Oxidative Stress In Chronic Kidney Disease Research Articles

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.

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

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.

Chronic kidney disease is associated with oxidative stress independent of hypertension.

Oxidative stress is implicated in the pathogenesis of chronic kidney disease (CKD) and essential hypertension (EHTN). However, the role of hypertension in causing increased oxidative stress in patients with CKD is unknown. We performed a case control study in patients with EHTN and those with equal blood pressure assessed by ambulatory blood pressure monitoring but with concomitant CKD. Those with diabetes mellitus and those taking renin angiotensin inhibitors were excluded. Biomarkers of oxidative stress, malondialdehyde (MDA) and protein carbonylation and total glutathione levels were measured. Average (SD) 24-hour ambulatory blood pressure in 12 patients with CKD was 134 (17)/75 (16) compared to 134 (10)/80 (9) in 11 patients with EHTN (p = NS). Plasma MDA in CKD was 0.89 +/- 0.38 micromol/l compared to 0.68 +/- 0.16 micromol/l in EHTN (p = 0.07). Urinary MDA/creatinine ratio was 1.78 (0.31) in CKD vs 1.43 (0.69) micromol/g in those with EHTN (p = 0.04). Thus, lipid peroxidation was increased in urine of CKD patients. Patients with CKD had higher (1.04 (0.20) nmol) carbonyl/mg protein compared to those with EHTN (0.80 (0.21) nmol carbonyl/mg protein) (p = 0.03). Thus, protein carbonylation was increased in CKD patients. Total glutathione in CKD and EHTN patients was 6.6 (1.8) ng/ml and 7.3 (3.1) ng/ml (p = NS). There was a good correlation between biomarkers of lipid (MDA) and protein oxidation (protein carbonyls) (r = 0.6, p = 0.004). Biomarkers of lipid and protein oxidation are higher in patients with CKD compared to EHTN despite similar blood pressure. Thus, nonhemodynamic factors such as inflammation and altered cellular redox state may play a greater role in the generation of oxidative stress in CKD.