In positive crossmatch kidney transplantation (+XM-KT) with high levels of donor-specific alloantibody (DSA), subclinical chronic injury is demonstrable at 1-yr in almost all grafts when sensitive methods are used (e.g. gene expression and protocol biopsies). Our goal was to determine if similar low levels of chronic injury are present in the kidney at 1-yr after +XM simultaneous liver-kidney transplantation (+XM-SLK) where the liver appears to protect the kidney from clinical injury. Methods: Surveillance 1-yr protocol kidney biopsies of 9 +XM-SLK and 15 age-, sex- and race-matched +XM-KT recipients with similar graft function (eGFR 42±12.6 and 53±21.9, respectively) were scored using Banff ‘97 and intragraft gene expression was assessed by Illumina microarrays. At transplant, all had a positive flow cytometric XM and DSA demonstrated by LABscreen solid phase assay (mean highest DSA MFI=10022 in +XM-SLK; 6339 in +XM-KT). Inflammatory cell-related (Ingenuity Knowledge base) and Pathogenesis-based transcript sets were used to calculate gene set scores of all detectable transcripts. Results: By light microscopy, peritubular capillaritis (PTC score>1) was less common after +XM-SLK (25 vs 83%, P<0.05). Gene expression also showed a lower incidence of subclinical microvascular inflammation (e.g. Macrophage adhesion and NK pathways) in +XM-SLK compared to +XM-KT. In addition, other individual transcripts associated with microvascular inflammation, such as vascular endothelial adhesion (VE-cadherin, CD34), activation (TEK-tyrosine kinase), leukocyte migration (PECAM) and monocyte chemoattractant protein were significantly lower in +XM-SLKT. Endothelial cell activation, a process associated with DSA in +XM-KT, was also less common after +XM-SLK (P<0.05). Two +XM-SLK had persistent circulating DSA at the time of the biopsy (* in Fig. 1); both had profiles similar to +XM-KT and PTC >1. Transcripts for T cell activation, proliferation and adhesion were not different between two groups. Conclusions: The data suggest that the liver truly protects kidneys from chronic antibody-associated injury. This effect appears to be related to the lack of circulating DSA after SLK.Figure: No Caption available.