Detection of Cytomegalovirus (CMV) Antigens in Kidney Biopsies and Transplant Nephrectomies as a Marker for Renal Graft Dysfunction

Gerstenkorn, C.; Robertson, Helen Lee; Mohamed, Mostafa; O’Donnell, Marie; Ali, Simi; Talbot, David

doi:10.1515/cclm.2000.188

Cited by 12 publications

(8 citation statements)

References 14 publications

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“…Our study did not identify evidence of significant viral replication in the renal allograft at 2 years after transplantation, suggesting that graft dysfunction is not related to chronic tissue infection. Thus, whether direct viral cytopathic effects, [25][26][27][28] indirect inflammatory effects, 25 or a combination of multiple mechanisms leads to allograft injury remains a key question for future studies.…”

Section: Discussionmentioning

confidence: 99%

Subclinical Viremia Increases Risk for Chronic Allograft Injury in Pediatric Renal Transplantation

Smith

Corey

Bittner

et al. 2010

Journal of the American Society of Nephrology

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The impact of subclinical viral infection on chronic allograft injury in the pediatric renal transplant population is not well defined. We prospectively assessed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia by monthly PCR in 55 pediatric renal transplant recipients for the first 2 years after transplantation. Subclinical CMV and EBV infection occurred in 22 and 36%, respectively. Multivariable linear regression analysis suggested that both subclinical CMV and EBV infection independently associate with significant declines in GFR during the first 2 years after transplantation. CMV seronegativity associated with a significantly greater decline in GFR than seropositivity (P Ͻ 0.01). Subclinical CMV infection and subclinical EBV infection each associated with approximately fourfold greater odds of histologic evidence of chronic allograft injury (odds ratio 4.61 [95% confidence interval 1.18 to 18.07] and odds ratio 4.33 [95% confidence interval 1.34 to 14.00], respectively). An increase in viral load of CMV or EBV also associated with increased risk for moderate to severe chronic allograft injury. Taken together, these results demonstrate an association between subclinical CMV and EBV infections, which occur despite standard antiviral prophylaxis, and chronic allograft injury in pediatric renal transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Subclinical Viremia Increases Risk for Chronic Allograft Injury in Pediatric Renal Transplantation

Smith

Corey

Bittner

et al. 2010

Journal of the American Society of Nephrology

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“…Seroepidemiologic studies have associated human CMV (HCMV)-positive donor or recipient serostatus with inferior graft outcome compared with HCMV-seronegative transplantations (6–10). HCMV antigens have been identified more often in biopsies from rejecting organs compared with those without rejection, supporting an association between expression of viral gene products and rejection (11–13). The combination of CMV and acute rejection has also been associated with more severe vascular changes in 6-month protocol renal allograft biopsies (14).…”

mentioning

confidence: 91%

Ganciclovir Transiently Attenuates Murine Cytomegalovirus-Associated Renal Allograft Inflammation

Shimamura

Saunders²,

Rha³

et al. 2011

Transplantation

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Background. Prophylactic ganciclovir (GCV) is used in high-risk renal transplant patients to prevent acute cytomegalovirus (CMV) disease, but its impact on inflammation within the allograft itself remains undefined. Methods. To study the effect of GCV prophylaxis on allograft inflammation, murine CMV (MCMV)-infected allo-grafts were analyzed in a murine donor positive/recipient negative allogeneic renal transplantation model by flow cytometry and immunofluorescent staining. Results. By flow cytometry, CD45+ leukocyte infiltrates were more abundant in MCMV-infected allografts at 14 days posttransplant compared with uninfected grafts (P<0.01) and decreased in the presence of GCV (P<0.05). CD11c+ dendritic cells, Gr-1+ myeloid cells, CD204+ macrophages, and CD49b+ natural killer cells were reduced in GCV-treated allografts compared with MCMV-infected grafts without GCV treatment (P<0.05). However, GCV failed to reduce these cell types to levels found in MCMV-uninfected allografts. By day 7 after cessation of GCV prophylaxis, dendritic cells, macrophages, and natural killer cells increased in number and became statistically indistinguishable from numbers of cells found in MCMV-infected allografts without GCV. GCV treatment did not affect the numbers of CD4+, CD8+, or CD19+/B220+ lymphocytes infiltrating the allografts. Infiltrates were confirmed histologically by immunofluorescent staining for CD3+ and CD11b+ cells. Conclusions. In this model, MCMV-infected allografts developed significantly greater innate and adaptive leukocytic infiltrates compared with uninfected grafts. GCV attenuated the MCMV-associated innate leukocyte infiltrates in infected allo-grafts but not the lymphocytic infiltrates. The attenuated innate response was limited to the period of GCV prophylaxis.

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“…HCMV antigens have also been detected in tubular cells of biopsies from HCMV seropositive patients with rejection [34]. Furthermore, HCMV has been detected more often in renal tubular epithelium of allograft biopsies with rejection compared to those without rejection using both immunohistochemistry and in situ hybridization [35], [36].…”

Section: Introductionmentioning

confidence: 99%

Human Cytomegalovirus Induces TGF-β1 Activation in Renal Tubular Epithelial Cells after Epithelial-to-Mesenchymal Transition

2010

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Human cytomegalovirus (HCMV) infection is associated epidemiologically with poor outcome of renal allografts due to mechanisms which remain largely undefined. Transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine, is more abundant in rejecting renal allografts that are infected with either HCMV or rat CMV as compared to uninfected, rejecting grafts. TGF-β1 induces renal fibrosis via epithelial-to-mesenchymal transition (EMT) of renal epithelial cells, a process by which epithelial cells acquire mesenchymal characteristics and a migratory phenotype, and secrete molecules associated with extracellular matrix deposition and remodeling. We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome.

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Detection of Cytomegalovirus (CMV) Antigens in Kidney Biopsies and Transplant Nephrectomies as a Marker for Renal Graft Dysfunction

Cited by 12 publications

References 14 publications

Subclinical Viremia Increases Risk for Chronic Allograft Injury in Pediatric Renal Transplantation

Subclinical Viremia Increases Risk for Chronic Allograft Injury in Pediatric Renal Transplantation

Ganciclovir Transiently Attenuates Murine Cytomegalovirus-Associated Renal Allograft Inflammation

Human Cytomegalovirus Induces TGF-β1 Activation in Renal Tubular Epithelial Cells after Epithelial-to-Mesenchymal Transition

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