Crossmatch tests of the prospective kidney-transplant donor's lymphocytes with the serum of the prospective recipient in 225 transplants showed that eight of 195 with negative crossmatch f...

Significance of the positive crossmatch test in kidney transplantation.

http://cybernephrology.ualberta.ca/Banff/2015/Publications/banff09.pdf

Banff '09 meeting report: Antibody mediated graft deterioration and implementation of Banff working groups

BACKGROUND The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.

https://www.nefro.cl/DOCS/evento1/papers/Consesus_Guide_lines_Anti-HLA_2013_Dr.%20Jimenez.pdf

Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.

Background Hyperacute rejection (HAR) and acute humoral rejection (AHR) remain recalcitrant conditions without effective treatments, and usually result in graft loss. Plasmapheresis (PP) has been shown to remove HLA- specific antibody (Ab) in many different clinical settings. Intravenous gamma globulin (IVIG) has been used to suppress alloantibody and modulate immune responses. Our hypothesis was that a combination of PP and IVIG could effectively and durably remove donor-specific, anti-HLA antibody (Ab), rescuing patients with established AHR and preemptively desensitizing recipients who had positive crossmatches with a potential live donor. Methods The study patients consisted of seven live donor kidney transplant recipients who experienced AHR and had donor-specific Ab (DSA) for one or more mismatched donor HLA antigens. The patients segregated into two groups: three patients were treated for established AHR (rescue group) and four cross-match-positive patients received therapy before transplantation (preemptive group). Results Using PP/IVIG we have successfully reversed established AHR in three patients. Four patients who were cross-match-positive (3 by flow cytometry and 1 by cytotoxic assay) and had DSA before treatment underwent successful renal transplantation utilizing their live donor. The overall mean creatinine for both treatment groups is 1.4+/-0.8 with a mean follow up of 58+/-40 weeks (range 17-116 weeks). Conclusions In this study, we present seven patients for whom the combined therapies of PP/IVIG were successful in reversing AHR mediated by Ab specific for donor HLA antigens. Furthermore, this protocol shows promise for eliminating DSA preemptively among patients with low-titer positive antihuman globulin-enhanced, complement-dependent cytotoxicity (AHG-CDC) cross-matches, allowing the successful transplantation of these patients using a live donor without any cases of HAR.

Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients

The Corneal Endothelium: Normal and Pathologic Structure and Function

Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells

Human Transplantation Antigens

A Danish family with twelve members and with two first cousin marriages was studied. Two inbred siblings (designated J) were found to be homozygous for HL–A2,27 (AJ) and therefore also presumably homozygous for all or most of the major histocompatibility complex. When used as stimulators in one-way MLC, these two individuals elicited a very low response in five members of the family possessing this same HL–A haplotype, which was clearly disjunct from the response by family members not possessing the HL–A2,27(AJ). When J cells were used as stimulators against cells from 27 unrelated individuals, the responses against J – expressed relative to the median response of a given responder against several unrelated persons – fell into two clearly disjunct groups. One group of seven gave low responses, from 13% to 41%. The individuals of this group are designated J-like. The rest gave responses from 83 % to 132 %. In one family with three children where the father was J-like and the mother was not J-like, the trait J-like segregated in coupling with the HL–A determinants. It is postulated that these specifically low responding, or J-like, individuals possess the MLC allele j, for which the individuals J are homozygous. Among the 27 unrelated individuals tested, there was no obvious association between the MLC allele j and any particular HL–A antigen. Another inbred HL–A homozygous individual did not stimulate the family members at a low level in compatible combinations and is thus presumably not homozygous at the MLC locus.

Mixed Lymphocyte Cultures with Inbred Individuals: An Approach to MLC Typing

Of 156 families who were HL-A typed and Chido-typed, 15 were found to be suitable for linkage analysis. It was calculated that the odds in favour of linkage of Chido and HL-A are 1,450,000:1. The maximum likelihood estimate of the Chido:1.HL-A recombination fraction is 2½% with 95% confidence limits, obtained graphically, of 0 and 12%; the estimate of the Chido:2.HL-A recombination fraction is 1½%, with limits of 0 and 9%. Among Chido negative subjects, the antigens HL-A12 and W5 occurred more frequently than in a control population.

Flemming Kissmeyer-Nielsen

Papers

Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells

Human Transplantation Antigens

Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells

Mixed Lymphocyte Cultures with Inbred Individuals: An Approach to MLC Typing

Linkage of Chido and HL‐A