Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Abstract

SummaryBackground and objectives Elevated plasma level of asymmetric dimethylarginine (ADMA) have been reported to be associated with endothelial dysfunction and atherosclerosis risk factors, and may predict cardiovascular events in patients with ESRD. In this study, we aimed to assess the association between plasma ADMA and long-term outcome in a cohort of patients with stage 3 to 4 chronic kidney disease (CKD).Design, setting, participants, & measurements From July 2006 to June 2009, 298 consecutive patients with stage 3 to 4 CKD scheduled to undergo coronary angiography were recruited. Plasma ADMA levels were determined using HPLC. ResultsThe mean age was 73 Ϯ 10 years. Approximately half of the patients had diabetes and 88 patients had proteinuria. The baseline estimated GFR (eGFR) was 44 Ϯ 13 ml/min per 1.73 m 2 . The plasma ADMA levels of the patients with proteinuria were significantly higher than those without. The plasma ADMA levels correlated significantly with eGFR. During the median follow-up period of 2.7 years, we observed 26 all-cause deaths, 12 nonfatal myocardial infarctions, and 2 strokes. Multivariate Cox analysis revealed that an increase of 0.1 mol/L in plasma ADMA level was associated with a 37% increased risk of the composite outcomes of all-cause deaths, nonfatal myocardial infarctions, and strokes. ConclusionsIn this elder and high-risk population with stage 3 to 4 CKD, high plasma ADMA level was associated with low eGFR and macroalbuminuria. Furthermore, high plasma ADMA level appeared to be an independent predictor of long-term outcome.

Endothelial dysfunction and oxidative stress in polycystic kidney disease

“…Interestingly, while ADMA is a known endogenous competitive NOS inhibitor, an established cardiovascular risk marker (31), and is mainly metabolized by dimethylarginine dimethylaminohydrolases (DDAH) (4), the biological role of SDMA is still not completely understood; however, it is believed that it does not directly affect NOS activity (56). Despite this, meta-analysis of multiple studies in patients with renal diseases showed a strong correlation between SDMA and renal function (24,33), suggesting that SDMA may indeed be a potential marker of renal function (24).…”

“…Furthermore, an abnormal sensory cilia function reported in PKD patients (1,2) disrupts NO biosynthesis, in which primary cilia act as mechanical switches to initiate a NO biochemical reaction (2,40). Therefore, it is not surprising that, within several population studies, plasma levels of the endogenous competitive NOS inhibitor asymmetric dimethylarginine (ADMA) (31,54) were found increased in selected ADPKD patients with preserved GFR (52,59,60).…”

Endothelial dysfunction in subjects with chronic cadmium exposure

“…Moreover, ADMA causes eNOS uncoupling, resulting in production of superoxide rather than NO (Antoniades et al, 2009). The raised ADMA levels are reported in diseases associated with endothelial dysfunction such as atherosclerosis, hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, and chronic kidney disease (Valkonen et al, 2001;Lu et al, 2011). Thrombomodulin is a transmembrane glycoprotein located on surface of endothelial cells, and functions as an anticoagulant.…”

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

“…A wealth of research has since been conducted into the contribution of ADMA to renal disease and it now seems that this endogenous NOS inhibitor is a key player in NO deficit, with levels being predictive of progression to dialysis and death in patients with CKD. 40,41 Accumulation is thought to be because of impaired breakdown of ADMA by the enzymes DDAH 1 and 2. The conditions of oxidative stress inherent in CKD negatively influence the efficacy of DDAH, reducing the catabolism of ADMA.…”