title: Endothelial activation, lymphangiogenesis, and humoral rejection of kidney transplants.
abstract: Antibody-mediated rejection (ABMR) is implicated in 45% of renal allograft failure and 57% of late allograft dysfunction. Peritubular capillary C4d is a specific but insensitive marker of ABMR. The 2013 Banff Conference ABMR revised criteria included C4d-negative ABMR with evidence of endothelial-antibody interaction. We hypothesized that endothelial activation and lymphangiogenesis are increased with C4d-negative ABMR and correlate with intragraft T-regulatory cells and T-helper 17. Seventy-four renal transplant biopsies were selected to include (a) ABMR with C4d Banff scores ≥2 (n = 35), (b) variable microvascular injury and C4d score 0-1 (n = 24), and (c) variable microvascular injury and C4d score = 0 (n = 15). Controls included normal preimplantation donor kidneys (n = 5). Immunohistochemistry for endothelial activation (P- and E-selectins [SEL]), lymphangiogenesis (D2-40), T-regulatory cells (FOXP3), and T-helper 17 (STAT3) was performed. Microvessel and inflammatory infiltrate density was assessed morphometrically in interstitium and peritubular capillaries. All transplants had significantly higher microvessel and lymph vessel density compared with normal. Increased expression of markers of endothelial activation predicted transplant glomerulopathy (P-SEL, P = .003). Increased P-SEL and D2-40 were associated with longer interval from transplant to biopsy (P = .005). All 3 markers were associated with increased interstitial fibrosis, tubular atrophy, and graft failure (P-SEL, P < .001; E-SEL, P = .0011; D2-40, P = .012). There was no association with the intragraft FOXP3/STAT3 ratio. We conclude that endothelial activation and lymphangiogenesis could represent a late response to injury leading to fibrosis and progression of kidney damage, and are independent of the intragraft FOXP3/STAT3 ratio. Our findings support the therapeutic potential of specifically targeting endothelial activation.
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232. Electronic address: sharon.phillips@vanderbilt.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: Phillips
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Electronic address: meghan.e.kapp@vanderbilt.edu.
authors.forename: Meghan
authors.initials: M
authors.lastname: Kapp
authors.affiliation: DCI Transplant Immunology Laboratory, Nashville, TN 37203. Electronic address: deborah.crowe@dciinc.org.
authors.forename: Deborah
authors.initials: D
authors.lastname: Crowe
authors.affiliation: Ochsner Abdominal Transplant Center, New Orleans, LA 70121. Electronic address: jgarces@ochsner.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Garces
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Electronic address: agnes.fogo@vanderbilt.edu.
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Electronic address: giovanna.giannico@vanderbilt.edu.
authors.forename: Giovanna A
authors.initials: GA
authors.lastname: Giannico
mesh_terms: D000328:Adult; D015935:Complement C4b / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000401:mortality; D042583:Lymphangiogenesis / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies
chemical_list: D015935:Complement C4b
keywords: Endothelial activation; Humoral rejection; Kidney transplant; Microvascular injury; Selectin; Transplant biopsy