Imlifidase for Highly Sensitized Kidney Transplant Recipients With a posItive crossmAtch Against a Deceased Donor: Results of Kidney Transplantations Performed in Accordance to the French Guidelines.

Обзор

Imlifidase is a recombinant cysteine protease derived from Streptococcus pyogenes and produced in Escherichia coli, which has the ability to cleave and degrade all human IgGs. Four to six hours after imlifidase infusion, the entire IgG pool is degraded into F(ab')2 and Fc fragments. In vitro, imlifidase inhibits HLA antibody-mediated NK cell activation and antibody-dependent cell-mediated cytotoxicity. Imlifidase degrades also the IgG of the B cell Receptor (BCR), inhibiting BCR-mediated cell signal, transiently preventing memory B cell response to antigenic stimulation and their transition into antibody-producing cells. Two clinical studies have been designed to determine whether imlifidase could inactivate IgG donor-specific antibodies as a desensitization strategy in highly sensitized candidates for kidney transplantation. In the phase I/II study, 25 patients were transplanted in Sweden and United States. Among them, 18 had a positive flow cytometry crossmatch (FCXM) and 2 a positive complement-dependent cytotoxicity crossmatch (CDCXM). In the phase II study (Highdes Trial), 19 patients with an incompatible living or deceased donor from the United States, Sweden, and France were included. Among them, 7, 18, 2, and 8 had respectively a positive T-cell FCXM, positive B-cell FCXM, positive T-cell CDCXM, and positive B-cell CDCCXM. The primary efficacy endpoint was the ability of Imlifidase to convert a positive XM to a negative one. Conversion of baseline positive XM to negative within 24 h after Imlifidase treatment occurred in 89.5% (n=17) of the 19 patients. In the follow-up study including all the patients transplanted after Imlifidase desensitization, the antibody-mediated rejection rate (AMR) was at 39%, most of them occurring during the first month post-transplantation. Three-year death-censored graft survival was 93% in patients with AMR and 77% in the others. Three-year patient survival was 85% in patients with AMR and 94% in the others. No safety signal was reported. Based on these data, Imlifidase is now indicated as a desensitization agent of highly sensitized adult kidney transplant patients with positive crossmatch against an available ABO-compatible deceased donor. It should be reserved for patients unlikely to be transplanted under the available kidney allocation system including the prioritization program for highly sensitized patients (https://www.ema.europa.eu). Therefore, the French Society of Transplantation (SFT), the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) and the French Society of Histocompatibility and Immunogenetics (SFHI) have proposed French recommendations for patient selection, choice of antibodies characteristics, treatment and follow-up in order to homogenize practices. Although this new treatment addressed an unmet medical need, its authorization was based on only two small-scale studies. Therefore, additional data on long-term graft function and survival are required in patients treated by imlifidase.

Подробное описание

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. However, highly sensitized patients have a very difficult access to transplantation because of a very low number of compatible donors. Imlifidase is a major breakthrough in kidney transplantation, because it allows transplanting these highly sensitized patients considered as untransplantable until now. The findings coming from the ISKIA study will help to refine the use and implementation of imlifidase in this population.

The main objective of this retrospective study is to analyze the efficacy and safety of kidney transplantations performed with a positive crossmatch against a deceased donor, where imlifidase is used in accordance to the French guidelines.

The secondary objectives of the ISKIA study are:

* To identify the characteristics and analyze the outcome of kidney recipients eligible to imlifidase but transplanted without imlifidase * To identify the characteristics of kidney recipients eligible to imlifidase but not transplanted

Первичные конечные точки

• Percentage of transplantations performed with or without imlifidase among the eligible patients [Срок оценки: Year 1, year 2 and year 3 after kidney transplantation]

Вторичные конечные точки (8)

• Incidence of HLA donor-specific antibodies (DSA) rebound after transplantation [Срок оценки: Days 3, 5, 7, 10, and month 1, month 3 and month 12, after kidney transplantation]
• Timing of HLA donor-specific antibodies (DSA) rebound after transplantation [Срок оценки: Days 3, 5, 7, 10, and month 1, month 3 and month 12, after kidney transplantation]
• Incidence of antibody-mediated rejection [Срок оценки: Day 10, month 3 and month 12 after kidney tranplantation]
• eGFR [Срок оценки: Days 7, 14, month 1, month 3 and month 12 after kidney transplantation]
• Description of infection on post-transplantation [Срок оценки: Year 1, year 2 and year 3 after kidney transplantation]
• Description of cancer post-transplantation [Срок оценки: Year 1, year 2 and year 3 after kidney transplantation]
• Patient and graft survivals [Срок оценки: Year 1, year 2 and year 3 after kidney transplantation]
• Patients placed on the waiting list after transplantation [Срок оценки: Year 1, year 2 and year 3 after kidney transplantation]

Критерии участия

Критерии включения

• Highly sensitized adult kidney transplant candidates
• Eligible to imlifidase (patient with a delisting of at least one A, B, DR, DQ HLA antibody)

Критерии исключения

• Age < 18 years-old

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Франция · 20 центров

• CHU Amiens Picardie Site Sud — Amiens
• Hôpital de Bois-Guillaume — Bois-Guillaume
• Hôpital Pellegrin — Bordeaux
• CHU Caen Normandie — Caen
• Hôpital Henri Mondor — Créteil
• CHU de Grenoble Alpes — Grenoble
• Hôpital Huriez — Lille
• Hôpital Edouard Herriot — Lyon
• … и ещё 12 центров

Идентификаторы

NCT: NCT07379957 · CHUBX2025/031

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗