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.

  • Review Article
  • Published:

Diuretic use in renal disease

Nature Reviews Nephrology volume 8, pages 100–109 (2012)Cite this article

Subjects

Abstract

Diuretics are agents commonly used in diseases characterized by excess extracellular fluid, including chronic kidney disease, the nephrotic syndrome, cirrhosis and heart failure. Multiple diuretic classes, including thiazide-type diuretics, loop diuretics and K+-sparing diuretics, are used to treat patients with these diseases, either individually or as combination therapies. An understanding of what determines a patient's response to a diuretic is a prerequisite to the correct use of these drugs. The response of patients with these diseases to diuretics, which is related to the dose, is best described by a sigmoid curve whose contour can become distorted by any of the several sodium-retaining states that are directly or indirectly associated with renal disease. Diuretic actions are of considerable importance to patients who have renal disease, as their effective use assists in extracellular fluid volume control, reducing excretion of protein in urine and lessening the risk of developing hyperkalemia. Diuretic-related adverse events that involve the uric acid, Na+ and K+ axes are not uncommon; therefore the clinician must be vigilant in looking for biochemical disturbances. As a result of diuretic-related adverse events, clinicians must be resourceful in the dose amount and frequency of dosing.

Key Points

  • Diuretic therapy is mainly used in renal disease to facilitate extracellular fluid volume control, lessen the tendency to develop hyperkalemia and lower blood pressure

  • The response to a loop diuretic is optimized by a clinically relevant time course of urinary drug delivery; a number of aspects of renal failure alter this relationship

  • Although thiazide-type diuretics can elicit a response in patients with a glomerular filtration rate <50 ml/min/1.73 m2, loop diuretics are generally the diuretic of choice in patients with renal insufficiency

  • K+-sparing diuretics should be used cautiously in patients with chronic kidney disease

  • In patients with end-stage renal disease who have some residual renal function, treatment with a loop diuretic can be a useful adjunct therapy to lessen interdialytic fluid restriction

  • Diuretic-related adverse events are typically dose-dependent and can be a particular problem when high diuretic doses are necessary to control excess extracellular fluid volume

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Determinants of loop diuretic response.
Figure 2: Decrease in overall sodium excretion from a maximally effective dose of a loop diuretic in renal insufficiency as a result of a decreased filtered load.
Figure 3: The stages of CKD showing classification of CKD and diuretic use according to the NKF K/DOQI guidelines.

Similar content being viewed by others

References

  1. Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Bakris, G. L. et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch. Intern. Med. 163, 1555–1565 (2003).

    Article  PubMed  Google Scholar 

  3. Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Berl, T. et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann. Intern. Med. 138, 542–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Brater, D. C. Diuretic therapy. N. Engl. J. Med. 339, 387–395 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Sica, D. A. & Gehr, T. W. Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic relationships. Clin. Pharmacokinet. 30, 229–249 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Almeshari, K. et al. A volume-independent component to postdiuretic sodium retention in man. J. Am. Soc. Nephrol. 3, 1878–1883 (1993).

    CAS  PubMed  Google Scholar 

  8. Ellison, D. H., Velázquez, H. & Wright, F. S. Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion. J. Clin. Invest. 83, 113–126 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Benet, L. Z. Pharmacokinetics/pharmacodynamics of furosemide in man: a review. J. Pharmacokinet. Biopharm. 7, 1–27 (1979).

    Article  CAS  PubMed  Google Scholar 

  10. Murray, M. D. et al. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacotherapy 17, 98–106 (1997).

    CAS  PubMed  Google Scholar 

  11. Brater, D. C. in The in vivo study of drug action: principles and applications of kinetic-dynamic modeling (eds van Boxtel, C. J., Holford, N. H. G. & Danhof, M.) 253–275 (Elsevier Science, Amsterdam, 1992).

    Google Scholar 

  12. Wilcox, C. S. New insights into diuretic use in patients with chronic renal disease. J. Am. Soc. Nephrol. 13, 798–805 (2002).

    PubMed  Google Scholar 

  13. Kim, G. H. Long-term adaptation of renal ion transporters to chronic diuretic treatment. Am. J. Nephrol. 24, 595–605 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Shankar, S. S. & Brater, D. C. Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am. J. Physiol. Renal Physiol. 284, F11–F21 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Beerman, B. Aspects on pharmacokinetics of some diuretics. Acta Pharmacol. Toxicol. 54 (Suppl. 1), 17–32 (1984).

    Google Scholar 

  16. van Olden, R. W. et al. Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency. Eur. J. Clin. Pharmacol. 47, 483–488 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Voelker, J. R. et al. Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int. 32, 572–578 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Rudy, D. W. et al. The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin. Pharmacol. Ther. 56, 39–47 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Brater, D. C. Pharmacokinetics of loop diuretics in congestive heart failure. Br. Heart J. 72 (2 Suppl.), S40–S43 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Murphy, C. A. & Dargie, H. J. Drug-induced cardiovascular disorders. Drug Saf. 30, 783–804 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Wilcox, C. S. et al. Response of the kidney to furosemide. I. Effects of salt intake and renal compensation. J. Lab. Clin. Med. 102, 450–458 (1983).

    CAS  PubMed  Google Scholar 

  22. Kelly, R. A. et al. Response of the kidney to furosemide. II. Effect of captopril on sodium balance. Kidney Int. 24, 233–239 (1983).

    Article  CAS  PubMed  Google Scholar 

  23. Wilcox, C. S. et al. Na+, K+, and BP homeostasis in man during furosemide: effects of prazosin and captopril. Kidney Int. 31, 135–141 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Ellison, D. H. Diuretic drugs and the treatment of edema: from clinic to bench and back again. Am. J. Kidney Dis. 23, 623–643 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Loon, N. R., Wilcox, C. S. & Unwin, R. J. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. 36, 682–689 (1989).

    Article  CAS  PubMed  Google Scholar 

  26. Ellison, D. H. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann. Intern. Med. 114, 886–894 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Sica, D. A. & Gehr, T. Diuretics in congestive heart failure. Cardiol. Clin. 7, 87–97 (1989).

    Article  CAS  PubMed  Google Scholar 

  28. Gehr, T. W. et al. The pharmacokinetics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin. Pharmacol. Ther. 56, 31–38 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Hassan, Z. U., Kruer, J. J. & Fuhman, T. M. Electrolyte changes during craniotomy caused by administration of hypertonic mannitol. J. Clin. Anesth. 19, 307–309 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Weaver, A. & Sica, D. A. Mannitol-induced acute renal failure. Nephron 45, 233–235 (1987).

    Article  CAS  PubMed  Google Scholar 

  31. Knauf, H. & Mutschler, E. Sequential nephron blockade breaks resistance to diuretics in edematous states. J. Cardiovasc. Pharmacol. 29, 367–372 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Wollam, G. L., Tarazi, R. C., Bravo, E. L. & Dustan, H. P. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am. J. Med. 72, 929–938 (1982).

    Article  CAS  PubMed  Google Scholar 

  33. Dargie, H. J., Allison, M. E., Kennedy, A. C. & Gray, M. C. High dosage metolazone in chronic renal failure. Br. Med. J. 4, 196–198 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kidney Disease Outcomes Initiative (K/DOGI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am. J. Kidney Dis. 43 (5 Suppl. 1), S1–S290 (2004).

  35. Rahman, M. et al. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann. Intern. Med. 144, 172–180 (2006).

    Article  PubMed  Google Scholar 

  36. Vasavada, N. & Agarwal, R. Role of excess volume in the pathophysiology of hypertension in chronic kidney disease. Kidney Int. 64, 1772–1779 (2003).

    Article  PubMed  Google Scholar 

  37. Dorhout Mees, E. J. Volaemia and blood pressure in renal failure: have old truths been forgotten. Nephrol. Dial. Transplant. 10, 1297–1298 (1995).

    Google Scholar 

  38. Calhoun, D. A. et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 51, 1403–1419 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Sica, D. A. The risks and benefits of aldosterone antagonists. Curr. Heart Fail. Rep. 2, 65–71 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Santos, J. et al. Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety. J. Hepatol. 39, 187–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Sica, D. A. Eplerenone: a new aldosterone receptor antagonist—are the FDA's restrictions appropriate. J. Clin. Hypertens. 4, 441–445 (2002).

    Article  CAS  Google Scholar 

  42. Besseghir, K., Mosiq, D. & Roch-Ramel, F. Facilitation by serum albumin of renal tubular secretion of organic anions. Am. J. Physiol. 256, F475–F484 (1989).

    CAS  PubMed  Google Scholar 

  43. Inoue, M. et al. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int. 32, 198–203 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Pichette, V., Geadah, D. & du Souich, P. The influence of moderate hypoalbuminemia on the renal metabolism and dynamics of furosemide in the rabbit. Br. J. Pharmacol. 119, 885–890 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Green, T. P. & Mirkin, B. L. Furosemide disposition in normal and proteinuric rats: urinary drug-protein binding as a determinant of drug excretion. J. Pharmacol. Exp. Ther. 218, 122–127 (1981).

    CAS  PubMed  Google Scholar 

  46. Agarwal, R., Gorski, J. C., Sundblad, K. & Brater, D. C. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J. Am. Soc. Nephrol. 11, 1100–1105 (2000).

    CAS  PubMed  Google Scholar 

  47. Kirchner, K., Voelker, J. R. & Brater, D. C. Tubular resistance to furosemide contributes to the attenuated diuretic response in nephrotic rats. J. Am. Soc. Nephrol. 2, 1201–1207 (1992).

    CAS  PubMed  Google Scholar 

  48. Danielsen, H., Pedersen, E. B., Madsen, M. & Jensen, T. Abnormal renal sodium excretion in the nephrotic syndrome after furosemide: relation to glomerular filtration rate. Acta Med. Scand. 217, 513–518 (1985).

    Article  CAS  PubMed  Google Scholar 

  49. Shapiro, M. D., Hasbargen, J., Hensen, J. & Schrier, R. W. Role of aldosterone in the sodium retention of patients with nephrotic syndrome. Am. J. Nephrol. 10, 44–48 (1990).

    Article  CAS  PubMed  Google Scholar 

  50. Esnault, V. L., Ekhlas, A., Delcroix, C., Moutel, M. G. & Nguyen, J. M. Diuretic and enhanced sodium restriction results in improved antiproteinuric response to RAS blocking agents. J. Am. Soc. Nephrol. 16, 474–481 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Kunz, R., Friedrich, C., Wolbers, M. & Mann, J. F. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin–angiotensin system on proteinuria in renal disease. Ann. Intern. Med. 148, 30–48 (2008).

    Article  PubMed  Google Scholar 

  52. Chalasani, N. et al. Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J. Am. Soc. Nephrol. 12, 1010–1016 (2001).

    CAS  PubMed  Google Scholar 

  53. Akcicek, F., Yalniz, T., Basci, A., Ok, E. & Mees, E. J. Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin? Br. Med. J. 310, 162–163 (1995).

    Article  CAS  Google Scholar 

  54. Fliser, D., Schröter, M., Neubeck, M. & Ritz, E. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int. 46, 482–488 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Asscher, A. W. Treatment of frusemide resistant oedema with metolazone. Clin. Trials J. 11, 134–139 (1974).

    Google Scholar 

  56. Sica, D. A. & Gehr, T. W. Diuretic use in stage five chronic kidney disease and end-stage renal disease. Curr. Opin. Nephrol. Hypertens. 12, 483–490 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Sica, D. A. Metolazone and its role in edema management. Congest. Heart Fail. 9, 100–105 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Allen, J. M., Hind, C. R. & McMichael, H. B. Synergistic action of metolazone with “loop” diuretics. Br. Med. J. (Clin. Res. Ed.) 282, 1873 (1981).

    Article  CAS  Google Scholar 

  59. Tilstone, W. J., Dargie, H., Dargie, E. N., Morgan, H. G. & Kennedy, A. C. Pharmacokinetics of metolazone in normal subjects and in patients with cardiac or renal failure. Clin. Pharmacol. Ther. 16, 322–329 (1974).

    Article  CAS  PubMed  Google Scholar 

  60. Rudy, D. W., Voelker, J. R., Greene, P. K., Esparza, F. A. & Brater, D. C. Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann. Intern. Med. 115, 360–366 (1991).

    Article  CAS  PubMed  Google Scholar 

  61. van Olden, R. W., van Meyel, J. J. & Gerlag, P. G. Acute and long-term effects of therapy with high-dose furosemide in chronic hemodialysis patients. Am. J. Nephrol. 12, 351–356 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Bragg-Gresham, J. L. et al. Diuretic use, residual renal function, and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Pattern Study (DOPPS). Am. J. Kidney Dis. 49, 426–431 (2007).

    Article  PubMed  Google Scholar 

  63. Sica, D. A. Diuretic-related side effects: development and treatment. J. Clin. Hypertens. (Greenwich) 6, 532–540 (2004).

    Article  Google Scholar 

  64. Cocco, G., Iselin, H. U., Strozzi, C., Cesana, B. & Baumeler, H. R. Magnesium depletion in patients on long-term chlorthalidone therapy for essential hypertension. Eur. J. Clin. Pharmacol. 32, 335–338 (1987).

    Article  CAS  PubMed  Google Scholar 

  65. Schrier, R. W. Vasopressin and aquaporin 2 in clinical disorders of water homeostasis. Semin. Nephrol. 28, 289–296 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Morgan, D. B. & Davidson, C. Hypokalemia and diuretics: an analysis of publications. Br. Med. J. 280, 905–908 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bakris, G. L. et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group. Kidney Int. 58, 2084–2092 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Sica, D. A. The risks and benefits of aldosterone receptor antagonists. Curr. Heart Fail. Rep. 2, 65–71 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Korgaonkar, S. et al. Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study. Clin. J. Am. Soc. Nephrol. 5, 762–769 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ljunghall, S. et al. Effects of bendroflumethiazide on urate metabolism during treatment of patients with renal stones. J. Urol. 127, 1207–1210 (1982).

    Article  CAS  PubMed  Google Scholar 

  71. Sica, D. A. & Schoolwerth, A. in The Kidney, 7th edn (eds Brenner, B. & Rector, F.) 637–662 (WB Saunders, Philadelphia, 2004).

    Google Scholar 

  72. Weinman, E. J., Eknoyan, G. & Suki, W. N. The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J. Clin. Invest. 55, 283–291 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Menè, P. & Punzo, G. Uric acid: bystander or culprit in hypertension and progressive renal disease? J. Hypertens. 26, 2085–2092 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. So, A. & Thorens, B. Uric acid transport and disease. J. Clin. Invest. 120, 1791–1799 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Isakova, T. et al. Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort. Nephrol. Dial. Transplant. 26, 1258–1265 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Reilly, R. F., Peixoto, A. J. & Desir, G. V. The evidence-based use of thiazide diuretics in hypertension and nephrolithiasis. Clin. J. Am. Soc. Nephrol. 5, 1893–1903 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Bolland, M. J. et al. The effect of treatment with a thiazide diuretic for 4 years on bone density in normal postmenopausal women. Osteoporos. Int. 18, 479–486 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Addo, H. A., Ferguson, J. & Frain-Bell, W. Thiazide-induced photosensitivity: a study of 33 subjects. Br. J. Dermatol. 116, 749–760 (1987).

    Article  CAS  PubMed  Google Scholar 

  79. Wall, G. C., Bigner, D. & Craig, S. Ethacrynic acid and the sulfa-sensitive patient. Arch. Intern. Med. 163, 116–117 (2003).

    Article  PubMed  Google Scholar 

  80. Rybak, L. P. Ototoxicity of loop diuretics. Otolaryngol. Clin. North Am. 26, 829–844 (1993).

    CAS  PubMed  Google Scholar 

  81. Sica, D. A. Pharmacotherapy in congestive heart failure: drug absorption in the management of congestive heart failure: loop diuretics. Congest. Heart Fail. 9, 287–292 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Allen, L. A. et al. Continuous versus bolus dosing of Furosemide for patients hospitalized for heart failure. Am. J. Cardiol. 105, 1794–1797 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Felker, G. M. et al. Diuretic strategies in patients with acute decompensated heart failure. N. Engl. J. Med. 364, 797–805 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Virginia Commonwealth University Health System, 1101 East Marshall Street, Sanger Hall, Room 8-062, Richmond, 23298-0160, VA, USA

    Domenic A. Sica

Authors
  1. Domenic A. Sica
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sica, D. Diuretic use in renal disease. Nat Rev Nephrol 8, 100–109 (2012). https://doi.org/10.1038/nrneph.2011.175

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2011.175

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing