In the population of patients with chronic kidney disease (CKD), particularly those with diabetes as the underlying cause of CKD, cardiovascular disease is a major cause of morbidity and mortality. While diabetic kidney disease (DKD) and cardiovascular disease have some risk factors in common, the pathogenesis of cardiovascular disease in the context of DKD is not completely understood, compounded by a lack of accurate biomarkers associated with cardiovascular outcomes in patients with DKD.
Compared with the general population, the association between the traditional risk factors for cardiovascular disease (age, sex, diabetes, duration, total cholesterol, high-density lipoprotein cholesterol, smoking, systolic blood pressure, hypertensive therapy) is not as strong in patients with CKD.
The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to cardiovascular disease in kidney failure with kidney replacement therapy (KFRT), but there are limited data in populations with diabetes and less severe kidney disease. Hima Sapa, PhD, and colleagues assayed plasma and urine for ADMA, SDMA, and TMAO in a random subcohort of participants with diabetes and baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study.
The results enabled the researchers to examine the associations with plasma concentrations and urine to plasma solute ratios with the primary outcome of cardiovascular mortality and the secondary outcomes of all-cause mortality and incident KFRT. Results were reported in the American Journal of Kidney Diseases [2022;80(4):502-511].
Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with the outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes were calculated per standard deviation and per doubling, and as interquartile comparisons.
There were 555 participants in the subcohort of patients with diabetes and eGFR <60 mL/min/1.73 m2. Of those, mean age was 70 years, 53% were Black, and 53% were women. The prevalence of hypertension, coronary heart disease, and stroke was 88%, 42%, and 16%, respectively. At baseline, mean eGFR was 44 mL/min/1.73 m2, and median urine albumin-creatinine ratio (UACR) was 32 mg/g.
Women, those with less education, and White participants tended to have higher levels of ADMA. Male sex and Black race were associated with higher SDMA levels. There were associations between male sex and White race and higher TMAO levels.
For all three uremic solutes, plasma levels inversely and moderately correlated with eGFR; SDMA had the strongest correlation. There was also direct correlation between the plasma concentrations and UACR; however, those correlations were weaker than those with eGFR. For the ratio of urine to plasma levels of the uremic solutes, there were very strong pairwise correlations with eGFR and urine creatinine and moderately strong correlations with UACR.
Mean follow-up was 6.2 years. During the follow-up period, there were 120 cardiovascular deaths (mean rate of 3.31% per year). The cardiovascular mortality rate increased progressively with greater uremic solute plasma concentration quartile. Hazard ratios (HRs) were attenuated following adjustment for demographic and traditional cardiovascular risk factors, including eGFR and UACR. There were no differences in results when HRs were adjusted using a race-independent GFR estimating equation.
There was a statistically significant association observed for higher plasma ADMA with cardiovascular mortality: each one standard deviation higher ADMA concentration was associated with a 20% higher risk of cardiovascular morality. The association became progressively stronger across quartiles of ADMA concentration.
In an analysis of associations of the ratio of urine to plasma concentrations of the uremic solutes with cardiovascular mortality, there were independent associations between lower ratios of all three uremic solutes and cardiovascular mortality. The strengths of the associations ranged from 38% higher risk per two-fold lower urine-to-plasma ratio of TMAO to 69% higher risk for the corresponding SDMA associations. There were no significant associations between urinary concentrations or fractional excretion of ADMA, SDMA, and TMAO with cardiovascular death.
Over the course of the study, there were 285 all-cause deaths (7.67% per year). There were significant associations between higher concentrations of all three solutes and all-cause mortality. There were also consistent associations between lower ratios of urine to plasma concentrations with all-cause mortality.
Eighty-nine participants developed KFRT. In multivariable-adjusted models, there were strong and significant associations with ascending quartiles of plasma SDMA concentration and incident KFRT risk; the association did not reach statistical significance in the continuous model. There was also an association between higher plasma ADMA with incident KFRT in the multiple-adjusted model by inter-quartile comparisons only. There were no statistically significant associations of KFRT with plasma TMAO concentration, or with any of the urine to plasma solute concentration ratios.
The researchers cited some limitations to the study, including the possibility of residual confounding by GFR, the single cohort design, and the lack of data on dietary intake.
In conclusion, the authors said, “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 cardiovascular disease pathogenesis.
“If validated in other cohorts, lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO could be used to identify the subset of patients with diabetes and cardiovascular disease who are at particularly high risk for cardiovascular and all-cause mortality.”
- Researchers reported results of a study to examine associations between three uremic solutes and cardiovascualr mortality in patients with diabetic kidney disease.
- There were independent associations between higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes and cardiovascualr and all-cause mortality in DKD.
- The associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and cardiovascular disease pathogenesis.