Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease

Abstract

Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumulate in plasma in tubular dysfunction. We here hypothesize that PBUT clearance may be a sensitive tubular function marker, and tested this in a DKD mouse model and in type 2 diabetic patients. Among the PBUTs with the highest OAT affinity (i.e., indoxyl sulfate (IS), hippuric acid (HA) and kynurenic acid (KA)), plasma concentrations were higher and urinary excretions were lower 6 and 8 months after DKD induction in mice. These parameters correlated better with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers. In patients, the clearance of IS, HA, KA and p-cresyl sulfate (PCS) was associated with urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), independent of eGFR. In multiple regression analysis, additionally adjusted for relevant risk factors for tubular injury, the clearance of IS, HA and PCS remained significantly associated with urinary NGAL. In conclusion, IS, HA, KA and PCS clearance may represent a biomarker of kidney tubular function in DKD.

Keywords: Diabetic kidney disease; Hippuric acid; Indoxyl sulfate; Protein-bound uremic toxins; Tubular function marker.

Fig. 1

PBUTs plasma concentration, surrogate clearance and fractional excretion in DKD mice and healthy controls. Data are presented as mean ± SD. The non-parametric Mann–Whitney U test or parametric unpaired t-test was performed for statistical analysis based on the data normality determined by the Kolmogorov–Smirnov test. ***P < 0.001, **P < 0.01, *P < 0.05. DKD: diabetic kidney disease; IS: indoxyl sulfate; HA: hippuric acid; KA: kynurenic acid.

Fig. 2

Correlation of f4/80 score with plasma concentration, clearance and fractional excretion of IS (A–C), HA (D–F), Cr clearance (G), plasma Cr (H), plasma Cys C (I). Non-parametric spearman correlation was performed, and the data are presented as spearman rank, where ‘-’ indicates negative correlation. **P < 0.01, *P < 0.05. IS: indoxyl sulfate; HA: hippuric acid; KA: kynurenic acid; Cr: creatinine; Cys C: cystatin C; uCr: Urinary creatinine.