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Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease – possible candidates for paradoxical epidemiology?

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Summary.

Background: Asymmetrical dimethylarginine (ADMA) is an inhibitor of nitric-oxide synthase. It has been linked to atherosclerotic risk in the general population as well as in end-stage renal disease patients (ESRD), whereas symmetrical dimethylarginine (SDMA) is thought to be biological inactive. Prospective data concerning the role of both dimethylarginines are rare in patients with chronic kidney disease.

Methods: 200 patients with chronic kidney disease (mean age 57.6 ± 13.0 years, 69 female, 131 male); 82 with chronic renal failure (CRF), 81 on maintenance haemodialysis (HD) and 37 renal transplant recipients (RTR) were prospectively followed for 24 months. ADMA and SDMA were measured by HPLC. The relation of plasma levels of ADMA and SDMA together with conventional risk factors for the cardiovascular and renal outcome was investigated with Cox proportional hazards model.

Results: Mean serum levels of SDMA were significantly increased in all groups compared to the control group (P ≤ 0.0005), ADMA was increased only in HD and RTR (P ≤ 0.004). Forty-seven cardiovascular events (CVE) occurred during follow-up, 35 patients died, and 39 patients reached ESRD. Multivariate analysis showed diabetes (RR 3.072, P = 0.01), ESRD (RR 11.915, P < 0.0005), elevated CRP levels (RR 3.916, P < 0.0005) and surprisingly a lower ADMA level (RR 0.271, P = 0.008) as independent risk factors for CVE. Serum creatinine (RR 11.378, P = 0.001), haemoglobin (RR 0.710, P = 0.038 for an increment of 1 mmol/l), and SDMA levels (RR 1.633, P = 0.006, per 1 µmol/l increment) were predictors for the progression to ESRD.

Conclusions: Data from a heterogeneous group of patients with chronic kidney disease provide evidence that conventional risk factors seem to play a more important role than elevated serum levels of ADMA or SDMA for cardiovascular events. Increasing serum SDMA concentration seems to play an additive role for the renal outcome besides serum creatinine and haemoglobin levels. Whether ADMA might possibly be a candidate for the phenomenon of “paradoxical epidemiology” in chronic kidney disease needs further investigation.

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Abbreviations

ADMA:

asymmetrical dimethylarginine

AMI:

acute myocardial infarction

AP:

angina pectoris

BMI:

body mass index

BP:

blood pressure

CI:

confidence interval

CRF:

chronic renal failure

CRP:

C-reactive protein

CV:

coefficient of variation

CVE:

cardiovascular events

DM:

diabetes mellitus

DMA:

dimethylarginine

ECG:

electrocardiogram

ELISA:

enzyme-linked immunosorbent assay

ESRD:

end-stage renal disease

GC-MS:

gas chromatographic-mass spectrometric assay

HD:

haemodialysis patients

HPLC:

high-performance liquid chromatography

NO:

nitric oxide

PAOD:

peripheral arterial occlusive disease

RR:

relative risk

RTR:

renal transplant recipients

SDMA:

symmetrical dimethylarginine

tHcy:

total homocysteine

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Authors and Affiliations

  1. Department of Internal Medicine III, University of Jena, Jena, Germany

    M. Busch, G. Wolf & G. Stein

  2. Institute of Pharmacology and Toxicology, University of Jena, Jena, Germany

    C. Fleck

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  1. M. Busch
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  4. G. Stein
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Busch, M., Fleck, C., Wolf, G. et al. Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease – possible candidates for paradoxical epidemiology?. Amino Acids 30, 225–232 (2006). https://doi.org/10.1007/s00726-005-0268-8

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