Inflammation in Scarred Areas (i-IF/TA): Defining the Response to Standard Treatment of T cell-mediated Rejection in Kidney Recipients

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The last Banff meeting held in 2017 has focused on the importance of defining the potential role of i-IF/TA as a component of the T cell-mediated rejection (TCMR) process in kidney allografts. We investigated the clinical value of i-IF/TA for evaluating the response to standard treatment of TCMR in kidney recipients.Among 1916 kidney recipients transplanted between 2004 and 2010, we prospectively included all patients with biopsy-proven acute TCMR within the first year post-transplant, who received standardized treatment by steroids pulses and rabbit anti-thymocyte globuline in refractory cases. Patients were systematically assessed at the time of diagnosis and at 3 months post-treatment for glomerular filtration rate (GFR), proteinuria, histology (including i-IF/TA Banff score) and presence of donor-specific anti-HLA antibodies (DSAs), and followed up to 2017 to assess allograft survival.We included 172 patients with biopsy-proven acute TCMR who received standard treatment. The distribution of TCMR grades was: 52 (30%) grade IA, 65 (38%) grade IB, 37 (22%) grade IIA, 11 (6%) grade IIB and 7 (4%) grade III TCMR. After TCMR treatment, patients showed increased GFR (p<0.001), decreased proteinuria (p<0.001), interstitial inflammation (p<0.001), tubulitis (p<0.001) and intimal arteritis (p<0.001), worsening IF/TA (p<0.001) and arteriosclerosis (p<0.001). Patients with post-treatment i-IF/TA (N=89, 52%) showed decreased 10-year graft survival compared to patients without post-treatment i-IF/TA (N=83, 48%): 64% vs 89%, respectively, p<0.001. In multivariable analysis, the independent predictors of allograft loss measured at the time of post-treatment evaluation were the presence of i-IF/TA (HR=3.4, p=0.005), the presence of transplant glomerulopathy (HR=2.4, p=0.001), GFR (HR=0.97, p=0.010) and the presence of anti-HLA DSAs (HR=2.3, p=0.021). Patients with post-treatment i-IF/TA showed higher incidence of de novo anti-HLA DSAs at 1 year post-transplantation (24% vs 6%, p=0.001) and accelerated progression of IF/TA up to 1000 days after transplantation (p=0.01 in mixed-effects model) on biopsies performed at any time after transplantation (N=704) compared to patients without post-treatment i-IF/TA.The presence of i-IF/TA after standard treatment of acute TCMR is associated with the occurrence of de novo anti-HLA DSAs, accelerated progression of interstitial fibrosis and allograft loss, and may identify patients with persisting active TCMR in whom additional therapies should be considered.

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