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

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Introduction Furosemide is commonly prescribed to patients with CKD but may impair the kidney's excretion of protein-bound uraemic toxins (PBUTs) via the organic anion transporters 1 and 3 (OAT1/OAT3). We evaluated the association between the furosemide prescription (status and dose level) and the serum concentrations of free OAT1/3-inhibiting uraemic toxins (UTs) in patients with CKD. Methods We included 2,342 patients with CKD (stages 2–5) from the 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 ( Σ UTs free ) as the dependent variable. Results Patients prescribed furosemide (n=799, 34%) were older and had a lower estimated glomerular filtration rate, a higher C-reactive protein 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 Σ UTs free (+19.1%), IS (+31.9%), Kyn (+9.3%), PCS (+29.3%) and IAA (+16.9%) than patients not prescribed furosemide. Using a smooth function to model the association between the furosemide dose level and PBUTs, we observed (for Σ UTs free and each free UT) a steep increase between 80 and 100 mg and then a high plateau. Conclusion In patients with CKD, furosemide (particularly at a dose level >100 mg) is independently associated with higher serum free PBUT concentrations. Our findings suggested that drug-UT competition contributes to PBUT accumulation.

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