Exploring the Interactions between Drugs and Metabolic Disturbances in CKD

Key Points Kidney function was independently associated with free drug concentration; the latter concentration was higher in patients with a lower eGFR. The conformational changes in albumin induced by carbamylation may alter its binding capacity to vitamin K antagonists. The results on the accumulation of free fraction of drugs in patients with low eGFR may be applicable to other drugs that are bound to plasma proteins. Background The metabolic disturbances associated with CKD might alter drug distribution, decrease albumin drug binding, and thus increase the free (unbound) drug concentrations. Uremic toxins (UTs) can affect the pharmacokinetic or pharmacodynamic activity of certain drugs. Vitamin K antagonists (VKAs) are interesting candidates for the evaluation of potential interactions between UTs and drugs. The primary objective of this study was to investigate the association between free VKA concentrations and the eGFR. Furthermore, we sought to determine whether this relationship was mediated by protein carbamylation (measured by homocitrulline levels) and/or the accumulation of protein-bound UTs (PBUTs). Methods In this prospective cross-sectional study, 389 adult patients treated with VKA were included between May 2021 and June 2023. Levels of free VKAs, total VKAs, homocitrulline, and PBUTs were assayed using liquid chromatography-tandem mass spectrometry. We used a linear regression model to explore the association between kidney function and free VKA levels and mediation analyses to determine whether the association between kidney function and free VKA levels was mediated (at least partly) by PBUTs and/or protein carbamylation. Results Patients with an eGFR <40 ml/min per 1.73 m 2 or those on chronic hemodialysis had lower total VKA levels, higher free VKA levels, and thus a higher of free/total VKA ratio than those with an eGFR ≥40 ml/min per 1.73 m 2 . Kidney function was independently associated with free VKA levels ( β 1 =0.31 [0.19 to 0.42], P < 0.001). Twenty-one percent (95% confidence interval, 1% to 35%) of the association between kidney function and free VKA levels was mediated by homocitrulline, but not by PBUTs. Conclusions Our results showed that a low kidney function was associated with an elevation in the VKA free drug fraction. This association was independent of blood albumin levels and appeared to be partly mediated by protein carbamylation.