Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance

Michael Emmett, MD
Ellie Kelepouris, MD, FAHA
Section Editor
Richard H Sterns, MD
Deputy Editor
John P Forman, MD, MSc


The lungs and the kidneys are responsible for the maintenance of acid-base balance within the body. Alveolar ventilation removes carbon dioxide (CO2), while the kidneys reclaim filtered bicarbonate (HCO3 ion) and excrete hydrogen ions produced by the metabolism of dietary protein (or bicarbonate when the diet generates more base than acid).

The term "renal tubular acidosis" (RTA) refers to a group of disorders in which, despite a relatively well-preserved glomerular filtration rate, metabolic acidosis develops because of defects in the ability of the renal tubules to perform the normal functions required to maintain acid-base balance [1]. All forms of RTA are characterized by a normal anion gap (hyperchloremic) metabolic acidosis. This form of metabolic acidosis usually results from either the net retention of hydrogen chloride or a salt that is metabolized to hydrogen chloride (such as ammonium chloride) or the net loss of sodium bicarbonate or its equivalent [2]. The major cause of a normal anion gap acidosis in patients without a significant impairment in renal function is diarrhea. (See "Approach to the adult with metabolic acidosis".)

This topic will review the classification and pathophysiology of the different forms of RTA and the impact these changes have on potassium balance. The major causes, diagnosis, and treatment of RTA are discussed separately. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Causes and evaluation of hyperkalemia in adults" and "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)


Prior to discussing RTA, it is helpful to briefly review the kidneys' role in the maintenance of acid-base balance and how disturbances in tubular function can result in metabolic acidosis. To maintain acid-base balance, the kidneys reclaim the filtered bicarbonate (HCO3 ion) and excrete the daily acid load, which is primarily derived from the metabolism of sulfur-containing amino acids.

Reclaiming filtered bicarbonate — Most of the bicarbonate that is filtered by the glomerulus returns to the circulation, predominately as a result of Na-H exchange by the proximal tubules (figure 1). Approximately 85 to 90 percent of the filtered load is reclaimed at this site. The remaining 10 percent is reclaimed in the distal nephron via hydrogen secretion by proton pumps (H-ATPase and H-K ATPase). Under normal conditions, when a typical Western diet is ingested, there is virtually no bicarbonate in the final urine.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Sep 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002; 13:2160.
  2. Gluck SL. Acid-base. Lancet 1998; 352:474.
  3. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.616.
  4. Sebastian A, McSherry E, Morris RC Jr. Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis. J Clin Invest 1971; 50:667.
  5. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.357.
  6. Stanton BA. Renal potassium transport: morphological and functional adaptations. Am J Physiol 1989; 257:R989.
  7. Unwin RJ, Luft FC, Shirley DG. Pathophysiology and management of hypokalemia: a clinical perspective. Nat Rev Nephrol 2011; 7:75.
  8. Young DB. Quantitative analysis of aldosterone's role in potassium regulation. Am J Physiol 1988; 255:F811.
  9. Poux JM, Peyronnet P, Le Meur Y, et al. Hypokalemic quadriplegia and respiratory arrest revealing primary Sjögren's syndrome. Clin Nephrol 1992; 37:189.
  10. Giebisch G, Wang W. Potassium transport: from clearance to channels and pumps. Kidney Int 1996; 49:1624.
  11. Giebisch G. Challenges to potassium metabolism: internal distribution and external balance. Wien Klin Wochenschr 2004; 116:353.
  12. Kim S, Lee JW, Park J, et al. The urine-blood PCO gradient as a diagnostic index of H(+)-ATPase defect distal renal tubular acidosis. Kidney Int 2004; 66:761.
  13. Strife CF, Clardy CW, Varade WS, et al. Urine-to-blood carbon dioxide tension gradient and maximal depression of urinary pH to distinguish rate-dependent from classic distal renal tubular acidosis in children. J Pediatr 1993; 122:60.
  14. Han JS, Kim GH, Kim J, et al. Secretory-defect distal renal tubular acidosis is associated with transporter defect in H(+)-ATPase and anion exchanger-1. J Am Soc Nephrol 2002; 13:1425.
  15. Cohen EP, Bastani B, Cohen MR, et al. Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis. J Am Soc Nephrol 1992; 3:264.
  16. Bastani B, Haragsim L, Gluck S, Siamopoulos KC. Lack of H-ATPase in distal nephron causing hypokalaemic distal RTA in a patient with Sjögren's syndrome. Nephrol Dial Transplant 1995; 10:908.
  17. Takemoto F, Hoshino J, Sawa N, et al. Autoantibodies against carbonic anhydrase II are increased in renal tubular acidosis associated with Sjogren syndrome. Am J Med 2005; 118:181.
  18. Walsh S, Borgese F, Gabillat N, et al. Cation transport activity of anion exchanger 1 mutations found in inherited distal renal tubular acidosis. Am J Physiol Renal Physiol 2008; 295:F343.
  19. Bruce LJ, Cope DL, Jones GK, et al. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. J Clin Invest 1997; 100:1693.
  20. Jarolim P, Shayakul C, Prabakaran D, et al. Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO3- exchanger. J Biol Chem 1998; 273:6380.
  21. Karet FE, Gainza FJ, Györy AZ, et al. Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc Natl Acad Sci U S A 1998; 95:6337.
  22. Wrong O, Bruce LJ, Unwin RJ, et al. Band 3 mutations, distal renal tubular acidosis, and Southeast Asian ovalocytosis. Kidney Int 2002; 62:10.
  23. Karet FE. Inherited distal renal tubular acidosis. J Am Soc Nephrol 2002; 13:2178.
  24. Yenchitsomanus PT, Vasuvattakul S, Kirdpon S, et al. Autosomal recessive distal renal tubular acidosis caused by G701D mutation of anion exchanger 1 gene. Am J Kidney Dis 2002; 40:21.
  25. Devonald MA, Smith AN, Poon JP, et al. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Nat Genet 2003; 33:125.
  26. Sritippayawan S, Sumboonnanonda A, Vasuvattakul S, et al. Novel compound heterozygous SLC4A1 mutations in Thai patients with autosomal recessive distal renal tubular acidosis. Am J Kidney Dis 2004; 44:64.
  27. Nicoletta JA, Schwartz GJ. Distal renal tubular acidosis. Curr Opin Pediatr 2004; 16:194.
  28. Fry AC, Su Y, Yiu V, et al. Mutation conferring apical-targeting motif on AE1 exchanger causes autosomal dominant distal RTA. J Am Soc Nephrol 2012; 23:1238.
  29. Toye AM. Defective kidney anion-exchanger 1 (AE1, Band 3) trafficking in dominant distal renal tubular acidosis (dRTA). Biochem Soc Symp 2005; :47.
  30. Rungroj N, Devonald MA, Cuthbert AW, et al. A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells. J Biol Chem 2004; 279:13833.
  31. Shayakul C, Alper SL. Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis. Clin Exp Nephrol 2004; 8:1.
  32. Ribeiro ML, Alloisio N, Almeida H, et al. Severe hereditary spherocytosis and distal renal tubular acidosis associated with the total absence of band 3. Blood 2000; 96:1602.
  33. Toye AM, Williamson RC, Khanfar M, et al. Band 3 Courcouronnes (Ser667Phe): a trafficking mutant differentially rescued by wild-type band 3 and glycophorin A. Blood 2008; 111:5380.
  34. Walsh S, Borgese F, Gabillat N, Guizouarn H. Southeast Asian AE1 associated renal tubular acidosis: cation leak is a class effect. Biochem Biophys Res Commun 2009; 382:668.
  35. Karet FE, Finberg KE, Nelson RD, et al. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 1999; 21:84.
  36. Vargas-Poussou R, Houillier P, Le Pottier N, et al. Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene. J Am Soc Nephrol 2006; 17:1437.
  37. Gueutin V, Vallet M, Jayat M, et al. Renal β-intercalated cells maintain body fluid and electrolyte balance. J Clin Invest 2013; 123:4219.
  38. Wang T, Egbert AL Jr, Aronson PS, Giebisch G. Effect of metabolic acidosis on NaCl transport in the proximal tubule. Am J Physiol 1998; 274:F1015.
  39. Wingo CS, Smolka AJ. Function and structure of H-K-ATPase in the kidney. Am J Physiol 1995; 269:F1.
  40. Dafnis E, Spohn M, Lonis B, et al. Vanadate causes hypokalemic distal renal tubular acidosis. Am J Physiol 1992; 262:F449.
  41. Douglas JB, Healy JK. Nephrotoxic effects of amphotericin B, including renal tubular acidosis. Am J Med 1969; 46:154.
  42. Atsmon J, Dolev E. Drug-induced hypomagnesaemia : scope and management. Drug Saf 2005; 28:763.
  43. Wazny LD, Brophy DF. Amiloride for the prevention of amphotericin B-induced hypokalemia and hypomagnesemia. Ann Pharmacother 2000; 34:94.
  44. Buckalew VM Jr, McCurdy DK, Ludwig GD, et al. Incomplete renal tubular acidosis. Physiologic studies in three patients with a defect in lowering urine pH. Am J Med 1968; 45:32.
  45. Donnelly S, Kamel KS, Vasuvattakul S, et al. Might distal renal tubular acidosis be a proximal tubular cell disorder? Am J Kidney Dis 1992; 19:272.
  46. Hamm LL. Renal handling of citrate. Kidney Int 1990; 38:728.
  47. Morris RC Jr, Sebastian A. Alkali therapy in renal tubular acidosis: who needs it? J Am Soc Nephrol 2002; 13:2186.
  48. Pongchaiyakul C, Domrongkitchaiporn S, Stitchantrakul W, et al. Incomplete renal tubular acidosis and bone mineral density: a population survey in an area of endemic renal tubular acidosis. Nephrol Dial Transplant 2004; 19:3029.
  49. Igarashi T, Sekine T, Inatomi J, Seki G. Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. J Am Soc Nephrol 2002; 13:2171.
  50. Igarashi T, Inatomi J, Sekine T, et al. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet 1999; 23:264.
  51. Sly WS, Whyte MP, Sundaram V, et al. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med 1985; 313:139.
  52. Shah GN, Bonapace G, Hu PY, et al. Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. Hum Mutat 2004; 24:272.
  53. Sonia HL, Mohamed F, Mohamed B, et al. [Osteopetrosis with carbonic anhydrase II deficiency: report of 24 cases]. Tunis Med 2005; 83:409.
  54. McSherry E. Renal tubular acidosis in childhood. Kidney Int 1981; 20:799.
  55. Manz F, Waldherr R, Fritz HP, et al. Idiopathic de Toni-Debré-Fanconi syndrome with absence of proximal tubular brush border. Clin Nephrol 1984; 22:149.
  56. Sirac C, Bridoux F, Essig M, et al. Toward understanding renal Fanconi syndrome: step by step advances through experimental models. Contrib Nephrol 2011; 169:247.
  57. Haque SK, Ariceta G, Batlle D. Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies. Nephrol Dial Transplant 2012; 27:4273.
  58. Lacy MQ, Gertz MA. Acquired Fanconi's syndrome associated with monoclonal gammopathies. Hematol Oncol Clin North Am 1999; 13:1273.
  59. Cogan MG, Rector FC Jr. Proximal reabsorption during metabolic acidosis in the rat. Am J Physiol 1982; 242:F499.
  60. Sebastian A, McSherry E, Morris RC Jr. On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA). J Clin Invest 1971; 50:231.
  61. Kurtzman NA. Disorders of distal acidification. Kidney Int 1990; 38:720.
  62. Batlle DC. Segmental characterization of defects in collecting tubule acidification. Kidney Int 1986; 30:546.
  63. Szylman P, Better OS, Chaimowitz C, Rosler A. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. N Engl J Med 1976; 294:361.
  64. Matsuda O, Nonoguchi H, Tomita K, et al. Primary role of hyperkalemia in the acidosis of hyporeninemic hypoaldosteronism. Nephron 1988; 49:203.
  65. Kurtzman NA. Renal tubular acidosis syndromes. South Med J 2000; 93:1042.
  66. Li SL, Liou LB, Fang JT, Tsai WP. Symptomatic renal tubular acidosis (RTA) in patients with systemic lupus erythematosus: an analysis of six cases with new association of type 4 RTA. Rheumatology (Oxford) 2005; 44:1176.
  67. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol 2009; 20:251.
  68. Batlle DC, von Riotte A, Schlueter W. Urinary sodium in the evaluation of hyperchloremic metabolic acidosis. N Engl J Med 1987; 316:140.
  69. Batlle DC, Arruda JA, Kurtzman NA. Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med 1981; 304:373.
  70. Sabatini S, Kurtzman NA. Enzyme activity in obstructive uropathy: basis for salt wastage and the acidification defect. Kidney Int 1990; 37:79.
  71. Bastani B, Underhill D, Chu N, et al. Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis. J Am Soc Nephrol 1997; 8:1109.
  72. Batlle D, Itsarayoungyuen K, Arruda JA, Kurtzman NA. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Am J Med 1982; 72:188.
  73. Batlle DC, Hizon M, Cohen E, et al. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med 1988; 318:594.
  74. Sebastian A, Hulter HN, Kurtz I, et al. Disorders of distal nephron function. Am J Med 1982; 72:289.
  75. Hulter HN, Ilnicki LP, Harbottle JA, Sebastian A. Impaired renal H+ secretion and NH3 production in mineralocorticoid-deficient glucocorticoid-replete dogs. Am J Physiol 1977; 232:F136.
  76. Hulter HN, Licht JH, Glynn RD, et al. Pathophysiology of chronic renal tubular acidosis induced by administration of amiloride. J Lab Clin Med 1980; 95:637.
  77. Schlueter W, Keilani T, Hizon M, et al. On the mechanism of impaired distal acidification in hyperkalemic renal tubular acidosis: evaluation with amiloride and bumetanide. J Am Soc Nephrol 1992; 3:953.