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DOI: 10.1055/s-0030-1255117
© Georg Thieme Verlag KG Stuttgart · New York
The Syndrome of Inappropriate Secretion of Antidiuretic Hormone: Diagnostic and Therapeutic Advances
Publication History
received 10.03.2010
accepted 02.06.2010
Publication Date:
06 July 2010 (online)
![](https://www.thieme-connect.de/media/hmr/201010/lookinside/thumbnails/10.1055-s-0030-1255117-1.jpg)
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
- 2 Sims EA, Welt LG, Orloff J, Needham JW. Asymptomatic hyponatremia in pulmonary tuberculosis. J Clin Invest. 1950; 29 1545-1557
- 3 Winkler AW, Crankshaw OF. Chloride Depletion in Conditions Other Than Addison's Disease. J Clin Invest. 1938; 17 1-6
- 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
- 5 Finberg L. Factors affecting prognosis of tuberculous meningitis treated with streptomycin. Pediatrics. 1951; 8 768-771
- 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
- 7 Ragnarsson U. The Nobel trail of Vincent du Vigneaud. J Pept Sci. 2007; 13 431-433
- 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
- 9 Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Semin Nephrol. 2009; 29 227-238
- 10 Gross P. Treatment of hyponatremia. Intern Med. 2008; 47 885-891
- 11 Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007; 356 2064-2072
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 19 Thibonnier M. Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists. Expert Opin Investig Drugs. 1998; 7 729-740
- 20 Knepper MA. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am J Physiol. 1997; 272 F3-F12
- 21 Schrier RW. The sea within us: disorders of body water homeostasis. Curr Opin Investig Drugs. 2007; 8 304-311
- 22 Morgan DB, Thomas TH. Water balance and hyponatraemia. Clin Sci (Lond). 1979; 56 517-522
- 23 Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med. 2006; 119 S36-S42
- 24 Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006; 17 1820-1832
- 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
- 26 Stormont JM, Waterhouse C. Severe hyponatremia associated with pneumonia. Metabolism. 1962; 11 1181-1186
- 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
- 28 Burrows BA, Ross JF. The use of radioactive sodium and potassium: tracer studies in man. BMQ. 1956; 7 54-57
- 29 Verbalis JG. Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis. Am J Physiol. 1994; 267 R1617-R1625
- 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
- 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
- 32 Verbalis JG. Whole-body volume regulation and escape from antidiuresis. Am J Med. 2006; 119 S21-S29
- 33 Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am. 2003; 32 459-481 , vii
- 34 Chonchol M. Hyponatremia. In: DuBose TD (ed). Acid-base and electrolyte disorders: a companion to Brenner & Rector's The Kidney. Philadelphia: Saunders; 2002
- 35 Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin. Kidney Int. 1976; 10 25-37
- 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
- 37 Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980; 31 315-327
- 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
- 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
- 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
- 41 Flear CT, Singh CM. Hyponatraemia and sick cells. Br J Anaesth. 1973; 45 976-994
- 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
- 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
- 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
- 45 Robertson GL. The use of vasopressin assays in physiology and pathophysiology. Semin Nephrol. 1994; 14 368-383
- 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
- 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
- 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
- 49 Fenske W, Störk S, Allolio B. Limitations of the traditional diagnostic approach to hyponatremia. Am J Med. 2010; in press
- 50 Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM. 2006; 99 505-511
- 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
- 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
- 53 Turchin A, Seifter JL, Seely EW. Clinical problem-solving. Mind the gap. N Engl J Med. 2003; 349 1465-1469
- 54 Musch W, Hedeshi A, Decaux G. Low sodium excretion in SIADH patients with low diuresis. Nephron Physiol. 2004; 96 P11-P18
- 55 Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987; 83 905-908
- 56 McGee S, Abernethy 3rd WB, Simel DL. The rational clinical examination. Is this patient hypovolemic?. JAMA. 1999; 281 1022-1029
- 57 Hoorn EJ, Zietse R. Hyponatremia revisited: translating physiology to practice. Nephron Physiol. 2008; 108 46-59
- 58 Musch W, Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline. QJM. 1998; 91 749-753
- 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
- 60 Curtis RH. Hyponatremia in primary myxedema. Ann Intern Med. 1956; 44 376-385
- 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
- 62 Croal BL, Blake AM, Johnston J, Glen AC, O’Reilly DS. Absence of relation between hyponatraemia and hypothyroidism. Lancet. 1997; 350 1402
- 63 Hoorn EJ, Halperin ML, Zietse R. Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options. QJM. 2005; 98 529-540
- 64 Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003; 361 1881-1893
- 65 Smith JC, Siddique H, Corrall RJ. Misinterpretation of serum cortisol in a patient with hyponatraemia. BMJ. 2004; 328 215-216
- 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
- 67 Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000; 342 1581-1589
- 68 McKenna K, Thompson C. Osmoregulation in clinical disorders of thirst appreciation. Clin Endocrinol (Oxf). 1998; 49 139-152
- 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
- 70 Palmer BF, Gates JR, Lader M. Causes and management of hyponatremia. Ann Pharmacother. 2003; 37 1694-1702
- 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
- 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
- 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
- 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
- 75 Dousa TP, Wilson DM. Effects of demethylchlortetracycline on cellular action of antidiuretic hormone in vitro. Kidney Int. 1974; 5 279-284
- 76 Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients. JAMA. 1980; 243 2513-2515
- 77 Curtis NJ, van Heyningen C, Turner JJ. Irreversible nephrotoxicity from demeclocycline in the treatment of hyponatremia. Age Ageing. 2002; 31 151-152
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 89 Madias NE. Effects of tolvaptan, an oral vasopressin V2 receptor antagonist, in hyponatremia. Am J Kidney Dis. 2007; 50 184-187
- 90 Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet. 2008; 371 1624-1632
- 91 Baylis PH. The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cell Biol. 2003; 35 1495-1499
- 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
- 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
- 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
- 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
- 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
- 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
Correspondence
B. AllolioMD
Endocrinology and Diabetes Unit
Department of Medicine I
University of Würzburg
Oberduerrbacher Straße 6
97080 Würzburg
Germany
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Fax: +49/931/201 36283
Email: allolio_b@medizin.uni-wuerzburg.de