Clinical Trial: Angiotensin II Antagonism of TGF-Beta 1

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Angiotensin II Antagonism of TGF-Beta 1: A Candesartan Dose - TGF-Beta 1 Response Relationship Study

Brief Summary: Diabetic nephropathy is a frequent microvascular complication that occurs in approximately 40% of patients with either type 1 or type 2 diabetes. The most common cause of end-stage renal disease (ESRD) in the United States and in the developed world is diabetic nephropathy. Currently, more than half the United States ESRD population has diabetes. More effective therapies to prevent and treat diabetic nephropathy are urgently needed. One way to increase therapeutic effectiveness is to refine treatment targets based on improved understanding of how treatments modulate disease processes. The purpose of this study is to determine whether a treatment for diabetic nephropathy, the angiotensin receptor blocker candesartan, modifies mediators of kidney injury independent of blood pressure and the relationships to drug dose.

Detailed Summary:

Transforming growth factor-beta 1 (TGF-beta 1) is a potent inducer of extracellular matrix production and of fibrogenesis and has been associated with the occurrence of diabetic micro- and macrovascular complications. Several in vitro and in vivo studies have implicated TGF-beta 1 in the pathogenesis of diabetic kidney disease. Recent animal and in vitro experiments have demonstrated that ACE inhibitors and Angiotensin II (AT-II) receptor antagonists, including candesartan, decrease the synthesis and secretion of renal TGF-beta 1 and prevent the development of glomerulosclerosis, interstitial fibrosis, and progressive renal dysfunction. These protective effects appear to be unrelated to the antihypertensive effects of the agents.

Limited data in humans have supported these findings in patients with diabetic nephropathy. A recent human study with the AT-II receptor antagonist losartan demonstrated that the ability to correct microalbuminuria was independent of blood pressure control and correlated with normalization of circulating levels of TGF-beta 1. The results were further supported by the observation that markers of collagen type 1 metabolism were normalized in hypertensives in whom TGF-beta 1 was normalized with treatment but remained unaltered in the remaining hypertensives despite blood pressure control. Such findings are consistent with the recent observation that the AT-II receptor antagonist irbesartan is renoprotective independently of its blood pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

The use of ACE-inhibitors and AT-II receptor antagonists as a means to reduce progression of renal fibrosis is becoming increasingly widespread. Dosage recommendations to achieve this goal are unclear prompting some experts to ask whether TGF-beta 1 rather than blood pressure should be a ther
Sponsor: Providence Health & Services

Current Primary Outcome:

  • Blood pressure
  • Urinary TGF-Beta 1
  • Serum angiotensin II
  • Urinary albumin
  • Urinary carboxymethyllysine


Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: Providence Health & Services

Dates:
Date Received: April 28, 2006
Date Started: August 2002
Date Completion: September 2004
Last Updated: August 1, 2007
Last Verified: March 2006