Physical/de facto cross-matching in order to complement its primary virtual variant prior to kidney allografting: Substantial benefit or only fishing for diagnostic artifacts?

Preformed Donor-specific anti-HLA antibodies (DSA) represent the most prominent cause for humoral hyper-acute and acute allograft rejections and, therefore, have strictly to be avoided prior to kidney allografting. Since April 2023 the so-called virtual crossmatch (vXM) as a procedure aligning the recipients' antibody specificities with the HLA-antigens of their donors has principally replaced the physical/de facto crossmatch regarding the detection/identification of Non Acceptable HLA Antigens. In spite of this pivotal meaning of vXM, the Lymphocytotoxicity- (LCT/CDC-) based cross-matching has not been disestablished but is still required by the guidelines of the German Federal Medical Association as a second catch-all in order to detect potential DSA. Due to well documented drawbacks of LCT cross-matching in terms of artifacts caused by recipients' autoimmune diseases and phamacological treatment this approach must critically be challenged.

We here present our data of ten positive LCT-based crossmatch outcomes appearing in our laboratory's emergency duties between April 2023 and 2024, all of which were observable in spite of prior negative virtual cross-matching. For the virtual approach donors' typing results were available for the 11 gene loci HLA-A*, B*, C*, DRB1*, DRB3*,4*,5*, DQB1*, DQA1*, DPB1* and DPA1* at the intermediate level of resolution defined by Eurotransplant. Antibody specifications of the respective recipients had been performed at the corresponding allelic level of resolution.

In all ten cases the source of LCT-based positive crossmatch outcomes was doubtlessly definable. Nine out of ten could be ascribed to artificial origins such as underlying autoimmune diseases (n=6). Furthermore, immunosuppressive treatment by rituximab (n=2) or intravenous immunoglobulins (IVIG) (n=1) also showed its falsifying effect. Only one case exhibited DSA which had not been included by prior vXM since a transfusion as immunizing event had not been adequately considered by a follow up antibody specification. However, representing a serious failure of the respective transplant center, this case should be beyond occurrence.

We conclude that the highly specific vXM taking into account all immunizing events represents an adequate tool in order to exclude DSA whereas subsequent LCT-based physical cross-matching rather raises artificial outcomes which with the utmost probability prevent recipients from receiving adequate allografts.

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