Synergism between asymmetric dimethylarginine (ADMA) and a genetic marker of uric acid in CKD progression

• The GLUT9 polymorphism, powerful marker of hyperuricemia, predicts faster CKD progression.
• ADMA is a strong predictors of CKD progression.
• ADMA and uric acid levels are directly related each other in several conditions.
• We found that ADMA amplifies the risk for CKD progression due to the risk allele of GLUT9 gene.

Background & aimsWe have recently reported that a polymorphism (rs734553) in a major urate transporter gene (GLUT9) is a strong predictor of incident renal events in stage 2–5 CKD patients implying that life-time exposure to high uric acid levels may be causally implicated in CKD progression. Since disturbed NO bioavailability is a major pathway whereby high uric may cause renal damage, we tested the interaction between the major endogenous inhibitor of NO synthase, asymmetric-dimethylargine (ADMA), and the rs734553 polymorphism for CKD progression in the same cohort.Methods & resultsOver a 29 ± 11 months follow-up the risk for incident renal events was higher in patients harboring the risk allele of the polymorphism (T) as compared to those without the risk allele (HR: 2.35, 95% CI: 1.25–4.42, P = 0.008) (p = 0.01). Similarly, patients with ADMA > median value had an increased risk for the same outcome (HR: 1.37, 95% CI: 1.06–1.76, P = 0.016). Interaction analysis showed a strong amplification by ADMA of the risk for renal events associated to the T allele because in adjusted (P = 0.016) and bootstrapping validated (P = 0.020) analyses the risk excess associated to this allele was progressively higher across increasing ADMA levels.ConclusionsThe rs734553 polymorphism, the strongest genetic marker of uric acid levels discovered so far, interacts with ADMA in determining the risk for CKD progression in CKD patients. This synergic interaction conforms to biological knowledge indicating that disturbed NO bio-availability is a critical pathway whereby life time exposure to high uric acid may engender renal damage.