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Published on: June 30, 2018
Molecular evaluation of BK polyomavirus nephropathy
R B Mannon1, S C Hoffmann, R L Kampen
1Transplantation Branch, National Institutes of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. rozm@mail.nih.gov
Abstract:
Understanding at a molecular level, the immunologic response of polyomavirus nephropathy (PVN), a critical cause of kidney graft loss, could lead to new targets for treatment and diagnosis. We undertook a transcriptional evaluation of kidney allograft biopsies from recipients with PVN or acute rejection (AR), as well as from recipients with stable allograft function (SF). In both the PVN and AR groups, Banff histologic scores and immunohistochemical analysis of inflammatory infiltrates were similar. Despite their different etiologies, the transcriptional profiles of PVN and AR were remarkably similar. However, transcription of genes previously linked to AR including CD8 (65.9 +/- 18.8) and related molecules IFN-gamma(55.1 +/- 17.0), CXCR3 (49.9 +/- 12.8) and perforin (153.8 +/- 50.4) were significantly higher in PVN compared to AR (30.9 +/- 2.0, 14.0 +/- 7.3, 12.1 +/- 7.3 and 15.6 +/- 3.8-fold, respectively; p < 0.01). Importantly, transcription of molecules associated with graft fibrosis including matrix collagens, TGFbeta, MMP2 and 9, as well as markers of epithelial-mesenchymal transformation (EMT) were significantly higher in PVN than AR. Thus, renal allografts with PVN transcribe proinflammatory genes equal in character and larger in magnitude to that seen during acute cellular rejection. BK infection creates a transcriptional microenvironment that promotes graft fibrosis. These findings provide new insights into the intrarenal inflammation of BK infection that promotes graft loss.
Insights
Polyomavirus nephropathy (PVN) in kidney transplants shows higher inflammation and fibrosis gene activity than acute rejection. This suggests PVN drives graft loss through similar, yet more intense, molecular pathways than acute rejection.
Area of Science:
- Nephrology
- Immunology
- Transplantation
Background:
- Polyomavirus nephropathy (PVN) is a major cause of kidney graft loss.
- Understanding the molecular basis of PVN is crucial for developing new treatments and diagnostic tools.
- Transcriptional analysis of kidney allografts can reveal underlying immunologic responses.
Purpose of the Study:
- To compare the transcriptional profiles of kidney allografts with PVN, acute rejection (AR), and stable function (SF).
- To elucidate the molecular mechanisms driving inflammation and fibrosis in PVN.
- To identify potential therapeutic targets for managing PVN and preventing graft loss.
Main Methods:
- Transcriptional evaluation of kidney allograft biopsies from recipients with PVN, AR, and SF.
- Analysis of Banff histologic scores and immunohistochemistry for inflammatory infiltrates.
- Quantification of gene transcription levels for AR-associated genes and fibrosis markers.
Main Results:
- Transcriptional profiles of PVN and AR were similar, but key AR-associated genes (CD8, IFN-gamma, CXCR3, perforin) were significantly higher in PVN.
- Genes linked to graft fibrosis, including matrix collagens, TGFbeta, MMP2/9, and EMT markers, were significantly upregulated in PVN compared to AR.
- PVN induces a transcriptional profile characterized by potent pro-inflammatory gene expression and enhanced fibrosis, exceeding that of AR.
Conclusions:
- Renal allografts with PVN exhibit a pro-inflammatory transcriptional signature comparable in character but greater in magnitude to acute cellular rejection.
- BK virus infection establishes a transcriptional environment that actively promotes graft fibrosis.
- These findings offer novel insights into the intrarenal inflammation driven by BK infection, contributing to kidney graft loss.
