Q:Should I avoid angiotensin-converting enzyme (ACE) inhibitors in my patients with progressive renal insufficiency?
A:This issue is extremely bothersome to clinicians. ACE inhibitors represent
a dual-edged sword with respect to their impact on renal function. On one
hand, major clinical trials have clearly demonstrated their benefit in patients with
congestive heart failure (CHF) and in patients with diabetic and nondiabetic renal
disease. In multiple large clinical trials, ACE inhibitors reduce the risk of hospitalizations
and death in patients with severe systolic dysfunction. In patients with
proteinuric renal disease, ACE inhibitors significantly reduce proteinuria and
slow the rate of progressive loss in renal function. Multiple benefits have been
observed in older patients with cardiovascular disease, with or without hypertension-
and with and without renal disease.1 These data, taken together, suggest
that a significant segment of the population may benefit from this class of agents.
Nevertheless, clinicians remain wary of prescribing ACE inhibitors for patients
with any degree of renal dysfunction-particularly when initiation is associated
with evidence of further renal dysfunction. Consequently, many patients
who could profit greatly from long-term treatment with ACE inhibitors are denied
their potential benefit.
EFFECT OF ACE INHIBITORS ON RENAL CIRCULATION
The renin-angiotensin system plays an important role in the autoregulation
of both renal blood flow and particularly of glomerular filtration rate (GFR). The
balance between afferent and efferent arteriolar tone in the renal glomerulus determines
glomerular hydrostatic pressure and, therefore, GFR. Suppression of
angiotensin II generation by ACE inhibitors, and the resulting decrease of efferent
arteriolar tone, causes a reduction in glomerular hydrostatic pressure, in
GFR, and in proteinuria. These changes are a predictable effect of ACE inhibitors
within the kidney and are reflected clinically by a decrease in GFR, a decrease in
quantitative proteinuria, and an increase in the serum creatinine concentration.
These observations, however, do not preclude the cautious administration
of ACE inhibitors in patients with renal insufficiency.
WHAT IS THE RISK OF FURTHER RENAL INSUFFICIENCY?
A postmarketing study observing prescription-related events in patients receiving
enalapril showed an increase in serum creatinine of greater than 50% in
only 8.2% of cases.2 In multiple studies of ACE inhibitors in patients with CHF,
the incidence of increased serum creatinine requiring discontinuation of the
medication ranged from 5% to 11%. These studies included patients with stages
1 to 4 heart failure, acute myocardial infarction, and baseline serum creatinine
concentrations as high as 3.4 mg/dL.
In a meta-analysis of almost 1600 patients with nondiabetic renal disease,
ACE inhibitors did not increase overall mortality.3 Baseline serum creatinine
concentrations in this meta-analysis ranged as high as 4.4 mg/dL.
In an earlier study in patients with type 1 diabetes mellitus who were treated
with captopril, slower progression of renal disease was observed in patients
with serum creatinine levels up to and exceeding 4 mg/dL.
In fact, in patients with diabetic and nondiabetic renal disease,
those with the highest levels of urine protein excretion
and higher levels of creatinine derived particular
benefit from ACE inhibitor therapy. However, renal protection
is maximized when ACE inhibition is started earlier
and when long-lasting treatment can result in stabilization
of renal function and subsequent prevention of end-stage
1. Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcome Prevention Evaluation
Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor,
ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;
2. Speirs CJ, Dollery CT, Inman WH, et al. Postmarketing surveillance of enalapril,
II: investigation of the potential role of enalapril in deaths with renal failure.
Br Med J. 1988;297:830-832.
3. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors
and progression of nondiabetic renal disease: a meta-analysis of patientlevel
data. Ann Intern Med. 2001;135:73-87.
4. Moser M. Lower Your Blood Pressure and Live Longer. New York: Berkley, Putnam