title: Preformed complement-activating low-level donor-specific antibody predicts early antibody-mediated rejection in renal allografts.
abstract: BACKGROUND.: Donor-specific anti-HLA antibodies (DSA) are a major cause of alloimmune injury. Transplant recipients with negative complement-dependent cytotoxic crossmatch (CDC-XM) and donor cell-based flow cytometric crossmatch (flow-XM) but low level DSA (i.e., by Luminex) have worse outcomes compared with nonsensitized patients. The aim of this study was to establish whether complement-activating ability in this low-level DSA, present before transplantation, as determined by this technique is important in dictating pathogenicity. METHODS.: We retrospectively studied 52 patients with preformed DSA detected by single-antigen flow cytometric fluorescent beads (SAFBs). Patients were transplanted using a steroid-sparing regimen consisting of alemtuzumab induction, 1 week of corticosteroids and tacrolimus monotherapy.Fifteen (29%) of 52 patients experienced antibody-mediated rejection (AMR), whereas 37 (71%) patients did not. There were no demographic differences between patients with AMR and those without. Pretransplant sera were retested using a modified (SAFB) assay, which detects the presence of the complement fragment C4d as a result of DSA-induced complement activation. RESULTS.: C4d+DSA were detected in 10 (19%) of 52 patients. Biopsy-proven AMR occurred in 7 (70%) of the 10 patients with C4d+DSA and in 8 (19%) of 42 patients with C4d-DSA. AMR-free survival was worse in patients with C4d+DSA (P<0.001). CONCLUSIONS.: The ability of preformed, low-level, DSA to trigger C4d fixation in vitro in patients with negative conventional crossmatch tests is predictive for AMR. C4d SAFB is potentially a powerful tool for risk stratification prior to transplantation and may allow identification of unacceptable donor antigens, or patients who may require enhanced immunosuppression.
authors.affiliation: Imperial College Kidney and Transplant Centre, The Hammersmith Hospital, London, UK. c.lawrence@doctors.net.uk
authors.forename: Christopher
authors.initials: C
authors.lastname: Lawrence
authors.forename: Michelle
authors.initials: M
authors.lastname: Willicombe
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brookes
authors.forename: Eva
authors.initials: E
authors.lastname: Santos-Nunez
authors.forename: Retesh
authors.initials: R
authors.lastname: Bajaj
authors.forename: Terry
authors.initials: T
authors.lastname: Cook
authors.forename: Candice
authors.initials: C
authors.lastname: Roufosse
authors.forename: David
authors.initials: D
authors.lastname: Taube
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Warrens
mesh_terms: D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D003167:Complement Activation; D015935:Complement C4b; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000097:blood*; D016030:Kidney Transplantation / Q000276:immunology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010446:Peptide Fragments; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d