Asymmetrical Dimethylarginine Predicts Progression to Dialysis and Death in Patients with Chronic Kidney Disease

Abstract

High plasma asymmetrical dimethylarginine (ADMA) signals endothelial dysfunction and atherosclerosis in the general population and predicts mortality in ESRD. The relationship among plasma levels of ADMA, renal function, and the risk for progression to ESRD (halving GFR or dialysis start) and death in an incident cohort of 131 patients with chronic kidney disease was investigated. Cox's competing risk regression was used to model double-failure times (progression to ESRD and death) as a function of ADMA. Covariates that were considered for adjustment included clinical characteristics, baseline GFR (Modification of Diet in Renal Disease equation 7 formula), proteinuria, traditional cardiovascular risk factors, serum C-reactive protein, homocysteine, and concomitant therapies. Mean age at enrollment was 71 ؎ 11 yr, and 24% of patients had diabetes. Baseline GFR ranged from 8 to 77 ml/min per 1.73 m 2 (average 31 ؎ 15 ml/min per 1.73 m 2 ). ADMA was inversely related to GFR, ranking as the third predicting factor (partial r ‫؍‬ ؊0.22, P ‫؍‬ 0.01), after hemoglobin and urinary protein, in a general linear model that included multiple correlates of GFR. After a mean follow-up of 27 mo (range 3.4 to 36), 29 patients progressed to ESRD and 31 died. ADMA (hazard ratio per 0.1 M/L 1.203; 95% confidence interval 1.071 to 1.350) predicted event occurrence independent of other potential confounders, including GFR, proteinuria, hemoglobin, and homocysteine. In patients with mild to advanced chronic kidney disease, plasma ADMA is inversely related to GFR and represents a strong and independent risk marker for progression to ESRD and mortality. These novel findings further expand the implications of previous observations in ESRD patients and generate hypotheses on the role of ADMA in progressive chronic nephropathies.

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

“…Zoccali et al reported for the first time that plasma ADMA concentration was a strong and independent predictor of overall mortality and cardiovascular outcomes in a cohort of 225 hemodialysis patients (17). In addition, they found that plasma ADMA concentration was inversely related to GFR and that it positively correlated with progression to ESRD and future mortality in 131 patients with mild to advanced CKD (13). In a prospective study Lajer et al reported that plasma ADMA levels pre- dicted the development of future fatal and nonfatal cardiovascular events as well as a rapid decline in GFR in a cohort of 397 type 1 diabetes patients with overt diabetic nephropathy as well as in 175 patients with persistently normal albuminuria after long-term follow-up for 11.3 years (21).…”

“…Elevated plasma ADMA level has been associated with endothelial dysfunction (7,9) and was observed in patients with various risk factors for atherosclerosis as well as CKD (10,11). Several studies have shown that plasma ADMA level may predict the progression of renal injury in patients with early-stage CKD (12,13). In addition, high plasma ADMA level has been reported to be an independent risk factor for cardiovascular disease and allcause mortality in a community-based population (14), in patients with coronary artery disease (CAD) (15,16), and in patients with ESRD (17,18).…”

The Relationship Between Nontraditional Risk Factors and Outcomes in Individuals With Stage 3 to 4 CKD

“…Additionally, this study examined only CVD death as an outcome; however, individuals with CKD are at high risk of all-cause mortality and this competing risk my obscure statistically significant risk factors. 21,22 An examination of the ARIC cohort by Muntner et al evaluated 391 individuals with CKD at baseline, and, in order to increase power, analyzed an additional 416 individuals who had developed CKD at the time of their second evaluation. 7 In multivariable analyses, increased waist circumference, apolipoprotein B, fibrinogen, anemia, and reduced albumin were all associated with cardiac events.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Keratin 18, an epithelial-specific cytoskeletal protein released into urine or serum upon tubular cell death, might also be a novel marker of CKD (395). Several other molecules are under investigation as biomarkers in CKD, including asymmetric dimethylarginine, an endogenous inhibitor of NO synthase (396), Creactive protein (CRP), tumor necrosis factor receptor (TNF-R) II, pentraxin-3, adiponectin and apolipoprotein A-IV, as metabolic factors involved in the regulation of kidney metabolism, or endostatin as an anti-angiogenic factor (396,397). In kidney allografts, increased urinary CCL-2 was associated with renal fibrosis (317).…”