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Current Heart Failure Reports

, Volume 16, Issue 2, pp 57–66 | Cite as

Diuretic Resistance in Heart Failure

  • Richa Gupta
  • Jeffrey Testani
  • Sean CollinsEmail author
Emergency Medicine (F Peacock, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Emergency Medicine

Abstract

Purpose of Review

Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF.

Recent Findings

The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose.

Summary

Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.

Keywords

Acute heart failure Loop diuretics Diuretic resistance Spot urine sodium Biomarkers 

Notes

Compliance with Ethical Standards

Conflict of Interest

Richa Gupta declares no conflicts of interest.

Jeffrey Testani received consultancy fees and/or research grants from AstraZeneca, Boehringer Ingelheim, Sanofi, Abbott, FIRE1, Sequana Medical, Otsuka, Bristol Myers Squibb, Reprieve Medical, Cardionomic, and 3ive labs.

Sean Collins received consultancy fees and/or research grants from Novartis, Vixiar, Ortho Clinical, NIH, AHRQ, PCORI, DOD, AHA, and CREAVO.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    Wang H, Dwyer-Lindgren L, Lofgren KT, Rajaratnam JK, Marcus JR, Levin-Rector A, et al. Age-specific and sex-specific mortality in 187 countries, 1970–2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2013;380:2071–94.CrossRefGoogle Scholar
  2. 2.
    Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18–e209.CrossRefGoogle Scholar
  3. 3.
    Ambrosy AP, Pang PS, Khan S, Konstam MA, Fonarow GC, Traver B, et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial. Eur Heart J. 2013;34:835–43.CrossRefGoogle Scholar
  4. 4.
    Gheorghiade M, Follath F, Ponikowski P, Barsuk JH, Blair JE, Cleland JG, et al. Assessing and grading congestion in acute heart failure: a scientific statement from the acute heart failure committee of the heart failure Association of the European Society of cardiology and endorsed by the European Society of Intensive Care Medicine. Eur J Heart Fail. 2010;12:423–33.CrossRefGoogle Scholar
  5. 5.
    Ambrosy AP, Cerbin LP, Armstrong PW, Butler J, Coles A, DeVore AD, et al. Body weight change during and after hospitalization for acute heart failure: patient characteristics, markers of congestion, and outcomes: findings from the ASCEND-HF trial. JACC Heart Fail. 2017;5:1–13.CrossRefGoogle Scholar
  6. 6.
    Lala A, McNulty SE, Mentz RJ, Dunlay SM, Vader JM, AbouEzzeddine OF, et al. Relief and recurrence of congestion during and after hospitalization for acute heart failure: insights from diuretic optimization strategy evaluation in acute decompensated heart failure (DOSE-AHF) and cardiorenal rescue study in acute decompensated heart failure (CARESS-HF). Circ Heart Fail. 2015;8:741–8.CrossRefGoogle Scholar
  7. 7.
    Yancy CW, Fonarow GC, ADHERE Scientific Advisory Committee. Quality of care and outcomes in acute decompensated heart failure: the ADHERE registry. Curr Heart Fail Rep. 2004;1:121–8.CrossRefGoogle Scholar
  8. 8.
    Kociol RD, McNulty SE, Hernandez AF, Lee KL, Redfield MM, Braunwald E, et al. Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure. Circ Heart Fail. 2013;6:240–5.CrossRefGoogle Scholar
  9. 9.
    Mentz RJ, Kjeldsen K, Rossi GP, Voors AA, Cleland JG, Anker SD, et al. Decongestion in acute heart failure. Eur J Heart Fail. 2014;16:471–82.CrossRefGoogle Scholar
  10. 10.
    Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology. 2001;96:132–43.CrossRefGoogle Scholar
  11. 11.
    Ter Maaten JM, Valente MA, Damman K, Hillege HL, Navis G, Voors AA. Diuretic response in acute heart failure-pathophysiology, evaluation, and therapy. Nat Rev Card. 2015;12:184–92.CrossRefGoogle Scholar
  12. 12.
    •• Testani JM, Brisco MA, Turner JM, Spatz ES, Bellumkonda L, Parikh CR, et al. Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail. 2014;7:261–70. This was the first study to define the concept of diuretic efficiency (DE) or the efficiency with which diuretic can facilitate diuresis and natriuresis. This study also showed that DE can capture prognostic information beyond raw fluid output or diuretic dose and is independently associated with survival. The authors also found no association between glomerular filtration rate and DE, suggesting that renal function and drug delivery or pharmacokinetics may be less important drivers of DE. CrossRefGoogle Scholar
  13. 13.
    • Valente MA, Voors AA, Damman K, Van Veldhuisen DJ, Massie BM, O’Connor CM, et al. Diuretic response in acute heart failure: clinical characteristics and prognostic significance. Eur Heart J. 2014;35:1284–93. This was one of the first studies to show that worse diuretic response was associated with more advanced heart failure among other adverse clinical conditions and predicts mortality and heart failure rehospitalizations. CrossRefGoogle Scholar
  14. 14.
    O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32–43.CrossRefGoogle Scholar
  15. 15.
    Teerlink JR, Cotter G, Davison BA, Felker BA, FIlippatos G, Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381:29–39.CrossRefGoogle Scholar
  16. 16.
    Packer M, O'Connor C, McMurray JJ, Wittes J, Abraham WT, Anker SD, et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017;376:1956–64.CrossRefGoogle Scholar
  17. 17.
    Vasavada N, Agarwal R. Role of excess volume in the pathophysiology of hypertension in chronic kidney disease. Kidney Int. 2003;64:1772–9.CrossRefGoogle Scholar
  18. 18.
    Hoorn EJ, Wilcox CS, Ellison DH. Diuretics. In: Skorecki K, Chertow GM, Marsden PA, Taal MW, Yu ASL, editors. Brenner and Rector’s the kidney. 10th ed. Philadelphia: Elsevier; 2016. p. 1702–33.Google Scholar
  19. 19.
    Murray MD, Haag KM, Black PK, Hall SD, Brater DC, et al. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacotherapy. 1997;17:98–106.Google Scholar
  20. 20.
    Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC, et al. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther. 1995;57:601–9.CrossRefGoogle Scholar
  21. 21.
    Sweet DH, Bush KT, Nigam SK. The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol. 2001;281:F197–205.CrossRefGoogle Scholar
  22. 22.
    Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther. 2000;295:261–5.Google Scholar
  23. 23.
    Chennavasin P, Seiwell R, Brater DC. Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man. J Pharmacol Exp Ther. 1980;215:77–81.Google Scholar
  24. 24.
    Krick W, Wolff NA, Burckhardt G. Voltage-driven p-aminohippurate, chloride, and urate transport in porcine renal brush- border membrane vesicles. Pflügers Arch. 2000;441:125–32.CrossRefGoogle Scholar
  25. 25.
    Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B, Michelson EL, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet. 2009;374:543–50.CrossRefGoogle Scholar
  26. 26.
    Besseghir K, Mosig D, Roch-Ramel F. Facilitation by serum albumin of renal tubular secretion of organic ions. Am J Phys. 1989;256:F475–84.Google Scholar
  27. 27.
    Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. 1989;36:682–9.CrossRefGoogle Scholar
  28. 28.
    Rao VS, Planavasky N, Hanberg JS, Ahmad T, Brisco-Bacik MA, Wilson FP, et al. Compensatory distal reabsorption drives diuretic resistance in human heart failure. J Am Soc Nephrol. 2017;28:3414–24.CrossRefGoogle Scholar
  29. 29.
    Wilcox CS. New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol. 2002;13:798–805.Google Scholar
  30. 30.
    Rose HJ, O’Malley K, Pruitt AW. Depression of renal clearance of furosemide in man by azotemia. Clin Pharmacol Ther. 1997;21:141–6.CrossRefGoogle Scholar
  31. 31.
    Brater DC, Anderson SA, Brown-Cartwright D. Response to furosemide in chronic renal insufficiency: rationale for limited doses. Clin Pharmacol Ther. 1986;40:134–9.CrossRefGoogle Scholar
  32. 32.
    Sica DA. Pharmacotherapy in congestive heart failure: drug absorption in the management of congestive heart failure: loop diuretics. Congest Heart Fail. 2003;9:287–92.CrossRefGoogle Scholar
  33. 33.
    • Shah S, Pitt B, Brater DC, Feig PU, Shen W, Khwaja FS, et al. Sodium and fluid excretion with torsemide in healthy subjects is limited by the short duration of diuretic action. J Am Heart Assoc. 2017;6:e006135. This study demonstrated the development of severe within-dose development of diuretic resistance (DR), providing some of the first evidence to suggest that DR at the level of the nephron, rather than pharmacokinetics, is important in dictating diuretic duration of action. Google Scholar
  34. 34.
    • Ter Maaten JM, Rao VS, Hanberg JS, Wilson FP, Bellumkonda L, Assefa M, et al. Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. Eur J Heart Fail. 2017;19:1014–22. This study highlights the importance of renal tubular defects in driving DR in acute heart failure. CrossRefGoogle Scholar
  35. 35.
    Kazory A. Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure. Am J Cardiol. 2010;106:694–700.CrossRefGoogle Scholar
  36. 36.
    Verbrugge FH, Nijst P, Dupont M, Penders J, Tang WH, Mullens W. Urinary composition during decongestive treatment in heart failure with reduced ejection fraction. Circ Heart Fail. 2014;7:766–72.CrossRefGoogle Scholar
  37. 37.
    Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122:265–72.CrossRefGoogle Scholar
  38. 38.
    Metra M, Cotter G, Senger S, Edwards C, Cleland JG, Ponikowski P, et al. Prognostic significance of creatinine increases during an acute heart failure admission in patients with and without residual congestion: a post hoc analysis of the PROTECT data. Circ Heart Fail. 2018;11:e004644.CrossRefGoogle Scholar
  39. 39.
    Vormfelde SV, Sehrt D, Toliat MR, Schirmer M, Meineke I, Tzvetkov M, et al. Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs. Clin Pharmacol Ther. 2007;82:300–9.CrossRefGoogle Scholar
  40. 40.
    Werner U, Werner D, Heinbuchner S, Graf B, Ince H, Kische S, et al. Gender is an important determinant of the disposition of the loop diuretic torasemide. J Clin Pharmacol. 2010;50:160–8.CrossRefGoogle Scholar
  41. 41.
    de Denus S, Rouleau JL, Mann DL, Huggins GS, Cappola TP, Shah SH, et al. A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of 3 clinical trials. Pharmacogenomics J. 2017;17:192–200.CrossRefGoogle Scholar
  42. 42.
    Murray MD, Deer MM, Ferguson JA, Dexter PR, Bennett SJ, Perkins SM, et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513–20.CrossRefGoogle Scholar
  43. 43.
    Stroupe KT, Forthofer MM, Brater DC, Murray MD. Healthcare costs of patients with heart failure treated with torsemide or furosemide. PharmacoEconomics. 2000;17:429–40.CrossRefGoogle Scholar
  44. 44.
    Ferguson JA, Sundblad KJ, Becker PK, Gorski JC, Rudy DW, Brater DC. Role of duration of diuretic effect in preventing sodium retention. Clin Pharmacol Ther. 1997;62:203–8.CrossRefGoogle Scholar
  45. 45.
    Wu MY, Chang NC, Su CL, Hsu YH, Chen TW, Lin YF, et al. Loop diuretic strategies in patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials. J Crit Care. 2014;29:2–9.CrossRefGoogle Scholar
  46. 46.
    Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797–805.CrossRefGoogle Scholar
  47. 47.
    • Kiernan MS, Stevens SR, WHW T, Butler J, Anstrom K, Birati EY, et al. Determinants of diuretic responsiveness and associated outcomes during acute heart failure hospitalization: an analysis from the NHLBI Heart Failure Network clinical trials. J Card Fail. 2018;24:428–38. This study defined DE as total 72-hour fluid output per total loop diuretic dose; lower DE was a marker of heart failure disease severity and associated with reduced survival. Poor diuretic response was associated with poor clinical markers. CrossRefGoogle Scholar
  48. 48.
    Garg LC, Kapturczak M. Renal compensatory response to hydrochlorothiazide changes Na-K-ATPase in distal nephron. In: Puschett JB, Greenberg A, editors. Diuretics II: chemistry, pharmacology, and clinical applications: proceedings of the Second International Conference on Diuretics, held June 22–27, 1986. Cascais: Elsevier Science Ltd.; 1987. p. 188–94.Google Scholar
  49. 49.
    Kaissling B, Bachmann S, Kriz W. Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment. Am J Phys. 1985;248:F374–81.Google Scholar
  50. 50.
    Doukky R, Avery E, Mangla A, Collado FM, Ibrahim Z, Poulin MF, et al. Impact of dietary sodium restriction on heart failure outcomes. JACC Heart Fail. 2016;4:24–35.CrossRefGoogle Scholar
  51. 51.
    Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, et al. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J Lab Clin Med. 1983;102:450–8.Google Scholar
  52. 52.
    Brisco-Bacik MA, Ter Maaten JM, Houser SR, Verdage NA, Rao V, Ahmad T, et al. Outcomes associated with a strategy of adjuvant metolazone or high-dose loop diuretics in acute decompensated heart failure: a propensity analysis. J Am Heart Assoc. 2018;7:e009149.CrossRefGoogle Scholar
  53. 53.
    Mullens W, Verbrugge FH, Nijst P, Martens P, Tartaglia K, Theunissen E, et al. Rationale and design of the ADVOR (acetazolamide in decompensated heart failure with volume overload) trial. Eur J Heart Fail. 2018;20:1591–600.CrossRefGoogle Scholar
  54. 54.
    Wilcox CS, Loon NR, Kanthawatana S, Pham MA, Cannizzaro R. Generation of alkalosis with loop diuretics: roles of contraction and acid excretion. J Nephrol. 1991;2:81–7.Google Scholar
  55. 55.
    Loon NR, Wilcox CS. Mild metabolic alkalosis impairs the natriuretic response to bumetanide in normal human subjects. Clin Sci. 1998;94:287–92.CrossRefGoogle Scholar
  56. 56.
    • Singh D, Shrestha K, Testani JM, Verbrugge FH, Dupont M, Mullens W, et al. Insufficient natriuretic response to continuous intravenous furosemide is associated with poor long-term outcomes in acute decompensated heart failure. J Card Fail. 2014;20:392–9. Describes urinary sodium (UNa) as a predictor of clinical outcomes or natriuretic response. Described in text and Table 2. CrossRefGoogle Scholar
  57. 57.
    • Ferreira JP, Girerd N, Medeiros PB, Santos M, Carvalho HC, Bettencourt P, et al. Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect. Clin Res Cardiol. 2016;105:489–507. Describes UNa as a predictor of clinical outcomes or natriuretic response. Described in text and Table 2. CrossRefGoogle Scholar
  58. 58.
    • Luk A, Groarke JD, Desai AS, Mahmood SS, Gopal DM, Joyce E, et al. First spot urine sodium after initial diuretic identifies patients at high risk for adverse outcome after heart failure hospitalization. Am Heart J. 2018;203:95–100. Describes UNa as a predictor of clinical outcomes or natriuretic response. Described in text and Table 2. CrossRefGoogle Scholar
  59. 59.
    • Testani JM, Hanberg JS, Cheng S, Rao V, Onyebeke C, Laur O, et al. Rapid and highly accurate prediction of poor loop diuretic natriuretic response in patients with heart failure. Circ Heart Fail. 2016;9:e002370. Describes UNa as a predictor of clinical outcomes or natriuretic response. Described in text and Table 2. CrossRefGoogle Scholar
  60. 60.
    • Brinkley DM, Burpee LJ, Chaudhry S, Smallwood JA, Lindenfeld J, Lakdawala NK, et al. Spot urine sodium as triage for effective diuretic infusion in an ambulatory heart failure unit. J Card Fail. 2018;24:349–54. Describes UNa as a predictor of clinical outcomes or natriuretic response. Described in text and Table 2. CrossRefGoogle Scholar
  61. 61.
    • Collins SC, Jenkins CA, Baughman A, Miller KF, Storrow A, Han JH, et al. Early urine electrolyte patterns are associated with in-hospital worsening heart failure in emergency department patients with acute heart failure. ESC Heart Fail. 2018. Describes UNa as a predictor of clinical outcomes or natriuretic response Described in text and Table 2. Google Scholar
  62. 62.
    • Mullens W, Damman K, Harjola V, Mebazaa A, Brunner-La Rocca H, Martens P, et al. The use of diuretics in heart failure with congestion—a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019.  https://doi.org/10.1002/ejhf.1369. This is a recent, important expert opinion/position paper focusing on the practical use of diuretics in AHF with congestion.
  63. 63.
    Strobeck JE, Feldschuh J, Miller WL. Heart failure outcomes with volume-guided management. JACC Heart Fail. 2018;6:940–8.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleUSA
  2. 2.Department of Cardiovascular MedicineYale Medical CenterNew HavenUSA
  3. 3.Department of Emergency MedicineVanderbilt University Medical CenterNashvilleUSA

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