Molecular insights into preventive effects of AST-120 on the progression of renal failure

Abstract

Circulating uremic toxins are considered to be involved in the progression of chronic renal failure (CRF). An oral adsorbent AST-120 (Kremezin) is effective in removing circulating uremic toxins from the digestive tract, and retards the progression of CRF. The administration of AST-120 combined with an angiotensin-converting enzyme inhibitor or a low-proein diet has an additive effect on the progression of CRF. In a variety of experimental models of CRF, AST-120 attenuates the progression of interstitial fibrosis and inflammation, as well as attenuating that of glomerular sclerosis. However, the precise mechanism by which AST-120 delays the progression of CRF had not been clear. Indoxyl sulfate, a dietary protein metabolite, is a circulating uremic toxin that stimulates the progression of CRF. AST-120 reduces the serum and urine levels of indoxyl sulfate and the accumulation of indoxyl sulfate in remnant tubular cells, by adsorbing its precursor, indole, in the intestine. The administration of indoxyl sulfate to uremic rats stimulated the expression of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinase (TIMP)-1, and pro-α1(I)collagen in the kidneys. The administration of AST-120 to uremic rats reduced the extent of glomerular sclerosis and interstitial fibrosis, as well as reducing the renal expression of TGF-β1 and TIMP-1, by alleviating the overload of indoxyl sulfate in remnant tubular cells. We propose the protein metabolite theory, i.e., that endogenous protein metabolites such as indoxyl sulfate play an important role in the progression of CRF, and that AST-120 is effective in retarding the progression of CRF by adsorbing these protein metabolites in the intestine.