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Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.

ABSTRACT: Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ? 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus-based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = -2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98-16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66-1.88] or graft failure (RR = 0.80, 95% CI = 0.45-1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14-5.36), rash (RR = 7.57, 95% CI = 1.75-32.70), ulcers (RR = 7.44, 95% CI = 2.03-27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32-9.89).Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting.

SUBMITTER: Asrani SK

PROVIDER: S-EPMC4130484 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.

Asrani Sumeet K SK Leise Michael D MD West Colin P CP Murad M Hassan MH Pedersen Rachel A RA Erwin Patricia J PJ Tian Jianmin J Wiesner Russell H RH Kim W Ray WR

Hepatology (Baltimore, Md.) 20101001 4

<h4>Unlabelled</h4>Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinin ...[more]

PMID: 20815021

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Project description:Background and aimsAs conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.Approach and resultsWe performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group.ConclusionsThis study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

Project description:BackgroundSirolimus (SRL) is an immunosuppressive drug and substrate of the P-glycoprotein (P-GP) encoded by ABCB1. The relationship between ABCB1 polymorphism and the pharmacokinetics of SRL in different studies were conflicting in renal transplant recipients. Thus, this meta-analysis aims to investigate the influence of ABCB1 C3435T, C1236T, and G2677T/A polymorphisms on the dose-adjusted trough level (C/D) of SRL in renal transplant recipients.MethodsPubMed, Embase, and the Cochrane Library were searched for relevant studies. The quality of each eligible study was assessed according to Newcastle-Ottawa Scale. The STATA 15.0 was adopted to perform the meta-analysis. The fixed-effects model was used for pooled results with low heterogeneity (I2 ≤50%); otherwise, the random-effects model was used.ResultsA total of 6 studies were included in the meta-analysis. Results of pooled analysis showed no significant association of SRL C/D ratio with ABCB1 C3435T polymorphism. The subgroup analysis based on different ethnic groups and different time-points after SRL initiation in renal transplant recipients were also conducted. No significant association was observed in these subgroups. Significant associations were showed between ABCB1 C1236T polymorphism and the C/D ratio of SRL in the homozygous model (TT vs. CC; WMD: -45.54; 95% CI: -75.15, -15.94; P=0.003), and also in subgroup of Caucasian (TT vs. CC; WMD: -46.57; 95% CI: -91.90, -1.25; P=0.044 and TT vs. CC + CT; WMD: -52.10; 95% CI: -95.38, -8.82; P=0.018). Significant differences were found in association between the ABCB1 G2677T/A polymorphism and the C/D ratio of SRL, including the homozygous model (TT vs. GG; WMD: -76.47; 95% CI: -126.37, -26.58; P= 0.003), the heterozygous model (GT vs. GG,WMD: 178.62; 95% CI: 125.03, 232.22; P= 0.000), the dominant model (GT + TT vs. GG; WMD: 82.23; 95% CI: 36.28, 128.17; P=0.000), the recessive model (TT vs. GG + GT; WMD: -179.38; 95% CI: -283.33, -75.42; P=0.001), and the over-dominant model (GT vs. GG + TT; WMD: 199.44; 95% CI: 84.84, 314.05; P=0.001).ConclusionsNo significant association exists between ABCB1 C3435T polymorphism and the C/D ratio of SRL in renal transplant recipients. To achieve target therapeutic concentrations, ABCB1 C1236T homozygous mutant TT genotype will require a higher dose of sirolimus than wild type GG, especially in Caucasian renal transplant recipients. ABCB1 G2677T/A TT genotype will also need a higher dose of sirolimus genotype. Genotyping of ABCB1 might help to improve the individualization of SRL for renal transplant recipients. Further studies are expected to provide high-quality evidence.

Project description:BackgroundImmunosuppression and comorbidities increase the risk of severe coronavirus disease-2019 (COVID-19) in solid organ transplant (SOT) recipients. The outcomes of COVID-19 in liver transplant (LT) recipients remain unclear. We aimed to analyse the outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients.MethodsThe electronic databases were searched for articles published from 1 December 2019 to 20 May 2021 with MeSH terms COVID-19, SARS-CoV-2, and liver transplantation. Studies reporting outcomes in more than 10 LT recipients were included for analysis. LT vs non-LT patients with COVID-19 infection were compared for all-cause mortality, which was the primary outcome studied. We also evaluated the relation between the timing of COVID-19 infection post-LT (< one year vs > one year) and mortality.FindingsEighteen articles reporting 1,522 COVID-19 infected LT recipients were included for the systematic review. The mean age (standard deviation [SD]) was 60·38 (5·24) years, and 68·5% were men. The mean time (SD) to COVID-19 infection was 5·72 (1·75) years. Based on 17 studies (I2 = 7·34) among 1,481 LT recipients, the cumulative incidence of mortality was 17·4% (95% confidence interval [CI], 15·4-19·6). Mortality was comparable between LT (n = 610) and non-LT (n = 239,704) patients, based on four studies (odds ratio [OR], 0·8 [0·6-1·08]; P = 0·14). Additionally, there was no significant difference in mortality between those infected within one year vs after one year of LT (OR, 1·5 [0·63-3·56]; P = 0·35). The cumulative incidence of graft dysfunction was 2·3% (1·3-4·1). Nearly 23% (20·71-25) of the LT patients developed severe COVID-19 infection. Before infection, 71% and 49% of patients were on tacrolimus and mycophenolate mofetil, respectively. Immunosuppression was modified in 55·9% (38·1-72·2) patients after COVID-19 infection.InterpretationLT and non-LT patients with COVID-19 have a similar risk of adverse outcomes.

Project description:BackgroundWhether overweight or obese end stage renal disease (ESRD) patients are suitable for renal transplantation (RT) is often debated. The objective of this review and meta-analysis was to systematically investigate the outcome of low versus high BMI recipients after RT.MethodsComprehensive searches were conducted in MEDLINE OvidSP, Web of Science, Google Scholar, Embase, and CENTRAL (the Cochrane Library 2014, issue 8). We reviewed four major guidelines that are available regarding (potential) RT recipients. The methodology was in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and written based on the PRISMA statement. The quality assessment of studies was performed by using the GRADE tool. A meta-analysis was performed using Review Manager 5.3. Random-effects models were used.ResultsAfter identifying 5,526 studies addressing this topic, 56 studies were included. We extracted data for 37 outcome measures (including data of more than 209,000 RT recipients), of which 26 could be meta-analysed. The following outcome measures demonstrated significant differences in favour of low BMI (<30) recipients: mortality (RR = 1.52), delayed graft function (RR = 1.52), acute rejection (RR = 1.17), 1-, 2-, and 3-year graft survival (RR = 0.97, 0.95, and 0.97), 1-, 2-, and 3-year patient survival (RR = 0.99, 0.99, and 0.99), wound infection and dehiscence (RR = 3.13 and 4.85), NODAT (RR = 2.24), length of hospital stay (2.31 days), operation duration (0.77 hours), hypertension (RR = 1.35), and incisional hernia (RR = 2.72). However, patient survival expressed in hazard ratios was in significant favour of high BMI recipients. Differences in other outcome parameters were not significant.ConclusionsSeveral of the pooled outcome measurements show significant benefits for 'low' BMI (<30) recipients. Therefore, we postulate that ESRD patients with a BMI >30 preferably should lose weight prior to RT. If this cannot be achieved with common measures, in morbidly obese RT candidates, bariatric surgery could be considered.

Project description:Robot-assisted radical prostatectomy (RARP) has been shown to achieve excellent oncological outcomes with a low rate of complications in patients with prostate cancer. However, data on RARP in renal transplant recipients (RT) are dispersed. A literature search was conducted through April 2023 using PubMed/Medline, Embase and Web of Science databases. The primary aim was to evaluate the safety, oncologic and clinical outcomes of RARP in RT recipients. The secondary aim was to identify surgical technique modifications required to avoid iatrogenic damage to the transplanted kidney. A total of 18 studies comprising 186 patients met the inclusion criteria. Age at the time of treatment ranged 43-79 years. Biopsy results showed a high prevalence of low- and intermediate-risk disease. Operative time ranged between 108.3 and 400 mins, while estimated blood loss ranged from 30 to 630 mL. Length of hospital stay ranged from 3 to 6 days whereas duration of catheterization was between 5 and 18 days. Perioperative complication rate was 17.1%. Overall positive surgical margin rate was 24.19%, while biochemical recurrence was observed in 10.21% (19/186 patients). Modifications to the standard surgical technique were described in 13/18 studies. Modifications in port placement were described in 7/13 studies and performed in 19/88 (21.6%) patients. Surgical technique for the development of the Retzius space was reported in 13/18 studies. Data on lymphadenectomy were reported in 15/18 studies. Bilateral lymphadenectomy was described in 3/18 studies and performed in 4/89 (4.5%) patients; contralateral lymphadenectomy was reported in 7/18 studies and performed in 41/125 (32.8%) patients. RARP in RTRs can be considered relatively safe and feasible. Oncological results yielded significantly worse outcomes in terms of PSM and BCR rate compared to the data available in the published studies, with an overall complication rate highly variable among the studies included. On the other hand, low graft damage during the procedure was observed. Main criticisms came from different tumor screening protocols and scarce information about lymphadenectomy techniques and outcomes among the included studies.

Dataset Information

Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.

Publications

Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.

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