End-stage Renal Disease, Hla-incompatible Kidney Transplant Candidates, Kidney Transplantation
Conditions
Keywords
Anti-HLA alloantibodies, Desensitization therapy, Tocilizumab, Rituximab
Brief summary
Kidney transplantation is the best renal-replacement in the setting of end-stage renal disease. However, some transplant candidates have developed anti-HLA alloantibodies (human leukocyte antigen). When they are numerous and when their strength assessed by mean fluorescence intensity (MFI) is high it is very complicated to find-out a suitable kidney allograft against which the recipient has a negative cross-match. In such a case the only hope for the patient is desensitization therapy, whereby the treatment will decrease anti-HLA alloantibodies below a threshold, i.e. MFI \< 3,000, enabling kidney transplantation without risking antibody-mediated rejection. Desensitization relies on i) apheresis technics in order to withdraw circulating anti-HLA antibodies, and ii) immunosuppression, i.e. rituximab or tocilizumab, targeting B-lymphocytes, and tacrolimus/mycophenolic acid/steroids targeting T-cells. The type of apheresis is guided by the pre-desensitization MFI of anti-HLA alloantibodies, e.g. double filtration plasmapheresis or semispecific immunoadsorption. Likely the choice between rituximab and tocilizumab depends also on predesensitization anti-HLA antibody MFIs. At the end of the desensitization process, the patient will be able to get a kidney transplant either from a live-donor or from a deceased donor.
Interventions
DRUGvisits of tocilizumab injection (every 4 weeks, up to 5 visits)
every 4 weeks, up to 5 visits (D-170, D-142, D-114, D-86, D-58).
DRUGRituximab 375 mg/m2 at Day-30
Rituximab 375 mg/m2 at Day-30
DRUGRituximab 375 mg/m2 at Day-15 (only for donors living)
Rituximab 375 mg/m2 at Day-15
OTHERTransplant Day-0
TRANSPLANTATION
Sponsors
University Hospital, Grenoble
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients on the kidney transplant list, waiting for a first or repeat transplant * Presence of anti HLA antibodies either class I and/or II * Sensitized against a potential living donor or have been on the waiting list for at least 3 years and having no potential live-donor * Patients eligible for desensitization will receive either rituximab alone, or rituximab plus apheresis, or tocilizumab before rituximab * Normal recent (\<6 months) cardiac workup * Vaccinated against pneumococcus and meningococcus B and C * Willingness of the patient to undergo the desensitization process and Express consent of the patient * for women of childbearing age, effective contraception or abstinence * Affiliated to a social security scheme or of such a scheme
Exclusion criteria
* Active underlying infections or neoplasia * Pregnant women, parturient or breastfeeding * Subject in exclusion period of another study * Subject under administrative or judicial control * Subject who cannot be contacted in an emergency * Rituximab contra indication: hypersensitivity (to active substance or murine protein), active and severe infections, patients in a severely immunocompromised state, severe heart failure or severe, uncontrolled cardiac disease. * Tocilizumab contra indication: hypersensitivity, active and severe infections. Apheresis contra indication: active and severe infection, untreated or instable coagulation disorders, unstable coronary disease, recent stroke, hemodynamic instability.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Description of the results of the strategy of desensitization in patients who will access to kidney transplantation from deceased or living donors. | at day 1 start of desensitization, at day 0 of Graft | Decrease of MFI for highest donor-specific alloantibody (DSA) between start and end of desensitization for every patient in each category |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| impairment of DSA synthesis | Day-198, at day-30 Graft, at day-15, at day0 of Graft, | Decrease in peripheral plasma cells and plasmablasts of \>50% |
| Impairment of immune response | Day-198, at day-30 Graft, at day-15, at day0 of Graft, | Decrease in complement factors of \>25% |
| Desensitization efficacy with regards to DSA decrease and kidney transplantation | Day-198, at day-30 Graft, at day-15, at day0 of Graft, | MFI for highest DSAs for each group |
| Incidence of treatment desensitization protocols, emergent adverse events (safety and Tolerability) | Day-198, at day-30 Graft, at day-15 | Emergent adverse events to the desensitization therapy will be carefully monitored during the treatment period and within the following three months. |
Countries
France
Outcome results
None listed