A critical review of the relationship between post-transplant atherosclerotic events and cytomegalovirus exposure in kidney transplant recipients

ABSTRACT

Introduction: Cytomegalovirus (CMV) infection after kidney transplantation (KT) has been implicated in the so-called ‘indirect effects’ attributable to the viral ability to evade host’s immunity and trigger sustained inflammation. Whether CMV exposure contributes to the development of post-transplant atherosclerotic events (AEs) remains controversial.

Areas covered: This review (based on a PubMed/MEDLINE search from database inception to October 2019) summarizes the proposed mechanisms for the role of CMV in atherogenesis, including accelerated immunosenescence, endothelial injury and inflammatory milieu in the vessel wall. Sero-epidemiological evidence linking CMV exposure and cardiovascular disease in the general population is discussed. Finally, we performed a comprehensive review of observational studies investigating the impact of CMV infection on the occurrence of AE after KT, as well as the potential protective effect of antiviral prophylaxis.

Expert opinion: Reviewed studies provide biological plausibility and preliminary clinical evidence pointing to the pathogenic role of CMV in post-transplant atherogenesis. However, no definitive recommendations can be made regarding the use of antiviral prophylaxis to prevent post-transplant AE, since existing evidence is mainly founded on inadequately powered post hoc analysis. Well-designed observational studies should clarify the differential impact of prophylactic or preemptive approaches on the occurrence of CMV-associated post-transplant AE among KT recipients.

KEYWORDS:

• Cytomegalovirus
• kidney transplantation
• cardiovascular risk
• atherosclerotic event
• pathogenesis

Article highlights

• Atherosclerotic events (AEs) constitute a leading cause of death with a functioning graft among kidney transplant (KT) recipients in whose pathogenesis the so-called ‘indirect effects’ attributable to cytomegalovirus (CMV) infection may have a relevant contribution.

• Various complementary mechanisms have been postulated to explain the potential role played by CMV in the development of post-transplant AE, such as the promotion of a local inflammatory milieu with dysfunction of endothelial and smooth muscle cells, accelerated immunosenescence, activation of coagulation cascade, and impairment in lipid metabolism leading to oxidative stress and cholesterol accumulation in the vessel wall.

• The presence of IgG antibodies against CMV has been associated with the development of cardiovascular disease in large sero-epidemiological studies in the general population, although serologic testing cannot differentiate viral latency from active infection or recent reactivation. In addition, CMV DNA is more commonly detected by PCR in vessel wall specimens obtained from patients with atherosclerosis than controls.

• Clinical studies investigating the association between CMV infection and AEs after KT are limited and yield conflicting results, with different methodological approaches to capturing CMV exposure (viral replication documented by pp65 antigenemia or PCR, clinical disease or recipient CMV serostatus), heterogeneous outcomes and potential confounding by pre-transplant comorbidities and effect of immunosuppressive agents. A recent meta-analysis (7 studies with 39,759 cases) reported an excess risk of nearly 30% (RR: 1.26; 95% CI: 1.01-1.65; P-value = 0.03) for KT recipients with CMV exposure.

• No clinical trials have been conducted to date in the KT population to evaluate the potential impact of prophylaxis with (val)ganciclovir on the cardiovascular risk or other CMV-associated indirect effects. Post hoc secondary analyses of previous studies (none of which had considered atherosclerotic complications as the primary outcome) would suggest a protective effect of antiviral prophylaxis over preemptive therapy in terms of incidence of post-transplant AEs and cardiovascular mortality.

• Well-designed cohort studies with appropriate follow-up, stringent outcome definition, close monitoring for CMV viremia, and controlling for confounders are needed to clarify the impact of different strategies (prophylaxis and preemptive therapy) on the occurrence of post-transplant AEs eventually induced by CMV.

Acknowledgments

The authors would thank David Navarro (Department of Microbiology, Hospital Clínico Universitario, Valencia, Spain) for his critical review of the manuscript and invaluable comments.

Declaration of interest

M Fernández-Ruiz holds a research contract ‘Miguel Servet’ (CP 18/00073) from the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was partially supported by Plan Nacional de I+D+I 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Spanish Ministry of Economy and Competitiveness, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0002) - co-financed by the European Development Regional Fund (EDRF) ‘A way to achieve Europe’.