The presence of donor‐specific anti‐HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Post-transplant diabetes mellitus (PTDM) is a frequent complication in renal transplantation. While both tacrolimus and ciclosporin are known to be associated with PTDM, the mechanisms underlying this metabolic disturbance and the relative contribution of concomitant corticosteroids have been unclear. At the University Hospital Maastricht, a series of studies have been conducted to investigate these issues. Administering tacrolimus to non-diabetic, dialysis patients was shown to result in a dose-related reduction in insulin secretion without altering insulin resistance. The patients who developed diabetes after transplantation already had impaired glucose metabolism pre-transplant. In a second study, corticosteroid withdrawal from tacrolimus-based immunosuppression reduced insulin resistance without changing insulin secretion. Moreover, reducing tacrolimus blood levels by 30% within the therapeutic window increased both insulin and C-peptide secretion by 24 and 36%, respectively. Accordingly, the effects of tacrolimus on insulin secretion are both dose dependent and reversible. A comparison of the effects of tacrolimus and ciclosporin on glucose metabolism revealed reduced insulin release with tacrolimus at week 3 post-transplant, but for the remainder of the 3 year follow-up there were no significant differences between the two treatment arms. Also, no difference was reported in glucose metabolism following conversion of stable renal recipients from ciclosporin to tacrolimus. Therefore, replacing tacrolimus with ciclosporin in patients experiencing glucose metabolism disturbances is unlikely to be helpful. In a recent study, early corticosteroid withdrawal from tacrolimus-based therapy resulted in a significantly lower incidence of new-onset diabetes mellitus than that achieved with a corticosteroid dose-tapering regimen. In conclusion, corticosteroid minimization plus dose-optimized tacrolimus immunosuppression is likely to be the best option for patients at risk of developing PTDM.

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor–recipient couples that were transplanted between 1995 and 2005. For these donors–recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04–1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10–1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.

Although there are experimental reports of cytochrome P450 3A4 iso-enzyme (CYP3A4) induction by glucocorticoids, there are no clinical reports about an interaction between tacrolimus and steroids. Therefore, tacrolimus trough level and dose were compared after dose-normalization before and after withdrawal of prednisolone. After withdrawal of 5 mg prednisolone, the median tacrolimus dose-normalized level increased by 14% in the retrospective ( n=54), and by 11% in the prospective ( n=8) part of the study. After withdrawal of 10 mg, this increase was 33% ( n=30) and 36% ( n=14), respectively. An additional pharmacokinetic part of the study ( n=8) revealed an 18% increase in AUC ( P=0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced metabolism after steroid withdrawal. The significant increase in tacrolimus exposure after steroid withdrawal may on the one hand counteract the reduction in immunosuppression intended by steroid withdrawal, and, on the other hand, may result in an increase of serum creatinine which could be misinterpreted as rejection.

The most prominent side effect of tacrolimus is the induction of posttransplant diabetes mellitus (PTDM). In this review, the authors discuss the incidence, mechanism, prevention, and treatment of tacrolimus-induced PTDM in renal patients.