*Purpose: Recent studies indicate that 25-36% of clinically stable pediatric renal transplant recipients will have subclinical rejection detected on surveillance biopsy. These findings highlight a critical need to advance care by implementing urinary biomarker profiling in the clinic to identify low- and high-risk patients, optimize immunosuppression and promote long-term graft survival.

*Methods: We tested a novel automated platform (ProteinSimple Inc.) that measures urinary CXCL9, CXCL10, CCL2 and VEGF-A simultaneously with high precision. We validated their diagnostic utility in training biorepository samples collected at the time of surveillance or indication renal biopsy from adult and pediatric recipients. Levels were normalized to urinary creatinine (UCr) and correlated with clinical histology as assessed in five centers. Principal component analysis (PCA), non-parametric rank sum analysis and area under ROC curve (AUC) were used to determine diagnostic performance. Risk algorithms were validated in two additional pediatric cohorts and the platform assay was cross-validated in three cores.

*Results: 517 training samples were assessed vs. histological diagnosis as normal (n=330), acute rejection (n=92) or borderline changes (n=95). Each biomarker independently discriminated normal vs. acute rejection (P< 1x10^-10), whereas only CCL2 trended higher with borderline changes (P=0.008); CXCL9 and CXCL10 provide the best performance for the diagnosis of acute rejection (AUC 0.85 and 0.82, respectively). In pediatric recipients, an algorithm utilizing all four biomarkers (‘score 4’) had excellent diagnostic performance for acute rejection (AUC 0.86) outperforming any individual biomarker. Also, there was an almost perfect cross-correlation among CXCL9 and CXCL10 (rank, r=0.86; regression slope=0.98) to identify risk. Pediatric urine samples collected from two independent validation cohorts of clinically stable patients (n=52 and n=120) were simultaneously evaluated in three mechanistic core sites with almost perfect inter-operator reproducibility. In these validation cohorts, score 4 retained excellent performance for acute rejection at the 75%ile specificity. In contrast, score 4 had limited performance in borderline rejection and in patients with BKV viremia (predominantly within 90days of diagnosis). Unsupervised PCA using all 4 biomarkers show a clear distinction between normal vs. acute rejection, but not normal vs. borderline rejection.

*Conclusions: This study represents one of the largest cohort analyses to date, and suggests that the integration of urinary biomarkers into pediatric point-of-care has potential to be transformative to optimize outcomes.

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