title: 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.
authors.affiliation: Nephrology Section, Ghent University Hospital, Ghent, Belgium Raymond.Vanholder@UGent.be.
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
authors.affiliation: Nephrology Section, Ghent University Hospital, Ghent, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Schepers
authors.affiliation: Nephrology Section, Ghent University Hospital, Ghent, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Pletinck
authors.affiliation: Nephrology Section, Ghent University Hospital, Ghent, Belgium.
authors.forename: Evi V
authors.initials: EV
authors.lastname: Nagler
authors.affiliation: Nephrology Section, Ghent University Hospital, Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Glorieux
mesh_terms: D000818:Animals; D003408:Cresols / Q000097:blood / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D007200:Indican / Q000097:blood / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008954:Models, Biological; D011485:Protein Binding; D051436:Renal Insufficiency, Chronic / Q000209:etiology; D013463:Sulfuric Acid Esters / Q000097:blood / Q000633:toxicity*; D014118:Toxins, Biological / Q000097:blood; D014511:Uremia / Q000097:blood / Q000139:chemically induced* / Q000150:complications
chemical_list: D003408:Cresols; D013463:Sulfuric Acid Esters; D014118:Toxins, Biological; C026865:uremia middle molecule toxins; C408690:4-cresol sulfate; D007200:Indican
keywords: CKD; indoxyl sulfate; p-cresyl; signaling; sulfate; uremic toxins