Nitric Oxide Precursors and Dimethylarginines as Risk Markers for Accelerated Measured GFR Decline in the General Population

Introduction: Nitric oxide (NO) deficiency is associated with endothelial dysfunction, hypertension, atherosclerosis, and chronic kidney disease (CKD). Reduced NO bioavailability is hypothesized to play a vital role in kidney function impairment and CKD. 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 glomerular filtration rate (GFR) and new-onset CKD.

Methods: In a prospective cohort study of 1407 healthy, middle-aged participants of Northern European origin in the Renal Iohexol Clearance Survey (RENIS), GFR was measured repeatedly with iohexol clearance during a median follow-up time of 11 years. GFR decline rates were analyzed using a linear mixed model, new-onset CKD (GFR < 60 ml/min per 1.73 m2) was analyzed with interval-censored Cox regression, and accelerated GFR decline (the 10% with the steepest GFR decline) was analyzed with logistic regression.

Results: Higher SDMA was associated with slower annual GFR decline. Higher levels of citrulline and ornithine were associated with accelerated GFR decline (odds ratio [OR], 1.43; 95% confidence interval [CI] 1.16-1.76 per SD higher citrulline and OR 1.23; 95% CI 1.01 to 1.49 per SD higher ornithine). Higher citrulline was associated with new-onset CKD, with a hazard ratio of 1.33 (95% CI 1.07-1.66) per SD higher citrulline.

Conclusions: 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.

Comments：

In this prospective cohort study, the researchers investigated the relationship between 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 glomerular filtration rate (GFR) and new-onset chronic kidney disease (CKD) in 1407 healthy, middle-aged participants of Northern European origin in the Renal Iohexol Clearance Survey (RENIS) over a median follow-up time of 11 years.

The study found that higher SDMA levels were associated with a slower annual decline in GFR. However, higher levels of citrulline and ornithine were associated with accelerated GFR decline and an increased risk of new-onset CKD. These findings 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.

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S5838	SDMA	SMDA (symmetric dimethylarginine) is a methylated form of arginine found within all nucleated cells that is released into circulation after proteolysis, then excreted through the kidneys, and correlates well with GFR (glomerular filtration rate) in people, dogs, and cats.

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