MO433: Nitric-Oxide Precursors and Dimethylarginines as Risk Factors for Accelerated GFR Decline in the Non-Diabetic General Population

Abstract

Abstract BACKGROUND AND AIMS Nitric oxide (NO) deficiency is associated with endothelial dysfunction, hypertension, vasoconstriction, atherosclerosis and chronic kidney disease (CKD) [1]. Reduced NO bioavailability is hypothesized to play a vital role in kidney function impairment and CKD. The worldwide prevalence of CKD is increasing and is a major contributor to morbidity and mortality. Differences in glomerular filtration rate (GFR) are only partly explained by conventional CKD risk factors [2]. Therefore, we investigated the association of serum levels of endogenous inhibitors of NO, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) and precursors of NO, arginine, citrulline and ornithine, with a decline in GFR and new-onset CKD. METHOD In a prospective cohort study of 1407 participants in the Renal Iohexol Clearance Survey (RENIS) without self-reported kidney disease, cardiovascular disease, or diabetes, GFR was measured repeatedly with iohexol clearance during a median follow-up time of 11 years [3]. GFR decline rates were analysed using a linear mixed model, new-onset CKD (GFR < 60 ml/min/1.73 m2) with interval-censored Cox regression and accelerated GFR decline (the 10% with the steepest GFR decline) with logistic regression. RESULTS Neither ADMA nor arginine was associated with any outcomes. Higher SDMA was associated with a slower annual GFR decline and a lower arginine/dimethylarginine ratio with a steeper GFR decline. Higher levels of citrulline and ornithine were associated with accelerated GFR decline with an odds ratio (OR) of 1.43 [95% confidential interval (CI) 1.16–1.76] per standard deviation (SD) higher citrulline and an OR of 1.23 (95% CI 1.01–1.49) per SD increase in ornithine (Table 1). Higher citrulline was associated with new-onset CKD, with a hazard ratio of 1.31 (95% CI 1.05–1.63) per SD higher citrulline. CONCLUSION Associations between NO precursors and the outcomes suggest that NO-metabolism plays a significant role in the pathogenesis of age-related GFR decline, and the development of CKD in middle-aged people. Our findings warrant further investigation into the pathogenesis of NO-metabolism and the possible therapeutic targets and preventive measures.