Citric acid or citrates in urine: which should we focus on in the prevention of calcium oxalate crystals and stones?

Abstract

In order to distinguish between normocitraturia and hypocitraturia, the 24 h urine excretion value of citric acid is evaluated in relation to the established limit value of 2.5 mmol/day. We propose changing this widely-used excretion value to a "minimum contribution" of citric acid to the total urine's ionic strength, since the inhibitory effect of citric acid on crystallization depends on citrate anions being available to complex calcium ions or to associate with the crystal surface. A total of 71424 h-urine samples, taken from 74 healthy persons and 58 calcium stone formers, were investigated for pH, citric acid concentration ([CA]), and related relative calcium oxalate supersaturation (RS). Based on the Henderson-Hasselbalch-equation, the individual concentrations of the differently charged citrate anion species in each of the urines were calculated from the urinary pH and [CA]. From the anion concentrations determined, the contribution of the urine's citric acid to the total urine's ionic strength, ISCA, was calculated. Referring to the limit value of 2.5 mmol/day and assuming an average urine volume of 1.5 l/day, a hypothetical concentration limit of 1.67 mmol/l can be obtained. Grouping the samples into "stone-formers" and "non-stone-formers" as well as into three different ranges of RS revealed: (1). that the groups' median [CA]-values were below 1.67 mmol/l, and (2). that [CA] was not inversely associated with the risk of stone formation. Within the pH-range of 5 and 7, the ISCA-values which are related to, for example, [CA]=1.67 mmol/l, vary considerably by a factor of nearly three between 2.48 mmol/l and 6.64 mmol/l. The use of a fixed citric acid excretion level for the distinction of normocitraturia from hypocitraturia does not take into account the different citrate species which actually modify the urine's crystallization behaviour. The proposed ISCA approach takes this fact into consideration. From this parameter, a desirable "minimum impact of citric acid" can be derived. In a first approach, a potential ISCA-limit value, which currently distinguishes between urines indicated by a "normo-protective" impact and those indicated by a "hypo-protective" impact with respect to calcium oxalate precipitation, may be set at 2.48 mmol/l.

Effect of citrus-based products on urine profile: A systematic review and meta-analysis

“…Furthermore, citrate fixes the inhibitory properties of Tamm-Horsfall protein 28 . Citrate and Tamm-Horsfall protein are related to inhibition of calcium oxalate agglomeration 29 . An increase in urine pH is due to metabolism of citrate into bicarbonate 13 .…”

Correspondence between Ca2+ and calciuria, citrate level and pH of urine in pediatric urolithiasis

“…However, alkalinizing the urine too much may increase the risk of calcium phosphate crystal formation [24]. Additionally, at high urinary pH, the fraction of triple-negatively charged citrate increases, thereby increasing the overall inhibitory effect of citrate as more calcium ions can be bound [25]. …”

NMR study of human biological fluids for detection of pathologies

“…Еще одной отличительной чертой спектра мочи здорового человека является достаточно интенсивный, характерный сигнал цитрата -двойной дублет, с центрами при 2,72 и 2,56 мд. Цитрат в мочевыделительной системе человека выполняет, в основном защитную функцию, препятствуя образованию и росту нерастворимых кристаллов оксалата кальция и формированию камней [10]. У здоровых людей отсутствуют в спектре сигналы ацетата и лактата, присутствующие в других биологических жидкостях.…”