Complement-Binding Anti-HLA Antibodies and Kidney-Allograft Survival

Loupy, Alexandre; Lefaucheur, Carmen; Vernerey, Déwi; Prugger, Christof; Huyen, Jean–Paul Duong Van; Mooney, Nuala; Suberbielle, Caroline; Frémeaux‐Bacchi, Véronique; Méjean, A.; Desgrandchamps, François; Anglicheau, Dany; Nochy, Dominique; Charron, Dominique; Empana, Jean‐Philippe; Delahousse, Michel; Legendre, Christophe; Glotz, Denis; Hill, Gary S.; Zeevi, Adriana; Jouven, Xavier

doi:10.1056/nejmoa1302506

Cited by 765 publications

(712 citation statements)

References 33 publications

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“…Recently published studies on pretransplant DSAs focused mainly on deceased donor transplants, as these are most prevalent in, for example, France, Germany, and the United States 17, 18, 19. Studies on living donor transplant are scarce; in a single‐center study, where 324 living donor transplants were analyzed, no significant difference in the 5‐year graft survival of patients with DSAs was found compared with patients with anti–blood type antibody, anti–HLA‐Abs, or no DSAs 20.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have shown that DSA assessments using MFI alone may not be sufficient for assessing the potential risk for graft damage and decreased survival. Multiple assays are used, such as Flow‐XM,21, 27 C1q‐SAB assays,17 C3d‐SAB assays,28 or IgG‐subclass analysis 29. Our cohort includes 63 patients participating in the Eurotransplant Acceptable Mismatch program with an HLA antibody profile based on CDC, in some cases supplemented with solid phase assays 30.…”

Section: Discussionmentioning

confidence: 99%

“…While recent large‐cohort studies of the impact of DSAs on graft survival have mainly focused on deceased donor transplants,17, 18, 19 the effect of SAB assay–detected DSAs on living donor transplants has not been studied in large cohorts. In a Japanese single‐center study, 324 living donor kidney transplant recipients were analyzed to investigate the outcome of the 92 kidney transplant recipients with DSAs in combination with anti–blood type, anti–HLA antibodies, or both; all were desensitized before transplant 20.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Kamburova

Wisse

Joosten

et al. 2018

American Journal of Transplantation

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The presence of donor‐specific anti‐HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Kamburova

Wisse

Joosten

et al. 2018

American Journal of Transplantation

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“…For example, the pathogenetic roles of different Ig subclasses or those of complement-and non-complement-fixing DSAs in antibody-mediated rejection are controversially discussed [29]. On the one hand, complement-fixation is considered to be a major criterion for the pathogenicity of HLA antibodies in antibody-mediated rejection and has recently been confirmed in a large study with more than 1,000 patients [30]. On the other hand, accumulating evidence indicates that non-complement-fixing antibodies are also crucially involved in graft rejection via direct endothelial cell activation [31].…”

Section: Detection Of Hla Antibodiesmentioning

confidence: 99%

Acute and chronic antibody-mediated rejection in pediatric kidney transplantation

et al. 2014

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Acute antibody-mediated rejection is a diagnostic challenge in renal transplantation medicine. However, it is an important diagnosis to make, since chronic antibody-mediated rejection (CAMR) is the main cause of long-term graft loss. Antibody-mediated rejection is diagnosed by detecting donorspecific antibodies (DSAs) in the blood in combination with observing typical histomorphological signs in kidney biopsy, as described in the Banff classification. Therapy is based on the removal of DSAs by administering intravenous immunoglobulins (IVIGs), plasmapheresis, or immunoadsorption. Reoccurrence of antibodies is diminished by the use of rituximab, increased immunosuppression, and in some cases additional experimental substances. A combination of these techniques has been shown to be successful in the majority of cases of acute and chronic antibody-mediated rejection. Routine DSA monitoring is warranted for early detection of antibody-mediated rejection.

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“…To enable a detailed characterization of the sequential steps of CP activation, we applied a flow bead assay 24, 25, 26, 27. The effect of anti‐C1s mAbs on HLA antibody–triggered CP activation was also analyzed in cellular assays using HLA‐mismatched donor lymphocytes and aortic endothelial cells (AECs).…”

Section: Introductionmentioning

confidence: 99%

Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody–Induced Complement Activation—A Preclinical In Vitro Study

Wahrmann

Mühlbacher

Marinova

et al. 2017

American Journal of Transplantation

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The classic pathway (CP) of complement is believed to significantly contribute to alloantibody‐mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti‐C1s monoclonal antibody TNT009 and its parental mouse variant, TNT003, in preclinical in vitro models of HLA antibody–triggered CP activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLA antigen–coated flow beads or HLA‐mismatched aortic endothelial cells and splenic lymphocytes. Anti‐C1s antibodies profoundly inhibited C3 activation at concentrations >20 μg/mL, in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline CP activation. This study demonstrates that anti‐C1s antibodies TNT009 and TNT003 are highly effective in blocking HLA antibody–triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement‐mediated tissue injury in sensitized transplant recipients.

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Complement-Binding Anti-HLA Antibodies and Kidney-Allograft Survival

Abstract: Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss.

Cited by 765 publications

References 33 publications

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Acute and chronic antibody-mediated rejection in pediatric kidney transplantation

Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody–Induced Complement Activation—A Preclinical In Vitro Study

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