HDCN Article Review/Hyperlink

Maschio G, Alberti D, Janin G, Locatelli F, et al.

Effect of ACE inhibitor benazepril on the progression of chronic renal insufficiency

N Engl J Med (Apr) 334:939-945 1996

It is now established practice to treat diabetic nephropathy with ACE inhibitors to slow the progression of renal injury. Although several small reports have suggested that these drugs may be of benefit in nondiabetic renal diseases also, this hypothesis has not been systematically evaluated.

Maschio et al report on the effect of once a day benazepril, a nonsulfhydryl ACE inhibitor, on the course of renal insufficiency in a prospective, double blind and randomized study conducted in Europe. 583 patients, with a variety of glomerular and tubulo-interstitial diseases, were randomized to receive benazepril (300 patients) or placebo (283 patients) following an observational period for three months to ensure stability of renal function and to adequately control blood pressure. The patients were followed for three years and the primary endpoint of the study was doubling of serum creatinine or need for dialysis. Patients were excluded from the study based on such criteria as insulin dependent diabetes.

The clinical profiles of the patients in the two groups were similar. Of the 300 patients in the benazepril group, 31 patients reached the primary endpoint in three years compared to 57 of the 283 patients treated with placebo (p<0.001), the overall risk reduction being 53% in the benazepril group. The protective effect was greater in patients with mild renal insufficiency (creatinine clearance 46 to 60 ml/min) compared to those with moderate impairment (creatinine clearance 30 to 45 ml/min): 71% vs. 46%. Patients with diabetic and nondiabetic glomerular diseases had a favorable response to benazepril; a significant benefit was not seen in those with polycystic kidney disease or tubulo-interstitial diseases.

Comment: I wonder whether a longer follow-up may have led to a different conclusion in patients with tubulo-interstitial diseases, as in 3 years of follow-up only 7 of 105 patients reached the endpoint. Proteinuria was reduced by nearly 30% in patients treated with benazepril. Blood pressures were lower in the benazepril treated patients who, therefore, received fewer additional anti-hypertensive drugs. The beneficial effect of benazepril on the course of renal disease was not entirely explained by its anti-hypertensive action. Adverse events in the benazepril group included more deaths (8 vs. 1), cough and higher average serum potassium levels.

The strengths of the study include its prospective randomized and double blinded strategy and representation of a variety of renal diseases in the patient groups. The increase in the number of deaths in a relatively brief follow-up period in the benazepril group is of serious concern. The authors do not propose a mechanism for increase in mortality. One wonders whether a continuous, round the clock blood pressure monitoring in patients treated with benazepril would reveal episodes of hypotension that, in the appropriate setting, may result in coronary hypoperfusion. The lack of beneficial effect of benazepril in the nonglomerular causes of renal insufficiency is also intriguing. This raises the issue of whether the pathogenesis of progression in tubulo-interstitial diseases is different from that in glomerular diseases. B.S. Kasinath, M.D., University of Texas at San Antonio

The abstract of this paper is available from the National Library of Medicine's PubMed site: click here .