Download PDF
Horm Metab Res 2010; 42(10): 691-702
DOI: 10.1055/s-0030-1255117
Review

© Georg Thieme Verlag KG Stuttgart · New York

The Syndrome of Inappropriate Secretion of Antidiuretic Hormone: Diagnostic and Therapeutic Advances

W. Fenske1 , B. Allolio1
  • 1Department of Medicine I, Endocrine and Diabetes Unit, University Hospital of Würzburg, Würzburg, Germany
Further Information

Publication History

received 10.03.2010

accepted 02.06.2010

Publication Date:
06 July 2010 (online)

Also available at
    Permissions and Reprints

Abstract

Hyponatremia is the most common electrolyte disorder and its presence predicts poor prognosis. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is among the most frequent causes of hyponatremia and is caused by a variety of disorders and pathomechanisms, mostly related to malignancy, pulmonary, or neurologic disorders. The introduction of small molecule vasopressin receptor-2 (VR2) antagonists, so called vaptans, into clinical medicine for the treatment of SIADH makes a reliable diagnosis of SIADH mandatory. This requires structured assessment of essential and supplemental criteria of SIADH, an approach that is currently frequently neglected in clinical routine. Hypertonic saline remains the gold standard in the initial treatment of symptomatic SIADH with severe neurological deficits. However, correction of hyponatremia needs to be slow (<10–12 mmol/l within the first 24 h, and <18 mmol/l within the first 48 h, respectively) to avoid osmotic myelinolysis. Fluid restriction and demeclocyclin have been the most widely used treatments for chronic hyponatremia in SIADH. However, fluid restriction suffers from poor long-term acceptance and demeclocyclin lacks broad availability and has been associated with safety concerns. In controlled clinical trials vaptans have been shown to be efficacious both during short-term and long-term administration (up to 12 months) for mild to moderate SIADH with an acceptable safety profile. However, clinical experience with vaptans in SIADH outside of carefully monitored clinical trials remains still rather limited. Thus, careful postmarketing surveillance will be crucial to fully appreciate the risks and benefits of this new class of drugs in SIADH.

Key words

hyponatremia - SIADH - diagnostic approach - treatment of hyponatremia - vasopressin receptor antagonists

References

  • 1 Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone.  Am J Med. 1967;  42 790-806
    Google Scholar
  • 2 Sims EA, Welt LG, Orloff J, Needham JW. Asymptomatic hyponatremia in pulmonary tuberculosis.  J Clin Invest. 1950;  29 1545-1557
    Google Scholar
  • 3 Winkler AW, Crankshaw OF. Chloride Depletion in Conditions Other Than Addison's Disease.  J Clin Invest. 1938;  17 1-6
    Google Scholar
  • 4 Cheek DB, West CD, Golden CC. The distribution of sodium and chloride and the extracellular fluid volume in the rat.  J Clin Invest. 1957;  36 340-351
    Google Scholar
  • 5 Finberg L. Factors affecting prognosis of tuberculous meningitis treated with streptomycin.  Pediatrics. 1951;  8 768-771
    Google Scholar
  • 6 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. 1957;  23 529-542
    Google Scholar
  • 7 Ragnarsson U. The Nobel trail of Vincent du Vigneaud.  J Pept Sci. 2007;  13 431-433
    Google Scholar
  • 8 Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma.  J Clin Invest. 1973;  52 2340-2352
    Google Scholar
  • 9 Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia.  Semin Nephrol. 2009;  29 227-238
    Google Scholar
  • 10 Gross P. Treatment of hyponatremia.  Intern Med. 2008;  47 885-891
    Google Scholar
  • 11 Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis.  N Engl J Med. 2007;  356 2064-2072
    Google Scholar
  • 12 Saito T, Ishikawa S, Abe K, Kamoi K, Yamada K, Shimizu K, Saruta T, Yoshida S. 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. 1997;  82 1054-1057
    Google Scholar
  • 13 Wong F, Blei AT, Blendis LM, Thuluvath PJ. A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial.  Hepatology. 2003;  37 182-191
    Google Scholar
  • 14 Soupart A, Gross P, Legros JJ, Alfoldi S, Annane D, Heshmati HM, Decaux G. Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.  Clin J Am Soc Nephrol. 2006;  1 1154-1160
    Google Scholar
  • 15 Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.  N Engl J Med. 2006;  355 2099-2112
    Google Scholar
  • 16 Konstam MA, Gheorghiade M, Burnett Jr JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.  JAMA. 2007;  297 1319-1331
    Google Scholar
  • 17 Verbalis JG. Syndrome of inappropriate antidiuretic hormone secretion and other hypoosmolar disorders. In: Schrier RW (ed). Diseases of the Kidney and Urinary Tract. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. Vol. III, Chap. 86
    Google Scholar
  • 18 Thibonnier M, Conarty DM, Preston JA, Wilkins PL, Berti-Mattera LN, Mattera R. Molecular pharmacology of human vasopressin receptors.  Adv Exp Med Biol. 1998;  449 251-276
    Google Scholar
  • 19 Thibonnier M. Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists.  Expert Opin Investig Drugs. 1998;  7 729-740
    Google Scholar
  • 20 Knepper MA. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin.  Am J Physiol. 1997;  272 F3-F12
    Google Scholar
  • 21 Schrier RW. The sea within us: disorders of body water homeostasis.  Curr Opin Investig Drugs. 2007;  8 304-311
    Google Scholar
  • 22 Morgan DB, Thomas TH. Water balance and hyponatraemia.  Clin Sci (Lond). 1979;  56 517-522
    Google Scholar
  • 23 Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis.  Am J Med. 2006;  119 S36-S42
    Google Scholar
  • 24 Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration.  J Am Soc Nephrol. 2006;  17 1820-1832
    Google Scholar
  • 25 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. 2001;  12 2860-2870
    Google Scholar
  • 26 Stormont JM, Waterhouse C. Severe hyponatremia associated with pneumonia.  Metabolism. 1962;  11 1181-1186
    Google Scholar
  • 27 Walser M, Seldin DW, Grollman A. An evaluation of radiosulfate for the determination of the volume of extracellular fluid in man and dogs.  J Clin Invest. 1953;  32 299-311
    Google Scholar
  • 28 Burrows BA, Ross JF. The use of radioactive sodium and potassium: tracer studies in man.  BMQ. 1956;  7 54-57
    Google Scholar
  • 29 Verbalis JG. Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis.  Am J Physiol. 1994;  267 R1617-R1625
    Google Scholar
  • 30 Kaye M. An investigation into the cause of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone.  Am J Med. 1966;  41 910-926
    Google Scholar
  • 31 Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations.  Am J Med. 2007;  120 S1-S21
    Google Scholar
  • 32 Verbalis JG. Whole-body volume regulation and escape from antidiuresis.  Am J Med. 2006;  119 S21-S29
    Google Scholar
  • 33 Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients.  Endocrinol Metab Clin North Am. 2003;  32 459-481 , vii
    Google Scholar
  • 34 Chonchol M. Hyponatremia. In: DuBose TD (ed). Acid-base and electrolyte disorders: a companion to Brenner & Rector's The Kidney. Philadelphia: Saunders; 2002
    Google Scholar
  • 35 Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin.  Kidney Int. 1976;  10 25-37
    Google Scholar
  • 36 Noakes TD, Wilson G, Gray DA, Lambert MI, Dennis SC. Peak rates of diuresis in healthy humans during oral fluid overload.  S Afr Med J. 2001;  91 852-857
    Google Scholar
  • 37 Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis.  Annu Rev Med. 1980;  31 315-327
    Google Scholar
  • 38 Michelis MF, Fusco RD, Bragdon RW, Davis BB. Reset of osmoreceptors in association with normovolemic hyponatremia.  Am J Med Sci. 1974;  267 267-273
    Google Scholar
  • 39 DeFronzo RA, Goldberg M, Agus ZS. Normal diluting capacity in hyponatremic patients. Reset osmostat or a variant of the syndrome of inappropriate antidiuretic hormone secretion.  Ann Intern Med. 1976;  84 538-542
    Google Scholar
  • 40 Robertson GL, Athar S. The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man.  J Clin Endocrinol Metab. 1976;  42 613-620
    Google Scholar
  • 41 Flear CT, Singh CM. Hyponatraemia and sick cells.  Br J Anaesth. 1973;  45 976-994
    Google Scholar
  • 42 Grantham JJ. Pathophysiology of hypoosmolar conditions: a cellular perspective. In: Andreoli TE, Grantham JJ, Rector FC Jr. (eds). Disturbances in body fluid osmolality. Bethesda, MD: American Physiological Society; 1977: 217-225
    Google Scholar
  • 43 Vincent JD, Arnauld E, Bioulac B. Activity of osmosensitive single cells in the hypothalamus of the behaving monkey during drinking.  Brain Res. 1972;  44 371-384
    Google Scholar
  • 44 Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE. Nephrogenic syndrome of inappropriate antidiuresis.  N Engl J Med. 2005;  352 1884-1890
    Google Scholar
  • 45 Robertson GL. The use of vasopressin assays in physiology and pathophysiology.  Semin Nephrol. 1994;  14 368-383
    Google Scholar
  • 46 Nielsen S, Marples D, Frokiaer J, Knepper M, Agre P. The aquaporin family of water channels in kidney: an update on physiology and pathophysiology of aquaporin-2.  Kidney Int. 1996;  49 1718-1723
    Google Scholar
  • 47 Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes.  Arch Intern Med. 2010;  170 294-302
    Google Scholar
  • 48 Gill G, Huda B, Boyd A, Skagen K, Wile D, Watson I, van Heyningen C. Characteristics and mortality of severe hyponatraemia--a hospital-based study.  Clin Endocrinol (Oxf). 2006;  65 246-249
    Google Scholar
  • 49 Fenske W, Störk S, Allolio B. Limitations of the traditional diagnostic approach to hyponatremia.  Am J Med. 2010;  in press
    Google Scholar
  • 50 Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome.  QJM. 2006;  99 505-511
    Google Scholar
  • 51 Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management.  Nephrol Dial Transplant. 2006;  21 70-76
    Google Scholar
  • 52 Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women.  N Engl J Med. 1986;  314 1529-1535
    Google Scholar
  • 53 Turchin A, Seifter JL, Seely EW. Clinical problem-solving.  Mind the gap. N Engl J Med. 2003;  349 1465-1469
    Google Scholar
  • 54 Musch W, Hedeshi A, Decaux G. Low sodium excretion in SIADH patients with low diuresis.  Nephron Physiol. 2004;  96 P11-P18
    Google Scholar
  • 55 Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia.  Am J Med. 1987;  83 905-908
    Google Scholar
  • 56 McGee S, Abernethy 3rd WB, Simel DL. The rational clinical examination. Is this patient hypovolemic?.  JAMA. 1999;  281 1022-1029
    Google Scholar
  • 57 Hoorn EJ, Zietse R. Hyponatremia revisited: translating physiology to practice.  Nephron Physiol. 2008;  108 46-59
    Google Scholar
  • 58 Musch W, Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline.  QJM. 1998;  91 749-753
    Google Scholar
  • 59 Fenske W, Stork S, Koschker AC, Blechschmidt A, Lorenz D, Wortmann S, Allolio B. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics.  J Clin Endocrinol Metab. 2008;  93 2991-2997
    Google Scholar
  • 60 Curtis RH. Hyponatremia in primary myxedema.  Ann Intern Med. 1956;  44 376-385
    Google Scholar
  • 61 Warner MH, Holding S, Kilpatrick ES. The effect of newly diagnosed hypothyroidism on serum sodium concentrations: a retrospective study.  Clin Endocrinol (Oxf). 2006;  64 598-599
    Google Scholar
  • 62 Croal BL, Blake AM, Johnston J, Glen AC, O’Reilly DS. Absence of relation between hyponatraemia and hypothyroidism.  Lancet. 1997;  350 1402
    Google Scholar
  • 63 Hoorn EJ, Halperin ML, Zietse R. Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options.  QJM. 2005;  98 529-540
    Google Scholar
  • 64 Arlt W, Allolio B. Adrenal insufficiency.  Lancet. 2003;  361 1881-1893
    Google Scholar
  • 65 Smith JC, Siddique H, Corrall RJ. Misinterpretation of serum cortisol in a patient with hyponatraemia.  BMJ. 2004;  328 215-216
    Google Scholar
  • 66 Pura M, Kreze Jr A, Kentos P, Vanuga P. The low-dose (1 mug) Cosyntropin Test (LDT) for Primary Adrenocortical Insufficiency: Defining the Normal Cortisol Response and Report on First Patients with Addison Disease Confirmed with LDT.  Exp Clin Endocrinol Diabetes. 2010;  118 151-157
    Google Scholar
  • 67 Adrogue HJ, Madias NE. Hyponatremia.  N Engl J Med. 2000;  342 1581-1589
    Google Scholar
  • 68 McKenna K, Thompson C. Osmoregulation in clinical disorders of thirst appreciation.  Clin Endocrinol (Oxf). 1998;  49 139-152
    Google Scholar
  • 69 Gross P, Reimann D, Neidel J, Doke C, Prospert F, Decaux G, Verbalis J, Schrier RW. The treatment of severe hyponatremia.  Kidney Int Suppl. 1998;  64 S6-S11
    Google Scholar
  • 70 Palmer BF, Gates JR, Lader M. Causes and management of hyponatremia.  Ann Pharmacother. 2003;  37 1694-1702
    Google Scholar
  • 71 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. 1973;  78 870-875
    Google Scholar
  • 72 Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective.  J Am Soc Nephrol. 1994;  4 1522-1530
    Google Scholar
  • 73 Gankam Kengne F, Soupart A, Pochet R, Brion JP, Decaux G. Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats.  Kidney Int. 2009;  76 614-621
    Google Scholar
  • 74 Cherrill DA, Stote RM, Birge JR, Singer I. Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion.  Ann Intern Med. 1975;  83 654-656
    Google Scholar
  • 75 Dousa TP, Wilson DM. Effects of demethylchlortetracycline on cellular action of antidiuretic hormone in vitro.  Kidney Int. 1974;  5 279-284
    Google Scholar
  • 76 Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients.  JAMA. 1980;  243 2513-2515
    Google Scholar
  • 77 Curtis NJ, van Heyningen C, Turner JJ. Irreversible nephrotoxicity from demeclocycline in the treatment of hyponatremia.  Age Ageing. 2002;  31 151-152
    Google Scholar
  • 78 White MG, Fetner CD. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with lithium carbonate.  N Engl J Med. 1975;  292 390-392
    Google Scholar
  • 79 Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study.  J Am Geriatr Soc. 2004;  52 794-798
    Google Scholar
  • 80 Decaux G, Mols P, Cauchi P, Delwiche F. Use of urea for treatment of water retention in hyponatraemic cirrhosis with ascites resistant to diuretics.  Br Med J (Clin Res Ed). 1985;  290 1782-1783
    Google Scholar
  • 81 Decaux G, Genette F. Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone.  Br Med J (Clin Res Ed). 1981;  283 1081-1083
    Google Scholar
  • 82 Decaux G, Prospert F, Penninckx R, Namias B, Soupart A. 5-year treatment of the chronic syndrome of inappropriate secretion of ADH with oral urea.  Nephron. 1993;  63 468-470
    Google Scholar
  • 83 Soupart A, Schroeder B, Decaux G. Treatment of hyponatraemia by urea decreases risks of brain complications in rats. Brain osmolyte contents analysis.  Nephrol Dial Transplant. 2007;  22 1856-1863
    Google Scholar
  • 84 Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, Czerwiec FS. Oral Tolvaptan Is Safe and Effective in Chronic Hyponatremia.  J Am Soc Nephrol. 2010;  21 705-710
    Google Scholar
  • 85 Decaux G. Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide.  Am J Med. 2001;  110 582-584
    Google Scholar
  • 86 Annane D, Decaux G, Smith N. Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia.  Am J Med Sci. 2009;  337 28-36
    Google Scholar
  • 87 Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia.  Am J Nephrol. 2007;  27 447-457
    Google Scholar
  • 88 Palm C, Pistrosch F, Herbrig K, Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.  Am J Med. 2006;  119 S87-S92
    Google Scholar
  • 89 Madias NE. Effects of tolvaptan, an oral vasopressin V2 receptor antagonist, in hyponatremia.  Am J Kidney Dis. 2007;  50 184-187
    Google Scholar
  • 90 Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans.  Lancet. 2008;  371 1624-1632
    Google Scholar
  • 91 Baylis PH. The syndrome of inappropriate antidiuretic hormone secretion.  Int J Biochem Cell Biol. 2003;  35 1495-1499
    Google Scholar
  • 92 Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N. 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. 2006;  91 2145-2152
    Google Scholar
  • 93 Mao ZL, Stalker D, Keirns J. Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study.  Clin Ther. 2009;  31 1542-1550
    Google Scholar
  • 94 Murphy T, Dhar R, Diringer M. Conivaptan bolus dosing for the correction of hyponatremia in the neurointensive care unit.  Neurocrit Care. 2009;  11 14-19
    Google Scholar
  • 95 Gheorghiade M, Gottlieb SS, Udelson JE, Konstam MA, Czerwiec F, Ouyang J, Orlandi C. Vasopressin v (2) receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia.  Am J Cardiol. 2006;  97 1064-1067
    Google Scholar
  • 96 Decaux G. 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 VPA-985.  J Lab Clin Med. 2001;  138 18-21
    Google Scholar
  • 97 Gerbes AL, Gulberg V, Gines P, Decaux G, Gross P, Gandjini H, Djian J. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial.  Gastroenterology. 2003;  124 933-939
    Google Scholar

Correspondence

B. AllolioMD 

Endocrinology and Diabetes Unit

Department of Medicine I

University of Würzburg

Oberduerrbacher Straße 6

97080 Würzburg

Germany

Phone: +49/931/201 39020

Fax: +49/931/201 36283

Email: allolio_b@medizin.uni-wuerzburg.de

      >