Pathophysiology, Evaluation, Outcomes, and Treatment of Hyponatremia
By:
Naoto TominagaDivision of Nephrology and Hypertension, Kawasaki Municipal Tama Hospital, Kawasaki, Kanagawa, Japan and Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan

Search for other papers by Naoto Tominaga in
Current site
Google Scholar
PubMed
Close
and
Joseph G. VerbalisDivision of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, DC

Search for other papers by Joseph G. Verbalis in
Current site
Google Scholar
PubMed
Close
  • Collapse
  • Expand
  • 1

    Adrogué HJ, Madias NE: Hyponatremia. N Engl J Med 342: 15811589, 2000 PubMed

  • 2

    Upadhyay A, Jaber BL, Madias NE: Incidence and prevalence of hyponatremia. Am J Med 119[Suppl 1]: S30S35, 2006 PubMed

  • 3

    Hoorn EJ, Zietse R: Diagnosis and treatment of hyponatremia: Compilation of the guidelines. J Am Soc Nephrol 28: 13401349, 2017 PubMed

  • 4

    Ellison DH, Berl T: Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 356: 20642072, 2007 PubMed

  • 5

    Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al..: Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med 126[Suppl 1]: S1S42, 2013 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al.; Hyponatraemia Guideline Development Group: Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 29[Suppl 2]: i1i39, 2014 10.1093/ndt/gfu040PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Henry DA: In the clinic: Hyponatremia. Ann Intern Med 163: ITC1ITC19, 2015 PubMed

  • 8

    DeVita MV, Gardenswartz MH, Konecky A, Zabetakis PM: Incidence and etiology of hyponatremia in an intensive care unit. Clin Nephrol 34: 163166, 1990 PubMed

    • Search Google Scholar
    • Export Citation
  • 9

    Flear CT, Gill GV, Burn J: Hyponatraemia: Mechanisms and management. Lancet 2: 2631, 1981 PubMed

  • 10

    Kleinfeld M, Casimir M, Borra S: Hyponatremia as observed in a chronic disease facility. J Am Geriatr Soc 27: 156161, 1979 PubMed

  • 11

    Natkunam A, Shek CC, Swaminathan R: Hyponatremia in a hospital population. J Med 22: 8396, 1991 PubMed

  • 12

    Brunsvig PF, Os I, Frederichsen P: Hyponatremi. En retrospektiv studie med henblikk på forekomst, årsak og mortalitet. [Hyponatremia. A retrospective study of occurrence, etiology and mortality] Tidsskr Nor Laegeforen 110: 23672369, 1990 PubMed

    • Search Google Scholar
    • Export Citation
  • 13

    Anderson RJ, Chung HM, Kluge R, Schrier RW: Hyponatremia: A prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 102: 164168, 1985 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Robinson AG: Disorders of antidiuretic hormone secretion. Clin Endocrinol Metab 14: 5588, 1985 PubMed

  • 15

    Mack GW, Weseman CA, Langhans GW, Scherzer H, Gillen CM, Nadel ER. Body fluid balance in dehydrated healthy older men: Thirst and renal osmoregulation. J Appl Physiol 76: 16151623, 1985 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Farrell MJ, Zamarripa F, Shade R, Phillips PA, McKinley M, Fox PT, et al..: Effect of aging on regional cerebral blood flow responses associated with osmotic thirst and its satiation by water drinking: A PET study. Proc Natl Acad Sci U S A 105: 382387, 2008 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Juul KV, Bichet DG, Nielsen S, Nørgaard JP: The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 306: F931F940, 2014 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Dunn FL, Brennan TJ, Nelson AE, Robertson GL: The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J Clin Invest 52: 32123219, 1973 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Gheorghe G, Ilie M, Bungau S, Stoian AMP, Bacalbasa N, Diaconu CC: Is there a relationship between COVID-19 and hyponatremia? Medicina (Kaunas) 57: 55, 2021 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Swart RM, Hoorn EJ, Betjes MG, Zietse R: Hyponatremia and inflammation: The emerging role of interleukin-6 in osmoregulation. Nephron, Physiol 118: 4551, 2011 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Edelman IS, Leibman J, O’Meara MP, Birkenfeld LW: Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37: 12361256, 1958 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Adrogué HJ, Madias NE: The challenge of hyponatremia. J Am Soc Nephrol 23: 11401148, 2012 PubMed

  • 23

    Hillier TA, Abbott RD, Barrett EJ: Hyponatremia: Evaluating the correction factor for hyperglycemia. Am J Med 106: 399403, 1999 PubMed

  • 24

    Aviram A, Pfau A, Czaczkes JW, Ullmann TD: Hyperosmolality with hyponatremia, caused by inappropriate administration of mannitol. Am J Med 42: 648650, 1967 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Desmond J: Serum osmolality and plasma electrolytes in patients who develop dilutional hyponatremia during transurethral resection. Can J Surg 13: 116121, 1970 PubMed

    • Search Google Scholar
    • Export Citation
  • 26

    Levin A, Klassen J, Halperin ML: Challenging consults: Application of principles of physiology and biochemistry to the bedside. Osmotic diuresis: The importance of counting the number of osmoles excreted. Clin Invest Med 18: 401405, 1995 PubMed

    • Search Google Scholar
    • Export Citation
  • 27

    Braun MM, Barstow CH, Pyzocha NJ: Diagnosis and management of sodium disorders: Hyponatremia and hypernatremia. Am Fam Physician 91: 299307, 2015 PubMed

    • Search Google Scholar
    • Export Citation
  • 28

    Fenske W, Störk S, Koschker AC, Blechschmidt A, Lorenz D, Wortmann S, et al..: Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. J Clin Endocrinol Metab 93: 29912997, 2008 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Schwartz WB, Bennett W, Curelop S, Bartter FC: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23: 529542, 1957 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Schwartz WB, Bennett W, Curelop S, Bartter FC: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. 1957. J Am Soc Nephrol 12: 28602870, 2001 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    George JC, Zafar W, Bucaloiu ID, Chang AR: Risk factors and outcomes of rapid correction of severe hyponatremia. Clin J Am Soc Nephrol 13: 984992, 2018 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Nagler EV, Haller MC, Van Biesen W, Vanholder R, Craig JC, Webster AC: Interventions for chronic non-hypovolaemic hypotonic hyponatraemia. Cochrane Database Syst Rev 6: CD010965, 2018 PubMed

    • Search Google Scholar
    • Export Citation
  • 33

    Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, et al..: Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 352: 18841890, 2005 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Levtchenko EN, Monnens LA: Nephrogenic syndrome of inappropriate antidiuresis. Nephrol Dial Transplant 25: 28392843, 2010 PubMed

  • 35

    Decaux G, Vandergheynst F, Bouko Y, Parma J, Vassart G, Vilain C: Nephrogenic syndrome of inappropriate antidiuresis in adults: High phenotypic variability in men and women from a large pedigree. J Am Soc Nephrol 18: 606612, 2007 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Byatt CM, Millard PH, Levin GE: Diuretics and electrolyte disturbances in 1000 consecutive geriatric admissions. J R Soc Med 83: 704708, 1990 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Barber J, McKeever TM, McDowell SE, Clayton JA, Ferner RE, Gordon RD, et al..: A systematic review and meta-analysis of thiazide-induced hyponatraemia: Time to reconsider electrolyte monitoring regimens after thiazide initiation? Br J Clin Pharmacol 79: 566577, 2015 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Liamis G, Milionis H, Elisaf M: A review of drug-induced hyponatremia. Am J Kidney Dis 52: 144153, 2008 PubMed

  • 39

    Cantini L, Merloni F, Rinaldi S, Lenci E, Marcantognini G, Meletani T, et al..: Electrolyte disorders in advanced non-small cell lung cancer patients treated with immune check-point inhibitors: A systematic review and meta-analysis. Crit Rev Oncol Hematol 151: 102974, 2020 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Seethapathy H, Rusibamayila N, Chute DF, Lee M, Strohbehn I, Zubiri L, Faje AT, Reynolds KL, Jhaveri KD, Sise ME. Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors. Nephrol Dial Transplant Dec 29: gfaa272, 2020 PubMed

    • Search Google Scholar
    • Export Citation
  • 41

    Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, et al..: Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: A systematic review and meta-analysis. JAMA Oncol 4: 173182, 2018 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Caturegli P, Di Dalmazi G, Lombardi M, Grosso F, Larman HB, Larman T, et al..: Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: Insights into pathogenesis from an autopsy series. Am J Pathol 186: 32253235, 2016 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Faje A, Reynolds K, Zubiri L, Lawrence D, Cohen JV, Sullivan RJ, et al..: Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis. Eur J Endocrinol 181: 211219, 2019 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Yatagai T, Kusaka I, Nakamura T, Nagasaka S, Honda K, Ishibashi S, et al..: Close association of severe hyponatremia with exaggerated release of arginine vasopressin in elderly subjects with secondary adrenal insufficiency. Eur J Endocrinol 148: 221226, 2003 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Dineen R, Hannon MJ, Thompson CJ: Hyponatremia and Hypernatremia. In: Endocrinology: Adult and Pediatric 7th Ed., edited by J. Larry Jameson, Leslie J De Groot, David M. de Kretser, Linda C. Giudice, Ashley B. Grossman, Shlomo Melmed, John T. Potts, and Gordon C. Weir, J. Larry Jameson, Leslie J De Groot, David M. de Kretser, Linda C. Giudice, Ashley B. Grossman, Shlomo Melmed, John T. Potts, and Gordon C. Weir, Philadelphia, Elsevier, 2016, pp 19531962

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    Verbalis JG, Drutarosky MD: Adaptation to chronic hypoosmolality in rats. Kidney Int 34: 351360, 1988 PubMed

  • 47

    Verbalis JG: Adaptation to acute and chronic hyponatremia: Implications for symptomatology, diagnosis, and therapy. Semin Nephrol 18: 319, 1998 PubMed

    • Search Google Scholar
    • Export Citation
  • 48

    Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 119: e1e8, 2006 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, et al.: Hyponatremia-induced osteoporosis. J Bone Miner Res 25: 554563, 2010 PubMed

  • 50

    Hoorn EJ, Rivadeneira F, van Meurs JB, Ziere G, Stricker BH, Hofman A, et al.: Mild hyponatremia as a risk factor for fractures: The Rotterdam Study. J Bone Miner Res 26: 18221828, 2011 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    Berghmans T, Paesmans M, Body JJ: A prospective study on hyponatraemia in medical cancer patients: Epidemiology, aetiology and differential diagnosis. Support Care Cancer 8: 192197, 2000 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    Terzian C, Frye EB, Piotrowski ZH: Admission hyponatremia in the elderly: Factors influencing prognosis. J Gen Intern Med 9: 8991, 1994 PubMed

  • 53

    Greenberg A, Verbalis JG, Amin AN, Burst VR, Chiodo JA 3rd, Chiong JR, et al.: Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney Int 88: 167177, 2015 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54

    Laville M, Burst V, Peri A, Verbalis JG: Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH): Therapeutic decision-making in real-life cases. Clin Kidney J 6[Suppl 1]: i1i20, 2013 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55

    Moritz ML, Ayus JC: Hospital-acquired hyponatremia--why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol 3: 374382, 2007 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56

    Keller WJ, Mullaj E: Antidiuretic hormone release associated with increased intracranial pressure independent of plasma osmolality. Brain Behav 8: e01005, 2018 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Battison C, Andrews PJ, Graham C, Petty T: Randomized, controlled trial on the effect of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased intracranial pressure after brain injury. Crit Care Med 33: 196202, discussion 257–258, 2005 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58

    Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, Stevens RD: Reversal of transtentorial herniation with hypertonic saline. Neurology 70: 10231029, 2008 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 59

    Garrahy A, Dineen R, Hannon AM, Cuesta M, Tormey W, Sherlock M, et al.: Continuous versus bolus infusion of hypertonic saline in the treatment of symptomatic hyponatremia caused by SIAD. J Clin Endocrinol Metab 104: 35953602, 2019 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 60

    Baek SH, Jo YH, Ahn S, Medina-Liabres K, Oh YK, Lee JB, et al.: Risk of overcorrection in rapid intermittent bolus vs slow continuous infusion therapies of hypertonic saline for patients with symptomatic hyponatremia: The SALSA randomized clinical trial. JAMA Intern Med 181: 8192, 2021 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61

    Adams RD, Victor M, Mancall EL: Central pontine myelinolysis: A hitherto undescribed disease occurring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry 81: 154172, 1959 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 62

    Sterns RH, Riggs JE, Schochet SS Jr: Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 314: 15351542, 1986 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 63

    Sterns RH: Adverse consequences of overly-rapid correction of hyponatremia. Front Horm Res 52: 130142, 2019 PubMed

  • 64

    Gankam Kengne F, Decaux G: Hyponatremia and the brain. Kidney Int Rep 3: 2435, 2017 PubMed

  • 65

    Berl T, Rastegar A: A patient with severe hyponatremia and hypokalemia: Osmotic demyelination following potassium repletion. Am J Kidney Dis 55: 742748, 2010 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66

    Sood L, Sterns RH, Hix JK, Silver SM, Chen L: Hypertonic saline and desmopressin: A simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 61: 571578, 2013 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 67

    Verbalis JG, Greenberg A, Burst V, Haymann JP, Johannsson G, Peri A, Poch E, Chiodo JA 3rd, Dave J. Diagnosing and treating the syndrome of inappropriate antidiuretic hormone secretion. Am J Med 129: e9-537, 2016 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68

    Garrahy A, Galloway I, Hannon AM, Dineen R, O'Kelly P, Tormey WP, O'Reilly MW, Williams DJ, Sherlock M, Thompson CJ. Fluid restriction therapy for chronic SIAD: Results of a prospective randomized controlled trial. J Clin Endocrinol Metab 105: dgaa619, 2020 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 69

    Hantman D, Rossier B, Zohlman R, Schrier R: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline. Ann Intern Med 78: 870875, 1973 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 70

    Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, Decaux G: Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 7: 742747, 2012 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71

    Krisanapan P, Vongsanim S, Pin-On P, Ruengorn C, Noppakun K: Efficacy of furosemide, oral sodium chloride, and fluid restriction for treatment of syndrome of inappropriate antidiuresis (SIAD): An open-label randomized controlled study (The EFFUSE-FLUID Trial). Am J Kidney Dis 76: 203212, 2020 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 72

    Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, et al.: OPC-41061, a highly potent human vasopressin V2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 287: 860867, 1998 PubMed

    • Search Google Scholar
    • Export Citation
  • 73

    Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al.; SALT Investigators: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355: 20992112, 2006 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 74

    Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, et al.; SALTWATER Investigators: Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 21: 705712, 2010 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75

    Sterns RH, Silver SM, Hix JK: Urea for hyponatremia? Kidney Int 87: 268270, 2015 PubMed

  • 76

    Decaux G, Andres C, Gankam Kengne F, Soupart A: Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit Care 14: R184, 2010 PubMed

  • 77

    Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, et al.: Urea for the treatment of hyponatremia. Clin J Am Soc Nephrol 13: 16271632, 2018 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 78

    Refardt J, Imber C, Sailer CO, Jeanloz N, Potasso L, Kutz A, et al.: A randomized trial of empagliflozin to increase plasma sodium levels in patients with the syndrome of inappropriate antidiuresis. J Am Soc Nephrol 31: 615624, 2020 PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 410 410 40
Full Text Views 549 549 48
PDF Downloads 692 692 63