NDT Advance Access originally published online on December 5, 2005
Nephrology Dialysis Transplantation 2006 21(3):683-689; doi:10.1093/ndt/gfi310
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Clinical Nephrology
Effect of low-dose dual blockade of renin–angiotensin system on urinary TGF-ß in type 2 diabetic patients with advanced kidney disease
1 Division of Nephrology and Hypertension, Department of Internal Medicine, 2 Department of Pharmacology and Toxicology, 3 Department of Preventative and Social Medicine and 4 Kidney Disease Research Group, Inha University College of Medicine, Incheon, Republic of Korea
Correspondence and offprint requests to: Moon-Jae Kim, Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea. Email: nhkimj{at}inha.ac.kr
Background. We evaluated the renoprotective effects of dual blockade of renin–angiotensin system (RAS) by using a low-dose combination of ACE inhibiter and angiotensin II receptor blocker in type 2 diabetic patients with advanced kidney disease. The amount of proteinuria and the urinary levels of bioassayable TGF-ß1 were used as surrogate markers of renal injury and sclerosis.
Methods. We performed a prospective double-blinded randomized crossover trial consisting of three 16-week treatment periods with ramipril alone (10 mg/day), candesartan alone (16 mg/day), and ramipril (5 mg/day) plus candesartan (8 mg/day) combination therapy. Twenty-one type 2 diabetic patients with overt nephropathy with a 24 h urinary protein excretion rate (UPER) of >1.0 g/24 h and creatinine clearance (Ccr) of 30 to 59 ml/min/1.73 m2 completed the entire study.
Results. Subjects consisted of 10 female and 11 male patients with a mean age of 49±8 years and duration of diabetes ranging from 4 to 13 years. At baseline, 24-h blood pressures (BPs) were 133±6/81±7 mmHg, Ccr 40.6±4.1 ml/min/1.73 m2, 24-h UPER 4.1±1.9 g/24 h, and urinary TGF-ß1 level 28.4±16.1 pg/mg creatinine (cr). Although there was no comparable change in BP and plasma/urinary biochemical parameters, 24-h UPER was significantly reduced by the combination therapy (2.9±1.4 g/24 h) compared with that of ramipril (3.5±1.8 g/24 h) and of candesartan (3.3±2.0 g/24 h) single therapy (P<0.05). Urinary TGF-ß1 level was reduced in all three therapies compared with that of the control (28.4±16.1 pg/mg cr) (P<0.05). However, the combination therapy showed the most significant change (combination 19.6±10.6 pg/mg cr; ramipril 24.7±13.3 pg/mg cr; candesartan; 23.4±11.7 pg/mg cr). No significant or irreversible adverse effect was observed in the 21 patients who completed the entire study.
Conclusions. The dual blockade of RAS with low-dose ramipril plus candesartan was found to be safe and offered additive benefits with respect to reducing proteinuria and urinary TGF-ß1 excretion in diabetic patients with advanced kidney disease. These benefits were evident as compared with single ramipril and candesartan therapies at doses two-fold greater. Further study on the dose-titration is mandatory in terms of safety and especially for maximizing renoprotection in this patient population.
Keywords: ACE inhibitors; angiotensin II antagonists; diabetic nephropathy; renin–angiotensin aldosterone system; TGF-ß
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