Nitric Oxide and Chronic Kidney Disease

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) reported that one in 10 American adults had some level of chronic kidney disease (CKD), and that kidney disease is the 9^th leading cause of death in the US. CKD accelerates cardiovascular disease, sometimes leading to sudden cardiac death, and CKD also hastens heart failure.

Researchers have been eager to identify markers of genetic predisposition to the development of heart failure (HF) in CKD patients. This search for genetic markers was the focus of a study published in PLOS One by a team of researchers from the United Kingdom. Their research points to nitric oxide (NO) as a culprit.

Some studies have determined that patients with diagnosed HF or progressing renal disease may possess an endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype. Having this SNP seemed to predict poor prognosis. The researchers set out to decide whether this SNP might be associated with early cardiac structural changes that occur in non-dialysis CKD.

Researchers enrolled 140 non-dialysis CKD patients who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of 2 previous clinical trials. Median estimated glomerular filtration rate (eGFR) was 50mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction. Using archived data, they genotyped participants looking for the eNOS Glu298Asp SNP.

The researchers successfully genotyped 132 (>94%) patients. LVEF varied significantly by eNOS genotypes.

Patients carrying a GG genotype—found in 46% of participants—were more likely to have compromised LVEF than patients with other genotypes. The researchers adjusted for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index, and gender. GG genotype remained associated with a worse LVEF, and it increased LV end-diastolic and systolic index.

GG genotype has been associated with increased NO levels, and studies of eNOS overexpression

within ventricular myocytes show reduced ventricular function. CKD spurs oxidative stress and could create eNOS uncoupling. eNOS uncoupling may lead to superoxide anion radicals that further exacerbate cardiac dysfunction.

eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodeling and may be an important genetic biomarker. If this is the case, once tests are available to identify this SNP, clinicians could potentially be able to tailor cardiac interventions in these high-risk patients.