Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis

Michael Emmett, MD
Biff F Palmer, MD
Section Editor
Richard H Sterns, MD
Deputy Editor
John P Forman, MD, MSc


Distal (type 1) and proximal (type 2) renal tubular acidosis (RTA) are uncommon disorders, particularly in adults. Proximal RTA is characterized by a reduction in proximal bicarbonate reabsorptive capacity that leads to bicarbonate wasting in the urine until the serum bicarbonate concentration has fallen to a level low enough to allow all of the filtered bicarbonate to be reabsorbed. By comparison, the primary defect in distal RTA is impaired distal acidification. These different pathogenetic mechanisms result in different clinical manifestations, but some degree of hypokalemia is commonly present with most forms of distal and proximal RTA (table 1).

The etiology and diagnosis of distal and proximal RTA will be reviewed here. The pathogenesis of the different forms of RTA, the treatment of these disorders, the impact they have on potassium balance, and an overview of RTA are discussed separately. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

Type 4 RTA is another form of RTA in which the primary problem is either decreased aldosterone secretion or aldosterone resistance. These patients typically have a mild metabolic acidosis (serum bicarbonate concentration above 17 meq/L) with the major manifestation being hyperkalemia. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Although initially used to describe a transiently severe form of distal RTA in infants, the term "mixed (type 3) RTA" is most often applied to a rare autosomal recessive syndrome (resulting from carbonic anhydrase II deficiency) with features of both proximal and distal RTA [1,2]. In addition to RTA, affected patients suffer from osteopetrosis, cerebral calcification, and mental retardation. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Mixed (type 3) RTA'.)


The different forms of renal tubular acidosis (RTA), which lead to a hyperchloremic (normal anion gap) metabolic acidosis, can be caused by a wide variety of disorders, most of which are rare [3]. The most frequent causes vary with the type of RTA.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: May 18, 2016.
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 ©2016 UpToDate, Inc.
  1. Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002; 13:2160.
  2. 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.
  3. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.612.
  4. Caruana RJ, Buckalew VM Jr. The syndrome of distal (type 1) renal tubular acidosis. Clinical and laboratory findings in 58 cases. Medicine (Baltimore) 1988; 67:84.
  5. Pun KK, Wong CK, Tsui EY, et al. Hypokalemic periodic paralysis due to the Sjögren syndrome in Chinese patients. Ann Intern Med 1989; 110:405.
  6. Bridoux F, Kyndt X, Abou-Ayache R, et al. Proximal tubular dysfunction in primary Sjögren's syndrome: a clinicopathological study of 2 cases. Clin Nephrol 2004; 61:434.
  7. Buckalew VM Jr. Nephrolithiasis in renal tubular acidosis. J Urol 1989; 141:731.
  8. Kobayashi T, Muto S, Nemoto J, et al. Fanconi's syndrome and distal (type 1) renal tubular acidosis in a patient with primary Sjögren's syndrome with monoclonal gammopathy of undetermined significance. Clin Nephrol 2006; 65:427.
  9. Batlle D, Haque SK. Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant 2012; 27:3691.
  10. Blackstock MJ, Lee A. Hypokalaemia and Renal Tubular Acidosis due to Abuse of Nurofen Plus. Case Rep Crit Care 2012; 2012:141505.
  11. Salter MD. Ibuprofen-Induced Hypokalemia and Distal Renal Tubular Acidosis: A Patient's Perceptions of Over-the-Counter Medications and Their Adverse Effects. Case Rep Crit Care 2013; 2013:875857.
  12. Carlisle EJ, Donnelly SM, Vasuvattakul S, et al. Glue-sniffing and distal renal tubular acidosis: sticking to the facts. J Am Soc Nephrol 1991; 1:1019.
  13. Maldonado JE, Velosa JA, Kyle RA, et al. Fanconi syndrome in adults. A manifestation of a latent form of myeloma. Am J Med 1975; 58:354.
  14. Leboulleux M, Lelongt B, Mougenot B, et al. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 1995; 48:72.
  15. Messiaen T, Deret S, Mougenot B, et al. Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients. Medicine (Baltimore) 2000; 79:135.
  16. Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol 2009; 68:655.
  17. Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS 2008; 22:99.
  18. Shi M, Chen L. Sjögren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis: Case report and literature review. J Int Med Res 2016; 44:753.
  19. Ram R, Swarnalatha G, Dakshinamurty KV. Renal tubular acidosis in Sjögren's syndrome: a case series. Am J Nephrol 2014; 40:123.
  20. Morris RC Jr, Sebastian A. Renal tubular acidosis and the Fanconi syndrome. In: The Metabolic Basis of Inherited Disease, 5th ed, Stanbury JB, Wyngaarden JB, Fredrickson DS, et al (Eds), McGraw-Hill, New York 1983.
  21. Gahl WA, Thoene JG, Schneider JA, et al. NIH conference. Cystinosis: progress in a prototypic disease. Ann Intern Med 1988; 109:557.
  22. Stöhr W, Paulides M, Bielack S, et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 2007; 48:447.
  23. Ho PT, Zimmerman K, Wexler LH, et al. A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer 1995; 76:2557.
  24. 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.
  25. Igarashi T, Inatomi J, Sekine T, et al. Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. J Am Soc Nephrol 2001; 12:713.
  26. Dinour D, Chang MH, Satoh J, 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 2004; 279:52238.
  27. Toye AM, Parker MD, Daly CM, et al. The human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia. Am J Physiol Cell Physiol 2006; 291:C788.
  28. Katzir Z, Dinour D, Reznik-Wolf H, et al. Familial pure proximal renal tubular acidosis--a clinical and genetic study. Nephrol Dial Transplant 2008; 23:1211.
  29. 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.
  30. Carlisle EJ, Donnelly SM, Halperin ML. Renal tubular acidosis (RTA): recognize the ammonium defect and pHorget the urine pH. Pediatr Nephrol 1991; 5:242.
  31. Tizianello A, Garibotto G, Robaudo C, et al. Renal ammoniagenesis in humans with chronic potassium depletion. Kidney Int 1991; 40:772.
  32. COOKE RE, SEGAR WE, CHEEK DB, et al. The extrarenal correction of alkalosis associated with potassium deficiency. J Clin Invest 1952; 31:798.
  33. 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.
  34. Batlle D, Grupp M, Gaviria M, Kurtzman NA. Distal renal tubular acidosis with intact capacity to lower urinary pH. Am J Med 1982; 72:751.
  35. 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.
  36. Kurtzman NA. Disorders of distal acidification. Kidney Int 1990; 38:720.
  37. Batlle DC, von Riotte A, Schlueter W. Urinary sodium in the evaluation of hyperchloremic metabolic acidosis. N Engl J Med 1987; 316:140.
  38. 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.
  39. Gault MH, Chafe LL, Morgan JM, et al. Comparison of patients with idiopathic calcium phosphate and calcium oxalate stones. Medicine (Baltimore) 1991; 70:345.
  40. Preminger GM, Sakhaee K, Skurla C, Pak CY. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985; 134:20.
  41. Weger M, Deutschmann H, Weger W, et al. Incomplete renal tubular acidosis in 'primary' osteoporosis. Osteoporos Int 1999; 10:325.
  42. Weger W, Kotanko P, Weger M, et al. Prevalence and characterization of renal tubular acidosis in patients with osteopenia and osteoporosis and in non-porotic controls. Nephrol Dial Transplant 2000; 15:975.
  43. 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.
  44. 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.
  45. Arampatzis S, Röpke-Rieben B, Lippuner K, Hess B. Prevalence and densitometric characteristics of incomplete distal renal tubular acidosis in men with recurrent calcium nephrolithiasis. Urol Res 2012; 40:53.
  46. Oster JR, Lopez R, Perez GO, et al. The stability of pH, PCO2, and calculated [HCO3] of urine samples collected under oil. Nephron 1988; 50:320.
  47. Yi JH, Shin HJ, Kim SM, et al. Does the exposure of urine samples to air affect diagnostic tests for urine acidification? Clin J Am Soc Nephrol 2012; 7:1211.
  48. Walsh SB, Shirley DG, Wrong OM, Unwin RJ. Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int 2007; 71:1310.
  49. Batlle DC. Segmental characterization of defects in collecting tubule acidification. Kidney Int 1986; 30:546.