TY - JOUR
T1 - Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation
AU - Akalin, Enver
AU - Weir, Matthew R.
AU - Bunnapradist, Suphamai
AU - Brennan, Daniel C.
AU - Delos Santos, Rowena
AU - Langone, Anthony
AU - Djamali, Arjang
AU - Xu, Hua
AU - Jin, Xia
AU - Dholakia, Sham
AU - Woodward, Robert N.
AU - Bromberg, Jonathan S.
N1 - Publisher Copyright:
Copyright © 2021 by the American Society of Nephrology.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Background Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here, we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). Methods A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: seven TCMR, ten ABMR, and one mixed rejection. The second validation set included eight quiescence and 11 rejection samples: seven TCMR, two ABMR, and two mixed rejection. AlloSure donor-derived cell-free DNA (dd-cfDNA) was also evaluated. Results AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median, 9.49; IQR, 7.68-11.53) and rejection (median, 13.09; IQR, 11.25-15.28), with P<0.001. In the second validation set, the cohorts were statistically different (P=0.03) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC, 0.894). Conclusion Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunologic activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence.
AB - Background Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here, we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). Methods A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: seven TCMR, ten ABMR, and one mixed rejection. The second validation set included eight quiescence and 11 rejection samples: seven TCMR, two ABMR, and two mixed rejection. AlloSure donor-derived cell-free DNA (dd-cfDNA) was also evaluated. Results AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median, 9.49; IQR, 7.68-11.53) and rejection (median, 13.09; IQR, 11.25-15.28), with P<0.001. In the second validation set, the cohorts were statistically different (P=0.03) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC, 0.894). Conclusion Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunologic activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence.
KW - T cell-mediated rejection
KW - allograft rejection
KW - antibody-mediated rejection
KW - donor-derived cell-free DNA
KW - gene expression profiling
KW - kidney transplantation
KW - transplantation
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U2 - 10.34067/KID.0005062021
DO - 10.34067/KID.0005062021
M3 - Article
AN - SCOPUS:85126683267
SN - 2641-7650
VL - 2
SP - 1998
EP - 2009
JO - Kidney360
JF - Kidney360
IS - 12
ER -