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Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists

A Corrigendum to this article was published on 01 April 2007

Abstract

Vasopressin-2 receptor antagonists, collectively known as the 'vaptans', provide a new approach to the treatment of hyponatremia; therefore, an updated Review of the pathophysiology of hyponatremia is particularly timely. After briefly defining hyponatremia and introducing its clinical aspects and complications, we present an approach to the diagnosis and evaluation of hyponatremia that is based primarily on the often-underused concept of free water clearance and, more specifically, the electrolyte-free water clearance. Then we review the use of vasopressin receptor antagonists in the management of hyponatremia from the standpoint of their pharmacology, their mechanism of action, and available efficacy data from clinical trials.

Key Points

  • Pathogenesis of hyponatremia involves an imbalance between water intake and water output

  • Hyponatremia is categorized according to severity, chronicity and patient volume status; there are therapeutic ramifications associated with each category

  • Calculating the electrolyte-free water clearance—especially the urine:plasma electrolyte ratio—can help to guide prescription of water restriction and response to other therapies

  • Vasopressin receptor antagonists (aquaretics) seem to be safe and effective for treatment of euvolemic and hypervolemic hyponatremia

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Figure 1: Correlation between solute-free water clearance and urinary AQP-2 excretion during the first 2 h of urine collection in chronic heart failure patients after administration of lixivaptan (VPA-985).
Figure 2: Effect of administration of lixivaptan (VPA-985) at different doses on urinary AQP-2 excretion.
Figure 3: Effect of conivaptan (YM087) on least-squares mean ± standard error change from baseline in (A) FWC and (B) EFWC.
Figure 4: Change in average daily area under the curve for serum sodium concentration (A) from baseline to day 4 and (B) from baseline to day 30 in patients who received either tolvaptan or placebo.

References

  1. 1

    Robertson GL (2001) Antidiuretic hormone: normal and disordered function. Endocrinol Metab Clin North Am 30: 671–694

    CAS  Article  Google Scholar 

  2. 2

    Costello-Boerrigter LC et al. (2003) Revisiting salt and water retention: new diuretics, aquaretics, and natriuretics. Med Clin North Am 87: 475–491

    CAS  Article  Google Scholar 

  3. 3

    Hayashi M et al. (1994) Expression and distribution of aquaporin of collecting duct are regulated by vasopressin V2 receptor in rat kidney. J Clin Invest 94: 1778–1783

    CAS  Article  Google Scholar 

  4. 4

    Wong LL and Verbalis JG (2002) Systemic diseases associated with disorders of water homeostasis. Endocrinol Metab Clin North Am 31: 121–140

    CAS  Article  Google Scholar 

  5. 5

    Decaux G et al. (2000) Hyponatremia in the intensive care: from diagnosis to treatment. Acta Clin Belg 55: 68–78

    CAS  Article  Google Scholar 

  6. 6

    Brown OA (2004) Understanding postoperative hyponatremia. Urol Nurs 24: 197–201

    PubMed  Google Scholar 

  7. 7

    Casulari LA et al. (2004) Differential diagnosis and treatment of hyponatremia following pituitary surgery. J Neurosurg Sci 48: 11–18

    CAS  PubMed  Google Scholar 

  8. 8

    Coenraad MJ et al. (2001) Hyponatremia in intracranial disorders. Neth J Med 58: 123–127

    CAS  Article  Google Scholar 

  9. 9

    Janicic N and Verbalis JG (2003) Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 32: 459–481

    CAS  Article  Google Scholar 

  10. 10

    Soupart A and Decaux G (1996) Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 46: 149–169

    CAS  PubMed  Google Scholar 

  11. 11

    Gross P et al. (2001) Treatment of severe hyponatremia: conventional and novel aspects. J Am Soc Nephrol 12 (Suppl): S10–S14

    CAS  PubMed  Google Scholar 

  12. 12

    Sterns RH (1987) Severe symptomatic hyponatremia: treatment and outcome: a study of 64 cases. Ann Intern Med 107: 656–664

    CAS  Article  Google Scholar 

  13. 13

    Fried LF and Palevsky PM (1997) Hyponatremia and hypernatremia. Med Clin North Am 81: 585–609

    CAS  Article  Google Scholar 

  14. 14

    Boscoe A et al. (2006) Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc 4: 10–20

    Article  Google Scholar 

  15. 15

    Greenberg A and Verbalis JG (2006) Vasopressin receptor antagonists. Kidney Int 69: 2124–2130

    CAS  Article  Google Scholar 

  16. 16

    Baylis PH (2003) The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cell Biol 35: 1495–1499

    CAS  Article  Google Scholar 

  17. 17

    Palmer BF (2003) Hyponatremia in patients with central nervous system disease: SIADH versus CSW. Trends Endocrinol Metab 14: 182–187

    CAS  Article  Google Scholar 

  18. 18

    Mulloy AL and Caruana RJ (1995) Hyponatremic emergencies. Med Clin North Am 79: 155–168

    CAS  Article  Google Scholar 

  19. 19

    Goh KP (2004) Management of hyponatremia. Am Fam Physician 69: 2387–2394

    PubMed  Google Scholar 

  20. 20

    Adrogue HJ and Madias NE (2000) Hyponatremia. N Engl J Med 342: 1581–1589

    CAS  Article  Google Scholar 

  21. 21

    Moritz ML and Ayus JC (2003) The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant 18: 2486–2491

    Article  Google Scholar 

  22. 22

    Fraser CL and Arieff AI (1997) Epidemiology, pathophysiology, and management of hyponatremic encephalopathy. Am J Med 102: 67–77

    CAS  Article  Google Scholar 

  23. 23

    Sterns RH et al. (1994) Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol 4: 1522–1530

    CAS  PubMed  Google Scholar 

  24. 24

    Ayus JC et al. (2006) Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents. Kidney Int 69: 1319–1325

    CAS  Article  Google Scholar 

  25. 25

    Ghali JK et al. (2006) Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin-receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab 91: 2145–2152

    CAS  Article  Google Scholar 

  26. 26

    Rabinstein AA and Wijdicks EF (2003) Hyponatremia in critically ill neurological patients. Neurologist 9: 290–300

    Article  Google Scholar 

  27. 27

    Harrigan MR (2001) Cerebral salt wasting syndrome. Crit Care Clin 17: 125–138

    CAS  Article  Google Scholar 

  28. 28

    Shoker AS (1994) Application of the clearance concept to hyponatremic and hypernatremic disorders: a phenomenological analysis. Clin Chem 40: 1220–1227

    CAS  PubMed  Google Scholar 

  29. 29

    Ayus JC et al. (1987) Treatment of symptomatic hyponatremia and its relation to brain damage. N Engl J Med 317: 1190–1195

    CAS  Article  Google Scholar 

  30. 30

    Rose BD (1986) New approach to disturbances in the plasma sodium concentration. Am J Med 81: 1033–1040

    CAS  Article  Google Scholar 

  31. 31

    Edelman IS et al. (1958) Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37: 1236–1256

    CAS  Article  Google Scholar 

  32. 32

    Furst H et al. (2000) The urine/plasma electrolyte ratio: a predictive guide to water restriction. Am J Med Sci 319: 240–244

    CAS  Article  Google Scholar 

  33. 33

    Schrier RW (1985) Treatment of hyponatremia. N Engl J Med 312: 1121–1123

    CAS  Article  Google Scholar 

  34. 34

    Decaux G and Soupart A (2003) Treatment of symptomatic hyponatremia. Am J Med Sci 326: 25–30

    Article  Google Scholar 

  35. 35

    Decaux G (2001) Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide. Am J Med 110: 582–584

    CAS  Article  Google Scholar 

  36. 36

    Decaux G et al. (1980) Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med 69: 99–106

    CAS  Article  Google Scholar 

  37. 37

    Decaux G et al. (1981) Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med 304: 329–330

    CAS  Article  Google Scholar 

  38. 38

    Forrest JN et al. (1978) Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 298: 173–177

    Article  Google Scholar 

  39. 39

    Han DS and Cho BS (2002) Therapeutic approach to hyponatremia. Nephron 92: 9–13

    Article  Google Scholar 

  40. 40

    Kleinschmidt-Demasters BK et al. (2006) Central and extrapontine myelinolysis: then...and now. J Neuropathol Exp Neurol 65: 1–11

    CAS  Article  Google Scholar 

  41. 41

    Laureno R and Karp BI (1997) Myelinolysis after correction of hyponatremia. Ann Intern Med 126: 57–62

    CAS  Article  Google Scholar 

  42. 42

    Birnbaumer M (2000) Vasopressin receptors. Trends Endocrinol Metab 11: 406–410

    CAS  Article  Google Scholar 

  43. 43

    Nielsen S et al. (1995) Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA 92: 1013–1017

    CAS  Article  Google Scholar 

  44. 44

    DiGiovanni SR et al. (1994) Regulation of collecting duct water channel expression by vasopressin in Brattleboro rat. Proc Natl Acad Sci USA 91: 8984–8988

    CAS  Article  Google Scholar 

  45. 45

    Rai T (1997) Urinary excretion of aquaporin-2 water channel protein in human and rat. J Am Soc Nephrol 8: 1357–1362

    CAS  PubMed  Google Scholar 

  46. 46

    Saito T et al. (1997) Urinary excretion of aquaporin-2 in the diagnosis of central diabetes insipidus. J Clin Endocrinol Metab 82: 1823–1827

    CAS  PubMed  Google Scholar 

  47. 47

    Martin P-Y et al. (1999) Selective V2-receptor vasopressin antagonism decreases urinary aquaporin-2 excretion in patients with chronic heart failure. J Am Soc Nephrol 10: 2165–2170

    CAS  PubMed  Google Scholar 

  48. 48

    Wong LL and Verbalis JG (2001) Vasopressin V2 receptor antagonists. Cardiovasc Res 51: 391–402

    CAS  Article  Google Scholar 

  49. 49

    Verbalis JG (2002) Vasopressin V2 receptor antagonists. J Mol Endocrinol 29: 1–9

    CAS  Article  Google Scholar 

  50. 50

    Schrier RW et al. (2001) Water-losing and water-retaining states: role of water channels and vasopressin receptor antagonists. Heart Dis 3: 210–214

    CAS  Article  Google Scholar 

  51. 51

    Goldsmith SR and Gheorghiade M (2005) Vasopressin antagonism in heart failure. J Am Coll Cardiol 46: 1785–1791

    CAS  Article  Google Scholar 

  52. 52

    Gheorghiade M (2006) The clinical effects of vasopressin receptor antagonists in heart failure. Cleve Clin J Med 73 (Suppl 2): S24–S29

    Article  Google Scholar 

  53. 53

    Saito T et al. (1997) Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Clin Endocrinol Metab 82: 1054–1057

    CAS  Article  Google Scholar 

  54. 54

    Gross P (2004) Conivaptan, a novel V1a/V2 antagonist, increases serum sodium and effective water clearance in hyponatremia. J Am Soc Nephrol 15: 353A

    Article  Google Scholar 

  55. 55

    Udelson JE et al. (2001) Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 104: 2417–2423

    CAS  Article  Google Scholar 

  56. 56

    Verbalis JG et al. (2004) Novel vasopressin V1a and V2 antagonist conivaptan increases serum sodium concentration and effective water clearance in hyponatremia. J Am Soc Nephrol 15: 356A

    Google Scholar 

  57. 57

    Lemmens-Gruber R and Kamyar M (2006) Vasopressin antagonists. Cell Mol Life Sci 63: 1766–1779

    CAS  Article  Google Scholar 

  58. 58

    Wong F et al. (2003) A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology 37: 182–191

    CAS  Article  Google Scholar 

  59. 59

    Gerbes AL et al. (2003) Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double blind multicenter trial. Gastroenterology 124: 933–939

    CAS  Article  Google Scholar 

  60. 60

    Abraham WT et al. (2006) Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor vasopressin antagonist, in New York Heart Association functional class II and III chronic heart failure patients. J Am Coll Cardiol 47: 1615–1621

    CAS  Article  Google Scholar 

  61. 61

    Decaux G (2001) Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V2 receptor antagonist VPS 985. J Lab Clin Med 138: 18–21

    CAS  Article  Google Scholar 

  62. 62

    Gheorghiade M et al. (2003) Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double blind, randomized trial. Circulation 107: 2690–2696

    CAS  Article  Google Scholar 

  63. 63

    Gheorghiade M et al. (2004) Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial (ACTIV in CHF). JAMA 291: 1963–1971

    CAS  Article  Google Scholar 

  64. 64

    Gheorghiade M et al. (2006) Vasopressin V2 receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia. Am J Cardiol 97: 1064–1067

    CAS  Article  Google Scholar 

  65. 65

    Costello-Boerrigter LC et al. (2006) Vasopressin-2 receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excetion in human heart failure. Am J Physiol Renal Physiol 290: F273–F278

    CAS  Article  Google Scholar 

  66. 66

    Gheorghiade M et al. (2005) Rationale and design of the multicenter, randomized, double blind, placebo-controlled study to evaluate the efficacy of vasopressin antagonism in heart failure: outcome study with Tolvaptan (EVEREST). J Card Fail 11: 260–269

    CAS  Article  Google Scholar 

  67. 67

    Schrier RW et al. (2006) Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355: 2099–2112

    CAS  Article  Google Scholar 

  68. 68

    Gunnet J et al. (2006) Characterization of RWJ-351647, a novel nonpeptide vasopressin V2 receptor antagonist. Clin Exp Pharmacol Physiol 33: 320–326

    CAS  Article  Google Scholar 

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Acknowledgements

We acknowledge the classic studies by Schrier and co-workers, and the recent work on vaptans. It is impossible to be inclusive, but we would like to collectively recognize the countless investigators who have advanced our understanding of hyponatremia and its treatment. S Chen and N Jalandhara declared no competing interests.

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Correspondence to Daniel Batlle.

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D Batlle has received consultation fees from Astellas. He will receive a grant from Otsuka as part of a multicenter study on PKD using tolvaptan, and possibly from Astellas for a study on hyponatremia using conivaptan. S Chen and N Jalandhara declared no competing interests.

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Chen, S., Jalandhara, N. & Batlle, D. Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists. Nat Rev Nephrol 3, 82–95 (2007). https://doi.org/10.1038/ncpneph0401

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