Evidence for Antibody-Mediated Injury as a Major Determinant of Late Kidney Allograft Failure

Gaston, Robert S.; Cecka, J. Michael; Kasiske, B. L.; Fieberg, Ann; Leduc, Robert; Cosio, Fernando; Gourishankar, Sita; Grande, Joseph P.; Halloran, Philip F.; Hunsicker, Lawrence G.; Mannon, Roslyn B.; Rush, David; Matas, Arthur J.

doi:10.1097/tp.0b013e3181e065de

Cited by 445 publications

(403 citation statements)

References 24 publications

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“…After censoring for death, however, similar findings remain, and it is likely that chronic alloimmune damage is a major cause of graft loss in this cohort as reported elsewhere. [28][29][30][31][32] Finally, HLA typing methods have evolved, such that the HLA antigens identified in one donor may be more fully resolved than the other donor or in the recipient. 33 Where this resolution discrepancy existed, we classified the antigens as equivalent.…”

Section: Discussionmentioning

confidence: 99%

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Tinckam

Rose

Hariharan

et al. 2016

JASN

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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

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Section: Discussionmentioning

confidence: 99%

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Tinckam

Rose

Hariharan

et al. 2016

JASN

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“…DGF is associated with reduced long-term outcomes in registry studies, but much of this is probably due to recipient comorbidities, which can contribute both to early dysfunction and late intercurrent illnesses and patient death. A common belief that DGF "causes" progressive late deterioration is not supported by phenotype data: recent biopsy studies of troubled transplants show that most late graft losses are attributable to definable entities such as antibody-mediated rejection (ABMR), nonadherence and recurrent disease (3,4), and no phenotype of late unexplained deterioration associated with early DGF has been identified.…”

Section: Introductionmentioning

confidence: 99%

“…3 Excluded pre-emptive kidney transplantation, n = 2. 4 Donors who have underlying hypertension, dyslipidemia or diabetes and died from hemorrhagic or ischemic stroke. 5 Correlation coefficient with donor age is 0.27, p = 0.02.…”

Section: Association Between Histologic Lesions and Early Functionmentioning

confidence: 99%

Comparing Molecular Assessment of Implantation Biopsies With Histologic and Demographic Risk Assessment

Kreepala

Famulski

Chang

et al. 2013

American Journal of Transplantation

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We hypothesized that measurement of previously defined acute kidney injury-induced transcripts at the time of implantation would add a new dimension to existing methods based on donor factors, histology and recipient factors. We analyzed microarray results from implantation biopsies taken after reperfusion from 70 kidneys from 53 deceased donors. We used two definitions of early dysfunction: serum creatinine > 265 umol/L at day 7 posttransplant; and dialysis in the first week. The strongest correlate with early dysfunction was the mean expression of 30 injury transcripts. Older donor and recipient age were associated with early dysfunction, but histologic lesions were not. Prediction was best when the injury transcript expression was combined with donor or recipient age, particularly in standard criteria donors. In contrast, although extended criteria donor kidneys had a high risk of early dysfunction, no variables tested, including injury transcripts, predicted risk significantly, probably because these kidneys were allocated preferentially to old, high risk recipients. The injury transcripts did not predict late function, which was mainly associated with donor age. Thus, measurement of injury-induced transcripts at the time of implantation improves the prediction of early kidney dysfunction, but risk prediction may fail when old kidneys are transplanted into old recipients.

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“…TG develops as a consequence of overt and covert episodes of antibody-mediated rejection (5,(18)(19)(20)(21)(22)(23)(24), typically, due to HLA class II anti-HLA antibodies (5,10,(25)(26)(27)(28)(29)(30). Antibodies against HLA develop when antibody-accessible polymorphic residues on HLA antigens are recognized as ''nonself.''…”

Section: Introductionmentioning

confidence: 99%

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

Sapir‐Pichhadze

Tinckam

Quach

et al. 2015

American Journal of Transplantation

116

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We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n ¼ 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n ¼ 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR þ DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR þ DQ eplet mismatches. Our study suggests that minimization of HLA-DR þ DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study.

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Evidence for Antibody-Mediated Injury as a Major Determinant of Late Kidney Allograft Failure

Abstract: Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Cited by 445 publications

References 24 publications

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Comparing Molecular Assessment of Implantation Biopsies With Histologic and Demographic Risk Assessment

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

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