Risk of Metabolic Complications in Kidney Transplantation After Conversion to mTOR Inhibitor: A Systematic Review and Meta-Analysis

Abstract

y These authors act as equivalent co-senior authors.Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR inhibitors are also associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversion from CNI to mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013 identified nine relevant trials (a total of 2323 patients). The primary end points were the relative risks (RRs) of new-onset diabetes after transplant (NODAT) and hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with mTOR inhibitors were 1.32 (95% confidence interval [CI] 0.92-1.87) and 2.15 (95% CI 1.35-3.41), respectively, compared with CNI-based regimen. Subgroup analyses revealed no differences in the incidence of NODAT or hypercholesterolemia between sirolimus-versus everolimus-based regimen, or between early versus late conversion. Analyses of secondary outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the conversion from CNI to mTOR inhibitor in low-to-moderate risk kidney transplant recipients was associated with nonsignificant trend toward increased risk of NODAT and significant increase in hypercholesterolemia, acute rejection, proteinuria and anemia.

Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus

“…Sirolimus, an antiproliferative agent that blocks T-lymphocyte activation via inhibition of mammalian target of rapamycin (mTOR) signaling inhibition (6), is not associated with the nephrotoxic effects observed with calcineurin inhibitors (CNIs) (9,10). However, proteinuria incidence increases in maintenance renal transplant patients receiving mTOR inhibitors, including sirolimus (SRL) (6,8,11,12). Proteinuria is generally <500 mg/day in patients treated de novo with SRL, but higher following conversion from CNI to SRL, especially in patients with preexisting renal damage (1,6,13).…”

Sirolimus-based, calcineurin inhibitor- free regimen in kidney transplant patients: An open-label, randomized, controlled trial

“…They found that when mTOR inhibitor replaced CNI, there was no difference in acute rejection. In a study done by Budd et al (28) on conversion of CsA to everolimus at 4.5 months posttransplant, found that the incidence of BPAR from randomization to month 36 was significantly higher in the everolimus group (13.0%) vs. (4.8%) in the CsA arm, P=0.015). On the other hand, Lebranchu and co-workers (30), although, they noticed a similar pattern of BPAR after SRL conversion, however, two graft losses due to acute rejection were observed in the SRL group during the follow-up period and they concluded that SRL may therefore expose to the risk of graft loss due to resistant acute rejection.…”

“…However, conversion from CNI to SRL therapy after transplantation improved short-term renal function but did not decrease allograft fibrosis (25,26). Moreover, in conversion trials, SRL treated patients typically experienced higher rejection rates and adverse events, further confounding the results (27,28).…”

Critical analysis of graft loss and death in kidney transplant recipients treated with mTOR inhibitors

“…Although specific causes of death and graft loss have not been studied systematically, adverse events typically associated with the use of imTORs such as proteinuria, [22][23][24] diabetes mellitus after transplantation [25][26][27] and dyslipidemia 27 may be involved in these findings. These complications, however, are associated with the relatively high blood concentrations of iCN and imTOR initially used.…”