Skip to main content
SpringerLink
Log in

Mineralocorticoid Receptor Blockade in Chronic Kidney Disease

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Aldosterone antagonists have been highly successful in treating congestive heart failure and resistant hypertension. Until recently, therapies targeting the mineralocorticoid receptor in chronic kidney disease (CKD) have received little attention, largely because of the risk of hyperkalemia and the incorrect assumption that traditional therapy with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both consistently reduces activity of the renin-angiotensin system in all patients. Control of extracellular volume and low-dose mineralocorticoid receptor blocker therapy may offer additional antihypertensive and anti-inflammatory benefits in select CKD populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3:486–92.

    Article  PubMed  CAS  Google Scholar 

  2. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.

    Article  PubMed  CAS  Google Scholar 

  3. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

    Article  PubMed  CAS  Google Scholar 

  4. Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt” culture. Circulation. 1975;52:146–51.

    PubMed  CAS  Google Scholar 

  5. Brunner HR, Laragh JH, Baer L, Newton MA, Goodwin FT, Krakoff LR, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972;286:441–9.

    Article  PubMed  CAS  Google Scholar 

  6. • Bomback AS, Kshirsagar AV, Ferris ME, Klemmer PJ: Disordered aldosterone-volume relationship in end-stage kidney disease. J Renin Angiotensin Aldosterone Syst 2009, 10:230–236. The results of this pilot study suggest that hemodialysis patients are unable to suppress their aldosterone appropriately in response to volume expansion (i.e., a state of relative hyperaldosteronism).

    Article  PubMed  CAS  Google Scholar 

  7. Krug AW, Ehrhart-Bornstein M. Aldosterone and metabolic syndrome: is increased aldosterone in metabolic syndrome patients an additional risk factor? Hypertension. 2008;51:1252–8.

    Article  PubMed  CAS  Google Scholar 

  8. Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis. 2010;52:401–9.

    Article  PubMed  CAS  Google Scholar 

  9. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150:776–83.

    PubMed  Google Scholar 

  10. Schrier RW, Masoumi A, Elhassan E. Aldosterone: role in edematous disorders, hypertension, chronic renal failure, and metabolic syndrome. Clin J Am Soc Nephrol. 2010;5:1132–40.

    Article  PubMed  CAS  Google Scholar 

  11. Wehling M, Christ M, Theisen K. Membrane receptors for aldosterone: a novel pathway for mineralocorticoid action. Am J Physiol. 1992;263:E974–9.

    PubMed  CAS  Google Scholar 

  12. Sato A, Saruta T. Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res. 2004;27:303–10.

    Article  PubMed  CAS  Google Scholar 

  13. Selye H, Hall C. Pathologic changes induced in various species by overdosage with desoxycorticosterone. Arch Pathol. 1943;36:19–31.

    CAS  Google Scholar 

  14. Quinkler M, Zehnder D, Eardley KS, Lepenies J, Howie AJ, Hughes SV, et al. Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria. Circulation. 2005;112:1435–43.

    Article  PubMed  CAS  Google Scholar 

  15. Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest. 1996;98:1063–8.

    Article  PubMed  CAS  Google Scholar 

  16. Krikken JA, Laverman GD, Navis G. Benefits of dietary sodium restriction in the management of chronic kidney disease. Curr Opin Nephrol Hypertens. 2009;18:531–8.

    Article  PubMed  CAS  Google Scholar 

  17. • Vogt L, Waanders F, Boomsma F, De ZD, Navis G: Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol 2008, 19:999–1007. In this crossover study, reduction of ECV (via diuretics and/or salt restriction) enhances the antiproteinuric effect of RAAS blockade.

    Article  PubMed  CAS  Google Scholar 

  18. Pimenta E, Gaddam KK, Pratt-Ubunama MN, Nishizaka MK, Aban I, Oparil S, et al. Relation of dietary salt and aldosterone to urinary protein excretion in subjects with resistant hypertension. Hypertension. 2008;51:339–44.

    Article  PubMed  CAS  Google Scholar 

  19. Vasavada N, Agarwal R. Role of excess volume in the pathophysiology of hypertension in chronic kidney disease. Kidney Int. 2003;64:1772–9.

    Article  PubMed  Google Scholar 

  20. Mathie A, Cull-Candy SG, Colquhoun D. Single-channel and whole-cell currents evoked by acetylcholine in dissociated sympathetic neurons of the rat. Proc R Soc Lond B Biol Sci. 1987;232:239–48.

    Article  PubMed  CAS  Google Scholar 

  21. Tattersall J. Bioimpedance analysis in dialysis: state of the art and what we can expect. Blood Purif. 2009;27:70–4.

    Article  PubMed  Google Scholar 

  22. Wabel P, Chamney P, Moissl U, Jirka T. Importance of whole-body bioimpedance spectroscopy for the management of fluid balance. Blood Purif. 2009;27:75–80.

    Article  PubMed  Google Scholar 

  23. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545–56.

    Article  PubMed  CAS  Google Scholar 

  24. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243–8.

    Article  PubMed  CAS  Google Scholar 

  25. • Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, Calhoun DA: Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med 2008, 168:1159–1164. This study documents the importance of a disordered aldosterone-ECV relationship in patients with resistant hypertension.

    Article  PubMed  CAS  Google Scholar 

  26. Pimenta E, Calhoun DA, Oparil S. Sleep apnea, aldosterone, and resistant hypertension. Prog Cardiovasc Dis. 2009;51:371–80.

    Article  PubMed  CAS  Google Scholar 

  27. Visser FW, Krikken JA, Muntinga JH, Dierckx RA, Navis GJ. Rise in extracellular fluid volume during high sodium depends on BMI in healthy men. Obesity (Silver Spring). 2009;17:1684–8.

    Article  CAS  Google Scholar 

  28. Kidambi S, Kotchen JM, Grim CE, Raff H, Mao J, Singh RJ, et al. Association of adrenal steroids with hypertension and the metabolic syndrome in blacks. Hypertension. 2007;49:704–11.

    Article  PubMed  CAS  Google Scholar 

  29. Kidambi S, Kotchen JM, Krishnaswami S, Grim CE, Kotchen TA. Aldosterone contributes to blood pressure variance and to likelihood of hypertension in normal-weight and overweight African Americans. Am J Hypertens. 2009;22:1303–8.

    Article  PubMed  CAS  Google Scholar 

  30. Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, et al. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat Med. 2010;16:67–74.

    Article  PubMed  CAS  Google Scholar 

  31. Hene RJ, Boer P, Koomans HA, Mees EJ. Plasma aldosterone concentrations in chronic renal disease. Kidney Int. 1982;21:98–101.

    Article  PubMed  CAS  Google Scholar 

  32. Gross E, Rothstein M, Dombek S, Juknis HI. Effect of spironolactone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric hemodialysis patients. Am J Kidney Dis. 2005;46:94–101.

    Article  PubMed  CAS  Google Scholar 

  33. Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea, and aldosterone: theory and therapy. Hypertension. 2004;43:518–24.

    Article  PubMed  CAS  Google Scholar 

  34. Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol. 2006;17:3438–46.

    Article  PubMed  CAS  Google Scholar 

  35. Rocha R, Stier Jr CT, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, et al. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology. 2000;141:3871–8.

    Article  PubMed  CAS  Google Scholar 

  36. Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001;358:2113–7.

    Article  PubMed  CAS  Google Scholar 

  37. 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;51:199–211.

    Article  PubMed  Google Scholar 

  38. • Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF: Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009, 4:542–551. This is one of two systematic reviews on the use of aldosterone blockade in CKD. In nearly all studies, spironolactone or eplerenone was added to ACE inhibitor or ARB therapy with relatively low risk of hyperkalemia.

    Article  PubMed  CAS  Google Scholar 

  39. 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;20:2641–50.

    Article  PubMed  CAS  Google Scholar 

  40. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1:940–51.

    Article  PubMed  CAS  Google Scholar 

  41. Bianchi S, Bigazzi R, Campese VM. Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases. Am J Kidney Dis. 2010;55:671–81.

    Article  PubMed  CAS  Google Scholar 

  42. Furumatsu Y, Nagasawa Y, Tomida K, Mikami S, Kaneko T, Okada N, 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;31:59–67.

    Article  PubMed  CAS  Google Scholar 

  43. Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med. 2001;110:438–41.

    Article  PubMed  CAS  Google Scholar 

  44. Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol. 2009;30:418–24.

    Article  PubMed  CAS  Google Scholar 

  45. • Klemmer PJ, Bomback AS: Extracellular volume and aldosterone interaction in chronic kidney disease. Blood Purif. 2009, 27:92–98.

    Article  PubMed  CAS  Google Scholar 

  46. Mitch WE, Wilcox CS. Disorders of body fluids, sodium and potassium in chronic renal failure. Am J Med. 1982;72:536–50.

    Article  PubMed  CAS  Google Scholar 

  47. Raimann JG, Liu L, Zhu F, Thijssen S, Carter M, Bomback AS, Derebail VK, Klemmer PJ, Levin NW, Kotanko P: Changes in serum aldosterone relate to reduction of extracellular volume in hemodialysis patients [abstract]. J Am Soc Nephrol 2010.

  48. Sato A, Funder JW, Saruta T. Involvement of aldosterone in left ventricular hypertrophy of patients with end-stage renal failure treated with hemodialysis. Am J Hypertens. 1999;12:867–73.

    Article  PubMed  CAS  Google Scholar 

  49. Taheri S, Mortazavi M, Shahidi S, Pourmoghadas A, Garakyaraghi M, Seirafian S, et al. Spironolactone in chronic hemodialysis patients improves cardiac function. Saudi J Kidney Dis Transpl. 2009;20:392–7.

    PubMed  Google Scholar 

  50. Park SH, Lee SW, Lee SJ, Shin WY, Jin DK, Gil HW, et al. The association between left ventricular hypertrophy and biomarkers in patients on continuous ambulatory peritoneal dialysis. Korean Circ J. 2009;39:488–93.

    Article  PubMed  CAS  Google Scholar 

  51. Okazaki A, Mori Y, Nakata M, Kimura T, Sonomura K, Sakoda C, et al. Peritoneal mesothelial cells as a target of local aldosterone action: upregulation of connective tissue growth factor expression via serum- and glucocorticoid-inducible protein kinase 1. Kidney Blood Press Res. 2009;32:151–60.

    Article  PubMed  Google Scholar 

  52. Nessim SJ, Perl J, Bargman JM. The renin-angiotensin-aldosterone system in peritoneal dialysis: is what is good for the kidney also good for the peritoneum? Kidney Int. 2010;78:23–8.

    Article  PubMed  CAS  Google Scholar 

  53. Hussain S, Dreyfus DE, Marcus RJ, Biederman RW, McGill RL. Is spironolactone safe for dialysis patients? Nephrol Dial Transplant. 2003;18:2364–8.

    Article  PubMed  CAS  Google Scholar 

  54. Saudan P, Mach F, Perneger T, Schnetzler B, Stoermann C, Fumeaux Z, et al. Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol Dial Transplant. 2003;18:2359–63.

    Article  PubMed  CAS  Google Scholar 

  55. • Matsumoto Y, Kageyama S, Yakushigawa T, Arihara K, Sugiyama T, Mori Y, Sugiyama H, Ohmura H, Shio N: Long-term low-dose spironolactone therapy is safe in oligoanuric hemodialysis patients. Cardiology 2009, 114:32–38. In this study, low-dose spironolactone was administered to 61 hemodialysis patients for 6 months without any episodes of severe hyperkalemia. Half of the patients were receiving concurrent therapy with an ACE inhibitor and/or ARB.

    Article  PubMed  CAS  Google Scholar 

  56. Hatch M, Freel RW, Vaziri ND. Local upregulation of colonic angiotensin II receptors enhances potassium excretion in chronic renal failure. Am J Physiol. 1998;274:F275–82.

    PubMed  CAS  Google Scholar 

  57. Michea L, Vukusich A, Gonzalez M, Zehnder C, Marusic ET. Effect of spironolactone on K(+) homeostasis and ENaC expression in lymphocytes from chronic hemodialysis patients. Kidney Int. 2004;66:1647–53.

    Article  PubMed  CAS  Google Scholar 

  58. Sugarman A, Brown RS. The role of aldosterone in potassium tolerance: studies in anephric humans. Kidney Int. 1988;34:397–403.

    Article  PubMed  CAS  Google Scholar 

  59. Hausmann MJ, Liel-Cohen N. Aldactone therapy in a peritoneal dialysis patient with decreased left ventricular function. Nephrol Dial Transplant. 2002;17:2035–6.

    Article  PubMed  Google Scholar 

  60. Fenwick S, Bell GM. Aldactone therapy in a peritoneal dialysis patient. Nephrol Dial Transplant. 2003;18:1232–3.

    Article  PubMed  Google Scholar 

  61. Raimann J, Liu L, Tyagi S, Levin NW, Kotanko P. A fresh look at dry weight. Hemodial Int. 2008;12:395–405.

    Article  PubMed  Google Scholar 

  62. 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;47:1936–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Jochen Raimann, MD; Peter Kotanko, MD; and Nathan Levin, MD, for sharing preliminary data [47] merged with our data [6•] in Fig. 1. We acknowledge funding from the Renal Research Institute for our pilot study.

Disclosure

Conflicts of Interest: M. Volk: none; A. Bomback: none; P. Klemmer: member of Speakers Bureau for Genzyme Corp.

Author information

Authors and Affiliations

  1. UNC Kidney Center, University of North Carolina-Chapel Hill, CB# 7155, Chapel Hill, NC, 27514, USA

    Philip J. Klemmer

  2. Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Matthew J. Volk

  3. Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Andrew S. Bomback

Authors
  1. Matthew J. Volk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew S. Bomback
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip J. Klemmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip J. Klemmer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Volk, M.J., Bomback, A.S. & Klemmer, P.J. Mineralocorticoid Receptor Blockade in Chronic Kidney Disease. Curr Hypertens Rep 13, 282–288 (2011). https://doi.org/10.1007/s11906-011-0202-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-011-0202-2

Keywords

Search

Navigation