Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States

Trifecta-Kidney Investigators; Patrick T. Gauthier; Katelynn S. Madill-Thomsen; Zachary Demko; Adam Prewett; Philippe Gauthier; Philip F. Halloran; Justyna Fryc; Beata Naumnik; Jonathan Bromberg; Matt Weir; Nadiesa Costa; Daniel Brennan; Sam Kant; Vignesh Viswanathan; Milagros Samaniego-Picota; Iman Francis; Anita Patel; Alicja Dȩbska-Ślizień; Joanna Konopa; Andrzej Chamienia; Andrzej Wiȩcek; Grzegorz Piecha; Željka Veceric-Haler; Miha Arnol; Nika Kojc; Maciej Glyda; Katarzyna Smykal-Jankowiak; Ondrej Viklicky; Petra Hruba; Silvie Rajnochová Bloudíčkova; Janka Slatinská; Marius Miglinas; Marek Myślak; Joanna Mazurkiewicz; Marta Gryczman; Leszek Domański; Mahmoud Kamel; Agnieszka Perkowska-Ptasińska; Dominika Dȩborska-Materkowska; Michal Ciszek; Magdalena Durlik; Ryszard Grenda; Miroslaw Banasik; Mladen Knotek; Ksenija Vucur; Zeljka Jurekovic; Thomas Müller; Thomas Schachtner; Andrew Malone; Tarek Alhamad; Arksarapuk Jittirat; Emilio Poggio; Richard Fatica; Ziad Zaky; Kevin Chow; Peter Hughes; Sanjiv Anand; Gaurav Gupta; Layla Kamal; Dhiren Kumar; Irfan Moinuddin; Sindhura Bobba

doi:10.1097/TP.0000000000004877

Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States

Trifecta-Kidney Investigators, Patrick T. Gauthier, Katelynn S. Madill-Thomsen, Zachary Demko, Adam Prewett, Philippe Gauthier, Philip F. Halloran, Justyna Fryc, Beata Naumnik, Jonathan Bromberg, Matt Weir, Nadiesa Costa, Daniel Brennan, Sam Kant, Vignesh Viswanathan, Milagros Samaniego-Picota, Iman Francis, Anita Patel, Alicja Dȩbska-Ślizień, Joanna KonopaAndrzej Chamienia, Andrzej Wiȩcek, Grzegorz Piecha, Željka Veceric-Haler, Miha Arnol, Nika Kojc, Maciej Glyda, Katarzyna Smykal-Jankowiak, Ondrej Viklicky, Petra Hruba, Silvie Rajnochová Bloudíčkova, Janka Slatinská, Marius Miglinas, Marek Myślak, Joanna Mazurkiewicz, Marta Gryczman, Leszek Domański, Mahmoud Kamel, Agnieszka Perkowska-Ptasińska, Dominika Dȩborska-Materkowska, Michal Ciszek, Magdalena Durlik, Ryszard Grenda, Miroslaw Banasik, Mladen Knotek, Ksenija Vucur, Zeljka Jurekovic, Thomas Müller, Thomas Schachtner, Andrew Malone, Tarek Alhamad, Arksarapuk Jittirat, Emilio Poggio, Richard Fatica, Ziad Zaky, Kevin Chow, Peter Hughes, Sanjiv Anand, Gaurav Gupta, Layla Kamal, Dhiren Kumar, Irfan Moinuddin, Sindhura Bobba

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Abstract

Background. Among all biopsies in the Trifecta-Kidney Study (ClinicalTrials.gov NCT04239703), elevated plasma donor-derived cell-free DNA (dd-cfDNA) correlated most strongly with molecular antibody-mediated rejection (AMR) but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. Methods. Dd-cfDNA was measured by the Prospera test. Molecular rejection and injury states were defined using the Molecular Microscope system. We studied the correlation between dd-cfDNA and the expression of genes, transcript sets, and classifier scores within specific disease states, and compared AMR, TCMR, and AKI to biopsies classified as normal and no injury (NRNI). Results. In all 604 biopsies, dd-cfDNA was elevated in AMR, TCMR, and AKI. Within AMR biopsies, dd-cfDNA correlated with AMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as MMDx Normal and archetypal No injury (NRNI), dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (eg, the TCMR_Probclassifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. Conclusions. In kidney transplants, elevated plasma dd-cfDNA is associated with 3 distinct molecular states in the donor tissue: AMR, recent parenchymal injury (including cell cycling), and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.

Original language	English
Pages (from-to)	898-910
Number of pages	13
Journal	Transplantation
Volume	108
Issue number	4
DOIs	https://doi.org/10.1097/TP.0000000000004877
State	Published - Apr 1 2024

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Trifecta-Kidney Investigators, Gauthier, P. T., Madill-Thomsen, K. S., Demko, Z., Prewett, A., Gauthier, P., Halloran, P. F., Fryc, J., Naumnik, B., Bromberg, J., Weir, M., Costa, N., Brennan, D., Kant, S., Viswanathan, V., Samaniego-Picota, M., Francis, I., Patel, A., Dȩbska-Ślizień, A., ... Bobba, S. (2024). Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States. Transplantation, 108(4), 898-910. https://doi.org/10.1097/TP.0000000000004877

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title = "Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States",

abstract = "Background. Among all biopsies in the Trifecta-Kidney Study (ClinicalTrials.gov NCT04239703), elevated plasma donor-derived cell-free DNA (dd-cfDNA) correlated most strongly with molecular antibody-mediated rejection (AMR) but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. Methods. Dd-cfDNA was measured by the Prospera test. Molecular rejection and injury states were defined using the Molecular Microscope system. We studied the correlation between dd-cfDNA and the expression of genes, transcript sets, and classifier scores within specific disease states, and compared AMR, TCMR, and AKI to biopsies classified as normal and no injury (NRNI). Results. In all 604 biopsies, dd-cfDNA was elevated in AMR, TCMR, and AKI. Within AMR biopsies, dd-cfDNA correlated with AMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as MMDx Normal and archetypal No injury (NRNI), dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (eg, the TCMRProbclassifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. Conclusions. In kidney transplants, elevated plasma dd-cfDNA is associated with 3 distinct molecular states in the donor tissue: AMR, recent parenchymal injury (including cell cycling), and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.",

author = "{Trifecta-Kidney Investigators} and Gauthier, {Patrick T.} and Madill-Thomsen, {Katelynn S.} and Zachary Demko and Adam Prewett and Philippe Gauthier and Halloran, {Philip F.} and Justyna Fryc and Beata Naumnik and Jonathan Bromberg and Matt Weir and Nadiesa Costa and Daniel Brennan and Sam Kant and Vignesh Viswanathan and Milagros Samaniego-Picota and Iman Francis and Anita Patel and Alicja Dȩbska-{\'S}lizie{\'n} and Joanna Konopa and Andrzej Chamienia and Andrzej Wiȩcek and Grzegorz Piecha and {\v Z}eljka Veceric-Haler and Miha Arnol and Nika Kojc and Maciej Glyda and Katarzyna Smykal-Jankowiak and Ondrej Viklicky and Petra Hruba and Bloud{\'i}{\v c}kova, {Silvie Rajnochov{\'a}} and Janka Slatinsk{\'a} and Marius Miglinas and Marek My{\'s}lak and Joanna Mazurkiewicz and Marta Gryczman and Leszek Doma{\'n}ski and Mahmoud Kamel and Agnieszka Perkowska-Ptasi{\'n}ska and Dominika Dȩborska-Materkowska and Michal Ciszek and Magdalena Durlik and Ryszard Grenda and Miroslaw Banasik and Mladen Knotek and Ksenija Vucur and Zeljka Jurekovic and Thomas M{\"u}ller and Thomas Schachtner and Andrew Malone and Tarek Alhamad and Arksarapuk Jittirat and Emilio Poggio and Richard Fatica and Ziad Zaky and Kevin Chow and Peter Hughes and Sanjiv Anand and Gaurav Gupta and Layla Kamal and Dhiren Kumar and Irfan Moinuddin and Sindhura Bobba",

year = "2024",

month = apr,

day = "1",

doi = "10.1097/TP.0000000000004877",

language = "English",

volume = "108",

pages = "898--910",

journal = "Transplantation",

issn = "0041-1337",

number = "4",

}

Trifecta-Kidney Investigators, Gauthier, PT, Madill-Thomsen, KS, Demko, Z, Prewett, A, Gauthier, P, Halloran, PF, Fryc, J, Naumnik, B, Bromberg, J, Weir, M, Costa, N, Brennan, D, Kant, S, Viswanathan, V, Samaniego-Picota, M, Francis, I, Patel, A, Dȩbska-Ślizień, A, Konopa, J, Chamienia, A, Wiȩcek, A, Piecha, G, Veceric-Haler, Ž, Arnol, M, Kojc, N, Glyda, M, Smykal-Jankowiak, K, Viklicky, O, Hruba, P, Bloudíčkova, SR, Slatinská, J, Miglinas, M, Myślak, M, Mazurkiewicz, J, Gryczman, M, Domański, L, Kamel, M, Perkowska-Ptasińska, A, Dȩborska-Materkowska, D, Ciszek, M, Durlik, M, Grenda, R, Banasik, M, Knotek, M, Vucur, K, Jurekovic, Z, Müller, T, Schachtner, T, Malone, A, Alhamad, T, Jittirat, A, Poggio, E, Fatica, R, Zaky, Z, Chow, K, Hughes, P, Anand, S, Gupta, G, Kamal, L, Kumar, D, Moinuddin, I & Bobba, S 2024, 'Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States', Transplantation, vol. 108, no. 4, pp. 898-910. https://doi.org/10.1097/TP.0000000000004877

TY - JOUR

T1 - Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States

AU - Trifecta-Kidney Investigators

AU - Gauthier, Patrick T.

AU - Madill-Thomsen, Katelynn S.

AU - Demko, Zachary

AU - Prewett, Adam

AU - Gauthier, Philippe

AU - Halloran, Philip F.

AU - Fryc, Justyna

AU - Naumnik, Beata

AU - Bromberg, Jonathan

AU - Weir, Matt

AU - Costa, Nadiesa

AU - Brennan, Daniel

AU - Kant, Sam

AU - Viswanathan, Vignesh

AU - Samaniego-Picota, Milagros

AU - Francis, Iman

AU - Patel, Anita

AU - Dȩbska-Ślizień, Alicja

AU - Konopa, Joanna

AU - Chamienia, Andrzej

AU - Wiȩcek, Andrzej

AU - Piecha, Grzegorz

AU - Veceric-Haler, Željka

AU - Arnol, Miha

AU - Kojc, Nika

AU - Glyda, Maciej

AU - Smykal-Jankowiak, Katarzyna

AU - Viklicky, Ondrej

AU - Hruba, Petra

AU - Bloudíčkova, Silvie Rajnochová

AU - Slatinská, Janka

AU - Miglinas, Marius

AU - Myślak, Marek

AU - Mazurkiewicz, Joanna

AU - Gryczman, Marta

AU - Domański, Leszek

AU - Kamel, Mahmoud

AU - Perkowska-Ptasińska, Agnieszka

AU - Dȩborska-Materkowska, Dominika

AU - Ciszek, Michal

AU - Durlik, Magdalena

AU - Grenda, Ryszard

AU - Banasik, Miroslaw

AU - Knotek, Mladen

AU - Vucur, Ksenija

AU - Jurekovic, Zeljka

AU - Müller, Thomas

AU - Schachtner, Thomas

AU - Malone, Andrew

AU - Alhamad, Tarek

AU - Jittirat, Arksarapuk

AU - Poggio, Emilio

AU - Fatica, Richard

AU - Zaky, Ziad

AU - Chow, Kevin

AU - Hughes, Peter

AU - Anand, Sanjiv

AU - Gupta, Gaurav

AU - Kamal, Layla

AU - Kumar, Dhiren

AU - Moinuddin, Irfan

AU - Bobba, Sindhura

PY - 2024/4/1

Y1 - 2024/4/1

N2 - Background. Among all biopsies in the Trifecta-Kidney Study (ClinicalTrials.gov NCT04239703), elevated plasma donor-derived cell-free DNA (dd-cfDNA) correlated most strongly with molecular antibody-mediated rejection (AMR) but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. Methods. Dd-cfDNA was measured by the Prospera test. Molecular rejection and injury states were defined using the Molecular Microscope system. We studied the correlation between dd-cfDNA and the expression of genes, transcript sets, and classifier scores within specific disease states, and compared AMR, TCMR, and AKI to biopsies classified as normal and no injury (NRNI). Results. In all 604 biopsies, dd-cfDNA was elevated in AMR, TCMR, and AKI. Within AMR biopsies, dd-cfDNA correlated with AMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as MMDx Normal and archetypal No injury (NRNI), dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (eg, the TCMRProbclassifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. Conclusions. In kidney transplants, elevated plasma dd-cfDNA is associated with 3 distinct molecular states in the donor tissue: AMR, recent parenchymal injury (including cell cycling), and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.

AB - Background. Among all biopsies in the Trifecta-Kidney Study (ClinicalTrials.gov NCT04239703), elevated plasma donor-derived cell-free DNA (dd-cfDNA) correlated most strongly with molecular antibody-mediated rejection (AMR) but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. Methods. Dd-cfDNA was measured by the Prospera test. Molecular rejection and injury states were defined using the Molecular Microscope system. We studied the correlation between dd-cfDNA and the expression of genes, transcript sets, and classifier scores within specific disease states, and compared AMR, TCMR, and AKI to biopsies classified as normal and no injury (NRNI). Results. In all 604 biopsies, dd-cfDNA was elevated in AMR, TCMR, and AKI. Within AMR biopsies, dd-cfDNA correlated with AMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as MMDx Normal and archetypal No injury (NRNI), dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (eg, the TCMRProbclassifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. Conclusions. In kidney transplants, elevated plasma dd-cfDNA is associated with 3 distinct molecular states in the donor tissue: AMR, recent parenchymal injury (including cell cycling), and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.

UR - http://www.scopus.com/inward/record.url?scp=85188839332&partnerID=8YFLogxK

U2 - 10.1097/TP.0000000000004877

DO - 10.1097/TP.0000000000004877

M3 - Article

C2 - 38150492

AN - SCOPUS:85188839332

SN - 0041-1337

VL - 108

SP - 898

EP - 910

JO - Transplantation

JF - Transplantation

IS - 4

ER -

Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release from Kidney Transplants in Different Disease States

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