The Significance of a Positive Flow Cytometry Crosshatch Test in Primary Kidney Transplantation

Ogura, Kaoru; Terasaki, Paul I.; Johnson, Catherine; R, Mendez; Rosenthal, J. Thomas; Ettenger, R; Martin, Donald C.; Dainko, Edward A.; Cohen, Loren H.; Mackett, T

doi:10.1097/00007890-199308000-00007

Cited by 126 publications

(58 citation statements)

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“…However, these low-titer antibodies could still result in negative transplant outcomes from memory responses. [13][14][15][16][17] RMM was potentially the best surrogate marker for low-titer (undetected) antibodies in previous era studies.…”

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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“…D eleterious sensitization to donor MHC Ags through random blood transfusions, prior failed grafts, or pregnancies is among the most critical of problems facing clinical organ transplantation in terms of magnitude and impact (1)(2)(3). Indeed, as many as 40% of patients on transplant waiting lists have elevated levels of broadly reactive alloantibodies to prospective donors.…”

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confidence: 99%

The CD154-CD40 T Cell Costimulation Pathway Is Required for Host Sensitization of CD8+ T Cells by Skin Grafts Via Direct Antigen Presentation

Zhai

Shen

Gao

et al. 2002

The Journal of Immunology

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Although the CD154-CD40 T cell costimulation pathway has been shown to mediate alloimmune responses in normal recipients, little is known about its role in sensitized hosts. In this work, by using novel models of cardiac allograft rejection in skin-sensitized CD154- and CD40-deficient mice, we reaffirm the key role of CD154-CD40 signaling in host sensitization to alloantigen in vivo. First, we identified CD8+ T cells as principal effectors in executing accelerated rejection in our model. Disruption of CD154-CD40 signaling in recipients at the T cell side (CD154-deficient) but not at the APC side (CD40-deficient) abrogated accelerated (<2 days) rejection and resulted in long-term (>100 days) graft survival. This suggests that the CD154-dependent mechanism in host CD8+ T cell sensitization operates via the direct Ag presentation. Then, in comparative studies of alloimmune responses in CD154-deficient and wild-type recipients, we showed that, although alloreactive B cell responses were inhibited, alloreactive T cell responses were down-regulated selectively in the CD8+ T cell compartment, leaving CD4+ T cells largely unaffected. This unique alteration in host alloreactivity, seen not only in peripheral lymphocytes but also in allograft infiltrate, may represent the key mechanism by which disruption of CD154-CD40 signaling prevents sensitization to alloantigen in vivo and leads to long-term allograft survival.

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“…Indeed, variable amplification of the fluorescence intensity for control AB sera will lead to a marked variation in criteria (i.e., actual difference in MC shift) for assigning a positive FCXM result. For example, the MC shift criteria for a positive B-cell UD FCXM has varied in different laboratories from 240 to 2150 channels, probably as a result of variable amplification in the fluorescence intensity for control AB sera [ 3 , 7,8,9,14,161. In the present study, with PD FCXM the MC with control AB sera (for both B and T cells) could be maintained at approximately five channels, as there was no binding of irrelevant IgG to cells.…”

Section: Discussionmentioning

confidence: 99%

“…One cannot differentiate by FCXM between irrelevant normal IgG binding to Fc IgG receptors present on B cells as well as activated T cells and specific IgG bound to HLA antigens. The lack of specificity with FCXM has led many transplant institutions to ignore a positive T cell FCXM assay, especially in the setting of a primary renal transplant and when the CdL assay with B and T cells is negative [7,8,9,14,15,161. In these reports, between 16% and 40% of recipients would have been denied renal transplants if a decision of "not to transplant" were to have been based solely on a positive donor-specific FCXM.…”

Section: Introductionmentioning

confidence: 99%

Improved specificity and sensitivity when using pronase-digested lymphocytes to perform flow-cytometric crossmatch prior to renal transplantation

Lobo¹,

Isaacs²,

Spencer³

et al. 2002

Transplant International

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Several laboratories have resorted to flow-cytometric crossmatch (FCXM) in an effort to prevent hyperacute and accelerated renal allograft rejections. The currently employed FCXM has problems with both false-positive and -negative reactions, largely as a result of irrelevant IgG binding to Fc IgG receptors. In 1980, we circumvented this problem by digesting Fc IgG receptors with pronase, and demonstrated that, with immunofluorescence microscopy (IF), detection of IgG anti-HLA antibodies was highly sensitive and specific. In 1995, we introduced the pronase technique to FCXM and showed that this enzyme did not decrease HLA expression. We present herein a prospective study at our institution to determine whether FCXM using pronase-digested (PD) lymphocytes is as sensitive and more specific than FCXM with undigested (UD) lymphocytes when compared with the highly sensitive and specific I F assay. In analyzing the 186 donor-specific prerenal-transplant crossmatches, we found that PD FCXM was as sensitive and specific as I F and was able to detect weak IgG anti-HLA antibodies that bound to B cells. Fourteen of these patients would have been denied transplants if one were to have relied on UD FCXM. The data clearly indicate that PD FCXM can reliably be used to detect weak IgG anti-HLA antibodies before renal transplantation.

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The Significance of a Positive Flow Cytometry Crosshatch Test in Primary Kidney Transplantation

Cited by 126 publications

References 0 publications

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

The CD154-CD40 T Cell Costimulation Pathway Is Required for Host Sensitization of CD8+ T Cells by Skin Grafts Via Direct Antigen Presentation

Improved specificity and sensitivity when using pronase-digested lymphocytes to perform flow-cytometric crossmatch prior to renal transplantation

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