Antibodies against ARHGDIB are associated with long-term kidney graft loss

Kamburova, Elena G.; Gruijters, Maartje L; Kardol‐Hoefnagel, Tineke; 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; Melchers, Rowena C A; 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; Hoitsma, Andries J.; Boog, Paul J.M. van der; Fijter, Johan W. de; Betjes, M.; Heidt, Sebastiaan; Roelen, Dave L.; Claas, Frans H.J.; Bemelman, Fréderike J.

doi:10.1111/ajt.15493

Cited by 45 publications

(41 citation statements)

References 33 publications

(42 reference statements)

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“…Also excluded from the panel were other emerging non‐HLA targets such as Rho‐GDP disassociation inhibitor 2 (ARHGDIB). Antibodies to this specific antigen were recently associated with graft loss in kidney transplant recipients 19 …”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, until recently, the lack of standardized multiplex assays has limited the simultaneous assessment of multiple non‐HLA antigens. A handful of studies, using microsphere or protein microarray technology, have screened serum samples for reactivity to non‐HLA antibodies and evaluated their clinical significance 9,12,15‐19 . In this retrospective, case‐control study, we profiled serum from heart transplant recipients collected at the time of AMR for their reactivity against a panel of non‐HLA autoantigens under development by Immucor and attempted to identify relevant antigenic targets.…”

Section: Introductionmentioning

confidence: 99%

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Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation

See

Mantell

Clerkin

et al. 2020

American Journal of Transplantation

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Antibody‐mediated rejection (AMR) driven by the development of donor‐specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non‐HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single‐center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non‐AMR (n = 21) were tested for reactivity against a panel of 44 non‐HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non‐AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA‐positive AMR patients exhibited greater reactivity to autoantigens compared to DSA‐negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta‐tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non‐AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non‐HLA are associated with DSA‐positive AMR although their specific role in mediating allograft injury is not yet understood.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation

See

Mantell

Clerkin

et al. 2020

American Journal of Transplantation

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“…This analysis showed that especially autoantibodies against ARHGDIB appear to be clinically relevant in recipients transplanted with a kidney from a deceased donor (N = 3274) but not in recipients of a living‐donor kidney (N = 1496), corrected for recipient and donor age, type of donor, cold ischemia time for deceased donors (after brain or cardiac death), dialysis years, induction therapy with IL‐2 receptor blocker and presence of DSA. The results indicate that these autoantibodies are related with graft loss, while they occur independently from DSA . Therefore, pre‐transplant risk stratification could be improved by determining the anti‐ARHGDIB antibodies.…”

Section: Non‐hla Antibodies In Kidney Transplantationmentioning

confidence: 99%

“…In the PROCARE study, assays to detect non‐HLA antibodies against these 14 proteins were developed in‐house, where proteins were coupled either directly to beads or coupled via a HaloTag, to retain the 3D protein structure . All pre‐transplant sera from 4770 transplantations were analyzed with these reagents showing a heterogeneity in results with regard to median‐fluorescent intensities (MFI) for the various antigens . Commercial companies delivering reagents for autoantibody analyses (eg, for connective tissue diseases or transplantation) define cutoffs discriminating positive from negative sera on the basis of autoantibody levels in healthy donors.…”

Section: Non‐hla Antibodies In Kidney Transplantationmentioning

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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“…In the event of humoral rejection, antibodies directed against the donor's human leukocyte antigens (HLA-DSA) are most often sought after to blame. However, multiple independent investigators have reported observations that non-HLA antibodies share in this ability to cause both antibody-mediated injury and antibodymediated rejection in kidney transplants [3][4][5][6][7][8][9]. Antiendothelial cell antibody (AECA) and antibody directed against the angiotensin II type 1 receptor (AT1R) are among the best characterized non-HLA antibodies [10].…”

Section: Introductionmentioning

confidence: 99%

Successful A2 to B Deceased Donor Kidney Transplant after Desensitization for High-Strength Non-HLA Antibody Made Possible by Utilizing a Hepatitis C Positive Donor

Karpel

Ali

Lawson

et al. 2020

Case Reports in Transplantation

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Desensitization using plasma exchange can remove harmful antibodies prior to transplantation and mitigate risks for hyperacute and severe early acute antibody-mediated rejection. Traditionally, the use of plasma exchange requires a living donor so that the timing of treatments relative to transplant can be planned. Non-HLA antibody is increasingly recognized as capable of causing antibody-mediated renal allograft rejection and has been associated with decreased graft longevity. Our patient had highstrength non-HLA antibody deemed prohibitive to transplantation without desensitization, but no living donors. As the patient was eligible to receive an A2 ABO blood group organ and was willing to accept a hepatitis C positive donor kidney, this afforded a high probability of receiving an offer within a short enough time frame to attempt empiric desensitization in anticipation of a deceased donor transplant. Fifteen plasma exchange treatments were performed before the patient received an organ offer, and the patient was successfully transplanted. Hepatitis C infection was treated posttransplant. No episodes of rejection were observed. At one-year posttransplant, the patient maintains good graft function. In this case, willingness to consider nontraditional donor organs enabled us to mimic living donor desensitization using a deceased donor.

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Antibodies against ARHGDIB are associated with long-term kidney graft loss

Cited by 45 publications

References 33 publications

Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation

Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation

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

Successful A2 to B Deceased Donor Kidney Transplant after Desensitization for High-Strength Non-HLA Antibody Made Possible by Utilizing a Hepatitis C Positive Donor

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