INTRODUCTION — Cytomegalovirus (CMV) is a globally widespread virus that becomes latent following primary infection but reactivates frequently and causes disease in kidney transplant recipients in the setting of immunocompromise [1]. After kidney transplantation, active CMV infection and disease are associated with increased risk of allograft failure and death; thus, CMV prevention strategies are commonly used in such patients. Preventive therapy decreases reactivation in the setting of latent infection in the transplant recipient and/or acquisition of acute infection in CMV-seronegative recipients of seropositive grafts. However, CMV disease may still occur despite preventive therapies, especially when they are not dosed adequately [2,3]. It also occurs following discontinuation of preventive therapy.
This topic reviews the risk factors, clinical significance, and prevention of CMV infection among kidney transplant recipients. The management of active CMV infection and disease in transplant recipients is discussed elsewhere. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients".)
The diagnosis of CMV infection and the epidemiology, clinical manifestations, and treatment of CMV infection in immunocompetent adults are also discussed elsewhere:
●(See "Overview of diagnostic tests for cytomegalovirus infection".)
●(See "Approach to the diagnosis of cytomegalovirus infection".)
DEFINITIONS — Like other members of the herpesvirus family, CMV establishes latent infection after the resolution of acute (or primary) infection. Patients who are CMV seropositive have latent infection. Secondary, symptomatic disease may present later, reflecting either reactivation of latent CMV or, less commonly, reinfection with a novel exogenous strain. The risk of CMV reactivation is highest in the setting of systemic immunosuppression.
CMV can present in kidney transplant recipients as either CMV infection or CMV disease [1,4-6]:
●Active CMV infection – Defined as the presence of CMV replication in the blood regardless of whether signs or symptoms are present.
●CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. CMV disease may manifest as either CMV syndrome or tissue-invasive CMV disease:
•CMV syndrome – Defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of tissue-invasive disease.
•Tissue-invasive CMV disease – Patients with tissue-invasive CMV disease have clinical symptoms and signs of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis). The diagnosis of tissue-invasive disease is discussed in more detail separately. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Diagnosis' and "Approach to the diagnosis of cytomegalovirus infection", section on 'Tissue-invasive disease'.)
IMPORTANCE OF PREVENTION
Risk factors for infection — Kidney transplant recipients receive immunosuppressive medications to prevent allograft rejection, which increases their risk of developing CMV infection and disease [1]. The primary risk factor for CMV infection or disease is the CMV serostatus of the donor/recipient pair:
●CMV donor-positive/recipient-negative (D+/R-) patients are at the highest risk of developing CMV disease through primary infection with the virus [7,8]. Without preventive therapy, active CMV infection and CMV disease occur in 69 and 56 percent of such patients, respectively [9].
●CMV R+ (D+/R+ or D-/R+) patients have a similar risk of CMV infection as CMV D+/R- patients but are at lower risk of CMV disease. Without preventive therapy, active CMV infection and CMV disease occur in 67 and 20 percent of patients, respectively [9].
●CMV D-/R- patients are at low risk for CMV infection and disease [10,11]. Without preventive therapy, active CMV infection or disease occurs in fewer than 5 percent of patients [10,11]. Such patients may acquire CMV infection from transfusions or community exposures or may have had false negative serology in either the donor or the recipient.
Other risk factors for CMV disease relate to increased net states of immunosuppression and include:
●Use of lymphocyte-depleting agents (eg, antithymocyte globulin [ATG]) for induction immunosuppression [12]
●Use of mycophenolate for maintenance immunosuppression [13]
●Administration of lymphocyte-depleting therapy or high-dose glucocorticoids to treat acute T cell-mediated rejection or other disorders (eg, gout flares or flares of autoimmune diseases) [14-16]
●Lymphopenia pretransplant or posttransplant [17,18]
●Initial use of belatacept for maintenance immunosuppression [19] or conversion to belatacept for rescue of kidney function [20]
●Hypogammaglobulinemia [21,22]
Multiple organ transplantation, such as combined kidney-pancreas transplantation, also appears to increase the risk of developing CMV infection or disease [23]. This may be related to the higher-intensity immunosuppressive regimens used with multiple organ transplantation and/or the greater likelihood of transmitting virus from donor to recipient with larger volumes of tissue.
Immune monitoring assays that measure CMV-specific T cell responses, such as the QuantiFERON-CMV [24] and ELISPOT [25], may be useful adjuncts in identifying patients at increased risk of CMV disease [24,26,27]. However, studies demonstrating safety and cost effectiveness of changing management based on results of immune assays are needed before these assays can be used widely [28].
Impact on graft function and mortality — CMV increases mortality and graft loss. Natural history studies have demonstrated that active CMV infection and disease are associated with a 1.4- and 2.5-fold increased risk of acute allograft rejection, respectively, and a 2.8- and 4.7-fold increased risk of death, respectively [9,29-31].
CMV has both direct and indirect effects on kidney transplant outcomes:
●Direct effects of CMV infection are cytopathic effects on kidney allograft cells that can lead to nephropathy and allograft loss [31-34], as well as morbidity and death from severe CMV disease [2,3,7].
●Indirect effects of CMV infection are upregulation of human leukocyte antigens and adhesion molecules that can promote acute allograft rejection; allograft loss; death; bacterial, fungal, and viral infections; cardiovascular disease; and posttransplant lymphoproliferative disorder [35,36].
PREVENTION OF DISEASE
Preventive strategies — Because CMV causes considerable morbidity and mortality and has been identified as a risk factor for rejection in kidney transplant recipients, there has been intense interest in prevention. Two strategies are generally used:
●Universal prophylaxis – Universal prophylaxis is the administration of antiviral medication to all transplant recipients or a subset of high-risk patients beginning within 10 days after transplant and continuing for a finite period (eg, three to six months). Valganciclovir is typically used. (See 'Universal prophylaxis (high risk)' below.)
●Preemptive therapy – Preemptive therapy refers to monitoring patients for CMV in the blood using quantitative polymerase chain reaction (PCR; viral load) at regular intervals (usually weekly). Oral valganciclovir is initiated when viral replication is detected at a certain threshold. The specific threshold varies by transplant center and by assay. (See 'Preemptive therapy (low risk)' below.)
An additional strategy that combines these two approaches is "surveillance after prophylaxis" (previously termed "hybrid approach"). This strategy is less commonly used. (See 'Surveillance after prophylaxis' below.)
Our approach — Our approach to CMV prevention, which is consistent with the 2018 international consensus guidelines on the management of CMV in solid organ transplantation [1], is presented below.
Universal prophylaxis (high risk) — For all kidney transplant recipients who are CMV seropositive or who have received an organ from a CMV-seropositive donor (CMV D+/R+, D-/R+, D+/R-), we suggest universal prophylaxis rather than preemptive therapy. We prefer universal prophylaxis over preemptive therapy, given its ease of administration and prevention of potentially harmful low-level CMV replication.
For prophylaxis, we suggest valganciclovir rather than valacyclovir, oral ganciclovir, or other antiviral agents because of its efficacy and high oral bioavailability [37]. However, clinical practice varies worldwide. Some transplant centers outside of the United States use valacyclovir. While limited trial data suggest it reduces rates of active CMV replication and CMV disease, it appears to be less effective than valganciclovir [37]. Oral ganciclovir is less bioavailable than valganciclovir and is no longer available in the United States.
We start valganciclovir in the immediate posttransplant period. The dose and duration of prophylactic valganciclovir depend upon the CMV serotype combination and on the patient's estimated glomerular filtration rate (eGFR):
●For CMV D+/R- patients, we use valganciclovir at 900 mg orally once daily for six months following transplantation, with the dose adjusted for kidney function.
●For CMV R+ patients, we use valganciclovir at 900 mg orally once daily for three months following transplantation, with the dose adjusted for kidney function.
As noted above, CMV D-/R- patients do not generally receive universal prophylaxis for CMV. We give such patients acyclovir or valacyclovir for three months following transplantation for herpes simplex virus (HSV) prophylaxis.
Support for the use of universal prophylaxis is based upon several randomized trials comparing prophylactic and preemptive strategies among kidney transplant recipients [11,38-44]. In a meta-analysis of seven randomized trials (560 patients), rates of CMV infection were higher with preemptive treatment than with universal prophylaxis (relative risk 1.67, 95% CI 1.21-2.30), but there were no significant differences in the rates of CMV disease, acute allograft rejection, graft loss, or death between the two strategies [45]. Similar findings were reported in a randomized trial in 296 kidney transplant recipients (all CMV R+) published after this meta-analysis, which found that universal prophylaxis with oral valganciclovir, compared with preemptive treatment, lowered rates of CMV infection and disease at 12 months posttransplant, particularly in D+/R+ patients (16 versus 54 percent and 4 versus 19 percent, respectively) [43]. A follow-up study found that this benefit persisted up to seven years posttransplant, at which time rates of graft loss, death, and rejection were similar between the groups [44]. A potential downside to universal prophylaxis is a higher risk of late-onset CMV disease (ie, CMV disease occurring after discontinuation of prophylaxis) when compared with a preemptive approach [46,47]. However, the absolute risk of late-onset CMV disease appears to be small, and the likelihood of immune control is greater outside of the early posttransplant period.
One randomized trial comparing prophylactic and preemptive strategies in liver transplant recipients found a lower incidence of CMV disease among those receiving preemptive treatment [48]. However, it is unclear whether these findings can be generalizable to kidney transplant recipients. (See "Infectious complications in liver transplantation", section on 'Prophylactic and pre-emptive CMV therapy'.)
Valganciclovir is preferred for the prevention of CMV infection after kidney transplantation based upon randomized trials showing its efficacy among kidney transplant recipients [11,37,46,49,50]. A network meta-analysis comparing valganciclovir, oral or intravenous (IV) ganciclovir, valacyclovir, and acyclovir for the prevention of CMV infection or disease in kidney transplant recipients concluded that among the antiviral therapies, valganciclovir may have the most favorable benefits and risks in this setting [37]. One randomized trial within the meta-analysis that compared valganciclovir (900 mg orally daily) with valacyclovir (2 g four times daily) for three months after transplantation showed similar efficacy in preventing CMV infection and disease between the regimens; however, rates of biopsy-proven acute rejection were higher with valacyclovir (31 versus 17 percent) [49].
The optimal duration of prophylaxis is unclear. Longer durations of prophylaxis may be preferred since shorter courses have been associated with an increased risk of late-onset CMV disease [46]. One trial showed that valganciclovir given for 200 days decreased the rate of active CMV infection and disease in CMV D+/R- patients compared with valganciclovir given for 100 days [46].
The toxicity profile of valganciclovir is similar to that of its parent compound, ganciclovir. Hematologic suppression, in particular leukopenia (including neutropenia), appears to be the most significant and common adverse event associated with these agents. When leukopenia occurs, dose reduction of valganciclovir should be avoided, given the risk of promoting resistance. Patients should be evaluated for other potential causes of leukopenia (eg, mycophenolate, trimethoprim-sulfamethoxazole). The addition of granulocyte colony-stimulating factor should be considered before discontinuing valganciclovir. (See "Ganciclovir and valganciclovir: An overview", section on 'Bone marrow suppression'.)
Letermovir has been used as CMV prophylaxis among hematopoietic cell transplant recipients. A randomized trial evaluating its efficacy in preventing CMV infection and disease among kidney transplant recipients is in progress (NCT03443869). (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Primary prophylaxis'.)
Preemptive therapy (low risk) — For patients at low risk for CMV infection (ie, CMV D-/R-), we use a preemptive approach. Universal prophylaxis is generally not administered to CMV D-/R- patients beyond administering acyclovir to prevent HSV infections, given their very low risk of CMV infection and disease.
We monitor patients for CMV replication using nucleic acid testing (ie, PCR) weekly for three months following transplantation. If active CMV infection is detected, we give valganciclovir or IV ganciclovir at treatment doses until repeat CMV nucleic acid testing is negative and for a minimum of 21 days. Treatment dosing of valganciclovir is 900 mg orally twice daily and of ganciclovir is 5 mg/kg IV twice daily; doses should be adjusted for kidney function. Viral load thresholds to start preemptive therapy have not been standardized across institutions given variability among diagnostic specimens and testing platforms.
If a CMV preemptive strategy is used, we would give HSV prophylaxis with acyclovir or valacyclovir for three months following transplantation. (See "Prophylaxis of infections in solid organ transplantation", section on 'Herpes simplex and varicella-zoster'.)
As discussed above, we prefer a prophylactic approach over a preemptive approach for kidney transplant recipients at significant risk of active CMV infection and disease. (See 'Universal prophylaxis (high risk)' above.)
Surveillance after prophylaxis — Some transplant centers employ a hybrid approach, in which the highest-risk patients are given prophylactic anti-CMV medications after transplant but, after completing prophylactic therapy, are monitored regularly for active CMV infection (by PCR of the blood). Among such patients, treatment doses of anti-CMV medications are given if viral replication is detected [51]. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Antiviral therapy'.)
Optimization of immunosuppression — For all kidney transplant recipients, maintaining an appropriate balance between over- and underimmunosuppression is critical to care. Overimmunosuppression, particularly lymphopenia, raises the risk of CMV infection [17,18]. Thus, as part of our approach to preventing CMV infection, we pay particular attention to lymphocyte counts and often adjust the immunosuppressive regimen (eg, reduce the antimetabolite dose) when lymphopenia is present, in addition to evaluating for other causes. (See "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Management of immunosuppression'.)
Special considerations
Patients treated for rejection — For kidney transplant recipients who are receiving treatment for acute rejection with rabbit antithymocyte globulin (rATG)-Thymoglobulin, alemtuzumab, high-dose glucocorticoids, or plasmapheresis, we recommence CMV prophylaxis. We administer prophylaxis for at least three months with a regimen that is identical to that administered in the immediate posttransplant period. Some centers may not recommence CMV prophylaxis for short courses of high-dose glucocorticoids or plasmapheresis. (See 'Universal prophylaxis (high risk)' above.)
Kidney transplant recipients with acute rejection may be at higher risk for CMV disease. In a retrospective study of 992 kidney transplant recipients, there was no significant difference in the incidence of CMV infection between those who developed acute rejection within six months of transplant and those without rejection (13 versus 10 percent, respectively) [52]. However, the incidence of tissue-invasive CMV disease, particularly gastrointestinal CMV disease, was greater among patients who experienced acute rejection (8 versus 3 percent). Another retrospective study found that transplant failure or rejection was a risk factor for delayed-onset CMV disease in kidney transplant recipients (hazard ratio 3.2) [3]
Patients who are critically ill — We do not routinely administer CMV prophylaxis to kidney transplant recipients who are critically ill, given insufficient data to support this practice. Although nontransplant patients who are critically ill have an increased risk of CMV infection and reactivation, there is no evidence showing that prophylaxis or suppression of CMV infection improves outcomes in this patient population. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Reactivation in critically ill patients'.)
Secondary prophylaxis — We do not routinely administer CMV prophylaxis to prevent recurrent CMV infection in kidney transplant recipients who have been treated for CMV infection or disease, especially if the antimetabolite has been discontinued indefinitely. This issue is discussed in more detail elsewhere. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Duration of therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cytomegalovirus in solid organ transplant recipients".)
SUMMARY AND RECOMMENDATIONS
●Risk factors for infection – The primary risk factor for CMV infection or disease is the CMV serostatus of the donor/recipient pair. CMV donor-positive/recipient-negative (D+/R-) patients are at the highest risk, CMV R+ patients are at intermediate risk, and CMV D-/R- patients are at low risk. Other risk factors relate to of the type and degree of immunosuppression in the individual patient. (See 'Risk factors for infection' above.)
●Impact on transplant outcomes – Through direct and indirect effects, active CMV infection and disease are associated with an increased risk of acute allograft rejection, death, other infections, cardiovascular disease, and posttransplant lymphoproliferative disorder. (See 'Impact on graft function and mortality' above.)
●Preventive strategies – There are two main strategies for CMV prevention: universal prophylaxis (administration of an antiviral for a finite period posttransplantation) and preemptive therapy (monitoring for active CMV replication in the blood at regular intervals by quantitative polymerase chain reaction [PCR] and initiating antiviral therapy if replication meets a certain threshold). (See 'Preventive strategies' above.)
●Our approach to prophylaxis – Our approach to CMV prevention is consistent with the 2018 international consensus guidelines on the management of CMV in solid organ transplantation.
•Universal prophylaxis for high-risk patients – For all kidney transplant recipients who are CMV seropositive or who have received an organ from a CMV-seropositive donor (CMV D+/R+, D-/R+, D+/R-), we suggest universal prophylaxis rather than preemptive therapy (Grade 2C). We prefer universal prophylaxis over preemptive therapy, given its ease of administration and prevention of potentially harmful low-level CMV replication. For prophylaxis, we suggest valganciclovir rather than other antiviral agents (Grade 2C). Valganciclovir is effective at reducing the risk of CMV infection and disease. Duration of prophylactic valganciclovir depends upon the CMV serotype combination and on the patient's estimated glomerular filtration rate (eGFR). (See 'Universal prophylaxis (high risk)' above.)
•Preemptive therapy for low-risk patients – For low-risk patients (CMV D-/R-), we use a preemptive approach and monitor patients for CMV replication using nucleic acid testing (ie, PCR) weekly for three months following transplantation. We give these patients acyclovir to prevent active herpes simplex virus (HSV) infection. (See 'Preemptive therapy (low risk)' above.)
●Optimizing immunosuppression – For all kidney transplant recipients, maintaining an appropriate balance between over- and underimmunosuppression is critical to care. Thus, as part of our approach to preventing CMV infection, we pay particular attention to lymphocyte counts and commonly adjust the immunosuppressive regimen (eg, reduce the antimetabolite dose) when lymphopenia is present, in addition to evaluating for other causes. (See 'Optimization of immunosuppression' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William M Bennett, MD, who contributed to earlier versions of this topic review.
