Advertisement

Heparin-induced aldosterone suppression and hyperkalemia

  • James R. Oster
    Correspondence
    Requests for reprints should be addressed to James R. Oster, MD, Professor of Medicine, Associate Chief, Medical Service, VA Medical Center, 1201 NW 16th Street, Miami, Florida 33125.
    Affiliations
    From the Medical and Research Services, Department of Veterans Affairs Medical Center and the Department of Medicine, University of Miami School of Medicine, Miami, Florida, USA
    Search for articles by this author
  • Irwin Singer
    Affiliations
    From the Medical and Research Services, Department of Veterans Affairs Medical Center and the Department of Medicine, University of Miami School of Medicine, Miami, Florida, USA
    Search for articles by this author
  • Lawrence M. Fishman
    Affiliations
    From the Medical and Research Services, Department of Veterans Affairs Medical Center and the Department of Medicine, University of Miami School of Medicine, Miami, Florida, USA
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.

      purpose

      To review the effects of heparin and heparinoid compounds on aldosterone physiology and associated induction of hyperkalemia.

      materials and methods

      A comprehensive literature search (of human and animal data) was carried out by computer and by using reference citations from primary sources.

      results

      Heparin and its congeners are predictable, potent inhibitors of aldosterone production. This inhibitory effect is specific for the zona glomerulosa; other corticosteroids are not affected. Aldosterone suppression occurs within a few days of initiation of therapy, is reversible, and is independent of either anticoagulant effect or route of administration. Decreases in aldosterone levels may occur with heparin dosages as low as 5,000 U bid. The most important, but probably not the only mechanism of aldosterone inhibition appears to involve reduction in both the number and affinity of the angiotensin-II receptors in the zona glomerulosa. Prolonged use of heparin causes marked reduction in the width of the adrenal zona glomerulosa.

      conclusions

      Aldosterone suppression results in natriuresis and less predictably in decreased excretion of potassium. Greater than normal serum potassium levels occur in about 7% of patients, but marked hyperkalemia generally requires the presence of additional factors perturbing potassium balance (in particular, renal insufficiency, diabetes mellitus, or the use of certain medications). Heparin-induced increases in serum potassium need to be better anticipated by clinicians. Serum potassium levels should be monitored periodically in patients being given heparin for 3 or more days, and in patients at relatively high risk for hyperkalemia, the monitoring interval should probably be no greater than 4 days.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hirsh J
        Heparin.
        NEJM. 1991; 324: 1565-1574
        • Hirsh J
        • Dalen JF
        • Deykin D
        • Poller L
        Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety.
        Chest. 1992; 102 (suppl): 337S-351S
        • Winternitz WW
        Adrenal hemorrhage complicating anticoagulant therapy.
        South Med J. 1983; 76: 1369-1371
        • Kloppenborg PWC
        • Casparie AF
        • Benraad ThJ
        • Majoor CLH
        Inhibition of adrenal function in man by heparin or heparinoid Ro 1-8307.
        Acta Med Scand. 1975; 197: 99-108
        • O'Kelly R
        • Magee F
        • McKenna TJ
        Routine heparin therapy inhibits adrenal aldosterone production.
        J Clin Endocrinol Metab. 1983; 56: 108-112
        • Sherman RA
        • Ruddy MC
        Suppression of aldosterone procuction by low-dose heparin.
        Am J Nephrol. 1986; 6: 165-168
        • Siebels M
        • Andrassy K
        • Vecsei P
        • et al.
        Dose dependent suppression of mineralocorticoid metabolism by different heparin fractions.
        Thromb Res. 1992; 66: 467-473
        • Conn JW
        • Rovner DR
        • Cohen EL
        • Anderson Jr, JE
        Inhibition by heparinoid of aldosterone biosynthesis in man.
        J Clin Endocrinol Metab. 1966; 26: 527-532
        • Abbott EC
        • Monkhouse FC
        • Steiner JW
        • Laidlaw JC
        Effect of a sulfated mucopolysaccharide (R01-8307) on the zona glomerulosa of the rat adrenal gland.
        Endocrinology. 1966; 78: 651-664
        • Schlatmann RJAFM
        • Prenen H
        • Jansen AP
        • Majoor CLH
        The natriuretic action of heparin and some related substances.
        Lancet. 1960; i: 314-317
        • Cejka V
        • DeVries LA
        • Van Daatselaar JJ
        • et al.
        Effect of heparinoid and spironolactone on the renal excretion of sodium and aldosterone.
        Lancet. 1960; i: 317-319
        • Abbott EC
        • Gornall AG
        • Sutherland DJA
        • et al.
        The influence of a heparin-like compound on hypertension, electrolytes and aldosterone in man.
        Can Med Assoc J. 1966; 94: 1155-1164
        • Bailey RE
        • Ford HC
        The effect of heparin on sodium conservation and on the plasma concentration, the metabolic clearance and the secretion and excretion rates of aldosterone in normal subjects.
        Acta Endocrinol. 1969; 60: 249-264
        • Ford HC
        • Bailey RE
        The effect of heparin on aldosterone secretion and metabolism in primary aldosteronism (1).
        Steroids. 1966; 7: 30-40
        • Cejka V
        • DeVries LA
        • van Daatselaar JJ
        • Borst JGG
        Het effect van aldosteron en aldosteron-antagonisten bij patiënten met hypo-aldosteronisme door heparinoid.
        Ned Tijdschr Geneeskd. 1962; 106: 617-620
        • Levesque H
        • Verdier S
        • Cailleux N
        • et al.
        Low molecular weight heparins and hypoaldosteronism.
        BMJ. 1990; 300: 1437-1438
        • Majoor CLH
        • Schlatmann RJAFM
        • Jansen AP
        • Prenen H
        Excretion pattern and mechanism of diuresis induced by heparin.
        Clin Chim Acta. 1960; 5: 591-606
        • Majoor CLH
        Waarnemingen over de excretie en de secretie van aldosteron en andere bijnierschors-steroïden tijdens toediening van heparine en heparinoïden en bij patiënten met decompensatio cordis.
        Ned Tijdschr Geneeskd. 1969; 113: 767-779
        • Susie D
        • Mandal AK
        • Jovovic O
        • et al.
        Antihypertensive action of heparin: role of the renin-angiotensin aldosterone system and prostaglandins.
        J Clin Pharmacol. 1993; 33: 342-347
        • Kageyama Y
        • Suzuki H
        • Saruta T
        Effects of routine heparin therapy on plasma aldosterone concentration.
        Acta Endocrinol. 1991; 124: 267-270
        • Kutyrina IM
        • Nikishova TA
        • Tareyeva IE
        Effects of heparin-induced aldosterone deficiency on renal function in patients with chronic glomerulonephritis.
        Nephrol Dial Transplant. 1987; 2: 219-223
        • Guérin C
        • Collomb M
        • Claudy A
        • Berthoux F
        Hyperkaliémie induite par l'héparine. Un cas.
        Nephrologie. 1990; 11: 183-184
        • Gonzalez-Martin G
        • Diaz-Molinas MS
        • Martinez AM
        • Ortiz M
        Heparin-induced hyperkalemia: a prospective study.
        Int J Clin Pharmacol Ther Toxicol. 1991; 29: 446-450
        • Monreal M
        • Lafoz E
        • Salvador R
        • et al.
        Adverse effects of three different forms of heparin therapy: thrombocytopenia, increased transaminases, and hyperkalemia.
        Eur J Clin Pharmacol. 1989; 37: 415-418
        • Weidmann P
        • Reinhart R
        • Maxwell MH
        • et al.
        Syndrome of hyporeninemic hypoaldosteronism and hyperkalemia in renal disease.
        J Clin Endocrinol Metab. 1973; 39: 965-977
        • Wilson ID
        • Goetz FC
        Selective hypoaldosteronism after prolonged heparin administration: a case report with postmortem findings.
        Am J Med. 1964; 36: 635-640
        • Ponz E
        • Fernández-Solá J
        • Navarro M
        • Ingelmo M
        Alteración de la biologia hepática e hiperpotasemia por heparina.
        Medicina Clinica. 1986; 87: 823-824
        • Phleps KR
        • Oh MS
        • Carrol HJ
        Heparin-induced hyperkalemia: report of a case.
        Nephron. 1980; 25: 254-258
        • Edes TE
        • Sunderrajan EV
        Heparin-induced hyperkalemia.
        Arch Intern Med. 1985; 145: 1070-1072
        • Margolies G
        Heparin-induced hyperkalemia.
        J Tenn Med Assoc. 1991; 84: 126
        • Aull L
        • Chao H
        • Coy K
        Heparin-induced hyperkalemia.
        DICP Ann Pharmacother. 1990; 24: 244-246
        • Sherman RA
        Quiz of the month: Hyponatremia.
        Am J Nephrol. 1983; 3: 218
        • Sherman RA
        Quiz of the month: Hyponatremia.
        Am J Nephrol. 1983; 3: 241
        • Brohee D
        • Neve P
        Heparin side effects.
        Arch Intern Med. 1984; 144: 1963
        • Leehey D
        • Gantt C
        • Lim V
        Heparin-induced hypoaldosteronism: report of a case.
        JAMA. 1981; 246: 2189-2190
        • Durand D
        • Ader J-L
        • Rey J-P
        • et al.
        Inducing hyperkalemia by converting enzyme inhibitors and heparin.
        Kidney Int. 1988; 34: S196-S197
      1. Package insert (publication 45460A): Heparin sodium injection. USP. Lyphomed, division of Fujisawa of USA, Inc., May, 1991
      2. Package insert (publication J-1432j): Heparin sodium injection. USP. Elkins-Sinn, Inc., a subsidiary of A.H. Robins Company, Deerfield, IllFebruary 1990
        • Donzelot E
        • Kaufmann H
        L'héparine dans le traitement de la maladie rhumatismale et de certains processus exudatifs.
        Arch Mal Coeur Vaiss. 1950; 43: 229-240
        • Schlatmann RJAFM
        • Jansen AP
        • Prenen H
        • et al.
        The natriuretic and aldosterone-suppressive action of heparin and some related polysulfated polysaccharides.
        J Clin Endocrinol Metab. 1964; 24: 35-47
        • Majoor CLG
        • Prenen H
        • Van Munster PJJ
        • Schlatmann RJAFM
        Het diuretische effect van heparine, in net bijzonder bij patiënten met het nefrotische syndroom.
        Ned Tijdschr Geneeskd. 1957; 101: 1301-1307
        • Majoor CLH
        • Jansen AP
        • Schlatmann RJAFM
        • et al.
        Heparin and related sulphated polysaccharides as diuretic and aldosterone suppressing drugs in man and dog.
        Acta Cardiol. 1962; 17: 657-671
        • Garrahan P
        • Yeyati N
        • Villamil MF
        Diuretic and saluretic effects of heparin.
        Acta Physiol Lat Amer. 1964; 14: 188-195
        • Engelberg H
        • Gofman J
        • Jones H
        Serum lipids and lipoproteins in diabetic glomerulosclerosis: preliminary observations of the effect of heparin upon the disease.
        Diabetes. 1952; 1: 425-433
        • Raynaud R
        • D'Eshougues R
        • Pasquet P
        • Karoubi E
        Effets remarquables de l'heparine dans deux cas d'asystolie.
        Algérie Med. 1952; 56: 135-142
        • Hoppeler A
        • Tutard M
        • Blanchard Bailly F
        La place de l'héparine dans le traitement du syndrome néphrotique.
        Gaz Hop. 1959; 131: 675-681
        • Ehrlich EN
        Heparinoid-induced inhibition of aldosterone secretion in pregnant women: the role of augmented aldosterone secretion in sodium conservation during normal pregnancy.
        Am J Obstet Gyn. 1971; 109: 963-970
        • Gláz E
        • Sugár K
        Effect of heparin and heparinoids on the synthesis of aldosterone and corticosterone by the rat adrenal gland.
        Endocrinology. 1964; 74: 159-164
        • Uchida K
        • Azukizawa S
        • Imaizumi N
        • et al.
        Effect of angiotensin II on aldosterone and its precursor steroid production in adrenal zone glomerulosa cells from heparin-treated rats.
        Acta Endocrinol. 1986; 111: 222-227
        • Abbott EC
        • James VHT
        • Parker RA
        • et al.
        The effect of a sulphated mucopolysaccharide (R01-8307) on adrenal and kidney morphology and function in the rat.
        Hormones. 1972; 3: 129-143
        • Azukizawa S
        • Iwasaki I
        • Kigoshi T
        • et al.
        Effect of heparin treatments in vivo and in vitro on adrenal angiotensin II receptors and angiotensin II-induced aldosterone production in rats.
        Acta Endocrinol. 1988; 119: 367-372
        • Laidlaw JC
        • Abbott EC
        • Sutherland DJA
        • Stiefel M
        The influence of a heparinlike compound on hypertension, electrolytes and aldosterone in man.
        Trans Am Clin Climatol Assoc. 1965; 77: 111-124
        • Cailleux N
        • Moore N
        • Levesque H
        • et al.
        A low molecular weight heparin decreases plasma aldosterone in patients with primary hyperaldosteronism.
        Eur J Clin Pharmacol. 1992; 43: 185-187
        • Majoor CLH
        Aldosterone suppression by heparin.
        Lancet. 1968; ii (Letter): 1172-1173
        • Marcelli JM
        • Lalau JD
        • Abourachid H
        • et al.
        Unlike heparin, low-molecular weight heparin does not suppress aldosterone production.
        Horm Metab Res. 1989; 21: 402
        • Young DB
        Quantitative analysis of aldosterone's role in potassium regulation.
        Am J Physiol. 1988; 255: F811-F822
        • Levesque H
        • Cailleux N
        • Noblet C
        • et al.
        Hypoaldostéronisme induit par les héparines de bas poids moléculaire.
        Presse Med. 1991; 20: 35
        • Vevrat R
        • Manning EL
        • Fabre J
        • Muller AF
        Mesure de la sécrétion de l'aldostérone sous administration d'un adrénostatique semi-synthétique, l'héparinoïd Ro I-8307.
        Rev Franç Étud Clin Biol. 1963; 8: 667-673
        • Mikolajczyk H
        Urinary output of 17-KS and microscopic changes in the adrenal cortex of rats treated with heparin, histamine, or serotonin.
        Endokrynol Pol. 1965; 16: 347-358
        • Sealey JE
        • Gerten JH
        • Ledingham JGG
        • Laragh JH
        Inhibition of renin by heparin.
        J Clin Endocrinol. 1967; 27: 699-705
        • Jaques R
        • Küttner K
        • Bein HJ
        • Meier R
        Bindung eines synthetischen polypeptides (hypertensin) an heparin und freisetzung des peptides durch compound 48/80 in vitro.
        Experientia. 1960; 16: 147
        • Azukizawa S
        • Uchida K
        • Imaizumi N
        • et al.
        Direct effects of heparin on basal and stimulated aldosterone production in rat adrenal glomerulosa cells.
        J Steroid Biochem Mol Biol. 1986; 25: 455-457
        • Douglas J
        • Catt KJ
        Regulation of angiotensin II receptors in the rat adrenal cortex by dietary electrolytes.
        J Clin Invest. 1976; 58: 834-843
        • Lefkowitz RJ
        • Roth J
        • Pricer W
        • Pastan I
        ACTH receptors in the adrenal: specific binding of ACTH-125I and its relation to adenyl cyclase.
        in: Proc Natl Acad Sci USA. 65. 1970: 745-752
        • Levine JH
        • Laidlaw JC
        • Ruse JL
        Effects of a sulfated mucopolysaccharide (R01-8307) on zona glomerulosa width and steroid production by the rat adrenal cortex.
        Can J Physiol Pharmacol. 1972; 50:: 270-275
        • Gláz E
        • Kiss R
        • Morvai V
        • et al.
        Functional and morphological changes in the adrenal-renal system during heparin and potassium treatment in rats.
        Acta Endocrinol. 1969; 138 (suppl): 127
        • Sharma DC
        • Nerenberg CA
        • Dorfman RI
        Studies on aldosterone biosynthesis in vitro II.
        Biochemistry. 1967; 6: 3472-3479
      3. (Abstract)
        • Sharma DC
        • Nerenberg C
        • Gabrilove JL
        • Dorfman RI
        Effect of heparin on aldosterone biosynthesis.
        in: Fed Proc. 25. 1966: 769
        • Casparie AF
        • Benraad ThJ
        • Kloppenborg PWC
        • Majoor CLH
        Effect of heparin on the corticosterone secretion rate with a description of the double isotope method used.
        Acta Endocrinol. 1967; 119 (suppl) (Abstract): 140
        • O'Kelly R
        • McKenna TJ
        Examination of the mechanisms whereby heparin impairs aldosterone biosynthesis.
        Ir J Med Sci. 1982; 151: 378-383
        • Aguilera G
        • Catt KJ
        Loci of action of regulation of aldosterone biosynthesis in isolated glomerulosa cells.
        Endocrinology. 1979; 104: 1046-1052
        • Palkovits M
        • Stark E
        • Fachet J
        Correlation between morphology and function of the adrenals.
        Acta Physiol Acad Sci Hung. 1965; 26: 56-57
        • Samoilova ZT
        • Sukhova ZI
        Comparison of subcellular changes in the adrenocortical glomerular zone induced by heparin and its diuretic effect.
        Probl Endokrinol. (Mosk). 1981; 27 (English translation): 69-75
        • Lustyik GY
        • Szabo J
        • Gláz E
        • Kiss R
        Electron microscopic investigation on the zona glomerulosa of rats after treatment with heparin and potassium.
        Exp Mol Pathol. 1977; 13: 189-197
        • Vallent K
        • Fachet J
        • Palkovits M
        • Dévényi I
        Über die Wirkung der heparinbehandlung auf das histologische bild der nebennierenrinde und auf den index der juxtaglomerulären granulierten zellen im nierengewebe.
        Zeitschrift für Zellforschung. 1964; 63: 728-734
        • Chremos AN
        • Laidlaw JC
        • Ruse JL
        Effect of a sulfated mucopolysaccharide (R01-8307) on the zona glomerulosa of regenerating rat adrenal glands and of intact glands in sodium-deprived rats.
        Endocrinology. 1969; 85: 337-341
        • Vallent von K
        • Feher T
        • Fachet J
        Über die Wirkung der heparinbehandlung auf die ausscheidung der einzelnen 17-ketosteroidfraktionen.
        Endokrinologie. 1965; 48: 51-58
      4. Billups NF Billups SM American Drug Index. Facts and Comparisions. 38th ed. Facts and Comparisons, A Wolters Kluwer Co, St. Louis, MO1994: 162
        • Sequeira SJ
        • McKenna TJ
        Chlorbutol, a new inhibitor of aldosterone biosynthesis identified during examination of heparin effect on aldosterone production.
        J Clin Endocrinol Metab. 1986; 63: 780-784
      5. Billups NF Billups SM American Drug Index. 25th ed. JB Lippincott, Philadelphia1981: 135
        • Maddux FW
        Heparin induced hyperkalemia.
        NC Med J. 1987; 48: 75-76
        • Busch EH
        • Ventura HO
        • Lavie CJ
        Heparin-induced hyperkalemia.
        South Med J. 1987; 80: 1450-1451
        • Edes TE
        Heparin-induced hyperkalemia.
        Postgrad Med. 1990; 87: 104-105
        • Negret P
        • Coudreuse JF
        Association hyperkaliémie-diabète-héparinothérapie.
        Presse Med. 1983; 12: 1874-1875
        • De Salas M
        • Coll J
        • Navarro G
        • et al.
        Hiperpotasemia inducida por heparina.
        Medicina Clinica. 1987; 88: 785-786
        • Ponce SP
        • Jennings AE
        • Madias NE
        • Harrington JT
        Drug-induced hyperkalemia.
        Medicine (Baltimore). 1985; 64: 357-370