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Renal cell carcinoma (RCC) stands among the most lethal urological malignancies. Most RCCs are incidentally diagnosed as initial symptoms are unspecific. Novel, minimally-invasive diagnostic and prognostic methods for RCC are needed, ideally in urine. Using UPLC-Q-ToF MS untargeted metabolomic analysis in urine, we previously revealed p-cresol glucuronide as potential RCC diagnostic marker. Additionally, urine samples one-year post-nephrectomy revealed isobutyryl- l -carnitine and L-proline betaine as potential RCC prognostic markers. Our present aim was to validate these differences in an independent cohort of RCC patients and healthy controls to strengthen their value as non-invasive biomarkers. In an independent cohort of 69 RCC patients and 52 controls we validated an increase in p-cresol glucuronide in urine from patients at diagnosis compared to controls (P = 0.0043). It remained increased one-year post-nephrectomy (P = 0.0288). The value of p-cresol glucuronide for RCC diagnosis was assessed with ROC curves analysis (AUC = 0.66, 95 % Confidence Interval 0.56–0.76). The role of isobutyryl- l -carnitine and L-proline betaine as prognostic markers could not be validated and will require a larger cohort. Our findings confirm the value of p-cresol glucuronide in urine as diagnostic marker for RCC in an independent cohort. This non-invasive method holds promise for enhancing patient care by reducing the need for potentially risky diagnostic procedures. Further metaproteomics-oriented approaches towards the tyrosine oxidation pathway and microbiota metagenomics studies may promote a holistic management of RCC. Current imaging techniques available to diagnose and monitor renal cell carcinoma (RCC) are harmful for the patient given the high-radiation dose, and unspecific in low-grade tumors. Thus, novel non-invasive biomarkers with diagnostic and prognostic capabilities are of utmost importance. Herein, we have validated urine p-cresol glucuronide as diagnostic marker for RCC. This novel non-invasive biomarker could improve accurate assessments of tumor behavior, while enhancing patient outcomes by reducing discomfort and detrimental side effects. • Current diagnostic techniques for renal cell carcinoma (RCC) are harmful for the patient and unspecific in low-grade tumors. • Urine metabolomics enables the identification of novel non-invasive biomarkers for RCC. • Urine p-cresol glucuronide is a diagnostic marker for RCC, which could reinforce current diagnostic techniques to reduce gold-standard harmful procedures. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is one of the most lethal type of tumors and is twice more frequent in men than in women. Initial symptoms are unspecific and belated thus increasing mortality. Moreover, current diagnostic and monitoring tools are harmful for the patient and unspecific in low-grade tumors. Therefore, novel minimally-invasive markers are needed to diagnose and monitor RCC patients. Urine represents the ideal sample source of non-invasive biomarkers for RCC. In our study we aimed to identify a urine metabolomic profile characteristic of RCC patients with diagnostic purposes and also to identify a profile with prognostic value. By an UPLC-Q-ToF MS untargeted metabolomic analysis, we compared the metabolomic profile of 23 RCC patients (14 clear cell RCC and 9 papillary RCC) before surgery and that of 23 healthy controls. Additionally, for the first time, we compared the metabolomic profile of these RCC patients pre-nephrectomy and 3 months and one year post-nephrectomy. We identified the dysregulated metabolomic variables by querying their exact mass against those presented in the Metlin and Human Metabolome Database. Next, we experimentally confirmed their identity. Both RCC subtypes showed similar metabolomic patterns at all stages. 51 metabolomic variables were significantly increased in RCC compared to controls and, among them, 4 were selected as potential discriminant metabolites between groups. We could experimentally confirm the identity of p-cresol glucuronide thus describing for the first time an increase in this metabolite in urine of RCC patients (fold change = 2.922, P =.012). Additionally, we confirmed that no metabolomic differences occur 3 months post-nephrectomy in RRC, while 188 variables were significantly increased one year post-nephrectomy. Of the 15 most discriminant metabolomic variables, we could experimentally confirm the identity of isobutyryl- l -carnitine (fold change = 2.098, P =.004) and l -proline betaine (fold change = 3.328, P =.004), for the first time. In summary, we have identified urine p-cresol glucuronide as potential diagnostic marker for RCC and isobutyryl- l -carnitine and l -proline betaine as potential prognostic markers. When confirmed in an independent cohort of RCC patients, these markers may improve the diagnosis and monitoring of RCC patients thus reducing current harmful diagnostic procedures. The high-radiation dose of current imaging techniques available to diagnose and monitor renal cell carcinoma (RCC) are harmful for the patient and unspecific in low-grade tumors. Our untargeted metabolomic analysis carried out in urine samples from RCC patients and healthy individual reveals p-cresol glucuronide as potential diagnostic marker for RCC. Additionally, the analysis of RCC urine samples one year post-nephrectomy reveals isobutyryl- l -carnitine and l -proline betaine as potential prognostic markers. These novel non-invasive urine biomarkers may improve RCC management thus reducing the use of current harmful diagnostic techniques. Unlabelled Image • Current diagnostic techniques for renal cell carcinoma (RCC) are harmful for the patient and unspecific in low-grade tumors. • Urine untargeted metabolomics may be a suitable and non-invasive source of RCC biomarkers. • Urine p-cresol glucuronide may represent a potential diagnostic marker for RCC. • Urine isobutyryl- l -carnitine and l -proline betaine may represent potential prognostic markers for RCC. [ABSTRACT FROM AUTHOR]