Prospective Iterative Trial of Proteasome Inhibitor-Based Desensitization

Woodle, E. Steve; Shields, A. R.; Ejaz, Nazia; Sadaka, Basma; Girnita, Alin; Walsh, R. C.; Alloway, Rita R.; Brailey, Paul; Cardi, M.; Jawdeh, Bassam G. Abu; Roy‐Chaudhury, Prabir; Govil, Amit; Mogilishetty, G.

doi:10.1111/ajt.13050

Cited by 138 publications

(139 citation statements)

References 22 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…However, approximately 25% of candidates with cPRA 100% (about 1400 candidates) were not compatible with even one donor in our simulation. These candidates will likely require additional attention, such as increasing the threshold (mean fluorescence intensity level) of HLA antibodies before considering the corresponding antigens unacceptable or desensitization therapy (29)(30)(31)(32) coupled with paired donor exchange (33,34). Some may not be candidates for transplant.…”

Section: Discussionmentioning

confidence: 99%

Allocating Deceased Donor Kidneys to Candidates with High Panel–Reactive Antibodies

Gebel

Kasiske

Gustafson

et al. 2016

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Background and objectives In December of 2014, the Organ Procurement and Transplant Network implemented a new Kidney Allocation System (KAS) for deceased donor transplant, with increased priority for highly sensitized candidates (calculated panel-reactive antibody [cPRA] .99%). We used a modified version of the new KAS to address issues of access and equity for these candidates.Design, setting, participants, & measurements In a simulation, 10,988 deceased donor kidneys transplanted into waitlisted recipients in 2010 were instead allocated to candidates with cPRA$80% (n=18,004). Each candidate's unacceptable donor HLA antigens had been entered into the allocation system by the transplant center. In simulated match runs, kidneys were allocated sequentially to adult ABO identical or permissible candidates with cPRA 100%, 99%, 98%, etc. to 80%. Allocations were restricted to donor/recipient pairs with negative virtual crossmatches.Results The simulation indicated that 2111 of 10,988 kidneys (19.2%) would have been allocated to patients with cPRA 100% versus 74 of 10,988 (0.7%) that were actually transplanted. Of cPRA 100% candidates, 74% were predicted to be compatible with an average of six deceased donors; the remaining 26% seemed to be incompatible with every deceased donor organ that entered the system. Of kidneys actually allocated to cPRA 100% candidates in 2010, 66% (49 of 74) were six-antigen HLA matched/zero-antigen mismatched (HLA-A, -B, and -DR) with their recipients versus only 11% (237 of 2111) in the simulation. The simulation predicted that 10,356 of 14,433 (72%) candidates with cPRA 90%-100% could be allocated an organ compared with 7.3% who actually underwent transplant.Conclusions Data in this simulation are consistent with early results of the new KAS; specifically, nearly 20% of deceased donor kidneys were (virtually) compatible with cPRA 100% candidates. Although most of these candidates were predicted to be compatible with multiple donors, approximately one-quarter are unlikely to receive a single offer.

show abstract

Section: Discussionmentioning

confidence: 99%

Allocating Deceased Donor Kidneys to Candidates with High Panel–Reactive Antibodies

Gebel

Kasiske

Gustafson

et al. 2016

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…102 A similar but transient reduction rate has also been observed for preformed anti-HLA antibodies in a prospective trial of PI-based desensitization. 103 Interestingly, Woodle et al 103 also reported a low rate of dnDSA formation (12.5%) in patients who were desensitized.…”

Section: The Effect Of B or Plasma Cell-targeted Therapy On Dsasmentioning

confidence: 99%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

View full text Add to dashboard Cite

The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

show abstract

“…Thus, other therapies are needed to target the antibody-producing plasma cells within bone marrow niches. Proteasome inhibitors such as bortezomib (76) and carfilzomib (77) may more effectively target metabolically active plasma cells. On its own, a single dose of bortezomib is insufficient to reduce Solid-phase assays to detect HLA antibodies, although quite sensitive, may not predict the true pathogenic potential of DSAs.…”

Section: Neutrophil Marginationmentioning

confidence: 99%

“…Figure 2 illustrates the mechanisms of allograft injury by HLA donor-specific antibodies, and provides exemplary histological images of AMR features in cardiac and renal allografts. His-DSA levels (78), but when bortezomib was combined with plasmapheresis and rituximab, 40% of renal transplant candidates with DSAs were successfully desensitized (76). Patients who undergo desensitization have higher rejection rates (79), but long-term outcomes are comparable to those of lower risk patients (80,81).…”

Section: Complement Depositionmentioning

confidence: 99%

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

Valenzuela¹,

Reed²

2017

Journal of Clinical Investigation

172

147

View full text Add to dashboard Cite

Prospective Iterative Trial of Proteasome Inhibitor-Based Desensitization

Cited by 138 publications

References 22 publications

Allocating Deceased Donor Kidneys to Candidates with High Panel–Reactive Antibodies

Allocating Deceased Donor Kidneys to Candidates with High Panel–Reactive Antibodies

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

Contact Info

Product

Resources

About