Reduced proteinuria using ramipril in diabetic CKD stage 1 decreases circulating cell death receptor activators concurrently with ADMA. A novel pathophysiological pathway?

• Published in: Nephrology, dialysis, transplantation Vol. 25; no. 10; pp. 3250 - 3256
• Main Authors: Yilmaz, Mahmut Ilker, Sonmez, Alper, Saglam, Mutlu, Yaman, Halil, Cayci, Tuncer, Kilic, Selim, Eyileten, Tayfun, Caglar, Kayser, Oguz, Yusuf, Vural, Abdulgaffar, Yenicesu, Mujdat, Axelsson, Jonas
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-10-2010
• Subjects: ADMA; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; angiotensin-converting enzyme inhibitor; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Arginine - analogs & derivatives; Arginine - blood; Associated diseases and complications; Biological and medical sciences; Chronic Disease; chronic kidney disease; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - drug therapy; Emergency and intensive care: renal failure. Dialysis management; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; fas Receptor - blood; Female; Humans; Intensive care medicine; Kidney Diseases - drug therapy; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Multivariate Analysis; Myostatin - blood; protein catabolism; proteinuria; Proteinuria - drug therapy; Ramipril - therapeutic use; Endocrinopathy; Kidney disease; chronic kidney disease; Urinary system disease; Enzyme; Hemodialysis; Diabetes mellitus; Enzyme inhibitor; Ramipril; ADMA; Peptidases; Extrarenal dialysis; Peptidyl-dipeptidase A; Cell death; angiotensin-converting enzyme inhibitor; Renal failure; Hydrolases; Peptidyl-dipeptidases; Antihypertensive agent; Catabolism; protein catabolism; ACE inhibitor; Proteinuria
• ISSN: 0931-0509; 1460-2385; 1460-2385
• DOI: 10.1093/ndt/gfq159

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.