Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

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

doi:10.1111/tan.15346

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.

Original language	English
Article number	e15346
Number of pages	14
Journal	HLA
Volume	103
Issue number	1
DOIs	https://doi.org/10.1111/tan.15346
Publication status	Published - 1 Jan 2024

Keywords

donor epitope specific antibodies
graft survival
kidney transplantation
MEDIATED REJECTION
COMPLEMENT
ACCOMMODATION
PERFORMANCE
VALIDATION
DEPOSITION
IMPUTATION
BOOTSTRAP

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10.1111/tan.15346Licence: CC BY-NC-ND

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Kardol-Hoefnagel, T., Senejohnny, D. M., Kamburova, E. G., Wisse, B. W., Reteig, L., Gruijters, M. L., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C. A. D., Plaisier, L., ... Otten, H. G. (2024). Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation. HLA, 103(1), Article e15346. https://doi.org/10.1111/tan.15346

@article{7157efcaf30a497c9a07c3ae1a3f715a,

title = "Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation",

abstract = "In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.",

keywords = "donor epitope specific antibodies, graft survival, kidney transplantation, MEDIATED REJECTION, COMPLEMENT, ACCOMMODATION, PERFORMANCE, VALIDATION, DEPOSITION, IMPUTATION, BOOTSTRAP",

author = "Tineke Kardol-Hoefnagel and Senejohnny, {Danial Mohammadi} and Kamburova, {Elena G.} and Wisse, {Bram W.} and Leon Reteig and Gruijters, {Maartje L.} and Irma Joosten and Allebes, {Wil A.} and {van der Meer}, Arnold and Hilbrands, {Luuk B.} and Baas, {Marije C.} and Eric Spierings and Hack, {Cornelis E.} and {van Reekum}, {Franka E.} and {van Zuilen}, {Arjan D.} and Verhaar, {Marianne C.} and Bots, {Michiel L.} and Drop, {Adriaan C. A. D.} and Loes Plaisier and Melchers, {Rowena C. A.} and Seelen, {Marc A. J.} and Sanders, {Jan Stephan} and Hepkema, {Bouke G.} and Lambeck, {Annechien J. A.} and Bungener, {Laura B.} and Caroline Roozendaal and Tilanus, {Marcel G. J.} and Voorter, {Christina E.} and Lotte Wieten and {van Duijnhoven}, {Elly M.} and Gelens, {Marielle A. C. J.} and Christiaans, {Maarten H. L.} and {van Ittersum}, {Frans J.} and Nurmohamed, {Shaikh A.} and Lardy, {Neubury M.} and Wendy Swelsen and {van der Pant}, {Karlijn A. M. I.} and {van der Weerd}, {Neelke C.} and {ten Berge}, {Ineke J. M.} and Andries Hoitsma and {van der Boog}, {Paul J. M.} and {de Fijter}, {Johan W.} and Betjes, {Michiel G. H.} and Roelen, {Dave L.} and Claas, {Frans H.} and Bemelman, {Frederike J.} and Aleksandar Senev and Maarten Naesens and Sebastiaan Heidt and Otten, {Henny G.}",

year = "2024",

month = jan,

day = "1",

doi = "10.1111/tan.15346",

language = "English",

volume = "103",

journal = "HLA",

issn = "2059-2302",

publisher = "Wiley",

number = "1",

}

Kardol-Hoefnagel, T, Senejohnny, DM, Kamburova, EG, Wisse, BW, Reteig, L, Gruijters, ML, Joosten, I, Allebes, WA, van der Meer, A, Hilbrands, LB, Baas, MC, Spierings, E, Hack, CE, van Reekum, FE, van Zuilen, AD, Verhaar, MC, Bots, ML, Drop, ACAD, Plaisier, L, Melchers, RCA, Seelen, MAJ, Sanders, JS, Hepkema, BG, Lambeck, AJA, Bungener, LB, Roozendaal, C, Tilanus, MGJ, Voorter, CE , Wieten, L , van Duijnhoven, EM , Gelens, MACJ , Christiaans, MHL, van Ittersum, FJ, Nurmohamed, SA, Lardy, NM, Swelsen, W, van der Pant, KAMI, van der Weerd, NC, ten Berge, IJM, Hoitsma, A, van der Boog, PJM, de Fijter, JW, Betjes, MGH, Roelen, DL, Claas, FH, Bemelman, FJ, Senev, A, Naesens, M, Heidt, S & Otten, HG 2024, 'Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation', HLA, vol. 103, no. 1, e15346. https://doi.org/10.1111/tan.15346

TY - JOUR

T1 - Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

AU - Kardol-Hoefnagel, Tineke

AU - Senejohnny, Danial Mohammadi

AU - Kamburova, Elena G.

AU - Wisse, Bram W.

AU - Reteig, Leon

AU - Gruijters, Maartje L.

AU - Joosten, Irma

AU - Allebes, Wil A.

AU - van der Meer, Arnold

AU - Hilbrands, Luuk B.

AU - Baas, Marije C.

AU - Spierings, Eric

AU - Hack, Cornelis E.

AU - van Reekum, Franka E.

AU - van Zuilen, Arjan D.

AU - Verhaar, Marianne C.

AU - Bots, Michiel L.

AU - Drop, Adriaan C. A. D.

AU - Plaisier, Loes

AU - Melchers, Rowena C. A.

AU - Seelen, Marc A. J.

AU - Sanders, Jan Stephan

AU - Hepkema, Bouke G.

AU - Lambeck, Annechien J. A.

AU - Bungener, Laura B.

AU - Roozendaal, Caroline

AU - Tilanus, Marcel G. J.

AU - Voorter, Christina E.

AU - Wieten, Lotte

AU - van Duijnhoven, Elly M.

AU - Gelens, Marielle A. C. J.

AU - Christiaans, Maarten H. L.

AU - van Ittersum, Frans J.

AU - Nurmohamed, Shaikh A.

AU - Lardy, Neubury M.

AU - Swelsen, Wendy

AU - van der Pant, Karlijn A. M. I.

AU - van der Weerd, Neelke C.

AU - ten Berge, Ineke J. M.

AU - Hoitsma, Andries

AU - van der Boog, Paul J. M.

AU - de Fijter, Johan W.

AU - Betjes, Michiel G. H.

AU - Roelen, Dave L.

AU - Claas, Frans H.

AU - Bemelman, Frederike J.

AU - Senev, Aleksandar

AU - Naesens, Maarten

AU - Heidt, Sebastiaan

AU - Otten, Henny G.

PY - 2024/1/1

Y1 - 2024/1/1

N2 - In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.

AB - In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.

KW - donor epitope specific antibodies

KW - graft survival

KW - kidney transplantation

KW - MEDIATED REJECTION

KW - COMPLEMENT

KW - ACCOMMODATION

KW - PERFORMANCE

KW - VALIDATION

KW - DEPOSITION

KW - IMPUTATION

KW - BOOTSTRAP

U2 - 10.1111/tan.15346

DO - 10.1111/tan.15346

M3 - Article

SN - 2059-2302

VL - 103

JO - HLA

JF - HLA

IS - 1

M1 - e15346

ER -