Box 1.

Tests useful in the DD of metabolic acidosis

Box 2.

Causes of metabolic acidosis

Box 3.

Recommendations for the treatment of acute metabolic acidosis

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).
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).
Kraut, J. A. & Kurtz, I. Metabolic acidosis of CKD: diagnosis, clinical characteristics, and treatment. Am. J. Kidney Dis. 45, 978-993 (2005).
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).
Kraut, J. A. & Kurtz, I. Controversies in the treatment of acute metabolic acidosis. NephSAP 5, 1-9 (2006).
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).
Rodriguez-Soriano, J. & Vallo, A. Renal tubular acidosis. Pediatr. Nephrol. 4, 268-275 (1990).
Wagner, C. A., Devuyst, O., Bourgeois, S. & Mohebbi, N. Regulated acid-base transport in the collecting duct. Pflugers Arch. 458, 137-156 (2009).
Boron, W. F. Acid base transport by the renal proximal tubule. J. Am. Soc. Nephrol. 17, 2368-2382 (2006).
Igarashi, T., Sekine, T. & Watanabe, H. Molecular basis of proximal renal tubular acidosis. J. Nephrol. 15, S135-S141 (2002).
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).
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).
Wagner, C. A. et al. Renal vacuolar H+-ATPase. Physiol. Rev. 84, 1263-1314 (2004).
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).
Karim, Z., Szutkowska, M., Vernimmen, C. & Bichara, M. Recent concepts concerning the renal handling of NH₃/NH₄+. J. Nephrol. 19, S27-S32 (2006).
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).
Weiner, I. D. & Hamm, L. L. Molecular mechanisms of renal ammonia transport. Annu. Rev. Physiol. 69, 317-340 (2007).
Biver, S. et al. A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility. Nature 456, 339-343 (2008).
Karet, F. E. Physiological and metabolic implications of V-ATPase isoforms in the kidney. J. Bioenerg. Biomembr. 37, 425^429 (2005).
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).
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).
Karet, F. E. Mechanisms in hyperkalemic renal tubular acidosis. J. Am. Soc. Nephrol. 20, 251-254 (2009).
Kamel, K. S. et al. A new classification for renal defects in net acid excretion. Am. J. Kidney Dis. 29, 136-146 (1997).
Kraut, J. A. & Madias, N. E. Approach to patients with acid-base disorders. Respir. Care 46, 392-403 (2001).
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).
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).
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).
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).
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).
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).
Rastegar, A. Use of the ΔAG/ ΔHCO₃ ^- ratio in the diagnosis of mixed acid-base disorders. J. Am. Soc. Nephrol. 18, 2429-2431 (2007).
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).
Emmett, M. Anion-gap interpretation: the old and the new. Nat. Clin. Pract. Nephrol. 2, 4-5 (2006).
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).
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).
Feldman, M., Soni, N. & Dickson, B. Influence of hypoalbuminemia or hyperalbuminemia on the serum anion gap. J. Lab. Clin. Med. 146, 317-320 (2005).
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).
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).
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).
Kim, H. Y. et al. Clinical significance of the fractional excretion of anions in metabolic acidosis. Clin. Nephrol. 55, 448-452 (2001).
Gabow, P. A. et al. Diagnostic importance of increased serum anion gap. N. Engl. J. Med. 303, 854-858 (1980).
Uribarri, J., Oh, M. S. & Carroll, H. J. r>Lactic acidosis: a review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine (Baltimore) 77, 73-82 (1998).
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).
Kraut, J. A. & Kurtz, I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin. J. Am. Soc. Nephrol. 3, 208-225 (2008).
Jacobsen, D. & McMartin, K. E. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med. Toxicol. 1, 309-334 (1986).
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).
Tailor, P et al. Recurrent high anion gap metabolic acidosis secondary to 5-oxoproline (pyroglutamic acid). Am. J. Kidney Dis. 46, E4-E10 (2005).
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).
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).
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).
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).
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).
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).
Dubose, T. D. Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int. 51, 591-602 (1997).
Anderson, R. J., Potts, D. E., Gabow, PA., Rumack, B. H. & Schrier, R. W. Unrecognized adult salicylate intoxication. Ann. Intern. Med. 85, 745-748 (1976).
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).
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).
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).
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).
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).
Field, M. Intestinal ion transport and the pathophysiology of diarrhea. J. Clin. Invest. 111, 931-943 (2003).
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).
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).
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).
Pessler, F. et al. The spectrum of renal tubular acidosis in paediatric Sjogren syndrome. Rheumatology 45, 85-91 (2006).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Orchard, C. H. & Cingolani, H. E. Acidosis and arrhythmias in cardiac muscle. Cardiovasc. Res. 28, 1312-1319 (1994).
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).
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).
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).
Seifter, J. Acid base disturbances and the central nervous system. Nephrol. Rounds 3, 1-6 (2005) .
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).
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).
Lardner, A. The effects of extracellular pH on immune function. J. Leukoc. Biol. 69, 522-530 (2001).
Cuthbert, C. & Alberti, K. G. Acidemia and insulin resistance in the diabetic ketoacidotic rat. Metabolism 27, 1903-1916 (1978).
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).
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).
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).
Kraut, J. A. Disturbances of acid-base balance and bone disease in end-stage renal disease. Semin. Dial. 13, 261-265 (2000).
Lemann, J., Bushinsky, D. A. & Hamm, L. L. Bone buffering of acid and base in humans. Am. J. Physiol. 285, F811-F832 (2003).
Mitch, W. E. Proteolytic mechanisms, not malnutrition, cause loss of muscle mass in kidney failure. J. Ren. Nutr. 16, 208-211 (2006).
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).
Mak, R. H. Insulin and its role in chronic kidney disease. Pediatr. Nephrol. 23, 355-362 (2008).
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).
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).
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).
Mitch, W. E. Metabolic and clinical consequences of metabolic acidosis. J. Nephrol. 19, S70-S75 (2006).
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).
Frassetto, L., Morris, R. C. & Sebastian, A. Potassium bicarbonate reduces urinary nitrogen excretion in postmenopausal women. J. Clin. Endocrinol. Metab. 82, 254-259 (1997).
Kraut, J. A. & Kurtz, I. Use of base in the treatment of severe acidemic states. Am. J. Kidney Dis. 38, 703-727 (2001).
Forsythe, S. & Schmidt, G. A. Sodium bicarbonate for the treatment of lactic acidosis. Chest 117, 260-267 (2000).
Glaser, N. et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N. Engl. J. Med. 344, 264-269 (2001).
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).
Wu, D. M. et al. Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs. Shock 29, 519-525 (2008).
Nahas, G. G., Sutin, K. M. & Fermon, C. Guidelines for the treatment of acidaemia with THAM. Drugs 55, 191-194 (1998).
Hoste, E. A. et al. Sodium bicarbonate versus THAM in ICU patients with mild metabolic acidosis. J. Nephrol. 18, 303-307 (2005).
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).
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).
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).
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).
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).
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).
Benveniste, M. & Dingledine, R. Limiting stroke-induced damage by targeting an acid channel. N. Engl. J. Med. 352, 85-86 (2005).
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).
Sabatini, S. & Kurtzman, N. A. Bicarbonate therapy in severe metabolic acidosis. J. Am. Soc. Nephrol. 20, 692-695 (2009).
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).
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).
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).
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).
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).
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).
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).
Husted, F. C. & Nolph, K. D. NaHCO₃ ^- and NaCl tolerance in chronic renal failure II. Clin. Nephrol. 1, 21-27 (1977).
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).
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).
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).

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Author(s)

Jeffrey A. Kraut, MD

Professor of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Chief of Dialysis, Division of Nephrology, Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California; Investigator, UCLA Membrane Biology Laboratory, Los Angeles, California

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Disclosure: Jeffrey A. Kraut, MD, has disclosed no relevant financial relationships.

Nicolaos E. Madias, MD

Maurice S. Segal, M.D. Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Chairman, Department of Medicine, St. Elizabeth's Medical Center, Boston, Massachusetts

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Disclosure: Nicolaos E. Madias, MD, has disclosed no relevant financial relationships.

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Susan Allison

Editor, Nature Reviews Nephrology

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Disclosure: Susan Allison has disclosed no relevant financial relationships.

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Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

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Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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CME

Metabolic Acidosis: Pathophysiology, Diagnosis and Management

Authors: Jeffrey A. Kraut, MD; Nicolaos E. Madias, MD
CME Released: 3/23/2010
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Describe the pathophysiology of metabolic acidosis
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Author(s)

Jeffrey A. Kraut, MD

Professor of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Chief of Dialysis, Division of Nephrology, Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California; Investigator, UCLA Membrane Biology Laboratory, Los Angeles, California

Disclosures

Disclosure: Jeffrey A. Kraut, MD, has disclosed no relevant financial relationships.

Nicolaos E. Madias, MD

Maurice S. Segal, M.D. Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Chairman, Department of Medicine, St. Elizabeth's Medical Center, Boston, Massachusetts

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Disclosure: Nicolaos E. Madias, MD, has disclosed no relevant financial relationships.

Editor

Susan Allison

Editor, Nature Reviews Nephrology

Disclosures

Disclosure: Susan Allison has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Sarah Fleischman

CME Program Manager, Medscape, LLC

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Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Adverse Effects of Metabolic Acidosis

The adverse effects of metabolic acidosis are divided into those primarily associated with acute metabolic acidosis and those primarily associated with chronic metabolic acidosis (Figure 1).

Figure 1.

Enlarge

Adverse effects of a | acute metabolic acidosis and b | chronic metabolic acidosis.

Acute Metabolic Acidosis

Although acute metabolic acidosis can affect a number of organ systems, animal studies suggest that it affects the cardiovascular system most critically. Cardiac contractility and cardiac output are reduced^[70-72] and arterial vasodilatation develops, which contributes to the development of hypotension.^[73] The cardiovascular dysfunction that occurs varies depending on pH. When blood pH decreases from 7.4 to 7.2, cardiac output can increase due to increased catecholamine levels.^[70,72] When blood pH falls below 7.1-7.2, however, a fall in cardiac output is inevitable.^[70] There is also resistance to the inotropic and vasoconstrictive effects of infused catecholamines with severe acidemia.^[70,74] A predisposition to ventricular arrhythmias is often found in animal models of metabolic acidosis.^[75] Similar abnormalities in cardiovascular function might be expected in humans, as patients with severe metabolic acidosis are often hypotensive. However, the limited controlled studies in humans with severe lactic acidosis and ketoacidosis performed so far have been unable to demonstrate impaired cardiovascular function that is directly attributable to the metabolic acidosis.^[76-78] Further studies are warranted to resolve this disparity.

Mental confusion and lethargy are often observed in patients with acute metabolic acidosis, despite minor changes in cerebrospinal and brain pH.^[79] A pH-dependent reduction in the affinity of hemoglobin for oxygen (Bohr effect) is seen immediately.^[80] Within 8 h, a decrease in 2,3-diphosphoglycerate production occurs, which increases the affinity of hemoglobin for oxygen. Given that the time-dependent changes in pH and in 2,3-diphosphoglycerate have disparate effects on the affinity of hemoglobin for oxygen, the final effect on the affinity of hemoglobin for oxygen will depend on the duration of the acidosis.

In acute metabolic acidosis, macrophage production of interleukins is stimulated and lymphocyte function is suppressed, leading to increased inflammation and an impaired immune response.^[81] The chemotactic properties and bactericidal capacity of leukocytes are dampened,^[82] potentially making patients with acute metabolic acidosis more susceptible to infection. In addition, the cellular response to insulin is impaired, partly as a result of a pH-dependent decrease in the binding of insulin to its receptor.^[83]

Cellular energy production can be compromised in metabolic acidosis^[84] as the activity of 6-phosphofructokinase, a critical enzyme in glycolysis, is pH dependent. Apoptosis is stimulated by metabolic acidosis predisposing to cellular death.^[85]

Chronic Metabolic Acidosis

Chronic metabolic acidosis does not seem to have a significant effect on cardiovascular function, although mortality is increased in patients with CKD when serum HCO₃^- concentration is <22 mmol/l.^[86] Chronic metabolic acidosis exerts its most prominent effects on the musculoskeletal system. Metabolic acidosis can produce or exacerbate pre-existing bone disease,^[87,88]accelerate muscle degradation leading to muscle loss,^[89]and retard growth in children.^[90] Glucose tolerance can be impaired because of interference with the actions of insulin,^[91] albumin synthesis can be reduced,^[2] progression of CKD can be accelerated,^[92] and production of ( β₂-microglobulin can be augmented, which predisposes patients to amyloidosis.^[93] Although once disputed, the concept that metabolic acidosis represents an important factor in accelerating the progression of CKD is gaining support.^[92]

Underlying the clinical abnormalities reported with chronic metabolic acidosis are the direct effects of metabolic acidosis on bone and muscle, and possibly kidney, as well as indirect effects on these tissues emanating from alterations in the secretion and/or action of several hormones, including corticosteroids,^[89] thyroid hormone,^[94]and parathyroid hormone.^[95] A generalized stimulation of inflammation also seems to contribute to the adverse effects of chronic metabolic acidosis.^[4] These abnormalities are more frequent and severe with greater degrees of metabolic acidosis, but even mild metabolic acidosis might contribute to the development of bone disease and muscle degradation,^[96,97] a finding that has important implications for treatment.

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Page 6 of 9

Management of Metabolic Acidosis

CME Information

Abstract and Introduction
Pathophysiology of Metabolic Acidosis
Diagnosis of Metabolic Acidosis
Additional Diagnostic Studies
Causes of Metabolic Acidosis
Adverse Effects of Metabolic Acidosis
Management of Metabolic Acidosis
Conclusions
Key Points

References

Box 1.

Box 2.

Box 3.

CME

Metabolic Acidosis: Pathophysiology, Diagnosis and Management

Target Audience and Goal Statement

Disclosures

Author(s)

Jeffrey A. Kraut, MD

Nicolaos E. Madias, MD

Editor

Susan Allison

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Metabolic Acidosis: Pathophysiology, Diagnosis and Management: Adverse Effects of Metabolic Acidosis

Adverse Effects of Metabolic Acidosis

Figure 1.

Acute Metabolic Acidosis

Chronic Metabolic Acidosis

Table of Contents

Box 1.

Box 2.

Box 3.

References

Faculty and Disclosures

Author(s)

Jeffrey A. Kraut, MD

Nicolaos E. Madias, MD

Editor

Susan Allison

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

CME

Metabolic Acidosis: Pathophysiology, Diagnosis and Management

Target Audience and Goal Statement

Disclosures

Author(s)

Jeffrey A. Kraut, MD

Nicolaos E. Madias, MD

Editor

Susan Allison

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Metabolic Acidosis: Pathophysiology, Diagnosis and Management: Adverse Effects of Metabolic Acidosis

Adverse Effects of Metabolic Acidosis

Figure 1.

Acute Metabolic Acidosis

Chronic Metabolic Acidosis

Table of Contents