Background: Distal renal tubular acidosis (dRTA) is characterized by an impairment of the urinary acidification process in the distal nephron. Complete or incomplete metabolic acidosis coupled with inappropriately alkaline urine are the hallmarks of this condition. Genetic forms of dRTA are caused by loss of function mutations of either SLC4A1, encoding the AE1 anion exchanger, or ATP6V1B1 and ATP6V0A4, encoding for the B1 and a4 subunits of the vH+ATPase, respectively. These genes are crucial for the function of A-type intercalated cells (A-IC) of the distal nephron. Summary: Alterations of acid-base homeostasis are variably associated with hypokalemia, hypercalciuria, nephrocalcinosis or nephrolithiasis, and a salt-losing phenotype. Here we report the diagnostic test and the underlying physiopathological mechanisms. The molecular mechanisms identified so far can explain the defect in acid secretion, but do not explain all clinical features. We review the latest experimental findings on the pathogenesis of dRTA, reporting mechanisms that are instrumental for the clinician and potentially inspiring a novel therapeutic strategy. Key Message: Primary dRTA is usually intended as a single-cell disease because the A-IC are mainly affected. However, novel evidence shows that different cell types of the nephron may contribute to the signs and symptoms, moving the focus from a single-cell towards a renal disease.

1.
Soriano JR: Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160-2170.
2.
Rodriguez-Soriano J, Vallo A: Renal tubular acidosis. Pediatr Nephrol 1990;4:268-275.
3.
Battle D, Haque SK: Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant 2012;27:3691-3704.
4.
Reddy P: Clinical approach to renal tubular acidosis in adult patients. Int J Clin Pract 2011;65:350-360.
5.
Gambaro G, Croppi E, Coe F, Lingeman J, Moe O, Worcester E, Buchholz N, Bushinsky D, Curhan GC, Ferraro PM, Fuster D, Goldfarb DS, Heilberg IP, Hess B, Lieske J, Marangella M, Milliner D, Preminger GM, Reis Santos JM, Sakhaee K, Sarica K, Siener R, Strazzullo P, Williams JC; Consensus Conference Group: Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. J Nephrol 2016;29:715-734.
6.
Karet FE, Gainza FJ, Gyory AZ, Unwin RJ, Wrong O, Tanner MJ, Nayir A, Alpay H, Santos F, Hulton SA, Bakkaloglu A, Ozen S, Cunningham MJ, Di Pietro A, Walker WG, Lifton RP: Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc Natl Acad Sci USA 1998;95:6337-6342.
7.
Chambrey R, Trepiccione F: Relative roles of principal and intercalated cells in the regulation of sodium balance and blood pressure. Curr Hypertens Rep 2015;17:538.
8.
Mumtaz R, Trepiccione F, Hennings JC, Huebner AK, Serbin B, Picard N, Ullah AKMS, Păunescu TG, Capen DE, Lashhab RM, Mouro-Chanteloup I, Alper SL, Wagner CA, Cordat E, Brown D, Eladari D, Hübner CA: Intercalated cell depletion and vacuolar H+-ATPase mistargeting in an Ae1 R607H knockin model. J Am Soc Nephrol 2017;28:1507-1520.
9.
Wrong O, Bruce LJ, Unwin RJ, Toye AM, Tanner MJ: Band 3 mutations, distal renal tubular acidosis, and Southeast Asian ovalocytosis. Kidney Int 2002;62:10-19.
10.
Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, Rodriguez-Soriano J, Santos F, Cremers CW, Di Pietro A, Hoffbrand BI, Winiarski J, Bakkaloglu A, Ozen S, Dusunsel R, Goodyer P, Hulton SA, Wu DK, Skvorak AB, Morton CC, Cunningham MJ, Jha V, Lifton RP: Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 1999;21:84-90.
11.
Fuster DG, Zhang J, Xie XS, Moe OW: The vacuolar ATPase B1 subunit in distal tubular acidosis: novel mutations and mechanisms for dysfunction. Kidney Int 2008;73:1151-1158.
12.
Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Lifton RP, Scherer SW, Karet FE: Mutations in ATP6N1B, in encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet 2000;26:71-75.
13.
Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, Giersch AB, Morton CC, Axon PR, Akil I, Al-Sabban EA, Baguley DM, Bianca S, Bakkaloglu A, Bircan Z, Chauveau D, Clermont MJ, Guala A, Hulton SA, Kroes H, Li Volti G, Mir S, Mocan H, Nayir A, Ozen S, Rodriguez Soriano J, Sanjad SA, Tasic V, Taylor CM, Topaloglu R, Smith AN, Karet FE: Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet 2002;39:796-803.
14.
Capasso G, Unwin R, Rizzo M, Pica A, Giebisch G: Bicarbonate transport along the loop of Henle: molecular mechanisms and regulation. J Nephrol 2002;15(suppl 5):S88-S96.
15.
Capasso G, Unwin R, Agulian S, Giebisch G: Bicarbonate transport along the loop of Henle. I. Microperfusion studies of load and inhibitor sensitivity. J Clin Invest 1991;88:430-437.
16.
Karim Z, Szutkowska M, Vernimmen C, Bichara M: Recent concepts concerning the renal handling of NH3/NH4+. J Nephrol 2006;19(suppl 9):S27-S32.
17.
Kim S, Lee JW, Park J, Na KY, Joo KW, Ahn C, Kim S, Lee JS, Kim GH, Kim J, Han JS: The urine-blood PCO gradient as a diagnostic index of H+-ATPase defect distal renal tubular acidosis. Kidney Int 2004;66:761-767.
18.
Batlle D, Grupp M, Gaviria M, Kurtzman NA: Distal renal tubular acidosis with intact capacity to lower urinary pH. Am J Med 1982;72:751-758.
19.
Wrong O, Davies HE: The excretion of acid in renal disease. Q J Med 1959;28:259-313.
20.
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;71:1310-1316.
21.
Al-Awqati Q: Terminal differentiation in epithelia: the role of integrins in hensin polymerization. Annu Rev Physiol 2011;73:401-412.
22.
Trepiccione F, Soukaseum C, Baudrie V, Kumai Y, Teulon J, Villoutreix B, Cornière N, Wangemann P, Griffith AJ, Byung Choi Y, Hadchouel J, Chambrey R, Eladari D: Acute genetic ablation of pendrin lowers blood pressure in mice. Nephrol Dial Transplant 2017, Epub ahead of print.
23.
Sinning A, Radionov N, Trepiccione F, López-Cayuqueo KI, Jayat M, Baron S, Cornière N, Alexander RT, Hadchouel J, Eladari D, Hübner CA, Chambrey R: Double knockout of the Na+-driven Cl-/HCO3- exchanger and Na+/Cl- cotransporter induces hypokalemia and volume depletion. J Am Soc Nephrol 2017;28:130-139.
24.
Trepiccione F, Zacchia M, Capasso G: The role of the kidney in salt-sensitive hypertension. Clin Exp Nephrol 2012;16:68-72.
25.
Trepiccione F, Soukaseum C, Iervolino A, Petrillo F, Zacchia M, Schutz G, Eladari D, Capasso G, Hadchouel J: A fate-mapping approach reveals the composite origin of the connecting tubule and alerts on “single-cell”-specific KO model of the distal nephron. Am J Physiol Renal Physiol 2016;311:F901-F906.
26.
Kovacikova J, Winter C, Loffing-Cueni D, Loffing J, Finberg KE, Lifton RP, Hummler E, Rossier B, Wagner CA: The connecting tubule is the main site of the furosemide-induced urinary acidification by the vacuolar H+-ATPase. Kidney Int 2006;70:1706-1716.
27.
Trepiccione F, Capasso G, Nielsen S, Christensen BM: Evaluation of cellular plasticity in the collecting duct during recovery from lithium-induced nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 2013;305:F919-F929.
28.
De Bruijn PI, Larsen CK, Frische S, Himmerkus N, Praetorius HA, Bleich M, Leipziger J: Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb. Am J Physiol Renal Physiol 2015;309:F146-F153.
29.
Wagner S, Vogel R, Lietzke R, Koob R, Drenckhahn D: Immunochemical characterization of a band 3-like anion exchanger in collecting duct of human kidney. Am J Physiol 1987;253:F213-F221.
30.
Peters LL, Shivdasani RA, Liu SC, Hanspal M, John KM, Gonzalez JM, Brugnara C, Gwynn B, Mohandas N, Alper SL, Orkin SH, Lux SE: Anion exchanger 1 (band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell 1996;86:917-927.
31.
Kittanakom S, Cordat E, Akkarapatumwong V, Yenchitsomanus PT, Reithmeier RA: Trafficking defects of a novel autosomal recessive distal renal tubular acidosis mutant (S773P) of the human kidney anion exchanger (kAE1). J Biol Chem 2004;279:40960-40971.
32.
Cordat E, Kittanakom S, Yenchitsomanus PT, Li J, Du K, Lukacs GL, Reithmeier RA: Dominant and recessive distal renal tubular acidosis mutations of kidney anion exchanger 1 induce distinct trafficking defects in MDCK cells. Traffic 2006;7:117-128.
33.
Walsh S, Borgese F, Gabillat N, Unwin R, Guizouarn H: Cation transport activity of anion exchanger 1 mutations found in inherited distal renal tubular acidosis. Am J Physiol Renal Physiol 2008;295:F343-F350.
34.
Walsh S, Turner MC, Toye A, Wagner CA, Jaeger P, Laing C, Unwin R: Immunohistochemical comparison of a case of inherited distal renal tubular acidosis (with a unique AE1 mutation) with an acquired case secondary to autoimmune disease. Nephrol Dial Transplant 2007;22:807-812.
35.
Stehberger PA, Shmukler BE, Stuart-Tilley AK, Peters LL, Alper SL, Wagner CA: Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl-/HCO3- exchanger (slc4a1). J Am Soc Nephrol 2007;18:1408-1418.
36.
Akel A, Wagner CA, Kovacikova J, Kasinathan RS, Kiedaisch V, Koka S, Alper SL, Bernhardt I, Wieder T, Huber SM, Lang F: Enhanced suicidal death of erythrocytes from gene-targeted mice lacking the Cl-/HCO3- exchanger AE1. Am J Physiol Cell Physiol 2007;292:C1759-C1767.
37.
Jarolim P, Shayakul C, Prabakaran D, Jiang L, Stuart-Tilley A, Rubin HL, Simova S, Zavadil J, Herrin JT, Brouillette J, Somers MJ, Seemanova E, Brugnara C, Guay-Woodford LM, Alper SL: 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;273:6380-6388.
38.
Coury F, Zenger S, Stewart AK, Stephens S, Neff L, Tsang K, Shull GE, Alper SL, Baron R, Aliprantis AO: SLC4A2-mediated Cl-/HCO3-exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts. Proc Natl Acad Sci USA 2013;110:2163-2168.
39.
Finberg KE, Wagner CA, Bailey MA, Paunescu TG, Breton S, Brown D, Giebisch G, Gaibel JP, Lifton RP: The B1-subunit of the H+ATPase is required for maximal urinary acidification. Proc Natl Acad Sci USA 2005;102:13616-13621.
40.
Dou H, Finberg KE, Cardell EL, Lifton RP, Choo D: Mice lacking the B1 subunit of H+-ATPase have normal hearing. Hear Res 2003;180:76-84.
41.
Gueutin V, Vallet M, Jayat M, Peti-Peterdi J, Cornière N, Leviel F, Sohet F, Wagner CA, Eladari D, Chambrey R: Renal β-intercalated cells maintain body fluid and electrolyte balance. J Clin Invest 2013;123:4219-4231.
42.
Hennings JC, Picard N, Huebner AK, Stauber T, Maier H, Brown D, Jentsch TJ, Vargas-Poussou R, Eladari D, Hubner CA: A mouse model for distal renal tubular acidosis reveals a previously unrecognized role of the V-ATPase a4 subunit in the proximal tubule. EMBO Mol Med 2012;4:1057-1071.
43.
Trepiccione F, Gerber SD, Grahammer F, Lopez-Cayuqueo KI, Baudrie V, Paunescu TG, Capen DE, Picard N, Alexander RT, Huber TB, Chambrey R, Brown D, Houillier P, Eladari D, Simons M: Renal Atp6ap2/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system. J Am Soc Nephrol 2016;27:3320-3330.
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