Hereditary Distal Renal Tubular Acidosis: New Understandings

Abstract

The primary or hereditary form of distal renal tubular acidosis (dRTA), although rare, has received increased attention recently because of dramatic advances in the understanding of its genetic basis. The final regulation of renal acid excretion is effected by various acid/base transporters localized in specialized cells in the cortical collecting and outer medullary collecting tubules. Inherited defects in two of the key acid/base transporters involved in distal acidification, as well as mutations in the cytosolic carbonic anhydrase gene, can cause dRTA. The syndrome is inherited in both autosomal dominant and recessive patterns; patients with recessive dRTA present with either acute illness or growth failure at a young age, sometimes accompanied by deafness, whereas dominant dRTA is usually a milder disease and involves no hearing loss. The AE1 gene encodes two Cl-/HCO3- exchangers that are expressed in the erythrocyte and in the acid-secreting intercalated cells of the kidney. AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several mutations in the AE1 gene cosegregate with dominant dRTA. The modest degree of hypofunction exhibited in vitro by these mutations, however, does not explain the abnormal distal acidification phenotype. Other AE1 mutations have been linked to a recessive syndrome of dRTA and hemolytic anemia in which hypofunction can be discerned by in vitro studies. Several mutations in the carbonic anyhdrase II gene are associated with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. Some of these individuals present with deafness of the conductive type. By contrast, more recent studies have shown that mutations in ATP6B1, encoding the B-subtype unit of the apical H(+) ATPase, are responsible for a group of patients with autosomal recessive dRTA associated with sensorineural deafness. Thus, the presence of deafness and the type provide an important clue to the genetic lesion underlying hereditary dRTA.

A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells

“…It is tempting to speculate that this is because these mutations result in net bicarbonate secretion into the urine rather than overall functional cellular failure, but this has not been assessed. One way to address this would be to measure urine pCO 2 , predicting that in affected members of this kindred and the R901X kindred, it would not be reduced to the extent usually observed in dRTA. It is unfortunate that severe nephrocalcinosis and consequent anatomical disruption renders the interpretation of pCO 2 levels unreliable.…”

“…This disorder is usually accompanied by hypokalemia, metabolic bone disease, nephrocalcinosis, and/or nephrolithiasis (1)(2)(3). Mutations in SLC4A1 (MIM 109270), encoding the polytopic chloride-bicarbonate exchanger known as AE1, have been reported as the sole genetic cause of autosomal dominant dRTA (ddRTA) (MIM #179800) (4 -9) and also rarely cause autosomal recessive dRTA (10 -14).…”

Aldosterone Requires Vasopressin V1a Receptors on Intercalated Cells to Mediate Acid-Base Homeostasis

“…BASIC RESEARCH www.jasn.org responsible for distal and type 4 RTA. [12][13][14][15][16][17] However, no previous reports have focused on the role of V1aR as a causative factor in type 4 RTA. Previously, we showed that the stimulation of V1aR in the macula densa is the first step of renin production and the deficient of V1aR in macula densa causes hyporeninemic hypoaldosteronism.…”

“…1,2,10,11 Thus far, many functional defects of these transporters have been hypothesized to cause distal type or type 4 renal tubular acidosis (RTA). [12][13][14][15][16][17] Type 4 RTA, which is a hyperkalemic distal RTA, is known to be caused by hyporeninemic hypoaldosteronism. 17,18 Although the treatment of patients with type 4 renal tubular acidosis by fludrocortisones has been shown to ameliorate acidosis, the precise mechanisms of type 4 RTA have been unknown.…”

Renal Tubular Acidosis

“…Primary distal RTA may be observed sporadically or with autosomal dominant or recessive transmission (20) (Tables 1 and 3). Autosomal dominant distal RTA has been found to be associated in several kindred with mutations in the gene encoding the Cl Ϫ -HCO 3 Ϫ exchanger AE1 or band 3 protein (21).…”