Elsevier

The Lancet

Volume 358, Issue 9299, 22–29 December 2001, Pages 2113-2117
The Lancet

Articles
Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study

https://doi.org/10.1016/S0140-6736(01)07217-8Get rights and content

Summary

Background

The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric-oxide synthase, which has been linked to endothelial dysfunction and atherosclerosis in the general population, is raised in patients with end-stage renal disease and could contribute to the high cardiovascular risk in patients with chronic renal failure. We investigated the relation between cardiovascular risk factors and plasma ADMA concentration in a cohort of haemodialysis patients (n=225), and tested the predictive power of ADMA for mortality and cardiovascular outcomes.

Methods

Patients had standard dialysis three times a week. We accurately recorded cardiovascular events over a mean follow-up of 33·4 months (SD 14·6); these events were reviewed by a panel of physicians. We identified correlates of plasma ADMA by univariate and multivariate analyses.

Findings

On univariate analysis, ADMA concentration in plasma was directly related to concentrations of fibrinogen and L-arginine in plasma, duration of dialysis treatment, and serum cholesterol concentration, and was inversely related to serum albumin concentration. On multivariate analysis, only plasma fibrinogen (p=0·0001) and serum albumin (p=0·04) concentrations were independently related to plasma ADMA concentration (multiple r=0·44, p=0·0001). 83 patients died, 53 (64%) by cardiovascular causes. In a Cox's proportional-hazards model, plasma ADMA ranked as the second factor predicting overall mortality (hazard ratio 1·26, 95% Cl 1·11–1·41, p=0·0001) and cardiovascular events (1·17, 1·04–1·33, p=0·008).

Interpretation

In haemodialysis patients, plasma ADMA is a strong and independent predictor of overall mortality and cardiovascular outcome. These findings lend support to the hypothesis that accumulation of ADMA is an important risk factor for cardiovascular disease in chronic renal failure.

Introduction

Cardiovascular disease is a major cause of death in patients with end-stage renal disease. The projected life expectancy of patients on dialysis is 20–25% that of the general population.1 Although patients with chronic renal failure commonly have associated diseases which have a high cardiovascular risk in themselves, such traditional risk factors account for only part of the very high cardiovascular morbidity and mortality in these patients.1 An expert panel from the USA National Kidney Foundation has recently identified the need for observational studies to ascertain the relation between established cardiovascular risk factors and cardiovascular outcomes and to identify new risk factors as a research priority.2

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric-oxide synthase.3 Concentrations of ADMA are related to endothelial dysfunction in hypercholesterolaemic individuals.4 ADMA and its biologically inactive stereoisomer—symmetrical dimethylarginine (SDMA)—are not excreted in patients with chronic renal failure, and concentrations of these substances in plasma are two to six times higher in uraemic patients than in healthy control individuals.3, 5, 6 ADMA concentrations in plasma are also raised in young hypercholesterolaemic patients with normal renal function,4 and correlate with intima media thickness in apparently healthy middle-aged individuals.7 Of note, ADMA concentrations are higher in dialysis patients with clinically manifest atherosclerosis than in those without atherosclerotic disease,6 which suggests that accumulation of ADMA might be an important cardiovascular risk factor in end-stage renal disease.

With this background in mind, we aimed to study prospectively the association between ADMA concentration in plasma, survival, and cardiovascular outcomes in a cohort of patients on chronic haemodialysis.

Section snippets

Patients

225 haemodialysis patients with end-stage renal disease (123 men, 102 women) who had undergone regular dialysis treatment for at least 6 months (median 42 months, IQR 21–109) without clinical evidence of circulatory congestion (defined as dyspnoea in addition to two of the following conditions: raised jugular venous pressure; bibasilar crackles; pulmonary venous hypertension or interstitial oedema on chest radiograph requiring admission to hospital or extra ultrafiltration; and ejection

Results

Table 1 shows the baseline characteristics of the patients. Median concentration of ADMA in plasma was 2·52 μmol/L (IQR 1·58–3·85). 133 (59%) patients had ADMA concentrations above the upper limit of the normal range (>2·2 mol/L). The median concentration of L-arginine and SDMA in plasma was 70·0 μmol/L (57·6–78·8) and 3·01 μmol/L (2·40–4·52), respectively.

On univariate analysis, concentration of ADMA in plasma correlated with the concentrations of fibrinogen (r=0·50, p=0·0001) and L-arginine (r

Discussion

Our findings show that ADMA is a stronger independent predictor of all-cause mortality and cardiovascular outcome in patients with chronic renal failure than some traditional risk factors. We observed a high occurrence of cardiovascular complications, with 81 (36%) patients having at least one cardiovascular event during mean follow-up of 33·4 months. This observation is in agreement with findings of other studies.9 Patients who died from cardiovascular complications had higher baseline ADMA

References (29)

  • B Anderstam et al.

    Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor, in dialysis patients

    J Am Soc Nephrol

    (1997)
  • JT Kielstein et al.

    Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease

    J Am Soc Nephrol

    (1999)
  • H Miyazaki et al.

    Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis

    Circulation

    (1999)
  • C Zoccali et al.

    Prediction of left ventricular geometry by clinic, pre-dialysis and 24–h ambulatory BP monitoring in hemodialysis patients

    J Hypertens

    (1999)
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