Sirolimus Versus Calcineurin Inhibitors As Initial Therapy In Kidney Transplant Recipients:a Meta-analysis Of Randomized Trials

BackgroundKidney transplantation is the most ideal therapy in patients with End stage renal disease. After kidney transplantation, immunosuppression is required to prevent rejection, so as to achieve patients and grafts survival. Calcineurin inhibitors (Cyclosporine and Tacrolimus) have been the cornerstone of maintenance immunosuppression in kidney transplantation, because they improve acute rejection rates and short-term graft survival in renal transplantation, their immunosuppressive effect depends on the formation of a complex with their cytoplasmic receptor proteins, cyclophilin for cyclosporine and FKBP for Tacrolimus, they can binds with calcineurin, then inhibit dephosphorylation of certain nuclear regulatory proteins, so they can damage the the cytokine genes expression which play important roles of the activation of T-cell. But nephrotoxicity associated with long-term calcineurin inhibitors use remains an important issue. The continuous use of CNI leads to histological changes in the kidney such as tubular atrophy, interstitial fibrosis, nodular arteriolar hyalinosis, and glomerular sclerosis. It is reported that over10%of extra kidney allograft recipients need renal replacement therapy after10years of continuous CNI use. Therefore, a potent immunosuppressive regimen without CNI properties would be of much help in the treatment of renal transplant patients, an alternative was substituting the mTOR inhibitor sirolimus for a CNI drug, since this agent does not appear to be nephrotoxic. Sirolimus (SRL, Mammalian Target of Rapamycin inhibitors, mTORi), a macro-cyclic lactone antibiotic which is produced by Streptomyces hygroscopicus that has presented potent antirejection activity. The immunosuppressive activity of SRL appears to be mediated through a mechanism distinct from that of CNI. Like CNI, they bind to acytoplasm-binding protein (FKBP). The resultant SRL-FKBP ligand, however, does not block calcineurin; instead, it engages a protein designated TOR. TOR is a key regulatory kinase, and its inhibition reduces cytokine-dependent cellular proliferation at G1to S phase of the cell-division cycle. In1999, the results of one RCT in11European centers suggested that at12months, graft loss, patient mortality, and incidence of biopsy-confirmed acute rejection were similar in kidney transplant recipients. Serum creatinine was lower with SRL. The results suggest that SRL can be used as base therapy in the prophylaxis of acute renal transplant rejection. Hereafter, the clinical outcomes of SRL has become controversy with increasingly number of the studies about SRL versus CNI as initial therapy in kidney transplant recipients, some studies reported the differences of renal function was not significant, and some studies reported higher incidence of acute rejection, graft loss and patients deaths in SRL groups. And, there are some controversial about delayed graft function, wound complications and cytomegalovirus infections.ObjectiveWe perform a meta-analysis of randomized controlled trials to compare the efficacy of calcineurin inhibitors-free regimens with sirolimus versus calcineurin inhibitors-based regimens as initial therapy for kidney transplant recipients. We hope to provide some guiding significance for choosing immunosuppressive regimens as initial therapy for kidney transplant recipients by this analysis.MethodsThis analysis follows a meta analysis of randomized controlled trials related guide to collection and analysis data. With the key words combined with all free-text aliases for "Sirolimus, The Calcineurin Inhibitors, Cyclosporine, Tacrolimus, Kidney Transplantation" in Chinese and in English, respectively, a computer-based search of articles was performed in PubMed, SCI, EMBASE, Cochrane Central Register of Controlled Trials, CNKI, WANFANG DATE, CBM, VIPC for randomized controlled trials about calcineurin inhibitors-free regimens with sirolimus versus calcineurin inhibitors-based regimens as initial therapy for kidney transplant recipients, and a manual searching of relevant journals and dissertations was performed as a supplement, such as Chinese Journal of Organ Transplantation, Chinese Journal of Urology, Chinese Journal of Nephrology, Chinese Journal of Nephrology Dialysis&Transplantation, Organ Transplantion, Journal of Clinical Urology, Journal of Clinical Nephrology, etc.Inclusion criteria specified all RCTs in which receiving CNI-free regimens with SRL versus CNI-based regimens (without SRL) as initial therapy for kidney transplant recipients. The exclusion criteria included the trials about dual-organ transplantation, paediatric kidney transplantation, conversion from CNI to SRL, CNI withdrawal from SRL-based therapy, SRL plus CNI versus CNI-based SRL-free, etc.The studies were assessed for quality by authors using a combination of the Jadad score (a score≥3is considered good quality) and the use of allocation concealment and ITT analysis. The outcomes of this meta-analysis were renal function (Serum Creatinine, Calculated Creatinine Clearances), BPAR, graft loss (excluding deaths and overall), patient mortality at6months and12months after transplantation, and delayed graft function (DGF), wound Complications and CMV infections. We pooled the incidence of delayed graft function (DGF), wound complications and CMV infections irrespective of the length of follow-up, as most complications would develop within the first few months after transplantation (DGF was defined as any need for dialysis treatment starting within the first week after grafting).Reviewer Manager (RevMan) version5.2was used to pool the outcomes among studies. Heterogeneity was quantified using the I2and Chi-square test. An I2value greater than50%or a P value less than0.1indicated significant levels of heterogeneity. When heterogeneity was not significant, we used a fixed effects model, sensitivity analysis or random effects model were performed to analysis when heterogeneity was significant. Dichotomous outcomes were expressed as relative risk (RR), and continuous scales of measurement were expressed as the weighted mean difference (WMD), both with95%confidence intervals (CI). We used u test, when P <0.05, the difference was significant. Funnel plot and fail-safe number were used to analysis publish bias.ResultA total of14RCTs (including1731patients) met the inclusion criteria. Twelve of14RCTs (86%) achieved a Jadad score of3. Nine studies (64%) described a method of randomization that was consistent with allocation concealment. Thirteen RCTs (93%) performed an intention-to-treat (ITT) analysis.Pooled analyses of serum creatinine (μmol/L)at6months (6RCTs;.P=0.0001;95%CI:-19.29～-6.32) and12months (5RCTs; P<0.0001;95%CI:-21.10～-8.24) after transplantation showed that the serum creatinine in the SRL group was lower than in the CNI group, and the differences were significant.Pooled analyses of calculated creatinine clearances (ml/min) at6months(7RCTs; P=0.002;95%CI:2.24～10.03) and12months (7RCTs; P=0.02;95%CI:1.08～11.10) after transplantation showed that the calculated creatinine clearances in the SRL group was higher than in the CNI group, and the differences were significant.Pooled analyses of BPAR at6months (6RCTs; P=0.15;95%CI:0.85～2.79) and12months (7RCTs; P=0.65;95%CI:0.66～1.94) after transplantation showed that differences between SRL group and CNI group were not significant.Pooled analyses of graft loss (excluding deaths) at6months (5RCTs; P=0.27;95%CI:0.73～3.10) and12months (7RCTs; P=0.23;95%CI:0.78～2.87) after transplantation showed that differences between SRL group and CNI group were not significant.Pooled analyses of graft loss (overall) at6months (5RCTs; P=0.17;95%CI:0.82～3.19)and12months (8RCTs; P=0.41;95%CI:0.75～2.04)after transplantation showed that differences between SRL group and CNI group were not significant.Pooled analyses of patient mortality at6months (7RCTs; P=0.07;95%CI:0.91～18.56) and12months (9RCTs; P=0.84;95%CI:0.49～2.39) after transplantation showed that differences between SRL group and CNI group were not significant.Pooled analyses of delayed graft function (6RCTs; P=0.50;95%CI:0.85～1.39) after transplantation showed that difference between SRL group and CNI group was not significant.Pooled analyses of wound complications (10RCTs; P<0.00001;95%CI:1.89～3.90) showed that the incidence of wound complications was higher in the SRL group, and the difference was significant.Pooled analyses of CMV infections (10RCTs; P<0.00001;95%CI:0.22～0.55) showed that the incidence of CMV infections was lower in the SRL group, and the difference was significant.Conclusion1. Our meta-analysis showed that CNI-free regimens with SRL may obtain better renal function when compared with CNI-based regimens at6months and12months after transplantation.2. Our meta-analysis showed that the differences about BPAR, graft loss and patient mortality at6months and12months after transplantation between CNI-free regimens with SRL and CNI-based regimens were not significant, and the difference about DGF was not significant between the two groups.3. Our meta-analysis showed that CNI-free regimens with SRL had lower incidence of CMV infection when compared with CNI-based regimens, but had higher incidence of wound complications.4. The CNI-free regimens with SRL can be a chose of initial therapy after kidney transplantation. The options of immunosuppressive regimens after kidney transplantation should be based on the patient’s specific condition, immunosuppressive regimen should be individualized and appropriate.5. The Meta analysis exist publication bias, because we didn’t identify the ongoing or unpublished studies, so the results of this meta-analysis are only for reference.6. To obtain more reliable and accurate clinical data, the RCTs with more rational design, higher methodological quality, larger sample size, longer follow-up are still needed.