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Preemptive anti-cytomegalovirus therapy in high-risk (donor-positive, recipient-negative cytomegalovirus serostatus) kidney transplant recipients

  • Jumpei Hasegawa
    Affiliations
    Department of Nephrology, Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital, Kabukicho, Shinjuku-ku, Tokyo, Japan

    Department of Urology, Tokyo Women’s Medical University, Kawadacho, Shinjuku-ku, Tokyo, Japan
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  • Shuji Hatakeyama
    Correspondence
    Corresponding author at: Division of General Internal Medicine/Division of Infectious Diseases, Jichi Medical University Hospital, Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
    Affiliations
    Division of General Internal Medicine/Division of Infectious Diseases, Jichi Medical University Hospital, Yakushiji, Shimotsuke-shi, Tochigi, Japan

    Department of Internal Medicine, Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital, Kabukicho, Shinjuku-ku, Tokyo, Japan
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  • Sachiko Wakai
    Affiliations
    Department of Nephrology, Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital, Kabukicho, Shinjuku-ku, Tokyo, Japan
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  • Kazuya Omoto
    Affiliations
    Department of Urology, Tokyo Women’s Medical University, Kawadacho, Shinjuku-ku, Tokyo, Japan
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  • Masayoshi Okumi
    Affiliations
    Department of Urology, Tokyo Women’s Medical University, Kawadacho, Shinjuku-ku, Tokyo, Japan
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  • Kazunari Tanabe
    Affiliations
    Department of Urology, Tokyo Women’s Medical University, Kawadacho, Shinjuku-ku, Tokyo, Japan
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  • Makiko Mieno
    Affiliations
    Department of Medical Informatics, Center for Information, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan
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  • Hiroki Shirakawa
    Affiliations
    Department of Urology, Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital, Kabukicho, Shinjuku-ku, Tokyo, Japan
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Open AccessPublished:October 03, 2017DOI:https://doi.org/10.1016/j.ijid.2017.09.023

      Abstract

      Objectives

      Universal prophylaxis and preemptive therapy are used to prevent cytomegalovirus (CMV) disease post-transplantation. Data regarding which strategy is superior are sparse, especially in high-risk recipients (donor CMV seropositive (D+) and recipient CMV seronegative (R−)).

      Methods

      This retrospective, single-center cohort study included recipients who underwent kidney transplantation between 2009 and 2015. The incidence of CMV infection/disease and patient and graft outcomes were analyzed and compared between high-risk recipients (D+/R−) and intermediate-risk recipients (D+/R+ or D−/R+), all managed with preemptive therapy.

      Results

      Of 118 kidney transplant recipients, 21 were high-risk and 97 were intermediate-risk. Over a median follow-up period of 3 years, asymptomatic CMV infection developed significantly more frequently in high-risk patients than in intermediate-risk patients (38.1% vs. 16.5%, p = 0.04), and CMV disease developed in a similar manner (28.6% vs. 3.1%, p< 0.01). Among high-risk patients, CMV infection developed within the first 3 months post-transplantation and CMV disease within the first 9 months post-transplantation. Kaplan–Meier analysis showed no difference in the probability of mortality (log-rank p = 0.63) or graft loss (log-rank p = 0.50) between the patient groups. Graft rejection occurred more frequently in high-risk than in intermediate-risk patients, but the difference was not significant (log-rank p = 0.24).

      Conclusions

      These results suggest that further studies on universal prophylaxis in high-risk patients are needed to elucidate whether preventing CMV infection/disease during the early post-transplant period leads to better outcomes, especially in terms of reducing graft rejection.

      Keywords

      Introduction

      Cytomegalovirus (CMV) infection is one of the most common and important infections to occur in solid organ transplantation (SOT) recipients (
      • Humar A.
      • Snydman D.
      • The AST Infectious Diseases Community of Practice
      Cytomegalovirus in solid organ transplant recipients.
      ,
      • Kotton C.N.
      • Kumar D.
      • Caliendo A.M.
      • et al.
      Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation.
      ). Discordant serostatus for CMV (CMV seropositive donor (D+) and seronegative recipient (R−)) poses the highest risk for developing CMV disease in recipients after transplantation (
      • Meylan P.R.
      • Manuel O.
      Late-onset cytomegalovirus disease in patients with solid organ transplant.
      ). Current guidelines suggest two possible strategies for preventing CMV disease after SOT: universal prophylaxis and preemptive therapy (
      • Razonable R.R.
      • Humar A.
      • The AST Infectious Diseases Community of Practice
      Cytomegalovirus in solid organ transplantation.
      ). Universal prophylaxis is the administration of anti-CMV agents to all transplant recipients for 3–6 months post-transplantation. In preemptive therapy, transplant recipients are closely monitored for CMV replication by means of serial CMV DNA or pp65 antigen detection tests and are treated with antiviral drugs when active CMV replication is detected, regardless of clinical symptoms (
      • Razonable R.R.
      • van Cruijsen H.
      • Brown R.A.
      • et al.
      Dynamics of cytomegalovirus replication during preemptive therapy with oral ganciclovir.
      ).
      Several previous studies have demonstrated equal efficacy in preventing symptomatic CMV disease in kidney transplant recipients using either strategy (
      • Khoury J.A.
      • Storch G.A.
      • Bohl D.L.
      • et al.
      Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients.
      ,
      • Reischig T.
      • Jindra P.
      • Hes O.
      • Svecova M.
      • Klaboch J.
      • Treska V.
      Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation.
      ), although controversial results have been reported: a study demonstrated that the overall incidence of CMV infection/disease was significantly higher in D+/R+ recipients given preemptive therapy than in those given universal prophylaxis. The rates of loss of graft and kidney function were similar in the two groups (
      • Witzke O.
      • Hauser I.A.
      • Bartels M.
      • Wolf G.
      • Wolters H.
      • Nitschke M.
      Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial.
      ). In another study, CMV infection and graft loss were significantly less frequent in patients with the D+/R+ serostatus who received universal prophylaxis than in those who received preemptive therapy (
      • Kliem V.
      • Fricke L.
      • Wollbrink T.
      • Burg M.
      • Radermacher J.
      • Rohde F.
      Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial.
      ).
      A recent meta-analysis (
      • Florescu D.F.
      • Qiu F.
      • Schmidt C.M.
      • Kalil A.C.
      A direct and indirect comparison meta-analysis on the efficacy of cytomegalovirus preventive strategies in solid organ transplant.
      ) showed that prophylactic and preemptive strategies in SOT recipients had similar efficacy in preventing CMV infection/disease, with no difference in rates of graft rejection, graft loss, and mortality, although prophylaxis was associated with less early post-transplant CMV viremia, more late-onset CMV infections, and a greater frequency of leukocytopenia (as a side effect of antiviral drugs). This meta-analysis included patients with both R+ and D+/R− CMV serostatus, but the majority were R+, and the study did not mention differences between the high-risk (D+/R−) and intermediate-risk (R+) recipients. Thus, it remains highly controversial which preventive therapy is more appropriate for high-risk (D+/R−) kidney transplant recipients, although universal prophylaxis tends to be preferred in this population, as suggested in the guidelines (
      • Razonable R.R.
      • Humar A.
      • The AST Infectious Diseases Community of Practice
      Cytomegalovirus in solid organ transplantation.
      ).
      The aim of this study was to evaluate and describe the incidence and characteristics of CMV infection/disease in high-risk (D+/R−) kidney transplant recipients compared to those in intermediate-risk (D+/R+ or D−/R+) recipients, where both groups were managed with preemptive therapy. Post-transplant outcomes, including graft rejection and graft and patient survival, were also analyzed.

      Patients and methods

      Patients and study setting

      This was a retrospective, single-center cohort study. Patients who underwent kidney transplantation between January 2009 and December 2015 in the Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital were enrolled. All kidney transplants performed were from living donors, and all recipients were managed with preemptive therapy to prevent CMV disease. Recipients with a post-transplant follow-up period of less than 180 days were excluded.
      The patients were divided into two groups, high-risk and intermediate-risk, according to the CMV donor/recipient serostatus. The high-risk group comprised donor CMV serostatus positive, recipient negative (D+/R−) patients. The intermediate-risk group comprised donor CMV serostatus positive or negative, recipient positive (D+/R+ or D−/R+) patients. The rates of development of CMV infection and CMV disease, patient survival, death-censored kidney-graft survival, and graft rejection without graft loss were assessed as major outcomes. Graft loss was defined as a return to requiring any kind of renal replacement therapy. Graft rejection was defined as biopsy-proven rejection according to the Banff 2013 criteria (
      • Haas M.
      • Sis B.
      • Racusen L.C.
      • et al.
      Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.
      ). Leukocytopenia was defined as a white blood cell count (WBC) <3.0 × 109/l.
      CMV events were identified through a review of laboratory parameters (including pp65 antigenemia), pathology, antiviral medications, and medical records. Blood samples were obtained weekly for the first 12 weeks post-transplant, every second week from 13 to 48 weeks post-transplant, and monthly thereafter. Other recipient-related clinical data were also reviewed, including patient characteristics, transplant type, comorbidities, mortality, immunosuppressive medications, allograft rejection events, and infectious events caused by agents other than CMV.
      This study was reviewed and approved by the Institutional Review Board of Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital (approval number 2015-16).

      Definitions of CMV infection and disease, and antiviral therapy

      The definition of CMV infection and CMV disease followed the American Society of Transplantation guidelines (
      • Razonable R.R.
      • Humar A.
      • The AST Infectious Diseases Community of Practice
      Cytomegalovirus in solid organ transplantation.
      ), with minor modifications: CMV infection was defined as the presence of CMV replication (i.e., not a state of latency) without symptoms. CMV disease was defined as CMV infection accompanied by clinical signs and symptoms including a viral syndrome, which manifests as fever and/or malaise, leukocytopenia or thrombocytopenia, and organ diseases (e.g., gastrointestinal disease, pneumonitis, hepatitis, nephritis, adrenalitis, pancreatitis, myocarditis, or retinitis). CMV replication was detected by pp65 antigen testing, and the threshold value of antigenemia for a positive diagnosis of CMV infection was set at ≥5 positive cells/100 000 WBC (
      • Baldanti F.
      • Lilleri D.
      • Gerna G.
      Monitoring human cytomegalovirus infection in transplant recipients.
      ).
      In this study, all patients, including high-risk recipients, received preemptive therapy guided by pp65 antigenemia to prevent CMV disease. For patients with a CMV infection, preemptive therapy was started at a pp65 antigenemia value of ≥5–10 cells/100 000 WBC and was stopped if the pp65 antigenemia value was <5 cells/100 000 WBC. The duration of treatment for patients who developed CMV disease was determined individually. However, treatment was usually continued for 2 weeks following clinical resolution and virological (antigenemia) clearance of infection.

      Statistical analysis

      Continuous variables are expressed as the median and interquartile range (IQR), unless otherwise indicated. P-values were based on the Mann–Whitney U-test or Student t-test for continuous variables, according to their distribution, and on Fisher’s exact test for categorical variables. Graft survival, patient survival, rejection-free survival, and CMV infection/disease-free survival analyses were performed using the Kaplan–Meier method; log-rank tests were used for comparisons between the groups. All p-values were two-sided, and p-values of <0.05 were considered to indicate statistical significance. Statistical analyses were performed using JMP software (ver. 10.0.0; SAS Institute Inc., Cary, NC, USA).

      Results

      Patients

      Of 122 kidney transplant recipients, four were excluded because their duration of follow-up post-transplantation was insufficient (<180 days; range 20–102 days). During the study period, none of the four patients died and none developed CMV infection/disease. Of the remaining 118 patients included in the analysis, 21 (17.8%) were categorized as high-risk for CMV infection or disease (D+/R−) and 97 (82.2%) were categorized as intermediate-risk (one patient D−/R+; 96 patients D+/R+) (Figure 1).
      The baseline characteristics of the patients are shown in Table 1. There was no significant difference between the high-risk and intermediate-risk patients in terms of age, sex, prevalence of diabetes mellitus, and type of kidney transplantation (ABO incompatible transplantation, presence of pre-transplant donor-specific antibodies, or donation from blood relatives). In terms of induction immunosuppressive therapy, 38.1% of patients at high-risk and 37.1% of patients at intermediate-risk received basiliximab (p = 1.00), and 61.9% of patients at high-risk and 62.9% of patients at intermediate-risk received basiliximab in combination with rituximab (p = 1.00). The majority of patients (all high-risk patients and 99.0% of intermediate-risk patients) received tacrolimus, mycophenolate mofetil, and methylprednisolone as maintenance immunosuppressive therapy. The median duration of post-transplant follow-up was 1182 days (IQR 503–1949 days) in the high-risk group and 1105 days (IQR 535–1617 days) in the intermediate-risk group (p = 0.45).
      Table 1Patient characteristics according to the cytomegalovirus serostatus of the donor and recipient.
      High-risk patients

      [D+/R−]

      (n = 21)
      Intermediate-risk patients

      [D+/R+, D−/R+]

      (n = 97)
      P-value
      P-values: Mann–Whitney U-test for continuous variables unless indicated otherwise; Fisher’s exact test for categorical variables.
      Age, years, mean ± SD42.6 ± 11.246.1 ± 12.60.25
      By Student t-test.
      Male, n (%)15 (71.4)71 (73.2)1.00
      Diabetes mellitus, n (%)2 (9.5)21 (21.7)0.36
      ABO incompatible transplantation, n (%)4 (19.1)28 (28.9)0.43
      Pre-transplant DSA, n (%)3 (14.3)8 (8.3)0.41
      Preemptive transplantation, n (%)6 (28.6)15 (15.5)0.21
      Related donor transplantation, n (%)15 (71.4)66 (68.0)1.00
      Induction immunosuppression
       Basiliximab, n (%)8 (38.1)36 (37.1)1.00
       Basiliximab + rituximab, n (%)13 (61.9)61 (62.9)1.00
      Maintenance immunosuppression
       TAC + MMF + MP, n (%)21 (100)96 (99.0)1.00
       TAC + MZB + MP, n (%)0 (0)1 (1.0)1.00
      Follow-up duration, days, median (IQR)1182 (503–1949)1105 (535–1617)0.45
      D+, donor CMV seropositive; R−, recipient CMV seronegative; D−, donor CMV seronegative; R+, recipient CMV seropositive; SD, standard deviation; IQR, interquartile range; DSA, donor specific antibody; TAC, tacrolimus; MMF, mycophenolate mofetil; MZB, mizoribine; MP, methylprednisolone.
      a P-values: Mann–Whitney U-test for continuous variables unless indicated otherwise; Fisher’s exact test for categorical variables.
      b By Student t-test.

      Clinical outcomes

      Clinical outcomes are shown in Table 2. The overall incidence of both asymptomatic CMV infection and CMV disease was significantly higher in the high-risk patients than in the intermediate-risk patients. CMV infection developed in eight (38.1%) of the 21 high-risk patients and in 16 (16.5%) of the 97 intermediate-risk patients (p = 0.04). CMV disease developed in six (28.6%) patients at high-risk and three (3.1%) patients at intermediate-risk (p< 0.01). There was no significant difference in the incidence of infectious complications caused by agents other than CMV between the two groups; seven (33.3%) of the high-risk patients and 30 (30.9%) of the intermediate-risk patients developed infectious complications (p = 0.80). These infections included bacterial infections and herpes zoster virus, adenovirus, or polyomavirus infections.
      Table 2Clinical course after transplantation.
      High-risk patients

      [D+/R−]

      (n = 21)
      Intermediate-risk patients

      [D+/R+, D−/R+]

      (n = 97)
      P-value
      P-values: Mann–Whitney U-test for continuous variables; Fisher’s exact test for categorical variables.
      CMV infection
      CMV infection is defined as the presence of CMV replication without symptoms detected by pp65 antigenemia of ≥5 positive cells/100 000 white blood cells.
      , n (%)
      8 (38.1)16 (16.5)0.04
      CMV disease, n (%)6 (28.6)3 (3.1)<0.01
      Infection except CMV
      Infection except CMV includes bacterial infections, herpes zoster virus, adenovirus, or polyomavirus infections.
      , n (%)
      7 (33.3)30 (30.9)0.80
      eGFR at 12 months, ml/min/1.73 m2, median (IQR)48.4 (44.0–64.0)

      (n = 18)
      47.5 (40.3–54.5)

      (n = 86)
      0.21
      Leukocytopenia
      Leukocytopenia was defined as a white blood cell count of <3.0×109/l.
      , n (%)
      14 (66.7)34 (35.1)0.01
      Length of hospitalization, days, median (IQR)37 (29–63)37 (31–61)0.96
      D+, donor CMV seropositive; R−, recipient CMV seronegative; D−, donor CMV seronegative; R+, recipient CMV seropositive; CMV, cytomegalovirus; eGFR, estimated glomerular filtration rate; IQR, interquartile range.
      a P-values: Mann–Whitney U-test for continuous variables; Fisher’s exact test for categorical variables.
      b CMV infection is defined as the presence of CMV replication without symptoms detected by pp65 antigenemia of ≥5 positive cells/100 000 white blood cells.
      c Infection except CMV includes bacterial infections, herpes zoster virus, adenovirus, or polyomavirus infections.
      d Leukocytopenia was defined as a white blood cell count of <3.0 × 109/l.
      The median estimated glomerular filtration rate (eGFR) at 12 months after transplantation was similar in the two groups: 48.4 (IQR 44.0–64.0) ml/min/1.73 m2 in 18 high-risk patients and 47.5 (IQR 40.3–54.5) ml/min/1.73 m2 in 86 intermediate-risk patients (p = 0.21). Leukocytopenia complicated the course of high-risk patients (n = 14, 66.7%) significantly more frequently than intermediate-risk patients (n = 34, 35.1%, p = 0.01). Of the 48 leukocytopenic patients, 18 (11 high-risk and seven intermediate-risk) developed leukocytopenia after starting anti-CMV drugs. Because the remaining 30 patients (three high-risk and 27 intermediate-risk) did not receive anti-CMV drugs, their leukocytopenia was likely caused by immunosuppressive medications. In none of the 48 patients was leukocytopenia considered to be due to CMV infection/disease itself.
      The median length of hospital stay post-transplantation was 37 (IQR 29–63) days for high-risk patients and 37 (IQR 31–61) days for intermediate-risk patients (p = 0.96).

      Course of CMV infection/disease

      During the follow-up period, CMV infection or disease developed in eight and six patients who were at high-risk, respectively, and in 16 and three patients who were at intermediate-risk, respectively (Table 2). There were no statistically significant differences between the two groups regarding anti-CMV medication use or the drugs used to treat CMV infection/disease: oral valganciclovir and intravenous ganciclovir were used as first-line agents for patients with CMV infection and CMV disease, respectively. All patients responded to (val)ganciclovir therapy; hence, the second-line drug (foscarnet) was not used. However, the durations of CMV treatment and CMV antigenemia were significantly longer in high-risk patients than in intermediate-risk patients. CMV infection/disease was treated for a median of 21 (IQR 14–60) days in high-risk patients and a median of 7 (IQR 6–17) days in intermediate-risk patients (p< 0.01); and the median duration until clearance of CMV antigenemia was 28 (IQR 19–56) days and 16 (IQR 7–26) days, respectively (p = 0.02). Peak pp65 antigenemia levels were also significantly greater (p< 0.01) in high-risk patients (median 111.5 cells/100 000 WBC, IQR 21.5–180.0 cells) than in intermediate-risk patients (median 19.0/100 000 WBC, IQR 8.0–46.0 cells) (Table 3).
      Table 3Clinical course of CMV infection/disease.
      High-risk patients

      [D+/R−]

      (n = 14)
      Intermediate-risk patients

      [D+/R+, D−/R+]

      (n = 19)
      P-value
      P-value: Mann–Whitney U-test for continuous variables; Fisher’s exact test for categorical variables.
      Anti-CMV medication use, n (%)14 (100.0)16 (84.2)0.24
       Valganciclovir, n (%)10 (71.4)11 (57.9)0.49
       Intravenous ganciclovir, n (%)8 (57.1)6 (31.6)0.17
      Treatment duration, days, median (IQR)21 (14–60)7 (6–17)<0.01
      Duration of CMV antigenemia clearance, days, median (IQR)28 (19–56)16 (7–26)0.02
      CMV antigenemia peak titer, cells/100 000 WBC, median (IQR)111.5 (21.5–180.0)19.0 (8.0–46.0)<0.01
      D+, donor CMV seropositive; R−, recipient CMV seronegative; D−, donor CMV seronegative; R+, recipient CMV seropositive; CMV, cytomegalovirus; IQR, interquartile range; WBC, white blood cell.
      a P-value: Mann–Whitney U-test for continuous variables; Fisher’s exact test for categorical variables.
      Kaplan–Meier estimates of the cumulative incidence of CMV infection, CMV disease, and CMV infection/disease are shown in Figure 2. Among high-risk patients, all CMV infection events occurred during the first 3 months post-transplantation and all CMV disease events occurred during the first 9 months post-transplantation. Among intermediate-risk patients, CMV infection and CMV disease events occurred within the first 9 and 21 months post-transplantation, respectively. In high-risk patients, the CMV infection-free survival was 61.9%, the CMV disease-free survival was 70.8%, and the CMV infection/disease-free survival was 32.7% at 12 months. In intermediate-risk patients, at 12 and 24 months, the CMV infection-free survival was 83.4% and 83.4%, respectively, the CMV disease-free survival was 97.8% and 96.4%, respectively, and the CMV infection/disease-free survival was 81.2% and 79.8%, respectively. The cumulative incidences of CMV infection, CMV disease, and CMV infection/disease were significantly higher in high-risk patients than in intermediate-risk patients (log-rank test; p< 0.01, p< 0.01, and p< 0.01, respectively) (Figure 2A–C).
      Figure 2
      Figure 2Kaplan–Meier curves for the estimation of the cumulative incidence stratified by serological CMV risk groups. (A) CMV infection-free survival; (B) CMV disease-free survival; (C) CMV infection- or CMV disease-free survival.

      Graft and patient survival and graft rejection

      Graft survival and patient survival, evaluated using Kaplan–Meier estimates (Figure 3A, B), were similar in the two groups (log-rank test; p = 0.50 and p = 0.63, respectively). In contrast, episodes of graft rejection were observed more frequently in high-risk than in intermediate-risk patients (Figure 3C), although this difference did not reach statistical significance (log-rank test; p = 0.24): graft rejection-free survival at 12, 24, and 36 months was 76.2%, 70.8%, and 61.9%, respectively, in high-risk patients, and 83.1%, 77.9%, and 76.0%, respectively, in intermediate-risk patients.
      Figure 3
      Figure 3Kaplan–Meier curves for the estimation of the cumulative incidence stratified by serological CMV risk groups. (A) Graft survival; (B) patient survival; (C) graft rejection-free survival.

      Discussion

      In this cohort of kidney transplant recipients managed with preemptive anti-CMV therapy, CMV infection/disease and leukocytopenia developed significantly more frequently in high-risk (D+/R−) patients than in intermediate-risk (D+/R+ or D−/R+) patients. In high-risk patients, leukocytopenia was caused mainly by adverse effects of anti-CMV agents such as ganciclovir and valganciclovir.
      Although universal prophylaxis may lower the initial risk of CMV infection and disease, there is concern about the higher risk of late-onset CMV disease, which often develops in D+/R− recipients after discontinuation of prophylaxis and can be associated with increased graft loss and/or mortality (
      • Reischig T.
      • Jindra P.
      • Hes O.
      • Svecova M.
      • Klaboch J.
      • Treska V.
      Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation.
      ,
      • Limaye A.P.
      • Bakthavatsalam R.
      • Kim H.W.
      • et al.
      Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis.
      ,
      • Arthurs S.K.
      • Eid A.J.
      • Pedersen R.A.
      • et al.
      Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation.
      ). Nonetheless, there are studies that suggest the benefit of universal prophylaxis.
      • Meije Y.
      • Fortún J.
      • Len Ó.
      • et al.
      Prevention strategies for cytomegalovirus disease and long-term outcomes in the high-risk transplant patient (D+/R-): experience from the RESITRA-REIPI cohort.
      compared preemptive therapy with universal prophylaxis in high-risk (D+/R−) kidney and liver transplant recipients. In their cohort, consistent with a previous study (
      • Cervera C.
      • Pineda M.
      • Linares L.
      • et al.
      Impact of valganciclovir prophylaxis on the development of severe late-cytomegalovirus disease in high-risk solid organ transplant recipients.
      ), late-onset CMV disease was not serious or life-threatening. They also showed that CMV replication during the first 2 years post-transplantation, regardless of the preventive strategy used, was a risk factor for graft dysfunction at 5 years post-transplantation (
      • Meije Y.
      • Fortún J.
      • Len Ó.
      • et al.
      Prevention strategies for cytomegalovirus disease and long-term outcomes in the high-risk transplant patient (D+/R-): experience from the RESITRA-REIPI cohort.
      ). It is noteworthy that all cases of CMV infection and disease occurring in the present study cohort of high-risk (D+/R−) patients receiving preemptive therapy developed within 3 and 9 months post-transplantation, respectively. Because universal prophylaxis is usually provided during the first 3–6 months after transplantation, it may have a positive impact during the most vulnerable period of CMV infection, even taking late-onset CMV disease into consideration.
      The median CMV antigenemia peak titer was significantly higher in high-risk patients than in intermediate-risk patients, and the median duration of CMV therapy and duration until CMV antigenemia clearance were significantly longer in high-risk patients than in intermediate-risk patients. Similar results were obtained in a previous study.
      • Atabani S.F.
      • Smith C.
      • Atkinson C.
      • et al.
      Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.
      analyzed CMV replication kinetics stratified by CMV serostatus in liver and kidney transplant recipients who received preemptive therapy. They reported that D+/R− CMV serostatus was a significant risk factor for CMV infection (adjusted hazard ratio 3.56, 95% confidence interval 2.49–5.10) with a significantly higher median peak CMV load. Further, the duration of CMV viremia and antiviral therapy were significantly longer in D+/R− recipients (
      • Atabani S.F.
      • Smith C.
      • Atkinson C.
      • et al.
      Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.
      ). These results suggest that more severe CMV infection/disease, including primary mononucleosis-like syndrome, occurred in high-risk patients when compared to intermediate-risk patients undergoing the preemptive strategy.
      In this study, the graft survival rate and mortality rate did not differ significantly between high-risk and intermediate-risk patients. However, graft rejection was more likely to develop in high-risk patients than in intermediate-risk patients, although this was not statistically significant (p = 0.24). CMV infection in SOT recipients most likely has indirect consequences, including acute rejection, graft failure, and death: these are referred to as the ‘indirect effects of CMV infection’ (
      • Freeman Jr, R.B.
      The ‘indirect’ effects of cytomegalovirus infection.
      ). It is possible that a risk of preemptive therapy is that it allows low-grade CMV replication during the early transplant period, which might lead to CMV-associated indirect effects. The results of the present and another study (
      • Meije Y.
      • Fortún J.
      • Len Ó.
      • et al.
      Prevention strategies for cytomegalovirus disease and long-term outcomes in the high-risk transplant patient (D+/R-): experience from the RESITRA-REIPI cohort.
      ) appear to support the benefit of universal prophylaxis rather than preemptive therapy to decrease the incidence of graft rejection, if universal prophylaxis efficiently suppresses CMV replication in the early post-transplant period, especially during the first 3 months after transplantation, in high-risk (D+/R−) kidney transplant recipients. Further prospective studies are required to evaluate which strategy – universal prophylaxis or preemptive therapy – is more suitable in high-risk kidney transplant recipients for preventing not only CMV infection/disease but also the indirect effects, including graft rejection.
      There are several limitations to this study. First, this was a retrospective, single-center observational study and the number of D+/R− recipients was small. Second, the median follow-up duration was approximately 3 years; hence, it is not know what the further long-term outcomes would be.
      In conclusion, in kidney transplant recipients receiving preemptive CMV therapy, significantly higher rates of CMV infection/disease were observed in high-risk patients than in intermediate-risk patients during the early post-transplant period. There were no differences in the rates of mortality or graft loss. However, graft rejection occurred more frequently in high-risk than in intermediate-risk patients, although this difference was not statistically significant. Further studies comparing prophylaxis and preemptive therapy in high-risk patients are warranted to develop more effective CMV prevention strategies.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflict of interest

      None.

      Acknowledgements

      We would like to express our gratitude to Yusuke Imaizumi, Hina Ogawa, Kanae Yoshikawa, Momoko Kono, Takako Saito, Ayumi Ishiwatari, Natsuho Sano, Tomoko Kawanishi, Toshie Ogawa, Yasutomo Abe, and Mariko Endo (Department of Nephrology, Tokyo Metropolitan Health and Medical Treatment Corporation Okubo Hospital, Tokyo, Japan) for their clinical and technical support.

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