Mineralocorticoid Receptor Antagonists for Nephroprotection: Current Evidence and Future Perspectives

Author(s): Pantelis A. Sarafidis*, Evangelos Memmos, Maria-Eleni Alexandrou, Aikaterini Papagianni.

Journal Name: Current Pharmaceutical Design

Volume 24 , Issue 46 , 2018


Abstract:

Background: The use of single RAS-blockade is currently the recommended first-line treatment for proteinuric diabetic or non-diabetic nephropathy, as these agents were repeatedly shown in studies with hard renal outcomes to retard the progression of renal injury. However, CKD will continue to progress on optimum single RAS-blockade, and other options to ameliorate renal injury were explored. Dual RAS-blockade was associated with an increased risk of adverse-events with no apparent benefits and, therefore, is currently abandoned.

Based on the phenomenon of aldosterone escape and the well-documented harmful effects of aldosterone on renal tissue, several randomized trials have studied the effects of a MRA in diabetic and non-diabetic nephropathy.

Method: This is a review of the literature in relevance to data evaluating the effect of MRA on renal outcomes.

Results: Studies with spironolactone and eplerenone added to single RAS-blockade showed that these agents are associated with greater reductions in urine albumin or protein excretion compared to either placebo or dual RASblockade. However, studies with these agents on hard renal outcomes are currently missing and the reasonable skepticism of physicians on the real-world incidence of hyperkalemia in CKD patients are limiting their use. A non-steroidal MRA, finerenone, has also great potency in decreasing albuminuria in diabetic nephropathy with possibly lower rates of hyperkalemia. Two multi-center clinical trials examining the effect of finerenone on hard cardiovascular and renal outcomes are currently ongoing.

Conclusion: MRAs are able to reduce albuminuria and proteinuria on top of single RAS-blockade in patients with proteinuric CKD. Ongoing clinical trials are expected to clarify whether such an effect is accompanied by delay in CKD progression.

Keywords: Chronic kidney disease, mineralocorticoid receptor antagonist, albuminuria, proteinuria, spironolactone, eplerenone, finerenone.

[1]
Sarafidis PA, Bakris GL. Microalbuminuria and chronic kidney disease as risk factors for cardiovascular disease. Nephrol Dial Transplant 2006; 21(9): 2366-74.
[2]
Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 2012; 380(9844): 807-14.
[3]
Couser WG, Riella MC. World Kidney Day 2011: protect your kidneys, save your heart. Kidney Int 2011; 79(5): 483-5.
[4]
Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis 2007; 49(1): 12-26.
[5]
Sarafidis PA, Sharpe CC, Wood E, et al. Prevalence, patterns of treatment, and control of hypertension in predialysis patients with chronic kidney disease. Nephron Clin Pract 2012; 120(3): c147-55.
[6]
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351(13): 1296-305.
[7]
Khosla N, Sarafidis PA, Bakris GL. Microalbuminuria. Clin Lab Med 2006; 26(3): 635-53. [vi-vii.].
[8]
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 2013; 3: 1-150.
[9]
Sarafidis PA, Whaley-Connell A, Sowers JR, Bakris GL. Cardiometabolic syndrome and chronic kidney disease: what is the link? J Cardiometab Syndr 2006; 1(1): 58-65.
[10]
Sarafidis PA. Proteinuria: natural course, prognostic implications and therapeutic considerations. Minerva Med 2007; 98(6): 693-711.
[11]
Sarafidis PA, Ruilope LM. Aggressive blood pressure reduction and renin-angiotensin system blockade in chronic kidney disease: time for re-evaluation? Kidney Int 2014; 85(3): 536-46.
[12]
Sarafidis PA, Ruilope LM. Cardiorenal disease development under chronic renin-angiotensin-aldosterone system suppression. J Renin Angiotensin Aldosterone Syst 2012; 13(1): 217-9.
[13]
Sarafidis PA, Bakris G. A reappraisal of renin-angiotensin system blockade on microalbuminuria development: do they offer anything unique? J Hypertens 2012; 30(1): 48-50.
[14]
Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007; 3(9): 486-92.
[15]
Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 2004; 66(1): 1-9.
[16]
Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens 2001; 19(3): 353-61.
[17]
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016; 18(8): 891-975.
[18]
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341(10): 709-17.
[19]
Faselis C, Boutari C, Doumas M, Imprialos K, Stavropoulos K, Kokkinos P. Novel drugs for hypertension and heart failure: struggling for a place under the sun. Curr Pharm Des 2017; 23(10): 1540-50.
[20]
Jeunemaitre X, Kreft-Jais C, Chatellier G, et al. Long-term experience of spironolactone in essential hypertension. Kidney Int Suppl 1988; 26: S14-7.
[21]
Weinberger MH. The use of selective aldosterone antagonists. Curr Hypertens Rep 2004; 6(5): 342-5.
[22]
Pericleous M, Sarnowski A, Moore A, Fijten R, Zaman M. The clinical management of abdominal ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: a review of current guidelines and recommendations. Eur J Gastroenterol Hepatol 2016; 28(3): e10-8.
[23]
Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; 386(10008): 2059-68.
[24]
Bakris GL, Agarwal R, Chan JC, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA 2015; 314(9): 884-94.
[25]
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329(20): 1456-62.
[26]
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345(12): 861-9.
[27]
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345(12): 851-60.
[28]
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(9069): 1857-63.
[29]
Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288(19): 2421-31.
[30]
Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358(15): 1547-59.
[31]
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(23): 2204-13.
[32]
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369(20): 1892-903.
[33]
Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71(6): 1269-324.
[34]
9. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018; 41(Suppl. 1): S86-S104.
[35]
Schjoedt KJ, Andersen S, Rossing P, Tarnow L, Parving HH. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004; 47(11): 1936-9.
[36]
Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1(2): 256-62.
[37]
van den Meiracker AH, Baggen RG, Pauli S, et al. Spironolactone in type 2 diabetic nephropathy: Effects on proteinuria, blood pressure and renal function. J Hypertens 2006; 24(11): 2285-92.
[38]
Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005; 28(9): 2106-12.
[39]
Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 2005; 68(6): 2829-36.
[40]
Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006; 70(3): 536-42.
[41]
Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009; 20(12): 2641-50.
[42]
Kato S, Maruyama S, Makino H, et al. Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial. Clin Exp Nephrol 2015; 19(6): 1098-106.
[43]
Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med 2008; 56(4): 714-9.
[44]
Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 2006; 70(12): 2116-23.
[45]
Bianchi S, Bigazzi R, Campese VM. Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases. Am J Kidney Dis 2010; 55(4): 671-81.
[46]
Furumatsu Y, Nagasawa Y, Tomida K, et al. Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens Res 2008; 31(1): 59-67.
[47]
Guney I, Selcuk NY, Altintepe L, Atalay H, Başarali MK, Büyükbaş S. Antifibrotic effects of aldosterone receptor blocker (spironolactone) in patients with chronic kidney disease. Ren Fail 2009; 31(9): 779-84.
[48]
Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006; 1(5): 940-51.
[49]
Boesby L, Elung-Jensen T, Klausen TW, Strandgaard S, Kamper AL. Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study. PLoS One 2011; 6(11): e26904.
[50]
Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa Y, Fujita T. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; 2(12): 944-53.
[51]
Tylicki L, Lizakowski S, Rutkowski P, et al. The enhanced renin-angiotensin-aldosteron system pharmacological blockade--which is the best? Kidney Blood Press Res 2012; 36(1): 335-43.
[52]
Bärfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem 2012; 7(8): 1385-403.
[53]
Sarafidis PA, Alexandrou ME, Ruilope LM. A review of chemical therapies for treating diabetic hypertension. Expert Opin Pharmacother 2017; 18(9): 909-23.
[54]
Katayama S, Yamada D, Nakayama M, et al. A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy. J Diabetes Complications 2017; 31(4): 758-65.
[55]
Sarafidis PA, Blacklock R, Wood E, et al. Prevalence and factors associated with hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc Nephrol 2012; 7(8): 1234-41.
[56]
Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy. Expert Opin Drug Saf 2010; 9(2): 259-73.
[57]
Palmer BF. A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis 2010; 56(2): 387-93.
[58]
Drawz PE, Babineau DC, Rahman M. Metabolic complications in elderly adults with chronic kidney disease. J Am Geriatr Soc 2012; 60(2): 310-5.
[59]
Drion I, Joosten H, Dikkeschei LD, Groenier KH, Bilo HJ. eGFR and creatinine clearance in relation to metabolic changes in an unselected patient population. Eur J Intern Med 2009; 20(7): 722-7.
[60]
Bakris GL, Siomos M, Richardson D, et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. Kidney Int 2000; 58(5): 2084-92.
[61]
Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334(15): 939-45.
[62]
Hannedouche T, Landais P, Goldfarb B, et al. Randomised controlled trial of enalapril and β blockers in non-diabetic chronic renal failure. BMJ 1994; 309(6958): 833-7.
[63]
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351(6): 543-51.
[64]
Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996; 78(8): 902-7.
[65]
Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 2008; 51(2): 199-211.
[66]
Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol 2009; 30(5): 418-24.
[67]
Sarafidis PA, Georgianos PI, Bakris GL. Advances in treatment of hyperkalemia in chronic kidney disease. Expert Opin Pharmacother 2015; 16(14): 2205-15.
[68]
Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011; 32(7): 820-8.
[69]
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015; 372(3): 211-21.
[70]
Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015; 372(3): 222-31.
[71]
Meaney CJ, Beccari MV, Yang Y, Zhao J. Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia. Pharmacotherapy 2017; 37(4): 401-11.


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Article Details

VOLUME: 24
ISSUE: 46
Year: 2018
Page: [5528 - 5536]
Pages: 9
DOI: 10.2174/1381612825666190306162658
Price: $58

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