Etiology and clinical manifestations of renal tubular acidosis in infants and children
- Tej K Mattoo, MD, DCH, FRCP
Tej K Mattoo, MD, DCH, FRCP
- Section Editor — Pediatric Nephrology
- Professor of Pediatrics
- Wayne State University School of Medicine
In children, renal tubular acidosis (RTA) is due to either an inherited or acquired defect that affects the kidney's ability to absorb filtered bicarbonate, or excrete ammonia or titratable acid. RTA is characterized by a normal anion gap (hyperchloremic) metabolic acidosis caused by the net retention of hydrogen or loss of bicarbonate.
There are four subgroups of RTA (table 1):
●Distal (type 1) RTA
●Proximal (type 2) RTA
●Mixed (type 3) RTA
- Besouw MTP, Bienias M, Walsh P, et al. Clinical and molecular aspects of distal renal tubular acidosis in children. Pediatr Nephrol 2017; 32:987.
- 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.
- 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.
- 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.
- Hu PY, Roth DE, Skaggs LA, et al. A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. Hum Mutat 1992; 1:288.
- Agroyannis B, Koutsikos D, Tzanatos-Exarchou H, Yatzidis H. Erythrocytosis in type I renal tubular acidosis with nephrocalcinosis. Nephrol Dial Transplant 1992; 7:365.
- Royer P, Broyer M, Nordmann Y. [Enzymatic anomalies and human nephropathies]. Pathol Biol 1967; 15:803.
- 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.
- Sterkers O, Saumon G, Tran Ba Huy P, et al. Electrochemical heterogeneity of the cochlear endolymph: effect of acetazolamide. Am J Physiol 1984; 246:F47.
- Herak-Kramberger CM, Breton S, Brown D, et al. Distribution of the vacuolar H+ atpase along the rat and human male reproductive tract. Biol Reprod 2001; 64:1699.
- Joshua B, Kaplan DM, Raveh E, et al. Audiometric and imaging characteristics of distal renal tubular acidosis and deafness. J Laryngol Otol 2008; 122:193.
- Karet FE, Finberg KE, Nayir A, et al. Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34. Am J Hum Genet 1999; 65:1656.
- Stover EH, Borthwick KJ, Bavalia C, et al. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet 2002; 39:796.
- Tanphaichitr VS, Sumboonnanonda A, Ideguchi H, et al. Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A. J Clin Invest 1998; 102:2173.
- Pessler F, Emery H, Dai L, et al. The spectrum of renal tubular acidosis in paediatric Sjögren syndrome. Rheumatology (Oxford) 2006; 45:85.
- Hataya H, Ikeda M, Ide Y, et al. Distal tubular dysfunction in lupus nephritis of childhood and adolescence. Pediatr Nephrol 1999; 13:846.
- Bagga A, Jain Y, Srivastava RN, Bhuyan UN. Renal tubular acidosis preceding systemic lupus erythematosus. Pediatr Nephrol 1993; 7:735.
- Batlle D, Ghanekar H, Jain S, Mitra A. Hereditary distal renal tubular acidosis: new understandings. Annu Rev Med 2001; 52:471.
- Rodríguez-Soriano J. New insights into the pathogenesis of renal tubular acidosis--from functional to molecular studies. Pediatr Nephrol 2000; 14:1121.
- Nash MA, Torrado AD, Greifer I, et al. Renal tubular acidosis in infants and children. Clinical course, response to treatment, and prognosis. J Pediatr 1972; 80:738.
- Rodriguez Soriano J, Boichis H, Stark H, Edelmann CM Jr. Proximal renal tubular acidosis. A defect in bicarbonate reabsorption with normal urinary acidification. Pediatr Res 1967; 1:81.
- Donckerwolcke RA, van Stekelenburg GJ, Tiddens HA. A case of bicarbonate-losing renal tubular acidosis with defective carboanhydrase activity. Arch Dis Child 1970; 45:769.
- 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.
- Jentsch TJ, Keller SK, Koch M, Wiederholt M. Evidence for coupled transport of bicarbonate and sodium in cultured bovine corneal endothelial cells. J Membr Biol 1984; 81:189.
- 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.
- Winsnes A, Monn E, Stokke O, Feyling T. Congenital persistent proximal type renal tubular acidosis in two brothers. Acta Paediatr Scand 1979; 68:861.
- Igarashi T, Ishii T, Watanabe K, et al. Persistent isolated proximal renal tubular acidosis--a systemic disease with a distinct clinical entity. Pediatr Nephrol 1994; 8:70.
- Brenes LG, Brenes JN, Hernandez MM. Familial proximal renal tubular acidosis. A distinct clinical entity. Am J Med 1977; 63:244.
- 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.
- Wang T, Yang CL, Abbiati T, et al. Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. Am J Physiol 1999; 277:F298.
- Knights MJ, Finlay E. The effects of sodium valproate on the renal function of children with epilepsy. Pediatr Nephrol 2014; 29:1131.
- Hall AM, Bass P, Unwin RJ. Drug-induced renal Fanconi syndrome. QJM 2014; 107:261.
- Chuang GT, Tsai IJ, Tsau YK, Lu MY. Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use. Nephrology (Carlton) 2015; 20:931.
- Foreman, JW. Fanconi syndrome and cystinosis. In: Pediatric Nephrology, 3rd ed, Holliday, MA, Barratt, TM, Avner, ED (Eds), Williams & Wilkins, Philadelphia 1994. p.537.
- Tashian RE. Genetics of the mammalian carbonic anhydrases. Adv Genet 1992; 30:321.
- Sly WS, Hewett-Emmett D, Whyte MP, et al. Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci U S A 1983; 80:2752.
- Whyte MP, Murphy WA, Fallon MD, et al. Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters. Am J Med 1980; 69:64.
- Roth DE, Venta PJ, Tashian RE, Sly WS. Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci U S A 1992; 89:1804.
- Pereira PC, Miranda DM, Oliveira EA, Silva AC. Molecular pathophysiology of renal tubular acidosis. Curr Genomics 2009; 10:51.
- Batlle DC, Arruda JA, Kurtzman NA. Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med 1981; 304:373.
- DISTAL (TYPE 1) RTA
- - Genetic causes
- - Acquired causes
- Clinical manifestations
- - Recessive form
- - Dominant form
- PROXIMAL (TYPE 2) RTA
- - Isolated proximal RTA
- - Fanconi syndrome
- Clinical features
- - Clinical findings of Fanconi syndrome
- MIXED (TYPE 3) RTA
- ALDOSTERONE DEFICIENCY OR RESISTANCE (TYPE 4 RTA)