Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead

Abstract

Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal acidification due to a failure of type A intercalated cells (A-ICs) in the collecting tubule. dRTA is characterized by persistent hyperchloremia, a normal plasma anion gap, and the inability to maximally lower urinary pH in the presence of systemic metabolic acidosis. Common clinical features of dRTA include vomiting, failure to thrive, polyuria, hypercalciuria, hypocitraturia, nephrocalcinosis, nephrolithiasis, growth delay, and rickets. Mutations in genes encoding three distinct transport proteins in A-ICs have been identified as causes of dRTA, including the B1/ATP6V1B1 and a4/ATP6V0A4 subunits of the vacuolar-type H+-ATPase (H+-ATPase) and the chloride–bicarbonate exchanger AE1/SLC4A1. Homozygous or compound heterozygous mutations in ATP6V1B1 and ATP6V0A4 lead to autosomal recessive (AR) dRTA. dRTA caused by SLC4A1 mutations can occur with either autosomal dominant or AR transmission. Red blood cell abnormalities have been associated with AR dRTA due to SLC4A1 mutations, including hereditary spherocytosis, Southeast Asia ovalocytosis, and others. Some patients with dRTA exhibit atypical clinical features, including transient and reversible proximal tubular dysfunction and hyperammonemia. Incomplete dRTA presents with inadequate urinary acidification, but without spontaneous metabolic acidosis and recurrent urinary stones. Heterozygous mutations in the AE1 or H+-ATPase genes have recently been reported in patients with incomplete dRTA. Early and sufficient doses of alkali treatment are needed for patients with dRTA. Normalized serum bicarbonate, urinary calcium excretion, urinary low-molecular-weight protein levels, and growth rate are good markers of adherence to and/or efficacy of treatment. The prognosis of dRTA is generally good in patients with appropriate treatment. However, recent studies showed an increased frequency of chronic kidney disease (CKD) in patients with dRTA during long-term follow-up. The precise pathogenic mechanisms of CKD in patients with dRTA are unknown.

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition

“…In distal renal tubular acidosis (dRTA), affected patients have a hyperchloremic normal anion-gap metabolic acidosis and alkaline urine (pH > 5.3) [10]. This characteristic biochemical profile arises as a consequence of type A intercalated cells in the collecting duct failing to acidify the urine [45].…”

“…Mutations in either the vacuolar H + -ATPase pump, which excretes H + into the urine, or the chloride bicarbonate counter transporter anion exchanger (AE1), which reabsorbs HCO 3 − into the circulation, account for 85% of known causes of primary dRTA [10]. Mutations in the B1 and A4 subunit of the vacuolar H + -ATPase pump, encoded by ATP6V1B1 and ATP6V0A4 respectively, demonstrate autosomal recessive transmission and produce a phenotype frequently associated with sensorineural hearing loss as well as the commonly recognised biochemical abnormalities [45]. Mutations in SLC4A1, which encodes AE1, can occur with either autosomal dominant or autosomal recessive transmission: autosomal recessive cases are associated with earlier age of symptom onset and a more severe phenotype [10].…”

“…Mutations in SLC4A1, which encodes AE1, can occur with either autosomal dominant or autosomal recessive transmission: autosomal recessive cases are associated with earlier age of symptom onset and a more severe phenotype [10]. Red blood cell abnormalities may also form part of the phenotype for patients with SLC4A1 mutations [45]. More recently, mutations in Forkhead box protein Il (encoded by FOXI1) and WD repeat-containing protein 72 (encoded by WDR72) have been recognised as alternative underlying genetic mutations in a small number of families with autosomal recessive inheritance of dRTA [46,47].…”

“…Nephrocalcinosis is an extremely common feature within the phenotype of primary dRTA patients [48]. Calcium phosphate precipitates at higher pH; the alkaline urine of dRTA patients acts as a predisposing factor for nephrolithiasis and nephrocalcinosis formation [45]. In addition, chronic metabolic acidosis leads to excessive bone demineralisation often resulting in hypercalciuria: this also increases the likelihood of nephrocalcinosis developing if patients do not receive early diagnosis and treatment [48].…”

“…However, potassium citrate treatment cannot reverse nephrocalcinosis if already present. Long-term follow-up of dRTA patients should include annual ultrasound screening to monitor for nephrocalcinosis and nephrolithiasis, as well as monitoring of their renal function [45].…”