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.

Figure 1

The 24-h output of NO₂ + NO₃ (i.e. NO_X, 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. Data obtained from references 2–4. *, significant difference (P <0.05 vs control). CKD, chronic kidney disease and approximately 25% residual renal function; ESRD, end-stage renal disease; HD, hemodialysis; PD, peritoneal dialysis.

Figure 2

Simplified schematic of the biosynthetic pathway for nitric oxide in vivo. Reproduced with permission from reference 113 © (2005) Elsevier. ADMA, asymmetric dimethylarginine; NO, nitric oxide; NOS, nitric oxide synthase.

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. Measurements were made in the baseline state (solid histograms) or in the presence of 5 mmol/l of the endogenous nitric oxide synthase inhibitor N-monomethyl-l-arginine (open histograms). Results show the mean ± SEM of three separate experiments, each performed in triplicate. Reproduced with permission from reference 26 © (2001) American Physiological Society. *, significant difference (P <0.01 vs control); ^#, significant difference (P<0.05 vs pre-hemodialysis and control). BAEC, bovine aortic endothelial cells; HD, hemodialysis; HDMEC, human dermal microvascular endothelial cells; HGEC, human glomerular endothelial cells; PD, peritoneal dialysis.

Figure 4

Pathways of l-arginine metabolism. The enzyme at 1 is arginine decarboxylase, at 2 is arginase, and at 3 is l-arginine:glycine amidinotransferase. Reproduced with permission from reference 22 © (1998) Portland Press.

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. Reproduced with permission from reference 94 © (2001) Blackwell Publishing. *, significant difference (P <0.05 vs control); ^#, significant difference (P <0.05 vs chronic kidney disease I patients with normal nitric oxide synthase activity in plasma). ADMA, asymmetric dimethylarginine; BUN, blood urea nitrogen; CKD, chronic kidney disease; Cr, creatinine; NOS, nitric oxide synthase; P, plasma; SDMA, symmetric dimethylarginine.

Figure 6

Kaplan–Meier plot of cardiovascular event rate in patients with end-stage renal disease. Patients were stratified according to percentiles of asymmetric dimethylarginine plasma concentration at baseline, and followed for a mean of 33.4 months. Data obtained from reference 96. Reproduced with permission from reference 15 © (2003) Elsevier. ADMA; asymmetric dimethylarginine.