Combined Apheresis for ABO-incompatible Transplantation - a Pilot Study

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

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.

Study Overview

• Status: Terminated
• Conditions: Antibody-mediated Rejection; Decreased Immunologic Activity
• Intervention / Treatment: Device: Combined apheresis

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Division of Medicine III, Dpt. of Nephrology and Dialysis, Medical University Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combined apheresis; Patients will be treated by semiselective immunoadsorption combined with membrane filtration	Device: Combined apheresis; Semiselective immunoadsorption combined with membrane filtration; Other Names: MONET; GLOBAFFIN

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Elisabethinen Hospital
• Investigators: Principal Investigator: Georg A Böhmig, MD, Medical University Vienna, Division of Medicine III, Dpt. of Nephrology and Dialysis

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Website of the VIETAC Lab

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): July 31, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: April 18, 2014
• First Submitted That Met QC Criteria: April 18, 2014
• First Posted (Estimate): April 22, 2014

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 22, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: immunoadsorption; plasmapheresis; ABO isoagglutinins; ABO incompatible transplantation; membrane filtration
• Other Study ID Numbers: EK2123/2013