WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

Michael E. Seifert; Joseph P. Gaut; Boyi Guo; Sanjay Jain; Andrew F. Malone; Feargal Geraghty; Deborah L. Della Manna; Eddy S. Yang; Nengjun Yi; Daniel C. Brennan; Roslyn B. Mannon

doi:10.1111/ajt.15372

WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

Michael E. Seifert, Joseph P. Gaut, Boyi Guo, Sanjay Jain, Andrew F. Malone, Feargal Geraghty, Deborah L. Della Manna, Eddy S. Yang, Nengjun Yi, Daniel C. Brennan, Roslyn B. Mannon

Radiation Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target.

Original language	English
Pages (from-to)	2833-2845
Number of pages	13
Journal	American Journal of Transplantation
Volume	19
Issue number	10
DOIs	https://doi.org/10.1111/ajt.15372
State	Published - Oct 1 2019

Bibliographical note

Funding Information:
Funding information This work was supported by grants K23 DK101690 and L40 DK099748 from the National Institute of Diabetes and Digestive and Kidney Diseases (to Dr Seifert). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors wish to thank Keith Hruska for his WNT pathway expertise and initial scientific discussions that helped shape this project and Jennifer Pollock for ongoing scientific discussion and advice throughout the project. The authors also wish to thank Diane Solomon for her assistance in procuring biospecimens from the Washington University Kidney Translational Research Center for this study.

Publisher Copyright:
© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

antibody-mediated rejection (ABMR)
genomics
graft survival
kidney (allograft) function/dysfunction
kidney transplantation/nephrology
pathology/histopathology
rejection
translational research/science
vascular biology

ASJC Scopus subject areas

Immunology and Allergy
Transplantation
Pharmacology (medical)

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10.1111/ajt.15372

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title = "WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure",

abstract = "Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target.",

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author = "Seifert, {Michael E.} and Gaut, {Joseph P.} and Boyi Guo and Sanjay Jain and Malone, {Andrew F.} and Feargal Geraghty and {Della Manna}, {Deborah L.} and Yang, {Eddy S.} and Nengjun Yi and Brennan, {Daniel C.} and Mannon, {Roslyn B.}",

note = "Funding Information: Funding information This work was supported by grants K23 DK101690 and L40 DK099748 from the National Institute of Diabetes and Digestive and Kidney Diseases (to Dr Seifert). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors wish to thank Keith Hruska for his WNT pathway expertise and initial scientific discussions that helped shape this project and Jennifer Pollock for ongoing scientific discussion and advice throughout the project. The authors also wish to thank Diane Solomon for her assistance in procuring biospecimens from the Washington University Kidney Translational Research Center for this study. Publisher Copyright: {\textcopyright} 2019 The American Society of Transplantation and the American Society of Transplant Surgeons",

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AU - Jain, Sanjay

AU - Malone, Andrew F.

AU - Geraghty, Feargal

AU - Della Manna, Deborah L.

AU - Yang, Eddy S.

AU - Yi, Nengjun

AU - Brennan, Daniel C.

AU - Mannon, Roslyn B.

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N2 - Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target.

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KW - translational research/science

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WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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