Evaluation of 2 Techniques of Apheresis to Desensitize ABO Incompatible Kidney Transplant Candidates

Study Overview
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Brief Summary
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Kidney transplantation is the treatment of choice for end-stage renal disease. ABO incompatible (ABOi) living donor kidney transplantation is one of the best ways to expand the donors' pool. However, breaking the ABO barrier is possible only with a preconditioning regimen that includes 1) an immunosuppressive strategy using a B-cell depleting agent (rituximab), an induction therapy with polyclonal antibodies, and a maintenance triple immunosuppressive therapy based on calcineurin inhibitors, and 2) a desensitization protocol aiming to decrease the titer of isoagglutinins. For this purpose, several techniques of apheresis are available. To date, two main techniques used in clinical setting are the Double-Filtration PlasmaPheresis (DFPP) and the Antigen-Specific Immunoadsorption (SIA). DFPP permits the depletion of the selective plasma fraction containing Immunoglobulins, while limiting the need for plasma substitution. SIA enables to remove ABO antibodies without a major loss in essential plasma components. To date, no randomized study comparing DFPP and SIA exist. SIA is less often used because of its high cost. However, in order to reduce the number of SIA sessions and consequently its cost, large plasma volume sessions of SIA are performed. ABOi is dramatically more expensive than ABO compatible kidney transplantation. A large part of the difference in the cost is related to the apheresis technique. Herein, the investigator proposes to describe the efficacy, the safety, and the cost of DFPP and SIA to desensitize ABO incompatible kidney transplant candidates.

Detailed Description
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All recipients will receive an induction therapy with rituximab and polyclonal antibodies, as well as a maintenance therapy by tacrolimus, mycophenolic acid (switched for mTOR (Mechanistic target of rapamycin) inhibitors 1 month after the transplantation to avoid viral infections) and steroids. The desensitization protocol will be based on the initial titer of isoagglutinin. All patients with an isoagglutinin titer between 1/8 and 1/128 will be included in this monocentric, open label study, and randomized between the DFPP arm (1 to 4 sessions according to the initial titer) and large-plasma SIA (1 to 2 sessions according to the titer). The effectiveness will be evaluated on the ability to obtain the targeted titer before transplantation (1/4) with less than 5 DFPP, or 2 large-plasma volume SIA. All recipients will be followed for 6 months, and examined for surgical complications, rejection rate, and kidney function. All complications related to desensitization protocol will be reported. Moreover, all cost associated with these two apheresis techniques will be evaluated.

Official Title
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Evaluation of 2 Techniques of Apheresis to Desensitize ABO Incompatible Kidney Transplant Candidates: Double Filtration PlasmaPheresis (DFPP) vs Large Plasma Volume Specific ImmunoAdsorption

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Procedure: Large volume specific immunoadsorption
* Procedure: Double Filtration Plasmapheresis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient eligible for living donor ABO incompatible kidney transplantation Presenting an IsoAgglutinin immunoglobulin G titer (anti-A-B) between 1/8 and 1/128, before desensitization Patient older than 18 years Women of childbearing age must have a pregnancy test before starting the study and undergoing study. They must take an effective and acceptable method of contraception before starting the study and throughout the study period. Sexually active men should use a condom throughout the course of the study Patient able to sign an informed consent form Patient affiliated with a social security scheme Exclusion Criteria: Presence of anti-HLA (Human Leucocyte Antigens) allo-antibodies Patient with comorbidities that prevent desensitization protocols Women who are pregnant, or who may become pregnant or breastfeeding women History of hypersensitivity related to a component of the apheresis membrane Subjects under legal protection Subjects participating in another interventional research protocol or in an exclusion period from another interventional research protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Large volume specific immunoadsorption<br>1 to 2 sessions of large volume specific immunoadsorption according to the initial isoagglutinin titer. | Procedure: Large volume specific immunoadsorption<br>* 1 to 2 sessions of large volume specific immunoadsorption using GLYCOSORB®-ABO column<br>|
| Experimental: Double Filtration Plasmapheresis<br>1 to 5 sessions of double filtration plasmapheresis according to the initial isoagglutinin titer. | Procedure: Double Filtration Plasmapheresis<br>* 1 to 5 sessions of double filtration plasmapheresis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success rate | % of subjects with the targeted isoagglutinin titer (≤1/4) before transplantation with less than 5 DFPP sessions (for the DFPP arm) or 2 large plasma volume specific immunoadsorption sessions (for the specific immunoadsorption arm) | the day of transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differential cost-efficacy ratio of support for patients receiving a live donor kidney transplant Incompatible ABO and benefiting from a desensitization procedure | Direct medical costs ( treatments costs, costs of hospital stays, costs of outpatient cares) will be evaluated from the society point of view. A cost-efficacy analysis, comparative of medical consequences, measured in terms of number of complications related to the technique and post surgical at 7 months, and the economic consequences will be realized. | 7 months | 
| Surgical complication rate during the desensitization sessions | % of subjects with surgical complications during the desensitization sessions | From the first desensitization session to the last one, assessed up to 10 days | 
| Surgical complication rate during the transplantation surgery | % of subjects with surgical complications during the transplantation surgery | During the transplantation surgery | 
| Thrombotic complication rate during the desensitization sessions | % of subjects with thrombotic complications during the desensitization sessions | From the first desensitization session to the last one, assessed up to 10 days | 
| Thrombotic complication rate 1 week after transplantation surgery | % of subjects with thrombotic complications until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Rate of bleeding and/or hematoma on vascular access during the desensitization sessions | % of subjects with bleeding and/or hematoma on vascular access during the desensitization sessions | From the first desensitization session to the last one, assessed up to 10 days | 
| Rate of hematoma occurrence during the transplantation surgery | % of subjects with hematoma during the transplantation surgery | During the transplantation surgery | 
| Rate of occurrences of hemorrhage away from vascular access during the desensitization sessions | % of subjects with hemorrhage away from vascular access during the desensitization sessions | From the first desensitization session to the last one, assessed up to 10 days | 
| Rate of occurrences of allergy to the components of the membrane or of the blood circuit (tube set) during the desensitization sessions | % of subjects with allergy to the components of the membrane or of the blood circuit (tube set) during the desensitization sessions | From the first desensitization session to the last one, assessed up to 10 days | 
| Rate of occurrences of allergy to the components of the membrane or of the blood circuit (tube set) 1 week after transplantation surgery | % of subjects with allergy to the components of the membrane or of the blood circuit (tube set) until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Blood transfusion rate before transplantation | % of subjects who received blood transfusion before transplantation | Before transplantation | 
| Blood transfusion rate during the transplantation surgery | % of subjects who received blood transfusion during the transplantation surgery | During the transplantation surgery | 
| Blood transfusion rate 1 week after transplantation surgery | % of subjects who received blood transfusion until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Occurrence rate of deep vein or graft vein thrombosis during the transplantation surgery | % of subjects with deep vein or graft vein thrombosis during the transplantation surgery | During the transplantation surgery | 
| Graft ablation rate 1 week after transplantation surgery | % of subjects with graft ablation until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Complication rate on surgical area 1 week after transplantation surgery | % of subjects with complication on the surgical area until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Infectious complication rate 1 week after transplantation surgery | % of subjects with Infectious complication until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Need for dialysis session(s) 1 week after transplantation surgery | number of subjects for which one or several dialysis session(s) is necessary until 1 week after transplantation surgery | 1 week after transplantation surgery | 
| Graft rejection rate 1 month after transplantation surgery | % of subjects with graft rejection until 1 month after transplantation surgery | 1 month after transplantation surgery | 
| Graft rejection rate 3 months after transplantation surgery | % of subjects with graft rejection until 3 months after transplantation surgery | 3 months after transplantation surgery | 
| Graft rejection rate 6 months after transplantation surgery | % of subjects with graft rejection until 6 months after transplantation surgery | 6 months after transplantation surgery | 
| Renal function 1 month after transplantation surgery | creatinine 1 month after transplantation surgery | 1 month after transplantation surgery | 
| Renal function 3 months after transplantation surgery | creatinine 3 months after transplantation surgery | 3 months after transplantation surgery | 
| Renal function 6 months after transplantation surgery | creatinine 6 months after transplantation surgery | 6 months after transplantation surgery | 
| Change in hemostasis parameters from before the desensitization protocol to after | plasma level of fibrinogen clotting factors | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | plasma level of factor XIII | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | plasma level of thrombin-antithrombin complex | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | plasma level of platelet secretion proteins (sCD40L, PF4) | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | plasma level of ADAMTS13 metalloprotease | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | Von Willebrand factor (cleaved form) | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | blood level of platelet-monocyte complexes | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | blood level of platelet-neutrophil polynuclear complexes | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | endogenous thrombin potential | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 
| Change in hemostasis parameters from before the desensitization protocol to after | peak thrombin | the day of the first desensitization session (just before the session) and the day after the last desensitization session (up to 11 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABO incompatible kidney transplantation, Desensitization, Double Filtration PlasmaPherisis (DFPP), Specific immunoadsorption, Living donor kidney transplantation