Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients

Abstract

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy‐associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety‐seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66–0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66–0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first‐year eGFR decline (ρ = −0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real‐time clinical monitoring in children.

Effectiveness of T cell–mediated rejection therapy: A systematic review and meta-analysis

“…While 60%–70% of clinicians rely on graft functional markers to define BPAR resolution, 11 , 12 serum creatinine is very insensitive with only an AUC 0.59 for detecting BPAR. 13 There is a dearth of evidence evaluating histologic persistence of BPAR after anti‐rejection therapy for TCMR. Indeed a systematic review of BPAR treatment from 1997 to 2015 identified only five studies that examined the response to anti‐rejection therapy and these studies used graft function, not histology.…”

Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings

“…In the search for biomarkers and therapeutic targets for acute rejection, several research groups have suggested to study cytokines, as they play a crucial role in the pathophysiology of rejection (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). However, studies focusing on only one or few molecules miss the complexity of the interactions and the interplay between the full landscape of cytokines.…”

Use of a donor‐derived cell‐free DNA assay to monitor treatment response in pediatric renal transplant recipients with allograft rejection

“…36 Urinary biomarkers including CXCL10 immune monitoring in pediatric transplant recipients using the urine CXCL10/Cr levels defined the risk of rejection, immune quiescence and decline in allograft function and are being studied for real-time clinical monitoring. 37 Similarly, a urinary composite score based on the measurements of six urinary DNA, protein, and metabolic markers demonstrated clinical utility for predicting acute rejection before the rise in serum creatinine levels. 38 Ultimately, it will likely be a combination of dd-cfDNA and other biomarkers which will be able to reliably diagnose and determine response to treatment for all types of rejection.…”