Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria

Abstract

BackgroundTo evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease.Methods200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model’s improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale.ResultsHigher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality.ConclusionIn persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0569-8) contains supplementary material, which is available to authorized users.

Targeted Clinical Metabolomics Platform for the Stratification of Diabetic Patients

“…Additionally, increased levels of plasma homocysteine have been found to be related to macroalbuminuria in diabetic patients (39). ADMA, on the other hand, has been suggested as a candidate biomarker for diabetic kidney complications, whilst elevated levels of ADMA have been shown to predict a more accelerated course of renal function loss and promoted the development of renal damage (14,15,40). Our results are also in line with literature data showing that bile acid metabolism is altered in T2D patients (41).…”

“…Also other metabolites, e.g. 1,5-anhydroglucitol, norvaline and l-aspartic acid, were found to be associated with macroalbuminuric diabetic kidney disease (11,12), while glutamine, glutamic acid and symmetric dimethylarginine (ADMA) were suggested as potentially-predictive biomarkers of diabetic complications (13)(14)(15). Several metabolites (e.g., α-hydroxybutyrate, βhydroxypyruvate and 1,5-anhydroglucitol (1,5-AG)), were associated with regulation of glycemic control (16,17).…”

Association of endothelial dysfunction with cardiovascular risk factors and new‐onset diabetes mellitus in patients with hypertension

“…Zobel and colleagues also demonstrated in a population of patients with type 2 DM with microalbuminuria and without symptoms of coronary artery disease the association of ADMA with all‐cause mortality. …”

Plausible diagnostic value of urinary isomeric dimethylarginine ratio for diabetic nephropathy

“…Increased risk of chronic kidney disease (CKD) progression and atherosclerotic cardiovascular events have been shown to be associated with elevated ADMA and SDMA levels 12,13 . Our earlier studies showed that circulatory ADMA had a causative role in the development of DN 14 .ADMA to SDMA ratio (ASR), also known as catabolism index, has been implicated in sepsis, hypertension, malnutrition, and inflammation [15][16][17][18][19] . A direct correlation between malnutrition, inflammatory markers, and ASR was also established in patients undergoing hemodialysis 16 .…”

“…ADMA to SDMA ratio (ASR), also known as catabolism index, has been implicated in sepsis, hypertension, malnutrition, and inflammation [15][16][17][18][19] . A direct correlation between malnutrition, inflammatory markers, and ASR was also established in patients undergoing hemodialysis 16 .…”