Transcriptome profile of subclinical kidney allograft rejection may help to identify patients at risk

Mariana Urbanova², Irena Brabcova¹, Eva Girmanova¹, Ondrej Viklicky^1,2.

¹Transplant Laboratory, Institute for Clinical and Experimental Medicine; ²Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Subclinical acute T-cell mediated rejection (SAR) diagnosed from protocol biopsies is thought to be a risk factor of long- term allograft dysfunction. It is unclear whether the degree of immune activation may explain the absence of graft dysfunction at the time biopsy. The aim of this study was to evaluate the transcriptome patterns of SAR and acute T cell mediated rejection (AR) from early case biopsies.

The intragraft expression of 375 target genes involved in chemokine defense, apoptosis, inflammation, tolerance and TGF-β signaling pathways was measured using quantitative real-time RT-PCR (2^-DDCt) method in SAR (n=10) and AR (n=10) and the results were correlated with the clinical outcome.

The gene expression patterns in SAR were different from AR and included the decreased expression of cytokines mediating chemotaxis (CCL1, CC17, CCL24, CCL25, CCL26), cytokine receptors (CCR1, CCRL2, IL1RAPL2), proinflammatory cytokines (IL12A, LTA), complement protein C3, executioner protein of apoptosis (CASP7), growth factor (TGFA), costimulation (CD274), colony stimulating factor (GM-CSF), proteins involved in dendritic cells differentiation and interaction (CD209, LAMP3) and in regulation of immune response (LILRB2, LILBRB4). The quantity of FoxP3 gene expression in SAR was lower than in AR. Differences in transcripts signature between SAR and AR are consistent with stronger proinflammatory setting of AR. There was no difference in incidence of renal function impairment between SCR and ACR group (4/10 vs. 3/10) at 2 years. Logistic regression analysis showed that lower prostaglandin E2 receptor (PTGER2) gene expression levels in studied biopsies predicted graft function deterioration (Nagelkerke R ²=0,74.3, p<0.0001) .

In conclusion, subclinical acute kidney allograft rejection has transcriptional profile of acute injury of lower extend than clinical acute rejection. The lower intragraft PTGER2 gene expression may predict the progression of kidney graft dysfunction.