Intragraft gene expression in native kidney BK virus nephropathy versus T cell–mediated rejection: Prospects for molecular diagnosis and risk prediction
Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n...
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Veröffentlicht in: | American journal of transplantation 2020-12, Vol.20 (12), p.3486-3501 |
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creator | Adam, Benjamin A. Kikic, Zeljko Wagner, Siegfried Bouatou, Yassine Gueguen, Juliette Drieux, Fanny Reid, Graeme Du, Katie Bräsen, Jan H. D'Agati, Vivette D. Drachenberg, Cinthia B. Farkash, Evan A. Brad Farris, Alton Geldenhuys, Laurette Loupy, Alexandre Nickeleit, Volker Rabant, Marion Randhawa, Parmjeet Regele, Heinz Mengel, Michael |
description | Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n = 5) vs pure T cell–mediated rejection (TCMR; n = 10). Five polyomavirus genes and seven immune‐related genes (five associated with BKVN and two associated with TCMR) were significantly differentially expressed between these entities (FDR |
doi_str_mv | 10.1111/ajt.15980 |
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A comparison of the molecular phenotype of native kidney biopsies with BK virus nephropathy versus transplant kidney biopsies with T cell–mediated rejection demonstrates significant differences in polyomavirus gene expression, but not immune‐related gene expression, between these two entities.</description><identifier>ISSN: 1600-6135</identifier><identifier>EISSN: 1600-6143</identifier><identifier>DOI: 10.1111/ajt.15980</identifier><identifier>PMID: 32372431</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Biopsy ; BK Virus - genetics ; clinical research/ practice ; Gene Expression ; Graft rejection ; Graft Rejection - etiology ; Graft Rejection - genetics ; Humans ; Immune system ; Immunosuppression ; infection and infectious agents ‐ viral: BK/ JC/ polyoma ; infectious disease ; Kidney ; Kidney Diseases - diagnosis ; Kidney Diseases - genetics ; Kidney Transplantation - adverse effects ; kidney transplantation/ nephrology ; Kidney transplants ; Kidneys ; Lymphocytes T ; Medical diagnosis ; molecular biology: mRNA/ mRNA expression ; Nephropathy ; pathology/ histopathology ; Polyomavirus Infections - diagnosis ; Predictions ; rejection: T cell–mediated (TCMR) ; Risk Assessment ; T-Lymphocytes ; Tumor Virus Infections - diagnosis ; Viruses</subject><ispartof>American journal of transplantation, 2020-12, Vol.20 (12), p.3486-3501</ispartof><rights>2020 The American Society of Transplantation and the American Society of Transplant Surgeons</rights><rights>2020 The American Society of Transplantation and the American Society of Transplant Surgeons.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3880-1a32a8a463fc1e74845762cf290678f95ad4d4e6bc8c2206e69f09c302fcf3a83</citedby><cites>FETCH-LOGICAL-c3880-1a32a8a463fc1e74845762cf290678f95ad4d4e6bc8c2206e69f09c302fcf3a83</cites><orcidid>0000-0003-1908-1739 ; 0000-0001-5534-7763 ; 0000-0002-7222-3356 ; 0000-0002-7523-3437 ; 0000-0003-3697-3886 ; 0000-0003-3388-7747 ; 0000-0001-5696-6478</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fajt.15980$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fajt.15980$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32372431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adam, Benjamin A.</creatorcontrib><creatorcontrib>Kikic, Zeljko</creatorcontrib><creatorcontrib>Wagner, Siegfried</creatorcontrib><creatorcontrib>Bouatou, Yassine</creatorcontrib><creatorcontrib>Gueguen, Juliette</creatorcontrib><creatorcontrib>Drieux, Fanny</creatorcontrib><creatorcontrib>Reid, Graeme</creatorcontrib><creatorcontrib>Du, Katie</creatorcontrib><creatorcontrib>Bräsen, Jan H.</creatorcontrib><creatorcontrib>D'Agati, Vivette D.</creatorcontrib><creatorcontrib>Drachenberg, Cinthia B.</creatorcontrib><creatorcontrib>Farkash, Evan A.</creatorcontrib><creatorcontrib>Brad Farris, Alton</creatorcontrib><creatorcontrib>Geldenhuys, Laurette</creatorcontrib><creatorcontrib>Loupy, Alexandre</creatorcontrib><creatorcontrib>Nickeleit, Volker</creatorcontrib><creatorcontrib>Rabant, Marion</creatorcontrib><creatorcontrib>Randhawa, Parmjeet</creatorcontrib><creatorcontrib>Regele, Heinz</creatorcontrib><creatorcontrib>Mengel, Michael</creatorcontrib><title>Intragraft gene expression in native kidney BK virus nephropathy versus T cell–mediated rejection: Prospects for molecular diagnosis and risk prediction</title><title>American journal of transplantation</title><addtitle>Am J Transplant</addtitle><description>Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n = 5) vs pure T cell–mediated rejection (TCMR; n = 10). Five polyomavirus genes and seven immune‐related genes (five associated with BKVN and two associated with TCMR) were significantly differentially expressed between these entities (FDR < 0.05). These three sets of genes were further evaluated in samples representing a spectrum of BK infection (n = 25), followed by a multicenter validation cohort of allograft BKVN (n = 60) vs TCMR (n = 10). Polyomavirus 5‐gene set expression reliably distinguished BKVN from TCMR (validation cohort AUC = 0.992), but the immune gene sets demonstrated suboptimal diagnostic performance (AUC ≤ 0.720). Within the validation cohort, no significant differences in index biopsy gene expression were identified between BKVN patients demonstrating resolution (n = 35), persistent infection (n = 14) or de novo rejection (n = 11) 6 months following a standardized reduction in immunosuppression. These results suggest that, while intragraft polyomavirus gene expression may be useful as an ancillary diagnostic for BKVN, assessment for concurrent TCMR and prediction of clinical outcome may not be feasible with current molecular tools.
A comparison of the molecular phenotype of native kidney biopsies with BK virus nephropathy versus transplant kidney biopsies with T cell–mediated rejection demonstrates significant differences in polyomavirus gene expression, but not immune‐related gene expression, between these two entities.</description><subject>Biopsy</subject><subject>BK Virus - genetics</subject><subject>clinical research/ practice</subject><subject>Gene Expression</subject><subject>Graft rejection</subject><subject>Graft Rejection - etiology</subject><subject>Graft Rejection - genetics</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunosuppression</subject><subject>infection and infectious agents ‐ viral: BK/ JC/ polyoma</subject><subject>infectious disease</subject><subject>Kidney</subject><subject>Kidney Diseases - diagnosis</subject><subject>Kidney Diseases - genetics</subject><subject>Kidney Transplantation - adverse effects</subject><subject>kidney transplantation/ nephrology</subject><subject>Kidney transplants</subject><subject>Kidneys</subject><subject>Lymphocytes T</subject><subject>Medical diagnosis</subject><subject>molecular biology: mRNA/ mRNA expression</subject><subject>Nephropathy</subject><subject>pathology/ histopathology</subject><subject>Polyomavirus Infections - diagnosis</subject><subject>Predictions</subject><subject>rejection: T cell–mediated (TCMR)</subject><subject>Risk Assessment</subject><subject>T-Lymphocytes</subject><subject>Tumor Virus Infections - diagnosis</subject><subject>Viruses</subject><issn>1600-6135</issn><issn>1600-6143</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtOHDEQhq0IFB7JIheILLEJiwG_2u3OjiDCU0oWk7Vl3OXBQ4_dsbsnzC53yC7H4yQYBlhEiiXL5dJXv131I_SBkgNa1qGZDwe0ahR5g7apJGQiqeAbrzGvttBOznNCaM0Ue4u2OOM1E5xuo7_nYUhmlowb8AwCYLjrE-TsY8A-4GAGvwR869sAK_zlEi99GjMO0N-k2JvhZoWXkHJJTbGFrrv__WcBrTcDtDjBHOxQhD7j7ynmvlwydjHhRezAjp1JuJCzELPP2IRS4PMtLq-3_qnsHdp0psvw_vncRT--nkyPzyZX307Pj4-uJpYrRSbUcGaUEZI7S6EWSlS1ZNaxhshauaYyrWgFyGurLGNEgmwcaSwnzFnHjeK76NNat0_x5wh50AufH5sxAeKYNeNNUzbnsqB7_6DzOKZQfqeZkJIIQpuqUPtrypa2cwKn--QXJq00JfrRMF0M00-GFfbjs-J4XSb3Sr44VIDDNfDLd7D6v5I-upiuJR8ACryi3Q</recordid><startdate>202012</startdate><enddate>202012</enddate><creator>Adam, Benjamin A.</creator><creator>Kikic, Zeljko</creator><creator>Wagner, Siegfried</creator><creator>Bouatou, Yassine</creator><creator>Gueguen, Juliette</creator><creator>Drieux, Fanny</creator><creator>Reid, Graeme</creator><creator>Du, Katie</creator><creator>Bräsen, Jan H.</creator><creator>D'Agati, Vivette D.</creator><creator>Drachenberg, Cinthia B.</creator><creator>Farkash, Evan A.</creator><creator>Brad Farris, Alton</creator><creator>Geldenhuys, Laurette</creator><creator>Loupy, Alexandre</creator><creator>Nickeleit, Volker</creator><creator>Rabant, Marion</creator><creator>Randhawa, Parmjeet</creator><creator>Regele, Heinz</creator><creator>Mengel, Michael</creator><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-1908-1739</orcidid><orcidid>https://orcid.org/0000-0001-5534-7763</orcidid><orcidid>https://orcid.org/0000-0002-7222-3356</orcidid><orcidid>https://orcid.org/0000-0002-7523-3437</orcidid><orcidid>https://orcid.org/0000-0003-3697-3886</orcidid><orcidid>https://orcid.org/0000-0003-3388-7747</orcidid><orcidid>https://orcid.org/0000-0001-5696-6478</orcidid></search><sort><creationdate>202012</creationdate><title>Intragraft gene expression in native kidney BK virus nephropathy versus T cell–mediated rejection: Prospects for molecular diagnosis and risk prediction</title><author>Adam, Benjamin A. ; Kikic, Zeljko ; Wagner, Siegfried ; Bouatou, Yassine ; Gueguen, Juliette ; Drieux, Fanny ; Reid, Graeme ; Du, Katie ; Bräsen, Jan H. ; D'Agati, Vivette D. ; Drachenberg, Cinthia B. ; Farkash, Evan A. ; Brad Farris, Alton ; Geldenhuys, Laurette ; Loupy, Alexandre ; Nickeleit, Volker ; Rabant, Marion ; Randhawa, Parmjeet ; Regele, Heinz ; Mengel, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3880-1a32a8a463fc1e74845762cf290678f95ad4d4e6bc8c2206e69f09c302fcf3a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Biopsy</topic><topic>BK Virus - genetics</topic><topic>clinical research/ practice</topic><topic>Gene Expression</topic><topic>Graft rejection</topic><topic>Graft Rejection - etiology</topic><topic>Graft Rejection - genetics</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunosuppression</topic><topic>infection and infectious agents ‐ viral: BK/ JC/ polyoma</topic><topic>infectious disease</topic><topic>Kidney</topic><topic>Kidney Diseases - diagnosis</topic><topic>Kidney Diseases - genetics</topic><topic>Kidney Transplantation - adverse effects</topic><topic>kidney transplantation/ nephrology</topic><topic>Kidney transplants</topic><topic>Kidneys</topic><topic>Lymphocytes T</topic><topic>Medical diagnosis</topic><topic>molecular biology: mRNA/ mRNA expression</topic><topic>Nephropathy</topic><topic>pathology/ histopathology</topic><topic>Polyomavirus Infections - diagnosis</topic><topic>Predictions</topic><topic>rejection: T cell–mediated (TCMR)</topic><topic>Risk Assessment</topic><topic>T-Lymphocytes</topic><topic>Tumor Virus Infections - diagnosis</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adam, Benjamin A.</creatorcontrib><creatorcontrib>Kikic, Zeljko</creatorcontrib><creatorcontrib>Wagner, Siegfried</creatorcontrib><creatorcontrib>Bouatou, Yassine</creatorcontrib><creatorcontrib>Gueguen, Juliette</creatorcontrib><creatorcontrib>Drieux, Fanny</creatorcontrib><creatorcontrib>Reid, Graeme</creatorcontrib><creatorcontrib>Du, Katie</creatorcontrib><creatorcontrib>Bräsen, Jan H.</creatorcontrib><creatorcontrib>D'Agati, Vivette D.</creatorcontrib><creatorcontrib>Drachenberg, Cinthia B.</creatorcontrib><creatorcontrib>Farkash, Evan A.</creatorcontrib><creatorcontrib>Brad Farris, Alton</creatorcontrib><creatorcontrib>Geldenhuys, Laurette</creatorcontrib><creatorcontrib>Loupy, Alexandre</creatorcontrib><creatorcontrib>Nickeleit, Volker</creatorcontrib><creatorcontrib>Rabant, Marion</creatorcontrib><creatorcontrib>Randhawa, Parmjeet</creatorcontrib><creatorcontrib>Regele, Heinz</creatorcontrib><creatorcontrib>Mengel, Michael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Adam, Benjamin A.</au><au>Kikic, Zeljko</au><au>Wagner, Siegfried</au><au>Bouatou, Yassine</au><au>Gueguen, Juliette</au><au>Drieux, Fanny</au><au>Reid, Graeme</au><au>Du, Katie</au><au>Bräsen, Jan H.</au><au>D'Agati, Vivette D.</au><au>Drachenberg, Cinthia B.</au><au>Farkash, Evan A.</au><au>Brad Farris, Alton</au><au>Geldenhuys, Laurette</au><au>Loupy, Alexandre</au><au>Nickeleit, Volker</au><au>Rabant, Marion</au><au>Randhawa, Parmjeet</au><au>Regele, Heinz</au><au>Mengel, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intragraft gene expression in native kidney BK virus nephropathy versus T cell–mediated rejection: Prospects for molecular diagnosis and risk prediction</atitle><jtitle>American journal of transplantation</jtitle><addtitle>Am J Transplant</addtitle><date>2020-12</date><risdate>2020</risdate><volume>20</volume><issue>12</issue><spage>3486</spage><epage>3501</epage><pages>3486-3501</pages><issn>1600-6135</issn><eissn>1600-6143</eissn><abstract>Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n = 5) vs pure T cell–mediated rejection (TCMR; n = 10). Five polyomavirus genes and seven immune‐related genes (five associated with BKVN and two associated with TCMR) were significantly differentially expressed between these entities (FDR < 0.05). These three sets of genes were further evaluated in samples representing a spectrum of BK infection (n = 25), followed by a multicenter validation cohort of allograft BKVN (n = 60) vs TCMR (n = 10). Polyomavirus 5‐gene set expression reliably distinguished BKVN from TCMR (validation cohort AUC = 0.992), but the immune gene sets demonstrated suboptimal diagnostic performance (AUC ≤ 0.720). Within the validation cohort, no significant differences in index biopsy gene expression were identified between BKVN patients demonstrating resolution (n = 35), persistent infection (n = 14) or de novo rejection (n = 11) 6 months following a standardized reduction in immunosuppression. These results suggest that, while intragraft polyomavirus gene expression may be useful as an ancillary diagnostic for BKVN, assessment for concurrent TCMR and prediction of clinical outcome may not be feasible with current molecular tools.
A comparison of the molecular phenotype of native kidney biopsies with BK virus nephropathy versus transplant kidney biopsies with T cell–mediated rejection demonstrates significant differences in polyomavirus gene expression, but not immune‐related gene expression, between these two entities.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>32372431</pmid><doi>10.1111/ajt.15980</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-1908-1739</orcidid><orcidid>https://orcid.org/0000-0001-5534-7763</orcidid><orcidid>https://orcid.org/0000-0002-7222-3356</orcidid><orcidid>https://orcid.org/0000-0002-7523-3437</orcidid><orcidid>https://orcid.org/0000-0003-3697-3886</orcidid><orcidid>https://orcid.org/0000-0003-3388-7747</orcidid><orcidid>https://orcid.org/0000-0001-5696-6478</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Biopsy BK Virus - genetics clinical research/ practice Gene Expression Graft rejection Graft Rejection - etiology Graft Rejection - genetics Humans Immune system Immunosuppression infection and infectious agents ‐ viral: BK/ JC/ polyoma infectious disease Kidney Kidney Diseases - diagnosis Kidney Diseases - genetics Kidney Transplantation - adverse effects kidney transplantation/ nephrology Kidney transplants Kidneys Lymphocytes T Medical diagnosis molecular biology: mRNA/ mRNA expression Nephropathy pathology/ histopathology Polyomavirus Infections - diagnosis Predictions rejection: T cell–mediated (TCMR) Risk Assessment T-Lymphocytes Tumor Virus Infections - diagnosis Viruses |
title | Intragraft gene expression in native kidney BK virus nephropathy versus T cell–mediated rejection: Prospects for molecular diagnosis and risk prediction |
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