Comparison of Pediatric Patients with Pure Antibody-mediated Rejection (AMR) and Recipients with both AMR and Vascular Rejection in the Development of Interstitial Fibrosis and Transplant Glomerulopathy

Abstract

Introduction: The importance of the vascular rejection (VR) on the graft survival in recipients with antibody-mediated rejection (AMR) is controversial. Thus, we aimed to understand first the prognostic value of the presence of VR in children with AMR and second the impact of AMR and VR on the development of interstitial fibrosis (IF) and transplant glomerulopathy (TG). Methods: Among 45 pediatric patients 25 had pure AMR (Group 1) while 20 had both AMR and VR (Group 2). Expressions of tubular TNF-α, TGF-β, and HLA-DR were studied. All infiltrated leukocytes both in the peritubular capillaries (PTCs) and interstitium highlighted with TNF-α, HLA-DR, and CD68. PTC HLA-DR expression examined to determine the extension of the destruction of PTCs. Follow-up biopsies analyzed for the development of diffuse IF and TG. Results: The response to rejection therapy was lower in Group 2 recipients compared to Group 1 patients (p < 0.001). The extensity of PTC C4d expression found higher in Group 2 compared to Group 1 (P < 0.001) and also, the PTC destruction which noted with decreasing expression of PTC-DR expression was found higher in Group 2. Compared to Group 1 patients, Group 2 patients showed a higher incidence of IF and TG in follow-up biopsies (p < 0.01). The development of IF and TG increases with the increasing degree of glomerulitis, C4d expression and PTC destruction (p < 0.01). Compared to Group 1 patients, Group 2 showed higher expression of TNF-α, TGF-β, and HLA-DR both on tubules and infiltrated inflammatory cells (p < 0.01). PTC C4d expression and the degree of PTC destruction increased with increasing degree of leukocyte and macrophage infiltration both in PTCs and interstitium (p < 0.001). The time of the development of IF and TG decreased with increasing intensity of PTC and interstitial infiltration, glomerulitis, PTC destruction and C4d expression (p < 0.01). Also, the development of IF and TG shortened with increasing HLA-DR, TNF-α expression in inflammatory cells and increasing TNF-α, TGF-β, HLA-DR expression in tubular cells (P < 0.01). Overall the 1-, 3- and 5-year graft survival was 96%, 92% and 79% respectively for Group 1 patients while it was 95%, 40%, and 10% respectively for Group 2 recipients (p < 0.001). Conclusion: We pointed out that the prognosis and course of antibody-mediated vascular rejection are noticeably different from pure AMR, with antibody-mediated vascular rejection having the poorest outcome through leading the early development of IF and TG via augmenting inflammatory and fibrotic pathways. Thus, the development of new treatment strategies for antibody-mediated vascular rejection could salvage many kidney allografts.