The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review

Abstract

A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

Keywords: CKD; indoxyl sulfate; p-cresyl; signaling; sulfate; uremic toxins.

Figure 1.

Flowchart of the review procedure and quality scoring.

Figure 2.

Effects as seen in the (A) endothelial cell and (B) renal tubular cell. The effects of indoxyl sulfate and p-cresyl sulfate are represented by orange and purple arrows, respectively. The transcellular membrane transport of indoxyl sulfate and p-cresyl sulfate by the organic anion transporters is represented by the thick white arrow. α-SMA, α-smooth muscle actin; 5-Aza-2dc, 5-Aza-2′-deoxycytidine; CpG, cytosine-phosphate-guanine (DNA sequence); DAG, diacylglycerol; DNMT, DNA methyltransferase; DPI, diphenylene iodonum chloride; EMT, epithelial-to-mesenchymal transition; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; G, G protein-coupled receptor; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IKB, inhibitor of κB; IP₃, inositol 1,4,5-triphosphate; IS, indoxyl sulfate; L-arg, l-arginine; LFA-1, lymphocyte function-associated antigen 1; MCP-1, monocyte chemoattractant protein-1; Me, Methylgroup; NAC, N-acetylcysteine; NADPH ox, NADPH oxidase; NO, nitric oxide; NQO1, NADPH guinone oxidoreductase 1; Nrf, NF (erythroid-derived 2) -like; OAT, organic anion transporter; 8-OHdG, 8-hydroxydeoxyguanosine; p, protein; PCS, p-cresyl sulfate; PIP₂, phosphatidylinositol 4,5-biphosphate; PLC, phospholipase C; PKC, protein kinase C; RAAS, renin angiotensin aldosterone system; ROS, reactive oxygen species; Vit C, vitamin C; Vit E, vitamin E; ZO-1, Zonula occludens protein 1.

Figure 2.

Effects as seen in the (A) endothelial cell and (B) renal tubular cell. The effects of indoxyl sulfate and p-cresyl sulfate are represented by orange and purple arrows, respectively. The transcellular membrane transport of indoxyl sulfate and p-cresyl sulfate by the organic anion transporters is represented by the thick white arrow. α-SMA, α-smooth muscle actin; 5-Aza-2dc, 5-Aza-2′-deoxycytidine; CpG, cytosine-phosphate-guanine (DNA sequence); DAG, diacylglycerol; DNMT, DNA methyltransferase; DPI, diphenylene iodonum chloride; EMT, epithelial-to-mesenchymal transition; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; G, G protein-coupled receptor; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IKB, inhibitor of κB; IP₃, inositol 1,4,5-triphosphate; IS, indoxyl sulfate; L-arg, l-arginine; LFA-1, lymphocyte function-associated antigen 1; MCP-1, monocyte chemoattractant protein-1; Me, Methylgroup; NAC, N-acetylcysteine; NADPH ox, NADPH oxidase; NO, nitric oxide; NQO1, NADPH guinone oxidoreductase 1; Nrf, NF (erythroid-derived 2) -like; OAT, organic anion transporter; 8-OHdG, 8-hydroxydeoxyguanosine; p, protein; PCS, p-cresyl sulfate; PIP₂, phosphatidylinositol 4,5-biphosphate; PLC, phospholipase C; PKC, protein kinase C; RAAS, renin angiotensin aldosterone system; ROS, reactive oxygen species; Vit C, vitamin C; Vit E, vitamin E; ZO-1, Zonula occludens protein 1.