Predictors of Success in Conversion from Calcineurin Inhibitor to Sirolimus in Chronic Allograft Dysfunction

Abstract

Chronic allograft dysfunction (CAD) is a major cause of graft loss in long-term kidney transplant recipients. To identify predictors of successful conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) we investigated 59 renal transplant patients with CAD without histological signs of acute rejection. They received 12-15 mg SRL once, then 4-5 mg/day, target trough level 8-12 ng/mL. CNI dose was reduced by 50% simultaneously, and withdrawn at 1-2 months. Concomitant immunosuppression remained unchanged. After 1 year patient survival was 100% and graft survival 92%. In responders (54%) creatinine improved (2.75 ± 0.75 to 2.22 ± 0.64 mg/dL; p < 0.01). In nonresponders (46%) creatinine deteriorated (3.15 ± 1.02 to 4.44 ± 1.60 mg/dL; p < 0.01). Baseline renal function did not differ, however, baseline proteinuria (519 ± 516 vs. 1532 ± 867 mg/day, p < 0.01), histological grade of chronic allograft nephropathy (CAN) (1.2 ± 0.5 vs. 1.9 ± 0.6; p < 0.01), grade of vascular fibrous intimal thickening (1.2 ± 0.7 vs. 1.7 ± 0.7; p = 0.048) and number of acute rejections before conversion (0.73 ± 0.69 vs. 1.27 ± 0.96; p < 0.05) differed significantly between responders and nonresponders. In a multivariate analysis low proteinuria was the only independent variable. Proteinuria below 800 mg/day has a positive predictive value of 90%. Proteinuria at conversion below 800 mg/day is the only independent predictor for positive outcome in conversion from CNI to SRL in CAD.

Rapamycin Induces Autophagy and Reduces the Apoptosis of Podocytes Under a Stimulated Condition of Immunoglobulin A Nephropathy

“…Preventive medication of rapamycin in renal transplant recipients was proven to protect renal function and histology [32]. However, the conversion from calcineurin inhibitor to sirolimus in later stages of chronic allograft nephropathy is often accompanied by adverse effects, including an elevated level of proteinuria and consequent deterioration of kidney function [33]. The reason for this discrepancy may be attributed to the action of mTOR, an important protein involved in many physical and pathological processes.…”

The mTOR Inhibitor Everolimus Attenuates the Time Course of Chronic Anti-Thy1 Nephritis in the Rat

“…Nevertheless, while several clinical renal transplant studies have suggested the beneficial effects of calcineurin inhibitor-free, mTOR inhibitor-based protocols, unexpected adverse effects of mTOR inhibitors have also been described during treatment of renal allograft nephropathy [4,5,6], human glomerulonephritis [7], as well as experimental kidney disease [8, 9]. The mTOR inhibitors are potent antiproliferative agents for lymphocytes, and also for other cell types such as vascular smooth muscle cells [1], endothelial cells [10] and mesangial cells [11].…”

Proteinuria and baseline renal function predict mortality and renal outcomes after sirolimus therapy in liver transplantation recipients

“…Most of the experience is with renal transplantation recipients. One study reported that proteinuria that was <800 mg/day was significantly associated with a better renal outcome in kidney transplant recipients who converted to SRL therapy [23]. Results from another study demonstrated a negative correlation between baseline proteinuria and rate of graft rejection and survival after kidney transplantation [24].…”