The vacuolar H+-ATPase B1 subunit polymorphism p.E161K associates with impaired urinary acidification in recurrent stone formers

Nasser A. Dhayat, Andre Schaller, Giuseppe Albano, John Poindexter, Carolyn Griffith, Andreas Pasch, Sabina Gallati, Bruno Vogt, Orson W. Moe, Daniel G. Fuster

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 theDallas 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 NH4Cl 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 phosphate- containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.

Original languageEnglish (US)
Pages (from-to)1544-1554
Number of pages11
JournalJournal of the American Society of Nephrology
Volume27
Issue number5
DOIs
StatePublished - May 1 2016

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Vacuolar Proton-Translocating ATPases
Single Nucleotide Polymorphism
Kidney Calculi
Renal Tubular Acidosis
Diet
Alkalies
Registries
Body Mass Index
Alleles
Genotype
Urine
Phenotype
Mutation
Acids
Genes

ASJC Scopus subject areas

  • Nephrology

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The vacuolar H+-ATPase B1 subunit polymorphism p.E161K associates with impaired urinary acidification in recurrent stone formers. / Dhayat, Nasser A.; Schaller, Andre; Albano, Giuseppe; Poindexter, John; Griffith, Carolyn; Pasch, Andreas; Gallati, Sabina; Vogt, Bruno; Moe, Orson W.; Fuster, Daniel G.

In: Journal of the American Society of Nephrology, Vol. 27, No. 5, 01.05.2016, p. 1544-1554.

Research output: Contribution to journalArticle

Dhayat, NA, Schaller, A, Albano, G, Poindexter, J, Griffith, C, Pasch, A, Gallati, S, Vogt, B, Moe, OW & Fuster, DG 2016, 'The vacuolar H+-ATPase B1 subunit polymorphism p.E161K associates with impaired urinary acidification in recurrent stone formers', Journal of the American Society of Nephrology, vol. 27, no. 5, pp. 1544-1554. https://doi.org/10.1681/ASN.2015040367
Dhayat, Nasser A. ; Schaller, Andre ; Albano, Giuseppe ; Poindexter, John ; Griffith, Carolyn ; Pasch, Andreas ; Gallati, Sabina ; Vogt, Bruno ; Moe, Orson W. ; Fuster, Daniel G. / The vacuolar H+-ATPase B1 subunit polymorphism p.E161K associates with impaired urinary acidification in recurrent stone formers. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 5. pp. 1544-1554.
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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 theDallas 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 NH4Cl 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 phosphate- containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.",
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AU - Poindexter, John

AU - Griffith, Carolyn

AU - Pasch, Andreas

AU - Gallati, Sabina

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AU - Fuster, Daniel G.

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