By applying mendelian randomization, we unveiled the causal association between urolithiasis and various metabolites. 3-hydroxybutyrate (BHBA), Isobutyrylcarnitine, Dehydroisoandrosterone sulfate (DHEA-S), Mannose and Bilirubin (Z, Z) were detected to possess protective effects against urolithiasis. On the contrary, a number of metabolites, incorporating glycerol, eicosenoate, pro-hydroxy-pro, erythronate, cysteine and cortisone, have negative effects on urolithiasis.
Browsing previous literatures, mounting evidences have hypothesized the causal correlation between urolithiasis and metabolites[19–22]. In an animal experiment, raising castrated rats with Dehydroisoandrosterone(DHEA) may directly modulate the hepatic enzyme activities of GRHPR and AGXT which subsequently regulate the endogenous oxalate production in the liver[23]. On the basis of it, Fuster et al. conducted a cross-sectional analysis aiming to reveal the relationship between urinary sex hormones and excretion of urinary components in kidney stone formers. Of note, their result shows that DHEA has an inverse association with urinary oxalate excretion and supports our finding[24]. Bilirubin, an endogenous antioxidant, has been highlighted to possess a positive effect on kidney protection.[25, 26] Wen and his colleagues used metabolomics to analysis serum metabolites of 50 children subjects and showed a significant decrease of serum bilirubin which is concomitant with the conclusion of its protective effects in our analysis.[27] On the basis of previous literatures, it might be hypothesized that bilirubin can serve as an antioxidant to alleviate oxidative stress damage caused by crystals in renal tubular epithelial cells.[28, 29] Theoretically, modulating serum bilirubin level to alleviate urolithiasis is a novel area with enormous potential. Additionally, In Franca Serafini-Cessi et al.’s study, they described N-Glycans, which are rich in mannose, were capable to resist urological diseases[30]. S Proietti et al. assessed a D-mannose-containing product possessing protective effects against infection-related urinary stones[31]. Their experimental conclusions fully support the analysis results obtained in our MR analysis regarding the protective effect of mannose.
In parallel to the protective metabolites, several lines of evidence suggest that a number of amino acid metabolic pathways are closely related to the formation of kidney stone[4, 32–34]. Correspondingly, our research results manifest that serum cysteine is stimulative factors towards urolithiasis. Apart from these amino acids, analysis of cortisone has captured our attention in our study. Several observational studies on hormone concentration in urine samples have indicated that glucocorticoids can mediate a negative impact on the excretion of inorganic salts and uric acid, even at normal physiological levels[35, 36]. Likewise, as an inactive precursor of glucocorticoids such as hydrocortisone, cortisone is a significant risk factor for stone formation in our analysis.
In addition, through metabolic pathway analysis, we found a significant relationship between synthesis and degradation of ketone bodies and the formation of urolithiasis. This has also been confirmed in previous studies. Eric H et. al have shown that a ketogenic diet can lead to urinary acidification, hypocitraturia and hypercalciuria, resulting in a high risk of developing uric acid and calcium stones[37]. Therefore, the 3-hydroxybutyrate in this pathway may be a potential target for preventing and treating urolithiasis.
However, our study also had some limitations. Firstly, we did not prove our study in other populations such as Asians while it also reduced population structure bias. Secondly, the number of SNPs in our study that can be used for whole genome level exposure was limited. In order to solve this problem, we eased slightly thresholds for our MR analysis which is also common practice in other studies. However, the F-statistic value of selected SNPs all exceeded 10, indicating that our IVs were robust enough. Moreover, it is significant that our study needs to be confirmed through careful basic research.