Significance of C4d Banff Scores in Early Protocol Biopsies of Kidney Transplant Recipients with Preformed Donor-Specific Antibodies (DSA)

Loupy, Alexandre; Hill, G. S.; Suberbielle, Caroline; Charron, Dominique; Anglicheau, Dany; Zuber, Julien; Timsit, Marc‐Olivier; Duong, Jean-Paul; Bruneval, Patrick; Vernerey, Déwi; Empana, Jean‐Philippe; Jouven, Xavier; Nochy, Dominique; Legendre, Christophe

doi:10.1111/j.1600-6143.2010.03364.x

Cited by 220 publications

(209 citation statements)

References 29 publications

(36 reference statements)

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“…These patients also had a higher rate of TGP (43%) in follow-up biopsy specimens at 1 year compared with biopsy specimens without subclinical AMR (0%), providing further evidence for C4d2 CAMR (7). The same group also reported that microvascular inflammation and DSA are more robust predictors of poor allograft outcome than C4d positivity (29).…”

Section: Discussionmentioning

confidence: 53%

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

Hayde

Bao

Pullman

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground This study investigated the mechanisms 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 The mean sum score of glomerulitis and peritubular capillaritis increased from 0.2860.78 in IFTA specimens to 0.7560.85 in DSA2/C4d2 TGP specimens, 1.7161.49 in DSA+/C4d2/TGP specimens, and 2.1161.74 in CAMR 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+/C4d2 TGP specimens had higher expression of not only QCAT but also IFN-g 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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Section: Discussionmentioning

confidence: 53%

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

Hayde

Bao

Pullman

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…In solid organ transplant patients, acute CMV infection increases the CD57+ NKGDC hi (memory phenotype) pool, which appears to be CMV specific (179). The effects of CMV and NK cells in the setting of MHC-mismatched grafts are linked to coronary vasculopathy and renal graft injury (180)(181)(182)(183)(184)(185)(186)(187)(188). In part, this is mediated by cytokine-mediated stimulation of alloreactive T cells and by direct alloimmune injury (156).…”

Section: Innate Immune Pathways In CMV Infectionmentioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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“…C4d staining was performed by immunohistochemistry on paraffin sections using the human C4d polyclonal antibody (Biomedica Gruppe, Austria). 23 C4d staining was graded from zero to three by the percentage of peritubular capillaries with linear staining, and grades 2 and 3 were considered to be positive. We integrated humoral parameters (g, ptc, v, cg, and C4d) in a humoral histologic score defined by the sum of these variables.…”

Section: Clinical Datamentioning

confidence: 99%

Molecular Microscope Strategy to Improve Risk Stratification in Early Antibody-Mediated Kidney Allograft Rejection

Loupy

Lefaucheur

Vernerey

et al. 2014

Journal of the American Society of Nephrology

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128

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Antibody-mediated rejection (ABMR) is the leading cause of kidney allograft loss. We investigated whether the addition of gene expression measurements to conventional methods could serve as a molecular microscope to identify kidneys with ABMR that are at high risk for failure. We studied 939 consecutive kidney recipients at Necker Hospital (2004-2010; principal cohort) and 321 kidney recipients at Saint Louis Hospital (2006-2010; validation cohort) and assessed patients with ABMR in the first 1 year post-transplant. In addition to conventional features, we assessed microarray-based gene expression in transplant biopsy specimens using relevant molecular measurements: the ABMR Molecular Score and endothelial donor-specific antibody-selective transcript set. The main outcomes were kidney transplant loss and progression to chronic transplant injury. We identified 74 patients with ABMR in the principal cohort and 54 patients with ABMR in the validation cohort. Conventional features independently associated with failure were donor age and humoral histologic score (g+ptc+v+cg+C4d). Adjusting for conventional features, ABMR Molecular Score (hazard ratio [HR], 2.22; 95% confidence interval [95% CI], 1.37 to 3.58; P=0.001) and endothelial donor-specific antibody-selective transcripts (HR, 3.02; 95% CI, 1.00 to 9.16; P,0.05) independently associated with an increased risk of graft loss. The results were replicated in the independent validation group. Adding a gene expression assessment to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 1.01; 95% CI, 0.57 to 1.46; P,0.001; integrated discrimination improvement, 0.16; P,0.001). Compared with conventional assessment, the addition of gene expression measurement in kidney transplants with ABMR improves stratification of patients at high risk for graft loss.

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Significance of C4d Banff Scores in Early Protocol Biopsies of Kidney Transplant Recipients with Preformed Donor-Specific Antibodies (DSA)

Cited by 220 publications

References 29 publications

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Molecular Microscope Strategy to Improve Risk Stratification in Early Antibody-Mediated Kidney Allograft Rejection

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