High water intake in preventing the risk of Uric Acid Nephrolithiasis: A systematic review and meta-analysis

Uric acid nephrolithiasis (UAN) refers to the formation of urinary stones containing uric acid or urate salts. UAN constitutes around 10% of kidney stones. The incidence of UAN has constantly increased over recent years [1-3]. The United States National Health and Nutrition Examination Surveys II and III reported that kidney stone prevalence increased from 3.8% in the year 1976 to 5.2% in the year 1994 in most developed countries [4]. There are global geographical diversities in the incidence of UAN. The worldwide incidence ranges from 5% to 40% [3]. The prevalence of UAN was Abstract


Introduction
Uric acid nephrolithiasis (UAN) refers to the formation of urinary stones containing uric acid or urate salts. UAN constitutes around 10% of kidney stones. The incidence of UAN has constantly increased over recent years [1][2][3]. The reported to be 15-16% in Japanese and Chinese descendants in San Francisco, 28% in Pakistan, 22% in Israel%. Approximately 13% of men and 7% of women will develop a kidney stone during their lifetime. UAN prevalence is higher in Middle Eastern and Hmong immigrant populations in the US [3,5,6]. The pathogenesis of UAN remains unclear. Three signi icant urinary abnormalities have been described as main etiological risk factors in the pathogenesis of UAN including hyperuricosuria, persistently low urinary pH, and low urinary volume [7]. From the viewpoint of treatment and prevention, hydration status, urine output and uric acid concentration are important factors that affect renal handling of uric acid [3]. Medical dissolution treatments including urine dilution and alkalization can be effective in many UA stone formers [8]. Indeed, increased luid intake has been universally advocated as a prevention strategy for all types of kidney stones [9,10]. Some intervention studies speci ically promote water, while some include other beverages that largely contain free water [10,11]. Increased water intake may help prevent the formation of UAN by diluting urinary uric acid concentration, and by lushing away uric acid micro-crystals [12]. Mineral waters may also decrease urine pH. Some studies support the ef icacy of water therapy to prevent and reduce the recurrence of all forms of kidney stones lumped together, presumably since high water intake increases urine low rates, lowers the super saturation for stone forming salts [10][11][12][13]. From that perspective, we hypothesized that UAN could be prevented by increasing urine volumes and lows via increased water intake [8][9][10].
Recently both the American College of Physicians (ACP) clinical guideline and American Urological Association (AUA) clinical guideline recommend suf icient water intake to prevent recurrent kidney stones [14,15]. However, the association between luid intake and kidney stone risk is not entirely clear. Several studies suggest that suf icient luid intake is an effective strategy to prevent kidney stones [12,[16][17][18]. Three meta-analyses concluded that water intake was associated with reduced kidney stone risk and long-term risk of recurrence [8,13,18]. However, some studies contain con licting results [19,20]. Further, neither the clinical guidelines nor the mate-analysis address the relationship between high water intake and prevention of UAN. Thus the objectives of this systematic review and meta-analysis were to de ine the quantitative relationship between high water intake and the UAN risk.

Materials and Methods
This systematic review and meta-analysis were performed using published studies including interventional and cross over studies.

Eligibility criteria
We included both healthy non stone formers and patients with a urolithiasis history in our selection criteria. Intervention study subjects must have been prescribed high water intake (any kind of water). Study designs could be interventional or prospective observational and included comparison to baseline or control untreated cohorts. Studies with urine pro iles (as opposed to stone events as the outcome) were included. All had full text articles available. We did not limit based upon year or published language.

Search strategy
The literature search was conducted in PubMed, Science Direct, Cochrane library, and two Chinese databases (China National Knowledge Infrastructure and Wang fang Database) through November 2018. A manual search of the article references and relevant reviews was also completed. The keywords used for the search were as follows: "uric acid", urate, kidney, renal, urinary, stone * , crystal * , nucleat * , * lithiasis, grow * , form, formation, forming, formed, precipitat * , solub * , water, coffee, tea, soda, luid * , liquid * . The terms "humans" or "patient" was used to limit search results.

Study inclusion and exclusion criteria
Studies were included in the meta-analysis if they: were based on a cohort, case-control, or cross over design published as original studies; contained exposure information water intake (water, coffee, tea, soda); evaluated the effects of high water intake on urinary risk factors for UAN; provided data on 24 hour urinary uric acid, urinary pH, urine volume, relative super saturation of uric acid, and other risk factors related to UAN. Additionally, studies must have included a reference group composed of subjects on a usual water intake (control or baseline). We excluded literature review, grey literature, and conference abstracts.

Study selection and data extraction
All studies were organized and screened for duplication using EndNote X8 software. Duplication-free articles underwent title and abstract examination using predetermined inclusion and exclusion criteria described above. Study selection was performed by two investigators independently. Opinion discrepancies were resolved by discussion and ultimate consensus. All studies which ful illed the inclusion and exclusion criteria underwent full text review. A standardized data collection form was used to extract the following information, if available: name of irst author, year of publication, country of origin, title of article, study design, sample size, year of study, subjects speci ic condition, de inition of high luid intake (If there was no information on water serving size in an article, an assumption was made that a serving size of 1 cup or glass was equal to 150 mL), control intervention or baseline. The outcome parameters were chosen on the basis of the hypothesis that three main risk factors of UAN were hyperuricosuria, persistently low urinary pH, and low urinary volume. We extracted urine pro ile data as follows: 24 hour urinary uric acid, urinary pH, urine volume, relative supersaturating of uric acid. Measurement units used in this study were mg/day for urinary uric acid level, L/day for urine volume, and % for relative supersaturating of uric acid. All data are continuous variables, and numbers were extracted as mean and standard deviation.

Statistical analysis
Mean and standard deviation were combined by Review Manager 5.3.5 software (The Cochrane Collaboration, Oxford, UK). The degree of heterogeneity was assessed calculating the Cochran' Q statistic with I2 and P heterogeneity. An I2 of 0%-25%, suggested no heterogeneity; 26%-50% represented low heterogeneity; 51%-75% represented moderate heterogeneity; and 75%-100% represented high heterogeneity [21,22]. The presence of publication bias was assessed by funnel plots [21]. Outcomes of 24 hour urinary uric acid, urinary pH, urine volume, and relative super saturation of uric acid were pooled under random-effects models and SMD as the effect size. If outcomes were observed in multiple follow-up times, we combined the mean and standard deviation, and pooled within-trial differences in SMDs [23]. Sensitivity analyses was used to ensure that no individual study was entirely responsible for the combined results, and this procedure was used to determine which study was the main source of heterogeneity [24]. We performed sensitivity analyses by removing each individual study in turn from the total and re-analyzing the remainder. We also performed subgroup analyses to detect possible sources of heterogeneity and potential difference among subgroups, by grouping the condition of subjects (healthy subjects or stone formers) and the type of water intake (regular water or mineral water). All P-values were 2-sided.

Search results
The search strategy identi ied 1811 potentially relevant articles. After removing duplicates, 1747 individual publications were screened by title and abstract, after removing review articles and not relevant studies. A total of 74 full manuscripts were identi ied for detailed evaluation. Fifty-three articles were excluded, including 2 articles with no full-text available. Nineteen articles were consistent with our selection criteria. Two of these 19 did not have suf icient quantitative analysis; therefore 17 studies remained for the full meta-analysis. A low diagram illustrating study selection is shown in igure 1.

Characteristics of included articles
Nineteen studies were consistent with our selection criteria. Two of the 19 studies had to be excluded from quantitative analysis because of the following reasons: ( [26]. Three of the remaining 17 studies were conducted in USA [27][28][29], two in China [30,31], two in Germany [32,33], one in Iran [34], four in Italy [12,[35][36][37], one in Poland [25], three in Russia [26,38,39], two in Saudi Arabia [40,41], one in South Africa [42]. Among the studies two were randomized controlled trial. This systematic review retrieved a total number of 895 participants in the articles included; number of participants per study ranged from 6 to 100. The 2 RCT studies enrolled 399 participants with a follow-up period of 14 days [35] and 5 years [12]. Six studies included only healthy subjects, eleven studies included kidney stone formers, and two studies included both healthy subjects and patients. Only one study included children (n=3), the remaining including only adult participants [39]. Water intervention duration ranged from 2 days to 5 years. Characteristics of the studies included are shown in table 1.

Defi nition of high water intake:
Fifteen studies speci ically de ined high water intake. Two studies calculated daily water intake volumes based on the volunteers' lean body weight [25,27]; one study calculated daily water intake volumes by 120 mL per 100 kcal/d [34]; one study described daily water intake by cups [30]. Sixteen studies reported the intervention as more than 1.2L of water intake, one study had unclear increased water intake [27], one study described high daily water intake as evidenced by a urine volume of at least 2L [12]. Only two studies described water or tea as an extra luid intake beside daily water consumption, with the amount less than 1L [30,39], which needed add up other forms of water (beverage, luid ingested from solid foods or other types of water intake) as total water intake daily. Three studies counted green tea [30], fruit tea [33], bag tea [40] drinking as the daily water consumption. Details were shown in table 1.

Overall analysis and sensitivity analysis
24h Urine Volume with High Water Intake: Fourteen studies were included in the quantitative synthesis of 24h urine volume with high water intake. In overall analyses, high water intake individuals had a signi icantly increased urine volume versus controls (SMD=0.52 L; 95% CI: 0.19, 0.84; p=0.002). High heterogeneity was apparent between all quali ied studies, with an I2 =99% and Pheterogeneity <0.00001 (Figure 2). A sensitivity analysis was also performed by removing 1 study at a time to see whether the omission of the study in luenced the overall results. None of included studies would be excluded, since there was no signi icant decrease the I2 when omission of each study at a time.

Relative Super saturation of Uric Acid with High
Water Intake: Four studies were included in a quantitative synthesis of relative supersaturation of uric acid with high water intake. The risk factor of relative supersaturation of uric acid decreased signi icantly versus controls (SMD=-0.96; 95% CI: -1.70, -0.22; p=0.01). High heterogeneity was apparent between all quali ied studies, with an I2=96% and Pheterogeneity <0.00001 (Figure 3). In a sensitivity analyses, the pooled SMD of relative supersaturation of uric acid changed to -0.61 (95% CI: -0.76, -0.46; p<0.00001) with a statistical signi icance remaining after omission of the LOURIS BORGHI Study. The heterogeneity was also reduced with this omission, with an I2=0% and Pheterogeneity =0.92.

Figure 2:
Forest plot of included studies comparing 24h urine volume in individuals with vs without high water intake; using random-effects meta-analysis. Diamond data markers, pooled SMD and 95% CIs for outcomes of interest.

Figure 3:
Forest plot of included studies comparing relative supersaturation of uric acid in individuals with vs without high water intake; using random-effects meta-analysis. Diamond data markers, pooled SMD and 95% CIs for outcomes of interest.

h Urinary pH with High Water Intake:
Eleven studies were included in quantitative synthesis of 24h urinary pH with high water intake. The UAN risk factor urinary pH was not signi icantly related to high water intake (SMD=0.14, 95% CI: -0.02, 0.31; p=0.09). ). It appeared a high heterogeneity, with an I2=93% and Pheterogeneity <0.00001 ( Figure 5). In sensitivity analyses, as omitting the O. V. Konstantinova Study led the results to become statistically signi icance versus controls, with the pooled SMD of relative 24h urinary pH changed to 0.18 (95% CI: 0.02, 0.33; p=0.02) . The heterogeneity was also reduced, with an I2=83% and Pheterogeneity <0.00001.

Subgroup analysis and sensitivity analysis
Subgroup analyses were conducted regarding subject category (healthy subjects vs stone formers), the type of water intake (regular water vs mineral water), and study type (Randomized Controlled Trial vs Self-controlled Study).

Subgroup Analysis on Healthy Subjects vs Stone
Formers: For 24h urinary uric acid, subgroup analysis stone former status revealed that there was moderate heterogeneity between healthy subjects and stone formers with an I2=61.6%, Pheterogeneity=0.11; and high water intake was associated with signi icantly decreased only in healthy subjects (SMD=-38. 61 (Figure 7).
The subgroup analysis revealed that there was high heterogeneity between randomized controlled trials and self-controlled studies for urine pH with an I2=91.9%, Pheterogeneity=0.00004. T Urine pH signi icantly increased only in the randomized controlled trials with SMD=0.45 (95% CI: 0.33, 0.57; p=0.03; Not applicable heterogeneity). There no signi icant changes in the mineral water group with SMD=0.11 (95% CI: -0.04, 0.26; p=0.14; I2=89%, Pheterogeneity<0.00001) (Figure 16). After omitting the Konstantinova study the pooled SMD of 24h urinary pH Figure 11: Forest plot of included studies comparing 24h urine volume in subgroup analyses on water type; using random-effects meta-analysis. Diamond data markers, pooled SMD and 95% CIs for outcomes of interest.

Figure 12:
Forest plot of included studies comparing 24h urinary pH in subgroup analyses on water type; using random-effects meta-analysis. Diamond data markers, pooled SMD and 95% CIs for outcomes of interest.

Figure 13:
Forest plot of included studies comparing relative supersaturation of uric acid in subgroup analyses on water type; using random-effects meta-analysis. Diamond data markers, pooled SMD and 95% CIs for outcomes of interest.

Figure 14:
Forest plot of included studies comparing 24h urinary uric acid excretion in subgroup analyses on study type; using random-effects meta-analysis. Diamond data markers, pooled SMD and 95% CIs for outcomes of interest.

Evaluation for publication bias
Assessment of publication bias was completed with a funnel summarized in igures 18-21. The overall funnel plot was moderately asymmetrical in shape con irming a publication bias.

Strength and limitations
The present study's comprehensive literature search with no languages restrictions and initial date of publication lends  credibility to the results. The studies were conducted in eight countries, including developed and developing countries. To our knowledge, this is the irst study employing a metaanalysis that evaluated the association of high water intake for preventing the risk of uric acid kidney stones, providing a more re ined analysis than some prior studies. The strengths of our study were that it assessed the magnitude of the effects of high water intake for preventing uric acid nephrolithiasis, and synthesized the standard mean difference changes of individual urinary pro iles. The results suggested that high water intake likely had effect to prevent uric acid nephrolithiasis. Furthermore, subgroup and sensitivity analyses suggested that our study's results were robust in most cases, which strengthens the conclusions of our study. Certain limitations of this study should be considered. The irst is the variability of water intervention. The included studies used several types of water including mineral water (with low hardness 110 mg/L, moderate hardness 180 mg/L, and high hardness 280 mg/L), regular water (tap water, carbonated, boiling water, bottled water, distilled water, tea, et al.). Only three studies described the pH of consumed water [30,34,36]. The volume and duration of water intake also varied. Furthermore we get water not only directly as water intake but from solid forms of food, fruits and vegetables, and also a small amount of metabolic water [43][44][45]. Although the water intake varied, the comparison was between water     intervention and baselines or controls, and in most studies the diet was the subject's usual diet. There was high heterogeneity in the overall analyses for 24h urinary uric acid excretion, urine volume, urinary pH and relative supersaturation of uric acid. However, in a sensitivity analysis for 24h urine volume and relative supersaturation of uric acid, when 1 or 2 studies are omitted to reduce heterogeneity, the results remained signi icant. In a sensitivity analysis for 24h urinary pH when the Konstantinova study was omitted the results became statistically signi icant.
Publication bias is one of the most important issues in meta-analysis, and we cannot deny the possibility of such bias [46]. Although the literature search was performed with no languages restrictions and beginning date of publication, we could have inadvertently missed eligible studies. There could be publication bias in this present systematic review. Indeed the funnel-plot assessment showed evidence for publication bias in this meta-analysis [47]. In present study the sensitive analysis indicated that the analysis used a small number of studies with high heterogeneity, which could also introduce bias. However, considering that the quality of studies of water intake may be affected by many confounding biases, these limitations may be acceptable. The subgroup analyses were similar to those of the overall analyses. The third limitation was the study design and small number of participants. This systematic review included 895 participants, and the number of participants per study ranged from 6 to 100. Most of the studies were self-controlled; only two RCT studies with 399 participants were included. Research indicates that random errors induced by a small numbers of studies might cause bias in the results of meta-analyses [48]. Furthermore, it was dif icult to include placebo control in water intake intervention, so that self-controlled studies were performed in most. However, the subgroup analysis of study type indicated that similar changes of urine volume, relative supersaturation of uric acid and 24h urinary pH were observed in randomized controlled trials and self-controlled studies.

Discussion
The prevalence of UAN is increasing recent years, and now accounts for approximately 7% to 10% of kidney stone formers [1,3]. Multiple factors contribute to the formation of uric acid kidney stones. The most important risk factor is persistently low urinary pH, followed by low urinary volume, and hyperuricosuria [7,49,50]. When urinary pH falls below 5.5, urinary urate exists largely as uric acid which can precipitate as uric acid crystals [51,52]. Hyperuricosuria is the second risk factor of UAN [50]. Low urinary output also increases the concentration of lithogenic solutes [53]. The prevention and treatment of UAN thus includes urine alkalinization as well as hydration (increasing urine volume above 2000 ml daily) [54,55]. Medical dissolution treatment including urine dilution, luid intake, and alkalization is effective in many [8]. This is the irst meta-analysis to con irm a signi icant association between high water intake and a lower risk of uric acid kidney stones. The overall analysis indicated that high water intake increased 24h urine volume (SMD=0.52 L; 95% CI: 0.19, 0.84; p=0.002) and decreasing relative supersaturation of uric acid (SMD=-0.96; 95% CI: -1.70, -0.22; p=0.01). Sensitivity analyses showed unstable results for 24h urinary pH. However after omitting the Konstantinova study results became statistically signi icant (SMD=0.18; 95% CI: 0.02, 0.33; p=0.02) After omitting the Dzeranov and Konstantinova studies results for UA excretion reversed with the SMD changing from 7.32mg/d (95% CI: -52.27, 66.91; p=0.81) to -17.98mg /d (95% CI: -41.65, 5.69; p=0.14). Further subgroup analyses revealed similar results for 24h urine volume and relative supersaturation of uric acid. The results persisted in a number of subgroup and sensitivity analyses, suggesting that the indings are not likely to be completely explained by confounding. In subgroup analysis 24h urinary pH signi icantly increased (Total SMD=0.14; 95% CI: 0.00, 0.27; p=0.04) with similar increases in healthy subjects (Subtotal SMD=0.14; 95% CI: -0.04, 0.31; p=0.12) and stone formers (Subtotal SMD=0.13; 95% CI: -0.08, 0.34; p=0.21). Subgroup analyses revealed high water intake decreased uric acid excretion more in healthy subjects than stone formers, with SMD -38.61 mg/d vs 26.61 mg/d; 24h urinary pH subgroup analyses shown signi icantly increased pH in mineral water intake group vs regular water intake group, with SMD 0.14 vs -0.00. This result suggests high water intake can signi icantly reduce relative supersaturation of uric acid and increase urine volume. Even though weak, the observed reduction in 24h urinary uric acid excretion and increased urinary pH with high water intake should favor uric acid crystal dissolution in renal tubules and lushing away of uric acid micro-crystals [12].
Overall, this meta-analysis presents evidence that high water intake intervention can reduce the risk factors of uric acid kidney stones. Drinking water is a simple and costeffective preventive method for kidney stone prevention, and is recommended by most healthcare facilities and clinical guidelines [14,15,56,57]. The current indings heave important public health implications in light of the current epidemic of uric acid kidney stones [3,58]. Recent epidemiological studies suggest that kidney stones are a risk factor for acute and chronic kidney injury [59,60], kidney cancer [61], metabolic disorders [62], and cardiovascular disease [63]. Therefore water intake for prevention of uric acid stones has multiple potential bene its.

Conclusion
High water intake can help prevent UAN by increasing urine volume, decreasing UA concentration, and depending on the luid type increasing urinary pH, thus decreasing relative super saturation of uric acid. Current evidence is not strong due to a relatively small number of studies and participants. Thus high quality clinical studies should be completed to con irm the effects of water intake for prevention of UAN.