Multicenter Validation of Urinary CXCL9 as a Risk-Stratifying Biomarker for Kidney Transplant Injury

Abstract

Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision-making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation-01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy-proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6-month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5–99.3% NPV). Our results support using urinary CXCL9 for clinical decision-making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Low urinary CXCL9 was the best predictor of longterm kidney graft stability (319). In renal transplants with delayed graft function, early expression of RANTES with the consecutive invasion of CCR1-positive cells was associated with subsequent renal fibrosis, tubular atrophy and worse renal allograft outcome (320).…”

Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody–Mediated Kidney Allograft Rejection

“…Suthanthiran et al 2 recently showed that the urinary cell mRNA profile can serve as a diagnostic and prognostic biomarker of TCMR. Protein markers have also been assessed for their ability to predict both clinical [3][4][5][6][7] and subclinical TCMR. 4,[8][9][10][11] C-X-C motif chemokine 9 (CXCL9) and CXCL10 are IFNg-dependent, C-X-C motif chemokine receptor 3-binding chemokines that are secreted by infiltrating inflammatory cells and renal tubular and mesangial cells.…”

“…10 A recent multicenter observational trial in 280 patients with kidney transplants reported that the CXCL9 protein level had a strong predictive value for noninvasively diagnosing TCMR. 5 Although there have been improvements in diagnosing TCMR using these new methods, it is noteworthy that, at the same time, the clinical presentation of renal allograft rejection has changed dramatically, with the incidence of TCMR progressively decreasing to 10%-15% using tacrolimus-based immunosuppression. For example, in the clinical trials in organ transplantation 4 (CTOT-4) Study, only 36 of 385 patients (9.3%) developed TCMR at 1 year post-transplant.…”

“…In the CTOT-01 Study, among 150 indication biopsies, only two ABMRs and four mixed rejections were diagnosed. 5 More recently, Matignon et al 13 focused on urinary cell mRNA biomarkers of acute kidney graft dysfunction and developed a six-gene diagnostic signature to differentiate acute rejection (AR; both TCMR and ABMR) from acute tubular injury and a five-gene signature to differentiate ABMR from TCMR.…”

Urinary MicroRNA as Biomarker in Renal Transplantation

“…Also, urinary CXCL‐10 mRNA has been shown to be elevated up to 6 to 7 days prior to an acute rejection episode 7. In a recent prospective multicenter study, urinary mRNA of CXCL‐9 (as well as urinary CXCL‐9 protein) was shown to be predictive for the presence of acute rejection 8.…”