Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy.

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.

Background: Calcific aortic valve disease (CAVD) is prevalent in chronic kidney disease (CKD), yet no pharmacological therapies exist. Preclinical models rarely incorporate CKD–mineral and bone disorder (CKD-MBD) features, limiting translational potential. We aimed to develop a comprehensive preclinical approach to study CKD-associated CAVD, suitable for standardized assessment of therapies on valvular, cardiac, vascular, and skeletal outcomes. Methods: Eight-week-old male Sprague Dawley rats were assigned to a control group (n=17) fed standard chow or an adenine-phosphate group (AP, n=21) fed chow supplemented with 0.3% adenine and 1.15% phosphate. Diets were enriched with 20% lactose and 19% casein to facilitate phosphate absorption and calcium solubility. Cardiac function was evaluated by echocardiography at baseline, week 5, and 9, with concurrent blood sampling. Aortic valve (AV) calcification was assessed by Alizarin Red and Osteosense staining, and aortic calcium quantified using O-Cresolphthalein Complexone. Gene expression in the aorta and left ventricle (LV) was analyzed by RNA-seq at week 9, and bone microarchitecture assessed by micro-CT. Results: AP rats showed progressive increases in serum creatinine, calcium-phosphorus product, and uremic toxins. By week 9, they exhibited significant AV calcification, with reduced valve area and cusp separation. Relative wall thickness and LV histology were preserved, though transcriptomics revealed early priming toward inflammation and fibrosis. AP rats’ aortas showed calcification, osteogenic features and reduced systolic expansion. Bone analysis revealed cortical thinning and increased porosity, while trabecular bone showed reduced trabecular number, increased trabecular spacing, and compensatory thickening. Together with elevated PTH and FGF23 levels, these changes suggest high bone turnover due to secondary hyperparathyroidism and are correlated with the extent of AV calcification. Conclusions: These results underscore the model’s translational relevance, addressing multiple facets of CKD-MBD and supporting its use for preclinical screening of novel therapies targeting CKD-associated cardiovascular calcification.