Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Abstract

Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39 -0.96; P ϭ 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58 -0.92; P ϭ 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08 -1.90; P ϭ 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80 -0.98; P ϭ 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.

Calcineurin Inhibitors: 40 Years Later, Can’t Live Without …

“…Although CNIs are associated with renal injury, whether acute or chronic, many trials to minimize or even avoid CNIs, particularly cyclosporine, have been conducted (51,(67)(68)(69)(70)(71)(72)(73)(74).…”

“…A recent meta-analysis compared CNI-sparing regimens, either through complete avoidance or minimization, to the standard of care, which is CNI-containing regimens (74). Although the 17 minimization studies, which included 4131 patients, showed no difference in acute rejection, CNI-minimizing regimens showed a reduction in graft failure (odds ratio, 0.73; 95% confidence interval, 0.34-1.31).…”

“…Although the 17 minimization studies, which included 4131 patients, showed no difference in acute rejection, CNI-minimizing regimens showed a reduction in graft failure (odds ratio, 0.73; 95% confidence interval, 0.34-1.31). However, the avoidance studies, which substituted CNI regimens with mammalian target of rapamycin (mTOR) inhibitors, showed an increase in graft failure in patients treated with mTOR inhibitors (74).…”

New-onset diabetes mellitus after renal transplantation

“…In their meta-analysis, Sharif et al found that CNI-sparing strategies are associated with less delayed graft function, improved graft function and less NODAT (ref. 33 ). Tacrolimus has usually been observed to be more diabetogenic 6 .…”

Moving Beyond Minimization Trials in Kidney Transplantation

“…Some but not all trials demonstrated better renal function (eGFR) with CNI minimization, perhaps slight improvement in some CNI-specific adverse events, but none showed improved patient or graft survival. 9,10 It seems increasingly evident that many of these trials were based on a false premise: that CNIs were the principal cause of chronic graft dysfunction. [11][12][13] As our understanding of late graft dysfunction evolved to recognize a critical role for antibody-mediated injury, it is ironic that evidence of the importance of antibody emerged in part from studying the impact of CNI withdrawal or avoidance.…”