Exploring the Interactions between Drugs and Metabolic Disturbances in CKD: An Example with Oral Anticoagulants.

Background: The metabolic disturbances associated with chronic kidney disease might alter drug distribution, decrease albumin drug binding, and thus increase the free (unbound) drug concentrations. Uremic toxins can affect the pharmacokinetic or pharmacodynamic activity of certain drugs. Vitamin K antagonists (VKA) are interesting candidates for the evaluation of potential interactions between uremic toxins and drugs. The primary objective of the present study was to investigate the association between free VKA concentrations and the estimated glomerular filtration rate (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 uremic toxins (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/1.73 m2 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/1.73 m2. Kidney function was independently associated with free VKA levels (β1=0.31 [0.19; 0.42], p<0.001). Twenty one percent [95%CI, 1%-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 free drug fraction. This association was independent of blood albumin levels and appeared to be partly mediated by protein carbamylation.