2006 Lewis K. Dahl Memorial Lecture—Nitric Oxide Deficiency in Renal Disease
Nitric oxide (NO) production is reduced in renal disease, in part because of decreased endothelial production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (eg, involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylamino-hydrolase (DDAH). The latter might be associated with loss-of-function polymorphisms of a DDAH gene and/or functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease. An increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably CKD). Raising endogenous L-arginine and/or lowering ADMA concentration is a major therapeutic goal to reduce endothelial dysfunction, cardiovascular risk, and possibly progression in renal disease.