Kidney Week

Abstract: TH-PO238

Higher Plasma ADMA Levels and Lower ADMA and SDMA Fractional Excretion Were Associated With Risk of Atherosclerotic Cardiovascular Disease in Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Clinical - I
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Schrauben, Sarah J., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Sarah J. Schrauben,

• Anderson, Amanda Hyre, Tulane University, New Orleans, Louisiana, United States

Amanda Hyre Anderson,

• Hsu, Chi-yuan, University of California San Francisco, San Francisco, California, United States

Chi-yuan Hsu,

• Ix, Joachim H., University of California San Diego, La Jolla, California, United States

Joachim H. Ix,

• Shafi, Tariq, University of Mississippi, University Park, Mississippi, United States

Tariq Shafi,

• Shlipak, Michael, San Francisco VA Health Care System, San Francisco, California, United States

Michael Shlipak,

• Chen, Jing, Tulane University School of Medicine, New Orleans, Louisiana, United States

Jing Chen,

• Hostetter, Thomas H., University of North Carolina System, Chapel Hill, North Carolina, United States

Thomas H. Hostetter,

• Brown, Julia, University of Illinois Chicago, Chicago, Illinois, United States

Julia Brown,

• Mehta, Rupal, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Rupal Mehta,

• Townsend, Raymond R., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Raymond R. Townsend,

• Seegmiller, Jesse C., University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, United States

Jesse C. Seegmiller,

• Kimmel, Paul L., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Paul L. Kimmel,

• Ramachandran, Vasan S., Boston University School of Medicine, Boston, Massachusetts, United States

Vasan S. Ramachandran,

• Feldman, Harold I., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Harold I. Feldman,

• Schelling, Jeffrey R., Case Western Reserve University, Cleveland, Ohio, United States

Jeffrey R. Schelling,

Background

CKD is associated with cardiovascular disease (CVD), especially among those with diabetes, but it is difficult to prospectively identify those who will experience such events. The uremic solutes asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and trimethyl methylamine-N-oxide (TMAO), may help identify these high-risk individuals.

Methods

We performed a case-cohort study among 766 Chronic Renal Insufficiency Cohort Study participants with diabetes, eGFR <60 ml/min/1.73m² and no atherosclerotic CVD (ASCVD) or heart failure at baseline. Cases were those who developed the primary outcome: incident ASCVD events (myocardial infarction, stroke, peripheral artery disease). Participants were randomly selected for the subcohort. Secondary outcomes were incident heart failure, and CKD progression (end-stage kidney disease or 40% eGFR decline). Uremic solute concentrations of TMAO, ADMA, SDMA in plasma and urine were determined with liquid chromatography-tandem mass spectrometry. Weighted Cox regression models related uremic solute concentrations in the plasma (modelled per SD) and urine (modeled as fractional excretion) with primary and secondary outcomes and were adjusted for: age, sex, race, education, blood pressure, cholesterol, hemoglobin A1c, smoking, BMI, hsCRP, serum creatinine, cystatin C, and proteinuria.

Results

Higher ADMA plasma concentrations were associated with risk of ASCVD (HR 1.52, 95% CI: 1.16-1.96) but not with heart failure. Plasma TMAO and SDMA concentrations were not associated with ASCVD, heart failure, or CKD progression. Lower ADMA and SDMA fractional excretion were associated with risk of ASCVD (HR 3.13, 95% CI: 1.41-6.67 and HR 2.33, 95% CI 1.11-4.76, respectively).

Conclusion

In persons with CKD and diabetes, higher plasma ADMA concentrations were associated with increased risk of ASCVD events. The data suggest new mechanistic insights whereby altered renal handling of ADMA and its enantiomer, SDMA, may lead to increased plasma concentrations and CVD risk. If confirmed, strategies to enhance renal ADMA and SDMA excretion could have potential therapeutic value.

Funding

• NIDDK Support