Polyomavirus BK Nephropathy-Associated Transcriptomic Signatures: A Critical Reevaluation

Abstract

BackgroundRecent work using DNA microarrays has suggested that genes related to DNA replication, RNA polymerase assembly, and pathogen recognition receptors can serve as surrogate tissue biomarkers for polyomavirus BK nephropathy (BKPyVN).MethodsWe have examined this premise by looking for differential regulation of these genes using a different technology platform (RNA-seq) and an independent set 25 biopsies covering a wide spectrum of diagnoses.ResultsRNA-seq could discriminate T cell–mediated rejection from other common lesions seen in formalin fixed biopsy material. However, overlapping RNA-seq signatures were found among all disease processes investigated. Specifically, genes previously reported as being specific for the diagnosis of BKPyVN were found to be significantly upregulated in T cell–mediated rejection, inflamed areas of fibrosis/tubular atrophy, as well as acute tubular injury.ConclusionsIn conclusion, the search for virus specific molecular signatures is confounded by substantial overlap in pathogenetic mechanisms between BKPyVN and nonviral forms of allograft injury. Clinical heterogeneity, overlapping exposures, and different morphologic patterns and stage of disease are a source of substantial variability in “Omics” experiments. These variables should be better controlled in future biomarker studies on BKPyVN, T cell–mediated rejection, and other forms of allograft injury, before widespread implementation of these tests in the transplant clinic.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…The search for renal tissue transcriptomic biomarkers of PVAN has not provided any solid result so far. Overlap in pathogenetic mechanisms and gene expression between PVAN and non-viral forms of allograft injury, such as TCMR and iIFTA, makes it difficult to identify peculiar molecular signatures [ 186 ].…”

Defining housekeeping genes suitable for RNA-seq analysis of the human allograft kidney biopsy tissue

“…Five native kidney biopsies with interstitial nephritis (ISN; n = 5) were also studied. The clinical and pathology parameters pertinent to these specimens have been published previously [13].…”

Proteomics in Kidney Allograft Transplantation—Application of Molecular Pathway Analysis for Kidney Allograft Disease Phenotypic Biomarker Selection

“…We restricted our search to gene enrichment analyses in human renal biopsies and to studies describing pathways specific for AMR, TCMR, IFTA, and PVAN. As presented in Table , we identified two studies for AMR, five for TCMR, eight for IFTA, and two for PVAN using statistically validated differentially regulated gene expression and appropriate GO‐, IPA‐, and KEGG‐derived pathway mappings. To perform semantic clustering on these kidney transplantation related disease phenotypes by the software tool ReviGO, we converted IPA and KEGG pathways to GO biological processes using QuickGO, AmiGO, and UniProt.…”

“…Interestingly a direct link of tyrosine kinase inhibition by the drug leflunomide and BK virus inactivation has been demonstrated, as well as the enhanced expression of chemokines and cytokines of BK virus infected collecting duct cells . This inflammatory response, and the resulting infiltration with immune‐responsive cells, can lead to difficulties in distinguishing PVAN from TCMR on a molecular level . The treemap analysis indicates that the urea cycle, through its linkage with the tricarboxylic acid‐cycle/gluconeogenesis axis and other up‐/down‐stream events, as well as cytosolic calcium release, potentially leading to apoptosis initiation, is affected in this type of nephropathy.…”