Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease

Rationale & Objective: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease. Study Design: Observational cohort. Settings & Participants: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mUmin/1.73 m(2) at study entry. Exposure: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine. Outcome: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes). Analytical Approach; Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons. Results: The mean baseline eGFR was 44 mL/ min/1.73 m(2). Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses. Limitations: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m(2), potential residual confounding by GFR, no dietary information. Conclusions: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.