Computer-assisted topological analysis of renal allograft inflammation adds to risk evaluation at diagnosis of humoral rejection.
Antibody-mediated rejection is associated with heterogeneous kidney allograft outcomes. Accurate evaluation of risk for graft loss at time of diagnosis is necessary to offer personalized treatment. In contrast with serological and molecular assessment, morpho-histological evaluation of antibody-mediated rejection lesions has not significantly evolved. This relies on Banff classifications designed to be of diagnostic discriminatory power rather than prognostic and face quantitative and qualitative limitations. Here we developed a method of Computer-assisted Analysis of Graft Inflammation (CAGI) to improve the classification of allograft inflammation. Digitization of immunostained biopsy sections, image processing and algorithm-driven analysis allowed quantification of macrophages, T cells, B cells, and granulocytes per unit surface of interstitium, capillaries or glomeruli. CAGI was performed on biopsy specimens of 52 patients with extensively phenotyped antibody-mediated rejection. Macrophage numbers in capillaries and interstitium, but not Banff scores or the amount of other immune cell subsets, correlated with donor-specific antibody (DSA) mean fluorescence intensity and DSA-C3d status. The quantity of macrophages in the interstitium and DSA-C3d status were the only independent predictors for significant allograft loss at the time of antibody-mediated rejection diagnosis (hazard ratio 3.71 and 2.34, respectively). A significant strategy integrating the DSA-C3d assay and the quantification of interstitial macrophages allowed identification of three groups with distinct renal prognosis: DSA-C3d-, DSA-C3d+/macrophages-low and DSAC3d+/macrophages-high. Thus, CAGI brings a missing piece to the antibody-mediated rejection puzzle by identifying morpho-histological processes that bridge in vitro parameters of DSA pathogenicity and graft loss. Hence, this approach could be useful in future integrated strategies of risk evaluation.
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; INSERM U1111, Centre International de Recherche en Infectiologie (CIRI), Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Faculté de medecine Lyon-Est, Lyon, France. Electronic address: antoinesicard@yahoo.com.
Antoine
A
Sicard
Unité d'Analyse d'Images Biologiques, Institut Pasteur Paris, France.
Vannary
V
Meas-Yedid
Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratoire d'anatomopathologie, Lyon, France.
Maud
M
Rabeyrin
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; INSERM U1111, Centre International de Recherche en Infectiologie (CIRI), Ecole Normale Supérieure de Lyon, Lyon, France.
Alice
A
Koenig
Etablissement Français du Sang, Lyon, France.
Stephanie
S
Ducreux
Service d'anatomopathologie, Groupement Hospitalier Lyon EST, Lyon, France.
Frederique
F
Dijoud
Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratoire d'anatomopathologie, Lyon, France.
Valerie
V
Hervieu
Université Lyon 1, Faculté de medecine Lyon-Est, Lyon, France; Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Urologie et Transplantation, Lyon, France.
Lionel
L
Badet
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; INSERM U1111, Centre International de Recherche en Infectiologie (CIRI), Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Faculté de medecine Lyon-Est, Lyon, France.
Emmanuel
E
Morelon
Unité d'Analyse d'Images Biologiques, Institut Pasteur Paris, France.
Jean Christophe
JC
Olivo-Marin
Etablissement Français du Sang, Lyon, France.
Valerie
V
Dubois
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; INSERM U1111, Centre International de Recherche en Infectiologie (CIRI), Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Faculté de medecine Lyon-Est, Lyon, France. Electronic address: olivier.thaunat@chu-lyon.fr.
Olivier
O
Thaunat
D000328:Adult; D000465:Algorithms; D064591:Allografts; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D015933:Complement C3d / Q000032:analysis; D003936:Diagnosis, Computer-Assisted / Q000379:methods*; D005260:Female; D005921:Glomerulonephritis / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology; D006085:Graft Survival; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D056724:Immunity, Humoral; D007150:Immunohistochemistry / Q000379:methods*; D007518:Isoantibodies / Q000032:analysis; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D015415:Biomarkers; D007518:Isoantibodies; D015933:Complement C3d
allograft pathology; antibody-mediated rejection; complement-binding DSA; donor-specific antibodies; inflammation quantification; macrophages