title: Novel biomarker combination predicts long-term allograft outcome.
abstract: Donor specific human leukocyte antigen (HLA) antibodies (DSA) are a significant cause of allograft failure. However, it has been reported that some DSA negative patients still experience allograft failure. In addition, some DSA positive patients maintain good graft function for >20 years. These findings suggest that while DSA is a cause of failure, it is not the sole risk factor for graft dysfunction and that the presence of DSA alone may not predict the time course of graft failure. Here, we report the predictive value of a proprietary panel of four biomarkers in long-term renal allograft outcome. A total of 310 consecutive patients, who received kidney transplants between 1999 and 2012, were included in this study. Recipient sera was tested for HLA antibodies and biomarkers at 3, 6, 12, 24, and 36 months post-transplant. HLA antibodies were identified using Labscreen single antigen beads. The biomarker combination (BMC) test consisted of a proprietary panel of 4 biomarkers and was performed using Luminex. Sera were defined as positive when any one of the 4 biomarkers became detectable. Sera of normal healthy people were used as negative controls. Graft survival analyses were performed and compared between different patient groups based on the positivity of DSA and BMC. Our results indicate that 57% of DSA negative patients and 54% of DSA positive patients had detectable biomarkers. There was no significant difference in BMC positive patients between the DSA positive and negative groups, which suggests that presence of BMC is not associated with HLA DSA. DSA positive patients had a 10% lower 10-year graft survival rate than patients without DSA, while BMC positive patients had a 25% lower 10-year graft survival rate than patients without detectable BMC. When DSA negative patients were divided into two groups based on the positivity of BMC, BMC positive patients had a 20% lower 10-year graft survival rate compared to BMC negative patients (p<0.05). Similarly, when DSA positive patients were divided into two groups based on the positivity of BMC, BMC positive patients had a 30% lower 10-year graft survival rate compared to BMC negative patients (p<0.01). When both DSA and BMC testing results were considered, DSA and BMC double positive patients had the lowest and double negative patients had the highest graft survival rates. The survival rates for the BMC alone and DSA alone positive groups were in between (p<0.001). Multivariate Cox models confirmed that BMC was an independent risk factor for graft failure, with a higher hazard ratio than DSA (BMC=2.60 versus DSA=1.64). In conclusion, serum BMC is an independent predictor of graft failure. BMC was more significantly associated with graft failure than DSA. In combination with DSA, BMC better predicted graft outcome than DSA or BMC alone.
authors.forename: Junchao
authors.initials: J
authors.lastname: Cail
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Paul I
authors.initials: PI
authors.lastname: Terasaki
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Everly
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Briley
authors.forename: Carl E
authors.initials: CE
authors.lastname: Haisch
authors.forename: Paul
authors.initials: P
authors.lastname: Bolin
authors.forename: William T
authors.initials: WT
authors.lastname: Kendrick
authors.forename: Scott A
authors.initials: SA
authors.lastname: Kendrick
authors.forename: Claire
authors.initials: C
authors.lastname: Morgan
authors.forename: Robert C
authors.initials: RC
authors.lastname: Harland
authors.forename: Lorita M
authors.initials: LM
authors.lastname: Rebellato
mesh_terms: D015415:Biomarkers; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology / Q000401:mortality; D006085:Graft Survival / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology; D016030:Kidney Transplantation / Q000401:mortality*; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D006680:HLA Antigens; D007518:Isoantibodies