ACE inhibitors and angiotensin receptor blockers for progression of non-diabetic renal disease

Evidence Summaries

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

A network meta-analysis 1 included 119 RCTS with a total of 64,768 CKD patients. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) reduced the odds of kidney failure by 39% and 30% (ORs of 0.61, 95% credible interval, 0.47 to 0.79 and 0.70, 95% credible interval, 0.52 to 0.89), respectively, compared to placebo, and by 35% and 25% (ORs of 0.65, 95% credible interval, 0.51 to 0.80 and 0.75, 95% credible interval, 0.54 to 0.97), respectively, compared with other active controls, whereas other active controls did not show evidence of a significant effect on kidney failure. Both ACEi and ARB produced odds reductions for major cardiovascular events (ORs of 0.82, 95% credible interval, 0.71 to 0.92 and 0.76, 95% credible interval, 0.62 to 0.89, respectively) versus placebo. Comparisons did not show significant effects on risk for cardiovascular death. ACEi but not ARB significantly reduced the odds of all-cause death versus active controls (OR, 0.72; 95% credible interval, 0.53 to 0.92). Compared with ARB, ACEi were consistently associated with higher probabilities of reducing kidney failure, cardiovascular death, or all-cause death.

A Cochrane review 2 included 6 open-label studies involving a total of 257 peritoneal dialysis (PD) patients. One study compared ACEi with other antihypertensive drugs, 3 compared angiotensin receptor blockers (ARB) 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.

Another meta-analysis 3 included 11 trials with a total of 1856 dialysis patients. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.

Another meta-analysis 5 included 7 RCTs with 628 patients, ACEI/ARB + calcium channel blocker (CCB) did not show additional benefit for the incidence of ESRD (RR 0.84; 95% CI 0.52 to 1.33) and cardiovascular events (RR 0.58; 95% CI 0.21 to 1.63) significantly, compared with ACEI/ARB monotherapy. There were no significant differences in change from baseline to the end points in diastolic BP (weighted mean difference [WMD] = -1.28 mmHg; 95% CI -3.18 to -0.62), proteinuria (standard mean difference = -0.55; 95% CI: -1.41 to -0.30), GFR (WMD = -0.32 ml/min; 95% CI -1.53 to -0.89), and occurrence of adverse events (RR = 1.05; 95% CI: 0.72-1.53). However, ACEI/ARB + CCB showed a greater reduction in systolic BP (WMD = -4.46 mmHg; 95% CI -6.95 to -1.97), compared with ACEI/ARB monotherapy.

Another meta-analysis 4 included 8 RCTs with 25,647 patients, assessing renoprotective effect of ACEi or ARB or dihydropyridine CCB. ESRD showed significantly higher frequency with CCB therapy compared with ACEi or ARB, though blood pressure was decreased similarly in both groups in every trial (OR 1.25; 95% CI, 1.05 to1.48; p = 0.01). In contrast, there was no significant difference in the incidence of all-cause mortality between these two groups, though ACEi or ARB exhibited better renoprotective effect compared to CCB (OR, 0.96; 95% CI 0.89 to 1.03; p = 0.24).

A Cochrane review 6 included 6 trials with a total of 9379 participants with CKD stages 1 to 3, without diabetes. There was insufficient evidence to determine the effectiveness of ACEi or ARB (death, cardiovascular events, or kidney failure progression) compared to placebo. The certainty of the evidence was very low.

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


1. Xie X, Liu Y, Perkovic V et al. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. Am J Kidney Dis 2016;67(5):728-41.  [PMID:26597926]
2. 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]
3. Liu Y, Ma X, Zheng J et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials. BMC Nephrol 2017;18(1):206.  [PMID:28666408]
4. Zhao HJ, Li Y, Liu SM et al. Effect of calcium channels blockers and inhibitors of the renin-angiotensin system on renal outcomes and mortality in patients suffering from chronic kidney disease: systematic review and meta-analysis. Ren Fail 2016;38(6):849-56.  [PMID:27055479]
5. Huang RS, Cheng YM, Zeng XX et al. Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease. Chin Med J (Engl) 2016;129(5):562-9.  [PMID:26904991]
6. Cooper TE, Teng C, Tunnicliffe DJ, ym. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev 2023;7(7):CD007751  [PMID:37466151]

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