Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody

Michelle Lubetzky, Nicole A.M. Hayde, Pilib Ó Broin, Maria Ajaimy, Yi Bao, Omar Mohammed, Daniel Schwartz, James M. Pullman, Enver Akalin

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Abstract

Background: We investigated clinical outcomes and molecular signatures of transplant glomerulopathy (TG) stratified by microvascular inflammation (MVI) and donor-specific antibody (DSA) status. Methods: We performed a retrospective review of 749 kidney transplant patients who received a for-cause kidney biopsy from 2009 to 2014. We classified TG as MVI positive (MVI+) or MVI negative (MVI−), and with or without DSA. We obtained gene expression profiles for 44 biopsies by Affymetrix HuGene 1.0 ST expression arrays. Results: A total of 100 patients had TG; 49 were MVI+, and 51 were MVI−. After a median post-biopsy follow-up of 2.08 years (range 0.43-4.59), Kaplan-Meier survival analysis demonstrated worse allograft survival in MVI+ TG patients compared with MVI− TG patients (P = 0.01), and time to graft failure was significantly shorter in MVI+ patients (1.08 ± 1.01 years vs 2.3 ± 1.8 years; P = 0.002). DSA status did not affect graft survival within MVI+ or MVI− groups. Analysis of pathogenesis-based transcripts (PBT) showed that MVI+ TG biopsies had increased expression of gamma interferon and rejection (GRIT) and DSA-associated transcripts (DSAST), as observed in antibody-mediated rejection. MVI− TG biopsies had increased expression of cytotoxic and regulatory T cell- and B cell-associated transcripts but not GRIT or DSAST. DSA status had no effect on expression of any PBTs studied in MVI− TG biopsies. Conclusions: Graft survival in TG is significantly worse in the presence of MVI. Gene expression profiles of MVI+ TG resemble antibody-mediated rejection while gene expression profiles of MVI− TG resemble cell-mediated rejection regardless of DSA status.

Original languageEnglish (US)
Article numbere13469
JournalClinical Transplantation
DOIs
StatePublished - Jan 1 2019

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Tissue Donors
Inflammation
Transplants
Antibodies
Biopsy
Transcriptome
Graft Survival
Kidney
Kaplan-Meier Estimate
Regulatory T-Lymphocytes
Survival Analysis
Interferon-gamma
Allografts
B-Lymphocytes

Keywords

  • kidney transplant
  • microarray
  • transplant glomerulopathy

ASJC Scopus subject areas

  • Transplantation

Cite this

@article{5f3a12b89c5f43789b0e87bbdb5a1669,
title = "Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody",
abstract = "Background: We investigated clinical outcomes and molecular signatures of transplant glomerulopathy (TG) stratified by microvascular inflammation (MVI) and donor-specific antibody (DSA) status. Methods: We performed a retrospective review of 749 kidney transplant patients who received a for-cause kidney biopsy from 2009 to 2014. We classified TG as MVI positive (MVI+) or MVI negative (MVI−), and with or without DSA. We obtained gene expression profiles for 44 biopsies by Affymetrix HuGene 1.0 ST expression arrays. Results: A total of 100 patients had TG; 49 were MVI+, and 51 were MVI−. After a median post-biopsy follow-up of 2.08 years (range 0.43-4.59), Kaplan-Meier survival analysis demonstrated worse allograft survival in MVI+ TG patients compared with MVI− TG patients (P = 0.01), and time to graft failure was significantly shorter in MVI+ patients (1.08 ± 1.01 years vs 2.3 ± 1.8 years; P = 0.002). DSA status did not affect graft survival within MVI+ or MVI− groups. Analysis of pathogenesis-based transcripts (PBT) showed that MVI+ TG biopsies had increased expression of gamma interferon and rejection (GRIT) and DSA-associated transcripts (DSAST), as observed in antibody-mediated rejection. MVI− TG biopsies had increased expression of cytotoxic and regulatory T cell- and B cell-associated transcripts but not GRIT or DSAST. DSA status had no effect on expression of any PBTs studied in MVI− TG biopsies. Conclusions: Graft survival in TG is significantly worse in the presence of MVI. Gene expression profiles of MVI+ TG resemble antibody-mediated rejection while gene expression profiles of MVI− TG resemble cell-mediated rejection regardless of DSA status.",
keywords = "kidney transplant, microarray, transplant glomerulopathy",
author = "Michelle Lubetzky and Hayde, {Nicole A.M.} and {{\'O} Broin}, Pilib and Maria Ajaimy and Yi Bao and Omar Mohammed and Daniel Schwartz and Pullman, {James M.} and Enver Akalin",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/ctr.13469",
language = "English (US)",
journal = "Clinical Transplantation",
issn = "0902-0063",
publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody

AU - Lubetzky, Michelle

AU - Hayde, Nicole A.M.

AU - Ó Broin, Pilib

AU - Ajaimy, Maria

AU - Bao, Yi

AU - Mohammed, Omar

AU - Schwartz, Daniel

AU - Pullman, James M.

AU - Akalin, Enver

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: We investigated clinical outcomes and molecular signatures of transplant glomerulopathy (TG) stratified by microvascular inflammation (MVI) and donor-specific antibody (DSA) status. Methods: We performed a retrospective review of 749 kidney transplant patients who received a for-cause kidney biopsy from 2009 to 2014. We classified TG as MVI positive (MVI+) or MVI negative (MVI−), and with or without DSA. We obtained gene expression profiles for 44 biopsies by Affymetrix HuGene 1.0 ST expression arrays. Results: A total of 100 patients had TG; 49 were MVI+, and 51 were MVI−. After a median post-biopsy follow-up of 2.08 years (range 0.43-4.59), Kaplan-Meier survival analysis demonstrated worse allograft survival in MVI+ TG patients compared with MVI− TG patients (P = 0.01), and time to graft failure was significantly shorter in MVI+ patients (1.08 ± 1.01 years vs 2.3 ± 1.8 years; P = 0.002). DSA status did not affect graft survival within MVI+ or MVI− groups. Analysis of pathogenesis-based transcripts (PBT) showed that MVI+ TG biopsies had increased expression of gamma interferon and rejection (GRIT) and DSA-associated transcripts (DSAST), as observed in antibody-mediated rejection. MVI− TG biopsies had increased expression of cytotoxic and regulatory T cell- and B cell-associated transcripts but not GRIT or DSAST. DSA status had no effect on expression of any PBTs studied in MVI− TG biopsies. Conclusions: Graft survival in TG is significantly worse in the presence of MVI. Gene expression profiles of MVI+ TG resemble antibody-mediated rejection while gene expression profiles of MVI− TG resemble cell-mediated rejection regardless of DSA status.

AB - Background: We investigated clinical outcomes and molecular signatures of transplant glomerulopathy (TG) stratified by microvascular inflammation (MVI) and donor-specific antibody (DSA) status. Methods: We performed a retrospective review of 749 kidney transplant patients who received a for-cause kidney biopsy from 2009 to 2014. We classified TG as MVI positive (MVI+) or MVI negative (MVI−), and with or without DSA. We obtained gene expression profiles for 44 biopsies by Affymetrix HuGene 1.0 ST expression arrays. Results: A total of 100 patients had TG; 49 were MVI+, and 51 were MVI−. After a median post-biopsy follow-up of 2.08 years (range 0.43-4.59), Kaplan-Meier survival analysis demonstrated worse allograft survival in MVI+ TG patients compared with MVI− TG patients (P = 0.01), and time to graft failure was significantly shorter in MVI+ patients (1.08 ± 1.01 years vs 2.3 ± 1.8 years; P = 0.002). DSA status did not affect graft survival within MVI+ or MVI− groups. Analysis of pathogenesis-based transcripts (PBT) showed that MVI+ TG biopsies had increased expression of gamma interferon and rejection (GRIT) and DSA-associated transcripts (DSAST), as observed in antibody-mediated rejection. MVI− TG biopsies had increased expression of cytotoxic and regulatory T cell- and B cell-associated transcripts but not GRIT or DSAST. DSA status had no effect on expression of any PBTs studied in MVI− TG biopsies. Conclusions: Graft survival in TG is significantly worse in the presence of MVI. Gene expression profiles of MVI+ TG resemble antibody-mediated rejection while gene expression profiles of MVI− TG resemble cell-mediated rejection regardless of DSA status.

KW - kidney transplant

KW - microarray

KW - transplant glomerulopathy

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U2 - 10.1111/ctr.13469

DO - 10.1111/ctr.13469

M3 - Article

JO - Clinical Transplantation

JF - Clinical Transplantation

SN - 0902-0063

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