Development of HLA donor specific antibodies after heart transplantation: importance of a new method to detect the first component of the complement cascade Marta Farrero Torres₁, Marcelo Pando₂, Dolly Tyan₂, Hannah Valantine₃, Spenser Smith₃, Kiran Khush₃ ₁ Insuficiencia Cardíaca y Trasplante, Hospital Clínic, Barcelona ₂ Laboratorio Histocompatibilidad, Stanford University Medical Center ₃Trasplante Cardíaco, Stanford University Medical Center
Conflict of interest Dr. Tyan receives royalties from the licensing of the C1q technology to One Lambda, Inc.
BACKGROUND The presence of donor specific HLA antibodies (DSA) has been associated with acute rejection after heart transplantation The development of sensitive methods to detect HLA antibodies has underscored the need for novel techniques that specifically identify antibodies that mediate allograft injury Complement-fixing capacity of some antibodies could be related to a higher pathogenicity
AIMS To define the association between the development of de novo DSA and rejection episodes (acute cellular rejection and antibody mediated rejection) To determine the clinical relevance of antibodies depending on their complement fixing capacity.
METHODS: population Single-center, retrospective analysis Population: 145 adult patients Consecutive heart transplant recipients Transplanted between January 2006 and July 2011 and followed up in the same institution
METHODS: studies performed Quarterly screening for DSA during the first year post-transplant with two methods: SAB IgG: MFI 1000 SAB C1q: increase >50% over background MFI Endomyocardial biopsies Acute cellular rejection (ACR): 2R/3A in ISHLT classification system Antibody mediated rejection: hystopathologic or immunohystopathologic findings
RESULTS 26 patients with DSA prior to transplantation were excluded from analysis Study population: 119 patients DSA 31 (26%) No DSA 88 (74%)
RESULTS: baseline characteristics No DSA (n=88) DSA (n=31) p Females 25 (28,4%) 6 (19,3%) 0,323 Age at transplant 52,95 ±12 44,19 ±14 0,002 Race White Hispanic Asian Pacific islander African-American Etiology Idiopathic Ischemic Other 57 (64,7%) 10 (11,3%) 10 (11,3%) 2 (2,2%) 8 (9,1%) 46 (52,3%) 15 (17%) 32 (36,3%) 19 (61,3%) 8 (25,8%) 3 (9,7%) 0 1 (3,2%) 20 (64,5%) 2 (6,4%) 10 (32,2%) 0,393 0,238 0,232 0,681 Multiorgan transplant 6 (6,8%) 0 0,338 Pre-transplant VAD 7 (7,9%) 3 (9,6%) 0,721 Re-trasplant 4 (4,5%) 1 (3,2%) 1 Prior cardiac surgery 35 (39,7%) 9 (29%) 0,287
Waiting list status 1A 1B 2 RESULTS: transplant No DSA (n=88) DSA (n=31) p 16 (18%) 42 (47%) 30 (34%) 8 (25%) 14 (45%) 9 (29%) 0,647 CMV D+/R- 24 (27%) 7 (22%) 0,609 Different ABO (compatible) 14 (16%) 4 (13%) 0,779 Donor age (years) 33,65 ±13 29,55 ±12 0,131 D-R sex mismatch 20 (23%) 6 (19%) 0,696 Total HLA mismatches (A, B, DQ) 4,56 ±1 4,86 ±1 0,212 Cause of donor death: explosive 43 (48%) 19 (61%) 0,234 Graft cold ischemic time(min) 227 ±48 227 ±60 0,945
RESULTS: treatment Induction Daclizumab RATG Basiliximab Treatment Ciclosporine Tacrolimus Mycophenolate Sirolimus Prednisone Statins No DSA (n=88) DSA (n=31) p 61 (75%) 18 (20%) 2 (2%) 47 (53%) 41 (46%) 81 (92%) 7 (8%) 80 (90%) 84 (95%) 26 (83%) 3 (9%) 2 (6%) 17 (54%) 14 (45%) 29 (93%) 2 (6%) 28 (90%) 26 (83%) 0,213 0,891 0,891 1 1 1 0,050 Follow up (days) 910 ±633 1012 ±518 0,375
DSA description IgG+/C1q- =16 IgG += 28 IgG+/C1q+ =12 IgG-/C1q+=3 C1q += 15 Class I Class II Class I + II DSA (n=31) 6 (19%) 15 (48%) 10 (32%) IgG + (n=28) 5 (17%) 14 (50%) 9 (32%) C1q + (n=15) 2 (13%) 6 (40%) 7 (46%) DQ most frequent
% free from ACR % free from AMR DSA AND REJECTION ACUTE CELLULAR REJECTION ANTIBODY MEDIATED REJECTION Post-transplant days p=0.003 RR 3.7 (1.5-9.1) Post-transplant days p=0.002 RR 6.8 (2.1-22.3) Recipients without DSA (n=88) Recipients with DSA (IgG+ and/or C1q+) (n=31)
Ejection fraction (%) Ejection fraction (%) EJECTION FRACTION AT THE TIME OF REJECTION ACUTE CELLULAR REJECTION ANTIBODY MEDIATED REJECTION p=0.022 p=0.015 No DSA DSA No DSA DSA
% free from ACR % free from AMR REJECTION AND IgG+ DSA ACUTE CELLULAR REJECTION ANTIBODY MEDIATED REJECTION p=0,001 RR 4,6 (1,8-11,7) p=0,002 RR 4 (1,2-12,6) Días post-trasplante cardíaco Recipients with no IgG+ DSA(n=91) Recipients with IgG+ DSA (n=28) Días post-trasplante cardíaco
% free from ACR % free from AMR REJECTION AND C1q+ DSA ACUTE CELLULAR REJECTION ANTIBODY MEDIATED REJECTION Días post-trasplante cardíaco p=0,758 RR 0,7 (0,2-2,7) p<0,001 RR 12,1 (3,4-43,2) Días post-trasplante cardíaco Recipients with no C1q+ DSA (n= 104) Recipients with C1q+ DSA (n=15)
LIMITATIONS Presence of DSA was known by the treating clinician Increased rejection surveillance? More agressive immunosupresive therapy?
CONCLUSION The development of de novo DSA after heart transplantation was associated with a higher incidence of rejection IgG+ DSA were associated with both ACR and AMR C1q+ DSA were specifically associated with AMR, but not with ACR Early detection of C1q+ DSA can identify a subgroup of recipients at risk for AMR, who could benefit from a tailored treatment
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