Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis

Abstract

Distal renal tubular acidosis (dRTA) is a tubular disorder with a primary defect of urinary acidification and acid excretion in the collecting duct system. Consequently, patients develop hyperchloremic metabolic acidosis with an inappropriately alkaline urine. Inherited forms of dRTA are due to mutations in at least three distinct genes: SLC4A1, ATP6V1B1, ATP6V0A4. Mutations in SLC4A1-(AE1) are inherited either in an autosomal dominant manner or in a recessive one. ATP6V1B and ATP6V0A4 mutations affect two different subunits of the vacuolar H-ATPase proton-pump, the B1 and a4 subunits, and are inherited in an autosomal recessive manner. Clinical manifestations of inherited forms of dRTA usually occur during infancy or childhood. However, heterozygous carriers of ATP6V1B1 and ATP6V0A4 mutations may have a higher risk of developing nephrolithiasis and nephrocalcinosis in adulthood, respectively. In full forms of dRTA, patients may present with mild clinical symptoms, such as mild metabolic acidosis and incidental detection of kidney stones, as well as with more severe manifestations such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. Progressive sensorineural hearing loss develops in the majority of patients with recessive dRTA (ATP6V1B1 and ATP6V0A4 mutations). Some patients with recessive dRTA may also develop abnormal widening of the vestibular aqueduct. This review will discuss our current understanding of the pathophysiology of inherited forms of dRTA, diagnosis and prognosis of patients, and therapy.

Treatment and long-term outcome in primary distal renal tubular acidosis

“…Most importantly, bicarbonate levels in this condition depend heavily on the timing of the last alkali dose taken. Yet, these limitations reflect routine clinical practice and for these reasons, urine calcium excretion is commonly used as another indicator of metabolic control in dRTA, as urine calcium excretion increases when acidosis is present (25).…”

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules

“…Lightwood provided the first description of congenital distal renal tubular acidosis (dRTA) in an autopsy series of six children in 1935 [96]. Five monogenetic forms of dRTA are currently known: autosomalrecessive and autosomal-dominant mutations in the anion exchanger 1 (AE1, encoded by SLC4A1 gene), autosomal-recessive mutations in the B1 and a4 subunits of the V-ATPase (encoded by ATP6V1B1 and ATP6V0A4 genes, respectively), autosomal-recessive mutations in the transcription factor Foxi1 (encoded by the FOXI1 gene) and autosomal-recessive mutations in carbonic anhydrase type II (encoded by the CA2 gene) ( Table 2) [97][98][99][100][101][102][103]. Sensu stricto, CA2 mutations cause a combined proximal-distal RTA, also known as type III RTA, but the renal phenotype is very similar to isolated cases of inherited dRTA.…”

A case series of distal renal tubular acidosis, Southeast Asian ovalocytosis and metabolic bone disease

“…Distal RTA is often associated with nephrocalcinosis, hypokalaemia and metabolic bone disease. Progression of nephrocalcinosis may lead to development of CKD [10]. If detected early in life, correction of the acidosis by alkali therapy could arrest progression of chronic kidney disease, and metabolic bone disease.…”