Early and Late Acute Antibody-Mediated Rejection Differ Immunologically and in Response to Proteasome Inhibition

Walsh, R. C.; Brailey, Paul; Girnita, Alin; Alloway, Rita R.; Shields, A. R.; Wall, G. E.; Sadaka, Basma; Cardi, M.; Tevar, Amit D.; Govil, Amit; Mogilishetty, G.; Roy‐Chaudhury, Prabir; Woodle, E. Steve

doi:10.1097/tp.0b013e318218e901

Cited by 143 publications

(152 citation statements)

References 22 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…We performed predefined stratified analyses to examine for the effect of RMM on outcomes considering certain biologically anticipated risk groups. Given the increasing evidence that class 2 antigen differences 9-11 and class 2 HLA antibodies [18][19][20] specifically affect graft survival, the effect of class 2 RMM versus only class 1 was explored, and we found that the presence of class 2 RMM was associated with graft loss, specifically in sensitized recipients. This information may be of value in further refining the classification of immunologic risk in recipients with RMM, such that unsensitized recipients with class 2 RMM may be considered at lower risk than their sensitized counterparts.…”

Section: Discussionmentioning

confidence: 99%

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Tinckam

Rose

Hariharan

et al. 2016

JASN

View full text Add to dashboard Cite

Kidney retransplantation is a risk factor for decreased allograft survival. Repeated mismatched HLA antigens between first and second transplant may be a stimulus for immune memory responses and increased risk of alloimmune damage to the second allograft. Historical data identified a role of repeated HLA mismatches in allograft loss. However, evolution of HLA testing methods and a modern transplant era necessitate re-examination of this role to more accurately risk-stratify recipients. We conducted a contemporary registry analysis of data from 13,789 patients who received a second kidney transplant from 1995 to 2011, of which 3868 had one or more repeated mismatches. Multivariable Cox proportional hazards modeling revealed no effect of repeated mismatches on all-cause or death-censored graft loss. Analysis of predefined subgroups, however, showed that any class 2 repeated mismatch increased the hazard of death-censored graft loss, particularly in patients with detectable panel-reactive antibody before second transplant (hazard ratio [HR], 1.15; 95% confidence interval [95% CI], 1.02 to 1.29). Furthermore, in those who had nephrectomy of the first allograft, class 2 repeated mismatches specifically associated with all-cause (HR, 1.30; 95% CI, 1.07 to 1.58) and death-censored graft loss (HR, 1.41; 95% CI, 1.12 to 1.78). These updated data redefine the effect of repeated mismatches in retransplantation and challenge the paradigm that repeated mismatches in isolation confer increased immunologic risk. We also defined clear recipient categories for which repeated mismatches may be of greater concern in a contemporary cohort. Additional studies are needed to determine appropriate interventions for these recipients. 27: 283327: -284127: , 201627: . doi: 10.1681 Kidney retransplantation is generally viewed to increase risk for immunologic damage and graft loss. The increased risk is attributed to the formation of T and B memory cells to mismatched HLA antigens in the original donors. Re-exposure to a repeated HLA antigen mismatched (RMM) in a subsequent donor potentially invokes alloimmune memory responses, resulting in earlier allograft damage and loss. J Am Soc NephrolThe nature and magnitude of this potential risk have changed with reanalysis over time. Whereas a number of studies have described worse allograft survival when repeated antigens are mismatched at the HLA-DR locus, 1-3 with RMM at class 1 (HLA-A or -B) not influencing outcomes, others have shown a beneficial effect of RMM on graft survival 4,5 or a neutral effect. 6,7 A more recent analysis showed an effect of class 1 RMM on graft survival, with no differences seen with class 2 RMM. 8

show abstract

Section: Discussionmentioning

confidence: 99%

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Tinckam

Rose

Hariharan

et al. 2016

JASN

View full text Add to dashboard Cite

show abstract

“…20,[24][25][26][27] This may explain the observed variation between centers about reported success frequencies of therapeutic response and graft outcomes. 6,18,[24][25][26] Therapeutic regimens for ABMR are similar to desensitization protocols and vary at different transplant centers. 4,6,18,19,23,24 They are costly and complex (Table 3).…”

Section: Monitoring Sensitized Patients After Transplantmentioning

confidence: 88%

“…Early therapeutic intervention and rapid reversal of the rejection is associated with improved graft survival compared with late intervention that may lead to refractory rejection and irreversible kidney damage. 26 Several factors affect the therapeutic response: time of ABMR diagnosis; type of desensitization and immunosuppressive antirejection regimens; level of graft dysfunction; other confounding factors such as coexisting or previous cellular rejection; transplant glomerulopathy; additional renal pathology such as focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and thrombotic microangiopathy; and poor drug compliance. 20,[24][25][26][27] This may explain the observed variation between centers about reported success frequencies of therapeutic response and graft outcomes.…”

Section: Monitoring Sensitized Patients After Transplantmentioning

confidence: 99%

“…26 Several factors affect the therapeutic response: time of ABMR diagnosis; type of desensitization and immunosuppressive antirejection regimens; level of graft dysfunction; other confounding factors such as coexisting or previous cellular rejection; transplant glomerulopathy; additional renal pathology such as focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and thrombotic microangiopathy; and poor drug compliance. 20,[24][25][26][27] This may explain the observed variation between centers about reported success frequencies of therapeutic response and graft outcomes. 6,18,[24][25][26] Therapeutic regimens for ABMR are similar to desensitization protocols and vary at different transplant centers.…”

Section: Monitoring Sensitized Patients After Transplantmentioning

confidence: 99%

See 1 more Smart Citation

Approach to Kidney Transplant in Sensitized Potential Transplant Recipients

Barbari

Abbas²,

Jaafar³

2012

Exp Clin Transplant

View full text Add to dashboard Cite

More than one-third of patients on waiting lists for kidney transplant are sensitized. Most have previously formed donor-specific and non-donorspecific serum antibodies and/or positive crossmatch by complement-dependent cytotoxity and/or flow cytometry. Two categories of alloantibodies include antibodies against major histocompatibility complex human leukocyte antigen class 1 and class 2 and antibodies against minor histocompatibility complex. A current positive crossmatch is an absolute contraindication for transplant. Positive historical panel reactive antibody and/or donor-specific antibodies (human leukocyte antigen and minor histocompatibility complex), even in the absence of a historical positive crossmatch, are associated with an increased risk for allosensitization, antibodymediated rejection, and accelerated graft failure. Desensitization protocols are numerous, complex, and expensive. It is recommended to perform a systematic determination of historical and current panel reactive antibody, donor-specific antibodies (human leukocyte antigen and minor histocompatibility complex), and crossmatch by the most sensitive assays. The risk of sensitization may be estimated from the combined results of the crossmatch with the donor and those of the recipient's panel reactive antibody and donor-specific antibodies at baseline. The adoption of a scoring system for risk stratification may facilitate the task of organ allocation for sensitized patients. Recipients with an estimated sensitization risk ≥ high may be referred preferably to the national waiting priority list and informed about the financial and the medical risks that may incur with future transplant. Sensitized patients at high risk for antibody-mediated rejection may benefit from a structured monitoring process involving systematic and regular immunologic, histologic, and functional assessments of the graft after transplant. We recommend the adoption and regular updating of these approaches to ensure safe and appropriate therapeutic standards in these sensitized patients, in accordance with best clinical practice.

show abstract

“…This agent is now being used to attempt reduction of DSA in sensitized patients [92,93]. While many centers have incorporated this agent into treatment of AMR [94][95][96], its use for immunomodulation is limited to case reports. There have been 2 case reports that examined the use of bortezomib as a desensitizing agent pre-transplant.…”

Section: Future Of Crossmatch Incompatible Donorsmentioning

confidence: 99%