October 31, 2004
American Society of Nephrology (ASN) Renal Week 2004, St. Louis, Missouri
Abstract SU-PO180
Poster: Clinical Nephrology / Diabetes Mellitus: Epidemiology/Treatment

Beneficial Effect of Dual Blockade of the Renin-Angiotensin System (RAS) on Urinary Connective Tissue Growth Factor (CTGF) in Type 2 Diabetic Patients with Nephropathy. F.A. van Nieuwenhoven, K. Rossing, S. Andersen, N. Oliver, R. Goldschmeding. HH Parving, HH Parving, Pathology UMCU, Utrecht, Netherlands; Steno Diabetes Center, Steno Diabetes Center, Gentofte, Denmark; FibroGen, FibroGen, Inc., SSF, CA.

CTGF is a profibrotic growth factor implicated in the pathogenesis of diabetic nephropathy (DN) and urinary CTGF (U-CTGF) is significantly increased in patients with DN. We evaluated short-term changes in U-CTGF of dual blockade of the RAS by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of ACE-inhibitor (ACEI) in patients with type 2 diabetes (T2D) and DN. Twenty T2D patients with hypertension and DN were enrolled in this double-blinded randomized two-period crossover trial. Patients received eight weeks therapy with the ARB candesartan 16 mg daily and placebo, added in random order to existing treatment with lisinopril/enalapril 40 mg or captopril 150 mg daily. At the end of each treatment period we evaluated: U-CTGF (ELISA), albuminuria (turbidimetry), 24-h ambulatory blood pressure measurement (ABPM), and glomerular filtration rate (GFR).

During dual blockade of the RAS by addition of candesartan, there was an overall mean reduction (95% CI) in U-CTGF of 18 (0 to 33) %, as compared to ACEI alone (p=.05). Albuminuria was reduced by 28 (17 to 38) % (p<0.001) and there was a modest reduction in systolic/diastolic 24-h ABPM and in GFR (NS). Interestingly, there was a significant carry-over effect by dual blockade on U-CTGF as reflected by a 36 (17 to 51) % (p<0.001) reduction in those 10 patients who received ACEI alone in the first period and dual blockade in the second period, whereas there was an insignificant change in U-CTGF of -5 (-38 to 20) % (p=0.71) in patients who received dual blockade in the first period and mono blockade with ACEI in the second period. A significant carry-over effect was not observed for albuminuria, SBP or GFR. Our short-term study demonstrates that ARB in combination with maximum recommended doses of ACEI significantly reduced U-CTGF and albuminuria as compared to monotherapy with ACEI. A significant carry-over effect on U-CTGF may suggest a prolonged effect of candesartan.

Scientific Advisor: FibroGen, Inc.

See also November 1, 2004 press release