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ACE Inhibitors:When-and For Which Patients?

ACE Inhibitors:When-and For Which Patients?

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.


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.


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
renal disease.

  Table 1 — Guidelines for safe use of ACE inhibitors
  1. Your clinical assessment should yield information regarding severe hyponatremia or volume depletion. If the clinical history suggests renal artery stenosis, a noninvasive renal duplex Doppler study will answer that issue.
  2. Begin the ACE inhibitor at a low dosage. You may elect to start with a
    short-acting agent, such as captopril once or twice daily. If this regimen is
    well tolerated, switch to a longer-acting once-daily ACE inhibitor after several
    weeks. Expect a modest, self-limited reduction in GFR in all patients who
    take an ACE inhibitor. In patients with established renal insufficiency (serum
    creatinine level > 1.4 mg/dL), expect to see a modest, self-limited increase
    in the serum creatinine level.
  3. Recheck the serum creatinine level 3 or 4 days after the start of therapy.
    Do so again after 2 weeks, then monthly for the next 2 months. An increase
    in the serum creatinine level of 20% to 30% is acceptable if that rise is selflimiting
    and stabilizes within the first 2 or 3 months of therapy.
  4. Take measures to correct hyperkalemia (potassium level > 5.5 mmol/L);
    this disorder may limit the use of an ACE inhibitor. Be sure the patient is not
    taking any potassium-sparing agents or potassium supplements. Be sure your
    patient is not eating potassium-rich foods (Table 2). Serum potassium levels
    during ACE inhibitor therapy are inversely related to the GFR; therefore,
    careful serial monitoring of potassium levels as well as renal function are
    necessary in patients with progressive renal disease.
  5. In patients who cannot tolerate an ACE inhibitor because of adverse effects,
    such as cough or angioedema, an angiotensin II receptor blocker may
    be substituted. This class of agents appears to duplicate the beneficial effects
    of ACE inhibitors via suppression of the renin-angiotensin-aldosterone system.
    In fact, there are limited clinical data to suggest that the risk of hyperkalemia
    may be less with angiotensin receptor blockers at similar levels of
    creatinine—an observation that may relate to higher levels of plasma aldosterone
    in patients taking angiotensin receptor blockers.
  6. Bilateral, high-grade renal artery stenosis is not an absolute contraindication
    for ACE inhibitors. These agents are being used increasingly in the
    long-term medical management of atherosclerotic renovascular disease.

ACE, angiotensin-converting enzyme; GFR, glomerular filtration rate.


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