Differential Effect of Bortezomib on HLA Class I and Class II Antibody

Philogene, Mary Carmelle; Sikorski, Paul; Montgomery, Robert A.; Leffell, Mary S.; Zachary, Andrea A.

doi:10.1097/tp.0000000000000132

Cited by 49 publications

(34 citation statements)

References 25 publications

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Section: Discussionsupporting

confidence: 92%

“…Consistent with previous studies [45–47], reduction in iDSA with bortezomib treatment was more effective for Class I antibodies than Class II. In vitro studies have shown that bortezomib treated lymphocytes [47] and multiple myeloma cells [48] preferentially reduce HLA Class I expression and decrease stimulation for continued Class I antibody production [47]. The effect of bortezomib on cell surface expression of HLA Class I but not Class II may explain why this therapy has not produced dramatic recovery of renal function or biopsy findings in many patients with late AMR associated with HLA Class II DSAs [22, 49].…”

Section: Discussionsupporting

confidence: 92%

“…Notably, patients treated for AMR with bortezomib have shown improvement in eGFR despite the persistence of DSAs [25, 26]. This suggests that bortezomib has additional immunomodulatory effects that may impact renal recovery from AMR [35–37]. In this case series, we aimed to report the safety and utility of bortezomib for stabilizing renal function, improving biopsy findings, and reducing DSA burden in 7 pediatric kidney transplant patients with treatment refractory C4d+AMR.…”

Section: Introductionmentioning

confidence: 99%

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Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection

et al. 2016

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Background Current therapeutic strategies to effectively treat antibody-mediated rejection (AMR) are insufficient. Thus, we aimed to determine the benefit of a therapeutic protocol using bortezomib for refractory C4d+ AMR in pediatric kidney transplant patients. Methods We examined 7 patients with treatment refractory C4d+ AMR. Immunosuppression included antithymocyte globulin or anti-CD25 monoclonal antibody for induction therapy with maintenance corticosteroids, calcineurin inhibitor, and antimetabolite. Estimated glomerular filtration rate (eGFR) calculated by the Schwartz equation, biopsy findings assessed by 2013 Banff criteria, and human leukocyte antigen (HLA) donor specific antibodies (DSA) performed using the Luminex single antigen bead assay were monitored pre- and post- bortezomib therapy. Results Seven patients (86% male, 86% with ≥6/8 HLA mismatch, and 14% with pre-formed DSA) age 5 to 19 (median 15) years developed refractory C4d + AMR between 1–145 (median 65) months post-transplantation. All patients tolerated bortezomib. One patient had allograft loss. Of the six patients with surviving grafts (86%), the mean pre-bortezomib eGFR was 42 mls/min/1.73 m2 and the mean 1 year post-bortezomib eGFR was 53 mls/min/1.73m2. Five of 7 (71%) had improvement of histological findings of AMR, C4d staining, and/or acute cellular rejection. Reduction in HLA DSAs was more effective for Class I than Class II. Conclusions Bortezomib appears safe and may correlate with stabilization of eGFR in pediatric kidney transplant patients with refractory C4d+ AMR.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection

et al. 2016

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“…Typically, the goal of therapy is to reduce the antibody level so the FCXM is negative or lower than a predetermined cutoff. Many different protocols have been used with varying success; however, most combine plasmapheresis, IVIG, rituximab, bortezomib, and early initiation of maintenance immunosuppression several weeks before the transplant (21,(34)(35)(36)(37). Single-center case series using these approaches for transplant have shown that 25%-50% of transplants will have an early AMR (28,36,(38)(39)(40).…”

Section: Advances In Desensitization Of the Highly Sensitized Candidatementioning

confidence: 99%

Approach to the Highly Sensitized Kidney Transplant Candidate

Keith

Vranic

2016

Clinical Journal of the American Society of Nephrology

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For patients with ESRD, kidney transplant offers significant survival and quality-of-life advantages compared with dialysis. But for patients seeking transplant who are highly sensitized, wait times have traditionally been long and options limited. The approach to the highly sensitized candidate for kidney transplant has changed substantially over time owing to new advances in desensitization, options for paired donor exchange (PDE), and changes to the deceased-donor allocation system. Initial evaluation should focus on determining living-donor availability because a compatible living donor is always the best option. However, for most highly sensitized candidates this scenario is unlikely. For candidates with an incompatible donor, PDE can improve the prospects of finding a compatible living donor but for many highly sensitized patients the probability of finding a match in the relatively small pools of donors in PDE programs is limited. Desensitization of a living donor/recipient pair with low levels of incompatibility is another reasonable approach. But for pairs with high levels of pathologic HLA antibodies, outcomes after desensitization for the patient and allograft are less optimal. Determining the degree of sensitization by calculated panel-reactive antibody (cPRA) is critical in counseling the highly sensitized patient on expected wait times to deceased-donor transplant. For candidates with a high likelihood of finding a compatible deceased donor in a reasonable time frame, waiting for a kidney is a good strategy. For the candidate without a living donor and with a low probability of finding a deceased-donor match, desensitization on the waiting list can be considered. The approach to the highly sensitized kidney transplant candidate must be individualized and requires careful discussion among the transplant center, patient, and referring nephrologist.Clin J Am Soc Nephrol 11: 684-693, 2016. doi: 10.2215/CJN.05930615 Case PresentationA 38-year-old black man with type 2 diabetes and ESRD due to diabetic nephropathy presented for evaluation for a second kidney transplant. He was receiving hemodialysis for 1 year before undergoing his first deceased-donor kidney transplant in 1997. His immediate post-transplant course was uncomplicated, without known episodes of rejection. The graft began to fail about 4 years before his resumption of dialysis. A renal allograft biopsy at that time showed calcineurin inhibitor toxicity and chronic allograft nephropathy but no acute rejection. He resumed peritoneal dialysis in 2010, at which time his immunosuppression was weaned to low-dose prednisone, 5 mg daily. He is blood type A, which portends wait times of 3-4 years in our organ procurement organization (OPO), the geographically defined unit of organ allocation. An historical panel-reactive antibody (PRA) on full immunosuppression was 0% but repeat testing at current evaluation reveals a calculated panel-reactive antibody (cPRA) of 100% with multiple HLA antibodies against class II antigens. See candidate HLA t...

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“…63 The finding that bortezomib has little effect on HLA class II antibody production may explain its lack of efficacy for late or chronic AMR. 64 …”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Antibody-mediated rejection: New approaches in prevention and management

Montgomery

Loupy

Segev

2018

American Journal of Transplantation

112

102

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Estimated Time to Complete this Activity: 1.25 hours OverviewThis article reviews the pathophysiology of antibody-mediated rejection (AMR) with emphasis on the role of complement in allograft injury. It reviews the required features for a definitive diagnosis of AMR according to the latest Banff criteria, which incorporate recent findings delineating the complex spectrum of AMR and the diverse phenotypes seen. Clinical data on current and investigational treatments are summarized, and strategies to improve outcomes are presented. Lastly, a discussion of relevant predictive and surrogate endpoints provides a framework for future studies. Target AudienceThis activity has been designed to meet the educational needs of physicians, surgeons, scientists, nurses, organ procurement personnel, and pharmacists who care for patients with AMR. Educational ObjectivesAfter participating in this educational initiative, the participant should be better able to:• Explain the significance of activation of the complement system in the development of AMR Statement of SupportThis activity is jointly provided by RMEI Medical Education, LLC and Postgraduate Institute for Medicine. This activity is supported by an independent medical educational grant from Shire. For questions, please contact PIM at www.pimed.com. Joint Accreditation StatementIn support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and RMEI Medical Education, LLC. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Continuing Medical EducationThe Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s) TM . Physicians should claim only the credit commensurate with the extent of their participation in the activity. Continuing Pharmacy EducationPostgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.Postgraduate Institute for Medicine designates this continuing education activity for 1.25 contact hour(s) (0.125 CEUs) of the Accreditation Council for Pharmacy Education.[Correction added on 22 March, 2018, after first online publication: The accreditation statement and CEUs were updated.] (Universal Activity Number -0809-9999-17-584-H01-P) Please note: If you participated in the activity with UAN 0809-9999-16-209-L01-P, you are not able to claim credit for this activity.For Pharmacists: Upon successfully completing the post-test with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service. Activity Type: Application Method of Participation and Request for CreditThere are no fees for participating and receiving CME credit for this...

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Differential Effect of Bortezomib on HLA Class I and Class II Antibody

Abstract: These data indicate that bortezomib reduces HLA class I antibody more effectively than class II antibody. This difference may be due to the reduced expression of class I molecules resulting from treatment with this proteasome inhibitor.

Cited by 49 publications

References 25 publications

Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection

Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection

Approach to the Highly Sensitized Kidney Transplant Candidate

Antibody-mediated rejection: New approaches in prevention and management

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