Dhayat, Nasser; Schaller, André; Albano, Giuseppe; Poindexter, John; Griffith, Carolyn; Pasch, Andreas; Gallati, Sabina; Vogt, Bruno; Moe, Orson; Fuster, Daniel Guido (2015). 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, 27(5), pp. 1544-1554. Lippincott Williams & Wilkins 10.1681/ASN.2015040367
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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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