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. 2023 Jul 19;7(7):CD007751.
doi: 10.1002/14651858.CD007751.pub3.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease

Tess E Cooper  1 , Claris Teng  2 , David J Tunnicliffe  1 , Brydee A Cashmore  3 , Giovanni Fm Strippoli  1   4   5
Affiliations

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease

Tess E Cooper et al. Cochrane Database Syst Rev. .

Abstract

Background: Chronic kidney disease (CKD) is a long-term condition that occurs as a result of damage to the kidneys. Early recognition of CKD is becoming increasingly common due to widespread laboratory estimated glomerular filtration rate (eGFR) reporting, raised clinical awareness, and international adoption of the Kidney Disease Improving Global Outcomes (KDIGO) classifications. Early recognition and management of CKD affords the opportunity to prepare for progressive kidney impairment and impending kidney replacement therapy and for intervention to reduce the risk of progression and cardiovascular disease. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are two classes of antihypertensive drugs that act on the renin-angiotensin-aldosterone system. Beneficial effects of ACEi and ARB on kidney outcomes and survival in people with a wide range of severity of kidney impairment have been reported; however, their effectiveness in the subgroup of people with early CKD (stage 1 to 3) is less certain. This is an update of a review that was last published in 2011.

Objectives: To evaluate the benefits and harms of ACEi and ARB or both in the management of people with early (stage 1 to 3) CKD who do not have diabetes mellitus (DM).

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 6 July 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and Embase, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria: Randomised controlled trials (RCTs) reporting the effect of ACEi or ARB in people with early (stage 1 to 3) CKD who did not have DM were selected for inclusion. Only studies of at least four weeks duration were selected. Authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria.

Data collection and analysis: Data extraction was carried out by two authors independently, using a standard data extraction form. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross-checked by another. When more than one study reported similar outcomes, data were pooled using the random-effects model. Heterogeneity was analysed using a Chi² test and the I² test. Results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach MAIN RESULTS: Six studies randomising 9379 participants with CKD stages 1 to 3 (without DM) met our inclusion criteria. Participants were adults with hypertension; 79% were male from China, Europe, Japan, and the USA. Treatment periods ranged from 12 weeks to three years. Overall, studies were judged to be at unclear or high risk of bias across all domains, and the quality of the evidence was poor, with GRADE rated as low or very low certainty. In low certainty evidence, ACEi (benazepril 10 mg or trandolapril 2 mg) compared to placebo may make little or no difference to death (any cause) (2 studies, 8873 participants): RR 2.00, 95% CI 0.26 to 15.37; I² = 76%), total cardiovascular events (2 studies, 8873 participants): RR 0.97, 95% CI 0.90 to 1.05; I² = 0%), cardiovascular-related death (2 studies, 8873 participants): RR 1.73, 95% CI 0.26 to 11.66; I² = 54%), stroke (2 studies, 8873 participants): RR 0.76, 95% CI 0.56 to 1.03; I² = 0%), myocardial infarction (2 studies, 8873 participants): RR 1.00, 95% CI 0.84 to 1.20; I² = 0%), and adverse events (2 studies, 8873 participants): RR 1.33, 95% CI 1.26 to 1.41; I² = 0%). It is uncertain whether ACEi (benazepril 10 mg or trandolapril 2 mg) compared to placebo reduces congestive heart failure (1 study, 8290 participants): RR 0.75, 95% CI 0.59 to 0.95) or transient ischaemic attack (1 study, 583 participants): RR 0.94, 95% CI 0.06 to 15.01; I² = 0%) because the certainty of the evidence is very low. It is uncertain whether ARB (losartan 50 mg) compared to placebo (1 study, 226 participants) reduces: death (any-cause) (no events), adverse events (RR 19.34, 95% CI 1.14 to 328.30), eGFR rate of decline (MD 5.00 mL/min/1.73 m2, 95% CI 3.03 to 6.97), presence of proteinuria (MD -0.65 g/24 hours, 95% CI -0.78 to -0.52), systolic blood pressure (MD -0.80 mm Hg, 95% CI -3.89 to 2.29), or diastolic blood pressure (MD -1.10 mm Hg, 95% CI -3.29 to 1.09) because the certainty of the evidence is very low. It is uncertain whether ACEi (enalapril 20 mg, perindopril 2 mg or trandolapril 1 mg) compared to ARB (olmesartan 20 mg, losartan 25 mg or candesartan 4 mg) (1 study, 26 participants) reduces: proteinuria (MD -0.40, 95% CI -0.60 to -0.20), systolic blood pressure (MD -3.00 mm Hg, 95% CI -6.08 to 0.08) or diastolic blood pressure (MD -1.00 mm Hg, 95% CI -3.31 to 1.31) because the certainty of the evidence is very low.

Authors' conclusions: There is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 CKD who do not have DM. The available evidence is overall of very low certainty and high risk of bias. We have identified an area of large uncertainty for a group of patients who account for most of those diagnosed as having CKD.

Trial registration: ClinicalTrials.gov NCT00235287 NCT00153101 NCT00242346 NCT00528385 NCT00171067.

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Conflict of interest statement

  1. TC: no relevant interests were disclosed

  2. CT: no relevant interests were disclosed

  3. DT: no relevant interests were disclosed

  4. BC: no relevant interests were disclosed

  5. GS: no relevant interests were disclosed

Figures

1
1
Flow diagram
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1: ACEi versus placebo, Outcome 1: Death (any cause)
1.2
1.2. Analysis
Comparison 1: ACEi versus placebo, Outcome 2: Cardiovascualar disease events: total (fatal and non‐fatal)
1.3
1.3. Analysis
Comparison 1: ACEi versus placebo, Outcome 3: Cardiovascular disease events: death
1.4
1.4. Analysis
Comparison 1: ACEi versus placebo, Outcome 4: Cardiovascular disease events: stroke
1.5
1.5. Analysis
Comparison 1: ACEi versus placebo, Outcome 5: Cardiovascular disease events: myocardial infarction
1.6
1.6. Analysis
Comparison 1: ACEi versus placebo, Outcome 6: Cardiovascular disease events: congestive heart failure
1.7
1.7. Analysis
Comparison 1: ACEi versus placebo, Outcome 7: Cardiovascular disease events: transient ischaemic attack
1.8
1.8. Analysis
Comparison 1: ACEi versus placebo, Outcome 8: Adverse events (number reporting an adverse event)
2.1
2.1. Analysis
Comparison 2: ARB versus placebo, Outcome 1: Death (any cause) at 12 months
2.2
2.2. Analysis
Comparison 2: ARB versus placebo, Outcome 2: Adverse events (number reporting an adverse event)
2.3
2.3. Analysis
Comparison 2: ARB versus placebo, Outcome 3: Kidney failure progression at 12 months: eGFR
2.4
2.4. Analysis
Comparison 2: ARB versus placebo, Outcome 4: Proteinuria at 12 months
2.5
2.5. Analysis
Comparison 2: ARB versus placebo, Outcome 5: Systolic blood pressure at 12 months
2.6
2.6. Analysis
Comparison 2: ARB versus placebo, Outcome 6: Diastolic blood pressure at 12 months
3.1
3.1. Analysis
Comparison 3: ACEi versus ARB, Outcome 1: Proteinuria at 12 weeks
3.2
3.2. Analysis
Comparison 3: ACEi versus ARB, Outcome 2: Proteinuria at 48 weeks
3.3
3.3. Analysis
Comparison 3: ACEi versus ARB, Outcome 3: Systolic blood pressure at 12 weeks
3.4
3.4. Analysis
Comparison 3: ACEi versus ARB, Outcome 4: Diastolic blood pressure at 12 weeks
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Garg 2005 {published data only}
    1. Garg JP, Ellis R, Elliott WJ, Hasabou N, Chua D, Chertow GM, et al. Angiotensin receptor blockade and arterial compliance in chronic kidney disease: a pilot study. American Journal of Nephrology 2005;25(4):393-9. [MEDLINE: ] - PubMed
Greenbaum 2000 {published data only}
    1. Greenbaum R, Zucchelli P, Caspi A, Nouriel H, Paz R, Sclarovsky S, et al. Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency. British Journal of Clinical Pharmacology 2000;49(1):23-31. [MEDLINE: ] - PMC - PubMed
Hannedouche 2001 {published data only}
    1. Hannedouche T, Chanard J, Baumelou B, French Collaborative Telmisartan Study Group. Evaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension. Journal of the Renin-Angiotensin-Aldosterone System 2001;2(4):246-54. [MEDLINE: ] - PubMed
Hemmelder 1996 {published data only}
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Homma 2004 {published data only}
    1. Homma K, Hayashi K, Kanda T, Yoshioka K, Takamatsu I, Tatematsu S, et al. Beneficial action of candesartan cilexetil plus amlodipine or ACE inhibitors in chronic nondiabetic renal disease. Journal of Human Hypertension 2004;18(12):879-84. [MEDLINE: ] - PubMed
HOPE 1996 {published data only}
    1. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators [Erratum in: Lancet 2000 Sep 2;356(9232):860]. Lancet 2000;355(9200):253-9. [MEDLINE: ] - PubMed
    1. Gerstein HC, Bosch J, Pogue J, Taylor DW, Zinman B, Yusuf S. Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE Study. Microalbuminuria, cardiovascular, and renal outcomes. Heart Outcomes Prevention Evaluation. Diabetes Care 1996;19(11):1225-8. [MEDLINE: ] - PubMed
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Hou 2006 {published data only}
    1. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. New England Journal of Medicine 2006;354(2):131-40. [MEDLINE: ] - PubMed
Ihle 1996 {published data only}
    1. Ihle B, Becker G, Whitworth J, Shahinfar S, Cnaan A, Kincaid-Smith P. The effect of angiotensin converting enzyme inhibition (ACEi) on progression of chronic renal insufficiency (CRI) [abstract]. Journal of the American Society of Nephrology 1992;3(3):284. [CENTRAL: CN-00460980]
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Kamper 1990 {published data only}
    1. Kamper A, Strandgaard S, Leyssac PP. Late outcome of a controlled trial of enalapril treatment in progressive chronic renal failure [abstract]. Journal of the American Society of Nephrology 1993;4(Program & Abstracts):251. [CENTRAL: CN-00484580]
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Kanno 2006 {published data only}
    1. Kanno Y, Takenaka T, Nakamura T, Suzuki H. Add-on angiotensin receptor blocker in patients who have proteinuric chronic kidney diseases and are treated with angiotensin-converting enzyme inhibitors. Clinical Journal of the American Society of Nephrology: CJASN 2006;1(4):730-7. [MEDLINE: ] - PubMed
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Keilani 1993 {published data only}
    1. Keilani T, Schlueter WA, Levin ML, Batlle DC. Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin-converting enzyme inhibitor. Annals of Internal Medicine 1993;118(4):246-54. [MEDLINE: ] - PubMed
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Kim 2000 {published data only}
    1. Kim HJ, Han SW. No more aggravation of hyperkalemia by the combined therapy of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor in renal diseases than either therapy alone [abstract no: FP.8.4]. In: 13th Asian Colloquium in Nephrology; 2000 Nov 23-25; Bali, Indonesia. 2000. [CENTRAL: CN-00615853]
Kincaid‐Smith 2002 {published data only}
    1. Kincaid-Smith P, Fairley K, Packham D. Comparison of the effect of 50% increase in angiotensin converting enzyme inhibitor (ACEI) with a combination of candesartan and ACEI on proteinuria and blood pressure in chronic renal disease [abstract no: A0392]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):75A. [CENTRAL: CN-00446096]
    1. Kincaid-Smith P, Fairley K, Packham D. Comparison of the effect of 50% increase in angiotensin converting enzyme inhibitor (ACEI) with a combination of candesartan and ACEI on proteinuria and blood pressure in chronic renal disease [abstract no: P99]. Nephrology 2002;7(Suppl 3):A25. [CENTRAL: CN-00792336]
    1. Kincaid-Smith P, Fairley K, Packham D. Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria. Nephrology Dialysis Transplantation 2002;17(4):597-601. [MEDLINE: ] - PubMed
    1. Kincaid-Smith P, Fairley K. A fall in urine protein with combined angiotensin converting enzyme inhibitor (ACEI) and aII receptor antagonist (AIIRA) treatment predicts a good outcome at three years in patients with chronic renal disease with continuing reduction in urine protein levels. Diabetic and obese patients with a poor response to combined ACEI and AIIRA treatment have a poor outcome [abstract no: M419]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):131. [CENTRAL: CN-00446094]
    1. Kincaid-Smith PS, Fairley KF, Packham D. Randomised controlled crossover study of the effect on proteinuria of adding an angiotensin 11-receptor antagonist (ARA) to an angiotensin converting enzyme inhibitor (ACEi) [abstract no: A1825]. Journal of the American Society of Nephrology 2000;11(Sept):349A. [CENTRAL: CN-00626048]
Klein 2003 {published data only}
    1. Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. Journal of the American Society of Nephrology 2003;14(2):425-30. [MEDLINE: ] - PubMed
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Lee 2011a {published data only}
    1. Lee YJ, Cho S, Kim SR, Jang HR, Lee JE, Huh W, et al. Effect of losartan on proteinuria and urinary angiotensinogen excretion in non-diabetic patients with chronic kidney disease. Postgraduate Medical Journal 2011;87(1032):664-9. [MEDLINE: ] - PubMed
LIRICO 2007 {published data only}
    1. Maione A, Nicolucci A, Craig JC, Tognoni G, Moschetta A, Palasciano G, et al. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in microalbuminuric patients with one or more cardiovascular risk factors. Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes randomized trial (LIRICO) [ACE-inibizione, antagonismo recettoriale e terapia combinata in soggetti microalbuminurici con fattori di rischio cardiovascolare. Protocollo dello studio randomizzato multicentrico ''Long-term impact of RAS inhibition on cardiorenal outcomes-LIRICO"]. Giornale Italiano di Nefrologia 2007;24(5):446-56. [MEDLINE: ] - PubMed
    1. Maione A, Nicolucci A, Craig JC, Tognoni G, Moschetta A, Palasciano G, et al. Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) randomized trial. Journal of Nephrology 2007;20(6):646-55. [MEDLINE: ] - PubMed
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    1. Strippoli GF, Palmer S, Saglimbene VM, Ruospo M, Hegbrant JB, Craig JC. ACE inhibitor, ARB, or combined therapy in patients with diabetes and microalbuminuria: the long-term impact of RAS inhibition on cardiorenal outcomes (LIRICO) randomized clinical trial [abstract no: SA-OR115]. Journal of the American Society of Nephrology 2017;28(Abstract Suppl):103. [EMBASE: 633700766]
MacGregor 2003 {published data only}
    1. MacGregor MS, Deighan CJ, Rodger RS, Boulton-Jones JM. A prospective open-label randomised trial of quinapril and/or amlodipine in progressive non-diabetic renal failure. Nephron 2005;101(3):c139-49. [MEDLINE: ] - PubMed
    1. MacGregor MS, Deighan CJ, Rodger RS, Boulton-Jones JM. A prospective open-label randomized trial of quinapril and/or amlodipine in progressive non-diabetic renal failure [abstract no: SA-PO667]. Journal of the American Society of Nephrology 2003;14(Nov):443A. [CENTRAL: CN-00583942]
    1. MacGregor MS, Deighan CJ, Rodger RS, Boulton-Jones JM. Effect of ACE inhibition on hemoglobin in chronic renal failure: a randomized controlled trial [abstract no: SA-PO666]. Journal of the American Society of Nephrology 2003;14:443A. [CENTRAL: CN-00583943]
Marcantoni 1998 {published data only}
    1. Marcantoni C, Oldrizzi L, Rugiu C, Maschio G, AIPRI Study Group. Antihypertensive therapy and progression of renal failure in hypertensive nephropathy (HN) [abstract]. Nephrology Dialysis Transplantation 1999;14(9):A150.
    1. Marcantoni C, Oldrizzi L, Rugiu C, Maschio G, AIPRI Study Group. Antihypertensive therapy and progression of renal failure in hypertensive nephropathy (HN) [abstract no: S124]. Journal of the American Society of Nephrology 1998;9(Program & Abstracts):75A. [CENTRAL: CN-00446593]
Meier 2011 {published data only}
    1. Meier P, Maillard M, Meier R, Burnier M. Antiproteinuric effect of losartan: is a higher dose as effective as an association with an ACE inhibitor? Results of a randomised triple-crossover study in proteinuric patients [abstract no: F-PO1920]. Journal of the American Society of Nephrology 2008;19:543A.
    1. Meier P, Maillard M, Tremblay S, Meier R, Burnier M. Comparative 24h blood pressure effects of increasing doses of losartan and the association of losartan and an ACE inhibitor in proteinuric patients [abstract no: SA-PO2249]. Journal of the American Society of Nephrology 2008;19:617A.
    1. Meier P, Maillard MP, Meier JR, Tremblay S, Gauthier T, Burnier M. Combining blockers of the renin-angiotensin system or increasing the dose of an angiotensin II receptor antagonist in proteinuric patients: a randomized triple-crossover study. Journal of Hypertension 2011;29(6):1228-35. [MEDLINE: ] - PubMed
Minetti 1995 {published data only}
    1. Guidi EP, Minetti EE, Cozzi MG. Acute and long-term effects of 2 different ACE inhibitors on renal hemodynamics [abstract]. Journal of the American Society of Nephrology 2000;11(Sept):619A. [CENTRAL: CN-00626080]
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Mitchell 1997 {published data only}
    1. Mitchell HC, Smith RD, Cutler RE, Sica D, Videen J, Thompsen-Bell S, et al. Racial differences in the renal response to blood pressure lowering during chronic angiotensin-converting enzyme inhibition: a prospective double-blind randomized comparison of fosinopril and lisinopril in older hypertensive patients with chronic renal insufficiency. American Journal of Kidney Diseases 1997;29(6):897-906. [MEDLINE: ] - PubMed
NEPHROS 2001 {published data only}
    1. Bader BD, Risler T. The NEPHROS study - effects of an ACE inhibitor, a calcium channel blocker, or their combination on progression of renal impairment [abstract]. Deutsche Medizinische Wochenschrift 1999;124(Suppl 3):S112. [CENTRAL: CN-00382241]
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ONTARGET 2008 {published data only}
    1. Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T, et al. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurology 2011;10(1):43-53. [MEDLINE: ] - PubMed
    1. Barzilay JI, Gao P, Clase CM, Mente A, Mann JF, Sleight P, et al. Albuminuria and rapid loss of GFR and risk of new hip and pelvic fractures. Clinical Journal of the American Society of Nephrology: CJASN 2013;8(2):233-40. [MEDLINE: ] - PMC - PubMed
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    1. Bohm M, Baumhakel M, Teo K, Sleight P, Probstfield J, Gao P, et al. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation 2010;121(12):1439-46. [MEDLINE: ] - PubMed
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Papadogiannakis 2006 {published data only}
    1. Papadogiannakis A, Xydakis D, Sfakianaki M, Zouridakis A, Kostakis K, Korsavas K, et al. Effect of angiotensin converting enzyme inhibitors and angiotensin Type I receptor antagonists on plasminogen activator inhibitor - 1 levels in patients with hypertensive nephrosclerosis [abstract no: MP127]. Nephrology Dialysis Transplantation 2006;21(Suppl 4):iv341.
Perico 1997 {published data only}
    1. Perico N, Spormann D, Peruzzi E, Bodin F, Sioufi A, Bertocchi F. Efficacy and tolerability of valsartan compared with lisinopril in patients with hypertension and renal insufficiency. Clinical Drug Investigation 1997;14(4):252-9. [EMBASE: 27477552]
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Plum 1998 {published data only}
    1. Plum J, Bunten B, Nemeth R, Grabensee B. Effects of the angiotensin II antagonist valsartan on blood pressure, proteinuria, and renal hemodynamics in patients with chronic renal failure and hypertension. Journal of the American Society of Nephrology 1998;9(12):2223-34. [MEDLINE: ] - PubMed
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Plum 2000 {published data only}
    1. Plum J, Bockenhoff U, Bockenhoff A, Grabensee B. Combined treatment with an angiotensin II receptor antagonist and an ACE inhibitor in patients with proteinuria hypertension [abstract no: P3-8]. Deutsche Medizinische Wochenschrift 2000;125(Suppl 3):S49. [CENTRAL: CN-00383974]
Praga 2003a {published data only}
    1. Ghosh AK, Ghosh K, Praga M. Anti-proteinuric effect of losartan: statistical vs clinical significance (multiple letters). Nephrology Dialysis Transplantation 2004;19(3):747-8. [EMBASE: 38263144] - PubMed
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PROGRESS 1995 {published data only}
    1. Arima H, Chalmers J, Woodward M, Anderson C, Rodgers A, Davis S, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. Journal of Hypertension 2006;24(6):1201-8. [MEDLINE: ] - PubMed
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PUTS 1992 {published data only}
    1. Bonner G, Lederle RM, Scholze J, Stumpe KO. Therapeutic safety of perindopril in the treatment of mild hypertension with concomitant nephropathy. Arzneimittel-Forschung 1993;43(8):852-5. [MEDLINE: ] - PubMed
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ROAD 2007 {published data only}
    1. Hou F, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, et al. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. Journal of the American Society of Nephrology 2007;18(6):1889-98. [MEDLINE: ] - PubMed
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    1. Xie D, Hou FF, Fu BL, Zhang X, Liang M. High level of proteinuria during treatment with renin-angiotensin inhibitors is a strong predictor of renal outcome in nondiabetic kidney disease. Journal of Clinical Pharmacology 2011;51(7):1025-34. [MEDLINE: ] - PubMed
Ruilope 2000 {published data only}
    1. Ruilope LM, Aldigier JC, Ponticelli C, Oddou-Stock P, Botteri F, Mann JF. Safety of the combination of valsartan (V) and benazepril (BZ) in patients with chronic renal disease (CRD) [abstract no: A0361]. Journal of the American Society of Nephrology 1997;8(Program & Abstracts):75A. [CENTRAL: CN-00447507]
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Rump 1999 {published data only}
    1. Rump LC, Baron A, Dendorfer A, Oberhauser V, Andre M. Angiotensin II receptor blockade in comparison to ACE inhibition in patients with chronic kidney failure [Angiotensin II-rezeptorblockade im vergleich zu ACE-hemmung bei patienten mit chronischem nierenversagen]. Journal fur Hypertonie 1999;3(4):25-33. [EMBASE: 30014539]
Rutkowski 2004 {published data only}
    1. Renke M, Tylicki L, Ruthkowski P, Wonjnarowski K, Lysiak-Szydlowska W, Rutkowski B. Low-dose dual blockade of the renin-angiotensin system improves tubular status in nondiabetic proteinuric patients [abstract no: MP093]. In: 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15-18; Lisbon, Portugal. 2004:260. [CENTRAL: CN-00509434]
    1. Renke M, Tylicki L, Rutkowski P, Wojnarowski K, Lysiak-Szydlowska W, Rutkowski B. Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients. Scandinavian Journal of Urology & Nephrology 2005;39(6):511-7. [MEDLINE: ] - PubMed
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SAVE 1991 {published data only}
    1. Hager WD, Davis BR, Riba A, Moye LA, Wun CC, Rouleau JL, et al. Absence of a deleterious effect of calcium channel blockers in patients with left ventricular dysfunction after myocardial infarction: The SAVE Study Experience. SAVE Investigators. Survival and Ventricular Enlargement. American Heart Journal 1998;135(3):406-13. [MEDLINE: ] - PubMed
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    1. Lamas GA, Pfeffer MA, Hamm P, Wertheimer J, Rouleau JL, Braunwald E. Do the results of randomized clinical trials of cardiovascular drugs influence medical practice? The SAVE Investigators. New England Journal of Medicine 1992;327(4):241-7. [MEDLINE: ] - PubMed
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Scaglione 2005 {published data only}
    1. Scaglione R, Argano C, Corrao S, Di Chiara T, Licata A, Licata G. Transforming growth factor beta1 and additional renoprotective effect of combination ACE inhibitor and angiotensin II receptor blocker in hypertensive subjects with minor renal abnormalities: a 24-week randomized controlled trial. Journal of Hypertension 2005;23(3):657-64. [MEDLINE: ] - PubMed
Schmieder 2005 {published data only}
    1. Fleischmann EH, Klingbeil AU, Schneider MP, Delles C, Schmieder RE. The effect of treatment with ultra high dose candesartan (64 mg) on proteinuria: interim results of a double-blind, randomized, multi-center study [abstract no: P1782]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):133-4. [CENTRAL: CN-00445352]
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    1. Schmieder RE, Klingbeil AU, Fleischmann EH, Veelken R, Delles C. Additional antiproteinuric effect of ultra high dose (64mg) candesartan: a double blind, randomized study. [abstract no: F-P0243]. Journal of the American Society of Nephrology 2004;15(Oct):119A. [CENTRAL: CN-00602112] - PubMed
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Schulz 1999 {published data only}
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Takagi 1990 {published data only}
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Toto 1996 {published data only}
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Vogt 2008 {published data only}
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Yilmaz 2007a {published data only}
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References to studies awaiting assessment

NCT04736329 {published data only}
    1. Telmisartan versus enalapril in heart failure with reduced ejection fraction patients with moderately impaired kidney functions. www.clinicaltrials.gov/show/NCT04736329 2021. - PMC - PubMed
NCT05402397 {published data only}
    1. Losartan and uric acid metabolism in children with proteinuric nephropathies. www.clinicaltrials.gov/show/NCT05402397 2022.
Osipova 2021 {published data only}
    1. Osipova OA, Gosteva EV, Belousova ON, Golivets TP, Chefranova J, Lykov Y et al. Effect of angiotensin II receptor blocker therapy on markers of fibrosis and immune inflammation in hypertensive patients with chronic kidney disease after ischemic stroke. Cardiovascular Therapy & Prevention (Russian Federation) 2021;20(7):121‐8. [DOI: 10.15829/1728-8800-2021-3078] - DOI
Segura 2003 {published data only}
    1. Segna J, Camp C, Praga M, Oddou P, Mann J, Ruilope LM. Relevance of BP control and angiotensin II blockade in controlling proteinuria [abstract no: A0417]. Journal of the American Society of Nephrology 2000;11(Sept):77a.
    1. Segura J, Praga M, Campo C, Rodicio JL, Ruilope LM. Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses. Journal of the Renin-Angiotensin-Aldosterone System 2003;4(1):43-7. [PMID: ] - PubMed
Shoji 2001 {published data only}
    1. Shoji T, Suzuki A, Takabatake Y, Oka K, Togawa M, Okada N, Imai E, Tsubakishara Y. The impact of the combination of losartan and enalapril on erythropoiesis in Japanese patients with chronic glomerulonephritis (cgn) [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):411a.
    1. Shoji T, Tomida K, Furumatsu Y, Kaneko T, Togawa M, Okada N, Imai E, Tsubakihar Y. The long term influence of the combination of losartan and enalapril on erythropoiesis in Japanese patients with chronic glomerulonephritis. [abstract no: SU-PO1080]. Journal of the American Society of Nephrology 2003;14(Nov):773a.
Suzuki 2003 {published data only}
    1. Suzuki H, Saitama Candesartan Study Group. Effects of candesartan on renal and cardiovascular outcomes in hypertensive patients with renal impairment [abstract no: SU-PO633]. Journal of the American Society of Nephrology 2003;14(Nov):672-3a.
TCTR20220426002 {published data only}
    1. Comparison of efficacy in renoprotection between azilsartan medoxomil and enalapril: a randomized, open-labeled controlled trial. www.trialsearch.who.int/Trial2.aspx?TrialID=TCTR20220426002 2022.

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References to other published versions of this review

Blackburn 2009
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Sharma 2011
    1. Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C. Angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No: CD007751. [DOI: 10.1002/14651858.CD007751.pub2] - DOI - PubMed

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