Distal renal tubular acidosis: a hereditary disease with an inadequate urinary H+ excretion

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"idiomaDefecto" => true "titulo" => "Distal renal tubular acidosis: a hereditary disease with an inadequate urinary H+ excretion" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "289" "paginaFinal" => "296" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Laura Escobar, Natalia Mejía, Helena Gil, Fernando Santos" "autores" => array:7 [ 0 => array:4 [ "nombre" => "Laura" "apellidos" => "Escobar" "email" => array:1 [ 0 => "dra.laurae@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:4 [ "nombre" => "Laura" "apellidos" => "Escobar" "email" => array:1 [ 0 => "atr.funatim@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 2 => array:3 [ "nombre" => "Natalia" "apellidos" => "Mejía" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 3 => array:3 [ "nombre" => "Helena" "apellidos" => "Gil" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 4 => array:3 [ "nombre" => "Helena" "apellidos" => "Gil" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 5 => array:3 [ "nombre" => "Fernando" "apellidos" => "Santos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 6 => array:3 [ "nombre" => "Fernando" "apellidos" => "Santos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Departamento de Fisiología, Facultad de Medicina. Universidad Nacional Autónoma de México, Ciudad de México, DF, México, " "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Departamento de Pediatría, Universidad de Oviedo, Oviedo, España, " "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Departamento de Pediatría, Universidad de Oviedo, Oviedo, Asturias, Spain, " "etiqueta" => "c" "identificador" => "affc" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La acidosis tubular renal distal: una enfermedad hereditaria en la que no se pueden eliminar los hidrogeniones" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11592_16025_44702_en_f211592i.jpg" "Alto" => 532 "Ancho" => 1018 "Tamanyo" => 147905 ] ] "descripcion" => array:1 [ "en" => "Topology of the erythrocyte AE1 Cl-/HCO3- exchanger" ] ] ] "textoCompleto" => "In daily clinical practice, the diagnosis of a disease is usually based on the study of its clinical, biochemical, radiological and anatomical pathology manifestations. However, we depend on the development of basic research to identify and understand the cellular and molecular mechanisms involved in the aetiology of a disease.Despite progress in the understanding of many diseases, the pathogenesis of many others has remained unknown. In many cases, although there are specific factors associated with the disease, we can not tell whether these are related to it by chance or whether they are actually a consequence of it.Currently, genetic studies may reveal the genes involved in a disease whose origin is unknown. The importance of this strategy is that no hypothesis is necessary with regard to the pathogenesis of the disease, except the hypothesis that genetic variation contributes to the disease and that genes, which are related to the disease by chance, can be identified easily. During the past 20 years, the enormous power of this concept has been demonstrated with the identification of more than 2000 disease-related genes, which has revolutionised our perspective regarding their origin.There are various genetic diseases in at least 10% of patients with renal failure1 and genetic factors that influence the progression of chronic damage in kidney diseases contracted.2-4 Hereditary kidney diseases have variable frequencies; for example, autosomal dominant polycystic kidney disease is the most common, affecting 1 in every 1000 people. By contrast, other hereditary kidney diseases are rare, which means that they only affect less than 5 people per 10 000.1There is no doubt that hereditary kidney disease deteriorates the quality of life of patients. Unfortunately, our knowledge of most of these diseases is limited due to low incidence, phenotypic variability, lack of standardised diagnostic procedures and fragmentation of biological and clinical information obtained from studies with small groups. Moreover, the low prevalence of these diseases is not attracting the interest of the pharmaceutical industry and funding for research is scarce. However, the study of ‘rare’ diseases is a unique opportunity to shed light on their origin and understand the molecular scaffold complex that explains the functioning of an organ and the factors that causes deterioration.The rapid development of exome and genome sequencing technologies opens new perspectives for the diagnosis of more than 17 000 Mendelian or monogenic diseases. Moreover, a functional study of the mutant proteins in animal models and cell models reveals the aetiology of the disease and constitutes the reference framework for drug design and/or prevention of the toxic effects of some drugs.5, 6 METABOLIC ACIDOSIS Metabolic acidosis is characterised by a decrease in blood pH with a drop in bicarbonate concentration in plasma. In individuals with normal respiratory response, metabolic acidosis causes compensatory hyperventilation which mitigates the fall in blood pH. Consequently, blood pH homeostasis is maintained as a result of the concentration quotient bicarbonate/CO2, which is the cell and blood buffer par excellence.The extracellular pH must be maintained within a very narrow range of 7.38 to 7.42. pH homeostasis is critical for cell function and, therefore, of our organs. A more acidic blood pH than normal may be the result of: an accumulation of acids (lactic acidosis, ketoacidosis, renal failure), loss of bicarbonate via the gastrointestinal tract (as in the case of chronic diarrhoea or malabsorption7) and bicarbonate loss due to a defect in its renal reabsorption or due to its consumption as a result of a defect in the urinary excretion of hydrogen ions by the kidney (hyperchloraemic acidosis or distal renal tubular acidosis, dRTA).8-13The catabolism of food ingested and that of the metabolites of our own cells produces two types of acids: volatile (CO2) and non-volatile (sulphuric, phosphoric and ammonium). Protein intake produces an acid load that results in H+ ions: from 1mEq/kg/day in adults and double this amount in children.12,14 The circulating nucleic acids consume the bicarbonate present in the plasma; however, the kidney can compensate this loss, since it produces and reabsorbs the bicarbonate.  ACID-BASE BALANCE IN THE KIDNEY The kidney maintains and controls the acid-base balance of  blood through three mechanisms: filtration and reabsorption of bicarbonate, acid (or alkali) excretion and synthesis of ammonium and bicarbonate. In the kidney, two connected biochemical processes take place: bicarbonate reabsorption and the synthesis, secretion, recycling and urinary excretion of ammonium.The presence of multiple transport systems in the different segments of the nephron tubules makes it possible to recover all the bicarbonate (HCO3-) filtered (4320mmol/day) in the glomerulus.14 In the first tubular segments of the nephron, the proximal tubules reabsorb approximately 80% of bicarbonate. In this tubular segment, bicarbonate reabsorption occurs through the Na+/HCO3-(NBCe1) cotransporter; this absorption is connected the secretion of acid in urine by the Na+/H+ (NHE3) exchanger.15 In the proximal tubules, circulating glutamine is reabsorbed from which ammonium and bicarbonate are simultaneously synthesised.The reabsorption of 15% of the bicarbonate occurs in the thick ascending loop of Henle and only about 5% of the bicarbonate is recovered in the distal tubules of the nephron.16,17 Lastly, kidney performs the excretion of the acid load in the urine: diacid phosphate H2PO4- (titratable acid) and ammonium sulphate.  THE IMPORTANCE OF URINARY ACIDIFICATION Urinary acidification, together with citrate excretion, is essential in the removal of organic and inorganic salts in soluble form. The urinary buffers are phosphates, but ammonium/ammonia acts as a buffer to a greater extent.The intake of an acid load such as in a high-protein meal, causes the kidneys to produce a more acidic urine (pH<5.5); it also decreases the rate of bicarbonate excretion and increases phosphate and ammonium excretion.18-21 TRANSPORT MECHANISMS WHICH PARTICIPATE IN ACID-BASE HOMEOSTASIS IN ALPHA INTERCALATED CELLS The secretion of H+ hydrogen ions in urine is carried out in the alpha-intercalated cells of cortical and medullary collecting ducts (Figure 1). H+ ATPase, V-ATPase, catalyses the passage of H+ from the cytoplasm to the tubular lumen. Anhydrase carbonic CA2 produces H+ hydrogen ions and simultaneously, bicarbonate is reabsorbed through the Cl-/HCO3- exchanger, corresponding to the AE1 isoform. The ammonium excretion mechanism takes place in two stages: firstly, there is uptake from the interstitium to the cytoplasm via HCN2 voltage-activated ammonium channels21 and Rhcg ammonia channels. 20 HCN2 channels are constitutive, they may uptake ammonium and/or sodium and are not regulated by metabolic acidosis.21 By contrast, Rhcg ammonia channels are located both in apical membranes and in basolateral membranes,22 and their destination to the membranes is regulated by metabolic acidosis.20 AE1 Cl-/HCO3- EXCHANGER  The SLC4A1 gene encodes the AE1 exchanger, a dimeric glycoprotein with 12-14 transmembrane domains23-25 (Figure 2). There are three genes in the AE1 family and in the tissues in which AE1 is expressed, AEI it participates in the regulation of pH, cell volume and the transcellular transport of acid and base in epithelial cells.26-28AE1 presents a specific isoform of erythrocytes and a specific short isoform of the kidney.29 In erythrocytes, AE1, in addition to exchanging chloride for the bicarbonate of the plasma, has a structural role in interacting with cytoskeletal proteins that contribute to AE1 traffic and its stability in the plasma membrane.23 As such, AE1 plays a central role in respiration by transporting and removing CO2 via the lungs and in acid-base homeostasis in the kidney.30 In the kidney, AE1 performs bicarbonate reabsorption into the interstitial space and blood vessels.31 There is a group of mutations in AE1 that cause deformations in the erythrocyte and whose inheritance is autosomal dominant: inherited spherocytic anaemia, Southeast Asian ovalocytosis and other stomatocytosis with normal kidney function.32 There are other series of AE1 mutations that generate dRTA associated with erythrocyte problems.10,33,34 AE1 mutations can be consulted at: www.ensembl.org and www.hgmd.org  V-ATPase Vacuolar H- ATPase (V-ATPase) belongs to an H+ hydrogen-ion pump family and is located in a variety of membranes: endosomes, lysosomes, secretory vesicles and in the plasma membranes of eukaryotes.35-37 V-ATPase is a multimeric enzyme complex that consists of 14 subunits (Figure 3); it has two domains: one in the cytoplasm (V1) and the other in the membrane (V0). V1 is the catalytic domain and it has 8 subunits (A-H). Domain V0 comprises 6 subunits (a, c, c”, d, e, and Ac45 in mammals) and translocates H+ through the membrane.35-37 There are three copies of subunits A and B that alternate in a ring-shaped arrangement (Figure 3). The catalytic sites are in subunit A1 and the interface between subunits A-B regulates the activity of the enzyme.38-39 Subunit 'a' in V0 allows access to hemichannels through which H+ hydrogen ions are exported to the luminal space.37 There are four isoforms of subunit 'a' (a1-a4) and they have a 47-61% identity in humans.35 Subunit 'a' also participates in traffiking of V-ATPase in mammal cells.37In alpha-intercalated cells of the collecting duct, V-ATPase is located on the apical membranes and secretes H+ in urine (Figure 1).35 Subunits B1 and a4 of V-ATPase are specific alpha-intercalated cells of the collecting duct. Defects in these subunits lead to “distal renal tubular acidosis” or dRTA.9,40 As the B1 subunit is also expressed in the ciliary cells of the inner ear,9 mutations in subunit B1 produce dRTA with deafness.The gene ATP6V1B1 encodes B1 subunit and comprises 14 exons, which produce a protein consisting of 513 amino acids. The gene ATP6V0A4 has 24 exons of which 20 encode the 840 amino acids of a4 subunit.35There are other transport systems in alpha-intercalated cells of the distal nephron which are also involved in acid-base homeostasis, such as carbonic anhydrase II,41 the KCC4 potassium/chloride cotransporter42, 43, Rhcg20,44 and the HCN2 ammonium channel (Figure 1).21 H-K-ATPase present in the apical membrane of alpha-intercalated cells does not seem to participate in secretion, but rather in reabsorption of K+ in hypokalemia.40.45Figure 1 illustrates  transporters, ion channels and V-ATPase in alpha-intercalated cells of the collecting duct. It is important to highlight that, traduction, and destination to the membrane of many transporters and ion channels depend on metabolic conditions.Collecting duct microperfusion trials and knockout mouse models have helped to elucidate transport pathways involved in acid-base homeostasis in alpha-intercalated cells. For example, the mouse not expressing KCC4 develops sensorineural deafness, as well as dRTA.42 There is another Cl/bicarbonate exchanger which also operates as a Cl- channel, Slc26a7, activated by hypertonicity.46 Mouse Slc26a7 -/- develops dRTA.47 It is noteworthy that mice that do not express the ammonia channel (Rhcg -/-) have problems in excreting only in metabolic acidosis, suchas in  incomplete dRTA.44 The ammonium channel HCN2 is a constitutive ion channel involved in baseline ammonium excretion but it does not appear to be regulated by metabolic acidosis. 21 DISTAL RENAL TUBULAR ACIDOSIS dRTA belongs to the group of renal diseases with a very low incidence in any population.In dRTA, the ability to acidify urine is lost due to a defect in the excretion of acid load (H+ and ammonium ions) in alpha-intercalated cells of the collecting duct. The acid load accumulation in the distal nephron results in consumption and reduction of the bicarbonate/CO2 buffer in blood. The symptoms accompanying dRTA include stunted growth, vomiting, diarrhoea and/or constipation, loss of appetite, polydipsia and polyuria, nephrocalcinosis and it may also present weakness and muscle paralysis due to loss of potassium (hypokalemia).To diagnose dRTA in the clinic, it is necessary to determine plasma creatinine and fractional sodium, potassium and chloride excretion, calciuria and citraturia. Acidosis is generally observed in blood (pH<7.35) as well as a marked decrease in the concentration of bicarbonate and CO2 (<15mEq/l). In dRTA, urine pH is higher than 6 in the presence of systemic metabolic acidosis.For cases in which diagnosis is uncertain, as in incomplete dRTA, it is advisable to perform acidification tests. These tests involve the administration of NH4Cl to determine pH, titratable acidity and urinary ammonium excretion.48 Due to complications of this test in children, acidification capacity can be evaluated by determining the maximum urinary pCO2 (UpCO2) with the intake of sodium bicarbonate (4mEq/kg).49 The pCO2 urinary test can be performed with sodium bicarbonate or acetazolamide stimuli or both, in this case administered at half the usual dose. Another test is furosemide with fludrocortisone.49-52Diagnostic tests confirm the inability to excrete acid loads by observing a urinary pH higher than 5.5.Ultrasound studies in patients with dRTA show the presence of calcium deposits in the renal tissue (nephrocalcinosis) and/or urinary tract stones (nephrolithiasis).Chronic acidosis and intercurrent secondary problems (vomiting, polyuria, dehydration, rejection of dose, etc..) affect growth and, consequently, there is a decrease in the size and weight of the patients. dRTA is accompanied by hyperchloraemia as a result of decreased HCO3- in blood. In dRTA, hypokalemia is observed ([K]<3.5mEq/l), along with hypercalciuria and hypocitraturia. Hypercalciuria occurs when there is urinary calcium excretion greater than 4mg/kg/day in both adults and in children. It is necessary to consider that the urinary calcium/creatinine quotient in infants varies with age. Normal values according to age are: 0-6 months <0.8 mg/mg, 6 to 12 months <0.6 mg/mg, 1 to 2 years <0.5 mg/mg.53 In adults, hypocitraturia is considered a value below 300 mg/day for both sexes, and/or a citrate/creatinine rate value below 250 mg/g. In children hypocitraturia is considered a value below 8 mg/kg/day and/or a citrate/creatinine quotient below 400 mg/g.53It is important to highlight that calcium excretion in urine is high in infants and decreases progressively with age. As such, hypocitraturia is most relevant in the development of nephrocalcinosis and urolithiasis, in which primarily calcium phosphate salts are deposited. It is also noteworthy that dRTA cases have been found without no hipercalciuria.54 Patients with dRTA display a positive urine anion gap and a normal plasma anion gap ([Na+] + [K+] - [Cl]), distinguishing it from other types of acidosis, such as ketoacidosis , lactic acidosis and acidosis due to poisoning with solvents or drugs, with a higher plasma anion gap than normal.7 Untreated, dRTA causes stunted growth, rickets in children and osteomalacia in adults, and deterioration of renal function over the years. Fortunately, dRTA has good prognosis if it is diagnosed at an early age and alkaline treatment is continued, which consists of periodic doses of sodium bicarbonate and/or potassium citrate during the day. HEREDITARY FORMS OF RENAL TUBULAR ACIDOSIS Mutations in genes produce varying effects: premature stop codons, shift of the open reading frame, alternate RNA processing and changes in the chemical nature of more than one amino acid. Mutations cause structural alterations in proteins which may lead to loss of function.In autosomal dominant dRTA, one parent suffers and is the carrier of the disease. The groups of Michael Tanner of the University of Bristol and Fiona Karet of the Medical Research Institute of Cambridge in the United Kingdom were the first to identify mutations in the SLC4A1 gene in families with autosomal dominant dRTA.55,56 AE1 mutations in autosomal dominant dRTA are always heterozygous. The loss of AE1 function in the erythrocyte causes hereditary spherocytosis and ovalocytosis.55The AE1 kidney-specific isoform is shorter: it does not have the first 65 amino acids of the NH2-terminus of the AE1 erythrocyte. As such, autosomal dominant dRTA only affects renal function in  patients when AE1 mutations are located in the transmembrane domain and in the carboxyl-terminus (Figure 2).23,25,32,57-59Autosomal dominant dRTA appears in later childhood or in adulthood.  AUTOSOMAL RECESSIVE DISTAL RENAL TUBULAR ACIDOSIS IS HETEROGENEOUS In autosomal recessive dRTA, parents do not suffer from the disease. Symptoms occur during the first months of life. Autosomal recessive dRTA is associated with mutations in any of the following genes: SLC4A160, ATP6V0A4 and ATP6V1B1.10,54,61Fiona Karet’s group pioneered lineage studies in families with autosomal recessive dRTA.9 The families that were analysed were of Turkish origin, mostly from consanguineous marriages. The age of children with autosomal recessive dRTA who participated in the study ranged from 1 month to 3 years; all had nephrocalcinosis and hypercalciuria, and more than 50% displayed sensorineural deafness. So far, around 20 mutations of the gene ATP6V1B1 have been identified.9,54,61,62 Most mutations are homozygous and exceptionally, compound heterozygous. These findings also revealed that the H-K-ATPase enzyme, present in the alpha-intercalated cells, can not compensate for the lack of function of V-ATPase.9There was an interesting case of dizygotic twins with deafness, only one of whom developed autosomal recessive dRTA.63dRTA in which deafness appears from the second decade of life is associated with mutations in the gene ATP6V0A440,61,64. So far, more than 20 mutations in ATP6V0A4 are known (www.ensembl.org and <a href="http://www.hgmd.org" class="elsevierStyleCrossRefs">www.hgmd.org</a>).Approximately 20% of cases with dRTA are not associated with mutations in any of these genes: there are dRTA patients with deafness who have no ATP6V1B1 gene mutations and others with normal hearing who do not have ATP6V0A4 gene mutations. These findings suggest that other transporters or channels (Figure 1) would be mutated. Therefore, recessive dRTA is heterogeneous because it may occur by mutations in more than one gene.Mutations have been identified in genes ATP6V1B1 and ATP6V0A4 in groups of Arab10,61 and Italian65 origin; and only mutations in ATP6V1B1 have been discovered in those of Spanish54, Greek66, Iranian67 and Serbian68 origin.Mutations in the SLC4A1 gene, which encodes the AE1 Cl-/HCO3- exchanger, also produce autosomal recessive dRTA. To date, 11 mutations of SLC4A1 are known that produce dRTA, in addition to ovalocytosis or spherocytosis13 (Figure 3). AE1 mutations have been found mostly in the Asian population. dRTA cases in Asia are an example of natural selection, since they are resistant to malaria.In conclusion, genetic studies have contributed to the identification of three genes affected in dRTA. Genetic studies of new molecular markers, such as Slc26a7 and KCC4 transporters or Rhcg and HCN2 channels in patients with dRTA are a challenge in the identification of new molecular targets that help the understanding of the disease and, consequently to the acid-base homeostasis in the kidney. Conflicts of interest The authors declare that they have no conflicts of interest related to the contents of this article. Laura Escobar receives an allowance and funding from the Dirección General de Asuntos del Personal Académico (DGAPA) de la Universidad Nacional Autónoma de México and the Fundación Carolina.<a href="grande/11592_16025_44702_en_f211592i.jpg" class="elsevierStyleCrossRefs"><img src="11592_16025_44702_en_f211592i.jpg" alt="Topology of the erythrocyte AE1 Cl-/HCO3- exchanger"></img></a>Figure 2. Topology of the erythrocyte AE1 Cl-/HCO3- exchanger<a href="grande/11592_16025_44703_en_f311592i.jpg" class="elsevierStyleCrossRefs"><img src="11592_16025_44703_en_f311592i.jpg" alt="Structure and composition of human V-ATPase"></img></a>Figure 3. Structure and composition of human V-ATPase<a href="grande/11592_16025_44710_en_f111592i.jpg" class="elsevierStyleCrossRefs"><img src="11592_16025_44710_en_f111592i.jpg" alt="Model of an acid-secreting alpha-intercalated cell"></img></a>Figure 1. Model of an acid-secreting alpha-intercalated cell" "pdfFichero" => "P1-E550-S4070-A11592-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:6 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec435981" "palabras" => array:1 [ 0 => "Retraso en el crecimiento" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec435983" "palabras" => array:1 [ 0 => "Hipopotasemia" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec435985" "palabras" => array:1 [ 0 => "Poliuria" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec435987" "palabras" => array:1 [ 0 => "Polidipsia" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec435989" "palabras" => array:1 [ 0 => "Nefrocalcinosis" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec435991" "palabras" => array:1 [ 0 => "Acidosis tubular renal distal" ] ] ] "en" => array:6 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec435982" "palabras" => array:1 [ 0 => "Stunted growth" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec435984" "palabras" => array:1 [ 0 => "Hypokalemia" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec435986" "palabras" => array:1 [ 0 => "Polyuria" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec435988" "palabras" => array:1 [ 0 => "Polydipsia" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec435990" "palabras" => array:1 [ 0 => "Nephrocalcinosis" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec435992" "palabras" => array:1 [ 0 => "Distal renal tubular acidosis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "La acidosis tubular renal distal (ATRD) o ATR tipo I se caracteriza por una disminución en la excreción urinaria de los hidrogeniones H+ y del amonio. En los niños afectados por ATRD hay retraso en el crecimiento, vómito, estreñimiento, falta de apetito, polidipsia y poliuria, nefrocalcinosis, debilidad y hasta parálisis muscular por la hipopotasemia. En este trabajo se resumen los avances en el estudio genético de la ATRD en las poblaciones hasta ahora estudiadas. La ATRD es heterogénea, por lo que también se analizan los transportadores y canales iónicos que se han identificado hasta ahora en las células intercaladas alfa del túbulo colector, y que podrían explicar los casos de ATRD que no se asocian con los genes hasta ahora estudiados. La ATRD puede ser autosómica dominante o autosómica recesiva. La ATRD autosómica recesiva se manifiesta en los primeros meses de vida, cursa con nefrocalcinosis y sordera temprana o tardía. La ATRD autosómica dominante es menos severa y aparece en la adolescencia o en la etapa adulta, y puede o no presentar nefrocalcinosis. En las células intercaladas alfa de los túbulos colectores se lleva a cabo la excreción urinaria de la carga ácida: los ácidos titulables (fosfatos) y el amonio. La ATRD autosómica recesiva se asocia con mutaciones en los genes ATP6V1B1, ATP6V0A4 y SLC4A1, los cuales codifican las subunidades a4 y B1 de la V-ATPasa y el intercambiador de bicarbonato/cloruro AE1, respectivamente. En contraste, la ATRD autosómica dominante se relaciona con mutaciones solo en AE1." ] "en" => array:1 [ "resumen" => "Distal renal tubular acidosis (dRTA) or RTA type I is characterised by reduced H+ hydrogen ions and ammonium urinary excretion. In children affected by dRTA there is stunted growth, vomiting, constipation, loss of appetite, polydipsia and polyuria, nephrocalcinosis, weakness and muscle paralysis due to hypokalaemia. This work summarises progress made in dRTA genetic studies in populations studied so far. DRTA is heterogeneous and as such, transporters and ion channels are analysed which have been identified in alpha-intercalated cells of the collecting duct, which could explain cases of dRTA not associated with the hitherto studied genes. DRTA can be autosomal dominant or autosomal recessive. Autosomal recessive dRTA appears in the first months of life and progresses with nephrocalcinosis and early or late hearing loss. Autosomal dominant dRTA is less severe and appears during adolescence or adulthood and may or may not develop nephrocalcinosis. In alpha-intercalated cells of the collecting duct, the acid load is deposited into the urine as titratable acids (phosphates) and ammonium. Autosomal recessive dRTA is associated with mutations in genes ATP6V1B1, ATP6V0A4 and SLC4A1, which encode subunits a4 and B1 of V-ATPase and the AE1 bicarbonate/chloride exchanger respectively. By contrast, autosomal dominant dRTA is only related to mutations in AE1." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11592_16025_44702_en_f211592i.jpg" "Alto" => 532 "Ancho" => 1018 "Tamanyo" => 147905 ] ] "descripcion" => array:1 [ "en" => "Topology of the erythrocyte AE1 Cl-/HCO3- exchanger" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11592_16025_44703_en_f311592i.jpg" "Alto" => 1248 "Ancho" => 1001 "Tamanyo" => 160755 ] ] "descripcion" => array:1 [ "en" => "Structure and composition of human V-ATPase" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11592_16025_44710_en_f111592i.jpg" "Alto" => 738 "Ancho" => 1009 "Tamanyo" => 125868 ] ] "descripcion" => array:1 [ "en" => "Model of an acid-secreting alpha-intercalated cell" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:68 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Devuyst O, Antignac C, Bindels RJM, Chauveau D, Emma F, Gansevoort R, et al. 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La acidosis tubular renal distal: una enfermedad hereditaria en la que no se pueden eliminar los hidrogeniones

Laura Escobara, Laura Escobara, Natalia Mejíab, Helena Gilc, Helena Gilb, Fernando Santosc, Fernando Santosb

a Departamento de Fisiología, Facultad de Medicina. Universidad Nacional Autónoma de México, Ciudad de México, DF, México,

b Departamento de Pediatría, Universidad de Oviedo, Oviedo, España,

c Departamento de Pediatría, Universidad de Oviedo, Oviedo, Asturias, Spain,

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  "doi" => "10.3265/Nefrologia.pre2012.Oct.11592"
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Unfortunately&#44; our knowledge of most of these diseases is limited due to low incidence&#44; phenotypic variability&#44; lack of standardised diagnostic procedures and fragmentation of biological and clinical information obtained from studies with small groups&#46; Moreover&#44; the low prevalence of these diseases is not attracting the interest of the pharmaceutical industry and funding for research is scarce&#46; However&#44; the study of &#8216;rare&#8217; diseases is a unique opportunity to shed light on their origin and understand the molecular scaffold complex that explains the functioning of an organ and the factors that causes deterioration&#46;</p><p class="elsevierStylePara">The rapid development of exome and genome sequencing technologies opens new perspectives for the diagnosis of more than 17&#160;000 Mendelian or monogenic diseases&#46; Moreover&#44; a functional study of the mutant proteins in animal models and cell models reveals the aetiology of the disease and constitutes the reference framework for drug design and&#47;or prevention of the toxic effects of some drugs&#46;<span class="elsevierStyleSup">5&#44; 6</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">METABOLIC ACIDOSIS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Metabolic acidosis is characterised by a decrease in blood pH with a drop in bicarbonate concentration in plasma&#46; In individuals with normal respiratory response&#44; metabolic acidosis causes compensatory hyperventilation which mitigates the fall in blood pH&#46; Consequently&#44; blood pH homeostasis is maintained as a result of the concentration quotient bicarbonate&#47;CO<span class="elsevierStyleInf">2</span>&#44; which is the cell and blood buffer par excellence&#46;</p><p class="elsevierStylePara">The extracellular pH must be maintained within a very narrow range of 7&#46;38 to 7&#46;42&#46; pH homeostasis is critical for cell function and&#44; therefore&#44; of our organs&#46; A more acidic blood pH than normal may be the result of&#58; 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a dimeric glycoprotein with 12-14 transmembrane domains<span class="elsevierStyleSup">23-25</span> &#40;Figure 2&#41;&#46; There are three genes in the AE1 family and in the tissues in which AE1 is expressed&#44; AEI it participates in the regulation of pH&#44; cell volume and the transcellular transport of acid and base in epithelial cells&#46;<span class="elsevierStyleSup">26-28</span></p><p class="elsevierStylePara">AE1 presents a specific isoform of erythrocytes and a specific short isoform of the kidney&#46;<span class="elsevierStyleSup">29</span> In erythrocytes&#44; AE1&#44; in addition to exchanging chloride for the bicarbonate of the plasma&#44; has a structural role in interacting with cytoskeletal proteins that contribute to AE1 traffic and its stability in the plasma membrane&#46;<span class="elsevierStyleSup">23</span> As such&#44; AE1 plays a central role in respiration by transporting and removing CO<span class="elsevierStyleInf">2</span> via the lungs and in acid-base homeostasis in the kidney&#46;<span class="elsevierStyleSup">30</span> In the kidney&#44; AE1 performs bicarbonate reabsorption into the interstitial space and blood vessels&#46;<span class="elsevierStyleSup">31</span> There is a group of mutations in AE1 that cause deformations in the erythrocyte and whose inheritance is autosomal dominant&#58; inherited spherocytic anaemia&#44; Southeast Asian ovalocytosis and other stomatocytosis with normal kidney function&#46;<span class="elsevierStyleSup">32</span> There are other series of AE1 mutations that generate dRTA associated with erythrocyte problems&#46;<span class="elsevierStyleSup">10&#44;33&#44;34</span> AE1 mutations can be consulted at&#58; www&#46;ensembl&#46;org and www&#46;hgmd&#46;org</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">V-ATPase</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Vacuolar H- ATPase &#40;V-ATPase&#41; belongs to an H<span class="elsevierStyleSup">&#43;</span> hydrogen-ion pump family and is located in a variety of membranes&#58; endosomes&#44; lysosomes&#44; secretory vesicles and in the plasma membranes of eukaryotes&#46;<span class="elsevierStyleSup">35-37</span> V-ATPase is a multimeric enzyme complex that consists of 14 subunits &#40;Figure 3&#41;&#59; it has two domains&#58; one in the cytoplasm &#40;V<span class="elsevierStyleInf">1</span>&#41; and the other in the membrane &#40;V<span class="elsevierStyleInf">0</span>&#41;&#46; V<span class="elsevierStyleInf">1</span> is the catalytic domain and it has 8 subunits &#40;A-H&#41;&#46; Domain V<span class="elsevierStyleInf">0</span> comprises 6 subunits &#40;a&#44; c&#44; c&#8221;&#44; d&#44; e&#44; and Ac45 in mammals&#41; and translocates H<span class="elsevierStyleSup">&#43;</span> through the membrane&#46;<span class="elsevierStyleSup">35-37</span> There are three copies of subunits A and B that alternate in a ring-shaped arrangement &#40;Figure 3&#41;&#46; The catalytic sites are in subunit A1 and the interface between subunits A-B regulates the activity of the enzyme&#46;<span class="elsevierStyleSup">38-39</span> Subunit &#39;a&#39; in V<span class="elsevierStyleInf">0</span> allows access to hemichannels through which H<span class="elsevierStyleSup">&#43;</span> hydrogen ions are exported to the luminal space&#46;<span class="elsevierStyleSup">37</span> There are four isoforms of subunit &#39;a&#39; &#40;a1-a4&#41; and they have a 47-61&#37; identity in humans&#46;<span class="elsevierStyleSup">35</span> Subunit &#39;a&#39; also participates in traffiking of V-ATPase in mammal cells&#46;<span class="elsevierStyleSup">37</span></p><p class="elsevierStylePara">In alpha-intercalated cells of the collecting duct&#44; V-ATPase is located on the apical membranes and secretes H<span class="elsevierStyleSup">&#43;</span> in urine &#40;Figure 1&#41;&#46;<span class="elsevierStyleSup">35</span> Subunits B1 and a4 of V-ATPase are specific alpha-intercalated cells of the collecting duct&#46; Defects in these subunits lead to &#8220;distal renal tubular acidosis&#8221; or dRTA&#46;<span class="elsevierStyleSup">9&#44;40</span> As the B1 subunit is also expressed in the ciliary cells of the inner ear&#44;<span class="elsevierStyleSup">9 </span>mutations in subunit B1 produce dRTA with deafness&#46;</p><p class="elsevierStylePara">The gene <span class="elsevierStyleItalic">ATP6V1B1 </span>encodes B1 subunit and comprises 14 exons&#44; which produce a protein consisting of 513 amino acids&#46; The gene <span class="elsevierStyleItalic">ATP6V0A4</span> has 24 exons of which 20 encode the 840 amino acids of a4 subunit&#46;<span class="elsevierStyleSup">35</span></p><p class="elsevierStylePara">There are other transport systems in alpha-intercalated cells of the distal nephron which are also involved in acid-base homeostasis&#44; such as carbonic anhydrase II&#44;<span class="elsevierStyleSup">41</span> the KCC4 potassium&#47;chloride cotransporter<span class="elsevierStyleSup">42&#44; 43</span>&#44; Rhcg<span class="elsevierStyleSup">20&#44;44</span> and the HCN2 ammonium channel &#40;Figure 1&#41;&#46;<span class="elsevierStyleSup">21</span> H-K-ATPase present in the apical membrane of alpha-intercalated cells does not seem to participate in secretion&#44; but rather in reabsorption of K<span class="elsevierStyleSup">&#43; </span>in hypokalemia&#46;<span class="elsevierStyleSup">40&#46;45</span></p><p class="elsevierStylePara">Figure 1 illustrates&#160; transporters&#44; ion channels and V-ATPase in alpha-intercalated cells of the collecting duct&#46; It is important to highlight that&#44; traduction&#44; and destination to the membrane of many transporters and ion channels depend on metabolic conditions&#46;</p><p class="elsevierStylePara">Collecting duct microperfusion trials and knockout mouse models have helped to elucidate transport pathways involved in acid-base homeostasis in alpha-intercalated cells&#46; For example&#44; the mouse not expressing KCC4 develops sensorineural deafness&#44; as well as dRTA&#46;<span class="elsevierStyleSup">42</span> There is another Cl&#47;bicarbonate exchanger which also operates as a Cl<span class="elsevierStyleSup">-</span> channel&#44; Slc26a7&#44; activated by hypertonicity&#46;<span class="elsevierStyleSup">46</span> Mouse Slc26a7 -&#47;- develops dRTA&#46;<span class="elsevierStyleSup">47</span> It is noteworthy that mice that do not express the ammonia channel &#40;Rhcg -&#47;-&#41; have problems in excreting only in metabolic acidosis&#44; suchas in&#160; incomplete dRTA&#46;<span class="elsevierStyleSup">44</span> The ammonium channel HCN2 is a constitutive ion channel involved in baseline ammonium excretion but it does not appear to be regulated by metabolic acidosis&#46; <span class="elsevierStyleSup">21</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISTAL RENAL TUBULAR ACIDOSIS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">dRTA belongs to the group of renal diseases with a very low incidence in any population&#46;</p><p class="elsevierStylePara">In dRTA&#44; the ability to acidify urine is lost due to a defect in the excretion of acid load &#40;H<span class="elsevierStyleSup">&#43;</span> and ammonium ions&#41; in alpha-intercalated cells of the collecting duct&#46; The acid load accumulation in the distal nephron results in consumption and reduction of the bicarbonate&#47;CO<span class="elsevierStyleInf">2</span> buffer in blood&#46; The symptoms accompanying dRTA include stunted growth&#44; vomiting&#44; diarrhoea and&#47;or constipation&#44; loss of appetite&#44; polydipsia and polyuria&#44; nephrocalcinosis and it may also present weakness and muscle paralysis due to loss of potassium &#40;hypokalemia&#41;&#46;</p><p class="elsevierStylePara">To diagnose dRTA in the clinic&#44; it is necessary to determine plasma creatinine and fractional sodium&#44; potassium and chloride excretion&#44; calciuria and citraturia&#46; Acidosis is generally observed in blood &#40;pH&#60;7&#46;35&#41; as well as a marked decrease in the concentration of bicarbonate and CO<span class="elsevierStyleInf">2</span> &#40;&#60;15mEq&#47;l&#41;&#46; In dRTA&#44; urine pH is higher than 6 in the presence of systemic metabolic acidosis&#46;</p><p class="elsevierStylePara">For cases in which diagnosis is uncertain&#44; as in incomplete dRTA&#44; it is advisable to perform acidification tests&#46; These tests involve the administration of NH<span class="elsevierStyleInf">4</span>Cl to determine pH&#44; titratable acidity and urinary ammonium excretion&#46;<span class="elsevierStyleSup">48</span> Due to complications of this test in children&#44; acidification capacity can be evaluated by determining the maximum urinary pCO<span class="elsevierStyleInf">2</span> &#40;UpCO<span class="elsevierStyleInf">2</span>&#41; with the intake of sodium bicarbonate &#40;4mEq&#47;kg&#41;&#46;<span class="elsevierStyleSup">49</span> The pCO<span class="elsevierStyleInf">2</span> urinary test can be performed with sodium bicarbonate or acetazolamide stimuli or both&#44; in this case administered at half the usual dose&#46; Another test is furosemide with fludrocortisone&#46;<span class="elsevierStyleSup">49-52</span></p><p class="elsevierStylePara">Diagnostic tests confirm the inability to excrete acid loads by observing a urinary pH higher than 5&#46;5&#46;</p><p class="elsevierStylePara">Ultrasound studies in patients with dRTA show the presence of calcium deposits in the renal tissue &#40;nephrocalcinosis&#41; and&#47;or urinary tract stones &#40;nephrolithiasis&#41;&#46;</p><p class="elsevierStylePara">Chronic acidosis and intercurrent secondary problems &#40;vomiting&#44; polyuria&#44; dehydration&#44; rejection of dose&#44; etc&#46;&#46;&#41; affect growth and&#44; consequently&#44; there is a decrease in the size and weight of the patients&#46;</p><p class="elsevierStylePara">&#160;dRTA is accompanied by hyperchloraemia as a result of decreased HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">-</span> in blood&#46; In dRTA&#44; hypokalemia is observed &#40;&#91;K&#93;&#60;3&#46;5mEq&#47;l&#41;&#44; along with hypercalciuria and hypocitraturia&#46; Hypercalciuria occurs when there is urinary calcium excretion greater than 4mg&#47;kg&#47;day in both adults and in children&#46; It is necessary to consider that the urinary calcium&#47;creatinine quotient in infants varies with age&#46; Normal values according to age are&#58; 0-6 months &#60;0&#46;8 mg&#47;mg&#44; 6 to 12 months &#60;0&#46;6 mg&#47;mg&#44; 1 to 2 years &#60;0&#46;5 mg&#47;mg&#46;<span class="elsevierStyleSup">53</span> In adults&#44; hypocitraturia is considered a value below 300 mg&#47;day for both sexes&#44; and&#47;or a citrate&#47;creatinine rate value below 250 mg&#47;g&#46; In children hypocitraturia is considered a value below 8 mg&#47;kg&#47;day and&#47;or a citrate&#47;creatinine quotient below 400 mg&#47;g&#46;<span class="elsevierStyleSup">53</span></p><p class="elsevierStylePara">It is important to highlight that calcium excretion in urine is high in infants and decreases progressively with age&#46; As such&#44; hypocitraturia is most relevant in the development of nephrocalcinosis and urolithiasis&#44; in which primarily calcium phosphate salts are deposited&#46; It is also noteworthy that dRTA cases have been found without no hipercalciuria&#46;<span class="elsevierStyleSup">54</span></p><p class="elsevierStylePara"><br></br>Patients with dRTA display a positive urine anion gap and a normal plasma anion gap &#40;&#91;Na&#43;&#93; &#43; &#91;K&#43;&#93; - &#91;Cl&#93;&#41;&#44; distinguishing it from other types of acidosis&#44; such as ketoacidosis &#44; lactic acidosis and acidosis due to poisoning with solvents or drugs&#44; with a higher plasma anion gap than normal&#46;<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara"><br></br>Untreated&#44; dRTA causes stunted growth&#44; rickets in children and osteomalacia in adults&#44; and deterioration of renal function over the years&#46;</p><p class="elsevierStylePara"><br></br>Fortunately&#44; dRTA has good prognosis if it is diagnosed at an early age and alkaline treatment is continued&#44; which consists of periodic doses of sodium bicarbonate and&#47;or potassium citrate during the day&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">HEREDITARY FORMS OF RENAL TUBULAR ACIDOSIS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Mutations in genes produce varying effects&#58; premature stop codons&#44; shift of the open reading frame&#44; alternate RNA processing and changes in the chemical nature of more than one amino acid&#46; Mutations cause structural alterations in proteins which may lead to loss of function&#46;</p><p class="elsevierStylePara">In autosomal dominant dRTA&#44; one parent suffers and is the carrier of the disease&#46; The groups of Michael Tanner of the University of Bristol and Fiona Karet of the Medical Research Institute of Cambridge in the United Kingdom were the first to identify mutations in the <span class="elsevierStyleItalic">SLC4A1</span> gene in families with autosomal dominant dRTA&#46;<span class="elsevierStyleSup">55&#44;56</span> AE1 mutations in autosomal dominant dRTA are always heterozygous&#46; The loss of AE1 function in the erythrocyte causes hereditary spherocytosis and ovalocytosis&#46;<span class="elsevierStyleSup">55</span></p><p class="elsevierStylePara">The AE1 kidney-specific isoform is shorter&#58; it does not have the first 65 amino acids of the NH2-terminus of the AE1 erythrocyte&#46; As such&#44; autosomal dominant dRTA only affects renal function in&#160; patients when AE1 mutations are located in the transmembrane domain and in the carboxyl-terminus &#40;Figure 2&#41;&#46;<span class="elsevierStyleSup">23&#44;25&#44;32&#44;57-59</span></p><p class="elsevierStylePara">Autosomal dominant dRTA appears in later childhood or in adulthood&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">AUTOSOMAL RECESSIVE DISTAL RENAL TUBULAR ACIDOSIS IS HETEROGENEOUS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In autosomal recessive dRTA&#44; parents do not suffer from the disease&#46; Symptoms occur during the first months of life&#46; Autosomal recessive dRTA is associated with mutations in any of the following genes&#58; <span class="elsevierStyleItalic">SLC4A1</span><span class="elsevierStyleSup">60</span>&#44; <span class="elsevierStyleItalic">ATP6V0A4</span> and <span class="elsevierStyleItalic">ATP6V1B1&#46;</span><span class="elsevierStyleSup">10&#44;54&#44;61</span></p><p class="elsevierStylePara">Fiona Karet&#8217;s group pioneered lineage studies in families with autosomal recessive dRTA&#46;<span class="elsevierStyleSup">9</span> The families that were analysed were of Turkish origin&#44; mostly from consanguineous marriages&#46; The age of children with autosomal recessive dRTA who participated in the study ranged from 1 month to 3 years&#59; all had nephrocalcinosis and hypercalciuria&#44; and more than 50&#37; displayed sensorineural deafness&#46; So far&#44; around 20 mutations of the gene <span class="elsevierStyleItalic">ATP6V1B1</span> have been identified&#46;<span class="elsevierStyleSup">9&#44;54&#44;61&#44;62</span> Most mutations are homozygous and exceptionally&#44; compound heterozygous&#46; These findings also revealed that the H-K-ATPase enzyme&#44; present in the alpha-intercalated cells&#44; can not compensate for the lack of function of V-ATPase&#46;<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara">There was an interesting case of dizygotic twins with deafness&#44; only one of whom developed autosomal recessive dRTA&#46;<span class="elsevierStyleSup">63</span></p><p class="elsevierStylePara">dRTA in which deafness appears from the second decade of life is associated with mutations in the gene <span class="elsevierStyleItalic">ATP6V0A4</span><span class="elsevierStyleSup">40&#44;61&#44;64</span>&#46; So far&#44; more than 20 mutations in <span class="elsevierStyleItalic">ATP6V0A4</span> are known &#40;www&#46;ensembl&#46;org and <a href="http&#58;&#47;&#47;www&#46;hgmd&#46;org" class="elsevierStyleCrossRefs">www&#46;hgmd&#46;org</a>&#41;&#46;</p><p class="elsevierStylePara">Approximately 20&#37; of cases with dRTA are not associated with mutations in any of these genes&#58; there are dRTA patients with deafness who have no <span class="elsevierStyleItalic">ATP6V1B1</span> gene mutations and others with normal hearing who do not have <span class="elsevierStyleItalic">ATP6V0A4</span> gene mutations&#46; These findings suggest that other transporters or channels &#40;Figure 1&#41; would be mutated&#46; Therefore&#44; recessive dRTA is heterogeneous because it may occur by mutations in more than one gene&#46;</p><p class="elsevierStylePara">Mutations have been identified in genes <span class="elsevierStyleItalic">ATP6V1B1</span> and <span class="elsevierStyleItalic">ATP6V0A4</span> in groups of Arab<span class="elsevierStyleSup">10&#44;61 </span>and Italian<span class="elsevierStyleSup">65</span> origin&#59; and only mutations in&#160;<span class="elsevierStyleItalic">ATP6V1B1</span>&#160;have been discovered in those of Spanish<span class="elsevierStyleSup">54</span>&#44; Greek<span class="elsevierStyleSup">66</span>&#44; Iranian<span class="elsevierStyleSup">67 </span>and Serbian<span class="elsevierStyleSup">68</span> origin&#46;</p><p class="elsevierStylePara">Mutations in the <span class="elsevierStyleItalic">SLC4A1</span> gene&#44; which encodes the AE1 Cl<span class="elsevierStyleSup">-</span>&#47;HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">-</span> exchanger&#44; also produce autosomal recessive dRTA&#46; To date&#44; 11 mutations of <span class="elsevierStyleItalic">SLC4A1</span> are known that produce dRTA&#44; in addition to ovalocytosis or spherocytosis<span class="elsevierStyleSup">13</span> &#40;Figure 3&#41;&#46; AE1 mutations have been found mostly in the Asian population&#46; dRTA cases in Asia are an example of natural selection&#44; since they are resistant to malaria&#46;</p><p class="elsevierStylePara">In conclusion&#44; genetic studies have contributed to the identification of three genes affected in dRTA&#46; Genetic studies of new molecular markers&#44; such as Slc26a7 and KCC4 transporters or Rhcg and HCN2 channels in patients with dRTA are a challenge in the identification of new molecular targets that help the understanding of the disease and&#44; consequently to the acid-base homeostasis in the kidney&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Laura Escobar receives an allowance and funding from the Direcci&#243;n General de Asuntos del Personal Acad&#233;mico &#40;DGAPA&#41; de la Universidad Nacional Aut&#243;noma de M&#233;xico and the Fundaci&#243;n Carolina&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11592&#95;16025&#95;44702&#95;en&#95;f211592i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11592_16025_44702_en_f211592i.jpg" alt="Topology of the erythrocyte AE1 Cl-&#47;HCO3- exchanger"></img></a></p><p class="elsevierStylePara">Figure 2&#46; Topology of the erythrocyte AE1 Cl-&#47;HCO3- exchanger</p><p class="elsevierStylePara"><a href="grande&#47;11592&#95;16025&#95;44703&#95;en&#95;f311592i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11592_16025_44703_en_f311592i.jpg" alt="Structure and composition of human V-ATPase"></img></a></p><p class="elsevierStylePara">Figure 3&#46; Structure and composition of human V-ATPase</p><p class="elsevierStylePara"><a href="grande&#47;11592&#95;16025&#95;44710&#95;en&#95;f111592i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11592_16025_44710_en_f111592i.jpg" alt="Model of an acid-secreting alpha-intercalated cell"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Model of an acid-secreting alpha-intercalated cell</p>"
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        "resumen" => "<p class="elsevierStylePara">La acidosis tubular renal distal &#40;ATRD&#41; o ATR tipo I se caracteriza por una disminuci&#243;n en la excreci&#243;n urinaria de los hidrogeniones H<span class="elsevierStyleSup"><span class="elsevierStyleSup">&#43;</span></span>&#160;y del amonio&#46; En los ni&#241;os afectados por ATRD hay retraso en el crecimiento&#44; v&#243;mito&#44; estre&#241;imiento&#44; falta de apetito&#44; polidipsia y poliuria&#44; nefrocalcinosis&#44; debilidad y hasta par&#225;lisis muscular por la hipopotasemia&#46;&#160;En este trabajo se resumen los avances en el estudio gen&#233;tico de la ATRD en las poblaciones hasta ahora estudiadas&#46; La ATRD es heterog&#233;nea&#44; por lo que tambi&#233;n se analizan los transportadores y canales i&#243;nicos que se han identificado hasta ahora en las c&#233;lulas intercaladas alfa del t&#250;bulo colector&#44; y que podr&#237;an explicar los casos de ATRD que no se asocian con los genes hasta ahora estudiados&#46; La ATRD puede ser autos&#243;mica dominante o autos&#243;mica recesiva&#46; La ATRD autos&#243;mica recesiva se manifiesta en los primeros meses de vida&#44; cursa con nefrocalcinosis y sordera temprana o tard&#237;a&#46; La ATRD autos&#243;mica dominante es menos severa y aparece en la adolescencia o en la etapa adulta&#44; y puede o no presentar nefrocalcinosis&#46; En las c&#233;lulas intercaladas alfa de los t&#250;bulos colectores se lleva a cabo la excreci&#243;n urinaria de la carga &#225;cida&#58; los &#225;cidos titulables &#40;fosfatos&#41; y el amonio&#46;&#160;La ATRD autos&#243;mica recesiva se asocia con mutaciones en los genes&#160;<span class="elsevierStyleItalic"><span class="elsevierStyleItalic">ATP6V1B1</span></span>&#44;&#160;<span class="elsevierStyleItalic"><span class="elsevierStyleItalic">ATP6V0A4</span></span>&#160;y&#160;<span class="elsevierStyleItalic"><span class="elsevierStyleItalic">SLC4A1</span></span>&#44; los cuales codifican las subunidades a4 y B1 de la V-ATPasa y el intercambiador de bicarbonato&#47;cloruro AE1&#44; respectivamente&#46; En contraste&#44; la ATRD autos&#243;mica dominante se relaciona con mutaciones solo en AE1&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">Distal renal tubular acidosis &#40;dRTA&#41; or RTA type I is characterised by reduced H<span class="elsevierStyleSup">&#43;</span>&#160;hydrogen ions and ammonium urinary excretion&#46; In children affected by dRTA there is stunted growth&#44; vomiting&#44; constipation&#44; loss of appetite&#44; polydipsia and polyuria&#44; nephrocalcinosis&#44; weakness and muscle paralysis due to hypokalaemia&#46; This work summarises progress made in dRTA genetic studies in populations studied so far&#46; DRTA is heterogeneous and as such&#44; transporters and ion channels are analysed which have been identified in alpha-intercalated cells of the collecting duct&#44; which could explain cases of dRTA not associated with the hitherto studied genes&#46; DRTA can be autosomal dominant or autosomal recessive&#46; Autosomal recessive dRTA appears in the first months of life and progresses with nephrocalcinosis and early or late hearing loss&#46; Autosomal dominant dRTA is less severe and appears during adolescence or adulthood and may or may not develop nephrocalcinosis&#46; In alpha-intercalated cells of the collecting duct&#44; the acid load is deposited into the urine as titratable acids &#40;phosphates&#41; and ammonium&#46; Autosomal recessive dRTA is associated with mutations in genes <span class="elsevierStyleItalic">ATP6V1B1&#44; ATP6V0A4</span>&#160;and&#160;<span class="elsevierStyleItalic">SLC4A1</span>&#44; which encode subunits a4 and B1 of V-ATPase and the AE1 bicarbonate&#47;chloride exchanger respectively&#46; By contrast&#44; autosomal dominant dRTA is only related to mutations in AE1&#46;</p>"
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Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2012.Oct.11592

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	8	13	21
2024 October	93	77	170
2024 September	108	75	183
2024 August	147	113	260
2024 July	78	75	153
2024 June	101	94	195
2024 May	186	73	259
2024 April	122	45	167
2024 March	122	44	166
2024 February	180	41	221
2024 January	110	43	153
2023 December	58	28	86
2023 November	117	73	190
2023 October	85	78	163
2023 September	96	514	610
2023 August	94	55	149
2023 July	141	75	216
2023 June	73	53	126
2023 May	112	61	173
2023 April	77	49	126
2023 March	105	42	147
2023 February	68	51	119
2023 January	77	53	130
2022 December	88	48	136
2022 November	69	43	112
2022 October	77	60	137
2022 September	73	47	120
2022 August	75	53	128
2022 July	55	57	112
2022 June	73	52	125
2022 May	67	55	122
2022 April	85	61	146
2022 March	97	54	151
2022 February	116	61	177
2022 January	123	46	169
2021 December	65	55	120
2021 November	48	43	91
2021 October	75	81	156
2021 September	57	47	104
2021 August	62	71	133
2021 July	102	69	171
2021 June	92	27	119
2021 May	83	42	125
2021 April	131	82	213
2021 March	102	70	172
2021 February	116	40	156
2021 January	84	28	112
2020 December	69	24	93
2020 November	67	19	86
2020 October	54	25	79
2020 September	43	23	66
2020 August	81	16	97
2020 July	68	15	83
2020 June	86	28	114
2020 May	105	34	139
2020 April	73	25	98
2020 March	126	25	151
2020 February	119	32	151
2020 January	129	40	169
2019 December	114	28	142
2019 November	113	30	143
2019 October	136	29	165
2019 September	139	35	174
2019 August	73	22	95
2019 July	108	35	143
2019 June	113	31	144
2019 May	119	20	139
2019 April	172	45	217
2019 March	123	29	152
2019 February	84	20	104
2019 January	93	36	129
2018 December	218	56	274
2018 November	150	27	177
2018 October	170	34	204
2018 September	242	31	273
2018 August	130	25	155
2018 July	102	23	125
2018 June	109	18	127
2018 May	121	14	135
2018 April	116	11	127
2018 March	113	13	126
2018 February	96	11	107
2018 January	113	5	118
2017 December	129	15	144
2017 November	133	20	153
2017 October	114	13	127
2017 September	117	16	133
2017 August	89	33	122
2017 July	78	13	91
2017 June	128	15	143
2017 May	188	17	205
2017 April	110	19	129
2017 March	133	13	146
2017 February	307	28	335
2017 January	129	29	158
2016 December	144	11	155
2016 November	227	26	253
2016 October	246	36	282
2016 September	372	17	389
2016 August	497	21	518
2016 July	399	32	431
2016 June	241	0	241
2016 May	246	0	246
2016 April	245	0	245
2016 March	183	0	183
2016 February	175	0	175
2016 January	165	0	165
2015 December	184	0	184
2015 November	152	0	152
2015 October	195	0	195
2015 September	143	0	143
2015 August	113	0	113
2015 July	137	0	137
2015 June	61	0	61
2015 May	111	0	111
2015 April	11	0	11

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