Urine Metabolomic Versus Standard Chemistry Analysis: What Can Metabolomic Analysis Bring to the Treatment and Prevention of Urolithiasis?

We read with great interest the recent publication entitled “Nuclear Magnetic Resonance (NMR) Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls.”1 In their prospective cohort study, researchers analyzed samples from 418 adults with first symptomatic kidney stones and 440 sex- and age-matched control individuals enrolled from the local community. All study participants underwent 24-hour urine collection, and these samples were then analyzed for 12 standard urine chemistries and a panel of 48 metabolites that were quantified using a NMR approach. Gradient-boosted machine methods revealed that NMR metabolomics failed to improve discrimination between individuals with and without kidney stones as compared with standard chemistry analysis. Analyses of covariance, however, revealed that individuals who developed kidney stones exhibited significantly reduced hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate excretion together with increased creatinine and alanine excretion, suggesting potential roles for these urine metabolites in the pathogenesis of kidney stone formation. As per the 2022 European Urological Guidelines, patients with urolithiasis can be stratified into low- and high-risk categories on the basis of whether patients meet one of 32 risk factors.2 Basic metabolic analyses are necessary for low-risk urolithiasis stone formers, whereas high-risk patients warrant specific metabolic analyses, including 24-hour urine analysis. Parameters that should be tested in the 24-hour urine analysis are listed in Table 2 in the published article and include 12 chemistries.1 Because these indices are highly important for the treatment and prevention of urolithiasis, the European Association of Urology incorporated these urine chemistries into their guidelines. Many recent omics-based studies of 24-hour urine samples from stone formers have been conducted as researchers seek to establish abnormalities linked to stone formation. However, the optimal approaches to applying the results of these omics-based studies to treating or preventing urolithiasis remain to be established. For example, in this published article, the authors observed that a drop in urine trigonelline levels was related to urolithiasis.1 This suggests a potential need to routinely analyze trigonelline levels in 24-hour urine samples from individuals at a high risk of stone formation and raises several questions: What are the normal trigonelline levels in urine samples? Does “hypotrigonellineuria” exist as a disease-like state? What are the causes of hypotrigonellineuria? Can increasing trigonelline concentrations provide a means of preventing urolithiasis? To answer these questions, further high-quality mechanistic investigations and clinical trials will be required. Overall, we hope to draw the attention of clinicians to the results of these recent omics studies that have yet to be incorporated into clinical guidelines so that these research findings can provide novel value to efforts to treat or prevent urolithiasis in the future.