Targeted Urine Metabolomics for Monitoring Renal Allograft Injury and Immunosuppression in Pediatric Patients

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.

Urinary metabolomic profiling from spontaneous tolerant kidney transplanted recipients shows enrichment in tryptophan-derived metabolites

“… 2 In urine, a recent study by Sigdel TK et al associated three main metabolites (increase in glycine, decrease in N-methylalanine and inulobiose) in the urine with histology proven heterogenous allo-immune dysfunctions of kidney transplants (acute rejections and IFTA). 35 Interestingly, glycine has been associated with broad anti-inflammatory properties, ischemia/reperfusion and thermic shock protection. 36 On the opposite, N-methylalanine was negatively correlated with active inflammation in patients with rheumatoid arthritis.…”

Omics-based biomarkers for diagnosis and prediction of kidney allograft rejection

“…Sigdel et al [ 64 ] analyzed the metabolomic profiles of biopsy-matched urine samples from 310 KTRs (106 AR). They identified 266 metabolites; a panel of 11 metabolites (glycine, glutaric acid, adipic acid, inulobiose, threose, sulfuric acid, taurine, N-methylalanine, asparagine, 5-aminovaleric acid lactam, and myo-inositol) enabled detection of AR.…”

Tackling Chronic Kidney Transplant Rejection: Challenges and Promises

“…In a recent study, a panel of nine differential metabolites in urine were identified as novel potential metabolite biomarkers of TCMR ( 73 ). The metabolomic biomarkers that considered as potential markers for rejection episodes are listed in Table 1 ( 72 – 78 ).…”