The clinical and molecular significance of C4d staining patterns in renal allografts

Nicole A.M. Hayde, Yi Bao, James M. Pullman, Bin Ye, Brent R. Calder, Monica Chung, Daniel Schwartz, Ahmed Alansari, Graciela De Boccardo, Min Ling, Enver Akalin

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Methods: Two hundred fifty-five clinically indicated transplant biopsies were included in the analyses. C4d staining was performed on paraffin sections using a polyclonal rabbit anti-C4d antibody. Gene expression profiles in a subset of patients were studied using Affymetrix HuGene 1.0ST arrays. Results: Immunohistochemistry for C4d of 255 biopsies showed 51% C4d negative, 4% minimal PTC C4d+, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+ biopsies. Patients with minimal and focal/diffuse PTC C4d+ staining had higher frequency of donor-specific anti-HLA antibodies (DSA) (67% and 82%) and antibody mediated rejection (AMR) (66% and 89%) when compared with C4d-negative biopsies (25% and 19%, respectively) (P<0.001). The glomerulitis, interstitial inflammation, and peritubular capillaritis scores were also significantly higher in minimal (0.88, 1.25, and 1.5) and focal/diffuse PTC C4d+ biopsies (0.65, 1.41, and 1.5), compared with C4d-negative biopsies (0.25, 079, and 0.34), respectively. There were no differences in the DSA frequency, AMR rate, or Banff scores between isolated glomerular C4d+ and C4d-negative patients. Although both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, interferon-gamma and rejection-induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis-based transcripts, there was no activation of immune-response- related genes in isolated glomerular C4d+ biopsies. CONCLUSION: Minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR, circulating DSAs and immune-response-related gene activation.

Original languageEnglish (US)
Pages (from-to)580-588
Number of pages9
JournalTransplantation
Volume95
Issue number4
DOIs
StatePublished - Feb 27 2013

Fingerprint

Allografts
Staining and Labeling
Kidney
Biopsy
Anti-Idiotypic Antibodies
Interferon-gamma
Antibodies
Tissue Donors
Transcriptome
Paraffin
Transcriptional Activation
Immunohistochemistry
Macrophages
Rabbits
Inflammation
T-Lymphocytes
Transplants
Gene Expression
Genes

Keywords

  • C4d
  • Donor-specific anti-HLA antibodies
  • Gene expression
  • Microarrays

ASJC Scopus subject areas

  • Transplantation

Cite this

The clinical and molecular significance of C4d staining patterns in renal allografts. / Hayde, Nicole A.M.; Bao, Yi; Pullman, James M.; Ye, Bin; Calder, Brent R.; Chung, Monica; Schwartz, Daniel; Alansari, Ahmed; De Boccardo, Graciela; Ling, Min; Akalin, Enver.

In: Transplantation, Vol. 95, No. 4, 27.02.2013, p. 580-588.

Research output: Contribution to journalArticle

Hayde, Nicole A.M. ; Bao, Yi ; Pullman, James M. ; Ye, Bin ; Calder, Brent R. ; Chung, Monica ; Schwartz, Daniel ; Alansari, Ahmed ; De Boccardo, Graciela ; Ling, Min ; Akalin, Enver. / The clinical and molecular significance of C4d staining patterns in renal allografts. In: Transplantation. 2013 ; Vol. 95, No. 4. pp. 580-588.
@article{8a59fbcf13c9450b936498d3f382e5d9,
title = "The clinical and molecular significance of C4d staining patterns in renal allografts",
abstract = "Background: We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Methods: Two hundred fifty-five clinically indicated transplant biopsies were included in the analyses. C4d staining was performed on paraffin sections using a polyclonal rabbit anti-C4d antibody. Gene expression profiles in a subset of patients were studied using Affymetrix HuGene 1.0ST arrays. Results: Immunohistochemistry for C4d of 255 biopsies showed 51{\%} C4d negative, 4{\%} minimal PTC C4d+, 15{\%} focal or diffuse PTC C4d+, and 31{\%} isolated glomerular C4d+ biopsies. Patients with minimal and focal/diffuse PTC C4d+ staining had higher frequency of donor-specific anti-HLA antibodies (DSA) (67{\%} and 82{\%}) and antibody mediated rejection (AMR) (66{\%} and 89{\%}) when compared with C4d-negative biopsies (25{\%} and 19{\%}, respectively) (P<0.001). The glomerulitis, interstitial inflammation, and peritubular capillaritis scores were also significantly higher in minimal (0.88, 1.25, and 1.5) and focal/diffuse PTC C4d+ biopsies (0.65, 1.41, and 1.5), compared with C4d-negative biopsies (0.25, 079, and 0.34), respectively. There were no differences in the DSA frequency, AMR rate, or Banff scores between isolated glomerular C4d+ and C4d-negative patients. Although both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, interferon-gamma and rejection-induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis-based transcripts, there was no activation of immune-response- related genes in isolated glomerular C4d+ biopsies. CONCLUSION: Minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR, circulating DSAs and immune-response-related gene activation.",
keywords = "C4d, Donor-specific anti-HLA antibodies, Gene expression, Microarrays",
author = "Hayde, {Nicole A.M.} and Yi Bao and Pullman, {James M.} and Bin Ye and Calder, {Brent R.} and Monica Chung and Daniel Schwartz and Ahmed Alansari and {De Boccardo}, Graciela and Min Ling and Enver Akalin",
year = "2013",
month = "2",
day = "27",
doi = "10.1097/TP.0b013e318277b2e2",
language = "English (US)",
volume = "95",
pages = "580--588",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - The clinical and molecular significance of C4d staining patterns in renal allografts

AU - Hayde, Nicole A.M.

AU - Bao, Yi

AU - Pullman, James M.

AU - Ye, Bin

AU - Calder, Brent R.

AU - Chung, Monica

AU - Schwartz, Daniel

AU - Alansari, Ahmed

AU - De Boccardo, Graciela

AU - Ling, Min

AU - Akalin, Enver

PY - 2013/2/27

Y1 - 2013/2/27

N2 - Background: We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Methods: Two hundred fifty-five clinically indicated transplant biopsies were included in the analyses. C4d staining was performed on paraffin sections using a polyclonal rabbit anti-C4d antibody. Gene expression profiles in a subset of patients were studied using Affymetrix HuGene 1.0ST arrays. Results: Immunohistochemistry for C4d of 255 biopsies showed 51% C4d negative, 4% minimal PTC C4d+, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+ biopsies. Patients with minimal and focal/diffuse PTC C4d+ staining had higher frequency of donor-specific anti-HLA antibodies (DSA) (67% and 82%) and antibody mediated rejection (AMR) (66% and 89%) when compared with C4d-negative biopsies (25% and 19%, respectively) (P<0.001). The glomerulitis, interstitial inflammation, and peritubular capillaritis scores were also significantly higher in minimal (0.88, 1.25, and 1.5) and focal/diffuse PTC C4d+ biopsies (0.65, 1.41, and 1.5), compared with C4d-negative biopsies (0.25, 079, and 0.34), respectively. There were no differences in the DSA frequency, AMR rate, or Banff scores between isolated glomerular C4d+ and C4d-negative patients. Although both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, interferon-gamma and rejection-induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis-based transcripts, there was no activation of immune-response- related genes in isolated glomerular C4d+ biopsies. CONCLUSION: Minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR, circulating DSAs and immune-response-related gene activation.

AB - Background: We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Methods: Two hundred fifty-five clinically indicated transplant biopsies were included in the analyses. C4d staining was performed on paraffin sections using a polyclonal rabbit anti-C4d antibody. Gene expression profiles in a subset of patients were studied using Affymetrix HuGene 1.0ST arrays. Results: Immunohistochemistry for C4d of 255 biopsies showed 51% C4d negative, 4% minimal PTC C4d+, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+ biopsies. Patients with minimal and focal/diffuse PTC C4d+ staining had higher frequency of donor-specific anti-HLA antibodies (DSA) (67% and 82%) and antibody mediated rejection (AMR) (66% and 89%) when compared with C4d-negative biopsies (25% and 19%, respectively) (P<0.001). The glomerulitis, interstitial inflammation, and peritubular capillaritis scores were also significantly higher in minimal (0.88, 1.25, and 1.5) and focal/diffuse PTC C4d+ biopsies (0.65, 1.41, and 1.5), compared with C4d-negative biopsies (0.25, 079, and 0.34), respectively. There were no differences in the DSA frequency, AMR rate, or Banff scores between isolated glomerular C4d+ and C4d-negative patients. Although both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, interferon-gamma and rejection-induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis-based transcripts, there was no activation of immune-response- related genes in isolated glomerular C4d+ biopsies. CONCLUSION: Minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR, circulating DSAs and immune-response-related gene activation.

KW - C4d

KW - Donor-specific anti-HLA antibodies

KW - Gene expression

KW - Microarrays

UR - http://www.scopus.com/inward/record.url?scp=84874665838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874665838&partnerID=8YFLogxK

U2 - 10.1097/TP.0b013e318277b2e2

DO - 10.1097/TP.0b013e318277b2e2

M3 - Article

C2 - 23274969

AN - SCOPUS:84874665838

VL - 95

SP - 580

EP - 588

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 4

ER -