Abstract
Despite new advancements in surgical tools and therapies, exposure to immunosuppressive drugs related to non-immune and immune injuries can cause slow deterioration and premature failure of organ transplants. Diagnosis of these injuries by non-invasive urine monitoring would be a significant clinical advancement for patient management, especially in pediatric cohorts. We investigated the metabolomic profiles of biopsy matched urine samples from 310 unique kidney transplant recipients using gas chromatography–mass spectrometry (GC-MS). Focused metabolite panels were identified that could detect biopsy confirmed acute rejection with 92.9% sensitivity and 96.3% specificity (11 metabolites) and could differentiate BK viral nephritis (BKVN) from acute rejection with 88.9% sensitivity and 94.8% specificity (4 metabolites). Overall, targeted metabolomic analyses of biopsy-matched urine samples enabled the generation of refined metabolite panels that non-invasively detect graft injury phenotypes with high confidence. These urine biomarkers can be rapidly assessed for non-invasive diagnosis of specific transplant injuries, opening the window for precision transplant medicine.
Highlights
Kidney transplantation (KTx) is the preferred method of treatment for end-stage kidney failure [1]
Metabolomics data on the remaining 310 biopsy-matched urine samples was used for the analyses of both post-Tx injury detection and associated metabolic pathways and their enrichment
Sophisticated interrogation of urine through advanced technologies for kidney diseases is important as urine provides an attractive alternative biospecimen [35] and unlike invasive biopsies, urine metabolite changes can be diagnostic of advanced tissue injury
Summary
Kidney transplantation (KTx) is the preferred method of treatment for end-stage kidney failure [1]. The application of high throughput technologies towards a more discovery-based approach for correlative biomarkers of graft injury have utilized sequencing [8] gene expression, proteomic [9,10,11,12,13,14], and metabolomic methods [15,16] Many of these approaches show background signals of other clinical confounders, such as immunosuppression exposure [17], and require the application of more customized and robust analytical techniques for improving the diagnostic accuracy of biomarkers in blood and urine to reflect different transplant (Tx) injury phenotypes [18,19,20]. These samples have been biopsy matched, providing an accurate phenotype characterization, and enabling exploration of metabolic pathways associated with KTx dysfunction
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