy of Evr-Tac is subject to a higher rate of drugs discontinuation due to adverse effects of 1 of the 2 drugs.

Topics: Adult; Aged; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Function Tests; Liver Transplantation; Male; Matched-Pair Analysis; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

Cardiac transplantation is the definitive therapy for eligible patients with end-stage heart failure. Hypertension is a widely accepted risk factor for its outcome.. We analyzed 169 heart transplant recipients. The diagnosis of hypertension was made on the basis of information gathered at 3 consecutive visits. Complete blood count, urea, serum lipids, fasting glucose, creatinine, and N-terminal pro-B-type natriuretic peptide were also studied.. In the orthotopic heart transplantation (OHT) population, 11% had diabetes and 68% had chronic kidney disease. Hypertension was diagnosed and treated in 68% of the OHT patients. Hypertensive patients were significantly older, with a lower estimated glomerular filtration rate and higher serum creatinine and erythrocyte count. Thirty-three percent of patients did not achieve target blood pressure despite optimal medical treatment. Patients treated with tacrolimus had similar systolic blood pressure compared with those treated with cyclosporine (with a tendency to have lower values). Patients treated with mammalian target of rapamycin inhibitors had similar systolic and diastolic blood pressures compared with those treated without these inhibitors. In the group of patients given steroids, systolic and diastolic blood pressures were significantly lower than in the group not treated with steroids. In addition, steroid-treated patients had a significantly lower estimated glomerular filtration rate, hemoglobin, and erythrocyte count and higher serum creatinine, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. Chronic kidney disease was also more prevalent in this group. Blood pressure was not related to the kidney function.. Despite polytherapy, optimal blood pressure control was not achieved in the majority of patients. OHT patients have a high prevalence of hypertension, which should be treated adequately. More efforts should be made to optimize blood pressure control, particularly when other comorbidities are present. Blood pressure was not related to patient kidney function.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Comorbidity; Creatinine; Cyclosporine; Erythrocyte Count; Female; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Tacrolimus

Furosemide test is a simple and useful test of renal physiology usually used for evaluating the capability of the collecting ducts to secrete potassium under the effect of this drug. Its behaviour pattern has already been established in healthy children, young, and old people, as well as in stage III-chronic kidney disease (III-CKD) patients. However, its behaviour has not been described in kidney transplant patients yet, which we explored in this study.. Twenty young volunteers on a standard western diet (50 mmol of potassium/day) were studied: Ten were III-CKD and the rest were kidney transplant (KT) patients on FK. Before, while the test was being carried out, and 180 min after a single dose of intravenous furosemide (1 mg/kg), urine and blood samples were obtained, for creatinine and potassium levels. From these data, we calculated fractional excretion of potassium (FEK). Statistical analysis was performed applying Wilcoxon test.. There was a significant difference regarding pre-furosemide (basal) FE of potassium between the III-CKD and KT groups 16 ± 5 (III-CKD) versus 7 ± 5 (KT), p = 0.008. Regarding the post-furosemide, peak FEK was significantly lower in the KT group (15 ± 11 %) compared to the III-CKD ones (49.8 ± 9 %, p = 0.01). In both groups, the peak FEK post-furosemide was reached later (120 min) compared to the conventional test (30 min).. Furosemide test showed significantly lower basal and post-furosemide peak FEK values in KT patients on tacrolimus compared with stage III-chronic renal disease.

Topics: Adolescent; Adult; Aged; Diuretics; Female; Furosemide; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Potassium; Renal Insufficiency, Chronic; Tacrolimus; Young Adult

To evaluate the prophylaxis of chronic kidney disease (CKD) after liver transplantation (LT) with low-dose calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF).. From March 1999 to December 2009, a total of 572 patients (478 males and 94 females) underwent LT enrolled in the study. Initial immunosuppression was by triple-drug regimens that included a CNI, MMF, and prednisone. The initial dose of CNI was 0.05-0.10 mg/kg per day for tacrolimus (TAC) and 5-10 mg/kg per d for cyclosporine A (CSA) respectively, and was gradually reduced based on a stable graft function. The serum trough level of CNI was 6-8 ng/mL for TAC and 120-150 ng/mL for CSA 3-mo post-operation, 4-6 ng/mL for TAC and 80-120 ng/mL for CSA 1-year after transplantation was expected with stable liver function. MMF was personalized between 1.0-1.5 g/d. Glomerular filtration rate (GFR) was estimated by an abbreviated Modification of Diet in Renal Disease formula. Risk factors of CKD were examined by univariate and multivariate logistic regression.. With a definition of GFR < 60 mL/min per 1.73 m(2), the incidence of CKD was 17.3% 5-year after LT. There were 68.3% (293 of 429 cases) patients managed to control their TAC trough concentrations within 8 ng/mL and 58.0% (83 of 143 cases) patients' CSA trough concentrations within 150 ng/mL. Of the 450 recipients followed-up over 1 year, 55.5% (183 of 330 cases) of which were treated with TAC had a trough concentration ≤ 6 ng/mL while 65.8% (79 of 120 cases) of which were treated with CSA had a concentration ≤ 120 ng/mL. The incidence of CKD in the groups of lower CNI trough concentrations was significantly lower than the groups with CNI concentrations above the ideal range. Patients with CKD had much higher CNI trough concentrations than that of patients without CKD. MMF was adopted in 359 patients (62.8%). Patients administrated with MMF had a relatively low CNI trough concentrations but with no significant difference. The graft function remained stable during follow-up. No difference was found between different groups of CNI trough concentrations. Pre-LT renal dysfunction, ages, acute kidney injury, high blood trough concentrations of CNI in 3 mo (TAC > 8 ng/mL, CSA > 150 ng/mL) and hypertension after operation were associated with CKD progression, while male gender and adoption of MMF were protection factors.. Low dose of CNI combined with MMF managed to prevent CKD after LT with stable graft function.

Topics: Adult; Aged; Calcineurin Inhibitors; China; Cyclosporine; Disease Progression; Female; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Young Adult

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

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

Heart transplantation is an established treatment for advanced heart failure. Heart transplant recipients experience a number of complications related to pharmacological immunosuppression and infections. Chronic kidney disease (CKD) is an important long-term complication of all forms of organ transplantation other than renal. It has been shown that a GFR <60ml/min is predictive of premature cardiovascular death. The aim of our study was to assess kidney function in relation to the type of immunosuppression regimen used.. We analyzed 169 patients who underwent their first orthotopic heart transplant. The immunosuppressive regimen of prevalent patients consisted of tacrolimus (n=60), cyclosporine (n=109), in combination with mycophenolate mofetil (n=134), azathioprine (n=4), everolimus (n=28) or sirolimus (n=8). GFR was estimated using 3 formulae: CKD-EPI, MDRD and the Cockcroft-Gault. Complete blood count, urea, serum lipids, fasting glucose, creatinine, and NT-proBNP were also analyzed.. In patients treated with tacrolimus, we observed a higher eGFR (all formulae), a greater 24-hour creatinine clearance, and lower serum cholesterol, LDL-cholesterol and triglyceride values than in patients treated with cyclosporine. Patients treated with tacrolimus were younger than those treated with cyclosporine. However, the time elapsed after OHT was similar in both groups. The prevalence of CKD (eGFR <60 ml/min) in the tacrolimus-treated patients was 45%, whereas in the cyclosporine treated group it was 87% (p<0.01).. The prevalence of CKD is high in heart transplant recipients. Tacrolimus-based immunosuppression was associated with better kidney function and more favorable lipid profile. Evaluation of renal function is important in order to select the appropriate strategy by individually tailored therapy to achieve the best possible outcomes.

Topics: Adult; Aged; Cyclosporine; Female; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Renal Insufficiency, Chronic; Tacrolimus

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

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

Topics: Antimetabolites; Calcineurin Inhibitors; Creatinine; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Renal Insufficiency, Chronic; Renal Replacement Therapy; Sirolimus; Tacrolimus; Treatment Outcome

The purpose of this study is to review the clinical experience with sirolimus immunosuppression in liver transplant patients with calcineurin inhibitor-induced chronic renal insufficiency. The study design is a case-control retrospective series. Fifty-seven liver transplant patients with renal insufficiency that were started on sirolimus at greater than 90 days postoperatively and treated for more than 90 days were identified. A control group of 57 patients maintained on low-dose calcineurin inhibitors, matched for gender, year of transplant, and baseline creatinine clearance, was also identified. There were no significant differences in the absolute creatinine clearance values between the sirolimus and control groups from 6 months before sirolimus conversion to 12 months after sirolimus conversion. Patients exposed to calcineurin inhibitors for more than 5 years or those with an initial creatinine clearance of less than 30 mL/minute who were converted to sirolimus did worse than control patients maintained on low-dose calcineurin inhibitors. Progression to renal replacement therapy, episodes of acute and chronic rejection, and death were similar between the sirolimus and control groups. The overall prevalence of side effects was significantly higher in the sirolimus group compared with the control group, although these were generally tolerable in most patients. In conclusion, this study suggests that conversion to sirolimus in liver transplant patients with chronic renal insufficiency is associated with stabilization of renal function but confers no additional benefit to low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of less than 30 mL/minute.

Topics: Adult; Aged; Antimetabolites; Calcineurin Inhibitors; Case-Control Studies; Creatinine; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Renal Replacement Therapy; Retrospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome