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Arginine, arginine analogs and nitric oxide production in chronic kidney disease

Abstract

Nitric oxide (NO) production is reduced in renal disease, partially due to decreased endothelial NO 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 (e.g. those 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 dimethylaminohydrolase (DDAH). The latter might be associated with loss-of-function polymorphisms of a DDAH gene, functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease, or both. These findings provide the rationale for novel therapies, including supplementation of dietary L-arginine or its precursor L-citrulline, inhibition of non-NO-producing pathways of L-arginine utilization, or both. Because an increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably also in CKD), lowering ADMA concentration is a major therapeutic goal; interventions that enhance the activity of the ADMA-hydrolyzing enzyme DDAH are under investigation.

Key Points

  • Production of nitric oxide (NO; from L-arginine and O2 via nitric oxide synthase [NOS]) is reduced in renal disease

  • As chronic NOS inhibition produces hypertension and renal dysfunction in animals, NO deficiency probably contributes to progression of kidney disease in humans

  • Net NO deficiency can develop in response to decreased substrate availability (e.g. perturbed synthesis or transport of arginine) and the action of endogenous NOS inhibitors (e.g. asymmetric dimethylarginine)

  • Potential therapies for kidney disease include supplementation of dietary L-arginine, inhibition of non-NO-producing biochemical processes that consume L-arginine, and decreasing the activity of asymmetric dimethylarginine

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Figure 1: The 24-h output of NO2 + NO3 (i.e. NOX, the stable oxidation products of NO) in subjects with normal renal function (control), patients with chronic kidney disease and approximately 25% residual renal function, and patients with end-stage renal disease undergoing peritoneal dialysis or hemodialysis.
Figure 2: Simplified schematic of the biosynthetic pathway for nitric oxide in vivo.
Figure 3: Effects on L-arginine transport in human dermal microvascular endothelial cells, human glomerular endothelial cells and bovine aortic endothelial cells of 6 h incubation with a 1 in 5 dilution of plasma from healthy subjects (control), or from patients undergoing peritoneal dialysis or hemodialysis.
Figure 4: Pathways of L-arginine metabolism.
Figure 5: Relationship between the nitric oxide synthase activity of plasma and plasma concentrations of: the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine, which is catabolized by dimethylarginine dimethylaminohydrolase; symmetric dimethylarginine, which is not a substrate of dimethylarginine dimethylaminohydrolase; and creatinine and blood urea nitrogen as indices of renal function.
Figure 6: Kaplan–Meier plot of cardiovascular event rate in patients with end-stage renal disease.

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Acknowledgements

The support of NIH grants R01 DK56843 and DK 45517 is gratefully acknowledged.

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Baylis, C. Arginine, arginine analogs and nitric oxide production in chronic kidney disease. Nat Rev Nephrol 2, 209–220 (2006). https://doi.org/10.1038/ncpneph0143

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