The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers

Abstract

Mutations in the vacuolar-type H + -ATPase B1 subunit gene ATP6V1B1 cause autosomal-recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G.A; p.E161K) that causes greatly diminished pump function in vitro. To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in the Dallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild-type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low-Ca and low-Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P,0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH 4 Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H + -ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphatecontaining kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.

Acute regulated expression of pendrin in human urinary exosomes

“…2B). Nadir urinary pH was achieved at 5 hrs, which is comparable to previous studies [5,44]. Venous blood pH and bicarbonate, measured at baseline and at 2 and 4 hrs, respectively, revealed the presence of a significant metabolic acidosis at 2 hrs with slight recovery after 4 hrs ( Fig.…”

“…As a matter of fact, Rab11a is responsible for apical recycling of endosomes [6,27]. Indeed Rab11a and Rab11b regulated the trafficking and recycling of the epithelial sodium channel (ENaC) within the CCD [5]. Urinary exosomes are released into the urine by fusion of the outer membrane of the multivesicular bodies (MVBs) with the apical plasma membrane [12,26].…”

Haploinsufficiency of the Mouse Atp6v1b1 Gene Leads to a Mild Acid-Base Disturbance with Implications for Kidney Stone Disease

“…In both species, the absence of functional B1 or a4 H + -ATPase subunits can be associated with the development of nephrocalcinosis or -lithiasis [6,9,12,14,16,17,21]. Moreover, recent studies described that monoallelic mutations in these 2 genes can also lead to urinary acidification defects with elevated risk for nephrocalcinosis or-lithiasis [10,11,22]. Along this line, a recent study investigated the ability of Atp6v0a4 heterozygous mice regarding to handle a chronic acid load.…”

“…2) which however did not reach statistical significance when compared to Atp6v1b1 +/+ . Patients with biallelic ATP6V1B1 mutations frequently develop nephrocalcinosis [9,11,12] and nephrocalcinosis has been also reported in some patients with only monoallelic ATP6V1B1 mutations [10,11]. We thus tested whether urinary calcium, phosphate and citrate excretion were different between genotypes and found no obvious difference at any of the time points tested (Tables 1 -3).…”

“…However, it has been shown recently in a kindred with a truncation mutation of ATP6V1B1, (p. Phe468fsX487), that heterozygosity could lead to a mild incomplete dRTA with more alkaline urine and nephrocalcinosis [10]. In a follow-up study the authors investigated the role of the p.E161K variant in a cohort of stone formers and could show that heretozygous carriers exhibited a mild urinary acidification deficit with an increased prevalence of calciumphosphate kidney stones [11]. In mouse, total ablation of the Atp6v1b1 gene causes dRTA with a decrease in ammonium excretion and more alkaline urine pH [7].…”