α-Klotho, Plasma Asymmetric Dimethylarginine, and Kidney Disease Progression

Abstract

Abstract Rationale & Objective We aimed to explore the associated factors of endothelial injury in CKD and the relationship between endothelial dysfunction and CKD prognosis. Study Design A prospective observational cohort study Setting & Participants 77 adults with CKD stage 1–5 were enrolled Jan 2010 to Dec 2010, and followed until Dec 2015. Exposure Serum ADMA level at baseline, α-klotho, sodium-phosphorus synergistic transporter, and dimethylarginine-dimethylamine hydrolase expression in kidney biopsy samples. Outcome Initiation of kidney replacement therapy (KRT). Analytical Approach Kaplan-Meier analysis was used for evaluation of the incidence rate of KRT. All tests were two-tailed, and statistical significance was defined as p Results The mean serum ADMA level of 77 patients was 64.3±34.6ng/mL. ADMA level increased with CKD stages (p=0.06) and declining kidney function (r=−0.267, p=0.02). The expression of α-klotho in kidney biopsy specimens also decreased. The median follow-up time was 56 (50.5, 62) months. Kaplan-Meier analyses showed that during a total follow-up of 6 years the incidence of KRT initiation in the high ADMA group was significantly higher than that in the low group (35.9% vs 13.2%, p=0.03). ADMA was negatively correlated with α-klotho (r=−0.233, p=0.04) and positively correlated with phosphorus (r=0.243, p=0.04). The expression of sodium-phosphorus synergistic transporter in kidney tubules, which promoted phosphorus reabsorption, and the expression of dimethylarginine-dimethylamine hydrolase (DDAH1), which regulated ADMA, were decreased. Correlation analysis also showed that ADMA level decreased while age increased at baseline (r = -0.292, p = 0.01) Limitations Small sample size with limited longer term follow-up. Conclusion Serum ADMA levels increased as kidney function declined, and high serum ADMA level was associated with incident kidney failure. Low tissue α-klotho and high levels of plasma phosphorus or tissue expression of type II Na/Pi-cotransporter in the kidney are associated with higher circulating ADMA, suggesting that they may be involved in the pathogenesis of endothelial dysfunction in CKD patients.