Add-on Angiotensin II Receptor Blockade Lowers Urinary Transforming Growth Factor-beta Levels

Progression of renal failure, despite renoprotection with angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuric nephropathies, may be caused by persistent renal production of transforming growth factor-beta1 (TGF-beta1) through the angiotensin II subtype 1 (AT1) receptors. We tested the hypothesis that AT1-receptor blocker therapy added to a background of chronic maximal ACE inhibitor therapy will result in a reduction in urinary TGF-beta1 levels in such patients. Sixteen patients completed a two-period, crossover, randomized, controlled trial, details of which have been previously reported. All patients were administered lisinopril, 40 mg/d, with either losartan, 50 mg/d, or placebo. Blood pressure (BP) was measured using a 24-hour ambulatory BP monitor. Overnight specimens of urine were analyzed for urine TGF-beta1, protein, and creatinine concentrations. Mean age of the study population was 53 +/- 9 (SD) years; body mass index, 38 +/- 5.7 kg/m2; seated BP, 156 +/- 18/88 +/- 12 mm Hg; and urine protein excretion, 3.6 +/- 0.71 g/g of creatinine. Twelve patients had diabetic nephropathy, and the remainder had chronic glomerulonephritis. At baseline, urinary TGF-beta1 levels were significantly increased in the study population compared with healthy controls (13.2 +/- 1.2 versus 1.7 +/- 1.1 ng/g creatinine; P < 0.001). There was a strong correlation between baseline urine protein excretion and urinary TGF-beta1 level (r2 = 0.53; P = 0.001), as well as systolic BP and urinary TGF-beta1 level (r2 = 0.57; P < 0.001). After 4 weeks of add-on losartan therapy, there was a 38% (95% confidence interval [CI], 16% to 55%) decline in urinary TGF-beta1 levels (13.3 [95% CI, 11.4 to 15.5] to 8.2 pg/mg creatinine [95% CI, 6.2 to 10.7]). The reduction in urinary TGF-beta1 levels occurred independent of changes in mean urinary protein excretion or BP. Thus, proteinuric patients with renal failure, despite maximal ACE inhibition, had increased urinary levels of TGF-beta1 that improved over 1 month of add-on therapy with losartan. We speculate that dual blockade with losartan and an ACE inhibitor may provide additional renoprotection by decreasing renal production of TGF-beta1.