Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients

Whether reexposure to mismatched HLA antigens (RMM) in the setting of a negative crossmatch is associated with increased immunological risk remains an area of uncertainty. This is due to evidence derived predominantly from registry data, which lacks comprehensive information on alloantibody and rejection. In this study, we analyze the impact of low‐level preformed donor‐specific antibodies (DSA) against an RMM on transplant outcomes. From 1988 consecutive renal transplant recipients, we analyzed 179 patients undergoing retransplantation, of whom 55 had a RMM. All patients were crossmatch negative and preformed DSA were detected by single antigen beads alone. Multivariate analysis revealed that patients with preformed DSA against an RMM were independently at risk of antibody‐mediated rejection (HR 8.70 [3.42‐22.10], P < .0001) and death‐censored allograft loss (HR 3.08 [1.17‐8.14], P = .023). In addition, prior transplant nephrectomy (HR 2.04 [1.00‐4.17], P = .0495) was also associated with allograft failure, whereas receiving a retransplant that was matched at HLA class II was associated with a favorable outcome (HR 0.37 [0.14‐0.99], P = .047). In the absence of preformed DSA, an RMM was not associated with de novo DSA development, rejection, or allograft loss. In conclusion, an RMM portends increased immunological risk only in the presence of a preformed DSA in patients undergoing retransplantation.

Section: Discussionmentioning

confidence: 99%

Donor-specific antibodies detected by single antigen beads alone can help risk stratify patients undergoing retransplantation across a repeat HLA mismatch

Lucisano

Thiruvengadam

Hassan

et al. 2020

“…32 The overall applicability of our study results beyond patients with preexisting DSA is not clear, as we primarily included patients with preexisting low-level DSA. Recent data suggested that de novo-DSA associate with worse outcome compared to pre-existing DSA, which was confirmed in our study.…”

Section: Ta B L E 4 (Continued)mentioning

confidence: 99%

Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: Clinical presentation and implications for outcome

Senev

Coemans

Lerut

et al. 2019

102

125

In this cohort study (n = 935 transplantations), we investigated the phenotype and risk of graft failure in patients with histological criteria for antibody-mediated rejection (ABMR) in the absence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA), and compared this to patients with definite ABMR and HLA-DSA-positivity. The histological picture did not differ between HLA-DSA-positive (n = 85) and HLA-DSA-negative (n = 123) cases of ABMR histology, apart from increased complement split product 4d (C4d) deposition in the peritubular capillaries in HLA-DSA-positive cases. Histology of ABMR without HLA-DSA was more transient than DSA-positive ABMR, and patients with ABMR histology without HLA-DSA had graft survival superior to that of HLA-DSA-positive patients, independent of concomitant T cell-mediated rejection (38.2%) or borderline changes (17.9%). Multivariate analysis showed that the risk of graft failure was not higher in patients with histological picture of ABMR (ABMR ) in the absence of HLA-DSA, compared to patients without ABMR . Despite an association between C4d deposition and HLA-DSA-positivity, using C4d deposition as alternative for the DSA criterion in the diagnosis of ABMR, as proposed in Banff 2017, did not contribute to the prognosis of graft function and graft failure. We concluded that biopsies with ABMR but without detectable HLA-DSA represent a distinct, often transient phenotype with superior allograft survival.

“…When incompatible allografts are transplanted into recipients with pre-existing DSA, it is reasonable to assume that they will also harbor donor-specific memB and memory T cells. These individuals are more likely to subsequently develop a recall DSA response post-transplantation that mediates acute or chronic antibody-mediated rejection, or mixed AMR plus TCMR rejection (52-54). Whether the de novo DSA response is the result of memB cells differentiating directly into PCs or reentering a GC response to subsequently generate PCs may affect the efficacy to immunosuppression.…”

Section: Resultsmentioning

confidence: 99%

Heterogeneity of memory B cells

Chong

Ansari

2018

Potential solid organ transplant recipients broadly sensitized to HLA have long wait times, low transplant rates and poor outcomes. The new kidney allocation system has improved access to the most highly sensitized recipients; however, their long-term outcomes are unknown. Emerging data suggest that memory B cell repertoire is broader than the plasma cell repertoire, therefore, despite refinements in anti-HLA antibody detection technology, donor-specific HLA- specific memory B cells may in fact be present in some, if not most, highly sensitized recipients with no detectable donor-specific antibodies. In addition, new findings have underscored the heterogeneity in memory B cell generation, and in the signals that determine memory versus plasma cell fate during primary antigen encounter, as well as memory B cell differentiation upon antigen reencounter into plasma cells or reentry into germinal centers to subsequently emerge as higher affinity and class-switched plasma cells. Thus, heterogeneity memory B cells generation may affect the efficacy of specific immunomodulation during the recall response. We propose that the ability to quantify donor-specific B cell in transplant recipients is urgently required to provide insights into the mechanisms of sensitization and recall, and for the early detection of acute and chronic AMR.