Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf^®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL × 1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

Fast tacrolimus metabolism is linked to inferior outcomes such as rejection and lower renal function after kidney transplantation. Renal calcineurin-inhibitor toxicity is a common adverse effect of tacrolimus therapy. The present contribution hypothesized that tacrolimus-induced nephrotoxicity is related to a low concentration/dose (C/D) ratio. We analyzed renal tubular epithelial cell cultures and 55 consecutive kidney transplant biopsy samples with tacrolimus-induced toxicity, the C/D ratio, C0, C2, and C4 Tac levels, pulse wave velocity analyses, and sublingual endothelial glycocalyx dimensions in the selected kidney transplant patients. A low C/D ratio (C/D ratio < 1.05 ng/mL×1/mg) was linked with higher C2 tacrolimus blood concentrations (19.2 ± 8.7 µg/L vs. 12.2 ± 5.2 µg/L respectively; p = 0.001) and higher degrees of nephrotoxicity despite comparable trough levels (6.3 ± 2.4 µg/L vs. 6.6 ± 2.2 µg/L respectively; p = 0.669). However, the tacrolimus metabolism rate did not affect the pulse wave velocity or glycocalyx in patients. In renal tubular epithelial cells exposed to tacrolimus according to a fast metabolism pharmacokinetic profile it led to reduced viability and increased Fn14 expression. We conclude from our data that the C/D ratio may be an appropriate tool for identifying patients at risk of developing calcineurin-inhibitor toxicity.

The assignment of human leucocyte antigens (HLAs) against which antibodies are detected as unacceptable antigens (UAGs) avoids allocation of HLA- incompatible allografts. There is uncertainty as to what extent UAGs decrease the probability of receiving a kidney offer. Kidney transplantations in 3264 patients on the waiting lists of six German transplant centres were evaluated for a period of at least 2 years. The proportion of excluded offers due to UAGs was calculated as virtual panel-reactive antibodies (vPRAs). In the common Eurotransplant Kidney Allocation Scheme, the transplant probability was unaffected by vPRAs in exploratory univariate analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 2.5 weeks. The model was confirmed using an external validation cohort of 1521 patients from seven centres. If only patients with standard risk were considered (e.g. no simultaneous transplantation of other organs), only 1.3 weeks additional waiting time was needed. In the Eurotransplant Senior Program, patients with vPRA values >50% had a strongly reduced transplant probability in the unadjusted analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 5 weeks. This study demonstrates that the assignment of UAGs decreases the transplant probability in both main Eurotransplant allocation programs because of insufficient compensatory mechanisms. At present, for immunized patients, a prolonged waiting time has to be weighed against the increased immunologic risk due to donor-specific antibodies not assigned as UAGs.

The authors wish to make the following corrections to this paper