Combined Apheresis for ABO-incompatible Transplantation - a Pilot Study

Study Overview
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Brief Summary
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Recipient desensitization is a prerequisite for successful ABO-incompatible kidney transplantation (ABOi-KTX). Published desensitization protocols commonly include the use of plasmapheresis or selective (i.e. antigen-specific) immunoadsorption (IA), together with distinct immunomodulatory measures (e.g. CD20 antibody rituximab). Selective IA represents an efficient but cost-intensive therapy. An alternative could be the use of semi-selective (non-antigen-specific) IA. Even though highly efficient in depleting ABO-specific IgG, semi-selective IA may only marginally affect levels of ABO-specific IgM, which might - due to the strong complement activating potential of this Ig class - exhibit a potential risk for (hyper)acute antibody-mediated rejection (Wahrmann et al. 2012, Nephrol Dial Transplant). In a randomized crossover trial (Eskandary et al. 2014, Nephrol Dial Transplant; www.clinicaltrials.gov, NCT01698736) we have recently shown that the combination of semi-selective IA together with membrane filtration, a technique primarily used in the field of LDL apheresis, can yield excellent elimination of both IgM and IgG reactivities, as well as essential macromolecules such as the classical complement key component C1q. In this two-center phase 2 pilot study (N=10) we plan to evaluate the safety and efficacy of this alternative desensitization strategy in ABOi-KTX.

Detailed Description
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-Background and study aims ABO-incompatible living donor kidney transplantation (ABOi-KTX) offers the possibility to expand the donor pool by approximately 30%. A variety of different desensitization protocols were shown to enable successful transplantation across major ABO barriers. In this context, apheresis for antibody depletion represents the therapeutic mainstay. Two distinct technical principles, plasmapheresis and ABO antigen-specific immunoadsorption, were shown to allow for excellent short- and intermediate-term outcomes. A particular technical advantage of immunoadsorption may be its high selectivity regarding antibody depletion, which precludes major losses of essential plasma constituents, including coagulation factors and albumin, even after treatment of large plasma volumes. Nevertheless, high treatment costs associated with the use of ABO-specific columns (that are not approved for reuse) and may limit their widespread clinical application. The efficiency of semi-selective immunoadsorption technologies regarding ABO antibody depletion and recipient desensitization is less well established. Theoretically, non-antigen-specific immunoglobulin depletion using protein A-, GAM peptide-, or anti-Ig antibody-based adsorbers, could bring about several advantages, such as lower treatment costs associated with the use of reusable twin columns, and the potential to simultaneously deplete antibodies also against HLA antigens. In a randomized controlled crossover study including patients with autoimmune disease, we could demonstrate that the combination of semi-selective immunoadsorption together with membrane filtration can efficiently deplete both ABO-specific IgM and IgG and also has a significant impact on complement levels and functionality (Eskandary et al. 2014, Nephrology Dialysis Transplantation; www.clinicaltrials.gov, NCT01698736). In this non-randomized, open, uncontrolled phase II multi center (N=10) pilot study, we will investigate whether our novel concept of combined apheresis can be safely and efficiently applied in the context of ABOi-KTX. - Recipient desensitization Four weeks before scheduled transplantation, patients will receive CD20 antibody rituximab (357mg/m2). Two weeks before ABOi-KTX baseline triple immunosuppression with tacrolimus (trough level 12-15 ng/mL), mycophenolate-mofetil (2g daily) and steroids (25mg daily) will be started. IL-2 receptor antibody basiliximab (20 mg) will be administered directly before and four days after KTX. Combined apheresis treatments (6-9) will be started 1-2 weeks before transplantation (One week if initial ABO-antibody titers are below 1:512, two weeks if initial ABO-antibody titers are ≥1:512). Instead of ABO-specific immunoadsorption columns (Glycosorb® AB-columns, Glycorex®, Lund, Sweden) we will use GAM-146 synthetic peptide columns (Globaffin®, Fresenius Medical Care, Bad Homburg, Germany). To optimize antibody and complement elimination a membrane filter will be connected to the circuit (MONET®, Fresenius Medical Care, Bad Homburg, Germany) during every second treatment [targeted pre-transplant antibody titers: <1:16 (IgG); <1:8 (IgM)]. Whenever reaching target titers is not possible, the treatment can be pursued by using antigen-specific immunoadsorption (Five to nine serial treatments including one immediately pre-transplant). If this treatment also fails to reach sufficiently low antibody titers, transplantation will not be carried out. In case of hypofibrinogenemia (<100 mg/dL) 2-4 units of fresh frozen plasma (pooled or single donor) will be administered. - Post transplantation management Postoperative management will adhere to center standard. ABO-antibody titers will be determined thrice weekly during the first weeks post KTX, after four weeks, three months and after six months. On-demand combined apheresis will only be performed if postoperative titers rise to >1:16 during the first week or >1:32 during the second week post KTX, or in case of an antibody-mediated rejection. A protocol biopsy will be performed on the 7th-10th day after transplantation. Prophylactic treatment with valacyclovir and trimethoprim/sulfamethoxazole will be carried out for six months. Patients will be regularly seen in our outpatient clinic according to center standard.

Official Title
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Semiselective Immunoadsorption and Membrane Filtration for Desensitization in ABO-incompatible Kidney Transplantation - a Phase 2 Pilot Study

Conditions
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Decreased Immunologic Activity, Antibody-mediated Rejection

Intervention / Treatment
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* Device: Combined apheresis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligibility for living donor ABO-incompatible kidney transplantation according to center standard Age >18 years Signed written informed consent Negative cytotoxic and flow-cytometric crossmatch Exclusion Criteria: Age<18 years No signed written informed consent Blood group AB (no isoagglutinins) Pregnant and breastfeeding women HLA-sensitized patients (i.e. patients with preformed antibodies against donor HLA antigens) Positive cytotoxic and flow-cytometric crossmatch Severe blood coagulation disorder precluding the use of membrane filtration or immunoadsorption Initial serum fibrinogen <200mg/dL IgA deficiency Any severe disease (e.g. severe infection) precluding ABOi-KTX Heparin intolerance Polysulfone intolerance Participation in any other intervention trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined apheresis<br>Patients will be treated by semiselective immunoadsorption combined with membrane filtration | Device: Combined apheresis<br>* Semiselective immunoadsorption combined with membrane filtration<br>* Other names: GLOBAFFIN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of antibody-mediated rejection (AMR) within three months after transplantation | Antibody-mediated rejection according to Banff 2013 criteria | First three months after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful desensitization for ABOi transplantation | Reduction of ABO antigen-specific IgG titers to <1:16 and IgM titers to <1:8 | Day of transplantation | 
| Kidney function | Evaluation of estimated GFR and serum creatinine trajectories | First six months after transplantation | 
| Rate of cellular rejection | The incidence of cellular rejection according to Banff 2011 histological classification | First six months after transplantation | 
| Graft survival | Graft loss will be determined as the need for permanent dialysis | First six months after transplantation | 
| Patient survival | Patient death within the first six months will be documented | First six months after transplantation | 
| Reduction in flow-cytometric ABO-specific IgM | The efficacy of percent ABO-specific IgM reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in flow-cytometric ABO-specific IgG | The efficacy of percent ABO-specific IgG reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in flow-cytometric ABO-specific IgG subclass III | The efficacy of percent ABO-specific IgG subclass III reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in ABO-specific IgM antibody titers | The efficacy of ABO-specific IgM titer reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in ABO-specific IgG antibody titers | The efficacy of ABO-specific IgG titer reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in serum IgM | The efficacy of serum IgM reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in serum IgG | The efficacy of serum IgG reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction of serum IgG subclasses I-IV | The efficacy of serum IgG subclass I-IV reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction of classical complement key component C1q | The efficacy of serum C1q reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction of complement component C3 | The efficacy of serum C3 reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction of complement component C4 | The efficacy of serum C4 reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction in complement functionality assessed by CH50 activity | The efficacy of CH50 activity reduction will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Reduction of classical complement functionality assessed by Luminex HLA-single bead assay technology | The efficacy of the reduction in classical complement functionality will be assessed at baseline and before and after each apheresis treatment and post transplantation. | Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation | 
| Delayed graft function | The incidence of delayed graft function will be assessed as the rate of patients with the need for dialysis during the first week post transplantation | First week post transplantation | 
| Surgical complications | Incidence of surgical complications, such as bleeding, arterial/venous graft thrombosis, will be assessed during the first month post transplantation | First month after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABO isoagglutinins, ABO incompatible transplantation, immunoadsorption, membrane filtration, plasmapheresis