Patients with lower urinary to plasma ratios of 3 uremic solutes – trimethylamine-N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) – are at higher risk of dying from cardiovascular and other causes, according to investigators.

Using the REGARDS (REasons for Geographic And Racial Differences in Stroke) study, investigators selected a random sample of 555 patients with diabetes and an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. TMAO, ADMA, and SDMA were assayed by liquid chromatography-mass spectrometry in plasma and urine from these patients.

Over a mean 6.2 years of follow-up, cardiovascular death, all-cause mortality, and kidney failure requiring replacement therapy occurred in 120, 285, and 89 patients, respectively. Each halving of the urine to plasma ratio for ADMA, SDMA, and TMAO was significantly associated with an approximately 1.5-, 1.7-, and 1.4-fold increased risk for cardiovascular death, respectively, corresponding author Jeffrey R. Schelling, MD, of MetroHealth Medical Center, Cleveland, Ohio, and colleagues reported in the American Journal of Kidney Diseases. Each doubling of plasma ADMA was significantly associated with a 2.1-fold increased risk for cardiovascular death. The investigators adjusted results for demographic and traditional cardiovascular risk factors, eGFR, and urine albumin to creatinine ratio.

Continue Reading

Higher plasma concentrations and lower urine to plasma ratios of all 3 uremic solutes were also associated with all-cause mortality. The investigators could not rule out the influence of GFR and diet.

“Our observations that [urine to plasma] ratios of all solutes have stronger associations with [cardiovascular] mortality, compared with the associations of plasma levels of these solutes suggest that renal handling and clearance of uremic solutes may influence CVD pathogenesis,” Dr Schelling’s team wrote.


Sapa H, Gutiérrez OM, Shlipak MG, et al. Association of uremic solutes with cardiovascular death in diabetic kidney disease. Am J Kidney Dis. Published online March 26, 2022. doi:10.1053/j.ajkd.2022.02.016