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

Abstract

Background Asymmetric and symmetric dimethylarginines (ADMA and 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 3–6 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, comorbidities, albumin, and residual kidney function). Results Mean age of patients was 57 ±14 (SD) years, 63% were Black and 57% were female. Mean ADMA (0.9 ± 0.2 µM) and SDMA (4.3 ± 1.4 µM) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis concentrations of ADMA or SDMA. In fully adjusted models, each doubling of ADMA 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 µM), the highest ADMA quintile (≥1.07 µM) 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 was associated with higher risk of cardiac death (1.40; 1.03–1.92) but this was no longer statistically significant after adjusting for ADMA (1.20; 0.86–1.68). Limitations Single time-point measurement of ADMA and SDMA. Conclusions ADMA and, to a lesser extent SDMA are associated with cardiovascular outcomes in hemodialysis patients.

Relation of Serum ADMA, Apelin‐13 and LOX‐1 Levels with Inflammatory and Echocardiographic Parameters in Hemodialysis Patients

“…Increased ADMA may also be an inaccurate prognostic marker for renal diseases (5). Moreover, a relationship was reported between elevated ADMA and the risk of cardiovascular events in patients with ESRD (6). The relationship of ADMA with flow-mediated dilation (FMD), which is the indicator of ED, hyperlipidemia, and insulin resistance was also demonstrated (7).…”

Symmetric dimethylarginine concentrations in dogs with International Renal Interest Society stage 4 chronic kidney disease undergoing intermittent hemodialysis

“…We confirmed the effectiveness of IH in the removal of urea, creatinine, and phosphorus from serum. Intermittent hemodialysis also was effective for SDMA clearance but limited as a long‐term treatment modality in dogs with IRIS CKD stage 4, similar to humans who underwent IH for end‐stage renal disease . In 1 study of humans, the marked increase in SDMA concentration was approximately 3.5‐fold higher in early stage CKD patients, whereas it was more than 7‐fold higher both in peritoneal dialysis and hemodialysis patients in end‐stage CKD when compared to healthy controls …”

Uremia Retention Molecules and Clinical Outcomes

“…Despite being structurally similar to urea, methylguanidines have a greater distribution volume, resulting in lower removal efficiency by dialysis procedures in comparison to urea [4] . Higher dialysis dose or longer sessions seem to be incapable of further lowering ADMA or SDMA concentrations [5] .…”

“…Several studies have reported a strong and independent association of higher serum levels of ADMA and mortality and cardiovascular events in general, predialysis and dialysis populations [6][7][8] . Recently, in a post-hoc analysis of the Hemodialysis (HEMO) study, Shafi et al [5] have found an association between ADMA levels and higher risk of cardiac death (HR 1.83; 95% CI 1.29-2.58), sudden cardiac death (HR 1.79; 95% CI 1.19-2.69), first cardiovascular event (HR 1.50; 95% CI 1.20-1.87), and anycause death (HR 1.44; 95% CI 1.13-1.83). Interestingly, they were also able to demonstrate an association between SDMA levels and the risk for cardiac death (HR 1.40; 95% CI 1.03-1.92), though it was no longer significant after adjusting for ADMA.…”