Background: Ischemia reperfusion (I/R) is influenced by both donor and recipient characteristics and affects early graft function and the recovery process. To understand underlying mechanisms of I/R injury and recovery in the complex setting of transplantation we performed an early longitudinal molecular analysis of pre-implant (K1) and post-reperfusion (K2) renal allograft biopsies.

Methods: Gene expression arrays in a total of 146 early longitudinal biopsies collected from 73 kidney transplant recipients were included. Gene expression analysis was done using expression and transcriptome console softwares. The similarity matrices between the arrays at two time points were measured. Significantly differentially expressed probesets (cut off range of of FDR < 5% and FC > 1.5) were analyzed using IPA software. Unsupervised principal component analysis (PCA) was done on all samples.

Results: PCA of gene expression data from K1 showed 2 separate clusters (grp I; grp II) and the same upon analyzing K2 biopsies. However, upon combining the longitudinal measures from each sample, and studying the similarity matrices, 3 distinct groups were observed. The third cluster (grp IIb) consisted of samples that grouped with grp I at pre-implant stage and shifted to grp II at post-reperfusion stage. These biopsies had the maximum differentially expressed genes between K1 and K2 biopsies. Groups II and IIb were the high risk groups for DGF and also lower recovery at one month post-transplantation. A detailed analysis of the pathways involved in I/R injury in each of these groups showed clear differences in metabolic and inflammatory pathways. The two high risk groups had contrasting molecular profiles of either exacerbated inflammatory response involving cytokines like TNF-α, LIF and other inflammatory molecules like C5AR1 (Grp II), or inhibition of majority of the inflammatory pathways like inhibition of dendritic cell maturation, eNOS signaling with down regulation of genes like CD40, MHC II, CD1 (Grp IIb).

Conclusion: The analysis shows that balanced gene expression and regulation are key for immediate functioning and recovery of the kidney post I/R injury. The markers from each of these groups together with clinical data can determine efficiently high risk group for DGF and worse short term outcomes. Further analysis will help delineate therapeutic intervention for recovery of kidney function post I/R injury.

CITATION INFORMATION: Bontha S., Fernandez A., Bardhi E., Gallon L., Mas V., Maluf D. Longitudinal Molecular Assessment of Renal Allograft and Short-Term Outcome: Markers of Injury and Recovery Am J Transplant. 2017;17 (suppl 3).

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