Effect of atorvastatin on renal NO availability and tubular function in patients with stage II-III chronic kidney disease and type 2 diabetes

Abstract

Background: Statins have beneficial effects on cardiovascular morbidity and mortality independently of reduction of plasma cholesterol. Purpose and methods: In patients with type 2 diabetes and nephropathy, chronic kidney disease stage II-III, we tested the hypothesis that atorvastatin increased systemic and renal nitric oxide (NO) availability using L-NMMA as an inhibitor of NO production. We performed a randomized, placebo-controlled, crossover study, using atorvastatin/placebo treatment for five days with a standardized diet and fluid intake. We measured brachial BP (bBP), central BP (cBP), GFR, urinary output (OU), free water clearance (C_H2O), fractional excretion of sodium (FE_Na), urinary excretion of albumin (UAER and UACR), AQP2 (u-AQP2) and ENaC (u-ENaC_γ) and plasma concentrations of vasoactive hormones: renin, angiotensin II, aldosterone, arginine vasopressin, endothelin-1 and brain natriuretic peptide. Results: During atorvastatin and placebo treatment, L-NMMA infusion, changed the effect variables significantly, but to the same extent, i.e. an increase in bBP and cBP, and a decrease in GFR, OU, C_H2O, FE_Na, u-AQP2 and u-ENaC_γ. In addition, renin and angiotensin II was reduced, aldosterone increased, and vasopressin, endothelin-1 and brain natriuretic hormone unchanged. Conclusion: During, atorvastatin and placebo treatment, inhibition of nitric oxide synthesis induced the same response in brachial and central blood pressure, GFR, renal tubular function and vasoactive hormones. Thus, atorvastatin did not change nitric oxide availability in type 2 diabetics with nephropathy.

Key Words::

• Statins
• renal insufficiency
• chronic
• nitric oxide
• natriuresis
• type 2 diabetes mellitus

Acknowledgements

We thank laboratory technicians Lisbeth Mikkelsen, Anne Mette Ravn, Henriette Vorup Simonsen and Kirsten Nyborg for skillful assistance in examining the subjects and doing laboratory analyses.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

The project was supported by grants from the Region Midt's Research Foundation, University of Aarhus, The A.P. Møller Foundation for the Advancement of Medical Science, Engineer Frode V. Nyegaard and Hustru's Foundation and Eva and Henry Fraenkel's Foundation. Clinical trial no: NCT 01208701.