Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade Paolo Ferrari, Hans-Peter Marti, Marc P®ster and Felix J. Frey Background Limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal function deterioration. Objective To investigate whether, in hypertensive patients with glomerulonephritis, a combination of an angiotensin converting enzyme inhibitor (ACEI, fosinopril 20 mg/day) with an angiotensin receptor blocker (ARB, irbesartan 150 mg/day) produces a more profound antiproteinuric effect than either drug alone. Methods Ten non-diabetic patients with glomerulonephritis, normal or slightly reduced but stable renal function (creatinine clearance 40±106 ml/min) without immunosuppression were studied. Clinical evaluations, 24 h blood pressure measurements and laboratory tests were performed as follows: (1) without medication (baseline) and in random sequence; (2) ACEI alone; (3) ARB alone; and (4) combination of ACEI ARB. Each period lasted for 6 weeks, separated by three washout periods of 4 weeks each without therapy. Results ACEI and ARB alone reduced proteinuria from 7.9 6 7.1 to 5.3 6 5.2 and 5.0 6 4.9 g/24 h (mean 6 SD), respectively. The combination of ACEI ARB induced a more remarkable reduction of proteinuria in every patient (to 3.3 6 3.7 g/24 h) than either drug alone ( P 0.039 by ANOVA). The enhanced antiproteinuric effect of the combined therapy could not be attributed to a more pronounced reduction of 24 h mean arterial pressure (basal, 106 6 8; ACEI, 97 6 5; ARB, 98 6 5; ACEI ARB, 95 6 5 mmHg) or creatinine clearance (basal, 77 6 27; ACEI, 73 6 31; ARB 80 6 30; ACEI ARB, 73 6 32 ml/min). Conclusions A combination of ACEI and ARB in patients with glomerulonephritis produces a more profound decrease in proteinuria than either drug alone. This additive antiproteinuric effect is not dependent on changes in blood pressure or creatinine clearance. A long-term controlled study is required to con®rm the positive effect of this treatment on the progression of renal function loss. J Hypertens 20:125±130 & 2002 Lippincott Williams & Wilkins. Journal of Hypertension 2002, 20:125±130 Keywords: nephropathy, proteinuria, hypertension, glomerular ®ltration rate, irbesartan, fosinopril Division of Nephrology and Hypertension, Inselspital, University of Berne, Switzerland. Sponsorship: This work was supported in part by grants from the Swiss National Foundation for Scienti®c Research (Nr. 3100-58889 and Nr. 3200-050820) and the Cloe È tta Foundation, Zurich, Switzerland. Correspondence and requests for reprints to Paolo Ferrari MD, Division of Nephrology and Hypertension, Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland. Tel: 4131-632 3142; fax: 4131-632 9734; email: paolo.ferrari@insel.ch Received 17 May 2001 Revised 2 August 2001 Accepted 5 September 2001 Introduction In chronic proteinuric glomerular diseases, glomerular ®ltration rate (GFR) continues to decline even after the initial insult has been removed, leading to end-stage renal failure in many patients [1]. Hypertension plays a major role in sustaining renal function deterioration [2]. Limitation of systemic and glomerular hypertension reduces urinary protein excretion and renal function deterioration in both experimental animals and also in humans with insulin-dependent diabetes mellitus [3±5]. In the latter, angiotensin converting enzyme (ACE) inhibitors (ACEI) are more effective than more conven- tional drugs with regard to the limitation of the progres- sion of renal disease, even with similar blood pressure control [6±8]. In the REIN study, the ACEI ramipril has also been shown to have a signi®cant renoprotective effect in non-diabetic proteinuric nephropathy [9]. The main mechanism underlying the antiproteinuric effect of ACEI is the reduction of the negative effects of angiotensin II on renal hemodynamics. It is known that chronic ACEI therapy may not completely inhibit the formation of angiotensin II [10,11], and that angiotensin II may also be produced through a non-ACE-dependent pathway, such as human chymase [12]. Owing to the potential advantage of angiotensin recep- tor blocker (ARB) versus ACEI in antagonizing the local production of angiotensin II by the tissue renin± angiotensin system, it is conceivable that a substantial blockade of the AT1-receptor with ARB would be at least equivalent to, if not superior than, the inhibition of the ACE. On the other hand, inhibition of bradyki- nin metabolism is observed with ACEI but not with ARB treatment. Gansevoort et al. [13] showed that the angiotensin II receptor blocker, losartan, had similar effects as the ACEI, enalapril, on renal function. In Original article 125 0263-6352 & 2002 Lippincott Williams & Wilkins