BACKGROUND The objective of this systematic evaluate and meta-analysis were to evaluate the effectiveness of high fluid intake for the prevention of incident and recurrent kidney stones as well as its adherence and safety. 269 patients; 7 observational studies with 273 685 individuals) were included in the meta-analysis. Pooled Vitexicarpin RRs of kidney stones in individuals with high-fluid intake were 0.40 (95% CI 0.20-0.79) and 0.49 (0.34-0.71) in RCTs and observational studies respectively. High fluid intake was significantly associated with reduced risk of recurrent kidney stones: RRs 0.40 (95% CI 0.20-0.79) and 0.20 (0.09-0.44) in RCTs and observational studies respectively. Adherence and security data on high fluid intake treatment were limited; 1 RCT reported no withdrawals due to adverse events. CONCLUSION This analysis demonstrated a significantly reduced risk of incident kidney stones among individuals with high fluid consumption. High fluid consumption also reduced the risk of recurrent kidney stones. Furthermore the magnitude of risk reduction was high. Although increased water intake appears to be safe future studies on its security in patients with high INTS6 risk of volume overload or hyponatremia may be indicated. RRs; 95% CIs with marker size reflecting statistical excess weight of study using random-effects … Physique 3 Forest plot of included observational studies comparing risk of kidney stones in individuals with vs without high fluid intake; RRs; 95% CIs with marker size reflecting statistical excess weight of study using random-effects … Vitexicarpin Sensitivity Analysis The benefit of high fluid intake for prevention of kidney stones remained significant in a sensitivity analysis that included only those studies that adjusted for potential confounders [10 13 14 17 25 with a pooled RR of 0.68 (95% CI 0.61-0.76). No significant statistical heterogeneity was apparent between all qualified studies with an I2 of 5% (Supplementary Fig. 1). A sensitivity meta-analysis was also performed excluding 2 studies by Curhan et al   since participants in these 2 studies were Vitexicarpin likely duplicated in 2 other studies by Curhan et al  and Taylor et al  that were also included yielding a RR 0.59 [95% CI 0.53-0.66]; I2 = 95%. Another sensitivity meta-analysis was also performed excluding the observational study by Linder et al  since it was the only study with a cross-sectional design. The result also remained significant suggesting a benefit of fluid intake (RR 0.57 [95% CI 0.51-0.63]; I2 = 93%). Another sensitivity meta-analysis was performed for observational studies using high fluid intake (as opposed to strictly water) exposing a pooled RR for kidney stones of 0.49 ([95% CI 0.34-0.71]; I2 = 92%) in the high fluid group. The pooled RR of kidney stones among individuals with high fluid intake remained significant after excluding 2 studies by Curhan et al [13 14 that potentially duplicated participants in 2 other studies by Curhan et al  and Taylor et al. Vitexicarpin remained low at 0.59 ([95% CI Vitexicarpin 0.53-0.66]; I2 = 95%). A sensitivity meta-analysis for observational studies excluding those 2 [15 16 that used urine volume as a surrogate for high fluid intake also revealed a low RR for stones in the high fluid group of 0.68 ([95% CI 0.61-0.76]). There was no significant heterogeneity with an I2 of 5%. Since only 2 RCT studies were available on that used fluid and the other water no further sensitivity analyses were performed to try to individual out the effects of water verus fluid in this group. The Effect of High Fluid Intake in Individuals with Recurrent Kidney Stones Two RCTs with 269 patients and 2 observational cohort studies with 289 individuals were included in the data analysis for the risk of kidney stones with high fluid consumption [10 11 14 15 In a meta-analysis of RCTs high fluid intake was significantly associated with reduced recurrent kidney stone risk (RR 0.40 [95% CI 0.20-0.79]; I2 = 6%; supplementary fig. 2). In a Vitexicarpin meta-analysis of observational studies high fluid intake was also associated with decreased risk of recurrent kidney stones (RR 0.20 [95% CI 0.09-0.44 ]; I2 = 86%; supplementary fig. 3). Evaluation for Publication Bias Overall assessment of publication bias was limited due to the small number of included studies. Funnel plots to evaluate publication bias of.