Estimation of Proximal Tubular Function by Stimulation of Organic Anion and Cation Transporters.

Abstract

Background: Tubular pathophysiology plays a critical role in the progression of chronic kidney disease (CKD). Exogenous stimulation of proximal tubule organic anion (OAT) and cation (OCT) transporters may be used to evaluate their responses independently of glomerular filtration rate (GFR) and their relation with clearance of protein-bound solutes and other biomarkers of tubular function.

Methods: A proof of principle study was conducted in nine healthy volunteers and 22 patients with CKD classified by their GFR in KDIGO stages. They were studied hourly during 4 hours with water-induced diuresis, after the ingestion of 5g of creatinine and intravenous injection of 1-1.5mg/kg of furosemide, as means to stimulate OCTs and OATs, respectively. GFR determination (iohexol urinary clearance) was done in hours 2 to 3 and 3 to 4 of the study. Indoxyl sulfate, pCresol sulfate and urinary biomarkers of tubular function were studied in the first hour.

Results: GFR was stable during the study. Maximal values of tubular secretion of creatinine (TScr) and furosemide (TSfuro) were obtained in the first hour. The KDIGO categories of GFR were widely distributed throughout the range of tubular secretory responses. One-hour stimulated response of organic anion transporters was negatively correlated with serum levels of Indoxyl sulfate (r=-0.59, p=0.005) and pCresol sulfate (r=-0.59, p=0.004). Urinary epidermal growth factor, ammonium, alpha 1 microglobulin, and uromodulin correlated with the increment of TScr and TSfuro. The urinary excretion rate of creatinine in the first hour after the ingestion of 5g of creatinine was strongly correlated with the TScr (r=0.836, p<0.001).

Conclusions: The functions of OATs and OCTs of the proximal tubule varied considerably between patients with similar GFRs and their impaired response was associated with retention of protein-bound uremic solutes and urine biomarkers of tubular dysfunction. The response of OCTs may be estimated by the urinary excretion of creatinine 1-hour after the ingestion of 5g of creatinine.