Uremic toxicity of indoxyl sulfate

Abstract

Indoxyl sulfate, a uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients. A part of the dietary protein-derived tryptophan is metabolized into indole by tryptophanase in intestinal bacteria. Indole is absorbed into the blood from the intestine, and is metabolized to indoxyl sulfate in the liver. Indoxyl sulfate is normally excreted into urine. In CKD, however, an inadequate renal clearance of indoxyl sulfate leads to its elevated serum levels. The oral adsorbent AST-120 reduces the serum levels of indoxyl sulfate by adsorbing indole in the intestines and stimulating its excretion into feces. I have proposed a protein metabolite theory by which endogenous protein metabolites such as indoxyl sulfate play a significant role in the progression of CKD. A progressive decline in the glomerular filtration rate leads to increased serum levels of endogenous protein metabolites such as indoxyl sulfate, and to the adverse effects of their overload on the remnant nephrons. Indoxyl sulfate stimulates progressive both tubulointerstitial fibrosis and glomerular sclerosis by increasing the expression of transforming growth factor-beta1, a tissue inhibitor of metalloproteinase-1 and proalpha1 (I) collagen, leading to a further loss of nephrons. AST-120 delays the progression of CKD by removing serum indoxyl sulfate. Moreover, indoxyl sulfate induces oxidative stress in tubular cells, mesangial cells, vascular smooth muscle cells, endothelial cells and osteoblasts as well as stimulating aortic calcification in hypertensive rats, it is also involved in the progression of CKD, cardiovascular disease (CVD) and osteodystrophy. Thus, the removal of indoxyl sulfate by AST-120 ameliorates the progression of not only CKD, but also of CVD and osteodystrophy.

Fig. 1

Chemical structure of indoxyl sulfate (molecular weight: 213). Indoxyl sulfate is a uremic toxin derived from dietary protein, and is synthesized from indole, a metabolite of tryptophan. Its serum levels are elevated in chronic kidney disease (CKD) patients. It is an accelerating factor of CKD, and a small hydrophobic anion.

Fig. 2

Metabolism of indoxyl sulfate and effect of AST-120 (Kremezin). Indoxyl sulfate is derived from dietary protein. A part of protein-derived tryptophan is metabolized into indole by tryptophanase in intestinal bacteria such as Escherichia coli. Indole is absorbed into the blood from the intestine, and is metabolized to indoxyl sulfate in the liver, it is normally excreted in urine. In uremia, however, reduced renal clearance of indoxyl sulfate leads to elevated serum levels of indoxyl sulfate. AST-120 reduces the serum and urine levels of indoxyl sulfate in chronic kidney disease (CKD) patients by adsorbing indole in the intestines, and consequently stimulating its excretion in feces.

Fig. 3

The protein metabolite theory, a mechanism for the progression of chronic kidney disease (CKD). Endogenous protein metabolites such as indoxyl sulfate play a significant role in the progression of CKD. The initial insult leads to a loss of functioning nephrons via a disease-specific pathophysiological process. A progressive decline in the glomerular filtration rate leads to increased circulating levels of endogenous protein metabolites such as indoxyl sulfate, and to the adverse effects of their overload on the remnant nephrons, especially proximal tubular cells. Indoxyl sulfate stimulates progressive tubulointerstitial fibrosis, glomerular sclerosis, and the progression of CKD by increasing the gene expression of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinase (TIMP)-1 and proα1 (I) collagen, leading to a further loss of nephrons and completing the vicious circle of progressive renal injury. If the overload of indoxyl sulfate, for example, is alleviated by a low-protein diet or by the administration of AST-120, the chain of events leading to the further progression of renal damage might be interrupted.

Fig. 4

Nephrotoxicity of indoxyl sulfate. Indoxyl sulfate in the blood is taken up by organic anion transporters (OAT1 and OAT3) at the basolateral membrane of renal tubular cells in which it is accumulated. Indoxyl sulfate generates free radicals, reduces superoxide scavenging activity, and consequently causes tubular cell injury by impairing the kidney’s anti-oxidative systems. The damaged tubular cells produce transforming growth factor (TGF)-β1 as well as chemokines such as intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), osteopontin and endothelin-1 (ET-1). These chemokines promote the infiltration of macrophages which produce TGF-β1. The secreted TGF-β1 stimulates production of tissue inhibitor of metalloproteinase (TIMP)-1 and collagen. The injured tubular cells are transformed into myofibroblasts through an epithelial-to-mesenchymal transition induced by TGF-β1. These changes facilitate interstitial fibrosis. Thus, indoxyl sulfate accumulated in chronic kidney disease (CKD) serum accelerates tubular cell injury and subsequent interstitial fibrosis.

Fig. 5

Uremic toxicity of indoxyl sulfate. Indoxyl sulfate induces the cellular production of free radicals such as superoxide by activating NADPH oxidase, especially Nox4, and/or by its uptake through organic anion transporters (OAT1 and OAT3), consequently impairing cellular anti-oxidative system. It also induces free radicals in renal tubular cells and glomerular mesangial cells, and stimulates the progression of chronic kidney disease (CKD), as well as inducing free radicals in vascular smooth muscle cells (VSMC) and vascular endothelial cells, and aggravating cardiovascular disease. Moreover, indoxyl sulfate induces free radicals in osteoblasts and causes osteodystrophy.