Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Does the temporary decrease in the estimated glomerular filtration rate (eGFR) after initiation of mineralocorticoid receptor (MR) antagonist treatment lead to a long-term renal protective effect?

Abstract

Recently, deleterious effects of aldosterone on the kidney via mineralocorticoid receptors (MRs) have been noted. MR antagonists have been reported to show significant antialbuminuric effects when added to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers. However, a decrease in the estimated glomerular filtration rate (eGFR) has been reported during MR antagonist treatment. On the other hand, although the eGFR often decreases, significant reductions in total mortality and cardiovascular events have been observed in large-scale clinical trials in patients with chronic heart failure. What are the implications of the changes in eGFR due to MR antagonist treatment? Glomerular hyperfiltration has been reported to occur with an aldosterone excess, and it can be seen that relative glomerular hyperfiltration is rapidly corrected with MR antagonism, even without aldosterone excess. This is reflected in the initial temporary decrease in the eGFR. After MR antagonist treatment, eGFR decreases temporarily, and it appears that renal function has deteriorated. However, if renal function has actually deteriorated, a reduction in all-cause and cardiovascular death is unlikely to occur in the clinical studies in patients with chronic heart failure. That is, the initial transient decrease in eGFR by the MR antagonist appears to work effectively to provide fine adjustment of glomerular pressure, and this approach works advantageously to suppress long-term cardiovascular events. It is expected that a number of long-term, large-scale clinical research trials targeting renal events and all-cause and cardiovascular death in CKD patients treated with an MR antagonist will be planned.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United State. JAMA. 2007;298:2038–47.

    CAS  PubMed  Google Scholar 

  2. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, 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;15:1307–15.

    PubMed  Google Scholar 

  3. Kottgen A, Russell SD, loehr LR, Crainiceanu CM, Rosamond WD, Chang PP, et al. Reduced kidney function as a risk factor for incident heart failure: the atherosclerosis risk in communities (ARIC) study. J Am Soc Nephrol. 2007;18:1307–15.

    CAS  PubMed  Google Scholar 

  4. Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for atherosclerosis cardiovascular outcomes in the community. J Am Coll Cardiol. 2003;41:47–55.

    PubMed  Google Scholar 

  5. Cheng TY, Wen SF, Astor BC, Tao XG, Samet JM, Wen CP. Mortality risks for all causes and cardiovascular diseases and reduced eGFR in a middle-aged working population in Taiwan. Am J Kidney Dis. 2008;52:1051–60.

    CAS  PubMed  Google Scholar 

  6. Sato A. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy. Hyertens Res. 2015;38:367–74.

    CAS  Google Scholar 

  7. Shibata S, Ishizawa K, Uchida S. Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension. Hypertens Res. 2017;40:221–5.

    CAS  PubMed  Google Scholar 

  8. Nishimoto M, Ohtsu H, Marumo T, Kawarazaki W, Ayuzawa N, Ueda K, et al. Mineralocortiocid receptor blockade suppresses dietary salt-induced ACEI/ARB-resistant albuminuria in non-diabetic hypertension: a sub-analysis of evaluate study. Hypertens Res. 2019;42:514–21.

    CAS  PubMed  Google Scholar 

  9. Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal failure. N Engl J Med. 2001;345:925–6.

    CAS  PubMed  Google Scholar 

  10. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 2005;68:2829–36.

    CAS  PubMed  Google Scholar 

  11. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int. 2006;70:536–42.

    CAS  PubMed  Google Scholar 

  12. Rachmani R, Slavachevsky I, Amit M, Levi Z, Kedar Y, Berla M, et al. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independentof blood pressure reduction: a randomized controlled study. Diabet Med. 2004;21:471–5.

    CAS  PubMed  Google Scholar 

  13. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003;41:64–8.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. for The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

    CAS  PubMed  Google Scholar 

  16. Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. for the EMPHASIS-HF Study Group. Eplrerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

    CAS  PubMed  Google Scholar 

  17. Rifkin DE, Shlipak MG, Katz R, Fried LF, Siscovick D, Chonchol M, et al. Rapid kidney function decline and mortality risk in older adults. Arch Intern Med. 2008;168:2212–8.

    PubMed  PubMed Central  Google Scholar 

  18. Matsushita K, Selvin E, Bash LD, Franceschini N, Astor BC, Coresh J. Change inestimated GFR association with coronary heart disease and mortality. J Am Soc Nephrol. 2009;20:2617–24.

    PubMed  PubMed Central  Google Scholar 

  19. Barzilay JI, Davis B, Pressel SL, Ghosh A, Rahman M, Einhorn PT, et al. The effects of eGFR change on CVD, renal, and mortality outcomes in a hypertensive cohoert treated with 3 different antihypertensive medications. Am J Hypertens. 2018;31:609–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Al-Aly Z, Zeringue A, Fu J, Rauchman MI, McDonald JR, El-Achkar TM, et al. Rate of kidney function decline associates with mortality. J Am Soc Nephrol. 2010;21:1961–9.

    PubMed  PubMed Central  Google Scholar 

  21. Clase CM, Barzillay J, Gao P, Smyth A, Schmieder RE, Tobe S, et al. Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcome. Kidney Int. 2017;91:683–90.

    CAS  PubMed  Google Scholar 

  22. Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJL, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease on long-term renal function. Kidney Int. 2011;80:282–7.

    CAS  PubMed  Google Scholar 

  23. Apperloo AJ, de Zeeuw D, de Jong PE. A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int. 1997;51:793–7.

    CAS  PubMed  Google Scholar 

  24. Hansen HP, Rossing P, Tarnow L, Nielsen FS, Jensen BR, Parving HH. Increased glomerular filtration rate after withdrawal of long-term antihypertensive treatment in diabetic nephropathy. Kidney Int. 1995;47:1726–31.

    CAS  PubMed  Google Scholar 

  25. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-asociated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685–93.

    CAS  PubMed  Google Scholar 

  26. Wright JT Jr., Bakris G, Green T, Agodoa LY, Appel LJ, Charleston J, et al. African American Study of Kidney Disease and Hypertension Study Group: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the ASSK trial. JAMA. 2002;288:2421–31.

    CAS  PubMed  Google Scholar 

  27. Collard D, Brouwer TF, Oeters RJG, Vogt L, van den Born BJH. Creatinine rise during blood pressure therapy and the risk of adverse clinical outcomes in patients with type 2 diabetes mellitus. A post hoc analysis of the ACCORD-BP randomized controlled trial. Hypertension. 2018;72:1337–44.

    CAS  PubMed  Google Scholar 

  28. Ku E, Bakris G, Johansen KL, Lin F, Sarnak MJ, Campese VM, et al. Acute declines in renal function during intensive BP lowering: implications for future ESRD risk. J Am Soc Nephrol. 2017;28:2794–801.

    PubMed  PubMed Central  Google Scholar 

  29. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al. for the SPRINT Research Group. Effects of intensive BP control in CKD. J Am Soc Nephrol. 2017;28:2812–23.

    PubMed  PubMed Central  Google Scholar 

  30. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    CAS  PubMed  Google Scholar 

  31. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    CAS  PubMed  Google Scholar 

  32. Cherney DZI, Zinman B, Inzucchi S, Koitka-Weber A, Mattheus M, von Eynatten M, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from EMPA-REG OUTCOME randomized, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5:610–21.

    CAS  PubMed  Google Scholar 

  33. Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomized clinical trials. Lancet Diabetes Endocrinol. 2018;6:691–704.

    CAS  PubMed  Google Scholar 

  34. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cariovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138:1537–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, et al. on behalf of the EMPA-REG OUTCOME investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137:119–29.

    CAS  PubMed  Google Scholar 

  36. Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, et al. for the GFR Study Investigators. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care. 2012;35:2061–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Anderson S, Brenner BM. Intraglomerular hypertension: implications and drug treatment. Annu Rev Med. 1988;39:243–53.

    CAS  PubMed  Google Scholar 

  38. Strtic M, Yang GK, Perkins BA, Soleymanlou N, Lytvyn Y, von Eynatten M, et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia. 2014;57:2599–602.

    Google Scholar 

  39. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, et al. Renal hemodynamics effect of sodium-glucose cotransporter-2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.

    CAS  PubMed  Google Scholar 

  40. Mima A. Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease. J Diabetes Complicat. 2018;32:720–5.

    PubMed  Google Scholar 

  41. Jerums G, Premaratne E, Panagiotopoulos P, Maclsaac RJ. The clinical significance of hyperfiltration in diabetes. Diabetologia. 2010;53:2093–2014.

    CAS  PubMed  Google Scholar 

  42. Christensen PK, Hansen HP, Parving HH. Impaired autoregulation of GFR in hypertensive non-insulin dependent diabetic patients. Kidney Int. 1997;52:1369–74.

    CAS  PubMed  Google Scholar 

  43. Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism. J Am Soc Nephrol. 2005;16:1320–5.

    PubMed  Google Scholar 

  44. Rossi GP, Bermini G, Desideri G, et al. PAPY Study Participants. Renal damage in primary aldosteronism; results of the PAPY study. Hypertension. 2006;48:232–8.

    CAS  PubMed  Google Scholar 

  45. Reincke M, Rump LC, Quinkler M, Hahner S, Diederich S, Lorenz R, et al. Risk factors associated with a low glomerular filtration rate in primary aldosteronism. J Clin Endocrinol Metab. 2009;94:869–75.

    CAS  PubMed  Google Scholar 

  46. Hannemann A, Rettig R, Dittmann K, Volzke H, Endlich K, Nauck M, et al. Aldosterone and glomerular filtration-observations in the general population. BMC Nephrol. 2014;15:44.

    PubMed  PubMed Central  Google Scholar 

  47. Arima S, Kohaguro K, Xu HL, Sugawara A, Abe T, Satoh F, et al. Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol. 2003;14:2255–63.

    CAS  PubMed  Google Scholar 

  48. Dworkin LD, Hosrerrer TH, Rennke HG, Brenner BM. Hemodynamic basis for glomerular injury in rats with deoxycorticosterone-salt hypertension. J Clin Invest. 1984;73:1448–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Funder JW. Aldosterone and mineralocorticoid receptors: A personal reflection. Mol Cell Endcrinol. 2012;350:146–50.

    CAS  Google Scholar 

  50. 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;70:2116–23.

    CAS  PubMed  Google Scholar 

  51. Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL, et al. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006;295:2635–45.

    Google Scholar 

  52. Sato A, Saruta T. Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens. 2003;16:781–8.

    CAS  PubMed  Google Scholar 

  53. Schjoedk KJ, Andersen S, Rossing P, Tarnow L, Parving HH. Aldosterone escape during blockade of renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia. 2004;47:1936–9.

    Google Scholar 

  54. Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa Y, Fujita T, for the EVALUATE Study Group. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: a double-blind, randomized, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:944–53.

    CAS  PubMed  Google Scholar 

  55. Albert NM, Yancy CW, Liant L, Zhao X, Hernandez AF, Peterson ED, et al. Use of aldosterone antagonists in heart failure. JAMA. 2009;302:1658–65.

    CAS  PubMed  Google Scholar 

  56. Rossignol P, Cleland JG, Bhandari S, Tala S, Gustafsson F, Fay R, et al. Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone post-acute myocardial infarction heart failure effeicacy and survival study. Circulation. 2012;125:271–9.

    CAS  PubMed  Google Scholar 

  57. Rossignol P, Dobre D, McMurray JJV, Swedberg K, Krum H, van Veldhuisen DJ, et al. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy. Results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7:51–8.

    CAS  PubMed  Google Scholar 

  58. Eschalier R, McMurray JJV, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, et al. for the EMPHASIS-HF Investigators. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function. J Am Coll Cardiol. 2013;62:1585–93.

    CAS  PubMed  Google Scholar 

  59. Hill NR, Lasserson D, Thompson B, Perera-Salazar R, Wolstenholme J, Bower P, et al. Benefits of aldosterone receptor antagonism in chronic kidney disease (BARACK D) trial-a multi-centre, prospective, randomized, open, blinded end-point, 36-month study of 2,616 patients with primary care with stage 3b chronic kidney disease to compare the efficacy of spironolactone 25 mg once daily in addition to routine care on mortality and cardiovascular outcomes versus routine care alone: study protocol for a randomized controlled trial. Trials. 2014;15:160.

    PubMed  PubMed Central  Google Scholar 

  60. Birkeland KI, Jørgensen ME, Carstensen B, Persson F, Gulseth HL, Thuresson M, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol 2017;5:709–17.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Atsuhisa Sato.

Ethics declarations

Conflict of interest

The author declare that he has no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sato, A. Does the temporary decrease in the estimated glomerular filtration rate (eGFR) after initiation of mineralocorticoid receptor (MR) antagonist treatment lead to a long-term renal protective effect?. Hypertens Res 42, 1841–1847 (2019). https://doi.org/10.1038/s41440-019-0320-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-019-0320-9

Keywords

  • Aldosterone
  • Mineralocorticoid receptor antagonists
  • Chronic kidney disease
  • Renin-angiotensin system inhibitors
  • Sodium–glucose cotransporter 2 inhibitor

This article is cited by

Search

Quick links