ACE inhibitors and progression of non-diabetic renal disease

Evidence Summaries

Level of Evidence = A
ACE inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage non-diabetic renal disease.

A systematic review 1 including 10 RCTs with a total of 1,594 subjects was abstracted in DARE. All patients had non-diabetic renal disease of varying aetiology: hypertensive nephrosclerosis, glomerular disease, interstitial disease, polycystic kidney disease, and other causes. The mean age ranged from 44 years to 66 years. ACE inhibitors studied included enalapril, captopril, cilazepril and benazepril. Control groups received placebo, beta-adrenergic blockers, calcium channel blockers and unspecified combinations of anti-hypertensive agents. The weighted mean systolic blood pressure was 150–151 mmHg and the mean diastolic blood pressure was 92 mmHg in both groups. Decline in weighted mean systolic pressure was 4.9 mmHg greater and the decline in weighted mean diastolic pressure was 1.2 mmHg greater in the ACE inhibitor group as compared to the control groups. The odds ratio for pooled end-stage renal disease was 0.70 (95% CI 0.51 to 0.97). The pooled relative risk of death was 1.24 (95% CI 0.55 to 2.83). If the one study with a very high relative risk (RR = 7.55) was included, the RR of death in the remaining studies was 0.89 (95% CI 0.36 to 2.17).

Another systematic review 2 including 16 studies with a total of 2,031 subjects was abstracted in DARE. ACE inhibitors included: enalapril (5 to 40 mg); captopril (75 to 100 mg); lisinopril (10 to 100 mg); benazepril (10 mg); and ramipril (2.5 to 5 mg). Co-interventions included antihypertensive agents. Post therapy, the average mean arterial pressure was less in ACE inhibitor treated patients across all studies but one. ACE inhibitors significantly reduced the risk of macroalbuminuria, RR = 0.35 (95% CI: 0.24 to 0.53), and the risk of macroalbuminuria, RR = 0.60 (95% CI: 0.49 to 0.73). There was no significant difference in the mortality rate between treatment groups, RR = 1.05 (95% CI: 0.57 to 1.95)

In an RCT 3 patients were assigned to receive 20 mg of benazepril (group 1, creatinine level 133–265 μmol/l), 20 mg of benazepril (group B2, creatinine level of 274–442 μmol/l) or placebo (group P2, creatinine 274–442 μmol/l). 22/102 (22%) in group 1 reached the primary end point (doubling of the serum creatinine level, end-stage renal disease, or death) in a follow-up of mean 3.4 years, as compared with 44/108 patients in group B2 (41 %) and 65/107 patients in group P2 (60 %). As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005) irrespective of blood-pressure control. The overall incidence of major adverse events in the benazepril and placebo subgroups of group 2 was similar.

A Cochrane review 4 included 6 open-label studies involving a total of 257 peritoneal dialysis (PD) patients. One study compared ACEi with other antihypertensive drugs, 3 compared ARBs with other antihypertensive drugs, and 2 studies compared an ARB with an ACEi. Long-term use (≥ 12 months) of an ARB showed significantly benefit of preserving residual kidney function in continuous ambulatory PD (CAPD) patients (MD 1.11 mL/min/1.73 m², 95% CI 0.38 to 1.83), although there was no significant benefit when an ARB were used short-term (≤ six months). One study showed that compared with other antihypertensive drugs, long-term use (12 months) of the ACEi ramipril showed a significant reduction in the decline of residual kidney function in patients on CAPD (MD -0.93 mL/min/1.73m², 95% CI -0.75 to -0.11), and delayed the progression to complete anuria (RR 0.64, 95% CI 0.41 to 0.99). There was no significant difference in serum potassium, urinary protein excretion, weekly creatinine clearance and blood pressure for ARBs versus other antihypertensive drugs. Compared with an ACEi, ARBs did not show any difference in residual kidney function.

The following decision support rules contain links to this evidence summary:


1. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 1997 Sep 1;127(5):337-45.  [PMID:9273824]

2. Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000 Apr;35(4):695-707.  [PMID:10739792]

3. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang GB, Liu ZR, Geng RW. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006 Jan 12;354(2):131-40.  [PMID:16407508]

4. Zhang L, Zeng X, Fu P et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for preserving residual kidney function in peritoneal dialysis patients. Cochrane Database Syst Rev 2014;(6):CD009120.  [PMID:24953826]

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