Furosemide and Serum Protein-Bound Uremic Toxin Concentrations in Patients With CKD

Furosemide is commonly prescribed to patients with chronic kidney disease (CKD) but may impair the kidney's excretion of protein-bound uremic toxins (PBUTs) via the organic anion transporters 1 and 3 (OAT1 and OAT3). We evaluated the association between furosemide prescription (status and dose level) and the serum concentrations of free OAT1/3-inhibiting uremic toxins (UTs) in patients with CKD.

We included 2342 patients with CKD (stages 2-5) from the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort and with centralized serum UT assay data at baseline. The UTs were assayed using liquid chromatography - tandem mass spectrometry. The OAT1/3-inhibiting UTs identified in a literature review included indoxyl sulphate (IS), kynurenine (Kyn), p-cresyl sulphate (PCS), and indole-3-acetic acid (IAA). Multiple linear regression was used to assess each PBUT or their sum ( $\Sigma \text{UTs}$ _free) as the dependent variable.

Patients prescribed furosemide (n = 799, 34%) were older and had a lower estimated glomerular filtration rate (eGFR), a higher C-reactive protein (CRP) concentration, more comorbidities, and more concomitant medications than patients not prescribed furosemide. After adjustment for potential confounders, patients prescribed > 120 mg furosemide had significantly higher serum concentrations of $\Sigma \text{UTs}$ _free (+19.1%), IS (+31.9%), Kyn (+9.3%), PCS (+29.3%), and IAA (+162.9%) than patients not prescribed furosemide. Using a smooth function to model the association between the furosemide dose level and PBUTs, we observed (for $\Sigma \text{UTs}$ _free and each free UT) a steep increase between 80 and 100 mg and then a high plateau.

In patients with CKD, furosemide (particularly at a dose level > 120 mg) is independently associated with higher serum free PBUT concentrations. Our findings suggest that drug-UT competition contributes to PBUT accumulation.