Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-beta in type 2 diabetic patients with advanced kidney disease.
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-beta1 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-beta1 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-beta1 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-beta1 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.
Song
Joon Ho
JH
Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea.
Cha
Seok Ho
SH
Lee
Hun Jae
HJ
Lee
Seoung Woo
SW
Park
Geun Ho
GH
Lee
Seung Won
SW
Kim
Moon-Jae
MJ
D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001713:Biphenyl Compounds; D003404:Creatinine / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017257:Ramipril / Q000008:administration & dosage / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000652:urine*; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D015415:Biomarkers; D001713:Biphenyl Compounds; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D003404:Creatinine; D017257:Ramipril; C081643:candesartan