title: Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-beta in type 2 diabetic patients with advanced kidney disease.
abstract: 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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Song
authors.forename: Seok Ho
authors.initials: SH
authors.lastname: Cha
authors.forename: Hun Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seoung Woo
authors.initials: SW
authors.lastname: Lee
authors.forename: Geun Ho
authors.initials: GH
authors.lastname: Park
authors.forename: Seung Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Moon-Jae
authors.initials: MJ
authors.lastname: Kim
mesh_terms: 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
chemical_list: 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