A Randomized Controlled Trial of Late Conversion from CNI‐Based to Sirolimus‐Based Immunosuppression Following Renal Transplantation

Abstract

Maintenance immunosuppression with calcineurin inhibitors (CNIs) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. We aimed to assess whether conversion to sirolimusbased immunosuppression would affect the progression of renal impairment.In this single center, randomized controlled trial, 40 renal transplant recipients between 6 months and 8 years post-transplant were randomly assigned to remain on their CNI (cyclosporin or tacrolimus) or to switch to sirolimus. The primary outcome measure was change in glomerular filtration rate (GFR) measurement at 12 months. Analysis was by intention-totreat.Of the 40 patients randomized, 2 patients never took the study drugs and were excluded, leaving 19 patients per group. There was a significant change in GFR at 12 months following conversion to sirolimus (12.9 mL/min, 95% CI 6.1-19.7; p < 0.001). Following conversion, the principal adverse events were the development of rashes (68%), particularly acne, and mouth ulcers (32%). No patient in either group experienced an acute rejection episode.In renal transplant recipients, a change in maintenance therapy from CNIs to sirolimus is associated with significant improvement in GFR at 12 months.

The role of mTOR inhibition in renal transplant immune suppression

“…Watson and colleagues examined renal outcomes in patients who were 6 months to 8 years posttransplant with "suboptimal graft function" and found that abrupt CNI discontinuation and SRL conversion resulted in signifi cantly higher GFRs at 3 and 13 months post-conversion. 33 Of note, there was a positive correlation between baseline renal function and change in GFR at 12 months (R 2 = 0.22; p = 0.05), suggesting that the greatest improvement in GFR occurred in SRL-converted patients with better baseline function. Another group utilized post-transplant biopsies and ␣-smooth muscle actin expression to determine the impact of SRL conversion on CAN progression.…”

“…74 However, infectious complications appear to be more common post conversion. 33,35,[75][76][77] Increased infection risk is more likely to occur early in the post-conversion period and may be associated with slower, gradual tapering of CNI and loading dosages. Immediate cessation or rapid reduction of CNI followed by SRL initiation does not appear to result in major infection.…”

Chronic Allograft Nephropathy Score Before Sirolimus Rescue Predicts Allograft Function in Renal Transplant Patients

“…The availability of SRL allows substitution for CNI therapy with a non nephrotoxic agent and potentially avoids risk of acute rejection. 21 No attempt was made in this study to quantify the burden of CAN prior to switching to SRL. 21 We did not do protocol kidney transplant biopsies in our study.…”

“…21 No attempt was made in this study to quantify the burden of CAN prior to switching to SRL. 21 We did not do protocol kidney transplant biopsies in our study. Such biopsies could help in documenting the progression of CAN in the low-CAN and high-CAN score groups during the period of follow-up.…”

“…H The immediate conversion to SRL has the 97 advantage of simplicity and avoids potential overimmunosuppression. 21 In the protocols with immediate conversion, the possibility of acute rejection might be increased, if the time to achieve target SRL levels is prolonged.…”