Table 1.

Potential Adverse Effects of Metabolite Alterations

Direct cellular toxicity	A major focus of uremia research, with metabolites such as p-cresol sulfate and indoxyl sulfate shown to impact cell proliferation, cell senescence, fibrosis, and inflammation/oxidative stress (see below).61
Inflammation and oxidative stress	Metabolites such as p-cresol sulfate and indoxyl sulfate can also increase leukocyte activation and adhesion, leukocyte free radical production, and renal cell cytokine expression, and lower endothelial cell glutathione levels.61
Enzyme inhibition	As substrates and products of defined biochemical reactions, some metabolites can modulate specific enzyme actions; e.g. ADMA inhibits nitric oxide synthase, preventing the synthesis of NO from arginine.62
Central nervous system activity	The presence of organic ion transporters at the blood-brain barrier, in some cases the same as expressed in renal tubules,63, 64 suggests that the accumulation of some metabolites that undergo active renal secretion are neurotoxic.65
Protein modification	Metabolites can covalently modify proteins in circulation and in tissue, altering structure and function. Examples include glycation (due to hyperglycemia and oxidative stress) and carbamylation (a urea derived modification).66
Metabolite depletion	Some metabolites are actually depleted in renal failure, for example due to reduced dietary intake, loss of renal biosynthesis, or increased clearance for patients on dialysis. Carnitine depletion has been hypothesized to contribute to skeletal and cardiac myopathy in ESRD.67
GPCR signaling	Several metabolites have emerged as extracellular signaling molecules that are ligands at specific GPCRs, with actions pertinent to blood pressure, metabolism, and inflammation.29