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 m2 (average 31 +/- 15 ml/min per 1.73 m2). 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 muM/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.