Highly sensitized (HS) patients in need of kidney transplantation (KTx) typically spend a longer time waiting for compatible kidneys, are unlikely to receive an organ offer, and are at increased risk of antibody-mediated rejection (AMR). Desensitization using imlifidase, which is more rapid and removes total body immunoglobulin G (IgG) to a greater extent than other methods, enables transplantation to occur between HLA-incompatible (HLAi) donor-recipient pairs and allows patients to have greater access to KTx. However, when the project was launched there was limited data and clinical experience with desensitization in general and with imlifidase specifically. Hence, this Delphi methodology was used to reach a consensus from a multi-disciplinary team (MDT) of experts from 15 countries on the management of HS patients undergoing imlifidase HLAi from a deceased donor (DD) KTx. This Delphi consensus provides clinical practice guidance on the use of imlifidase in the end-to-end management of HS patients undergoing an HLAi DD KTx and supports centers in the development of guidelines for the utilization and integration of imlifidase into clinical practice.

Abteilung für Nephrologie Klinikum Rechts der Isar Technische Universität München Munich Germany

Clinic for Nephrology Renal Transplant Program Transplant Institute University Hospital Zurich Zurich Switzerland

Clinic of Nephrology and Transplantation Medicine Cantonal Hospital St Gallen St Gallen Switzerland

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Immunology Leiden University Medical Center Leiden Netherlands

Department of Microbiology Immunology and Transplantation KU Leuven Leuven Belgium

Department of Nephrology and Kidney Transplantation Hospital Clínic Barcelona Barcelona Spain

Department of Nephrology and Renal Transplantation National and Kapodistrian University of Athens Laiko Hospital Athens Greece

Department of Nephrology and Renal Transplantation Saint Louis Hospital in Paris Paris France

Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium

Department of Nephrology Hospital del Mar Nephropathies Research Group Hospital del Mar Research Institute Barcelona Spain

Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czechia

Department of Nephrology of Technische Universität München München Munich Germany

Department of Nephrology Transplantation Dialysis and Apheresis Bordeaux University Hospital Bordeaux France

Department of Nephrology UZ Antwerpen Antwerpen Belgium

Department of Surgery Duke University Durham NC United States

Department of Transplantation Transplant Surgery at Guy's and Great Ormond Street Hospitals London United Kingdom

Dipartimento di Medicina e Chirurgia Università di Parma UO Nefrologia Trapianti Rene Pancreas Programma Regionale Trapianti Emilia Romagna Azienda Ospedaliero Universitaria di Parma Parma Italy

Division of Nephrology and Dialysis Department of Medicine 3 Medical University Vienna Vienna Austria

Division of Nephrology Department of Medicine and Leiden Transplant Center Leiden University Medical Center Leiden Netherlands

Erasmus MC Transplant Institute Department of Internal Medicine University Medical Center Rotterdam Netherlands

Eurotransplant Reference Laboratory Department of Immunohaematology and Blood Transfusion Leiden University Medical Center Albinusdreef Netherlands

Histocompatibility and Immunogenetics Laboratory Birmingham Centre NHS Blood and Transplant UK NHS Blood and Transplant Birmingham United Kingdom

Immunology Department and National Tissue Typing Center G Gennimatas Hospital Athens Greece

Kidney and Pancreas Transplantation Unit Department of Surgery Oncology and Gastroenterology DISCOG University Hospital of Padova Padova Italy

Klinika Transplantologii Immunologii Nefrologii i Chorób Wewnętrznych Warszawski Uniwersytet Medyczny ul Warszawa Poland

Laboratory of Immunology and Histocompatibility Hôpital Saint Louis APHP Paris Paris France

Medical University of Vienna Vienna Austria

National and Kapodistrian University of Athens Clinic of Nephrology and Transplantation Laiko General Hospital Athens Greece

Nephrologist and Head of the Nephrology and Kidney Transplantation Department Saint Louis Hospital APHP Paris France

Nephrology and Kidney Transplant Department Vall d'Hebron University Hospital Barcelona Spain

Nephrology and Transplant Immunology Medical Director Kidney Transplant Program Cedars Sinai Medical Center Pediatrics and Medicine David Geffen School of Medicine at UCLA Los Angeles CA United States

Nephrology at Université Paris Cité and Head of Nephrology and Transplantation Unit at Necker Hospital in Paris Paris France

Transplant Immunology Unit Department of Cardiac National Transplant Centre Thoracic and Vascular Sciences Padua University Hospital Ospedale Giustinianeo Padova Italy

Transplantation and Liver Surgery Helsinki University Hospital and University of Helsinki Helsinki Finland

Uppsala University Department of Surgical Sciences Section of Transplant Surgery Uppsala Sweden

Zobrazit více v PubMed

De Ferrante H, Smeulders B, Tieken I, Heidt S, Haasnoot GW, Claas FHJ, et al. Immunized Patients Face Reduced Access to Transplantation in the Eurotransplant Kidney Allocation System. Transplantation (2023) 107(10):2247–54. 10.1097/TP.0000000000004687 PubMed DOI

Habal MV, Farr M, Restaino S, Chong A. Desensitization in the Era of Precision Medicine: Moving from the Bench to Bedside. Transplantation (2019) 103(8):1574–81. 10.1097/TP.0000000000002737 PubMed DOI

Jackson KR, Holscher C, Motter JD, Desai N, Massie AB, Garonzik-Wang J, et al. Posttransplant Outcomes for cPRA-100% Recipients under the New Kidney Allocation System. Transplantation (2020) 104(7):1456–61. 10.1097/TP.0000000000002989 PubMed DOI PMC

Schinstock CA, Smith BH, Montgomery RA, Jordan SC, Bentall AJ, Mai M, et al. Managing Highly Sensitized Renal Transplant Candidates in the Era of Kidney Paired Donation and the New Kidney Allocation System: Is There Still a Role for Desensitization? Clin Transpl (2019) 33(12):e13751. 10.1111/CTR.13751 PubMed DOI

Schinstock CA, Mannon RB, Budde K, Chong AS, Haas M, Knechtle S, et al. Recommended Treatment for Antibody-Mediated Rejection after Kidney Transplantation: The 2019 Expert Consensus from the Transplantation Society Working Group. Transplantation (2020) 104(5):911–22. 10.1097/TP.0000000000003095 PubMed DOI PMC

Keith DS, Vranic GM. Approach to the Highly Sensitized Kidney Transplant Candidate. Clin J Am Soc Nephrol (2016) 11(4):684–93. 10.2215/CJN.05930615 PubMed DOI PMC

Huber L, Lachmann N, Drr M, Matz M, Liefeldt L, Neumayer HH, et al. Identification and Therapeutic Management of Highly Sensitized Patients Undergoing Renal Transplantation. Drugs (2012) 72(10):1335–54. 10.2165/11631110-000000000-00000 PubMed DOI

Mamode N, Bestard O, Claas F, Furian L, Griffin S, Legendre C, et al. European Guideline for the Management of Kidney Transplant Patients with HLA Antibodies: By the European Society for Organ Transplantation Working Group. Transpl Int (2022) 35:10511. 10.3389/TI.2022.10511 PubMed DOI PMC

Stewart DE, Kucheryavaya AY, Klassen DK, Turgeon NA, Formica RN, Aeder MI. Changes in Deceased Donor Kidney Transplantation One Year after KAS Implementation. Am J Transpl (2016) 16(6):1834–47. 10.1111/AJT.13770 PubMed DOI

Jatana SS, Zhao H, Bow LM, Cozzi E, Batal I, Horak T, et al. Seeking Standardized Definitions for HLA-Incompatible Kidney Transplants: A Systematic Review. Transplantation (2022) 107(1):231–53. 10.1097/TP.0000000000004262 PubMed DOI

Maldonado A, Jordan S, Sjoholm K, Lagergren A, Lonze B, Montgomery R. Long-term Follow up of Imlifidase Desensitized Kidney Transplant Recipients: 5-year Pooled Analysis (2024) Presented at American Transplant Congress, June 1–5, 2024, Philadelphia, US. Abstract 24-A-4219-ATC. Presented at

Claas FHJ, Rahmel A, Doxiadis IIN. Enhanced Kidney Allocation to Highly Sensitized Patients by the Acceptable Mismatch Program. Transplantation (2009) 88(4):447–52. 10.1097/TP.0B013E3181B04A5F PubMed DOI

Lonze BE, Tatapudi VS, Weldon EP, Min ES, Ali NM, Deterville CL, et al. IdeS (Imlifidase): A Novel Agent that Cleaves Human IgG and Permits Successful Kidney Transplantation across High-Strength Donor-specific Antibody. Ann Surg (2018) 268(3):488–96. 10.1097/SLA.0000000000002924 PubMed DOI

Furian L, Bestard O, Budde K, Cozzi E, Diekmann F, Mamode N, et al. European Consensus on the Management of Sensitized Kidney Transplant Recipients: A Delphi Study. Transpl Int (2024) 37:12475. 10.3389/ti.2024.12475 PubMed DOI PMC

Kjellman C, Maldonado AQ, Sjöholm K, Lonze BE, Montgomery RA, Runström A, et al. Outcomes at 3 Years Posttransplant in Imlifidase-Desensitized Kidney Transplant Patients. Am J Transplant (2021) 21(12):3907–18. 10.1111/ajt.16754 PubMed DOI PMC

Marfo K, Lu A, Ling M, Akalin E. Desensitization Protocols and Their Outcome. Clin J Am Soc Nephrol (2011) 6(4):922–36. 10.2215/CJN.08140910 PubMed DOI

Okada D, Okumi M, Kakuta Y, Unagami K, Iizuka J, Takagi T, et al. Outcome of the Risk-Stratified Desensitization Protocol in Donor-specific Antibody-Positive Living Kidney Transplant Recipients: A Retrospective Study. Transpl Int (2018) 31(9):1008–17. 10.1111/TRI.13269 PubMed DOI

Sethi S, Choi J, Toyoda M, Vo A, Peng A, Jordan SC. Desensitization: Overcoming the Immunologic Barriers to Transplantation. J Immunol Res (2017) 2017:6804678. 10.1155/2017/6804678 PubMed DOI PMC

Ge S, Chu M, Choi J, Louie S, Vo A, Jordan SC, et al. Imlifidase Inhibits HLA Antibody-Mediated NK Cell Activation and Antibody-dependent Cell-Mediated Cytotoxicity (ADCC) In Vitro . Transplantation (2020) 104(8):1574–9. 10.1097/TP.0000000000003023 PubMed DOI

Jordan SC, Lorant T, Choi J. IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation. N Engl J Med (2017) 377(5):1693–4. 10.1056/NEJMc1711335 PubMed DOI

Lorant T, Bengtsson M, Eich T, Eriksson BM, Winstedt L, Järnum S, et al. Safety, Immunogenicity, Pharmacokinetics, and Efficacy of Degradation of Anti-HLA Antibodies by IdeS (Imlifidase) in Chronic Kidney Disease Patients. Am J Transpl (2018) 18(11):2752–62. 10.1111/AJT.14733 PubMed DOI PMC

Committee for Medicinal Products for Human Use (CHMP). Idefirix® Public Assessment Report (EPAR) (2020). Available from: https://www.ema.europa.eu/en/documents/assessment-report/idefirix-epar-public-assessment-report_en.pdf (Accessed May 16, 2024).

European Medicines Agency. Idefirix® 11 Mg Powder for Concentrate for Solution for Infusion SmPC (2024). Available from: https://www.ema.europa.eu/en/documents/product-information/idefirix-epar-product-information_en.pdf (Accessed July 17, 2024).

Couzi L, Malvezzi P, Amrouche L, Anglicheau D, Blancho G, Caillard S, et al. Imlifidase for Kidney Transplantation of Highly Sensitized Patients with a Positive Crossmatch: The French Consensus Guidelines. Transpl Int (2023) 36:11244. 10.3389/TI.2023.11244 PubMed DOI PMC

Gattrell WT, Hungin AP, Price A, Winchester CC, Tovey D, Hughes EL, et al. ACCORD Guideline for Reporting Consensus-Based Methods in Biomedical Research and Clinical Practice: A Study Protocol. Res Integr Peer Rev (2022) 7(1):3. 10.1186/S41073-022-00122-0 PubMed DOI PMC

Fink-Hafner D, Dagen T, Doušak M, Novak M, Hafner-Fink M. Delphi Method: Strengths and Weaknesses. Metodološki zvezki (2019) 16(2):1–19. 10.51936/fcfm6982 DOI

McMillan SS, King M, Tully MP. How to Use the Nominal Group and Delphi Techniques. Int J Clin Pharm (2016) 38(3):655–62. 10.1007/S11096-016-0257-X PubMed DOI PMC

O’Connell PJ, Brown M, Chan TM, Claure-Del Granado R, Davies SJ, Eiam-Ong S, et al. The Role of Kidney Transplantation as a Component of Integrated Care for Chronic Kidney Disease. Kidney Int Suppl (2011) (2020) 10(1):e78–e85. 10.1016/J.KISU.2019.11.006 PubMed DOI PMC

Argani H. Anti-HLA Antibody: The Role of Epitopes in Organ Transplantation. Exp Clin Transpl (2019) 17(Suppl. 1):38–42. 10.6002/ECT.MESOT2018.L41 PubMed DOI

van den Broek DAJ, Meziyerh S, Budde K, Lefaucheur C, Cozzi E, Bertrand D, et al. The Clinical Utility of Post-Transplant Monitoring of Donor-specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report with Guideline Statements for Clinical Practice. Transpl Int (2023) 36:11321. 10.3389/TI.2023.11321 PubMed DOI PMC

Steiner RW, Awdishu L. Steroids in Kidney Transplant Patients. Semin Immunopathol (2011) 33(2):157–67. 10.1007/S00281-011-0259-7 PubMed DOI PMC

Meziyerh S, van Gelder T, Kers J, van der Helm D, van der Boog PJM, de Fijter JW, et al. Tacrolimus and Mycophenolic Acid Exposure Are Associated with Biopsy-Proven Acute Rejection: A Study to Provide Evidence for Longer-Term Target Ranges. Clin Pharmacol Ther (2023) 114(1):192–200. 10.1002/CPT.2915 PubMed DOI

Peters-Sengers H, Houtzager JHE, Idu MM, Heemskerk MBA, van Heurn ELW, Homan van der Heide JJ, et al. Impact of Cold Ischemia Time on Outcomes of Deceased Donor Kidney Transplantation: An Analysis of a National Registry. Transpl Direct (2019) 5(5):e448. 10.1097/TXD.0000000000000888 PubMed DOI PMC

Greenshields AL, Liwski RS. The ABCs (DRDQDPs) of the Prozone Effect in Single Antigen Bead HLA Antibody Testing: Lessons from Our Highly Sensitized Patients. Hum Immunol (2019) 80(7):478–86. 10.1016/J.HUMIMM.2019.04.019 PubMed DOI

Legendre C, Canaud G, Martinez F. Factors Influencing Long-Term Outcome after Kidney Transplantation. Transpl Int (2014) 27(1):19–27. 10.1111/TRI.12217 PubMed DOI

Karim A, Farrugia D, Cheshire J, Mahboob S, Begaj I, Ray D, et al. Recipient Age and Risk for Mortality after Kidney Transplantation in England. Transplantation (2014) 97(8):832–8. 10.1097/01.TP.0000438026.03958.7B PubMed DOI

Wu DA, Robb ML, Forsythe JLR, Bradley C, Cairns J, Draper H, et al. Recipient Comorbidity and Survival Outcomes after Kidney Transplantation: A UK-wide Prospective Cohort Study. Transplantation (2020) 104(6):1246–55. 10.1097/TP.0000000000002931 PubMed DOI

National Institute for Health and Care Excellence (UK). Imlifidase for Preventing Kidney Transplant Rejection in People with Chronic Kidney Disease (ID1672) (2022). Available from: https://fundingawards.nihr.ac.uk/award/NIHR131818 (Accessed May 16, 2024).

von Moos S, Akalin E, Mas V, Mueller TF. Assessment of Organ Quality in Kidney Transplantation by Molecular Analysis and Why It May Not Have Been Achieved, Yet. Front Immunol (2020) 11:833. 10.3389/FIMMU.2020.00833 PubMed DOI PMC

Aubert O, Kamar N, Vernerey D, Viglietti D, Martinez F, Duong-Van-Huyen JP, et al. Long Term Outcomes of Transplantation Using Kidneys from Expanded Criteria Donors: Prospective, Population Based Cohort Study. BMJ (2015) 351:h3557. 10.1136/BMJ.H3557 PubMed DOI PMC

Laperrousaz S, Tiercy JM, Villard J, Ferrari-Lacraz S. HLA and Non-HLA Polymorphisms in Renal Transplantation. Swiss Med Wkly (2012) 142:w13668. 10.4414/SMW.2012.13668 PubMed DOI

Hariharan S, Israni AK, Danovitch G. Long-Term Survival after Kidney Transplantation. N Engl J Med (2021) 385(8):729–43. 10.1056/NEJMRA2014530 PubMed DOI

Naesens M, Roufosse C, Haas M, Lefaucheur C, Mannon RB, Adam BA, et al. The Banff 2022 Kidney Meeting Report: Reappraisal of Microvascular Inflammation and the Role of Biopsy-Based Transcript Diagnostics. Am J Transplant (2024) 24(3):338–49. 10.1016/J.AJT.2023.10.016 PubMed DOI