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

摘要

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.