Uricosuric agents in uremic sera. Identification of indoxyl sulfata and hippuric acid.

Abstract

A B S T R A C T Serum and urine from chronically uremic patients and normal individuals were subjected to gel filtration on Sephadex-G10. The effects of the eluted fractions on the uptake of urate and para-aminohippurate by isolated cortical tubules of rabbit kidney were investigated. According to the origin of the samples, one to three major groups of fractions inhibiting both urate and para-aminohippurate transport were disclosed. The first eluted group occurred for all the samples under study. The second one was demonstrated in both sera and urines from uremic patients but only in urines from normal individuals. The third one was exclusively detected in uremic sera and urines. Among all the compounds identified, only hippuric acid, eluted in the fractions of the second group, was capable of inhibiting the uptake of urate and para-aminohippurate in vitro. The concentration for which this inhibitory effect of hippuric acid occurred was in the range of that existing in uremic sera. Indoxyl sulfate, which accumulates to very high concentrations in uremic serum, could not be disclosed in the above-mentioned fractions. This is explained by the strong adsorption of this indole derivative to Sephadex gel. Potassium indoxyl sulfate, when tested in vitro at the concentration existing in uremic serum, substantially inhibited the uptake of both urate and para-aminohippurate. In normal subjects, ingestion of hippuric acid or potassium indoxyl sulfate significantly increased fractional urinary excretion of uric acid. On the basis of these results, it is suggested that progressive retention of hippuric acid, indoxyl sulfate, and other yet unidentified inhibitors may explain the gradual increase in urinary fractional excretion of urate This work was presented in part at a symposium on uremia sponsored by the International

Renal Clearance of Endogenous Hippurate Correlates with Expression Levels of Renal Organic Anion Transporters in Uremic Rats

“…2; Table 4). HA significantly inhibited PAH transport in the kidney (Boumendil-Podevin et al, 1975), suggesting that both compounds are transported by the organic anion transport system. Recently, we demonstrated that rOat1 and human OAT1 (hOAT1) play an important role in renal uptake of HA (Deguchi et al, 2004).…”

“…Serum levels of the uremic toxin hippurate (HA) are markedly elevated in patients with uremia ( Vanholder et al, 2003). It has been suggested that HA plays a role in a variety of pathological conditions, including stimulation of ammoniagenesis (Dzurik et al, 2001), and inhibition of both plasma protein binding (Sakai et al, 1995) and organic anion secretion by the kidney (Boumendil-Podevin et al, 1975). HA also inhibits glucose utilization in muscles and so may be involved in development of muscular weakness in uremia (Spustova et al, 1987(Spustova et al, , 1989.…”

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…17,18 More recently, in vitro studies found that the uremic toxins hippuric acid and indoxyl sulfate effectively inhibited uptake of PAH in isolated rabbit renal tubules and that indoxyl sulfate administered in vivo significantly reduced the renal clearance of PAH in rats. 19,20 These data strongly implicate involvement of the classic organic anion transport system in the renal elimination of uremic 21 Today, this system has been identified as comprising (in part) the OATs within the organic cation/anion/ zwitterion (SLC22) transporter family and it is clear that OATs are key mediators of the transepithelial flux of many endogenous compounds, including acidic uremic toxins. 16,22,23 As such, renally expressed OATs are poised to play a central role in the pathophysiology associated with the intracellular accumulation and toxicity of uremic retention solutes.…”

Estimated Glomerular Filtration Rate Is a Poor Predictor of Concentration for a Broad Range of Uremic Toxins

“…However, over time it became more and more clear that the concentration of these solutes can be influenced by many factors. These could be, as also summarized in the review by Stevens and Levey (12), renal tubular secretion (indoxyl sulfate [IS], hippurate) (13), enzymatic metabolism (asymmetric dimethylarginine [ADMA]) (14), intestinal secretion/absorption (uric acid) (15), generation by intestinal flora (indoles, phenols) (16), and/or dietary habits or changes in distribution volume. Therefore, the question can be raised whether GFR predicts elimination and concentration of those solutes and thus their effect on the uremic status in a sufficiently robust manner.…”