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PURPOSE: To determine the association between the early rise in serum creatinine levels associated with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and the long-term renoprotective properties of these drugs in patients with chronic renal insufficiency.

BACKGROUND: Large-scale clinical trials have demonstrated survival benefits of ACE inhibitors in patients with heart failure. In patients with renal insufficiency, whether associated with diabetes mellitus or not, use of ACE inhibitors is associated with slowing in the progression of renal disease. In fact, patients who have the most advanced renal insufficiency at baseline are the ones who show the maximum slowing of the disease progression, but these patients are also more likely to show an early rise in serum creatinine levels after ACE inhibitor therapy. There is evidence that patients with renal insufficiency often do not receive ACE inhibitors. There is also evidence that patients with heart failure are not receiving this life-saving drug or are receiving it at dosages lower than that used in the clinical trials. One of the main reasons for this underutilization of ACE inhibitors in patients with heart failure is the underlying renal insufficiency or the rise in serum creatinine level after initiation of therapy with an ACE inhibitor.

METHODS: The authors reviewed 12 randomized clinical trials of ACE inhibitor or ARB therapy in patients with preexisting chronic renal insufficiency, with or without diabetes mellitus or heart failure. Studies were included for review if they met the following criteria: subjects were randomized to receive ACE inhibitor; subjects were followed up for a minimum of 2 years; and most of the subjects had baseline chronic renal insufficiency (≥25% loss of renal function), irrespective of cause. Of the 12 studies that met these criteria, six were multicenter double-blind placebo-controlled studies. The other six were smaller randomized studies. The studies had a mean ± standard deviation follow-up of 3.2 ± 0.3 years. One thousand one hundred two patients were randomized to receive ACE inhibitors or ARBs. Of these, 705 (64%) had data on renal function at baseline (within 6 months of the start) and at the end of the study. The authors examined the changes in serum creatinine levels or glomerular filtration rates (GFR) in patients who were randomized to receive ACE inhibitors. The authors also assessed the blood pressures achieved in the trials.

RESULTS: Patients with preexisting chronic renal insufficiency who achieved their blood pressure control goals were likely to demonstrate an early rise in serum creatinine levels, approximately 25% above the baseline (≈1.7 mg/dL) after initiation of ACE inhibitor or ARB therapy. This rise in serum creatinine was more acute (by ≈15% from the baseline) during the first 2 weeks of therapy and was more gradual (additional ≈10%) during the third and fourth weeks of therapy (Figure 1). The serum creatinine level was likely to stabilize after about 4 weeks, provided patients had a normal salt and fluid intake. In addition, patients who did not show a rise in serum creatinine level during the first 2 to 4 weeks of therapy, were less likely to experience one after that period, unless they were dehydrated from use of diuretics or gastroenteritis or had used a nonsteroidal antiinflammatory drug (NSAID). In spite of this early rise in serum creatinine in patients with chronic renal insufficiency (a serum creatinine level of ≥124 μmol/L or ≥1.4 mg/dL) who were randomized to receive an ACE inhibitor, these patients receiving the drug showed a 55% to 75% lower risk of worsening renal function than those with normal renal function receiving the drug. The rate of risk reduction was inversely related to the severity of renal impairment at baseline, but data were limited on the benefit of ACE inhibitors in patients with more advanced renal insufficiency (GFR <30 mL/min). The authors noted that those aged 65 and older were likely to have much lower GFRs for given levels of serum creatinine than younger patients and were therefore likely to have advanced renal insufficiency at serum creatinine levels as low as 2 mg/dL (vs 4 mg/dL for younger patients).

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Figure 1. Projected possible rise in serum creatinine levels in patients with heart failure and impaired renal function treated with angiotensin-converting enzyme (ACE) inhibitors, based on data from subjects with normal renal function, patients with impaired renal function, and patients with heart failure and normal renal function. Modified from Figure 1 of the systematic review.33

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Patients with normal renal function were likely to show a much smaller rise in serum creatinine level (≈10% above the baseline of 0.9 mg/dL), mostly occurring during the first week after initiation of therapy, with subsequent stabilization, whereas patients with normal renal function suffering from heart failure, volume depletion, or bilateral renal artery stenosis experienced a significant rise (≈225% above baseline) in serum creatinine level, much higher in magnitude and rate than that experienced by those with renal insufficiency (Figure 1). Serum creatinine levels in these patients sharply increased (by ≈75% above baseline) in the 2 weeks after the initiation of therapy with an ACE inhibitor, followed by an even sharper increase (another ≈150%) during the subsequent 2 weeks. Patients with chronic renal insufficiency (serum creatinine>1.5 mg/dL) who received therapy with ACE inhibitors had about a five times higher risk of developing hyperkalemia than those with normal renal function, whereas presence of heart failure increased the risk of hyperkalemia by about three times over those without heart failure. Concomitant use of diuretics was associated with an approximately 60% reduction in risk of hyperkalemia.

CONCLUSION: The authors conclude that, in patients with renal insufficiency (serum creatinine>1.4 mg/dL) treated with ACE inhibitors, there is a strong association between early (within the first 2 months) and moderate (not exceeding 30% over baseline) rise in serum creatinine and slowing of the renal disease progression in the long run. The authors recommend that ACE inhibitor therapy should not be discontinued unless serum creatinine level rise above 30% over baseline during the first 2 months after initiation of therapy or hyperkalemia (serum potassium level ≥5.6 mmol/L) develops.