2011 - Transplantomics and Biomarkers in Transplantation

Abstract Driven Session

9.4 - Intragraft Gene Expression in Positive Crossmatch Kidney Allografts: Accommodation or Chronic Injury?

Presenter: Walter, Park, Rochester, MN, USA
Authors: Mark Stegall, Walter Park, Lynn Cornell, James Gloor, Patrick Dean

Intragraft Gene Expression in Positive Crossmatch Kidney Allografts: Accommodation or Chronic Injury?

Mark Stegall1, Walter Park1, Lynn Cornell2, James Gloor3, Patrick Dean1.
Departments of 1Surgery, 2Pathology, and 3Nephrology and Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA.
Protocol biopsies in kidney transplants with high levels of DSA (positive crossmatch, XM+) may develop features attributed to chronic injury [transplant glomerulopathy (TG) or endothelial cell activation] or have relatively normal histology, termed accommodation.The goal of this study was to assess intragraft gene expression phenotypes in XM+ living donor kidney transplants.

Methods: Whole genome microarray analysis and quantitative RT-PCR of 30 transcripts previously associated with TG and endothelial cell activation were performed on RNA from protocol renal allograft biopsies in 3 groups: 1) XM+TG+ biopsies both before (≤1 yr post-txp, n=16) and after TG (≥1 yr post-txp) was diagnosed (TG+, n=22); 2) XM+TG- biopsies (≥2 yr post-txp; n=11); 3) negative crossmatch (XM-) kidney transplants without TG (paired early [≤1 yr] and late [≥1 yr] biopsies; n=10).

Results: XM+ vs XM- biopsies (Groups 1 vs 3): Significantly altered expression was seen for 2,447 genes (18%) and 3,200 genes (24%) at early and late time points, respectively.Canonical pathway analyses of differentially expressed genes identified many inflammatory genes associated with innate and adaptive immune responses.At the late time point (≥1 yr), RT-PCR showed significantly altered expression of Bcl-xL; HO-1; tribbles-1; and VEGF.At the early time point (≤1 yr), altered expression of multiple endothelial cell activation genes were identified (CDH5; PECAM-1; E-selectin; von Willebrand factor, etc.).

XM+ pre-TG+ vs TG+ (Group 1): Whole-genome microarrays showed relatively few differentially expressed genes (579 genes; 4%).By RT-PCR no endothelial cell activation genes were differentially expressed.

XM+ ≤1 yr vs ≥2 yr biopsies without TG (Groups 1 vs 2): Using RT-PCR, only IFNg and SELE were significantly altered.

Conclusion: The presence of pre-transplant DSA results in a gene expression profile characterized by genes associated with inflammation and cellular infiltration when compared to XM- biopsies.The development TG was not associated with altered expression in selected endothelial cell activation genes.The few genes altered in the XM+TG- comparisons may represent true accommodation.However, the bulk of gene expression data suggests that all XM+ grafts are exposed to chronic injury.

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