4.1.1. Transcriptomic Studies

Growing evidence of highly shared deregulated gene pathways between IFTA and AR suggests a common immunological etiology in most cases of late CAD [154].

Recent studies have focused on upregulation of genes involved in IFTA. Inflammation in IFTA areas ("inflammatory IFTA", i-IFTA) has been identified as pivotal element in prompting development of chronic renal damage, further underlying the relationship between chronic, subclinical immunological activity and irreversible fibrosis [161,162].

Several transcriptomic studies have shed light on specific genes and miRNAs involved in fibrotic evolution of chronic rejection.

In a study by Mas V. et al. an upregulation of genes related to fibrosis (TGFβ), extracellular matrix deposition, and immune response was found [155].

In the already quoted CTOT-04 trial, Lee J. R. et al. identified a four-gene urinary signature (mRNA for vimentin, NKCC2, E-cadherin, and 18S rRNA) which predicted IFTA [86].

In the study of Genomics of Chronic Allograft Rejection (GoCAR), renal biopsy transcriptome expression analysis identified a set of 13 genes which independently predicted development of CAD at the 12th month, despite normal histology at the 3rd month after KTx, in more than 200 prospectively followed patients with stable graft function. This multicenter study was validated in two independent

cohorts and first raised hope that allograft injury may be detected before it becomes clinically evident [87].

Halloran et al. employed the "molecular microscope" approach (already discussed in the paragraph on AR) and demonstrated a progressively higher prevalence of IFTA lesions over time and its association with transcripts related to rejection and glomerulonephritis in late biopsies. This suggests a continuing, active tissue response rather than autonomous fibrogenesis and that early abrogation of the immunological process may be critical to block this evolution and preserve long-term graft function [93,161].

Another transcriptomic study employed an 85-gene signature related to IFTA and employed it to test targeted new anti-fibrotic drugs [156].
