Chronic kidney disease (CKD) is a worldwide public health problem associated with a high prevalence of cardiovascular disease (CVD) and impaired quality of life. Previous research for preventing loss of glomerular filtration rate (GFR) has focused on reducing blood pressure (BP) and proteinuria. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor antagonists (ARB) are commonly used in patients with early CKD, but their value in advanced CKD (estimated GFR (eGFR) ≤30 ml/min/1.73 m2) is unknown. There remains a debate about the omission of ACEi/ARB in patients with advanced CKD and their use in association with CVD or heart failure. Does the potential gain in eGFR with ACEi/ARB cessation outweigh the potential adverse cardiovascular outcomes? This paper reviews the current literature that addresses this issue. Several controversies are discussed. Although lowering BP reduces cardiovascular events, evidence suggests that ACEi/ARBs are not superior to other antihypertensive agents. There are no studies assessing the benefits of ACEi/ARB therapy in cardiovascular risk reduction in advanced non-dialysis CKD. The STOP ACEi trial will strengthen the evidence base and shed light on the potential merits and dangers of ACEi/ARB use in advanced CKD on renal function and cardiovascular outcomes.

Keywords:
Chronic kidney disease, Angiotensin-converting enzyme inhibitor, Angiotensin receptor blocker
1.
Levey AS, Andreoli SP, Dubose T, et al: Chronic kidney disease: common, harmful and treatable - world kidney day. Am J Nephrol 2007;27:108-112.
2.
De Lusignan S, Chan T, Stevens P, et al: Identifying patients with chronic kidney disease from general practice computer records. Fram Pract 2005;22:234-241.
3.
Strippoli GF, Craig JC Schena FP: The number, quality, and coverage of randomized controlled trials in nephrology. J Am Soc Nephrol 2004;15:411-419.
4.
De Zeeuw D, Akizawa T, Audhya P, et al; BEACON Trial Investigators: Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369:2492-2503.
5.
The EVOLVE Trial Investigators, Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS: Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012;367:2482-2494.
6.
Baigent C, Landray MJ, Reith C, et al: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-2192.
7.
Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.
8.
Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN): A long term, randomized clinical trial to evaluate the effects of ramipril on the evolution of renal function in chronic nephropathies. J Nephrol 1991;3:193-202.
9.
Ruggenenti P, Fassi A, Ilieva AP, et al; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators: Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-1951.
10.
Lewis EJ, Hunsicker LG, Bain RP, et al: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med 1993;329:1456-1462.
11.
Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
12.
De Zeeuw D, Remuzzi G, Parving HH, et al: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-2320.
13.
Maschio G, Alberti D, Janin G, et al: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The angiotensin-converting-enzyme inhibition in progressive renal insufficiency study group. N Engl J Med 1996;334:939-945.
14.
Hou FF, Zhang X, Zhang GH, et al: Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-140.
15.
Wu HY, Huang JW, Lin HJ, et al: Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and Bayesian network meta-analysis. BMJ 2013;347:f6008.
16.
Blood Pressure Lowering Treatment Trialists' Collaboration, Ninomiya T, Perkovic V, Turnbull F, Neal B, Barzi F, Cass A, Baigent C, Chalmers J, Li N, Woodward M, MacMahon S: Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 2013;347:f5680.
17.
Zannad F, Kessler M, Lehert P, et al: Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int 2006;70:1318-1324.
18.
Chan KE, Ikizler TA, Gamboa JL, Yu C, Hakim RM, Brown NJ: Combined angiotensin-converting enzyme inhibition and receptor blockade associate with increased risk of cardiovascular death in hemodialysis patients. Kidney Int 2011;80:978-985.
19.
Jain P, Cockwell P, Little J, et al: Survival and transplantation in end-stage renal disease: a prospective study of a multiethnic population. Nephrol Dial Transplant 2009;24:3840-3846.
20.
Matsushita K, Selvin E, Bash LD, Franceschini N, Astor BC, Coresh J: Change in estimated GFR associates with coronary heart disease and mortality. J AM Soc Nephrol 2009;20:2617-2624.
21.
Rifkin DE, Shlipak MG, Katz R, et al: Rapid kidney function decline and mortality risk in older adults. Arch Intern Med 2008;168:2212-2218.
22.
Shlipak MG, Katz R, Kestenbaum B, et al: Rapid decline of kidney function increases cardiovascular risk in the elderly. J Am Soc Nephrol 2009;20:2625-2630.
23.
McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines: ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur Heart J 2012;14:1787-1847.
24.
Bhandari S, Ives N, Brettell EA, et al: Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease; the STOP-ACEi trial. Nephrol Dial Transplant 2016;31:255-261.
25.
Black C, Sharma P, Scotland G, et al: Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis. Health Technol Assess 2010;14:1-184.
26.
Steenkamp R, Rao A, Roderick P: UK renal registry 17th annual report: chapter 5 survival and cause of death in UK adult patients on renal replacement therapy in 2013: national and centre-specific analyses. Nephron 2015;129(suppl 1):99-129.
27.
The 2015 Annual Data Report: Volume 2 - End-Stage Renal Disease in the United States. http://www.usrds.org/adr.aspx (accessed March 2, 2016).
28.
Gansevoort RT, Matsushita K, van der Velde M, et al; Chronic Kidney Disease Prognosis Consortium: Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011;80:93-104.
29.
Landray MJ, Emberson JR, Blackwell L, et al: Prediction of ESRD and death among people with CKD: the chronic renal impairment in Birmingham (CRIB) prospective cohort study. Am J Kidney Dis 2010;56:1082-1094.
30.
Quinn MP, Cardwell CR, Kee F, et al: The finding of reduced estimated glomerular filtration rate is associated with increased mortality in a large UK population. Nephrol Dial Transplant 2011;26:875-880.
31.
Neovius M, Jacobson SH, Eriksson JK, Elinder CG, Hylander B: Mortality in chronic kidney disease and renal replacement therapy: a population-based cohort study. BMJ Open 2014;4:e004251.
32.
O'Hare AM, Bertenthal D, Covinsky KE, et al: Mortality risk stratification in chronic kidney disease: one size for all ages? J Am Soc Nephrol 2006;17:846-853.
33.
Chronic Kidney Disease Prognosis Consortium; Matsushita K, van der Velde M, Astor BC, et al: Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375:2073-2081.
34.
Weiner DE, Tighiouart H, Amin MG, et al: Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol 2004;15:1307-1315.
35.
Wen CP, Cheng TY, Tsai MK, et al: All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan. Lancet 2008;371:2173-2182.
36.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular eventsin high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med 2000;342:145-153.
37.
Granger CB, McMurray JJ, Yusuf S, et al: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772-776.
38.
McMurray JJ, Ostergren J, Swedberg K, et al: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-771.
39.
Pitt B, Segal R, Martinez FA, et al: Randomised trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study, ELITE). Lancet 1997;349:747-752.
40.
Pitt B, Poole-Wilson PA, Segal R, et al: Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial - the losartan heart failure survival study ELITE II. Lancet 2000;355:1582-1587.
41.
Massie BM, Armstrong PW, Cleland JG, et al: Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The assessment of treatment with lisinopril and survival. Arch Intern Med 2001;161:165-171.
42.
Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med 1992;327:685-691.
43.
Cohn JN, Tognoni G, et al: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.
44.
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293-302.
45.
Cohn JN, Johnson G, Ziesche S, et al: A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.
46.
Effects of enalapril on mortality in severe congestive heart failure. Results of the cooperative north scandinavian enalapril survival study (CONSENSUS). The CONSENSUS trial study group. N Engl J Med 1987;316:1429-1435.
47.
Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J: Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE substudy. Hypertension 2001;38:E28-E32.
48.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288:2981-2997.
49.
Haller H, Ito S, Izzo JL Jr, et al; ROADMAP Trial Investigators: Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907-917.
50.
Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators: benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-2428.
51.
Hou FF, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, Guo ZJ, Jiang JP: Renoprotection of optimal antiproteinuric doses (ROAD) study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol 2007;18:1889-1898.
52.
Appel LJ, Wright JT Jr, Greene T, et al: Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010;363:918-929.
53.
Yusuf S, Pfeffer MA, Swedberg K, et al: Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet 2003;362:777-781.
54.
Faul C, Amaral AP, Oskouei B, et al: FGF23 induces left ventricular hypertrophy. J Clin Invest 2011;121:4393-4408.
55.
Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American heart association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Circulation 2003;108:2154-2169.
56.
Coca SG: Acute kidney injury in elderly persons. Am J Kidney Dis 2010;56:122-131.
57.
Molnar MZ, Kalantar-Zadeh K, Lott EH, et al: Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker use, and mortality in patients with chronic kidney disease. J Am Coll Cardiol 2014;63:650-658.
58.
Price DA, Porter LE, Gordon M, et al: The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol 1999;10:2382-2391.
59.
Remuzzi G, Ruggenenti P, Perna A, et al: Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results. J Am Soc Nephrol 2004;15:3117-3125.
60.
Strippoli GF, Bonifati C, Craig M, et al: Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev 2006;4:CD006257.
61.
Bangalore S, Fakheri R, Toklu B, Messerli FH: Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ 2016;352:i438.
62.
Parving HH, Brenner BM, McMurray JJ, et al: Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-2213.
63.
Muskiet MH, Tonneijck L, Smits MM, Kramer MH, et al: Pleiotropic effects of type 2 diabetes management strategies on renal risk factors. Lancet Diabetes Endocrinol 2015;3:367-381.
64.
Heerspink HJ, Kröpelin TF, Hoekman J, de Zeeuw D; Reducing Albuminuria as Surrogate Endpoint (REASSURE) Consortium: Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J Am Soc Nephrol 2015;26:2055-2064.
65.
Cheng J, Zhang W, Zhang X, et al: Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med 2014;174:773-785.
66.
Mann JF, Schmieder RE, Dyal L, et al: Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med 2009;151:1-10, w1-w2.
67.
Zhang GH, Hou FF, Zhang X, et al: [Can angiotensin-converting enzyme inhibitor be used in chronic kidney disease patients with serum creatinine level greater than 266 micromol/L?]. Zhonghua Nei Ke Za Zhi 2005;44:592-596.
68.
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. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997;349:1857-1863.
69.
Ruggenenti P, Perna A, Remuzzi G; Gruppo Italiano di Studi Epidemiologici in Nefrologia: ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril efficacy in nephropathy. J Am Soc Nephrol 2001;12:2832-2837.
70.
Ruggenenti P, Perna A, Loriga G, et al: Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005;365:939-946.
71.
Kunz R, Friedrich C, Wolbers M, Mann JF: Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148:30-48.
72.
Mann JF, Schmieder RE, McQueen M, et al; ONTARGET Investigators: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-553.
73.
Fried LF, Emanuele N, Zhang JH, et al: Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892-1903.
74.
Hsu TW, Liu JS, Hung SC, Kuo KL, Chang YK, Chen YC, Hsu CC, Tarng DC: Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med 2014;174:347-354.
75.
Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32(5 suppl 3):S112-S119.
76.
Hillege HL, Nitsch D, Pfeffer MA, et al: Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006;113:671-678.
77.
Bhandari S: Risk factors and metabolic mechanisms in the pathogenesis of uraemic cardiac disease. Front Biosci (Landmark Ed) 2011;16:1364-1387.
78.
Knight EL, Glynn RJ, McIntyre KM, et al: Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction (SOLVD). Am Heart J 1999;138(5 pt 1):849-855.
79.
Shih CJ, Chu H, Ou SM, Chen YT: Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on major adverse cardiac events in patients with newly diagnosed type 2 diabetes: a nationwide study. Int J Cardiol 2015;199:283-289.
80.
Sutton MG, Sharpe N: Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981-2988.
81.
Manabe S, Okura T, Watanabe S, Fukuoka T, Higaki J: Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension. J Cardiovasc Pharmacol 2005;46:735-739.
82.
Luo J, Brunelli SM, Jensen DE, Yang A: Association between serum potassium and outcomes in patients with reduced kidney function. Clin J Am Soc Nephrol 2016;11:90-100.
83.
National Institute for Health and Clinical Excellence: Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. https://www.nice.org.uk/guidance/cg73 (accessed September 10, 2015).
84.
Morimoto T, Gandhi TK, Fiskio JM, et al: An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. J Eval Clin Pract 2004;10:499-509.
85.
Ahmed AK, Kamath NS, El Kossi M, El Nahas AM: The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010;25:3977-3982.
86.
Kovesdy CP, Anderson JE: Reverse epidemiology in patients with chronic kidney disease who are not yet on dialysis. Semin Dial 2007;20:566-569.
87.
Perkins RM, Bucaloiu ID, Kirchner HL, Ashouian N, Hartle JE, Yahya T: GFR decline and mortality risk among patients with chronic kidney disease. Clin J Am Soc Nephrol 2011;6:1879-1886.
88.
Bhatia RT, Browne OT, Naudeer S, Allgar V, Bhandari S: Examining determinants of patient outcome in a low clearance clinic. Nephron 2015;129:263-268.
89.
KDIGO: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, vol 3, issue 1, 2013. http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf.
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