IntroductionEpidemiologyI. Epidemiology of kidney stonesI.1. Prevalence of kidney stonesI.2. An increasing trend in childrenPathophysiology II. Pathophysiology of kidney stonesII.1. LithogenesisII.1.1. Urine supersaturation : the driving force of crystallogenesisII.1.2. Promoters and inhibitors of stone formationII.2. Urine volume and composition: a necessary balanceRisk factorsIII. Risk factors for kidney stonesIII.1. Individual, non-modifiable risk factorsIII.1.1 Family historyIII.1.2. Race and ethnicityIII.1.3. Age and genderIII.1.4. Current change in gender prevalenceIII.2. Lifestyle related factorsIII.2.1. Calcium intakeIII.2.2. Emerging dietary risk factorsIII.2.3. Association with other chronic diseasesDehydrationIV. Dehydration: a risk factor for kidney stonesIV.1. Low urine volume: a key risk factor for kidney stonesIV.2. Environmental factors predisposing to low urine volumeIV.2.1. Occupational risk of kidney stonesIV.2.2. Climate and temperature as risk factorsWater & recurrenceV. Prevention of stone recurrence with high water intakeV.1. Reduction of recurrence rate with increased water intakeV.2. Water intake and urinary parameters in stone formersWater & incidenceVI. Primary prevention of stones with high water intakeVI.1. Reduction of stone incidence with increased water intakeVI.2. Water intake and urinary parameters in healthy subjectsWater & health costsVII. Water intake and health costs of kidney stonesVII.1. Reduction of stone recurrence costs via adequate water intakeVII.2. Reduction of first stone costs with adequate water intakeRecommendationsVIII. Dietary and water recommendations for stone preventionVIII.1. Guidelines for the prevention of recurrence in patientsVIII.2. Dietary and water guidelines for general populationConclusion References
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Figure 2. Main steps of lithogenesis.
(Adapted from Daudon et al. 2012).
Urine supersaturation initiates stone formation (Daudon et al. 2012; Evan 2010). Moderate urine supersaturation is common in healthy subjects, and doesn’t result in crystal formation (Fleisch 1978). In this case, urine is described as metastable, existing crystals can grow but new crystals cannot form. When urine supersaturation exceeds a certain threshold, called the Upper Limit of Metastability (ULM), urine becomes unstable and new crystals are more likely to form (Brenner and Rector 2008; Finlayson 1978).
These crystals are formed through the nucleation of ions dissolved in urine. There are two types of nucleation. Homogeneous nucleation is rare and corresponds to the spontaneous formation of new crystals in crystal-free urine. In most cases it is the presence of particles or crystals of one substance that will facilitate nucleation of other substances on their surface. This phenomenon is called heterogeneous nucleation. About 90% of urinary stones are composed of several substances and form by heterogeneous nucleation (Brenner and Rector 2008; Daudon et al. 2012).
Stone formation can also be promoted or inhibited by other compounds present in the urine. These components are respectively referred to as promoters and inhibitors (Coe et al. 2011).
Promoters are ions which can associate and form larger stone forming molecules. Calcium and oxalate are called promoters because they can associate to form calcium oxalate, which is a stone forming compound. As a result, recommendations state that a balanced intake of calcium is necessary to prevent kidney stones recurrence. An insufficient intake of calcium may actually favor oxalate absorption and therefore also appears to increase the propensity of kidney stones formation (Curhan et al. 1993).
Inhibitors include various types of compounds. Some inhibitors (e.g. citrate and magnesium) have a small molecular weight and will associate with promoters to prevent the formation of stone forming compounds. Other inhibitors are macromolecules that associate with crystals and reduce the propensity of crystal growth, aggregation and agglomeration (Daudon et al. 2012).
Kidney stones formation results from an imbalance in urine composition. This is summarized in Figure 3. Observational studies have shown differences between individuals who form stones and control subjects in several urinary parameters. Stone formers often present with high frequencies of excessive urinary concentrations of calcium (hypercalciuria), oxalate (hyperoxaluria) and uric acid (hyperuricosuria), as well as insufficient urinary concentration of citrate (hypocitraturia) and low urine volume (Curhan et al. 2001; Peres et al. 2003). Given the mechanism of lithogenesis, all these parameters appear to act on urine supersaturation and on urinary concentrations of promoters and inhibitors of stone formation.
Supersaturation state can be assessed by different methods and formulas among which the Tiselius Crystallization Risk Index (CRIT). This index is calculated from urinary analysis and takes into urinary excretion of calcium (Ca), oxalate (Ox), citrate (Cit), magnesium (Mg) and urine volume (V) (Tiselius 1991).
Urine volume is clearly an essential component in the pathogenesis of kidney stones. Borghi et al. acknowledged that increasing urine volume is the simplest way to reduce urine supersaturation (Borghi et al. 1999c). It was however hypothesized that increasing urine volume could also dilute promoters and inhibitors. The question of how concomitant dilutions of promoters and inhibitors impact the risk of forming a stone has been addressed in several papers. In vitro, urine dilution had no impact on the inhibitory effect of citrate and magnesium on calcium oxalate crystallization (Guerra et al. 2006). Similarly, in vivo studies have shown that urine dilution does not impact the inhibitory effect of macromolecules over 10kDa on calcium oxalate crystallization (Borghi et al. 1999a). Moreover, it appears that urine dilution can lead to an increase of the upper limit of metastability (Pak et al. 1980).
Daudon et al. postulated that urine dilution reduces the effect of promoters without any impact on inhibitors. It is actually the product of molar concentrations of oxalate and calcium which drives crystallization. A twofold urine dilution will for instance reduce both calcium and oxalate concentrations, and will result in a fourfold decrease of their product of molar concentrations. The inhibitory effect of compounds such as oxalate is also dependent on the molar ratio between promoters and inhibitors (e.g. calcium and oxalate). This inhibitory effect is thus not affected by urine dilution. They concluded that an increase in urine volume may reduce the risk of forming a stone (Daudon et al. 2012).
Figure 3. Urinary risk factors leading to stone formation.
Take home messages
Low urine volume contributes to urine supersaturation, which drives stone formation. Increasing urine volume reduces urine supersaturation as it lowers the effect of promoters, with only a small effect on inhibitors.