Nephrology Dialysis Transplantation

Mahmut Ilker Yilmaz¹, Alper Sonmez², Mutlu Saglam³, Halil Yaman⁴, Tuncer Cayci⁴, Selim Kilic⁵, Tayfun Eyileten¹, Kayser Caglar¹, Yusuf Oguz¹, Abdulgaffar Vural¹, Mujdat Yenicesu¹ and Jonas Axelsson⁶

¹ Department of Nephrology ² Department of Endocrinology ³ Department of Radiology ⁴ Department of Biochemistry ⁵ Department of Epidemiology, Gülhane School of Medicine, 06018 Etlik, Ankara, Turkey ⁶ Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden

Abstract

Background. Renin–angiotensin system (RAS) blockade improves proteinuria and the endothelial functions in diabetic nephropathy. Plasma asymmetric dimethylarginine (ADMA), abundant in the cell than in the plasma, is also improved by RAS blockage. We hypothesized that RAS blockade may reduce ADMA by reducing injurious cell death.

Methods. In a hypothesis-generating study, we assessed circulating levels of apoptotic signalling peptides in incident chronic kidney disease (CKD) stage 1 patients (aged >18 years with diabetes mellitus type 2 as the only cause of nephropathy) not previously prescribed statins or RAS blockade. Ninety-three (29 M, 47 ± 5 years) patients with CKD 1 diabetic nephropathy and 38 healthy subjects (20 M, 47 ± 5 years) were enrolled. Ramipril was given (5 mg daily for 12 weeks), and circulating ADMA, soluble Fas (sFas), myostatin and endothelial function [flow-mediated vasodilation (FMD); ultrasound)] were measured.

Results. After the study, ADMA, sFas, myostatin, insulin resistance, high-sensitive C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), blood pressure and proteinuria levels were decreased, and FMD and serum albumin levels increased (P < 0.05 for all). ADMA and sFas levels were independently related to FMD levels both before (rho = –0.33; P < 0.005 and rho = –0.26; P < 0.02, respectively) and after (rho = –0.39; P < 0.001 and rho = –0.28; P < 0.002, respectively) ramipril treatment. Changes in sFas and ADMA were related to the change in FMD (–0.32; P > 0.004 and –0.31; P < 0.004, respectively).

Conclusion. A reduction of proteinuria in CKD 1 diabetic kidney disease is accompanied by lower circulating sFas, myostatin and ADMA, suggesting that increased cell death may contribute to ADMA formation and endothelial dysfunction in diabetic CKD.

Keywords: ADMA; angiotensin-converting enzyme inhibitor; chronic kidney disease; protein catabolism; proteinuria