Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: high immunogenicity of HLA class II graft molecules

Abstract

Summary Τhe clinical significance of de novo post‐transplant anti‐HLA donor‐specific antibodies (DSA) was evaluated using 4241 serum samples collected between 2000 and 2007 from 597 renal transplant recipients. Patients transplanted before December 1996 (n = 77) were included in the historic group and those transplanted thereafter (n = 520) were included in the study group. All recipients were negative for DSA before transplantation (Tx). Post‐Tx, de novo DSA were detected in 92/597 (15.4%) patients, while 196 had third party anti‐HLA antibodies (DSA‐negative). DSA were more frequent in the historic group (33.8%) compared with the study group (12.7%) (P < 0.001). Anti‐HLA class‐II DSA predominated in both groups (84.6% vs. 69.7%). Recipients of HLA class II‐incompatible grafts developed DSA more frequently than those receiving HLA class II‐compatible grafts (17.9% vs.7.9%, P = 0.003), directed mainly against HLA‐DQ graft molecules (64/446, 14.4%). DSA production was not different between presensitized and nonsensitized patients (P = 0.842). Graft survival was higher in patients without antibodies compared with DSA‐positive (log‐rank test, P = 0.002) and DSA‐negative patients (log‐rank test, P = 0.002). Univariate and multivariate analysis showed independent association for DSA class I (HR = 31.78), DSA class II (HR = 20.92) and non‐DSA (HR = 5.94) and graft failure. We conclude that HLA class II incompatible graft transplantations need careful monitoring and should be avoided in high immunological risk cases.

Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

“…4,5 Alternatively, de novo DSAs (dnDSAs) emerge after transplantation in 13%-27% of previously nonsensitized recipients when detected with current highly sensitive single-antigen flow beads (SAFB) assays. 6,7 They mostly appear during the first year 7 but also up to 10 years later. 8,9 Most dnDSA are anticlass II.…”

“…6,[8][9][10] dnDSA are associated with acute and chronic antibody-mediated renal lesions, 6,7,9,11,12 chronic graft dysfunction, 6 and lower graft survival. [6][7][8][9] Because a fraction of dnDSA-positive patients escape rejection or graft dysfunction, 9,13 the current challenge is to identify clinically relevant dnDSAs in order to better stratify the individual immunologic risk. Several proposed approaches rely on serum dnDSA SAFB mean fluorescence intensity (MFI) strength, 14,15 IgG subclass analysis, 16 or complement-binding ability.…”

“…8,9 Most dnDSA are anticlass II. 6,8 The putative risk factors are young recipient age, HLA mismatches, deceased donor, mammalian target of rapamycin inhibitor-based immunosuppression and nonadherence to treatment. 6,[8][9][10] dnDSA are associated with acute and chronic antibody-mediated renal lesions, 6,7,9,11,12 chronic graft dysfunction, 6 and lower graft survival.…”

“…6,8 The putative risk factors are young recipient age, HLA mismatches, deceased donor, mammalian target of rapamycin inhibitor-based immunosuppression and nonadherence to treatment. 6,[8][9][10] dnDSA are associated with acute and chronic antibody-mediated renal lesions, 6,7,9,11,12 chronic graft dysfunction, 6 and lower graft survival. [6][7][8][9] Because a fraction of dnDSA-positive patients escape rejection or graft dysfunction, 9,13 the current challenge is to identify clinically relevant dnDSAs in order to better stratify the individual immunologic risk.…”

Transfer of HLA-Specific Allosensitization From a Highly Sensitized Deceased Organ Donor to the Recipients of Each Kidney

“…While DSA, either alone or in combination with microscopic evidence of microcirculation injury with or without C4d staining on kidney biopsy, are of most concern, the development of de novo nondonor HLA-specific (third party) antibodies are also, for reasons that are not clear, sometimes associated with an increased risk of graft loss (2,(4)(5)(6). One possible explanation for the association between de novo third party HLA-specific antibodies and inferior transplant outcome is that third party antibodies occur in conjunction with low level DSA or other non-HLAspecific antibodies that are not detected in the circulation because they have been absorbed by the kidney graft (2).…”