In this study, we have used two-sample MR to evaluate the causal relationship between a variety of food intakes and the risk of urolithiasis. In line with previous publications, our study supported a protective role of tea intake in calculus of kidney and ureter, but not in calculus of lower urinary tract [25, 26]. Furthermore, we have identified fresh fruit intake, instead of dry fruit intake, as a reverse causal factor for urolithiasis. After adjusting for the effect of vitamin C and vitamin D, fresh fruit intake remained to have a protective effect on calculus of kidney and ureter.

It is now well-accepted that dietary factors are crucial in the prevention of urolithiasis and its recurrence, even though the underlying mechanism is still unclear [6, 27]. DASH-style diet, a diet with high consumption of fruit, vegetables, and low-fat dairy products, has been reported to be associated with a decreased risk of urolithiasis [28]. In an observational study, large cohorts with adequate fluid intake, high consumption of fruits and vegetables, and low-fat dairy food, adequate calcium intake, showed a clinically meaningful reduced risk of urolithiasis [29]. However, most of the previous publications studied the effects of food intakes in combinations, and which individual food intake is beneficial for the prevention of urolithiasis is still unclear. Our MR analyses indicated that fresh fruit intake and tea intake generated a beneficial effect to prevent calculus of kidney and ureter.

One previous MR study found that tea intake was identified to reduce the risk of kidney stones [25]. The protective role of tea intake was proposed to be associated with the high content of antioxidative chemicals such as polyphenols, and caffeine that can reduce the adhesion of calcium oxalate crystals to the surface of renal tubular epithelial cells [25]. We also examined the effects of tea intake in the calculus of lower urinary tract. However, no causal relationship was identified. Our findings on fresh fruit intake are consistent with previous publications that increasing fruit intake reduced calculus risks [4, 30]. Some publications reported that the beneficial effect of fruit intake on urolithiasis is mainly mediated by the supplementation of citrate and bicarbonate [31]. Alkalosis and administration of citrate can increase urine citrate secretion and protect against stone formation [32]. A previous study on both normal and stone formers proved that withdrawing fruit and vegetable intakes for two weeks significantly reduced the urinary secretion of magnesium, citrate, potassium, and oxalate, together with an increase in urinary calcium and ammonium [33]. The European Association of Urology (EAU) guideline has encouraged the consumption of fruit and vegetables in the prevention of urolithiasis for their high content of fiber, even though the effect of vegetables are still under debate [34]. Our study may help to tailor personalized nutrition advice in the future, especially in the individuals with risk factors of urolithiasis.

There are several advantages of this current study. Firstly, the MR design we employed is suitable for causal inference. As RCT is not optional in our condition, an MR study can strengthen the causal estimation while minimizing the risk of confounding biases and reverse causality. Besides, we have performed the MR in a two-sample design, which can efficiently reduce the risk of over-fitting and false-positive findings. Additionally, we have examined the associations with several different MR methods in the sensitivity analyses, and the consistency of the results guaranteed the robustness of our findings. Furthermore, participants included in this study are constrained to the European population, which minimized the bias from population stratification. However, this also restricted the generalization of our findings to other populations. Another restriction is that using SNPs to proxy exposures mimics a life-long exposure, short-term effects of dietary habits may have a different effect. Besides, an important limitation of MR analyses is possible horizontal pleiotropy, which means that the genetic variants might affect urolithiasis not via food intakes. However, no significant pleiotropy was identified with MR-Egger analyses. Besides, the causal estimates of food intakes on urolithiasis may still be biased by potential reverse causality. For this sake, we have performed a reverse MR to estimate the effects of urolithiasis on food intakes, while no significant effects were observed. Furthermore, we employed a MVMR method to adjust the effect of fresh fruit intake on urolithiasis; however, the causal estimations may still be biased by other potential confounding factors such as lifestyle, socioeconomic status, and comorbidities. Another limitation is that the proportions of variance explained by the IVs (R2) are relatively low, thus null results of some associations do not necessarily mean that these food intakes are not associated with urolithiasis. Low R2 is also associated with a relatively low statistical power for the MR analyses. The statistical power may also be improved when future studies include a larger sample size and more cases of urolithiasis patients. Lastly, the investigation of food intakes was based on questionnaire investigations, and the accuracy of the information collection needs to be improved.

In conclusion, our MR study provided genetic evidence that fresh fruit intake may have a causal protective effect on the risk of calculus of kidney and ureter, but not lower urinary tract. An increase in the consumption of fresh fruit may provide good prevention to the development of calculus of kidney and ureter.