Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-beta in type 2 diabetic patients with advanced kidney disease

Nephrol Dial Transplant. 2006 Mar;21(3):683-9. doi: 10.1093/ndt/gfi310. Epub 2005 Dec 5.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage*
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / therapeutic use
  • Biomarkers / blood
  • Biomarkers / urine
  • Creatinine / blood
  • Creatinine / urine
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / prevention & control*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Prospective Studies
  • Ramipril / administration & dosage
  • Ramipril / therapeutic use
  • Renin-Angiotensin System / drug effects*
  • Tetrazoles / administration & dosage
  • Tetrazoles / therapeutic use
  • Transforming Growth Factor beta / drug effects
  • Transforming Growth Factor beta / urine*
  • Treatment Outcome

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Benzimidazoles
  • Biomarkers
  • Tetrazoles
  • Transforming Growth Factor beta
  • Creatinine
  • Ramipril
  • candesartan