2022-05-05
Uremic toxins and cardiovascular mortality in diabetic chronic kidney disease
Cardiology and Vascular Medicine Endocrinology and Metabolism Urology-nephrology
Cardiovascular diseases are undeniably a major cause of morbidity and mortality in patients with chronic kidney disease (CKD), particularly when diabetes is the underlying cause. However, traditional cardiovascular risk factors alone do not fully explain the pathophysiology and increased risk in these patients.
The accumulation of certain uremic toxins, particularly trimethylamine-N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), has been linked to cardiovascular events in patients with end-stage renal disease (ESRD) requiring renal replacement therapy. However, data on diabetic patients with earlier stages of CKD remain limited.
SDMA and ADMA originate from protein metabolism, while TMAO is derived from metabolic byproducts of gut microbiota processing of quaternary ammonium compounds such as choline and L-carnitine. These toxins are primarily excreted via the kidneys. Could these specific toxins serve as new prognostic biomarkers in diabetic CKD patients?
A random subcohort from the REGARDS (REasons for Geographic And Racial Differences in Stroke) prospective study, conducted between 2003 and 2007, included 555 diabetic patients aged over 45 years with at least moderate CKD (baseline eGFR < 60 ml/min/1.73m²). For these patients, plasma and urinary concentrations of ADMA, SDMA, and TMAO were analyzed using liquid chromatography-mass spectrometry. The urine-to-plasma (U/P) concentration ratios for each uremic toxin were calculated.
SDMA and ADMA originate from protein metabolism, while TMAO is derived from metabolic byproducts of gut microbiota processing of quaternary ammonium compounds such as choline and L-carnitine. These toxins are primarily excreted via the kidneys. Could these specific toxins serve as new prognostic biomarkers in diabetic CKD patients?
A random subcohort from the REGARDS (REasons for Geographic And Racial Differences in Stroke) prospective study, conducted between 2003 and 2007, included 555 diabetic patients aged over 45 years with at least moderate CKD (baseline eGFR < 60 ml/min/1.73m²). For these patients, plasma and urinary concentrations of ADMA, SDMA, and TMAO were analyzed using liquid chromatography-mass spectrometry. The urine-to-plasma (U/P) concentration ratios for each uremic toxin were calculated.
The primary outcome was cardiovascular mortality associated with these toxin levels. Secondary outcomes included all-cause mortality and the initiation of renal replacement therapy (dialysis). The results were published in the American Journal of Kidney Diseases.
The average age of the 555 included patients was 70 years, with 53% being women. The mean baseline eGFR was 44 ± 12 ml/min/1.73m². The median albuminuria/creatininuria ratio was 32 mg/g (11 - 203). Eighty-eight percent of patients were hypertensive, 42% had a history of coronary artery disease, and 16% had suffered strokes. Plasma concentrations of the three uremic toxins were inversely and moderately correlated with eGFR, especially for SDMA.
Cardiovascular deaths, overall mortality, and the initiation of dialysis occurred in 120 patients (average rate of 3.31% per year), 285 patients (average rate of 7.67% per year), and 89 patients, over an average follow-up of 6.2 years. Higher plasma ADMA concentrations were associated with cardiovascular mortality in the multivariate model (20% increased risk). Lower U/P ratios of ADMA, SDMA, and TMAO were independently associated with cardiovascular mortality.
The risk increased by 38% for a two-fold lower U/P ratio of TMAO and by 69% for the U/P ratio of SDMA. Neither urinary concentrations nor the fractional excretion of ADMA, SDMA, and TMAO were significantly associated with cardiovascular mortality. Regarding secondary endpoints, higher plasma concentrations (HR 1.1-2.8) and lower U/P ratios (HR 1.3-2.3) of these three solutes were associated with all-cause mortality. A higher plasma concentration of SDMA was associated with the initiation of dialysis (HR 1.2-3.0).
Overall, higher plasma concentrations and lower U/P ratios of the studied uremic toxins were independently associated with cardiovascular and all-cause mortality in this population with diabetic CKD. These associations between U/P ratio and mortality suggest a link between renal clearance of uremic toxins (declining eGFR, potential tubular dysfunction?) and the pathogenesis of cardiovascular diseases. The authors discuss the potential cardiovascular pathophysiological mechanisms of each toxin, such as the inhibition of nitric oxide synthase by ADMA, contributing to vasoconstriction, hypertension, and ischemia, as well as inflammation, oxidative stress, and impaired macrophage lipid metabolism. The clinical utility of these biomarkers in routine practice warrants further validation in future studies.
Cardiovascular deaths, overall mortality, and the initiation of dialysis occurred in 120 patients (average rate of 3.31% per year), 285 patients (average rate of 7.67% per year), and 89 patients, over an average follow-up of 6.2 years. Higher plasma ADMA concentrations were associated with cardiovascular mortality in the multivariate model (20% increased risk). Lower U/P ratios of ADMA, SDMA, and TMAO were independently associated with cardiovascular mortality.
The risk increased by 38% for a two-fold lower U/P ratio of TMAO and by 69% for the U/P ratio of SDMA. Neither urinary concentrations nor the fractional excretion of ADMA, SDMA, and TMAO were significantly associated with cardiovascular mortality. Regarding secondary endpoints, higher plasma concentrations (HR 1.1-2.8) and lower U/P ratios (HR 1.3-2.3) of these three solutes were associated with all-cause mortality. A higher plasma concentration of SDMA was associated with the initiation of dialysis (HR 1.2-3.0).
Overall, higher plasma concentrations and lower U/P ratios of the studied uremic toxins were independently associated with cardiovascular and all-cause mortality in this population with diabetic CKD. These associations between U/P ratio and mortality suggest a link between renal clearance of uremic toxins (declining eGFR, potential tubular dysfunction?) and the pathogenesis of cardiovascular diseases. The authors discuss the potential cardiovascular pathophysiological mechanisms of each toxin, such as the inhibition of nitric oxide synthase by ADMA, contributing to vasoconstriction, hypertension, and ischemia, as well as inflammation, oxidative stress, and impaired macrophage lipid metabolism. The clinical utility of these biomarkers in routine practice warrants further validation in future studies.
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