Advertisement

Abstract

Metabolic alkalosis is induced by increasing body alkali stores and is manifested by a primary increase in serum [HCO 3 ] and a secondary increase in PaCO2. The disorder only becomes clinically significant when the increase in serum [HCO 3 ] is sustained by impaired excretion of the excess HCO 3 by the kidney. Such impairment can occur with kidney failure, but occurs much more commonly as a result of functional changes in collecting duct ion transport, primarily sodium uptake via the epithelial sodium channel (ENaC), which stimulates continued abnormal bicarbonate reabsorption. The most common form of the disorder is caused by combined chloride and potassium depletion, which causes a secondary stimulation of ENaC that appears to be independent of aldosterone. More rarely the disorder is induced and sustained by primary stimulation of ENaC, either due to autonomous aldosterone secretion or due to genetic defects that stimulate ENaC independent of aldosterone. This chapter presents a new classification of the causes of metabolic alkalosis based on pathophysiology rather than response to treatment, and an approach to the diagnosis and treatment of this common disorder.

Keywords

Congenital Adrenal Hyperplasia Primary Aldosteronism Metabolic Alkalosis Aldosterone Secretion Bartter Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Huber L, Gennari FJ. Severe metabolic alkalosis in a hemodialysis patient. Am J Kidnes Dis. 2011;58(1):144–9.CrossRefGoogle Scholar
  2. 2.
    Gennari FJ, Pathophysiology of metabolic alkalosis: A new classification based on the centrality of stimulated collecting duct ion transport. Am J Kidney Dis. 2011;58(4):626–636.PubMedCrossRefGoogle Scholar
  3. 3.
    Kassirer JP, Schwartz WB. The response of normal man to selective depletion of hydrochloric acid. Factors in the genesis of persistent gastric alkalosis Am J Med. 1966;40(1):10–8.Google Scholar
  4. 4.
    Kassirer JP, Schwartz WB. Correction of metabolic alkalosis in man without repair of potassium deficiency. A re-evaluation of the role of potassium Am J Med. 1966;40(1):19–26.Google Scholar
  5. 5.
    Rosen RA, Julian BA, Dubovsky EV, Galla JH, Luke RG. On the mechanism by which chloride corrects metabolic alkalosis in man. Am J Med. 1988;84(3 Pt 1):449–58.PubMedCrossRefGoogle Scholar
  6. 6.
    Kassirer JP, Appleton FM, Chazan JA, Schwartz WB. Aldosterone in metabolic alkalosis. J Clin Invest. 1967;46(10):1558–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Hernandez RE, Schambelan M, Cogan MG, Colman J, Morris Jr RC, Sebastian A. Dietary NaCl determines severity of potassium depletion-induced ­metabolic alkalosis. Kidney Int. 1987;31(6): 1356–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Galla JH, Gifford JD, Luke RG, Rome L. Adaptations to chloride-depletion alkalosis. Am J Physiol. 1991;261(4 Pt 2):R771–81.PubMedGoogle Scholar
  9. 9.
    Berger BE, Cogan MG, Sebastian A. Reduced glomerular filtration and enhanced bicarbonate reabsorption maintain metabolic alkalosis in humans. Kidney Int. 1984;26(2):205–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Wesson DE. Augmented bicarbonate reabsorption by both the proximal and distal nephron maintains chloride-deplete metabolic alkalosis in rats. J Clin Invest. 1989;84(5):1460–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Maddox DA, Gennari FJ. Load dependence of proximal tubular bicarbonate reabsorption in chronic metabolic alkalosis in the rat. J Clin Invest. 1986;77(3):709–16.PubMedCrossRefGoogle Scholar
  12. 12.
    Gennari FJ. Hypokalemia in metabolic alkalosis. A new look at an old controversy. In: Hatano M, editor. Nephrology (proceedings, XIth International Society of Nephrology). Tokyo: Springer-Verlag; 1991. p. 262–9.Google Scholar
  13. 13.
    Amlal H, Wang Z, Soleimani M. Potassium depletion downregulates chloride-absorbing transporters in rat kidney. J Clin Invest. 1998;101(5):1045–54.PubMedCrossRefGoogle Scholar
  14. 14.
    Schwartz WB. Pathogenesis and replacement of diuretic-induced potassium and chloride loss. Ann N Y Acad Sci. 1966;139(2):506–11.PubMedCrossRefGoogle Scholar
  15. 15.
    Galla JH, Bonduris DN, Luke RG. Effects of chloride and extracellular fluid volume on bicarbonate reabsorption along the nephron in metabolic alkalosis in the rat. Reassessment of the classical hypothesis of the pathogenesis of metabolic alkalosis J Clin Invest. 1987;80(1):41–50.Google Scholar
  16. 16.
    Royaux IE, Wall SM, Karniski LP, et al. Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion. Proc Natl Acad Sci U S A. 2001;98(7):4221–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Wall SM, Kim YH, Stanley L, et al. NaCl restriction upregulates renal Slc26a4 through subcellular redistribution: role in Cl- conservation. Hypertension. 2004;44(6):982–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Verlander JW, Kim YH, Shin W, et al. Dietary Cl(-) restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells. Am J Physiol Renal Physiol. 2006;291(4):F833–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Gifford JD, Sharkins K, Work J, Luke RG, Galla JH. Total CO2 transport in rat cortical collecting duct in chloride-depletion alkalosis. Am J Physiol. 1990;258(4 Pt 2):F848–53.PubMedGoogle Scholar
  20. 20.
    Verlander JW, Madsen KM, Galla JH, Luke RG, Tisher CC. Response of intercalated cells to chloride depletion metabolic alkalosis. Am J Physiol. 1992;262(2 Pt 2):F309–19.PubMedGoogle Scholar
  21. 21.
    Levine DZ, Vandorpe D, Iacovitti M. Luminal chloride modulates rat distal tubule bidirectional bicarbonate flux in vivo. J Clin Invest. 1990;85(6):1793–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim YH, Verlander JW, Matthews SW, et al. Intercalated cell H+/OH- transporter expression is reduced in Slc26a4 null mice. Am J Physiol Renal Physiol. 2005;289(6):F1262–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Pech V, Pham TD, Hong S, et al. Pendrin modulates ENaC function by changing luminal HCO3. J Am Soc Nephrol. 2010;21(11):1928–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Wesson DE, Dolson GM. Augmented bidirectional HCO3 transport by rat distal tubules in chronic alkalosis. Am J Physiol. 1991;261(2 Pt 2):F308–17.PubMedGoogle Scholar
  25. 25.
    Verlander JW, Hassell KA, Royaux IE, et al. Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney: role of pendrin in mineralocorticoid-induced hypertension. Hypertension. 2003;42(3):356–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Wagner CA, Finberg KE, Stehberger PA, et al. Regulation of the expression of the Cl-/anion exchanger pendrin in mouse kidney by acid-base status. Kidney Int. 2002;62(6):2109–17.PubMedCrossRefGoogle Scholar
  27. 27.
    Satlin LM, Carattino MD, Liu W, Kleyman TR. Regulation of cation transport in the distal nephron by mechanical forces. Am J Physiol Renal Physiol. 2006;291(5):F923–31.PubMedCrossRefGoogle Scholar
  28. 28.
    Bhalla V, Hallows KR. Mechanisms of ENaC regulation and clinical implications. J Am Soc Nephrol. 2008;19(10):1845–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Woda CB, Bragin A, Kleyman TR, Satlin LM. Flow-dependent K  +  secretion in the cortical collecting duct is mediated by a maxi-K channel. Am J Physiol Renal Physiol. 2001;280(5):F786–93.PubMedGoogle Scholar
  30. 30.
    Ahn KY, Park KY, Kim KK, Kone BC. Chronic hypokalemia enhances expression of the H(+)-K(+)-ATPase alpha 2-subunit gene in renal medulla. Am J Physiol. 1996;271(2 Pt 2):F314–21.PubMedGoogle Scholar
  31. 31.
    Luke RG. Effect of adrenalectomy on the renal response to chloride depletion in the rat. J Clin Invest. 1974;54(6):1329–36.PubMedCrossRefGoogle Scholar
  32. 32.
    Madias NE, Adrogue HJ, Cohen JJ. Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol. 1980;238(4):F283–9.PubMedGoogle Scholar
  33. 33.
    Kassirer JP, London AM, Goldman DM, Schwartz WB. On the pathogenesis of metabolic alkalosis in hyperaldosteronism. Am J Med. 1970;49(3):306–15.PubMedCrossRefGoogle Scholar
  34. 34.
    Javaheri S, Kazemi H. Metabolic alkalosis and hypoventilation in humans. Am Rev Respir Dis. 1987;136(4):1011–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Javaheri S, Nardell EA. Severe metabolic alkalosis: a case report. Br Med J (Clin Res Ed). 1981;283(6298):1016–7.CrossRefGoogle Scholar
  36. 36.
    Eiro M, Katoh T, Watanabe T. Use of a proton-pump inhibitor for metabolic disturbances associated with anorexia nervosa. N Engl J Med. 2002;346(2):140.PubMedCrossRefGoogle Scholar
  37. 37.
    Kirsch BM, Sunder-Plassmann G, Schwarz C. Metabolic alkalosis in a hemodialysis patient—­successful treatment with a proton pump inhibitor. Clin Nephrol. 2006;66(5):391–4.PubMedGoogle Scholar
  38. 38.
    Hoglund P, Haila S, Socha J, et al. Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet. 1996;14(3):316–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Aichbichler BW, Zerr CH. Santa Ana CA, Porter JL. Fordtran JS Proton-pump inhibition of gastric chloride secretion in congenital chloridorrhea N Engl J Med. 1997;336(2):106–9.Google Scholar
  40. 40.
    Babior BM. Villous adenoma of the colon. Study of a patient with severe fluid and electrolyte disturbances Am J Med. 1966;41(4):615–21.Google Scholar
  41. 41.
    Weise WJ, Serrano FA, Fought J, Gennari FJ. Acute electrolyte and acid-base disorders in patients with ileostomies: a case series. Am J Kidney Dis. 2008;52(3):494–500.PubMedCrossRefGoogle Scholar
  42. 42.
    DeFoor W, Minevich E, Reeves D, Tackett L, Wacksman J, Sheldon C. Gastrocystoplasty: long-term followup. J Urol. 2003;170(4 Pt 2):1647–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Bates CM, Baum M, Quigley R. Cystic fibrosis presenting with hypokalemia and metabolic alkalosis in a previously healthy adolescent. J Am Soc Nephrol. 1997;8(2):352–5.PubMedGoogle Scholar
  44. 44.
    Shaer AJ. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci. 2001;322(6):316–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Simon DB, Lifton RP. The molecular basis of inherited hypokalemic alkalosis: Bartter’s and Gitelman’s syndromes. Am J Physiol. 1996;271(5 Pt 2):F961–6.PubMedGoogle Scholar
  46. 46.
    Zelikovic I, Szargel R, Hawash A, et al. A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int. 2003;63(1):24–32.PubMedCrossRefGoogle Scholar
  47. 47.
    Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB. Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int. 2001;59(2):710–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Schwartz WB, Relman AS. Metabolic and renal studies in chronic potassium depletion resulting from overuse of laxatives. J Clin Invest. 1953;32(3):258–71.PubMedCrossRefGoogle Scholar
  49. 49.
    Garella S, Chazan JA, Cohen JJ. Saline-resistant metabolic alkalosis or “chloride-wasting nephropathy”. Report of four patients with severe potassium depletion Ann Intern Med. 1970;73(1):31–8.Google Scholar
  50. 50.
    Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355(6357):262–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci. 2002;970:134–44.PubMedCrossRefGoogle Scholar
  52. 52.
    Islam M, Paul RV. Correction of metabolic alkalosis by potassium chloride in ectopic adrenocorticotropic hormone syndrome. Am J Kidney Dis. 1996;28(4):610–3.PubMedCrossRefGoogle Scholar
  53. 53.
    Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am. 2001;30(1):101–19.PubMedCrossRefGoogle Scholar
  54. 54.
    Mantero F, Armanini D, Opocher G, et al. Mineralocorticoid hypertension due to a nasal spray containing 9 alpha-fluoroprednisolone. Am J Med. 1981;71(3):352–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Warnock DG. Liddle syndrome: genetics and mechanisms of Na  +  channel defects. Am J Med Sci. 2001;322(6):302–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Stewart PM, Wallace AM, Valentino R, Burt D, Shackleton CH, Edwards CR. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet. 1987;2(8563):821–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Morineau G, Sulmont V, Salomon R, et al. Apparent mineralocorticoid excess: report of six new cases and extensive personal experience. J Am Soc Nephrol. 2006;17(11):3176–84.PubMedCrossRefGoogle Scholar
  58. 58.
    Cogan MG, Carneiro AV, Tatsuno J, et al. Normal diet NaCl variation can affect the renal set-point for plasma pH-(HCO3-) maintenance. J Am Soc Nephrol. 1990;1(2):193–9.PubMedGoogle Scholar
  59. 59.
    Madias NE, Levey AS. Metabolic alkalosis due to absorption of “nonabsorbable” antacids. Am J Med. 1983;74(1):155–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Beall DP, Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an ­estimate of prevalence among patients hospitalized with hypercalcemia. Medicine (Baltimore). 1995;74(2):89–96.CrossRefGoogle Scholar
  61. 61.
    Hulter HN, Peterson JC. Acid-base homeostasis during chronic PTH excess in humans. Kidney Int. 1985;28(2):187–92.PubMedCrossRefGoogle Scholar
  62. 62.
    McAuliffe JJ, Lind LJ, Leith DE, Fencl V. Hypoproteinemic alkalosis. Am J Med. 1986;81(1):86–90.PubMedCrossRefGoogle Scholar
  63. 63.
    Madias NE, Ayus JC, Adrogue HJ. Increased anion gap in metabolic alkalosis: the role of plasma-protein equivalency. N Engl J Med. 1979;300(25):1421–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineUniversity of VermontBurlingtonUSA

Personalised recommendations