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

Rationale & objective: We aimed to explore the associated factors of endothelial injury in chronic kidney disease (CKD) and the relationship between endothelial dysfunction and CKD prognosis.

Study design: A prospective observational cohort study.

Setting & participants: 77 adults with CKD stages 1-5 were enrolled January 2010 to December 2010 and followed up until December 2015.

Exposure: Serum asymmetric dimethylarginine (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 2 tailed, and statistical significance was defined as P < 0.05.

Results: Mean serum ADMA level of 77 patients was 64.3 ± 34.6 ng/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. Median follow-up time was 56 (interquartile range, 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 level was negatively correlated with α-klotho (r = -0.233; P = 0.04) and positively correlated with phosphorus level (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 isoform 1, 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.

Conclusions: 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 sodium/phosphate cotransporter in the kidney are associated with higher circulating ADMA levels, suggesting that they may be involved in the pathogenesis of endothelial dysfunction in patients with CKD.