Serum Asymmetric and Symmetric Dimethylarginine and Morbidity and Mortality in Hemodialysis Patients

Abstract

Background: Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are putative uremic toxins that may exert toxicity by a number of mechanisms, including impaired nitric oxide synthesis and generation of reactive oxygen species. The study goal was to determine the association between these metabolites and cardiovascular outcomes in hemodialysis patients.

Study design: Post hoc analysis of the Hemodialysis (HEMO) Study.

Setting & participants: 1,276 prevalent hemodialysis patients with available samples 3 to 6 months after randomization.

Predictor: ADMA and SDMA measured in stored specimens.

Outcomes: Cardiac death, sudden cardiac death, first cardiovascular event, and any-cause death. Association with predictors analyzed using Cox regression adjusted for potential confounders (including demographics, clinical characteristics, comorbid conditions, albumin level, and residual kidney function).

Results: Mean age of patients was 57±14 (SD) years, 63% were black, and 57% were women. Mean ADMA (0.9±0.2μmol/L) and SDMA levels (4.3±1.4μmol/L) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis ADMA or SDMA concentrations. In fully adjusted models, each doubling of ADMA level was associated with higher risk (HR per 2-fold higher concentration; 95% CI) of cardiac death (1.83; 1.29-2.58), sudden cardiac death (1.79; 1.19-2.69), first cardiovascular event (1.50; 1.20-1.87), and any-cause death (1.44; 1.13-1.83). Compared to the lowest ADMA quintile (<0.745 μmol/L), the highest ADMA quintile (≥1.07μmol/L) was associated with higher risk (HR; 95% CI) of cardiac death (2.10; 1.44-3.05), sudden cardiac death (2.06; 1.46-2.90), first cardiovascular event (1.75; 1.35-2.27), and any-cause death (1.56; 1.21-2.00). SDMA level was associated with higher risk for cardiac death (HR, 1.40; 95% CI, 1.03-1.92), but this was no longer statistically significant after adjusting for ADMA level (HR, 1.20; 95% CI, 0.86-1.68).

Limitations: Single time-point measurement of ADMA and SDMA.

Conclusions: ADMA and, to a lesser extent, SDMA levels are associated with cardiovascular outcomes in hemodialysis patients.

Keywords: Cardiovascular mortality; asymmetric dimethylarginine (ADMA); cardiac death; cardiovascular morbidity; dialysis outcomes; end-stage renal disease (ESRD); hemodialysis; sudden cardiac death; symmetric dimethylarginine (SDMA); uremic toxins.

Figure 1. Association of ADMA and SDMA with Cardiac Death in the HEMO Study

Relative hazard predicted using Cox proportional hazards regression adjusted for age, sex, race, Index of Coexisting Disease (ICED) severity score, cause of end-stage renal disease, body mass index (categorized as <18, 18–25 and >25 kg/m2), systolic blood pressure (categorized as <130, 130–160 and >160 mm Hg), albumin, relative volume removed on dialysis, and residual kidney function (urinary standardized Kt/V_urea calculated from urinary urea clearance). ADMA and SDMA are modeled as a restricted cubic spline with 5 knots (5^th, 27.5^th, 50^th, 72.5^th and 95^th percentiles); 10th percentile is used as the reference (HR = 1). The lines represent the adjusted HR and the shaded area is the 95% CI of the HR. Vertical bars are the frequency histogram, showing the distribution of the solutes. Extreme observations, defined as values >99^th percentile, are excluded; ADMA >1.8 µM (n=12) and SDMA >8.6 µM (n=12). Panel A (left): Asymmetric Dimethylarginine (ADMA) and Cardiac Death Panel B (right): Symmetric Dimethylarginine (SDMA) and Cardiac Death.

Figure 2. Association of ADMA and SDMA with single-pool Kt/V_urea and Dialysis Treatment Time in the HEMO Study

Scatterplot of ADMA and SDMA concentrations and single-pool Kt/V_urea (Panel A) and dialysis treatment time (Panel B). Patients randomized to standard dose intervention are represented by open circles and those randomized to high dose intervention are represented by solid circles. Lines represent linear regression of the solute on single-pool Kt/V_urea or treatment time with broken line representing standard dose group and solid line representing high dose group. Pearson and Spearman correlation coefficients are also displayed.