title: Immunohistochemical markers of tissue injury in biopsies with transplant glomerulitis.
abstract: Transplant glomerulitis is associated with suboptimal graft function. To understand its pathogenesis and to assess the parameters of potential prognostic value, we immunostained 25 paraffin-embedded allograft biopsies showing glomerulitis for markers of complement activation (C4d), cytotoxicity (Granzyme-B), apoptosis (Bcl-XL, Bcl-2, and Fas-L), and endothelial injury (von Willebrand factor). Staining was semiquantitatively assessed in different anatomical compartments, and comparison was made with 40 control allograft biopsies without glomerulitis. Biopsies with glomerulitis had more frequent incidence of "mixed" T-cell and antibody-mediated rejection compared with controls [8/25 (32%) versus 4/40 (10%), P = .046]. Furthermore, they had higher glomerular capillary-C4d scores (1.9 ± 1.1 versus 1.2 ± 1.2, P = .015), which tended to persist when biopsies showing transplant glomerulopathy were excluded. Higher glomerular capillary-C4d scores were observed in samples with versus without donor-specific antibody (2.5 ± 0.9 versus 1.2 ± 1.2, P = .01). Compared with controls, biopsies with glomerulitis had more intraglomerular (4.8 ± 4.5 versus 0.9± 0.8 cells/glomerulus, P < .001) and interstitial mainly peritubular capillary (6.1 ± 4.1 versus 3.2 ± 3.4 cells/hpf, P = .002) Granzyme-B(+) leukocytes. Higher mesangial-von Willebrand factor scores were noted in the glomerulitis group (1.8 ± 1.0 versus 0.8 ± 0.8, P = .003) and correlated with the percentage of inflamed glomeruli (r = 0.54, P < .001). Interstitial-von Willebrand factor was associated with a higher peritubular capillaritis score (interstitial-von Willebrand factor: 1.6 ± 1.2 versus no interstitial-von Willebrand factor: 0.6 ± 0.9, P = .02). Glomerular capillary-Bcl-XL was not associated with accommodation. Finally, no difference in Bcl-2 or Fas-L was observed upon comparing glomerulitis to controls. In conclusion, glomerular injury in transplant glomerulitis appears to be mediated by complement activation and cellular cytotoxicity. Mesangial- or interstitial-von Willebrand factor identified cases with more severe microcirculation injury.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. ibatal@partners.org
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Batal
authors.forename: Jamil
authors.initials: J
authors.lastname: Azzi
authors.forename: Najib
authors.initials: N
authors.lastname: El-Haddad
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.forename: John G
authors.initials: JG
authors.lastname: Lunz
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Eizaburo
authors.initials: E
authors.lastname: Sasatomi
authors.forename: Amit
authors.initials: A
authors.lastname: Basu
authors.forename: Henkie
authors.initials: H
authors.lastname: Tan
authors.forename: Ron
authors.initials: R
authors.lastname: Shapiro
authors.forename: Parmjeet
authors.initials: P
authors.lastname: Randhawa
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002196:Capillaries / Q000473:pathology; D053222:Fas Ligand Protein / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology* / Q000502:physiology; D016030:Kidney Transplantation; D011183:Postoperative Complications; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D015415:Biomarkers; D053222:Fas Ligand Protein; D051020:bcl-X Protein; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human