Complementary Roles of Tissue-based Gene Expression and Donor-derived Cell-free DNA for Therapy of Mild and Moderate T-cell–mediated Rejection in Kidney Transplants
Dhiren Kumar, Louiza Azzouz, Irfan Moinuddin, Mary C. Philogene, Amber Paulus, Layla Kamal, Selvaraj Muthusamy, Pawan Sinhmar, Shreya Shah, Stephen R. Seelam, Gaurav GuptaBackground.
We recently reported on the Molecular Microscope Diagnostic System (MMDx) to guide T-cell–mediated rejection (TCMR) therapy. Donor-derived cell-free DNA (dd-cfDNA) could also assist in risk stratification of TCMR.
Methods.
In this cohort of 141 adult kidney transplant recipients, we assessed 3 groups based on histology, MMDx findings, and treatment decisions: untreated histologic TCMR with molecular quiescence (H+M−Rx−); treated histologic and molecular TCMR (H+M+Rx+; high-dose steroids and/or anti-thymocyte globulin); and controls without rejection (H−M−Rx−). We evaluated a 12-mo composite outcome comprising graft loss, patient death, recurrent rejection, or a ≥30% decline in estimated glomerular filtration rate from baseline. Serial dd-cfDNA levels were trended at biopsy and post-biopsy.
Results.
At biopsy, median dd-cfDNA was higher in H+M+Rx+ (0.94%; interquartile range [IQR], 0.38%–2.30%) versus H+M−Rx− (0.30%; IQR, 0.17%–0.40%) and H−M−Rx− (0.26%; IQR, 0.18%–0.51%;
Conclusions.
dd-cfDNA correlated more closely with molecular TCMR than with histologic tubulitis and interstitial inflammation. Untreated histologic TCMR with molecular quiescence (by MMDx and dd-cfDNA) had clinical outcomes comparable to cases without rejection, and serial dd-cfDNA remained low despite lack of TCMR therapy.