Effect of spironolactone on vascular stiffness in hemodialysis patients: a randomized crossover trial

  • Michael Eklund Department of Internal Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden https://orcid.org/0000-0001-7706-1758
  • Olof Hellberg Department of Internal Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
  • Hans Furuland Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden https://orcid.org/0000-0002-9001-614X
  • Yang Cao Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden https://orcid.org/0000-0002-3552-9153
  • Kent Wall Department of Clinical Physiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
  • Erik Nilsson Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; and Faculty of Medicine and Health, Örebro University, Örebro, Sweden https://orcid.org/0000-0001-6968-6934
Keywords: Mineralocorticoid receptor antagonists, pulse wave velocity, systolic function, diastolic function


Background: The role of spironolactone treatment in hemodialysis patients is debated, but a survival benefit is suggested. Mineralocorticoids and chronic kidney disease have been linked to cardiovascular fibrosis. Therefore, we hypothesized that spironolactone would affect vascular stiffness, cardiac systolic, and diastolic function in hemodialysis patients.

Methods: This was a randomized crossover study in hemodialysis patients supplemented with an echocardiographic case series. All outcomes reported here were secondary in the trial and were assessed without blinding. Block randomization and allocation determined treatment order. Participants received 50 mg spironolactone daily for 12 weeks and untreated observation for another 12 weeks. Pulse wave velocity (PWV) was measured before and after treatment and observation. Doppler-echocardiography was conducted before and after treatment. Systemic arterial compliance indexed to body surface area (SACi), left ventricular ejection fraction (LVEF), the peak early diastolic mitral inflow velocity (E), the peak late diastolic mitral inflow velocity (A), and the peak early diastolic myocardial lengthening velocity (E’) were measured. E/A and E/E’ were then calculated. Statistical analyses were conducted per protocol. A generalized linear mixed model with random participant effects was used for PWV. The Wilcoxon signed-rank test was used for echocardiographic variables.

Results: Thirty participants were recruited, 18 completed follow-up, and 17 were included in PWV-analyses. Spironolactone treatment showed a tendency toward an increase in PWV of 1.34 (95% confidence interval: −0.11 to 2.78) m/s, which was not statistically significant (P = 0.07). There were no significant changes in any of the other variables (LVEF, E/A, E/Eʹ, or SACi).

Conclusions: We found no evidence supporting an effect of 12-week administration of spironolactone 50 mg daily on vascular stiffness, cardiac systolic, or diastolic function in hemodialysis patients.


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  1. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014;63:528–36. doi: 10.1016/j.jacc.2013.09.056

  2. Lin C, Zhang Q, Zhang H, Lin A. Long-term effects of low-dose spironolactone on chronic dialysis patients: a randomized placebo-controlled study. J Clin Hypertens (Greenwich). 2016;18:121–8. doi: 10.1111/jch.12628

  3. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219–29. doi: 10.1056/NEJMoa2025845

  4. Quach K, Lvtvyn L, Baigent C, Bueti J, Garg AX, Hawley C, et al. The safety and efficacy of mineralocorticoid receptor antagonists in patients who require dialysis: a systematic review and meta-analysis. Am J Kidney Dis. 2016;68:591–8. doi: 10.1053/j.ajkd.2016.04.011

  5. Carrero JJ, de Jager DJ, Verduijn M, Ravani P, De Meester J, Heaf JG, et al. Cardiovascular and noncardiovascular mortality among men and women starting dialysis. Clin J Am Soc Nephrol. 2011;6:1722–30. doi: 10.2215/cjn.11331210

  6. Calvier L, Miana M, Reboul P, Cachofeiro V, Martinez-Martinez E, de Boer RA, et al. Galectin-3 mediates aldosterone-induced vascular fibrosis. Arterioscler Thromb Vasc Biol. 2013;33:67–75. doi: 10.1161/atvbaha.112.300569

  7. Liu S, Kompa AR, Kumfu S, Nishijima F, Kelly DJ, Krum H, et al. Subtotal nephrectomy accelerates pathological cardiac remodeling post-myocardial infarction: implications for cardiorenal syndrome. Int J Cardiol. 2013;168:1866–80. doi: 10.1016/j.ijcard.2012.12.065

  8. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–27. doi: 10.1016/j.jacc.2009.10.061

  9. Edwards NC, Steeds RP, Stewart PM, Ferro CJ, Townend JN. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol. 2009;54:505–12. doi: 10.1016/j.jacc.2009.03.066

  10. McQuarrie EP, Freel EM, Mark PB, Fraser R, Patel RK, Dargie HG, et al. Urinary corticosteroid excretion predicts left ventricular mass and proteinuria in chronic kidney disease. Clin Sci (Lond). 2012;123:285–94. doi: 10.1042/cs20120015

  11. Deo R, Yang W, Khan AM, Bansal N, Zhang X, Leonard MB, et al. Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. Hypertension. 2014;64:103–10. doi: 10.1161/hypertensionaha.114.03311

  12. Boesby L, Elung-Jensen T, Strandgaard S, Kamper AL. Eplerenone attenuates pulse wave reflection in chronic kidney disease stage 3–4 – a randomized controlled study. PLoS One. 2013;8:e64549. doi: 10.1371/journal.pone.0064549

  13. Davies J, Gavin A, Band M, Morris A, Struthers A. Spironolactone reduces brachial pulse wave velocity and PIIINP levels in hypertensive diabetic patients. Br J Clin Pharmacol. 2005;59:520–3. doi: 10.1111/j.1365-2125.2005.02363.x

  14. Vukusich A, Kunstmann S, Varela C, Gainza D, Bravo S, Sepulveda D, et al. A randomized, double-blind, placebo-controlled trial of spironolactone on carotid intima-media thickness in nondiabetic hemodialysis patients. Clin J Am Soc Nephrol. 2010;5:1380–7. doi: 10.2215/cjn.09421209

  15. Hammer F, Buehling SS, Masyout J, Malzahn U, Hauser T, Auer T, et al. Protective effects of spironolactone on vascular calcification in chronic kidney disease. Biochem Biophys Res Commun. 2021;582:28–34. doi: 10.1016/j.bbrc.2021.10.023

  16. Ito Y, Mizuno M, Suzuki Y, Tamai H, Hiramatsu T, Ohashi H, et al. Long-term effects of spironolactone in peritoneal dialysis patients. J Am Soc Nephrol. 2014;25:1094–102. doi: 10.1681/asn.2013030273

  17. Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian S, Alipour Z, Karimi S. A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis. Saudi J Kidney Dis Transpl. 2012;23:507–12.

  18. Hauser T, Dornberger V, Malzahn U, Grebe SJ, Liu D, Stork S, et al. The effect of spironolactone on diastolic function in haemodialysis patients. Int J Cardiovasc Imaging. 2021;37:1927–36. doi: 10.1007/s10554-021-02176-5

  19. Hammer F, Malzahn U, Donhauser J, Betz C, Schneider MP, Grupp C, et al. A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients. Kidney Int. 2019;95:983–91. doi: 10.1016/j.kint.2018.11.025

  20. 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.

  21. Eklund M, Hellberg O, Furuland H, Cao Y, Nilsson E. Effects of spironolactone on extrasystoles and heart rate variability in haemodialysis patients: a randomised crossover trial. Ups J Med Sci. 2021;126:e5660. doi: 10.48101/ujms.v126.5660

  22. Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30:445–8. doi: 10.1097/HJH.0b013e32834fa8b0

  23. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1–39. doi: 10.1016/j.echo.2014.10.003

  24. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539–50. doi: 10.1093/eurheartj/ehm037

  25. Mohty D, Pibarot P, Echahidi N, Poirier P, Dagenais GR, Dumesnil JG. Reduced systemic arterial compliance measured by routine Doppler echocardiography: a new and independent predictor of mortality in patients with type 2 diabetes mellitus. Atherosclerosis. 2012;225:353–8. doi: 10.1016/j.atherosclerosis.2012.09.025

  26. Senn S. Cross-over trials in clinical research. Chichester, United Kingdom: John Wiley & Sons; 2002.

  27. Sims TJ, Rasmussen LM, Oxlund H, Bailey AJ. The role of glycation cross-links in diabetic vascular stiffening. Diabetologia. 1996;39:946–51. doi: 10.1007/bf00403914

  28. Charytan DM, Himmelfarb J, Ikizler TA, Raj DS, Hsu JY, Landis JR, et al. Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. Kidney Int. 2019;95:973–82. doi: 10.1016/j.kint.2018.08.034

  29. Edwards NC, Ferro CJ, Kirkwood H, Chue CD, Young AA, Stewart PM, et al. Effect of spironolactone on left ventricular systolic and diastolic function in patients with early stage chronic kidney disease. Am J Cardiol. 2010;106:1505–11. doi: 10.1016/j.amjcard.2010.07.018

  30. Matsumoto R, Yoshiyama M, Omura T, Kim S, Nakamura Y, Izumi Y, et al. Effects of aldosterone receptor antagonist and angiotensin II type I receptor blocker on cardiac transcriptional factors and mRNA expression in rats with myocardial infarction. Circ J. 2004;68:376–82. doi: 10.1253/circj.68.376

  31. Maisel A, Xue Y, van Veldhuisen DJ, Voors AA, Jaarsma T, Pang PS, et al. Effect of spironolactone on 30-day death and heart failure rehospitalization (from the COACH Study). Am J Cardiol. 2014;114:737–42. doi: 10.1016/j.amjcard.2014.05.062

How to Cite
Eklund M., Hellberg O., Furuland H., Cao Y., Wall K., & Nilsson E. (2022). Effect of spironolactone on vascular stiffness in hemodialysis patients: a randomized crossover trial. Upsala Journal of Medical Sciences, 127(1). https://doi.org/10.48101/ujms.v127.8594