The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy

Nicole A.M. Hayde, Yi Bao, James M. Pullman, Bin Ye, R. Brent Calder, Monica Chung, Daniel Schwartz, Michelle Lubetzky, Maria Ajaimy, Graciela de Boccardo, Enver Akalin

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Abstract

Background This study investigated themechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays. Design, Setting, Participants, & Measurements This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d2 TGP, 25 DSA2/C4d2 TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays. Results Themean sumscore of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA2/C4d2TGP specimens, 1.71±1.49 in DSA+/C4d2/TGP specimens, and 2.11±1.74 inCAMR specimens (P<0.001).During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d2 TGP specimens (14.3%), and DSA2/C4d2 TGP specimens (16%) (P=0.01).With use of microarrays, comparison of the gene expression profiles of DSA2/C4d2 TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT).However, both CAMR and DSA+/C4d2TGP specimens had higher expression of not onlyQCATbut also IFN-γ and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens. Conclusions These results suggested that DSA+/C4d2 TGP biopsy specimens may be classified as CAMR. In contrast, DSA2/C4d2 TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.

Original languageEnglish (US)
Pages (from-to)2141-2148
Number of pages8
JournalClinical Journal of the American Society of Nephrology
Volume8
Issue number12
DOIs
StatePublished - Dec 6 2013

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Tissue Donors
Transplants
Antibodies
Biopsy
Atrophy
Fibrosis
T-Lymphocytes
Kidney
Transcriptome
Natural Killer Cells
Allografts
Cohort Studies
Endothelial Cells
Macrophages
Wounds and Injuries
Population
Genes

ASJC Scopus subject areas

  • Nephrology
  • Transplantation
  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

@article{2a1bf879b8a1404faa619db7f87aab71,
title = "The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy",
abstract = "Background This study investigated themechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays. Design, Setting, Participants, & Measurements This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d2 TGP, 25 DSA2/C4d2 TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays. Results Themean sumscore of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA2/C4d2TGP specimens, 1.71±1.49 in DSA+/C4d2/TGP specimens, and 2.11±1.74 inCAMR specimens (P<0.001).During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8{\%}) compared to IFTA specimens (8.5{\%}), DSA+/C4d2 TGP specimens (14.3{\%}), and DSA2/C4d2 TGP specimens (16{\%}) (P=0.01).With use of microarrays, comparison of the gene expression profiles of DSA2/C4d2 TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT).However, both CAMR and DSA+/C4d2TGP specimens had higher expression of not onlyQCATbut also IFN-γ and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens. Conclusions These results suggested that DSA+/C4d2 TGP biopsy specimens may be classified as CAMR. In contrast, DSA2/C4d2 TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.",
author = "Hayde, {Nicole A.M.} and Yi Bao and Pullman, {James M.} and Bin Ye and {Brent Calder}, R. and Monica Chung and Daniel Schwartz and Michelle Lubetzky and Maria Ajaimy and {de Boccardo}, Graciela and Enver Akalin",
year = "2013",
month = "12",
day = "6",
doi = "10.2215/CJN.04240413",
language = "English (US)",
volume = "8",
pages = "2141--2148",
journal = "Clinical Journal of the American Society of Nephrology",
issn = "1555-9041",
publisher = "American Society of Nephrology",
number = "12",

}

TY - JOUR

T1 - The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy

AU - Hayde, Nicole A.M.

AU - Bao, Yi

AU - Pullman, James M.

AU - Ye, Bin

AU - Brent Calder, R.

AU - Chung, Monica

AU - Schwartz, Daniel

AU - Lubetzky, Michelle

AU - Ajaimy, Maria

AU - de Boccardo, Graciela

AU - Akalin, Enver

PY - 2013/12/6

Y1 - 2013/12/6

N2 - Background This study investigated themechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays. Design, Setting, Participants, & Measurements This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d2 TGP, 25 DSA2/C4d2 TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays. Results Themean sumscore of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA2/C4d2TGP specimens, 1.71±1.49 in DSA+/C4d2/TGP specimens, and 2.11±1.74 inCAMR specimens (P<0.001).During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d2 TGP specimens (14.3%), and DSA2/C4d2 TGP specimens (16%) (P=0.01).With use of microarrays, comparison of the gene expression profiles of DSA2/C4d2 TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT).However, both CAMR and DSA+/C4d2TGP specimens had higher expression of not onlyQCATbut also IFN-γ and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens. Conclusions These results suggested that DSA+/C4d2 TGP biopsy specimens may be classified as CAMR. In contrast, DSA2/C4d2 TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.

AB - Background This study investigated themechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays. Design, Setting, Participants, & Measurements This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d2 TGP, 25 DSA2/C4d2 TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays. Results Themean sumscore of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA2/C4d2TGP specimens, 1.71±1.49 in DSA+/C4d2/TGP specimens, and 2.11±1.74 inCAMR specimens (P<0.001).During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d2 TGP specimens (14.3%), and DSA2/C4d2 TGP specimens (16%) (P=0.01).With use of microarrays, comparison of the gene expression profiles of DSA2/C4d2 TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT).However, both CAMR and DSA+/C4d2TGP specimens had higher expression of not onlyQCATbut also IFN-γ and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens. Conclusions These results suggested that DSA+/C4d2 TGP biopsy specimens may be classified as CAMR. In contrast, DSA2/C4d2 TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.

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JO - Clinical Journal of the American Society of Nephrology

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SN - 1555-9041

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