Six-Month Low-Dose Valganciclovir Prophylaxis in Cytomegalovirus Dⴙ/Rⴚ Kidney Transplant Patients Receiving Thymoglobulin Induction F.L. Luan ABSTRACT Background. The use of T-cell-depleting antibody, such as thymoglobulin, is a risk factor for cytomegalovirus (CMV) infection. We studied the effectiveness of 6 months of low-dose valganciclovir prophylaxis in CMV-naive kidney transplant recipients of CMVpositive donor kidney (D⫹/R⫺) receiving thymoglobulin induction. Methods. We included all D⫹/R⫺ kidney transplant patients between October 2005 and December 2010 who received valganciclovir 450 mg daily for 6 months as per center protocol. CMV infection was confirmed by positive viremia. Kaplan-Meier and multivariate Cox proportional regression analyses were employed to compare the risk of CMV infection between patients with and without the use of thymoglobulin induction. Results. Out of 170 D⫹/R⫺ kidney transplant patients, 42 cases of CMV infection (24.6%) were diagnosed after a median follow-up of 3.2 years: six patients from the noninduction (9.4%) and 36 from the induction cohort (34.0%). The induction with thymoglobulin was associated with four times greater risk of developing CMV infection (adjusted hazard ratio: AHR 4.15, 95% 1.75, 9.86, P ⫽ .001). The use of thymoglobulin was associated with leukopenia but not neutropenia. Conclusions. Additional measures are needed to reduce the elevated incidence of CMV infection in D⫹/R⫺ kidney transplant patients receiving induction with thymoglobulin. HE SINGLE MOST IMPORTANT RISK FACTOR for cytomegalivirus (CMV) infection is donor and recipient CMV serological mismatch such that CMV-naive kidney transplant recipients of CMV-positive donor kidney (D⫹/R⫺) have as high as 56% of CMV infection and/or disease rate in the absence of prophylaxis.1 The use of T-cell-depleting antibodies, such as thymoglobulin, enhances the risk of CMV infection even furthter.2,3 Most literature supports the use of universal prophylaxis as compared to preemptive therapy in D⫹/R⫺ kidney transplant recipients.4 – 6 Evidence suggests that longer prophylaxis may be better; however, different opinion exist.7–9 Valganciclovir, an ester form of ganciclovir with improved oral bioavailability, is the most frequently used agent for the prophylaxis, though the appreopriate dosing for prophylaxis has not been determined.10 –12 Here we report the effectiveness of 6 months of prophylaxis using low-dose valganciclovir in D⫹/R⫺ kidney transplant patients with and without the use of thymoglobulin as an induction agent.
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© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 45, 175–177 (2013)
METHODS Study Design and Patients This is a retrospective study of a single-center experience involving D⫹/R⫺ solitary kidney transplant patients between October 1, 2005, and December 31, 2010. Patients were followed to the end of 2011. The study was approved by the Institutional Review Board. All patients received valganciclovir 450 mg daily for 6 months after transplantation according to the institutional protocol. Patients who lost their kidney graft and/or died before the completion of CMV prophylaxis and patients who received induction with agents other than thymoglobulin were excluded.
From the Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan. Address correspondence to F.L. Luan, 3914 Taubman Center, Box 5364, 1500 East Medical Center Drive, Ann Arbor, 48109 – 5364. 0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.04.036 175
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Immunosuppression Thymoglobulin was used as an induction agent for patients at increased immunologic risks according to the institutional protocols. Maintenance immunosuppression included a combination of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus), mycophenolate mofetil, and prednisone. Target trough levels for cyclosporine and tacrolimus were 150 to 300 ng/mL and 5 to 15 ng/mL, respectively, during the first 3 months. Subsequently, cyclosporine and tacrolimus through levels were maintained at 100 to 150 ng/mL, and 5 to 8 ng/mL, respectively. Prednisone was tapered to 10 mg/d at about 6 weeks posttransplant and remained at 5 to 10 mg/d over the study period.
Study Assessments The primary endpoint was the incidence of CMV infection, defined as positive viremia using CMV/DNA determination by polymerase chain reaction. The secondary endpoints included the incidence of CMV disease defined as positive viremia with symptoms and/or signs of organ involvement and episodes of leukopenia/neutropenia during the period of prophylaxis. The lowest cell counts during the period of prophylaxis were recorded. Leukopenia and neutropenia were defined as a cell count of less than 4000/L and 1500/L, respectively.
Statistical Analysis Univariate statistics, including Stuent t test and chi-square test were used to compare continuous and categorical variables of demographic and baseline characteristics between the two cohorts. The Kaplan-Meier method was used to estimate the incidence of CMV infection stratified by the use of thymoglobulin induction. Multivariate Cox proportional regression analysis was used to identify the risk factors for CMV infection and disease. Linear regression analysis was employed to assess the predictors of leukopenia and neutropenia. Statistical significance was set at P ⬍ .05.
RESULTS
A total of 170 kidney transplant patients were included in this study. Of them, 64 received no induction and 106 received thymoglobulin induction. Demographic and baseline clinical characteristics are shown in Table 1. Patients from both cohorts were similar with regard to age, gender, underlying renal diagnosis, the use of expanded criteria donor/donation after cardiac death, the occurrence of delayed graft function, and the baseline renal function. However, they differed significantly with respect to several important demographic and baseline characteristics, including African-American race, the levels of panel-reactive antibodies, living donor, repeat transplant, and the use of tacrolimus; all of these factors were indications for the use of thymoglobulin induction in the first place by the center protocols. During the study period, 42 cases of CMV infection (24.5%) were documented by positive CMV viremia: 6 (9.4%) from the noninduction and 36 (34.0%) from thymoglobulin induction cohorts, respectively. Of all CMV infection, 30 cases had CMV disease (17.7%), characterized predominantly by gastrointestinal symptoms with and/or
LUAN Table 1. Demographic and Baseline Characteristics of Study Population
Recipient age, years (SD) Recipient gender, male (%) Recipient race, AA (%) Living donor, yes (%) First transplant, yes (%) ECD/DCD, yes (%) Renal diagnosis, (%) Polycystic Diabetes Hypertension Glomerulonephritis Others Positive hepatitis C, yes (%) Donor age, y (SD) Tacrolimus, yes (%) Panel-reactive antibodies, mean (SD) Delayed graft function, yes (%) Serum creatinine, mg.dL (SD) CrCI3, mL/min (SD) Acute rejection, yes (%)
No Induction (n ⫽ 64)
Induction (n ⫽ 106)
46.5 (14.0) 48 (75.0) 0 (0) 23 (35.9) 63 (98.4) 10 (15.6)
46.2 (13.0) 73 (68.9) 29 (27.4) 64 (60.4) 87 (82.1) 9 (8.5)
6 (9.4) 19 (29.7) 4 (6.3) 22 (34.4) 13 (20.3) 1 (1.6) 44.6 (14.1) 4 (6.3) 3.8 (8.3)
7 (6.6) 29 (27.4) 17 (16.4) 29 (27.4) 24 (22.6) 7 (6.6) 46.2 (13.2) 26 (24.5) 20.9 (31.2)
.26 .88 .003 ⬍.001
4 (6.3) 1.39 (0.38) 73.5 (19.3) 16 (25.0)
14 (13.2) 1.38 (0.42) 76.1 (25.6) 15 (14.2)
.20 .88 .46 .08
P
.88 .39 ⬍.001 .002 .006 .15 .36
AA, African-American; ECD/DCD, expanded criteria donor/donation after cardiac death; CrCl, creatinien clearance by Cockcroft-Gault equation; SD, standard deviation.
without signs of hepatitis and pancreatitis (70.0%), CMV syndrome (26.7%), and pneumonitis (3.3%). No CMV disease occurred during the prophylaxis. The median time to the diagnosis of CMV infection/disease was 232 days (80, 720). Kaplan-Meier actuarial event-free survival showed significantly more cases of CMV infection in patients who received thymoglobulin induction than in those without induction (Fig 1, log-rank P ⫽ .0003). Multivariate Cox proportional regression analyses were performed adjusting various demographic and baseline characteristics including age, gender, race, episodes of acute rejection, first transplant, type of transplant, underlying kidney diagnosis, use of different CNIs, and baseline renal function using a stepwise selection approach. The use of thymoglobulin for induction appeared to be the strongest risk factor for the developement of CMV infection and disease (adjusted hazard ratio [AHR] 4.15, 95% confidence interval [CI] 1.75, 9.86, P ⬍ .001, and AHR 2.85, 95% [CI] 1.16, 6.98, P ⫽ .012, respectively). The only other risk factor associated with the increased risk fo CMV infection and disease was old donor age (AHR 1.04, 95% CI 1.01, 1.06, P ⫽ .005, and AHR 1.03, 95% CI 1.00, 1.06, P ⫽ .03, respectively). Compared to noninduction patients, patients from the induction cohort had lower leukocyte counts during the prophylaxis period (4053 ⫾ 2016 and 3173 ⫾ 1593, P ⫽ .004) but not neutrophil counts (2345 ⫾ 1717 and 2232 ⫾ 1450, P ⫽ .66). Similarly, a greater proportion of induced patients had at least one episode of leukopenia than
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CMV infection despite 6 months of low-dose valganciclovir prophylaxis. Additional studies, such as using higher dose and/or longer duration or combining prophylaxis with postprophylaxis monitoring, are needed. REFERENCES
Fig 1. Kaplan-Meier CMV infection-free survival for patients with and without thymoglobulin induction.
uninduced patients (72.6% versus 56.3%, P ⫽ .028). Multiple linear regression analysis confirmed that the use of thymoglobulin for induction was associated with leukopenia but not neutropenia (P ⫽ .012 and P ⫽ .947, respectively). DISCUSSION
Our results show that 6 months of prophylaxis with lowdose valganciclovir is effective, but not sufficient, for the prevention of CMV infection and disease in D⫹/R⫺ kidney transplant patients. This is particularly evident when thymoglobulin was used as an induction agent. In fact, more than one-third of such patients had developed CMV infection compared to less than one-tenth of patients who did not receive thymoglobulin induction. Despite the widespread use of universal prophylaxis in the recent years, CMV infection remains a significant problem, particularly for D⫹/R⫺ mismatched patients. One of the reason is the concomitant increase in the use of stronger immunosuppression in the recent era.13 CMV infection and disease are associated with poor kidney transplant outcomes as well as increased health care cost.14 –18 Valganciclovir is the most commonly used drug for the prophylaxis with an improved oral bioavailability compared to oral ganciclovir.10 Retrospective data suggested that valganciclovir at 450 mg daily could produce clinical efficacy similar to that of valganciclovir 900 mg daily, yet no randomized clinical trials comparing the two dosing regiments have been conducted.12,18 There are several limitations in our study. First, because of its retrospective nature, patients receiving thymoglobulin induction differed from noninduced patients on several demographic and baseline characteristics. The use of appropriate statistical approaches may have not completely eliminated the influence of those differneces. Second, since the monitoring was not routinely applied, the diagnosis of CMV infection is based on clinical suspicions by various transplant and nontransplant physicians caring for those patients. Thus underdiagnosis is a possibility. In conclusion, more than one-third of thymoglobulininduced D⫹/R⫺ kidney transplant patients developed
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