Identification of Primary Hyperoxaluria Type III by Gas Chromatography/Mass Spectrometry-Based Urine Metabolomics

Objectives: Primary hyperoxaluria type III (PH3) causes kidney stones in children and adults. Gas chromatography/mass spectrometry (GC/MS)-based metabolomics has been applied to study patients with primary hyperoxaluria types I and II, 2,8-dihydroxyadenine lithiasis, and xanthinuria types I to III. This study was performed to verify the usefulness of this technique for the diagnosis of PH3. Specifically, we evaluated an 8-month-old infant with recurrent kidney stones. Methods: GC/MS-based metabolomics was performed on spot urine samples using initial urease pretreatment without fractionation. Results: Metabolomics revealed increased levels of 2,4-dihydroxyglutarate and 4-hydroxyglutamate. No simultaneous elevations of these two critical biomarkers were observed in other patients, except for one case of PH3 confirmed by the identification of HOGA1 mutations. A moderate increase in 4-hydroxyglutamate has been observed only in cases of primary hyperammonemia, in which analytes such as orotate, uridine, glutamine, or proline, but not 2,4-dihydroxyglutarate, are biomarkers, thus distinguishing PH3 from primary hyperammonemia. Conclusions: GC/MS-based urine metabolomics enables the rapid screening and chemical diagnosis of PH3 and other congenital anomalies that cause urolithiasis. This technique can also be used to monitor disease progression, as patients with PH3 benefit from long-term follow-up, particularly when transitioning from childhood to adulthood. The timely identification of patients with hereditary urolithiasis is crucial. To address this, a discussion was had about the current diagnostic criteria.