Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure

Kamburova, Elena G.; Wisse, Bram W.; Joosten, Irma; Allebes, Wil A.; Meer, Arnold van der; Hilbrands, Luuk B.; Baas, Marije C.; Spierings, Eric; Hack, C. E.; Reekum, Franka E. van; Zuilen, Arjan D. van; Verhaar, Marianne C.; Bots, Michiel L.; Drop, Adriaan C.A.D.; Plaisier, Loes; Seelen, Marc A.; Sanders, Jan-Stephan; Hepkema, Bouke; Lambeck, Annechien J. A.; Bungener, Laura; Roozendaal, Caroline; Tilanus, Marcel G.J.; Voorter, Christina E.M.; Wieten, Lotte; Duijnhoven, Elly M. van; Gelens, M.; Christiaans, Maarten H. L.; Ittersum, Frans J. van; Nurmohamed, Shaikh A.; Lardy, Neubury M.; Swelsen, Wendy; Pant, Karlijn A M I van der; Weerd, Neelke C. van der; Berge, Ineke J. M. ten; Bemelman, Fréderike J.; Hoitsma, Andries J.; Boog, Paul J.M. van der; Fijter, Johan W. de; Betjes, M.; Heidt, Sebastiaan; Roelen, Dave L.; Claas, Frans H.J.; Otten, Henny G.

doi:10.1681/asn.2018020205

Cited by 26 publications

(23 citation statements)

References 19 publications

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“…It is not surprising that most studies found a very strong correlation of the MFI value and C1q or C3d binding . While some studies including a recent meta‐analysis found that C1q or C3d binding assays add some prediction beyond the MFI value, other studies did not .…”

Section: Modifications Of the Generic Sab Assaymentioning

confidence: 99%

Caveats of HLA antibody detection by solid‐phase assays

2019

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All authors contributed equally to the review SUMMARY Solid-phase assays for human leukocyte antigens (HLA) antibody detection have clearly revolutionized the field of HLA diagnostics and transplantation. The key advantages are a high sensitivity and specificity for detection of HLA antibodies compared with cell-based assays, as well as the potential for standardization. Solid-phase assays enabled the broad introduction of tools such as "virtual crossmatching" and "calculated panel reactive antibodies," which are essential components in many organ allocation systems, kidney-paired donation programs, and center-specific immunological risk stratification procedures. The most advanced solid-phase assays are the socalled single antigen beads (SAB). They are available now for more than 15 years, and the transplant community embraced their significant advantages. However, SAB analysis and interpretation is complex and many pitfalls have to be considered. In this review, we will discuss problems, limitations, and challenges using SAB. Furthermore, we express our wishes for improvements of SAB as well as their future use for immunological assessment and research purposes.

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Section: Modifications Of the Generic Sab Assaymentioning

confidence: 99%

Caveats of HLA antibody detection by solid‐phase assays

2019

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“…Kamburova et al reported that 95% of C3d-positive antibodies exhibit SAB MFI values of 4000 or more, but only 56% of antibodies exhibiting an MFI of 4000 or more possessed C3d-binding capacity. Based on this, they suggested that the C3d-binding capacity was correlated with the SAB MFI; however, positivity cannot be completely predicted based on SAB MFI [34].…”

Section: Complement-binding Capacities and Clinical Outcomementioning

confidence: 99%

“…dnDSAs harboring C1q-binding capacity were known to affect clinical outcomes such as graft survival, acute AMR, and transplant glomerulopathy [8,[22][23][24][25][26][27], but the role of pDSA in AMR or poor graft survival prediction is controversial [28][29][30][31]. C3d-positive dnDSA increased the risk of graft loss, AMR, proteinuria, C4d histological staining, and rapid progression to graft dysfunction [3,6,32,33]; however, C3d-positive pre-pDSA was reported not to increase the risk of graft failure significantly [34]. In the present study, we performed a C3d-binding assay, rather than a C1q-binding assay, for two reasons.…”

Section: Complement-binding Capacities and Clinical Outcomementioning

confidence: 99%

C3d-Positive Preformed DSAs Tend to Persist and Result in a Higher Risk of AMR after Kidney Transplants

Choi

Lee

Park

et al. 2020

JCM

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C3d-binding assays have been introduced as methods for the prediction of the presence of complement-binding functional antibodies; however, the prognostic value of C3d-positive preformed donor-specific antibodies (pDSAs) has not been fully evaluated. In this study, we performed a retrospective investigation of the association of pDSAs and their C3d-binding capacity with one-year clinical outcomes. pDSAs were defined as donor-specific antibodies (DSAs) that were produced before kidney transplants (KTs) (pre-pDSAs) or within the first four weeks after KTs, owing to rebound immune response (post-pDSAs). Of 455 adult KT recipients, pre-pDSAs and post-pDSAs were found in 56 (12.3%) and 56 (12.3%) recipients, respectively, and C3d-positive post-pDSAs were found in 13 recipients (2.9%) in total. Approximately half of the C3d-negative pre-pDSAs (37/73, 50.7%) disappeared after transplantation; however, all C3d-positive pre-pDSAs (8/8, 100%) persisted after transplantation despite desensitization (p = 0.008). C3d-positive pDSAs were significantly associated with a higher incidence and risk of AMR (p < 0.001, OR 94.467–188.934). Identification of the C3d-binding activity of pDSAs before and early after KT is important for predicting the persistence of pDSAs and the risk of AMR induced by the presence of pDSAs.

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“…One of the key differences between HLA molecules present on beads vs cells is that HLA‐molecules are immovably fixed to beads whereas on the cell‐surface, HLA molecules float in the phospholipid bilayer and can be clustered rapidly by HLA‐antibodies leading to a clustered formation of IgG Fc‐tails. On beads, the detection of complement fixation is therefore a parameter of the amount of antibodies bound, irrespective of affinity or precise specificity, which explains the direct relation between MFI values found when detecting IgG vs deposition of complement components . In a small study with 34 kidney recipients, 19 with biopsy‐proven antibody‐mediated rejection (AMR) and 15 who did not have AMR, the C1q‐binding activity was shown to be largely due to differences in antibody strength (or higher MFI) .…”

Section: Effector Mechanisms Of Hla and Non‐hla Antibodiesmentioning

confidence: 99%

“…The PROCARE study allowed analysis of outcome of transplantations, with donor acceptance unbiased by results and knowledge that were post‐hoc obtained with techniques used in PROCARE study. Recommendations reflecting the impact of parameters from that study are currently well appreciated …”

Section: Introductionmentioning

confidence: 99%

Results and reflections from the PROfiling Consortium on Antibody Repertoire and Effector functions in kidney transplantation: A mini‐review

Kamburova

Hoitsma

Claas

et al. 2019

HLA

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Kidney transplantation is the best treatment option for patients with end‐stage renal disease (ESRD). The waiting time for a deceased donor kidney in the Netherlands is approximately 3 years. Mortality among patients on the waiting list is high. The aim of the PROCARE consortium (PROfiling Consortium on Antibody Repertoire and Effector functions) was to decrease the waiting time by providing a matching algorithm yielding a prolonged graft survival and less HLA‐immunization compared with the currently used Eurotransplant Kidney allocation system. In this study, 6097 kidney transplants carried out between January 1995 and December 2005 were re‐examined with modern laboratory techniques and insights that were not available during that time period. In this way, we could identify potential new parameters that can be used to improve the matching algorithm and prolong graft survival. All eight University Medical Centers in the Netherlands participated in this multicenter study. To improve the matching algorithm, we used as central hypothesis that the combined presence of class‐I and ‐II single‐antigen bead (SAB)‐defined donor‐specific HLA antibodies (DSA) prior to transplantation, non‐HLA antibodies, the number of B‐ and/or T‐cell epitopes recognized on donor HLA, and specific polymorphisms in effector mechanisms of IgG were associated with an increased risk for graft failure. The purpose of this article is to relate the results obtained from the PROCARE consortium study to other studies published in recent years. The clinical relevance of SAB‐defined DSA, complement‐fixing DSA, non‐HLA antibodies, and the effector functions of (non)‐HLA‐antibodies will be discussed.

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Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure

Cited by 26 publications

References 19 publications

Caveats of HLA antibody detection by solid‐phase assays

Caveats of HLA antibody detection by solid‐phase assays

C3d-Positive Preformed DSAs Tend to Persist and Result in a Higher Risk of AMR after Kidney Transplants

Results and reflections from the PROfiling Consortium on Antibody Repertoire and Effector functions in kidney transplantation: A mini‐review

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