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

Abstract

BackgroundChronic kidney disease is a significant complication after liver transplantation (LT), but the role of pre-existing renal insufficiency and proteinuria remains unclear among LT recipients receiving sirolimus.MethodsWe assessed the effects of proteinuria and baseline renal function on long-term renal and survival outcomes among 576 LT recipients who received SRL in a medical center between 2005 and 2014. Renal outcomes were the incidences of >50% reduction in their baseline estimated glomerular filtration rate and end stage kidney disease requiring renal replacement therapy. Proteinuria was identified using morning dipstick results (≥30 mg/dL) at baseline and within the first year after the initiation of SRL therapy. A Kaplan-Meier analysis was performed to estimate time to event. Factors associated with the outcomes were determined using the Cox proportional hazards model with a significance level set at P <0.05.ResultsDuring the study period, renal function deteriorated in 135 (25.3%) patients and 68 (11.8%) patients died. Persistent and new onset proteinuria contributed to a high rate of mortality and the deterioration of renal function (both log-rank tests, P <0.0001). After adjustments, new onset proteinuria within the first year after the initiation of SRL therapy increased the risk of deteriorating renal function, regardless of baseline estimated glomerular filtration rate. Moreover, pre-existing (hazard ratio = 1.91; P <0.001) and new onset diabetes (hazard ratio = 2.34; P <0.0001) were significantly associated with new onset proteinuria among SRL users.ConclusionsThese findings support the effective monitoring and early management of the predictable risks for proteinuria among new SRL users in order to delay the progression of renal disease.

Effects of Conversion From Calcineurin Inhibitors to Sirolimus or Everolimus on Renal Function and Possible Mechanisms in Liver Transplant Recipients

“…Patients with a higher risk of renal function deterioration, such as preexisting CKD, higher Model for End-Stage Liver Disease score, renal function, and proteinuria, should be carefully monitored after mTORI conversion to reevaluate the necessity of mTORI. 4 Although everolimus has higher oral bioavailability and better metabolic stability than sirolimus, the difference on renoprotection was insignificant in our study cohort. Glover et al conducted a systemic review and meta-analysis of randomized control trials in liver transplant recipients with mTORI conversion, in which both arms showed favorable trends towards everolimus or sirolimus (mean differences of eGFR in everolimus vs sirolimus = +0.44,95% CI [0.16,0.71] vs +0.37, 95% CI -0.04-0.77).…”

“…Notably, mTORIs present adverse effects such as oral ulcer, dyslipidemia, impairment of wound healing, and proteinuria. 4,5,11 The adverse events observed in our patients, who failed to remain on a same mTORI for at least 6 months, were oral ulceration, dyslipidemia, and unsatisfactory trough concentrations in up to 11.4% and 13.3% in sirolimus and everolimus users, respectively. Our findings and previous evidence suggested that when assessing the appropriateness of mTORI conversion therapy, the benefits and risks should be balanced individually.…”

“…4 The indicators of mTORI conversion therapy included at least 1 of the following conditions: eGFR <60 mL/min/1.73 m 2 (renal dysfunction), history of hepatic cellular carcinoma or recurrence, biopsy-proved rejection, and CNI-related adverse drug reactions. 4 Because sirolimus (2002) was introduced earlier than everolimus (2010) in Taiwan, the number of liver transplant recipients on sirolimus therapy was more than that on everolimus. The recipients were randomly assigned to receive either everolimus or sirolimus conversion therapy based on the indications of the mTORI conversion therapy during the study period.…”

“…2,3 Introduced in the 1990s, sirolimus was the first mTORI and has been widely used in long-term liver transplant recipients. Several centers, including ours, 4 have robust clinical experiences with sirolimus in liver transplant recipients who are intolerable to CNI or have concomitant malignant diseases. Everolimus was the second mTORI to be developed, and it differs from sirolimus by the addition of a hydroxyethyl group; it has been used for kidney and liver transplantations.…”

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

“…Post-transplant diabetes mellitus represents a major adverse effect of immunosuppressive drugs 1 – 4 and is associated with high cumulative incidence of cardiac events, vascular disease, and overall impaired survival rates 5 . Sirolimus (rapamycin) was introduced in the Edmonton immunosuppression protocol in islet transplant recipients 6 , 7 , attempting to minimize the diabetogenic effects observed with corticosteroids and other immunosuppressive regimens.…”