Indoxyl sulphate and the kidneys

Robert J Ellis, David M Small, David A Vesey, David W Johnson, Ross Francis, Luis Vitetta, Glenda C Gobe, Christudas Morais

In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate [GFR] < 60 mL/min/1.73m(2) ) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest growing public health concerns worldwide. CKD is characterised by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes), such as indoxyl sulphate (IS), a protein-bound, tryptophan-derived metabolite that is generated by intestinal micro-organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) review reported effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarise both established and hypothetical therapeutic options for reducing serum IS or antagonising its reported downstream effects in the kidney.