Randomized Placebo-Controlled Trial Assessing a Treatment Strategy Consisting of Pravastatin, Vitamin E, and Homocysteine Lowering on Plasma Asymmetric Dimethylarginine Concentration in Mild to Moderate CKD

Background

Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). The Anti-oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study showed that a multistep treatment strategy improved carotid intima-media thickness, endothelial function, and microalbuminuria in patients with stages 2 to 4 CKD. Increased plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been linked to greater CVD risk in patients with CKD. The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study.

Study Design

Secondary analysis of a randomized double-blind placebo-controlled trial.

Setting & Participants

93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m² (according to the Cockcroft-Gault equation) from 7 outpatient clinics in Amsterdam, The Netherlands.

Intervention

The treatment group received sequential treatment consisting of pravastatin, 40 mg/d. After 6 months, vitamin E, 300 mg/d, was added, and after another 6 months, homocysteine-lowering therapy (folic acid, 5 mg/d; pyridoxine, 100 mg/d; and vitamin B₁₂, 1 mg/d, all in 1 tablet) were added and continued for another year. The control group received matching placebos.

Outcome & Measures

Plasma ADMA levels.

Results

36 participants (77%) in the treatment group and 38 (83%) in the placebo group completed the study. Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 ± 0.07 (SD) and 1.14 ± 0.46 μmol/L, respectively. After 24 months, there was no overall effect of the treatment strategy on ADMA concentrations (β = −0.006; P = 0.27). Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4% in the treatment group compared with the placebo group (multiple adjusted P = 0.02).

Limitations

The study was a secondary analysis, power calculation was based on the primary end point of carotid intima-media thickness, mean plasma ADMA levels were relatively low.

Conclusion

Overall, a multistep treatment strategy consisting of pravastatin, vitamin E, and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population. This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels. Possible ADMA-lowering effects of vitamin E deserve further attention.

Index Words: Chronic kidney disease (CKD), antioxidants, statins, B vitamins, folic acid, vitamin E, pravastatin, asymmetric dimethylarginine (ADMA), homocysteine