Interstitial Inflammation Currently considered to be T cell-mediated process Plasma cell rich acute rejection often associated with AMR Preliminary data suggests that interstitial follicular helper T cells interact differently with B cells Liarsky et al. Cell Distance mapping. Science Translational Medicine April 2014;6(230)1
Banff Classification Type I (tubulointerstitial) >25% interstitial inflammation >5 lymphocytes for tubulitis Type I Always considered TCMR Type II (intimal arteritis or endarteritis) IIA = <25% luminal narrowing IIB = >25% luminal narrowing Type II initially TCMR, now may also be AMR Type III (transmural arteritis or fibrinoid necrosis) Type III may be TCMR or AMR
Case #1A 62 yo male status kidney transplant (November 1986), who now has an elevated serum creatinine
C4d
C4d
Case #1 Final Diagnosis Peritubular capillaritis and diffuse C4d peritubular capillary deposition, consistent with antibody-mediated rejection. Focal features of chronic transplant glomerulopathy
Case #1B 63 yo male status kidney transplant (November 1986), who now has an elevated serum creatinine after treatment for urinary tract infection with antibiotics
C4d
Case #1B Final Diagnosis Chronic transplant glomerulopathy Focal peritubular capillaritis and focal C4d peritubular capillary deposition.
Cardiac Antibody-Mediated Rejection Role of antibody-mediated immunity in early and late cardiac allograft rejection now becoming established AMR of cardiac allografts Largely a clinical diagnosis Commonly invoked as the cause of biopsy-negative cardiac transplant rejection estimated to occur in 10-20% patients Involves antibody activation of complement pathway
A PROGNOSTIC ROLE FOR C4D IN SURVEILLANCE ENDOMYOCARDIAL BIOPSIES AFTER HEART TRANSPLANTATION M. Kamran Mirza MD PhD, Savitri Fedson MD*, Susana R. Marino MD PhD, & Aliya N. Husain MD Departments of Pathology and Medicine*
Design Prospective study 2004-2012 (8 years) 5862 endomyocardial surveillance biopsies 241 heart transplant recipients C4d immunostaining (prospectively from 2004) Strong diffuse endothelial staining was considered positive All patients had at least 1 year of follow-up Cardiac dysfunction at the time of positive biopsy was evaluated by echocardiography Cellular rejection was graded per ISHLT 1990 criteria
No C4d staining Interstitial staining Serum staining
A B C Antibody mediated rejection: (A) H&E section of myocardium shows diffuse increase in intraluminal lymphocytes and endothelial swelling. (B & C ) C4d immunostaining reveals strong, diffuse, endothelial positivity in this patient
207 C4d ve (86%) 241 patients 34 C4d +ve (14%)
207 C4d ve (86%) 241 patients 12 alive (35%) 34 C4d +ve (14%) 22 deaths (65%) Significant Cardiac Dysfunction 9 (26%) 5 deaths (55%)
207 C4d ve (86%) 241 patients 12 alive (35%) 34 C4d +ve (14%) 22 deaths (65%) 11 autopsies Significant Cardiac Dysfunction 9 (26%) 5 deaths (55%) CAV in all 11 (100%)
139 alive (83%) 36 deaths (17%) 207 C4d ve (86%) 241 patients 12 alive (35%) 34 C4d +ve (14%) 22 deaths (65%) 11 autopsies Significant Cardiac Dysfunction 9 (26%) 5 deaths (55%) CAV in all 11 (100%)
139 alive (83%) 36 deaths (17%) 8 autopsies 207 C4d ve (86%) CAV in 2 (25%) 241 patients 12 alive (35%) 34 C4d +ve (14%) 22 deaths (65%) 11 autopsies Significant Cardiac Dysfunction 9 (26%) 5 deaths (55%) CAV in all 11 (100%)
139 alive (83%) 36 deaths (17%) 8 autopsies 207 C4d ve (86%) CAV in 2 (25%) 241 patients 12 alive (35%) 34 C4d +ve (14%) 22 deaths (65%) 11 autopsies Significant Cardiac Dysfunction 9 (26%) 5 deaths (55%) CAV in all 11 (100%) Time to first episode of C4d positivity: 406 days, + 383 days (7-1302 days) Time to C4d positivity in 12 surviving patients: 224 days, + 191 days Time to C4d positivity in 22 expired patients: 505 days, + 427 days
A B C D Cardiac Allograft Vasculopathy (CAV): H&E (A, B, C) and Trichrome (D) staining reveal concentric intimal fibrosis of epicardial arteries with near complete luminal obliteration
% 100 80 60 40 20 0 All C 4d negative C 4d pos itive Total deaths Non-cardiac C ardiac C ancer Infectious
60 50 40 30 20 10 0 0 1A 1B 2 3B
18 16 14 12 10 8 6 4 2 0 C4d neg C4d pos 35 30 25 20 15 10 5 0 * C4d neg C4d pos
Conclusions 22/34 (65%) of C4d positive patients died C4d positive patients were 10 years younger (at transplant) than C4d negative Later C4d positivity is not benign; warranting long-term surveillance Both class 1 and class 2 PRAs were significantly higher in C4d positive patients
Conclusions - All 11 C4d positive autopsies revealed CAV as the cause of death - Even 1 episode of C4d positivity correlated with a poorer outcome These findings show a positive association of C4d with CAV and death. Our results indicate a prognostic role for C4d in heart transplantation warranting routine detection (including long-term surveillance) of this marker in the pathologic evaluation of cardiac AMR
C4D IMMUNOREACTIVITY AND CARDIAC ALLOGRAFT VASCULOPATHY LEADING TO DEATH IN PEDIATRIC HEART TRANSPLANT RECIPIENTS
No C4d DIFFUSE STRONG ENDOTHELIAL STAINING
C4d + 276 bx 4 patients (18%) in 9 biopsies 22 patients C4d - Mean age: Range: 7.9 years 2 months to 17 years 18 patients (82%) in 267 biopsies
C4d + 4 CAV 276 bx 22 patients 5 patients died (23%) 17 patients survived (77%) C4d - Respiratory failure 1 PTLD No CAV 17