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  • Review Article
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Metabolic acidosis: pathophysiology, diagnosis and management

Abstract

Metabolic acidosis is characterized by a primary reduction in serum bicarbonate (HCO3) concentration, a secondary decrease in the arterial partial pressure of carbon dioxide (PaCO2) of 1 mmHg for every 1 mmol/l fall in serum HCO3 concentration, and a reduction in blood pH. Acute forms (lasting minutes to several days) and chronic forms (lasting weeks to years) of the disorder can occur, for which the underlying cause/s and resulting adverse effects may differ. Acute forms of metabolic acidosis most frequently result from the overproduction of organic acids such as ketoacids or lactic acid; by contrast, chronic metabolic acidosis often reflects bicarbonate wasting and/or impaired renal acidification. The calculation of the serum anion gap, calculated as [Na+] – ([HCO3] + [Cl]), aids diagnosis by classifying the disorders into categories of normal (hyperchloremic) anion gap or elevated anion gap. These categories can overlap, however. Adverse effects of acute metabolic acidosis primarily include decreased cardiac output, arterial dilatation with hypotension, altered oxygen delivery, decreased ATP production, predisposition to arrhythmias, and impairment of the immune response. The main adverse effects of chronic metabolic acidosis are increased muscle degradation and abnormal bone metabolism. Using base to treat acute metabolic acidosis is controversial because of a lack of definitive benefit and because of potential complications. By contrast, the administration of base for the treatment of chronic metabolic acidosis is associated with improved cellular function and few complications.

Key Points

  • Categorizing metabolic acidosis into acute and chronic varieties can be valuable for anticipating adverse effects and for determining the risks and benefits of therapy

  • A systematic approach to diagnosis of metabolic acidosis is valuable; use of the serum anion gap is an important initial tool although its limitations should be understood

  • The adverse effects of acute metabolic acidosis primarily involve the cardiovascular system, whereas the adverse effects of chronic metabolic acidosis primarily involve the musculoskeletal system

  • The treatment of acute metabolic acidosis with the administration of base has not proven beneficial in improving cardiovascular function; alternative therapies are needed

  • The treatment of chronic metabolic acidosis with the administration of base is beneficial but the goal of therapy remains unclear

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References

  1. Gunnerson, K. J., Saul, M., He, S. & Kellum, J. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients. Crit. Care Med. 10, R22–R32 (2006).

    Google Scholar 

  2. Eustace, J. A., Astor, B., Muntner, P. M., Ikizler, T. A. & Coresh, J. Prevalence of acidosis and inflammation and their association with low serum albumin in chronic kidney disease. Kidney Int. 65, 1031–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Kraut, J. A. & Kurtz, I. Metabolic acidosis of CKD: diagnosis, clinical characteristics, and treatment. Am. J. Kidney Dis. 45, 978–993 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Kalantar-Zadeh, K., Mehrotra, R., Fouque, D. & Kopple, J. D. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin. Dial. 17, 455–465 (2004).

    Article  PubMed  Google Scholar 

  5. Kraut, J. A. & Kurtz, I. Controversies in the treatment of acute metabolic acidosis. NephSAP 5, 1–9 (2006).

    Google Scholar 

  6. Cohen, R. M., Feldman, G. M. & Fernandez, P. C. The balance of acid base and charge in health and disease. Kidney Int. 52, 287–293 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Rodriguez-Soriano, J. & Vallo, A. Renal tubular acidosis. Pediatr. Nephrol. 4, 268–275 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Wagner, C. A., Devuyst, O., Bourgeois, S. & Mohebbi, N. Regulated acid-base transport in the collecting duct. Pflugers Arch. 458, 137–156 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Boron, W. F. Acid base transport by the renal proximal tubule. J. Am. Soc. Nephrol. 17, 2368–2382 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Igarashi, T., Sekine, T. & Watanabe, H. Molecular basis of proximal renal tubular acidosis. J. Nephrol. 15, S135–S141 (2002).

    CAS  PubMed  Google Scholar 

  11. Sly, W. S., Sato, S. & Zhu, X. L. Evaluation of carbonic anhydrase isozymes in disorders involving osteopetrosis and/or renal tubular acidosis. Clin. Biochem. 24, 311–318 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Dinour, D. et al. A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. J. Biol. Chem. 279, 52238–52246 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Wagner, C. A. et al. Renal vacuolar H+-ATPase. Physiol. Rev. 84, 1263–1314 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Gumz, M. L., Lynch, I. J., Greenlee, M. M., Cain, B. D. & Wingo, C. S. The renal H+-K+-ATPases: physiology, regulation, and structure. Am. J. Physiol. 298, F12–F21 (2010).

    CAS  Google Scholar 

  15. Karim, Z., Szutkowska, M., Vernimmen, C. & Bichara, M. Recent concepts concerning the renal handling of NH3/NH4+. J. Nephrol. 19, S27–S32 (2006).

    CAS  PubMed  Google Scholar 

  16. Nagami, G. T. Ammonia production and secretion by S3 proximal tubule segments from acidotic mice: role of ANG II. Am. J. Physiol. 287, F707–F712 (2004).

    Article  CAS  Google Scholar 

  17. Weiner, I. D. & Hamm, L. L. Molecular mechanisms of renal ammonia transport. Annu. Rev. Physiol. 69, 317–340 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Biver, S. et al. A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility. Nature 456, 339–343 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Karet, F. E. Physiological and metabolic implications of V-ATPase isoforms in the kidney. J. Bioenerg. Biomembr. 37, 425–429 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Wagner, C. A. et al. Regulation of the expression of the Cl-/anion exchanger pendrin in mouse kidney by acid-base status. Kidney Int. 62, 2109–2117 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Petrovic, S., Wang, Z. H., Ma, L. Y. & Soleimani, M. Regulation of the apical Cl/HCO3 exchanger pendrin in rat cortical collecting duct in metabolic acidosis. Am. J. Physiol. 284, F103–F112 (2003).

    Article  CAS  Google Scholar 

  22. Karet, F. E. Mechanisms in hyperkalemic renal tubular acidosis. J. Am. Soc. Nephrol. 20, 251–254 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Kamel, K. S. et al. A new classification for renal defects in net acid excretion. Am. J. Kidney Dis. 29, 136–146 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Kraut, J. A. & Madias, N. E. Approach to patients with acid-base disorders. Respir. Care 46, 392–403 (2001).

    CAS  PubMed  Google Scholar 

  25. Pierce, N. F. et al. The ventilatory response to acute base deficit in humans: time course during development and correction of metabolic acidosis. Ann. Intern. Med. 72, 633–640 (1970).

    Article  CAS  PubMed  Google Scholar 

  26. Wiederseiner, J. M., Muser, J., Lutz, T., Hulter, H. N. & Krapf, R. Acute metabolic acidosis: characterization and diagnosis of the disorder and the plasma potassium response. J. Am. Soc. Nephrol. 15, 1589–1596 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Madias, N. E., Schwartz, W. B. & Cohen, J. J. Maladaptive renal response to secondary hypocapnia during chronic HCl acidosis in dog. J. Clin. Invest. 60, 1393–1401 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Albert, M. S., Dell, R. B. & Winters, R. W. Quantitative displacement of acid-base equilibrium in metabolic acidosis. Ann. Intern. Med. 66, 312–322 (1967).

    Article  CAS  PubMed  Google Scholar 

  29. Asch, M. J., Dell, R. B., Williams, G. S., Cohen, M. & Winters, R. W. Time course for development of respiratory compensation in metabolic acidosis. J. Lab. Clin. Med. 73, 610–615 (1969).

    CAS  PubMed  Google Scholar 

  30. Bushinsky, D. A., Coe, F. L., Katzenberg, C., Szidon, J. P. & Parks, J. H. Arterial PCO2 in chronic metabolic acidosis. Kidney Int. 22, 311–314 (1982).

    Article  CAS  PubMed  Google Scholar 

  31. Rastegar, A. Use of the ΔAG/ΔHCO3 ratio in the diagnosis of mixed acid-base disorders. J. Am. Soc. Nephrol. 18, 2429–2431 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Kraut, J. A. & Madias, N. E. Serum anion gap: its uses and limitations in clinical medicine. Clin. J. Am. Soc. Nephrol. 2, 162–174 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Emmett, M. Anion-gap interpretation: the old and the new. Nat. Clin. Pract. Nephrol. 2, 4–5 (2006).

    Article  PubMed  Google Scholar 

  34. Frohlich, J., Adam, W., Golbey, M. J. & Bernstein, M. Decreased anion gap associated with monoclonal and pseudomonoclonal gammopathy. Can. Med. Assoc. J. 114, 231–232 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Winter, S. D., Pearson, J. R., Gabow, P. A., Schultz, A. L. & Lepoff, R. B. The fall of the serum anion gap. Arch. Intern. Med. 150, 311–313 (1990).

    Article  CAS  PubMed  Google Scholar 

  36. Feldman, M., Soni, N. & Dickson, B. Influence of hypoalbuminemia or hyperalbuminemia on the serum anion gap. J. Lab. Clin. Med. 146, 317–320 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Oster, J. R., Singer, I., Contreras, G. N., Ahmad, H. I. & Vieira, C. F. Metabolic acidosis with extreme elevation of anion gap: case report and literature review. Am. J. Med. Sci. 317, 38–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Adrogue, H. J., Brensilver, J. & Madias, N. E. Changes in plasma anion gap during chronic metabolic acid-base disturbances. Am. J. Physiol. 235, F291–F297 (1978).

    CAS  PubMed  Google Scholar 

  39. Madias, N. E., Homer, S. M., Johns, C. A. & Cohen, J. J. Hypochloremia as a consequence of anion gap metabolic acidosis. J. Lab. Clin. Med. 104, 15–23 (1984).

    CAS  PubMed  Google Scholar 

  40. Kim, H. Y. et al. Clinical significance of the fractional excretion of anions in metabolic acidosis. Clin. Nephrol. 55, 448–452 (2001).

    CAS  PubMed  Google Scholar 

  41. Gabow, P. A. et al. Diagnostic importance of increased serum anion gap. N. Engl. J. Med. 303, 854–858 (1980).

    Article  CAS  PubMed  Google Scholar 

  42. Uribarri, J., Oh, M. S. & Carroll, H. J. D-Lactic acidosis: a review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine (Baltimore) 77, 73–82 (1998).

    Article  CAS  Google Scholar 

  43. Schelling, J. R., Howard, R. L., Winter, S. D. & Linas, S. L. Increased osmolal gap in alcoholic ketoacidosis and lactic acidosis. Ann. Intern. Med. 113, 580–582 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Kraut, J. A. & Kurtz, I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin. J. Am. Soc. Nephrol. 3, 208–225 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Jacobsen, D. & McMartin, K. E. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med. Toxicol. 1, 309–334 (1986).

    Article  CAS  PubMed  Google Scholar 

  46. Winter, M. L., Ellis, M. D. & Snodgrass, W. R. Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestions. Ann. Emerg. Med. 19, 663–667 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Tailor, P. et al. Recurrent high anion gap metabolic acidosis secondary to 5-oxoproline (pyroglutamic acid). Am. J. Kidney Dis. 46, E4–E10 (2005).

    Article  PubMed  Google Scholar 

  48. Batlle, D., Hizon, M., Cohen, E., Gutterman, C. & Gupta, R. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N. Engl. J. Med. 318, 594–599 (1988).

    Article  CAS  PubMed  Google Scholar 

  49. Richardson, R. M. A. & Halperin, M. L. The urine pH: a potentially misleading diagnostic test in patients with hyperchloremic metabolic acidosis. Am. J. Kidney Dis. 10, 140–143 (1987).

    Article  CAS  PubMed  Google Scholar 

  50. Sebastian, A., Schambelan, M., Lindenfeld, S. & Morris, R. C. Amelioration of metabolic acidosis with fludrocortisone therapy in hyporeninemic hypoaldosteronism. N. Engl. J. Med. 297, 576–583 (1977).

    Article  CAS  PubMed  Google Scholar 

  51. Goldstein, M. B., Bear, R., Richardson, R. M. A., Marsden, P. A. & Halperin, M. L. The urine anion gap a clinically useful index of ammonium excretion. Am. J. Med. Sci. 292, 198–202 (1986).

    Article  CAS  PubMed  Google Scholar 

  52. Kamel, K. S., Ethier, J. H., Richardson, R. M., Bear, R. A. & Halperin, M. L. Urine electrolytes and osmolality: when and how to use them. Am. J. Nephrol. 10, 89–102 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Kamel, K. S. & Halperin, M. L. An improved approach to the patient with metabolic acidosis: a need for four amendments. J. Nephrol. 19, S76–S85 (2006).

    CAS  PubMed  Google Scholar 

  54. Dubose, T. D. Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int. 51, 591–602 (1997).

    Article  PubMed  Google Scholar 

  55. Anderson, R. J., Potts, D. E., Gabow, P. A., Rumack, B. H. & Schrier, R. W. Unrecognized adult salicylate intoxication. Ann. Intern. Med. 85, 745–748 (1976).

    Article  CAS  PubMed  Google Scholar 

  56. Arbour, R. & Esparis, B. Osmolar gap metabolic acidosis in a 60-year-old man treated for hypoxemic respiratory failure: propylene glycol toxicity caused by escalating lorazepam infusion. Chest 118, 545–546 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Fenves, A. Z., Kirkpatrick, H. M., Patel, V. V., Sweetman, L. & Emmett, M. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin. J. Am. Soc. Nephrol. 1, 441–447 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Chan, J. C. M., Asch, M. J., Lin, S. & Hays, D. M. Hyperalimentation with amino acid and casein hydrolysate solutions: mechanism of acidosis. JAMA 220, 1700–1705 (1972).

    Article  CAS  PubMed  Google Scholar 

  59. Chang, S. S. et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat. Genet. 12, 248–253 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Xie, J., Craig, L., Cobb, M. H. & Huang, C. L. Role of with-no-lysine [K] kinases in the pathogenesis of Gordon's syndrome. Pediatr. Nephrol. 21, 1231–1236 (2006).

    Article  PubMed  Google Scholar 

  61. Field, M. Intestinal ion transport and the pathophysiology of diarrhea. J. Clin. Invest. 111, 931–943 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cieza, J., Sovero, Y., Estremadoyro, L. & Dumler, F. Electrolyte disturbances in elderly patients with severe diarrhea due to cholera. J. Am. Soc. Nephrol. 6, 1463–1467 (1995).

    CAS  PubMed  Google Scholar 

  63. Igarashi, T., Sekine, T., Inatomi, J. & Seki, G. Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. J. Am. Soc. Nephrol. 13, 2171–2177 (2002).

    Article  PubMed  Google Scholar 

  64. Laing, C. M., Toye, A. M., Capasso, G. & Unwin, R. J. Renal tubular acidosis: developments in our understanding of the molecular basis. Int. J. Biochem. Cell. Biol. 37, 1151–1161 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Pessler, F. et al. The spectrum of renal tubular acidosis in paediatric Sjogren syndrome. Rheumatology 45, 85–91 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Simpson, A. M. & Schwartz, G. J. Distal renal tubular acidosis with severe hypokalaemia probably caused by colonic H+-K+-ATPase deficiency. Arch. Dis. Child. 84, 504–507 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hall, M. C., Koch, M. O. & McDougal, W. S. Metabolic consequences of urinary diversion through intestinal segments. Urol. Clin. North Am. 18, 725–735 (1991).

    CAS  PubMed  Google Scholar 

  68. Streicher, H. Z., Gabow, P. A., Moss, A. H., Kono, D. & Kaehny, W. D. Syndromes of toluene sniffing in adults. Ann. Intern. Med. 94, 758–762 (1981).

    Article  CAS  PubMed  Google Scholar 

  69. Adrogue, H. J., Wilson, H., Boyd, A. E., Suki, W. N. & Eknoyan, G. Plasma acid-base patterns in diabetic ketoacidosis. N. Engl. J. Med. 307, 1603–1610 (1982).

    Article  CAS  PubMed  Google Scholar 

  70. Mitchell, J. H., Wildenthal, K. & Johnson, R. L. Jr. The effects of acid-base disturbances on cardiovascular and pulmonary function. Kidney Int. 1, 375–389 (1972).

    Article  CAS  PubMed  Google Scholar 

  71. Teplinsky, K., Otoole, M., Olman, M., Walley, K. R. & Wood, L. D. Effect of lactic acidosis on canine hemodynamics and left ventricular function. Am. J. Physiol. 258, H1193–H1199 (1990).

    CAS  PubMed  Google Scholar 

  72. Wildenthal, K., Mierzwiak, D. S., Myers, R. W. & Mitchell, J. H. Effects of acute lactic acidosis on left ventricular performance. Am. J. Physiol. 214, 1352–1359 (1968).

    Article  CAS  PubMed  Google Scholar 

  73. Kellum, J. A., Song, M. C. & Venkataraman, R. Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest 125, 243–248 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Davies, A. O. Rapid desensitization and uncoupling of human beta adrenergic receptors in an in vitro model of lactic acidosis. J. Clin. Endocrinol. Metab. 59, 398–404 (1984).

    Article  CAS  PubMed  Google Scholar 

  75. Orchard, C. H. & Cingolani, H. E. Acidosis and arrhythmias in cardiac muscle. Cardiovasc. Res. 28, 1312–1319 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Cooper, D. J., Walley, K. R., Wiggs, B. R. & Russell, J. A. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. Ann. Intern. Med. 112, 492–498 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Mathieu, D., Neviere, R., Billard, V., Fleyfel, M. & Wattel, F. Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit. Care Med. 19, 1352–1356 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. Khazel, A., McLaughlin, J. S., Suddhimonadala, C., Atar, S. & Cowley, R. A. The effects of acidosis and alkalosis on cardiac output and peripheral resistance in humans. Am. Surg. 35, 600–605 (1969).

    CAS  PubMed  Google Scholar 

  79. Seifter, J. Acid base disturbances and the central nervous system. Nephrol. Rounds 3, 1–6 (2005).

    Google Scholar 

  80. Bellingham, A. J., Detter, J. C. & Lenfant, C. Regulatory mechanisms of hemoglobin oxygen affinity in acidosis and alkalosis. J. Clin. Invest. 50, 700–706 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kellum, J. A., Song, M. C. & Li, J. Y. Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Crit. Care 8, 331–336 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Lardner, A. The effects of extracellular pH on immune function. J. Leukoc. Biol. 69, 522–530 (2001).

    CAS  PubMed  Google Scholar 

  83. Cuthbert, C. & Alberti, K. G. Acidemia and insulin resistance in the diabetic ketoacidotic rat. Metabolism 27, 1903–1916 (1978).

    Article  CAS  PubMed  Google Scholar 

  84. Halperin, F. A., Cheema-Dhadli, S., Chen, C. B. & Halperin, M. I. Alkali therapy extends the period of survival during hypoxia: studies in rats. Am. J. Physiol. 271, R381–R387 (1996).

    CAS  PubMed  Google Scholar 

  85. Kubasiak, L. A., Hernandez, O. M., Bishopric, N. H. & Webster, K. A. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc. Natl Acad. Sci. USA 99, 12825–12830 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kovesdy, C. P., Anderson, J. E. & Kalantar-Zadeh, K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD. Nephrol. Dial. Transplant. 24, 1232–1237 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Kraut, J. A. Disturbances of acid-base balance and bone disease in end-stage renal disease. Semin. Dial. 13, 261–265 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Lemann, J., Bushinsky, D. A. & Hamm, L. L. Bone buffering of acid and base in humans. Am. J. Physiol. 285, F811–F832 (2003).

    CAS  Google Scholar 

  89. Mitch, W. E. Proteolytic mechanisms, not malnutrition, cause loss of muscle mass in kidney failure. J. Ren. Nutr. 16, 208–211 (2006).

    Article  PubMed  Google Scholar 

  90. McSherry, E. & Morris, R. C. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J. Clin. Invest. 61, 509–527 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mak, R. H. Insulin and its role in chronic kidney disease. Pediatr. Nephrol. 23, 355–362 (2008).

    Article  PubMed  Google Scholar 

  92. Shah, S. N., Abramowitz, M., Hostetter, T. H. & Melamed, M. H. S. Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am. J. Kidney Dis. 54, 270–277 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sonikian, M. et al. Potential effect of metabolic acidosis on beta 2-microglobulin generation: in vivo and in vitro studies. J. Am. Soc. Nephrol. 7, 350–356 (1996).

    CAS  PubMed  Google Scholar 

  94. Wiederkehr, M. R., Kalogiros, J. & Krapf, R. Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients. Nephrol. Dial. Transplant. 19, 1190–1197 (2004).

    Article  PubMed  Google Scholar 

  95. Mitch, W. E. Metabolic and clinical consequences of metabolic acidosis. J. Nephrol. 19, S70–S75 (2006).

    CAS  PubMed  Google Scholar 

  96. Sebastian, A., Harris, S. T., Ottaway, J. H., Todd, K. M. & Morris, R. C. Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N. Engl. J. Med. 330, 1776–1781 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Frassetto, L., Morris, R. C. & Sebastian, A. Potassium bicarbonate reduces urinary nitrogen excretion in postmenopausal women. J. Clin. Endocrinol. Metab. 82, 254–259 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Kraut, J. A. & Kurtz, I. Use of base in the treatment of severe acidemic states. Am. J. Kidney Dis. 38, 703–727 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Forsythe, S. & Schmidt, G. A. Sodium bicarbonate for the treatment of lactic acidosis. Chest 117, 260–267 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Glaser, N. et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N. Engl. J. Med. 344, 264–269 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Kraut, J. A. & Kurtz, I. Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey. Clin. Exp. Nephrol. 10, 111–117 (2006).

    Article  PubMed  Google Scholar 

  102. Wu, D. M. et al. Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs. Shock 29, 519–525 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Nahas, G. G., Sutin, K. M. & Fermon, C. Guidelines for the treatment of acidaemia with THAM. Drugs 55, 191–194 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Hoste, E. A. et al. Sodium bicarbonate versus THAM in ICU patients with mild metabolic acidosis. J. Nephrol. 18, 303–307 (2005).

    CAS  PubMed  Google Scholar 

  105. Weber, T. et al. Tromethamine buffer modifies the depressant effect of permissive hypercapnia on myocardial contractility in patient with acute respiratory distress syndrome. Am. J. Resp. Crit. Care Med. 162, 1361–1365 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Klepper, I. D., Kucera, R. F., Kindig, N. B., Sherrill, D. L. & Filley, G. F. A comparative study of bicarbonate and Carbicarb in the treatment of metabolic acidosis induced by hemorrhagic shock. J. Crit. Care 3, 256–261 (1988).

    Article  CAS  Google Scholar 

  107. Zhou, F. Q. Pyruvate in the correction of intracellular acidosis: a metabolic basis as a novel superior buffer. Am. J. Nephrol. 25, 55–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Hilton, P. J., Taylor, L. G., Forni, L. G. & Treacher, D. F. Bicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis. QJM 91, 279–283 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Wu, D. M., Bassuk, J., Arias, J., Doods, H. & Adams, J. A. Cardiovascular effects of Na+/H+ exchanger inhibition with BIIB513 following hypovolemic circulatory shock. Shock 23, 269–274 (2005).

    CAS  PubMed  Google Scholar 

  110. Sikes, P. J., Zhao, P., Maass, D. L., White, J. & Horton, J. W. Sodium/hydrogen exchange activity in sepsis and in sepsis complicated by previous injury: 31P and 23Na NMR study. Crit. Care Med. 33, 605–615 (2005).

    Article  PubMed  Google Scholar 

  111. Benveniste, M. & Dingledine, R. Limiting stroke-induced damage by targeting an acid channel. N. Engl. J. Med. 352, 85–86 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Xiong, Z. G., Chu, X. P. & Simon, R. P. Acid sensing ion channels: novel therapeutic targets for ischemic brain injury. Front. Biosci. 12, 1376–1386 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Sabatini, S. & Kurtzman, N. A. Bicarbonate therapy in severe metabolic acidosis. J. Am. Soc. Nephrol. 20, 692–695 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Garella, S., Dana, C. L. & Chazan, J. A. Severity of metabolic acidosis as a determinant of bicarbonate requirements. N. Engl. J. Med. 289, 121–126 (1973).

    Article  CAS  PubMed  Google Scholar 

  115. Fernandez, P. C., Cohen, R. M. & Feldman, G. M. The concept of bicarbonate distribution space: the crucial role of body buffers. Kidney Int. 36, 747–752 (1989).

    Article  CAS  PubMed  Google Scholar 

  116. Kallet, R. H., Jasmer, R. M., Luce, J. M., Lin, L. H. & Marks, J. D. The treatment of acidosis in acute lung injury with tris-hydroxymethyl aminomethane (THAM). Am. J. Resp. Crit. Care Med. 161, 1149–1153 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Adrogue, H. J., Rashad, M. N., Gorin, A. B., Yacoub, J. & Madias, N. E. Assessing acid-base status in circulatory failure. Differences between arterial and central venous blood. N. Engl. J. Med. 320, 1312–1316 (1989).

    Article  CAS  PubMed  Google Scholar 

  118. Roderick, P., Willis, N. S., Blakeley, S., Jones, C. & Tomson, C. Correction of chronic metabolic acidosis for chronic kidney disease patients. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD001890. doi:10.1002/14651858.CD001890.pub3 (2007).

  119. Ballmer, P. E. et al. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J. Clin. Invest. 95, 39–45 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. de Brito-Ashurst, I., Varagunam, M., Raftery, M. J. & Yaqoob, M. M. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol. 20, 2075–2084 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Husted, F. C. & Nolph, K. D. NaHCO3 and NaCl tolerance in chronic renal failure II. Clin. Nephrol. 1, 21–27 (1977).

    Google Scholar 

  122. Szylman, P., Better, O. S., Chaimowitz, C. & Rosler, A. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. N. Engl. J. Med. 294, 361–365 (1976).

    Article  CAS  PubMed  Google Scholar 

  123. Harris, D. C. H., Yuill, E. & Chesher, D. W. Correcting acidosis in hemodialysis: effect on phosphate clearance and calcification risk. J. Am. Soc. Nephrol. 6, 1607–1612 (1995).

    CAS  PubMed  Google Scholar 

  124. Kopple, J. D., Kalantar-Zadeh, K. & Mehrotra, R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney Int. 67, S21–S27 (2005).

    Article  Google Scholar 

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Acknowledgements

J. A. Kraut's work is supported in part by research funds from the Veterans Administration.

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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Correspondence to Nicolaos E. Madias.

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Kraut, J., Madias, N. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 6, 274–285 (2010). https://doi.org/10.1038/nrneph.2010.33

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