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
Hauptverfasser: 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
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container_issue 12
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container_title American journal of transplantation
container_volume 20
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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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 &lt; 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><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 &lt; 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. ; 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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 &lt; 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. 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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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