Introduction
(Article introduction authored by Conquest Editorial Team)
Antibody-mediated rejection (AMR) has been- recognized as a prominent contributor to acute and chronic kidney allograft dysfunction, eventually leading to graft failure.
Despite substantial progress in understanding its mechanisms, the incidence of graft failure remains high, with limited improvement since the late 1980s.
Current treatment guidelines advocate a multifaceted approach, including plasmapheresis, intravenous immunoglobulin, anti-CD20 antibodies, and lymphocyte-depleting therapies.
But their effectiveness in altering long-term outcomes is limited, and no FDA-approved medications for AMR exist.
The emergence of novel therapies and the implementation of surveillance protocols for early detection offer promising avenues to address this persistent challenge. Ongoing clinical trials hold the potential to further enhance the management of AMR in kidney transplant recipients.
In this article, we review the emerging therapies for managing AMR in kidney transplantation along with the ongoing clinical trials.
CARFILZOMIB
Carfilzomib, a second-generation irreversible proteasome inhibitor similar to Bortezomib.
It has been used off-label in relapsed or refractory multiple myeloma (MM) treatment.
Bortezomib, an FDA-approved proteasome inhibitor for MM, has also been used off-label as a desensitizing agent in sensitized kidney transplant recipients by inducing apoptosis of plasma cells to reduce alloantibody production.
Several studies have examined Bortezomib’s – effectiveness in antibody-mediated rejection (AMR)
Studies reported adverse events including fatigue, diarrhea, peripheral neuropathy, thrombocytopenia, neutropenia, and infections, including cases of septic shock-related deaths.
INTERLEUKIN-6 TARGETED THERAPIES
Tocilizumab
Tocilizumab, a recombinant humanized monoclonal antibody targeting the interleukin-6 receptor (IL-6R), inhibits IL-6 signaling crucial for B- and T-cell activity and linked to transplant rejection pathways. FDA-approved for rheumatoid arthritis and juvenile idiopathic arthritis, its use carries infection risks (e.g., tuberculosis, fungal, bacterial, viral) and complications like gastrointestinal perforation and transaminase elevation.
A phase I/II trial showed tocilizumab and IVIG to be a safe and effective desensitization strategy in sensitized kidney transplant recipients, reducing DSA titer and preventing AMR.
Tocilizumab, used in the treatment of acute antibody-mediated rejection (AMR) in kidney transplant recipients, has shown some positive effects, including renal function improvement and reduced donor-specific antibody (DSA) titers in some cases. However, recurrence of rejection is more common in patients with less than 6 months of tocilizumab therapy.
Clazakizumab
Clazakizumab, a potent, long-acting monoclonal antibody binding to IL-6, has shown effectiveness in reducing inflammatory markers and cytokines in sensitized kidney transplant recipients.
It is being investigated in solid organ transplantation and arthritis. A phase 2 study in refractory active AMR patients demonstrated clazakizumab’s potential to stabilize eGFR, reduce DSA titers, and alleviate graft inflammation.
A phase 3 trial (IMAGINE) is now recruiting participants globally to further evaluate clazakizumab in chronic active AMR.
Daratumumab
Daratumumab is an FDA-approved human monoclonal antibody targeting CD38-expressing plasma cells, also including regulatory T- and B-cells, used for multiple myeloma.
It exerts its effect through various immune mechanisms but can lead to adverse events like infusion reactions, hypogammaglobulinemia, myelosuppression, and infections.
Daratumumab can interfere with cross-matching and RBC antibody screening due to its binding to CD38 on RBCs, potentially leading to false-positive results. Resistance and the development of antidrug antibodies are concerns.
A study in nonhuman primates showed significant DSA titer reduction when used as a desensitizing agent for AMR management in combined heart-kidney transplant recipients, although the effect was not maintained in the long term.
Belimumab
Belimumab, a humanized anti-B lymphocyte stimulator (BLyS) monoclonal antibody.
It is FDA-approved for systemic lupus erythematosus and has been effective in lupus nephritis.
BLyS plays a role in promoting B-cell maturation and activation, with high serum BLyS levels associated with increased risk of antibody-mediated rejection (AMR) in kidney transplant recipients.
Adverse events with belimumab include gastrointestinal upset, dizziness, infection, depression, and diabetes, with rare cases of progressive multifocal leukoencephalopathy reported.
Studies have explored its use in preventing AMR, demonstrating effectiveness without increased infection risk.
Its application in active AMR cases remains limited but has shown promise in reducing DSA and improving graft function in some individuals.
Imlifidase
Imlifidase, derived from Streptococcus pyogenes, cleaves human IgG antibodies, reducing comple- ment-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, B-cell receptor activity, and natural killer cell function.
It is mainly evaluated in desensitization protocols and being studied in a clinical trial for chronic or active antibody-mediated rejection (AMR) management in kidney transplant recipients.
Potential limitations include the risk of antibody rebound, including anti-imlifidase antibodies, donor-specific antibodies, and total IgG.
Drug interactions may occur, affecting co-administered antibody-based therapies, and proper separation intervals should be considered to maintain therapy efficacy.
NEW CD-20 AGENTS Ofatumumab
Ofatumumab is an alternative anti-CD20 agent that is approved by the FDA for the treatment of relapsing multiple sclerosis.
A case report of a sensitized combined heart–kidney transplant recipient who failed her first heart transplant due to cardiac allograft vasculopathy was treated with TPE, IVIG, ofatumumab, and tocilizumab as desensitization therapy.
During the first-year follow-up after transplant, she maintained good cardiac and kidney grafts function. No episodes of rejection were reported, but she did develop persistent BK viremia
Obinutuzumab
Obinutuzumab, a glyco-engineered type II anti-CD20 monoclonal antibody, offers more profound B-cell depletion compared to rituximab, the current standard in AMR treatment.
In highly sensitized kidney transplant candidates, obinutuzumab shows promise for B-cell depletion but has inconsistent effects on anti-HLA antibodies. It’s mainly used as an alternative in refractory cases or for rituximab-intolerant patients, and direct comparisons with rituximab are limited.
However, cases of rituximab-resistant AMR have reported successful reductions in DSA titers and improved graft function with obinutuzumab.
Inebilizumab
Inebilizumab is a CD19 targeting agent. CD19 is expressed in B-cells; inebilizumab targets these B-cells and depletes them. It has been approved in 2020 for use in neuromyelitis [63].
It has been studied for use in highly sensitized patients awaiting first or second kidney transplants from deceased donors, but the study has been withdrawn due to no recruitment
Conclusions
Traditional treatments for AMR remain suboptimal, resulting in elevated rates of graft loss and unfavorable patient results. It is evident that further research is necessary to establish the most effective approach to treating AMR.
Emerging therapies that focus on unique pathways within the AMR pathogenic process offer hope, but it is essential to conduct randomized studies.
This is particularly crucial due to the scarcity of randomized studies with sufficient statistical significance to compare the safety and effectiveness of these innovative treatments.
References
1. Racusen, L.C.; Solez, K.; Colvin, R.B.; Bonsib, S.M.; Castro, M.C.; Cavallo, T.; Croker, B.P.; Demetris, A.J.; Drachenberg, C.B.; Fogo, A.B.; et al. The Banff 97 Working Classification of Renal Allograft Pathology. Kidney Int. 1999, 55, 713–723. [Google Scholar] [CrossRef][Green Version]
2. Van Loon, E.; Bernards, J.; Van Craenenbroeck, A.H.; Naesens, M. The Causes of Kidney Allograft Failure: More Than Alloimmunity. A Viewpoint Article. Transplantation 2020, 104, e46–e56. [Google Scholar] [CrossRef]
3. Scherberger,R.R.;Kaess,H.;Brückner,S.Studiesontheactionofananticholinergicagentincombinationwithatranquilizerongastricjuicesecretioninman.Arzneimittelfor- schung 1975, 25, 1460–1463. [Google Scholar]
4. Hart, A.; Schladt, D.P.; Matas, A.J.; Itzler, R.; Israni, A.K.; Kasiske, B.L. Incidence, Risk Factors, and Long-term Outcomes Associated with Antibody-mediated Rejection—The Long-term Deterioration of Kidney Allograft Function (DeKAF) Prospective Cohort Study. Clin. Transpl. 2021, 35, e14337. [Google Scholar] [CrossRef]
5. Lamb,K.E.;Lodhi,S.;Meier-Kriesche,H.-U.Long-TermRenalAllograftSurvivalintheUnitedStates:ACriticalReappraisal.Am.J.Transplant.2011,11,450–462.[Google Scholar] [CrossRef]
6. Kasiske,B.L.;Zeier,M.G.;Chapman,J.R.;Craig,J.C.;Ekberg,H.;Garvey,C.A.;Green,M.D.;Jha,V.;Josephson,M.A.;Kiberd,B.A.;etal.KDIGOClinicalPracticeGuideline for the Care of Kidney Transplant Recipients: A Summary. Kidney Int. 2010, 77, 299–311. [Google Scholar] [CrossRef][Green Version]
7. Schinstock, C.A.; Mannon, R.B.; Budde, K.; Chong, A.S.; Haas, M.; Knechtle, S.; Lefaucheur, C.; Montgomery, R.A.; Nickerson, P.; Tullius, S.G.; et al. Recommended Treatment for Antibody-Mediated Rejection after Kidney Transplantation: The 2019 Expert Consensus from the Transplantion Society Working Group. Transplantation 2020, 104, 911–922. [Google Scholar] [CrossRef]
8. Bross, P.F.; Kane, R.; Farrell, A.T.; Abraham, S.; Benson, K.; Brower, M.E.; Bradley, S.; Gobburu, J.V.; Goheer, A.; Lee, S.-L.; et al. Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma. Clin. Cancer Res. 2004, 10, 3954–3964. [Google Scholar] [CrossRef][Green Version]
9. Lemy,A.;Toungouz,M.;Abramowicz,D.Bortezomib:ANewPlayerinPre-andPost-TransplantDesensitization?Nephrol.Dial.Transplant.2010,25,3480–3489.[Google Scholar] [CrossRef][Green Version]
10. Shah, N.; Meouchy, J.; Qazi, Y. Bortezomib in Kidney Transplantation. Curr. Opin. Organ Transplant. 2015, 20, 652–656. [Google Scholar] [CrossRef]
11. Puttarajappa, C.; Shapiro, R.; Tan, H.P. Antibody-Mediated Rejection in Kidney Transplantation: A Review. J. Transplant. 2012, 2012, 193724. [Google Scholar] [CrossRef][Green Version]
12. Kim, M.; Martin, S.T.; Townsend, K.R.; Gabardi, S. Antibody-Mediated Rejection in Kidney Transplantation: A Review of Pathophysiology, Diagnosis, and Treatment Options. Pharmacotherapy 2014, 34, 733–744. [Google Scholar] [CrossRef]
13. Jordan, S.C.; Ammerman, N.; Choi, J.; Huang, E.; Peng, A.; Sethi, S.; Najjar, R.; Kim, I.; Toyoda, M.; Kumar, S.; et al. The Role of Novel Therapeutic Approaches for Prevention of Allosensitization and Antibody-Mediated Rejection. Am. J. Transplant. 2020, 20, 42–56. [Google Scholar] [CrossRef]
14. Freedman, J.E. CD40-CD40L and Platelet Function: Beyond Hemostasis. Circ. Res. 2003, 92, 944–946. [Google Scholar] [CrossRef] 15. Dubois, E.A.; Cohen, A.F. Eculizumab. Br. J. Clin. Pharmacol. 2009, 68, 318–319. [Google Scholar] [CrossRef][Green Version]
16. Djamali, A.; Kaufman, D.B.; Ellis, T.M.; Zhong, W.; Matas, A.; Samaniego, M. Diagnosis and Management of Antibody-Mediated Rejection: Current Status and Novel Approaches. Am. J. Transplant. 2014, 14, 255–271. [Google Scholar] [CrossRef][Green Version]
17. Gupta, G.; Abu Jawdeh, B.G.; Racusen, L.C.; Bhasin, B.; Arend, L.J.; Trollinger, B.; Kraus, E.; Rabb, H.; Zachary, A.A.; Montgomery, R.A.; et al. Late Antibody-Mediated Rejection in Renal Allografts: Outcome after Conventional and Novel Therapies. Transplantation 2014, 97, 1240–1246. [Google Scholar] [CrossRef]
18. Ezekian, B.; Schroder, P.M.; Mulvihill, M.S.; Barbas, A.; Collins, B.; Freischlag, K.; Yoon, J.; Yi, J.S.; Smith, F.; Olaso, D.; et al. Pretransplant Desensitization with Costimula- tion Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients. J. Am. Soc. Nephrol. 2019, 30, 2399–2411. [Google Scholar] [CrossRef]
19. Sacha,L.;Teuteberg,J.J.;Zeevi,A.;Bermudez,C.;Kormos,R.;Ensor,C.;McDyer,J.;Shullo,M.A.CarfilzomibforRefractoryAntibodyMediatedRejectionandAllosensiti- zation in Heart Transplantation. J. Heart Lung Transplant. 2014, 33, S31. [Google Scholar] [CrossRef]
20. Pham, C.; Pierce, B.J.; Nguyen, D.T.; Graviss, E.A.; Huang, H.J. Assessment of Carfilzomib Treatment Response in Lung Transplant Recipients with Antibody-Mediated Rejection. Transplant. Direct 2021, 7, e680. [Google Scholar] [CrossRef]
