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Therapeutics

Enalapril slowed the progression of chronic renal failure in patients with progressive chronic nephropathy

ACP J Club. 1993 Jan-Feb;118:7. doi:10.7326/ACPJC-1993-118-1-007


Source Citation

Kamper AL, Strandgaard S, Leyssac PP. Effect of enalapril on the progression of chronic renal failure. A randomized controlled trial. Am J Hypertens. 1992 Jul;5:423-30.


Abstract

Objective

To evaluate the effect of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on the progression of chronic renal failure.

Design

Randomized controlled trial with ≥ 2 years of follow-up.

Setting

Outpatient nephrology clinic in Denmark.

Patients

Patients aged 15 to 75 years with progressive chronic nephropathy (plasma creatinine values from 150 to 900 mol/L) were eligible. Exclusion criteria were renal artery stenosis, urinary tract obstruction, serious nonrenal disease, treatment with immunosuppressive or nonsteroidal anti-inflammatory drugs, and past or current treatment with ACE inhibitors. 70 patients with chronic renal disease of various causes (including diabetes mellitus) were randomized. 11 were normotensive on no therapy. Median follow-up was 26 months (range, 1 to 42 mo).

Intervention

The therapeutic goal for the 59 hypertensive patients was a systolic blood pressure (BP) of 120 to 140 mm Hg and diastolic BP of 80 to 90 mm Hg. 35 patients were assigned to oral enalapril, increased from 2.5 mg/d as required (mean dose at end of follow-up, 6.9 mg/d), and to a reduction or discontinuation of other antihypertensive treatment. The 35 control patients continued antihypertensive therapy as required with β-blockers, diuretics, vasodilators, and calcium channel blockers. Nondiabetic patients with a glomerular filtration rate (GFR) of < 30 mL/min per 1.73 m2 body surface area were advised to follow a restricted protein diet starting 3 months before randomization.

Main outcome measures

Progression of renal failure determined from changes in GFR measured by clearance of 51Cr-EDTA; incidence of end-stage renal failure requiring dialysis (GFR approximately 5 mL/min per 1.73 m).

Main results

In the enalapril group the median GFR declined from baseline by 0.20 mL/min per 1.73 m per month compared with 0.31 mL/min per 1.73 m2 per month (P <0.05) in controls. Baseline GFR was 13.0 mL and 18.8 mL/min per 1.73 m2 in the enalapril and control groups, respectively. 10 patients assigned to enalapril (29%) and 13 control patients (37%) progressed to renal failure requiring dialysis {difference 8%, 95% CI -13% to 30%}*. 3 of 6 normotensive control patients compared with none of 5 normotensive patients in the enalapril group progressed to dialysis {difference 50%, CI 10% to 90%}*. The groups did not differ in increases in plasma creatinine or in median BP.

Conclusion

Progression of renal failure was slower when patients with progressive chronic nephropathy were treated with enalapril than with conventional antihypertensive drugs.

Source of funding: Merck Sharp & Dohme (enalapril).

For article reprint: Dr. A.L. Kamper, Department of Nephrology B, Herlev Hospital, DK-2730 Herlev, Denmark. FAX 45-44-883627.

*Numbers calculated from data in article.


Commentary

Many patients with chronic renal insufficiency experience a progressive decline in GFR. As has been reported for diabetic nephropathy (1), ACE inhibitors may slow the decline in nondiabetic renal diseases by effects on systemic hypertension, glomerular hemodynamics, and other direct actions on the glomerulus (2). A meta-analysis of nearly 1600 patients bmc in 10 published and unpublished studies (3) concluded that ACE inhibitors were more effective than other antihypertensives in reducing the risk for end-stage renal failure caused by nondiabetic nephropathy, with a pooled relative risk ratio of 0.70 with ACE inhibitors. The authors were not able to determine whether this benefit occurred because of greater lowering of blood pressure compared with the other drugs or because of other more direct or specific effects of ACE inhibitors. Since the report by Kamper and colleagues, 2 large placebo-controlled trials of ACE inhibitors in patients with chronic renal insufficiency of various etiologies (including diabetes mellitus) have been reported. In the first study, benazepril reduced the risk for progressive renal insufficiency by 53% (4). This beneficial effect was most prominent in patients with heavy proteinuria caused by nondiabetic glomerular diseases and diabetic nephropathy. In a more recent trial, the Ramipril Efficacy in Nephropathy (REIN) study of patients with chronic renal disease and proteinuria of 3.0 g/d greater, there was a substantially slower rate of GFR decline in ramipril-treated patients, with nearly twice the risk in the placebo group compared with the ramipril group for doubling the serum creatinine or reaching end-stage renal disease over a period of about 3 years (5).

Toxicities of ACE inhibitors, such as acute renal failure, hyperkalemia, cough, and angioneurotic edema require that patients be carefully monitored. Finally, it remains to be proven whether the newer angiotension II receptor blockers exert a similar renoprotective effect to that seen with ACE inhibitors (6). Experimental data are contradictory, and there are no long-term human studies yet available. For the time being, ACE inhibitors should remain the preferred antihypertensive agents in patients with proteinuria and chronic renal insufficiency.

Jeffrey S. Berns, MD
The Graduate HospitalPhiladelphia, Pennsylvania, USA


References

1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, and the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Eng J Med. 1993;329:1456-62.

2. Matsusaka T, Hymes J, Ichikawa I. Angiotensin in progressive renal diseases: theory and practice. J Am Soc Nephrol. 1996;7:2025-43.

3. Giatras I, Lau J, Levey AS, and the Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med. 1997;127:337-45.

4. Masachio G, Alberti D, Janin G, et al., and the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Effect of the antiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med. 1996;334:939-45.

5. The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997;349:1857-63.

6. Ichikawa I. Will angiotensin II receptor antagonists be renoprotective in humans? Kidney Int. 1996;50:684-92.