In animal models, ACE inhibitors have been shown to slow the progression of renal failure, presumably by decreasing glomerular filtration pressure and thereby decreasing proteinuria. In diabetic patients, these drugs have been shown to slow the increase in proteinuria and the progression to renal failure. This study was designed to look at an ACE inhibitor in the setting of non-diabetic renal failure.
The difference was significant in the mild and moderate renal failure groups and remained significant, although lower, after adjustment for blood pressure control. The difference was not significant for polycystic disease; also not significant for nephrosclerosis and interstitial nephritis (the numbers of patients reaching an endpoint were too small).
There was an early and sustained decrease in proteinuria in the benazepril
group, compared with placebo.
The authors note that the benefit from benazepril was most pronounced in glomerular and diabetic nephropathy, and not at all in polycystic disease (which also does not respond to protein restriction). They argue that, although some of the beneficial effect of ACE inhibition may have been related to better blood pressure control, adjustment for BP shows that there is an independent effect of ACE inhibition. They note that the protective effect of benazepril was greatest in the patients with substantial proteinuria, which suggests that reduction of proteinuria may be responsible for the protective effect of ACE inhibitors in renal failure.
The authors are unable to explain the higher mortality found in the benazepril group. Although serum potassium was higher in this group, the patients with sudden death did not have hyperkalemia at their last visit.
The benefit of ACE inhibitors has been demonstrated in animal models, in diabetic patients and in small numbers of patients with non-diabetic renal failure. The study presented here shows a benefit in a fairly large group of patients with predominently non-diabetic kidney disease. Although some of the drug effect seems to be due to better blood pressure control, some of the benefit is independent of BP and presumably occurs by a mechanism such as that mentioned above.
The increase in mortality that was unexpectedly noted is troublesome and hard to explain. Of the 8 deaths in the benazepril group, 3 were deemed sudden deaths and 3 from myocardial infarction. It is noteworthy that there were only 4 non-fatal myocardial infarctions that led to withdrawal from the study: 2 in the placebo group and 2 in the treatment group. If benazepril led to a high risk of sudden death/MI, one would expect a higher incidence of non-fatal MI as well.
The increased mortality could be a statistical fluke. The p-value of 0.04 means that there is a 1 in 25 probability that this result is a purely chance occurrence. The fact that it seems to fly in the face of what one would expect, given other studies on ACE inhibitors in cardiac disease and in renal disease, lends some credence to this hypothesis.
Nevertheless, this disturbing result should not be totally ignored. It could represent a risk particular to the drug tested here, or a hitherto unknown risk of ACE inhibitor therapy in chronic renal failure patients. A meta-analysis of other ACE inhibitor trials in renal failure might be useful in looking at this question.
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