Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation

Abstract

Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers.

Development and Validation of a New Score to Assess the Risk of Posttransplantation Diabetes Mellitus in Kidney Transplant Recipients

“…1,6,11 PTDM also increases the risk of graft rejection, graft failure, and mortality because of premature cardiovascular diseases. 2,4,7,9,[11][12][13] A retrospective analysis of the United States Renal Data System, which included >11 000 kidney transplant recipients, showed that PTDM is an independent predictor of mortality and graft failure. 14 PTDM is also a major cause of chronic kidney disease in liver transplants.…”

“…PTDM is a disease distinct from type 1 and type 2 diabetes mellitus. The pathophysiology of PTDM is multifactorial, 2,9,10 involving not only genetic, environmental, and physiological factors that are related to insulin resistance but also impaired insulin secretion because of β-cell damage. 8,11 Multiple modifiable and nonmodifiable risk factors have been implicated in the risk of PTDM, 3,6 such as age, male gender, higher body mass index (BMI), hepatitis C virus infection, hypomagnesemia, genetic susceptibility, reduced physical activity, and unhealthy diet.…”

Renal Lesions and Nephrotoxicity: Contemporary Challenges and Future Directions

“…Diabetes is related to some of the most widely studied renal complications globally. Jehn and coauthors investigated the impact of tacrolimus metabolism [ 2 ], which is associated with increased nephrotoxicity and unfavorable outcomes in kidney transplantation, with an increase in the risk for post-transplant diabetes mellitus. Data from patients and experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells showed that fast tacrolimus metabolism is not associated with an increased incidence of diabetes, either in vitro or in vivo.…”