T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts

Inflammation in fibrosis areas (i-IF/TA) of kidney allografts is associated with allograft loss; however, its diagnostic significance remains to be determined. We investigated the clinicohistologic phenotype and determinants of i-IF/TA in a prospective cohort of 1539 kidney recipients undergoing evaluation of i-IF/TA and tubulitis in atrophic tubules (t-IF/TA) on protocol allograft biopsies performed at 1 year posttransplantation. We considered donor, recipient, and transplant characteristics, immunosuppression, and histological diagnoses in 2260 indication biopsies performed within the first year posttransplantation. Nine hundred forty-six (61.5%) patients presented interstitial fibrosis/tubular atrophy (IF/TA Banff grade>0) at 1 year posttransplant, among whom 394 (41.6%) showed i-IF/TA. i-IF/TA correlated with concurrent t-IF/TA (P<.001), interstitial inflammation (P<.001), tubulitis (P<.001), total inflammation (P<.001), peritubular capillaritis (P<.001), interstitial fibrosis (P<.001), and tubular atrophy (P=.02). The independent determinants of i-IF/TA were previous T cell-mediated rejection (TCMR) (P<.001), BK virus nephropathy (P=.007), steroid therapy (P=.039), calcineurin inhibitor therapy (P=.011), inosine-5-monophosphate dehydrogenase inhibitor therapy (P=.011), HLA-B mismatches (P=.012), and HLA-DR mismatches (P=.044). TCMR patients with i-IF/TA on posttreatment biopsy (N=83/136, 61.0%) exhibited accelerated progression of IF/TA over time (P=.01) and decreased 8-year allograft survival (70.8% vs 83.5%, P=.038) compared to those without posttreatment i-IF/TA. Our results support that i-IF/TA may represent a manifestation of chronic active TCMR. This observational study, performed in a prospective cohort of 1,539 kidney transplant recipients, demonstrates that the occurrence of inflammation in scarred areas of the kidney allograft is mainly determined by T cell-mediated rejection and the intensity of the immunosuppressive regimen, and is associated with poor transplant outcomes. See related articles on pages 293, 321, and 364.