Pathologic diagnosis incorporating molecular monitoring highlights new pathophysiological mechanisms in kidney xenotransplantation.

Kidney xenotransplantation addresses organ shortages; however, short-term clinical observations provide limited insights into long-term graft changes. A pathology-molecular framework integrating biopsy phenotyping, transcript analysis, and spatial profiling can improve the interpretation of long-surviving pig-to-nonhuman primate kidney xenografts. B-HOTX, a xenograft-adapted version of the Banff Human Organ Transplant gene panel, distinguishes donor from recipient transcripts, reducing the misclassification of physiological leukocyte signals as rejection. Key insights include macrophage-dominant infiltrates, progressive vascular endothelial growth factor A decline associated with thrombotic microangiopathy, and the systemic transfer of endothelial molecules hypothesis. If confirmed, this strategy may refine xenograft-specific diagnostics, guide monitoring and therapy, and support the safe translation of these findings.