A Low Tacrolimus Concentration/Dose Ratio Increases the Risk for the Development of Acute Calcineurin Inhibitor-Induced Nephrotoxicity

Abstract

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 Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

“…As a result, the tacrolimus peak levels in the first hours after oral administration are higher. Evidence for this hypothesis was obtained in an additional study in 56 renal transplant recipients, in whom the tacrolimus concentrations 2 h after drug intake (C 2 ) in patients with a low C 0 /D ratio (high metabolizers) were increased compared to the other patients (20.2 ± 10.3 ng/ml vs. 9.8 ± 4.2 ng/ml, respectively; p = 0.004) (Thölking et al, 2019). In daily practice most centers only monitor pre-dose tacrolimus concentrations, and the higher peak levels often go unnoticed.…”

“…Besides avoiding high peaks this will also improve adherence. Another option would be to switch to mTOR-inhibitors as suggested by Thölking et al (Schütte-Nütgen et al, 2019). There are no studies available that show that either of these options is beneficial.…”

Conversion from Standard-Release Tacrolimus to MeltDose® Tacrolimus (LCPT) Improves Renal Function after Liver Transplantation

“…The Tac blood concentration to daily dose ratio (C/D ratio) has been identified as a simple tool to describe patients' metabolism rate in a steady state, in which a low C/D ratio reflects a high rate of metabolism [13][14][15]. A low IR-Tac C/D ratio is linked with higher C2 Tac blood concentrations despite comparable trough levels in patients with high C/D ratios [16]. In this regard, a low C/D ratio is strongly associated with an increased risk of CNIT and a faster decline of renal function in both kidney transplant (KT) and LT recipients [13,[16][17][18][19].…”

Proteomic Characterization of Urinary Extracellular Vesicles from Kidney-Transplanted Patients Treated with Calcineurin Inhibitors

“…To avoid this scenario, CNI levels in patients should be maintained within a narrow therapeutic window, a big challenge due to the high inter- and intraindividual pharmacokinetic variability of these drugs [ 17 , 18 ]. There are currently no specific markers of CNIT, and tacrolimus or cyclosporine A trough levels not always correlate with CNIT [ 19 ].…”