Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

Abstract

Indoxyl sulfate is an extensively studied uremic solute. It is a small molecule that is more than 90% bound to plasma proteins. Indoxyl sulfate is derived from the breakdown of tryptophan by colon microbes. The kidneys achieve high clearances of indoxyl sulfate by tubular secretion, a function not replicated by hemodialysis. Clearance by hemodialysis is limited by protein binding since only the free, unbound solute can diffuse across the membrane. Since the dialytic clearance is much lower than the kidney clearance, indoxyl sulfate accumulates to relatively high plasma levels in hemodialysis patients. Indoxyl sulfate has been most frequently implicated as a contributor to renal disease progression and vascular disease. Studies have suggested that indoxyl sulfate also has adverse effects on bones and the central nervous system. The majority of studies have assessed toxicity in cultured cells and animal models. The toxicity in humans has not yet been proven, as most data have been from association studies. Such toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means. The largest randomized trial showed no benefit in renal disease progression with AST-120. No trials have yet tested cardiovascular or mortality benefit. Without such trials, the toxicity of indoxyl sulfate cannot be firmly established.

Effect of Ionic Strength, pH and Chemical Displacers on the Percentage Protein Binding of Protein-Bound Uremic Toxins

“…Normally excreted by the kidneys, all of these toxins exert pleiotropic toxic biological effects in CKD. For example, PCS and IS have repeatedly been associated with overall mortality, cardiovascular disease and progression of CKD [3][4][5]. Notwithstanding Shafi et al [20] failed to confirm an association between total PCS and IS and cardiovascular outcomes in prevalent HD patients in a latest post hoc analysis on the HEMO trial, a commentary in the same issue suggested that analytical issues and case-mix may explain the discrepant findings [21].…”

“…Their generation results from a sulfatation of p-cresol and indole by the enterocytes and hepatocyte, respectively, 2 solutes generated in the gut by the microbiota metabolism of tryptophan, phenylalanine and tyrosine [19]. In serum, they are both approximately 90% or more bound to Sudlow's site II of albumin and hence often as prototypes of tightly albumin-bound toxins [3][4][5]. 3-IAA, with an MW of 175 Da and a protein-binding of 70-75%, is issued from tryptophan metabolism [19].…”

“…Although PBUTs have a major impact on the morbidity and mortality of patients with chronic kidney diseases (CKD), their clearances by conventional extracorporeal therapies have been low until now [3][4][5][6][7][8].…”

The systems biology of uric acid transporters

“…For instance, one of the major uremic toxins, indoxyl sulfate, arises as a tryptophan derivative in the gut microbiome that is transported across the intestine, sulfated by phase 2 enzymes in the liver, and in the absence of severe CKD, eliminated via OAT1 and OAT3 in the proximal tubule [59]. As with uric acid, indoxyl sulfate can affect cellular function, in this case by binding the aryl hydrocarbon receptor [60].…”

Limited Effect of Intravenously Administered Indoxyl Sulfate, a Uremic Toxin, on the Hepatic Transport of Pravastatin in Normal Rats

“…Elevated IS levels leads to the induction of various unfavorable events such as progression to renal failure, and cardiovascular and bone toxicities [2] [3]. IS accumulation is attributed primarily to the fact that IS is a potent substrate of organic anion transporter (OAT) and OAT3 presents on the basal membrane of the renal epithelial cells [4] [5].…”