The significance of Focal C4d+: The WU experience Helen Liapis, M.D. Professor of Pathology & immunology Kedainis RL et al. Am J Transplant Apr;9(4):812-9.

Patients & Methods Retrospective review of 301 patients (368 biopsies) Inclusion criteria: - indication bx - adequate tissue for evaluation - at least 6 month follow up - DSA test results

Patient demographics Cause of ESRD Therapy (>90% Thymo); CNI (Tacrolimus) antimetabolite and prednisone for maintenance Hx of previous transplantation Donor source HLA match/mismatch Time interval to transplantation Renal function at the time of bx Follow-up period Graft failure (return to dialysis or re-transplt)

Question Focal, diffuse C4d+,C4d- correlation with histopathological findings and graft survival Statistics: Chi-square, ANOVA, Cox regression

C4d+ as defined by BANFF by IF >50% = diffusely % = focal +

C4d results Diffuse C4d+ = 9.5% Focal C4d+ = 20.9% C4d- = 69.4%

p<001

Diffuse C4d+ & PTC 2 PTC 2 = ≥10% with max 5 to 10 luminal inflammatory cells

PTC1 = ≥10% max 3 to 4 luminal inflammatory cells Focal C4d+ and PTC1

Focal C4d+ & TGP: p=0.01 Diffuse +Focal C4d+ =0.02

C4d+ & DSA Variable Diffuse C4d+ (N=29) Focal C4d+ (N=32) C4d- (N=71) DSA+ 23/29 (79.3%)22/32 (68.8%) 7/71 (9.9%) Class I 6 (20.7%) 5 (15.6%) 0 Class II 11 (37.9%) 10 (31.3%) 3 (4.2%) Class I and II 6 (20.7%) 7 (21.9%) 4 (5.7%) 132/301 (43%) had DSA

Cox proportional hazard

Conclusions Focal C4d+ has histopathology similar to diffuse C4d+ Correlation with DSA is similar Focal C4d+ and TGP not significant but there is a trend association Allograft loss: worse prognosis trend at 1 year Overall, focal C4d+ should be taken into account in treatment strategies

Caveats Retrospective study Relatively short follow up DSA only in ~ 50% (44%) C4d- cases were less frequently tested