Tissue-based Gene Expression Diagnosis of Mild and Moderate T-cell-mediated Rejection to Guide Therapy in Kidney Transplants

Abstract

Background: Mild histologic lesions of tubulo-interstitial inflammation could represent a "response-to-wounding" rather than allorecognition. Tissue gene expression may complement histopathology for T-cell-mediated rejection (TCMR) diagnostics.

Methods: We report on the incorporation of tissue gene expression testing using a Molecular Microscope Diagnostic System into the management of kidney transplant biopsies with suspected TCMR. Patients (N = 209) were divided into 3 groups based upon diagnosis and TCMR therapy (with high-dose steroids and/or anti-thymocyte globulin): Group 1: Untreated histologic TCMR with molecular quiescence (H+M-); Group 2: Treated histologic and molecular TCMR (H+M+); and Group 3: Controls, with no histologic or molecular (H-M-) rejection.

Results: At biopsy, estimated glomerular filtration rate was worse ( P = 0.006) in H+M+ (N = 35; 33 ± 22 mL/min/1.73 m 2 ) and H+M- (N = 30; 40 ± 18 mL/min/1.73 m 2 ) groups; compared with H-M- (N = 144; 47 ± 24 mL/min/1.73 m 2 ) group. In H+M- biopsies, mean molecular acute kidney injury scores (0.33 versus 0.10; P = 0.03) were higher than in H-M-; while molecular TCMR was lower compared with H+M+ (0.04 versus 0.54; P < 0.001). At 12 m postbiopsy estimated glomerular filtration rate remained low ( P < 0.001) in H+M+ (38 ± 22 mL/min/1.73 m 2 ) but improved in untreated H+M- (44 ± 22 mL/min/1.73 m 2 ) and H-M- (50 ± 23 mL/min/1.73 m 2 ) groups. At a mean follow-up of 2.1 ± 1.2 y post-index biopsy, death-censored graft survival was lower in H+M+ (74%) than in H+M- (90%) and H-M- (92%; P = 0.001). H+M+ cases had numerically higher rejection on follow-up biopsy (20%) than H+M- (7%) ( P = 0.12) and de novo donor-specific antibody formation (H+M+ 24%; H+M- 10%; P = 0.13).

Conclusions: In this large single-center study, biopsies with untreated histological TCMR and molecular quiescence had comparable clinical outcomes to cases with no rejection, whereas those with histologic and tissue gene expression confirmed TCMR had inferior outcomes.