A urine score for noninvasive accurate diagnosis and prediction of kidney transplant rejection

Abstract

Accurate and noninvasive monitoring of renal allograft posttransplant is essential for early detection of acute rejection (AR) and to affect the long-term survival of the transplant. We present the development and validation of a noninvasive, spot urine–based diagnostic assay based on measurements of six urinary DNA, protein, and metabolic biomarkers. The performance of this assay for detecting kidney injury in both native kidneys and renal allografts is presented on a cohort of 601 distinct urine samples. The urinary composite score enables diagnosis of AR, with a receiver-operator characteristic curve area under the curve of 0.99 and an accuracy of 96%. In addition, we demonstrate the clinical utility of this assay for predicting AR before a rise in the serum creatinine, enabling earlier detection of rejection than currently possible by standard of care tests. This noninvasive, sensitive, and quantitative approach is a robust and informative method for the rapid and routine monitoring of renal allografts.

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review

“…In accordance with previous studies, the most extensively assessed urinary biomarkers were C-X-C motif chemokine ligand 9 (CXCL9) and 10 (CXCL10), usually adjusted for urinary creatinine concentration. In detail, 12/38 (32%) studies either addressed CXCL9 and CXCL10 alone, in combination, or in the context of particular scores or formulas [16,17,24,26,[34][35][36]44,47,[50][51][52]. Other directly targeted cytokines and interleukins were chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 [22,31,43], CXCL13 [29], interleukin 10 (IL10) with interferon gamma (IFNγ) [46] and tumor necrosis factor alpha (TNFα) [32].…”

“…ABMR score [41] CTOT-4 formula [54] Q score [17] uCRM score [24] Signature of 133 unique metabolites CD3ε mRNA + CXCL10 mRNA + 18S rRNA Cell-free DNA + Clusterin + Creatinine + CXCL10 + Methylated Cell-free DNA + Total Urinary Protein 11 genes expression score on urinary cell pellet (including CXCL9 and CXCL10)…”

“…Two studies [35,44] investigated the diagnostic accuracy of the CTOT4 formula (CXCL10 mRNA, CD3ε mRNA, 18S rRNA), previously validated by the CTOT-4 (clinical trials in organ transplantation-4) multicenter study group [54]. CXCL10 was also included in newly derived scores such as the Q score, composed of six DNA, protein, and metabolite urinary biomarkers (cell-free DNA, methylated cell-free DNA, clusterin, total protein, creatinine, and CXCL10) [17], while CXCL9 and CXCL10 genes were included in the uCRM score [24]. Finally, the ABMR score comprised more than 130 unique metabolites [41].…”

“…Results confirmation in at least one validation cohort was available in less than one third of studies (7/29, 24%). Of these, two were case-control studies [25,33], while the others were the previously mentioned five cross-sectional studies with the lowest risk of bias score [16,17,21,41,45]. Sensitivity and specificity values were highly variable between studies, ranging from 9% to 100% and from 34% and 100%, respectively.…”

Challenges to Transplantation by the Assault of CoVid-19: Emergence of Molecular Diagnostics as Surveillance

“…To this end, significant advances in biomarker allograft surveillance now exist in our armamentarium -"Gene Expression Profiling" (GEP) [AlloMap  ] in peripheral blood mononuclear cells for assessment of cardiac allograft quiescence or rejection [2][3][4] and biomarkers representing "allograft injury" such as donor-derived cell-free DNA (dd-cfDNA) [AlloSure  ] [5][6][7][8][9][10][11][12] after renal, cardiac and lung transplantation that provide further insights. Indeed, novel validated composite biomarker panels that incorporate GEP, cfDNA, and chemokine proteomics have recently emerged within the clinical arena and have potential for further expanding our biomarker surveillance repertoire [13]. Therefore, our traditional clinical protocols may and probably should be challenged in light of the present global pandemic that severely impacts the field of organ transplantation.…”