Therapeutic action of citrate in urolithiasis explained by chemical speciation: increase in pH is the determinant factor

Rodgers, Allen L.; Allie-Hamdulay, Shameez; Jackson, Graham E.

doi:10.1093/ndt/gfi211

Cited by 75 publications

(53 citation statements)

References 17 publications

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“…An alkaline urine favors CaP stone formation but decreases the risk of uric acid precipitation. Using computerbased methods (EQUIL2 21 and JESS 22 ) as well as empirical physicochemical methods, Pak et al 23 showed that raising urinary pH from 6.0 to 6.5, such as we have observed in our two groups, will increase the brushite relative supersaturation In addition to defects in urinary acidification, B1 subunit mutations are associated with sensorineural hearing loss. 3,13 In this study, we did not detect obvious hearing abnormalities in recurrent SFs with the p.E161K carriers, but audiometric investigations were not performed, and thus, the effect of the p.E161K SNP on inner ear function remains unknown at the moment.…”

Section: Discussionmentioning

confidence: 64%

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

Dhayat

Schaller

Albano

et al. 2015

JASN

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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 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.

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Section: Discussionmentioning

confidence: 64%

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

Dhayat

Schaller

Albano

et al. 2015

JASN

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“…This method assumes about a 50% reduction in the free calcium ion through soluble complexes formed by citrate. This provides a good representation for urine in general, but for the inhibition study here it is only an approximation because in reality the degree of speciation varies with the amount of urinary citrate (28). To account for this variation, resorting to a speciation code such as Equil2 (36) or JESS (19) is necessary.…”

Section: Effect Of Citrate Inhibitionmentioning

confidence: 99%

Prediction of renal crystalline size distributions in space using a PBE analytic model. 2. Effect of dietary countermeasures

Kassemi

Thompson

2016

American Journal of Physiology-Renal Physiology

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is used to assess the efficacy of citrate, pyrophosphate, and augmented fluid intake as dietary countermeasures aimed at reducing the risk of renal stone formation for astronauts. The model uses the measured biochemical profile of the astronauts as input and predicts the steady-state size distribution of the nucleating, growing, and agglomerating renal calculi subject to biochemical changes brought about by administration of these dietary countermeasures. Numerical predictions indicate that an increase in citrate levels beyond its average normal groundbased urinary values is beneficial but only to a limited extent. Unfortunately, results also indicate that any decline in the citrate levels during space travel below its normal urinary values on Earth can easily move the astronaut into the stone-forming risk category. Pyrophosphate is found to be an effective inhibitor since numerical predictions indicate that even at quite small urinary concentrations, it has the potential of shifting the maximum crystal aggregate size to a much smaller and plausibly safer range. Finally, our numerical results predict a decline in urinary volume below 1.5 liters/day can act as a dangerous promoter of renal stone development in microgravity while urinary volume levels of 2.5-3 liters/day can serve as effective space countermeasures.nephrolithiasis; gravity; weightlessness; crystal nucleation; crystal growth; agglomeration; inhibition; dietary countermeasures NEPHROLITHIASIS IS NOT ONLY a problem within the general population on Earth but is also a risk to the astronauts' health and survival during future long-duration missions where exposure to microgravity and other space conditions are likely to increase the risk of renal stone formation. The concern seems to be justified since a recent survey of renal stone formation in US astronauts has revealed 14 recorded postflight episodes (13, 26). Whether on Earth or in space, the development of calcium oxalate (CaOx) renal stones is initiated with nucleation of the sparingly soluble salt from a supersaturated urine as the necessary first step, followed by simultaneous growth and agglomeration of the crystals as two effective stone size-enhancing mechanisms. While the extent of urinary CaOx supersaturation in the nephron changes continuously depending on the level of hydration and the extent of other dietary intake, the urine of most individuals, healthy or stone former, remains supersaturated under normal everyday conditions.The progression from crystal nucleation and growth to a clinical colic situation is not yet well understood, but it is thought to occur by either free-or fixed-particle mechanisms (13, 32). Recent studies by Kim et al. (14) and Evan et al. (7) using advanced endoscopic imaging and comprehensive physiological biopsies suggest three possible free/fixed pathways to stone formation: 1) nucleation and growth on the Randall plaque deposits in the papillae; 2) growth after adherence to a possibly injured section of collecting or Bellini ducts; and 3) homogeneous nucleatio...

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“…Because of its high affinity for divalent cations, citrate reduces Ca 2+ activity and thus the relative supersaturation of urine with respect to calcium-containing minerals. Citrate also causes changes in many ionic species, notably a large increase in the complex [Ca-Citrate-PO 4 ] 4-, an effect that is mainly due to alkalinization of the urine [Rodgers et al, 2006]. However, there are also direct interactions between citrate and urinary crystals, at least those of COM.…”

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confidence: 99%

Citrate Modulates Calcium Oxalate Crystal Growth by Face-Specific Interactions

Grohe¹,

O’Young²,

Langdon³

et al. 2011

Cells Tissues Organs

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Because of its ability to inhibit the growth of calcium oxalate monohydrate (COM) crystals, citrate plays an important role in preventing the formation of kidney stones. To determine the mechanism of inhibition, we studied the citrate-COM interaction using a combination of microscopic and simulation techniques. Using scanning confocal interference microscopy, we found that addition of citrate preferentially inhibits crystal growth in <100> and, to a lesser extent, <001> directions, suggesting that citrate adsorbs to the faces of COM in the order {100} > {121} > {010}. Scanning electron microscopy showed that the resulting crystals are plate shaped, with large {100} faces and rounded ends. Molecular-dynamics simulations predicted, however, that citrate interacts with the faces of COM in a different order, i.e. {100} > {010} > {121}. Our simulations showed that citrate molecules align with the rows of Ca²⁺ ions on the {010} face but do not form close contacts, presumably because of electrostatic repulsion by the carboxylate groups that project from the Ca²⁺-rich plane. We propose that this weak interaction is responsible for citrate’s limited inhibition of COM growth in <010> directions. Overall, these findings indicate that electrostatic interactions with the Ca²⁺-rich faces of COM crystals are responsible for the growth-modulating properties of citrate.

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Therapeutic action of citrate in urolithiasis explained by chemical speciation: increase in pH is the determinant factor

Abstract: The therapeutic action of citrate in the management of calcium oxalate urolithiasis is due to the formation of a pH dependent calcium-citrate-phosphate complex which reduces the concentration of the free calcium ion species, thereby reducing the risk of stone formation.

Cited by 75 publications

References 17 publications

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

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

Prediction of renal crystalline size distributions in space using a PBE analytic model. 2. Effect of dietary countermeasures

Citrate Modulates Calcium Oxalate Crystal Growth by Face-Specific Interactions

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