The protein metabolite theory as a mechanism for the progression of renal failure

Abstract

WE HAVE SHOWN that indoxyl sulfate is one of the circulating uremic toxins accelerating the progression of chronic renal failure (CRF).1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 2Niwa T Ise M Miyazaki T Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate.Am J Nephrol. 1994; 14: 207-212Crossref PubMed Scopus (157) Google Scholar, 3Miyazaki T Ise M Seo H et al.Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and proα1(l) collagen in kidneys of uremic rats.Kidney Int. 1997; 52: S15-S22Google Scholar 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 into indoxyl sulfate in the liver. Indoxyl sulfate is normally excreted into urine. In uremia, however, reduced renal clearance of indoxyl sulfate leads to elevated serum levels of indoxyl sulfate. In fact, the serum levels of indoxyl sulfate are markedly increased in both uremic rats and patients.1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 4Niwa T Tsukushi S Ise M et al.Indoxyl sulfate and progression of renal failure: Effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.Miner Electrol Metab. 1997; 23: 179-194PubMed Google Scholar, 5Niwa T Nomura T Sugiyama S et al.The protein metabolite hypothesis, a model for the progression of renal failure: An oral sorbent lowers indoxyl sulfate levels in undialyzed uremic patients.Kidney Int. 1997; 52: S23-S28Google Scholar An oral sorbent (AST-120) reduces the serum and urine levels of indoxyl sulfate in uremic rats and patients by adsorbing indole in the intestines and, consequently, stimulating its excretion into feces.1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 4Niwa T Tsukushi S Ise M et al.Indoxyl sulfate and progression of renal failure: Effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.Miner Electrol Metab. 1997; 23: 179-194PubMed Google Scholar, 5Niwa T Nomura T Sugiyama S et al.The protein metabolite hypothesis, a model for the progression of renal failure: An oral sorbent lowers indoxyl sulfate levels in undialyzed uremic patients.Kidney Int. 1997; 52: S23-S28Google Scholar, 6Miyazaki T Aoyama I Ise M et al.An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys.Nephrol Dial Transplant. 2000; 15: 1773-1781Crossref PubMed Scopus (139) Google Scholar The administration of indoxyl sulfate to 5/6-nephrectomized rats promoted the progression of CRF accompanied by increased gene expression of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinase (TIMP)-1, and proβ1(l)collagen.3Miyazaki T Ise M Seo H et al.Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and proα1(l) collagen in kidneys of uremic rats.Kidney Int. 1997; 52: S15-S22Google Scholar These findings support the notion that indoxyl sulfate is one of the uremic toxins stimulating the progression of CRF by increasing the renal expression of these fibrosis-related genes.I proposed the protein metabolite theory that endogenous protein metabolites, such as indoxyl sulfate, play a significant role in the progression of CRF.5Niwa T Nomura T Sugiyama S et al.The protein metabolite hypothesis, a model for the progression of renal failure: An oral sorbent lowers indoxyl sulfate levels in undialyzed uremic patients.Kidney Int. 1997; 52: S23-S28Google Scholar The initial insult leads to a loss of functioning nephrons via a disease-specific pathophysiologic process. A progressive decline in the glomerular filtration rate leads to increased circulating levels of endogenous protein metabolites, such as indoxyl sulfate, and the adverse effects of their overload on the remnant nephrons, especially proximal tubular cells. Indoxyl sulfate is normally excreted into urine mainly by active secretion by the proximal tubular cells. Indoxyl sulfate, for example, stimulates progressive tubulointerstitial fibrosis, glomerular sclerosis, and the progression of CRF by increasing the gene expression of TGF-β1, TIMP-1, and proβ1(l)collagen, leading to a further loss of nephrons.3Miyazaki T Ise M Seo H et al.Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and proα1(l) collagen in kidneys of uremic rats.Kidney Int. 1997; 52: S15-S22Google Scholar Thus, the vicious circle of progressive of renal injury is complete. A low-protein diet delays the progression of CRF by suppressing renal TGF-β1 expression in uremic animals, and it also reduces the serum levels of indoxyl sulfate.1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 4Niwa T Tsukushi S Ise M et al.Indoxyl sulfate and progression of renal failure: Effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.Miner Electrol Metab. 1997; 23: 179-194PubMed Google Scholar The administration of AST-120 decreases the serum and urine levels of indoxyl sulfate, and delays the progression of CRF by reducing the gene expression of TGF-β1, TIMP-1, and proβ1(l)collagen.6Miyazaki T Aoyama I Ise M et al.An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys.Nephrol Dial Transplant. 2000; 15: 1773-1781Crossref PubMed Scopus (139) Google Scholar AST-120 is widely used as an approved drug in Japan to treat more than 30,000 patients with uremia not receiving dialysis to delay the progression of CRF. If the overload of indoxyl sulfate, for example, is alleviated by a low-protein diet or by the administration of the oral sorbent, the chain of events leading to progression of renal damage might be interrupted. In fact, many clinical and experimental studies have found that both dietary protein restriction and the oral sorbent can suppress the progression of CRF. However, indoxyl sulfate may not be the only stimulating factor for the progression of CRF, but a representative of the endogenous protein metabolites stimulating CRF progression. WE HAVE SHOWN that indoxyl sulfate is one of the circulating uremic toxins accelerating the progression of chronic renal failure (CRF).1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 2Niwa T Ise M Miyazaki T Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate.Am J Nephrol. 1994; 14: 207-212Crossref PubMed Scopus (157) Google Scholar, 3Miyazaki T Ise M Seo H et al.Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and proα1(l) collagen in kidneys of uremic rats.Kidney Int. 1997; 52: S15-S22Google Scholar 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 into indoxyl sulfate in the liver. Indoxyl sulfate is normally excreted into urine. In uremia, however, reduced renal clearance of indoxyl sulfate leads to elevated serum levels of indoxyl sulfate. In fact, the serum levels of indoxyl sulfate are markedly increased in both uremic rats and patients.1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 4Niwa T Tsukushi S Ise M et al.Indoxyl sulfate and progression of renal failure: Effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.Miner Electrol Metab. 1997; 23: 179-194PubMed Google Scholar, 5Niwa T Nomura T Sugiyama S et al.The protein metabolite hypothesis, a model for the progression of renal failure: An oral sorbent lowers indoxyl sulfate levels in undialyzed uremic patients.Kidney Int. 1997; 52: S23-S28Google Scholar An oral sorbent (AST-120) reduces the serum and urine levels of indoxyl sulfate in uremic rats and patients by adsorbing indole in the intestines and, consequently, stimulating its excretion into feces.1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 4Niwa T Tsukushi S Ise M et al.Indoxyl sulfate and progression of renal failure: Effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.Miner Electrol Metab. 1997; 23: 179-194PubMed Google Scholar, 5Niwa T Nomura T Sugiyama S et al.The protein metabolite hypothesis, a model for the progression of renal failure: An oral sorbent lowers indoxyl sulfate levels in undialyzed uremic patients.Kidney Int. 1997; 52: S23-S28Google Scholar, 6Miyazaki T Aoyama I Ise M et al.An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys.Nephrol Dial Transplant. 2000; 15: 1773-1781Crossref PubMed Scopus (139) Google Scholar The administration of indoxyl sulfate to 5/6-nephrectomized rats promoted the progression of CRF accompanied by increased gene expression of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinase (TIMP)-1, and proβ1(l)collagen.3Miyazaki T Ise M Seo H et al.Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and proα1(l) collagen in kidneys of uremic rats.Kidney Int. 1997; 52: S15-S22Google Scholar These findings support the notion that indoxyl sulfate is one of the uremic toxins stimulating the progression of CRF by increasing the renal expression of these fibrosis-related genes. I proposed the protein metabolite theory that endogenous protein metabolites, such as indoxyl sulfate, play a significant role in the progression of CRF.5Niwa T Nomura T Sugiyama S et al.The protein metabolite hypothesis, a model for the progression of renal failure: An oral sorbent lowers indoxyl sulfate levels in undialyzed uremic patients.Kidney Int. 1997; 52: S23-S28Google Scholar The initial insult leads to a loss of functioning nephrons via a disease-specific pathophysiologic process. A progressive decline in the glomerular filtration rate leads to increased circulating levels of endogenous protein metabolites, such as indoxyl sulfate, and the adverse effects of their overload on the remnant nephrons, especially proximal tubular cells. Indoxyl sulfate is normally excreted into urine mainly by active secretion by the proximal tubular cells. Indoxyl sulfate, for example, stimulates progressive tubulointerstitial fibrosis, glomerular sclerosis, and the progression of CRF by increasing the gene expression of TGF-β1, TIMP-1, and proβ1(l)collagen, leading to a further loss of nephrons.3Miyazaki T Ise M Seo H et al.Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and proα1(l) collagen in kidneys of uremic rats.Kidney Int. 1997; 52: S15-S22Google Scholar Thus, the vicious circle of progressive of renal injury is complete. A low-protein diet delays the progression of CRF by suppressing renal TGF-β1 expression in uremic animals, and it also reduces the serum levels of indoxyl sulfate.1Niwa T Ise M Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis.J Lab Clin Med. 1994; 124: 96-104PubMed Google Scholar, 4Niwa T Tsukushi S Ise M et al.Indoxyl sulfate and progression of renal failure: Effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.Miner Electrol Metab. 1997; 23: 179-194PubMed Google Scholar The administration of AST-120 decreases the serum and urine levels of indoxyl sulfate, and delays the progression of CRF by reducing the gene expression of TGF-β1, TIMP-1, and proβ1(l)collagen.6Miyazaki T Aoyama I Ise M et al.An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys.Nephrol Dial Transplant. 2000; 15: 1773-1781Crossref PubMed Scopus (139) Google Scholar AST-120 is widely used as an approved drug in Japan to treat more than 30,000 patients with uremia not receiving dialysis to delay the progression of CRF. If the overload of indoxyl sulfate, for example, is alleviated by a low-protein diet or by the administration of the oral sorbent, the chain of events leading to progression of renal damage might be interrupted. In fact, many clinical and experimental studies have found that both dietary protein restriction and the oral sorbent can suppress the progression of CRF. However, indoxyl sulfate may not be the only stimulating factor for the progression of CRF, but a representative of the endogenous protein metabolites stimulating CRF progression.