The Kidney in Genetic and Rare Diseases: Review Kidney Dis 2017;3:98–105 Received: April 20, 2017 DOI: 10.1159/000478781 Accepted after revision: June 7, 2017 Published online: August 24, 2017 New Findings on the Pathogenesis of Distal Renal Tubular Acidosis a a, b a, b Francesco Trepiccione Federica Prosperi Luigi Regenburgh de la Motte c d e Christian A. Hübner Regine Chambrey Dominique Eladari a, b Giovambattista Capasso a Department of Cardiothoracic and Respiratory Science, University of Campania “Luigi Vanvitelli,” Naples , and b c Biogem S.c.a.r.l., Research Institute Gaetano Salvatore, Ariano Irpino , Italy; Institute of Human Genetics, Jena d University Hospital, Friedrich Schiller University, Jena , Germany; Inserm U1188, Diabète athérothrombose e Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, and Service d’Explorations Fonctionnelles Rénales, Hôpital Felix Guyon, CHU de la Réunion, Saint-Denis , Ile de la Réunion, France Keywords instrumental for the clinician and potentially inspiring a nov- AE1 · Intercalated cells · Metabolic acidosis · Renal tubular el therapeutic strategy. Key Message: Primary dRTA is usu- acidosis · vH + ATPase ally intended as a single-cell disease because the A-IC are mainly affected. However, novel evidence shows that differ- ent cell types of the nephron may contribute to the signs and Abstract symptoms, moving the focus from a single-cell towards a re- Background: Distal renal tubular acidosis (dRTA) is charac- nal disease. © 2017 S. Karger AG, Basel terized 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 Clinical Aspects by loss of function mutations of either SLC4A1 , encoding the AE1 anion exchanger, or ATP6V1B1 and ATP6V0A4 , encoding Distal renal tubular acidosis (dRTA) has been the first for the B1 and a4 subunits of the vH+ ATPase, respectively. type of RTA identified and is thus also known as type I These genes are crucial for the function of A-type interca- RTA. dRTA is characterized by impaired renal acid secre- lated cells (A-IC) of the distal nephron. Summary: Alter- tion (with normal glomerular filtration rate) causing met- ations of acid-base homeostasis are variably associated with abolic acidosis. On the clinical side, this leads to the excre- hypokalemia, hypercalciuria, nephrocalcinosis or nephroli- tion of alkaline urine relative to systemic metabolic aci- thiasis, and a salt-losing phenotype. Here we report the di- dosis [1] . Additional signs associated with dRTA can be agnostic test and the underlying physiopathological mecha- hypokalemia, hypercalciuria, nephrocalcinosis or neph- nisms. The molecular mechanisms identified so far can ex- plain the defect in acid secretion, but do not explain all clinical features. We review the latest experimental findings This work was presented as the international conference “The Kidney on the pathogenesis of dRTA, reporting mechanisms that are in Genetic and Rare Diseases,” Naples, October 27–29, 2016. © 2017 S. Karger AG, Basel Francesco Trepiccione Department of Cardiothoracic and Respiratory Science University of Campania “Luigi Vanvitelli” E-Mail [email protected] Via Pansini 5, IT–80131 Naples (Italy) www.karger.com/kdd E-Mail francesco.trepiccione @ unicampania.it rolithiasis, and sometimes salt-losing disease [2] . The Systemic bicarbonate refilling is dependent on inten- term “incomplete dRTA” instead refers to patients with sive reabsorption of almost all the filtered bicarbonate – – no overt metabolic acidosis at baseline who are screened (FE HCO3 <1%) and on the synthesis of new HCO3 for dRTA, usually because of nephrolithiasis or nephro- molecules during ammoniagenesis. These mechanisms calcinosis, and who can not maximally acidify urine (uri- have been extensively detailed elsewhere [14] . Briefly, bi- nary pH >5.3) following the administration of an acid carbonate reabsorption occurs mainly along the proximal load [1] . tubule (PT) and the thick ascending limb (TAL) and de- Primary dRTA is a genetic disease and usually mani- pends on a similar machinery of proteins [15] . On the fests during childhood or adolescence [3] , while second- apical side, NHE3 and carbonic anhydrase IV mediate – ary dRTA can occur at any age, either induced by drugs, intracellular HCO3 intake and, on the basolateral side, autoimmune or urological diseases, or dysproteinemia NBCe-1 (for the PT) and AE2 (for the TAL) contribute to [4, 5] . Mutations in the chloride-bicarbonate exchanger its final reabsorption in the bloodstream. – + AE1, known as band 3 protein in erythrocytes (RBC), Finally, in the PT, new HCO3 and NH4 are gener- have been found to cause autosomal dominant or reces- ated during deamination of glutamine and other amino + sive dRTA [6] . AE1 is expressed at the basolateral mem- acids, and then NH4 is secreted in the urine while the brane of A-type intercalated cells (A-IC) in the distal bicarbonate is reabsorbed in the bloodstream. Secreted + nephron, where it is required to transport bicarbonate NH4 is then reabsorbed along the TAL and accumulated + generated during acid secretion from the cytosol to the in the medullary interstitium as NH3 /NH4 where it con- renal interstitium [7] . Loss of function mutations of AE1 tributes to medulla hypertonicity [16] . Final ammonia are not always associated with both renal and hemato- secretion in the urine is strictly connected to the renal logical phenotype simultaneously, even though band 3 is excretion of nonvolatile acids along the distal nephron. the most abundant protein of the membrane of RBC [8] , Indeed, to maximize H + excretion, the urine contains dif- revealing a different functional setting in these two cell ferent buffer systems. Titratable acids (mainly creatinine, types. Indeed, AE1 dysfunction leading to hereditary phosphate, and to a lesser extent urate and citrate) and + ovalocytosis or spherocytosis is commonly associated the NH3 /NH4 buffers are the most effective along the with the autosomal recessive form of dRTA, but not with outer and inner medulla collecting duct (CD), respec- autosomal dominant dRTA [6] . Since autosomal reces- tively. sive mutations are common in the tropical area, whereas Under normal conditions, the residual buffer capacity – the dominant ones prevail in Western countries, Wrong of HCO3 /pCO2 is poor in the distal nephron, but it can et al. [9] proposed that this geographic distribution could play a major role when the upstream bicarbonate reab- confer protection against malaria in heterozygous carri- sorption threshold is decreased as during proximal RTA, ers, especially in South Asia. or saturated as during sodium bicarbonate load. Indeed, Mutations in two subunits of the vH + ATPase, namely by increasing the delivery of bicarbonate to the distal – ATP6V1B1 and ATP6V0A4 , also cause autosomal reces- nephron, the HCO3 buffered by the protons secreted lo- sive dRTA. Mutations of ATP6V1B1 , encoding for the B1 cally will increase urinary pCO2 excretion. Since this pro- subunit of vH + ATPase, are usually associated with bilat- cess is an effect of distal urine proton secretion, the urine eral sensorineural hearing loss [10] . Consistent with this to blood pCO2 ratio after a challenge with NaHCO3 load finding, ATP6V1B1 expression is found in the cochlea is an efficient method to explore distal urine acidification and endolymphatic sac [11] . Mutations of ATP6V0A4 , in humans [17] . encoding for the a4 subunit of vH + ATPase, cause autoso- The overall urinary evaluation of titratable acidity, + – mal recessive dRTA, associated in some cases with hear- NH4 , and HCO3 allows to estimate renal net acid excre- ing impairment in late childhood [12, 13] . tion. Clinical physiological tests to diagnose renal acid- base disorders were based on these principles already be- fore the molecular players of acid secretion were known. Renal Acidification Mechanisms: Indeed, the acid-secreting ability of the kidney was inves- From Molecular Mechanisms to Clinical Tests tigated by studying the urine to blood pCO 2 ratio after NaHCO3 load [18] or by challenging patients with an acid In order to contribute to the acid-base homeostasis, load through NH4 Cl administration [19] and, more re- the kidneys regenerate bicarbonate and excrete nonvola- cently, by the administration of furosemide/fludrocorti- tile acids. sone [20] ( Table 1 ). All these tests are still used in clinics Pathogenesis of Distal Renal Tubular Kidney Dis 2017;3:98–105 99 Acidosis DOI: 10.1159/000478781 Table 1. Clinical tests to diagnose renal acid-base disorders The presence of an active transport allows the secretion of protons even in the presence of a steep gradient (about Challenge Measure Positive × Ref. 1 unit of pH). However, the efficacy of the proton secre- dRTA tion requires the presence of a buffer system able to de- NaHCO3 (U-B) pCO2 <20 mm Hg 15 crease the free proton concentration in the lumen and NH4Cl urinary pH >5.3 16 thus to prevent the gradient-driven back leak of protons. Furosemide/fludrocortisone urinary pH >5.3 17 The diffusion of NH3 from the interstitium to the tubular lumen, mainly in the inner stripe of the outer medulla, al- dRTA, distal renal tubular acidosis; U-B, urine to blood. + lows proton buffering and trapping. Hence, NH4 be- comes the molecular readout of efficient distal acid se- cretion. This mechanism is maximized during acidosis, where not only the abundance of vH + ATPase, but also the nowadays and their underlying molecular mechanisms number of A-IC is increased in the inner stripe of the out- are mostly known. er medulla [8] . This is the rationale for using NH4 Cl to Acid secretion along the distal nephron mainly occurs evocate a maximal urinary acidification. Indeed, liver con- + through A-IC. These cells are equipped at the apical side version of NH4 to urea dissipates bicarbonate and so in- with the vH + ATPase and at their basolateral side with the duces a metabolic acidosis which persists until the kidney anion exchanger AE1, showing an acid-secreting pheno- has completely excreted this acid load.