Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion.

Silvia M Mihaila,Rosalinde Masereeuw,Dimitrios Stamatialis,Karin G F Gerritsen,Marianne C Verhaar,João Faria,Maurice F J Stefens

doi:10.3390/toxins12060391

Silvia M Mihaila, Rosalinde Masereeuw + Show 5 more

Open Access

https://doi.org/10.3390/toxins12060391

Copy DOI

Abstract

In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake. We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equipped with OAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay. We show that selected ARBs and furosemide significantly reduced fluorescein uptake, with the highest potency for ARBs. This was exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function.

Highlights

Chronic kidney disease (CKD) is a worldwide public health problem associated with considerable prevalence of comorbidities, impaired quality of life and premature mortality [1]
Our major findings are that protein-bound uremic toxins (PBUTs) may directly interact with drugs commonly prescribed in chronic kidney disease (CKD) management for OAT1-mediated renal transport at concentrations found in uremic serum
These interactions could exert widespread and unpredictable effects in CKD patients that already have a high burden of co-existing diseases, poor health-related quality of life and are prescribed many medications [16,17]

Summary

Introduction

Chronic kidney disease (CKD) is a worldwide public health problem associated with considerable prevalence of comorbidities, impaired quality of life and premature mortality [1]. In patients with advanced CKD, uremic solutes accumulate due to impaired renal clearance [2]. CKD patients are routinely treated with many drugs that require transporters and DMEs for their disposition [11,16]. The daily medication burden in kidney patients is one of the highest reported to date in any chronic disease state [17], and drugs are prescribed mainly at alleviating the metabolic, endocrine and cardiovascular complications in renal insufficiency [18,19,20,21]. With drug–drug interactions occurring even in patients without renal impairment, such interactions are likely more prevalent in CKD owing to the presence of high levels of uremic solutes that compete with the administered drugs and with each other for transporters and DMEs [7]

Objectives

Methods

Results

Conclusion