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Published ahead of print on June 8, 2005
J Am Soc Nephrol 16: 2449-2455, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2005010076
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Epidemiology and Outcomes

Asymmetrical Dimethylarginine Predicts Progression to Dialysis and Death in Patients with Chronic Kidney Disease: A Competing Risks Modeling Approach

Pietro Ravani*, Giovanni Tripepi{ddagger}, Fabio Malberti*, Sophie Testa{dagger}, Francesca Mallamaci{ddagger} and Carmine Zoccali{ddagger}

* Divisione di Nefrologia e Dialisi; {dagger} Servizio di Patologia Clinica, Azienda Istituti Ospitalieri di Cremona, Cremona; and {ddagger} IBIM-CNR, Epidemiologia Clinica e Fisiopatologia delle Malattie Renali e dell’Ipertensione Arteriosa, Reggio Calabria, Italy

Address correspondence to: Dr. Carmine Zoccali, CNR-IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, c/o Ki Point Gransial Srl, via Filippini 85, 89123 Reggio Calabria, Italy. Phone: 0039-0965-397010; Fax: 0039-0965-397000; E-mail: carmine.zoccali{at}tin.it

Received for publication January 19, 2005. Accepted for publication April 20, 2005.

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 µM/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.




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