www.medigraphic.org.mx Bol Med Hosp Infant Mex 2013;70(3):178-193 REVIEW ARTICLE Renal tubular acidosis in children: state of the art, diagnosis and treatment Ricardo Muñoz-Arizpe,1 Laura Escobar,2 Mara Medeiros3 ABSTRACT Overdiagnosis of renal tubular acidosis (RTA) has been recently detected in Mexican children, perhaps due to diagnostic errors as well as due to a lack of knowledge regarding the pathophysiology and molecular biochemistry involved in this illness. The objective of the present study is to facilitate the knowledge and diagnosis of RTA, a clinical condition infrequently seen worldwide. RTA is an alteration of the acid-base equilibrium due to a bicarbonate wasting in the proximal renal tubules [proximal RTA, (pRTA) or type 2 RTA] or due to a distal nephron hy- drogen ion excretion defect [distal RTA (dRTA) or type 1 RTA]. Hyperkalemic, or type 4 RTA, is due to alterations in aldosterone metabolism. RTA may be primary, secondary, acquired or hereditary and frequently presents secondary to an array of systemic diseases, usually accom- panied by multiple renal tubular defects. The main defect occurs in the transmembrane transporters such as carbonic anhydrase (CA I and + - - + - II), H -ATPase, HCO3 /Cl (AE1) exchanger and Na /HCO3 (NBCe1) cotransporter. Diagnosis should include the presence of hyperchloremic metabolic acidosis with normal serum anion gap (done in an arterial or arterialized blood sample), lack of appetite, polyuria, thirst, growth failure, and rickets; nephrocalcinosis and renal stones (in dRTA); abnormal urine anion gap and abnormal urine/serum pCO2 gradient. Diagnosis of a primary systemic disease must be made in cases of secondary RTA. Bicarbonate or potassium citrate therapy as well as potassium, calcium and vitamin D administration depends on the type and severity of the RTA. Key words: acidosis, renal tubular acidosis, transmembrane transporters. INTRODUCTION countries, the incidence is also rare. Genetic studies esti- mate a ratio of ~1 case/million population in the UK and Renal tubular acidosis (RTA) is pathophysiological disor- France.4-6 The population with distal RTA (dRTA) is con- der of acid-base metabolism characterized by the presence centrated on immigrants of Arabic origin. Although RTA of hyperchloremic metabolic acidosis caused by renal loss is a rare alteration worldwide, in recent years an alarming of bicarbonate or by reduced renal tubular excretion of hy- rate of over-diagnosis has occurred in Mexico.7 This is drogen ions.1 In Mexico the incidence of RTA is unknown, likely due to errors in interpretation of the pathophysiol- mainly due to the lack of recording of renal diseases. Gar- ogy involved in the different types of RTA and lack of cía de la Puente reported a prevalence of 35 cases/10,000 detection of the primary disease causing the RTA, as well in the Instituto Nacional de Pediatría (INP).2 However, the as diagnostic errors. diagnostic methodology is not mentioned and biochemical The aim of this article is to report the classifi cation, parameters of patients are not shown. pathophysiology, management and treatment of this renal In Spain, with a population of 45 million, only 50 cas- disorder so as to guide pediatricians and other specialists on es of hereditary RTA in the renal tubule have been report- the physiological basis and complicated biochemical pro- ed and of these only 20 are Spaniards.3 In most European cesses involved in this alteration of acid-base metabolism. www.medigraphic.org.mx 1 Médico Investigador, Hospital Infantil de México Federico Gómez 2 Laboratorio de Canales Iónicos y Fisiología Renal, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autóno- ma de México 3 Laboratorio de Nefrología, Hospital Infantil de México Federico Gómez México, D.F., México Received for publication: 11-20-12 Accepted for publication: 4-23-13 178 Bol Med Hosp Infant Mex Renal tubular acidosis in children: state of the art, diagnosis and treatment Under physiological conditions, the extracellular space is the loss of bicarbonate by the kidneys due to reabsorption in maintained at an alkaline pH with a narrow gap, pH 7.40 ± 0.5, the proximal tubule; type 1 RTA or dRTA, also called clas- indicating a low presence of free hydrogen ions ([H+]: ([H+]) sical type RTA, which occurs due to failure in the excretion 0.0000000398 mmol/l) despite the large amounts of hydrogen of hydrogen ions in the distal and collecting tubules and, ions produced daily in the organism as a result of the ability of fi nally, type 4 RTA or dRTA with hyperkalemia, presented the kidneys to eliminate them. The principal source of organic by alterations in aldosterone metabolism.9,10 H+ production is derived from dietary protein and hence the metabolism of amino acids, particularly leucine, isoleucine, ETIOLOGY methionine and lysine, as well as the formation of hydroxyap- atite from calcium and phosphate deposits for bone growth in pRTA children. Hydrogen ion production in adults is 60-100 mmol/ pRTA is classifi ed as follows: day, on average 1 mmol/kg body weight, whereas in children (A) Primary or isolated―clinically presents with only bi- it is 2-3 mmol/kg/day. In order to achieve an acid-base bal- carbonaturia, without other urinary disorders. It may ance, elimination of hydrogen ions must equal the rate of pro- be sporadic or genetic. In turn, those genetically de- duction, which occurs during fi ne regulation in the collecting termined are transmitted in an autosomal dominant or tubules. For the kidneys to excrete large amounts of hydrogen recessive manner. The most common hereditary dis- ions in their free form would require reducing urinary pH to eases that manifest with pRTA are the following: 1.5, which does not happen because it would cause irreparable damage to urinary tract tissues. However, under physiologi- a) pRTA with mental retardation and eye disorders cal conditions, the urine maintains a stable acidic pH (5.5-6.5) b) defi ciency of the enzyme pyruvate carboxylase because free hydrogen ions bind to buffer ammonia molecules c) mitochondrial diseases + (NH3) to later form ammonia (NH4 ) to be excreted by this route. Also, free hydrogen ions bind to phosphates (to form (B) Secondary―when pRTA does not occur in isolation phosphoric acid) and sulfates (to form sulfuric acid). Measure- but is simultaneously present with other tubular alter- ment of the latter two in the urine is called titratable acidity. ations it is called Toni-Debre-Fanconi syndrome and causes different genetic, toxic or immunological alter- CLASSIFICATION ations such as nephropathic cystinosis, galactosemia, Lowe’s syndrome, Dent’s disease, tyrosinemia, heavy RTA classifi cation has undergone changes over time and cur- metal poisoning (lead), Wilson’s disease, chronic ac- rently is called type 1 RTA or dRTA when excretion of hy- tive hepatitis, accumulation diseases (glucogenosis), drogen ion does not occur and, therefore, renal tubular reab- Sjögren’s syndrome, drug toxicity (such as acetazol- sorption of HCO3. The defect is located in the connector, the amide, gentamicin, cisplatin, lefl uonamide, cyclospo- initial collector, the cortical collector and external medullary rine, etc.). Fanconi’s syndrome (Toni-Debre-Fanconi) tubules. Type 2 RTA is characterized by a reduction in the is characterized by the appearance of multiple proxi- - reabsorption of bicarbonate (HCO3 ) in the proximal tubule mal tubular functional alterations such as glycosuria, (pRTA).8 The classifi cation is confusing because according tubular proteinuria, aminoaciduria, phosphaturia, cal- to the logic of physiological events involved, type 1 RTA ciuria, citraturia, uricosuria, in addition to renal tubu- should involve the proximal tubule and type 2 RTA the distal lar acidosis. Some of the changes mentioned present nephron. However, in chronological order, the fi rst form of the risk of progressing to terminal uremia, such as ty- RTA described was dRTA; therefore,www.medigraphic.org.mx it is called type 1. Type rosinemia and cystinosis.11 - 3 RTA is the combination of reabsorption defects of HCO3 , both in the proximal and distal tubules. Type 4 RTA or dRTA dRTA with hyperkalemia is caused due to the resistance to the effect of aldosterone or to a defi cit of this hormone. (A) Occurs mainly in young children and may be sporadic In summary, the current classifi cation takes into consid- or hereditary. Some authors include sporadic transient eration three types of RTA: type 2 or pRTA, which refl ects dRTA, but its existence is questionable.5 Vol. 70, May-June 2013 179 Ricardo Muñoz-Arizpe, Laura Escobar, Mara Medeiros (B) Secondary―vasculitis (Sjögren’s syndrome, systemic ions occurs with a normal concentration of blood chlorine lupus erythematosus, etc.), Fabry’s disease, osteopetro- and, therefore, with an elevated blood anion gap.14 - sis, chronic active hepatitis, liver cirrhosis, sickle cell Moreover, loss of bicarbonate (HCO3 ) may occur via anemia, hyperthyroidism, malnutrition, chronic pyelo- the intestines or the kidneys. Intestinal loss of bicarbonate nephritis, renal transplantation, administration of drugs occurs during episodes of diarrhea and, less often, with the such as amiloride, amphotericin B, lithium, nonsteroi- presence of intestinal fi stulas, duodenal-jejunal anastomo- - dal antiinfl ammatory drugs, topiramate, macrolide an- sis or uretero-sigmoidostomy. When loss of HCO3 occurs tibiotics and toxic substances such as toluene. via the kidneys it is manifested as a systemic hyperchlore- (C) Hereditary―mutations