Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease

Abstract

Indoxyl sulfate (IS) is a protein-bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single-pass intestinal perfusion in a rat model of renal insufficiency, MRP2- and BCRP-overexpressing Sf9 membrane vesicles, and Caco-2 cell monolayers. An in situ single-pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC-dependently. An excess amount of IS (3 mm) partially inhibited the MRP2- and BCRP-mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco-2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p-Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH-sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end-stage renal disease.

The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial

“…While IS and pCS are liver metabolites, IAA can be produced directly in the intestine before being absorbed [3]. IS, IAA and pCS are mainly cleared from the body by urinary excretion, but both biliary excretion and intestine secretion are possible and can be strengthened in the case of renal deficiency [4,5,6]. Moreover, the most part of p-cresol metabolites (and other phenolic compounds) excreted in the bile is known to undergo enterohepatic circulation [7].…”

The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction

“…Like other members of the ABC superfamily, its activity is dependent on ATP hydrolysis [ 166 , 167 ]. BCRP is found expressed in the kidney, intestine, liver, placenta, and blood vessels [ 168 , 169 , 170 , 171 ]. However, studies have reported a decrease in Bcrp expression in the kidneys of nephrectomized animals compared to the sham group, demonstrating that CKD may alter the expression of this transporter [ 172 , 173 ].…”

Indoxyl sulfate impairs in vitro erythropoiesis by triggering apoptosis and senescence

“…14 IS can bind with albumin, which causes a high accumulation in CKD patients even when maintaining dialysis. 15 It has been suggested that pathological mechanisms of uremic toxins to promote renal cell damage leading to renal failure include induction of reactive oxygen species (ROS), inflammation, fibrosis, and oxidative stress. [16][17][18] In addition, uremic toxins have also been reported to cause red blood cell death 19 and neutrophil apoptosis.…”