Clinical trial NCT02120482: Combined Apheresis for ABO-incompatible Transplantation - a Pilot Study
Official title: Semiselective Immunoadsorption and Membrane Filtration for Desensitization in ABO-incompatible Kidney Transplantation - a Phase 2 Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Decreased Immunologic Activity
Antibody-mediated Rejection
Keywords: ABO isoagglutinins
ABO incompatible transplantation
immunoadsorption
membrane filtration
plasmapheresis
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
Collaborators: name: Elisabethinen Hospital
First posted: 2014-04-22
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: -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.

Eligibility criteria: 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

Primary outcomes:
measure: The incidence of antibody-mediated rejection (AMR) within three months after transplantation
timeFrame: First three months after transplantation
Secondary outcomes:
measure: Successful desensitization for ABOi transplantation
timeFrame: Day of transplantation
measure: Kidney function
timeFrame: First six months after transplantation
measure: Rate of cellular rejection
timeFrame: First six months after transplantation
measure: Graft survival
timeFrame: First six months after transplantation
measure: Patient survival
timeFrame: First six months after transplantation
measure: Reduction in flow-cytometric ABO-specific IgM
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in flow-cytometric ABO-specific IgG
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in flow-cytometric ABO-specific IgG subclass III
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in ABO-specific IgM antibody titers
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in ABO-specific IgG antibody titers
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in serum IgM
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in serum IgG
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction of serum IgG subclasses I-IV
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction of classical complement key component C1q
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction of complement component C3
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction of complement component C4
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction in complement functionality assessed by CH50 activity
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Reduction of classical complement functionality assessed by Luminex HLA-single bead assay technology
timeFrame: Pre and post apheresis treatment and 1, 2, 4 weeks and 3 and 6 months post transplantation
measure: Delayed graft function
timeFrame: First week post transplantation
measure: Surgical complications
timeFrame: First month after transplantation
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Division of Medicine III, Dpt. of Nephrology and Dialysis, Medical University Vienna
Study officials:
affiliation: Medical University Vienna, Division of Medicine III, Dpt. of Nephrology and Dialysis
name: Georg A Böhmig, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eskandary F, Wahrmann M, Biesenbach P, Sandurkov C, Konig F, Schwaiger E, Perkmann T, Kunig S, Derfler K, Zlabinger GJ, Bohmig GA. ABO antibody and complement depletion by immunoadsorption combined with membrane filtration--a randomized, controlled, cross-over trial. Nephrol Dial Transplant. 2014 Mar;29(3):706-14. doi: 10.1093/ndt/gft502. Epub 2013 Dec 29.
citation: Wahrmann M, Schiemann M, Marinova L, Kormoczi GF, Derfler K, Fehr T, Stussi G, Bohmig GA. Anti-A/B antibody depletion by semiselective versus ABO blood group-specific immunoadsorption. Nephrol Dial Transplant. 2012 May;27(5):2122-9. doi: 10.1093/ndt/gfr610. Epub 2011 Nov 15.