Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival

Džabić, Mensur; Rahbar, Afsar; Yaiw, Koon-Chu; Naghibi, Mansour; Religa, Piotr; Fellström, Bengt; Larsson, Erik; Söderberg‐Nauclér, Cecilia

doi:10.1093/cid/cir619

Cited by 56 publications

(47 citation statements)

References 199 publications

(214 reference statements)

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“…CMV has multiple additional survival strategies that target hosts' adaptive and innate immune functions, that diminish mobilization of phagocytes and antigen presentation, and that produce homologs of host cytokine and chemokine receptors (1-7); however, the mechanisms linking CMV infection with diminished graft function are incompletely understood (8). CMV infections of grafts cause what have been termed "direct effects" in the allograft, including inflammation, vasculopathy and fibrosis with resultant chronic allograft dysfunction (9)(10)(11)(12). "Indirect effects," or systemic effects beyond those attributable to direct viral injury, are mediated by upregulation of specific T and B cell alloimmune responses by innate immune mechanisms (inflammatory mediators, mobilization of antigenpresenting cells with improved antigen presentation, diminished regulatory responses) or by stimulation of alloimmunity by cross-reactive viral antigens with resultant graft injury.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

“…Furthermore, most studies have indicated that successful antiviral prophylaxis has a beneficial effect on long-term graft function (8). This suggests that viral replication is a component of risk, but the precise mechanisms underlying this effect are debated (9,11,(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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“…Persistent CMV infection measured by immunohistochemistry in the allograft biopsy of kidney transplant recipients was associated with increased expression of TGF-b and PDGF in the tubule and vascular endothelium (43), these molecules being directly involved in the pathogenesis of CAN. Intra-allograft CMV protein expression correlated with the development of chronic allograft dysfunction in a small series of kidney transplant recipients (44). Moreover, in in vitro models, CMV upregulated the expression of IL-8 in fibroblasts; this major mediator of the inflammatory response may play a role in the pathogenesis of bronchiolitis (23).…”

Section: Viral Infections and Chronic Allograft Dysfunctionmentioning

confidence: 99%

“…In renal transplant recipients, CMV infection has been related to acute rejection and chronic allograft dysfunction (36,44,65,66). In a retrospective cohort study, 2740 kidney and simultaneous pancreas-kidney transplants were analyzed to evaluate the strength of acute rejection and CMV disease as risk factors for allograft loss.…”

Section: Type Of Organ Transplantmentioning

confidence: 99%

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Martín-Gandul

Mueller

Pascual

et al. 2015

American Journal of Transplantation

134

103

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Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community-acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction.

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“…Only one in four adults (black or white) living below the 200% poverty level have health insurance. 1,2 In this issue of JASN, Grams et al examine the effect of race on the incidence of AKI-related hospitalizations. 3 They used selfidentified black and white participants from the Atherosclerosis Risk in Communities (ARIC) study.…”

Section: President Barack Obama 2007 Iowa Brown and Black Presidentialmentioning

confidence: 99%

Race, Class, and AKI

Demirjian

2014

Journal of the American Society of Nephrology

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with Kaposi's sarcoma virus had normal EPO production under normoxic conditions and increased EPO mRNA production under hypoxic conditions, in contrast with the effects of CMV in this cell line. Further studies showed that it was the CMV-IE gene expression (identical to CMV-IE proteins detected in CMV-infected HEPCs and human kidneys with CKD) that directly mediated the lowering of the EPO mRNA. In a clinically relevant cellular study, treatment of the cells with valganciclovir, an inhibitor of CMV-late gene expression, had no effect on EPO mRNA production and supported that IE or early CMV gene expression was required to reduce EPO production. In several additional elegant experiments, the investigators showed that CMV infection reduces EPO mRNA production by inhibiting the expression of hypoxiainduced transcription factor-2a and that there was a dose response with CMV-IE gene expression. The working model shown in Figure 8 by Butler et al. is a brilliant figure synthesizing this novel mechanistic work.A major strength of this study is the authors' use of clinical observations, human biospecimens, animal models, and cell culture experiments to conduct true translational research that addresses an important question for clinicians. The finding of CMV-IE proteins in kidneys from humans with CKD but no overt symptoms of the CMV syndrome is important but must be confirmed in larger prospective studies. These should include studies of immunosuppressed and nonimmunosuppressed patients with native CKD, as well as the effect of CMV on resistance to recombinant EPO therapy. An intriguing extension of this mechanistic study would include a treatment arm to determine the effect of antiviral medications that target CMV on CKD-associated anemia. We applaud this innovative study that has the potential for broad applications in transplantation but more importantly in native CKD, which currently affects .20 million people in the United States. ACKNOWLEDGMENTSM.E

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Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival

Cited by 56 publications

References 199 publications

The Cell Biology of Cytomegalovirus: Implications for Transplantation

The Cell Biology of Cytomegalovirus: Implications for Transplantation

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Race, Class, and AKI

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