Early Sirolimus Use With Cyclosporine Elimination Does Not Induce Progressive Proteinuria

Abstract

Proteinuria has been reported in several papers after conversion from calcineurin inhibitors to Sirolimus (SRL), but this complication has not been analyzed in randomized clinical trials using de novo SRL. It is not known whether de novo use of SRL is a risk factor for proteinuria. We analyzed a series of patients included in a big multicenter randomized trial (RMR trial) corresponding to all patients in Spain and Portugal with respect to this issue. We retrospectively evaluated 24-hour proteinuria in all the patients during the study period (5 years postransplant) for comparison between treatment arms group A, continuous cyclosporine (CyA) ϩ SRL and group B SRL with CyA elimination at 3 months postransplant. The elimination of CyA after the third month was not followed by significant changes in proteinuria. Nevertheless, during the last year of follow-up (between 48 and 60 months postransplant) an impressive increase in proteinuria was observed in group A. This surprising finding seemed to be a consequence of a protocol amendment that recommended CyA elimination in patients of group A, due to poorer results in the intermediate analysis of the trial. This fact suggests that the hemodynamic changes induced by elimination of the vasoconstrictor CyA might be responsible for the proteinuria but only in the long term probably when significant pathological lesions are already present. This finding argues for earlier conversion.S IROLIMUS (SRL) conversion after the initial postransplant phase has been frequently associated with increasing proteinuria (PU) in a significant number of patients either in the case of renal transplant recipients or in the recipients of other solid organs. [1][2][3] The mechanism of appearance of this complication is unclear. Various hypotheses have been proposed, namely, a direct tubular toxicity and especially hemodynamic effects derived from calcineurin inhibitor (CNI) elimination, ie. increased glomerular pressure due to afferent vasodilatation. 4 This complication is reversible in most cases and PU returns to preconversion values after SRL elimination and CNI reintroduction. 3 This complication was surprisingly not reported in de novo trials using SRL before approval for clinical use, but the reason for that was that this parameter was not evaluated in those trials. Especially the Rapamune Maintenance Regimen (RMR) trial demonstrated a significant improvement in renal function after early cyclosporine (CyA) elimination in a regimen including SRL, a better pathological profile at 3 years postransplant and better graft survival at 4 years postransplant 5-8 when compared with the control group who maintained CyA treatment. The objective of this work was to analyze the evolution of PU after early CyA withdrawal in a combination of CyA ϩ SRL compared with a control arm with continuous CyA ϩ SRL.

Conversion to Sirolimus in Renal Transplant Recipients: A Single‐Center Experience

“…It has been shown that there is an association between successful conversion and time lag between conversion and transplantation; shorter durations have more favorable outcomes (35,37,44,45). In accordance with this hypothesis, in the present study, no increase in serum creatinine and proteinuria were noted in the patients who were converted within the first year of transplantation; however, proteinuria values increased in the patients who received SRL conversion after the first year.…”

Everolimus in kidney transplantation

“…Sirolimus use has been frequently associated with proteinuria. 86 This finding appears to occur mainly in patients converted from calcineurin inhibitors to sirolimus, 87,88 but has also been reported with de novo sirolimus use as well. 89,90 While the mechanism of proteinuria in the former scenario is likely to involve hemodynamic glomerular changes after calcineurin inhibitor removal, the mechanism associated with de novo sirolimus use is unclear.…”

Sirolimus Conversion Efficacy for Graft Function Improvement and Histopathology in Renal Recipients with Mild to Moderate Renal Insufficiency

“…Proteinuria after conversion from calcineurin inhibitors to SRL has been reported in several studies (30, 31, 32), but SRL may not be a direct factor for proteinuria (33). Proteinuria after SRL conversion could be related to the previous use of CsA but not SRL, but early SRL use with CsA elimination does not induce progressive proteinuria (33, 34). The current study demonstrated a rapid increase in proteinuria after SRL conversion.…”