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Molecular patterns of isolated tubulitis differ from tubulitis with interstitial inflammation in early indication biopsies of kidney allografts

ABSTRACT: Banff 2019 update of kidney allograft pathology excluded isolated tubulitis without interstitial inflammation (ISO-T) from category of borderline (suspicious) for acute T cell-mediated rejection due to its proposed benign clinical outcome. However, molecular assessment of ISO-T has not been explored yet. ISO-T or interstitial inflammation with tubulitis (I+T) were diagnosed in indication biopsies within first 14 postoperative days. Molecular patterns of ISO-T was compared to I+T either by using RNA sequencing (n=16) or by Molecular Microscope Diagnostic System (MMDx, n=51). In ISO-T group, RNA sequencing showed lower expression of genes related to interferon-y (p=1.5 *10-16), cytokine signaling (p=2.1 *10-20) and inflammatory response (p=1.0*10-13) than in I+T groups. Increased transcripts in I+T group had significant overlap with previously described pathogenesis-based transcript sets associated with T cell-mediated rejection (TCMR), cytotoxic and effector T cell transcripts. In ISO-T, MMDx classified biopsies as no-rejection in 25/32 (78%) while in I+T in 12/19 (63%). ISO-T had significantly lower MMDx scores for interstitial inflammation (p=0.014), tubulitis (p=0.035) and TCMR (p=0.016) compared to I+T. Less inflammatory molecular signals of isolated tubulitis suggest its benign phenotype also on molecular level.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161705 | GEO | 2020/11/19

REPOSITORIES: GEO

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Project description:Polyoma virus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. Microscopic descriptions of PVAN are very similar to T-cell mediated rejection (TCMR) and have unclear underlying molecular mechanisms. To identify PVAN-specific gene expression, we analyzed 162 kidney biopsies with and without PVAN for global gene expression. Unsupervised hierarchical clustering analysis of all 162 biopsies revealed high similarity between PVAN and TCMR gene expression. Increasing the stringency for the specificity (p <0.001 and >2-fold expression) between PVAN and TCMR, 158 and 252 unique PVAN and TCMR injury-specific probesets were observed, respectively. While TCMR-specific probeset were overwhelmingly involved in immune response costimulation (CTLA4, CD28, CD86) and TCR (NFATC2, LCP2) signaling, PVAN-specific probesets were mainly related to viral replication process (IFITM1, LTF, NOSIP, RARRES3), RNA polymerase assembly (POLR2l, TAF10, RPS15) and pathogen recognition receptors (C1QA, C3, CFD). A principal component analysis using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific probesets (RPS15, CFD, LTF, and NOSIP) by QPCR and further confirmation by IHC of 2 PVAN-specific proteins with anti-viral function (LTF and IFITM1) was done, showing significantly higher expression within interstitial cellular infiltrates and in tubuli in PVAN specimens as compared to TCMR and NL kidney biopsies. In conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, particular PVAN-specific transcripts were identified with well-known anti-viral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design. A total of 168 kidney biopsies from kidney transplant patients were used. The kidney biopsies included renal biopsies from PVAN (n=10), T cell mediated cellular rejection (n=26), patients with IFTA (n=59), patients with stable grafts (STA) (n=73). This dataset is part of the TransQST collection.

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Molecular patterns of isolated tubulitis differ from tubulitis with interstitial inflammation in early indication biopsies of kidney allografts

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