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Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial

Witzke, Oliver1,8; Hauser, Ingeborg A.2; Bartels, Michael3; Wolf, Gunter4; Wolters, Heiner5; Nitschke, Martin6for the VIPP Study Group

doi: 10.1097/TP.0b013e318238dab3
Clinical and Translational Research
Free

Background. Cytomegalovirus (CMV) prevention can be achieved by prophylaxis or preemptive therapy. We performed a prospective randomized trial to determine whether renal transplant recipients with a positive CMV serostatus (R+) had a higher rate of CMV infection and disease after transplantation when treated preemptively for CMV infection, compared with primary valganciclovir prophylaxis.

Methods. Prophylaxis was 2×450 mg oral valganciclovir/day for 100 days; preemptive patients were monitored by CMV-polymerase chain reaction (PCR), and after a positive PCR test received 2×900 mg valganciclovir/day for at least 14 days followed by secondary prophylaxis. Valganciclovir dosage was adjusted according to renal function. Patients are followed up for 5 years and initial 12-month data are presented. Two hundred and ninety-six recipients were analyzed (168 donor/recipient seropositive [D+/R+], 128 donor seronegative/recipient seropositive [D−/R+]; 146 receiving prophylaxis and 150 preemptive therapy).

Results. Overall, CMV infection (asymptomatic CMV viral load ≥400 CMV DNA copies/mL proven by CMV-PCR) was significantly higher in recipients under preemptive therapy (38.7% vs. 11.0%, P<0.0001), with the highest incidence in D+/R+ preemptive patients (53.8% vs. 15.6%, P<0.0001). D+/R+ recipients with preemptive therapy also had the highest rate of CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) (19.2% vs. 4.4%, P=0.003). Renal function assessed by creatinine clearance was similar for both groups. Graft loss occurred in 7 vs. 4 patients on preemptive versus prophylactic therapy (P>0.05). Tolerability was similar for both treatment groups.

Conclusions. Oral valganciclovir prophylaxis significantly reduces CMV infection and disease, particularly for D+/R+ patients. Hence, our study supports routine prophylaxis for all D+/R+ recipients.

1 Department of Nephrology, University Duisburg-Essen, Essen, Germany.

2 Clinic for Internal Medicine, Department of Nephrology, University Hospital, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany.

3 Surgical Clinic, University of Leipzig, Leipzig, Germany.

4 Clinic for Internal Medicine III, Department of Nephrology, Friedrich Schiller University Jena, Jena, Germany.

5 Department of General and Visceral Surgery, University Clinics Münster, Münster, Germany.

6 Clinic for Internal Medicine I, Department of Nephrology, Transplantation Center, University Hospital Schleswig-Holstein, Luebeck, Germany.

7 Institutions in the VIPP Study Group (see Appendix to this article).

The work was supported in part by Roche Pharma AG, Grenzach-Wyhlen, Germany.

This manuscript was prepared, in part, by the clinical research organization PRA International and funded by Roche Pharma AG. All authors have received honoraria for providing advice to, and speaking for, Roche Pharma AG. All authors have attended study-specific advisory board and investigator meetings sponsored by Roche Pharma AG. All authors have received Grants/Research Support from Roche Pharma AG.

8 Address correspondence to: Oliver Witzke, Department of Nephrology, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.

E-mail: oliver.witzke@uk-essen.de

All the authors participated in research design, the performance of the research, data analysis, and in the writing of the manuscript.

Received 11 April 2011. Revision requested 27 April 2011.

Accepted 20 September 2011.

Cytomegalovirus (CMV) remains the most important serious viral infection complicating solid organ transplantation (SOT) (1). Solid organ transplant recipients are at high risk of CMV infection especially during the first 3 to 6 months after transplantation, owing to high initial immunosuppression. CMV infection (viremia) may develop into symptomatic CMV disease, which increases overall morbidity and mortality in transplant recipients. Furthermore, CMV infection is recognized as a risk factor for other poor short-term outcomes including acute allograft rejection (2). Within the last few years, evidence is growing that not only CMV disease but also asymptomatic (subclinical) CMV infection correlates in SOT patients with increased long-term morbidity, graft loss (3, 4), diabetes (4, 5), atherosclerosis in cardiac transplantation (6, 7), and mortality (3, 4). Results from a recently published prospective randomized clinical trial showed that routine oral prophylaxis improves long-term (4-year) graft survival for most renal transplant recipients, supporting the concept that routine prevention of asymptomatic CMV infection may have a significant positive impact on overall long-term clinical outcome (8).

To date, two approaches to CMV prevention, universal prophylaxis or preemptive therapy, are routinely used, aiming to minimize the acute complications of CMV, that is, symptomatic CMV disease. Recipients who have never had contact with CMV and lack CMV immunity (R−) and receive an organ from a CMV-positive donor (D+) are at the highest risk of developing CMV disease through primary infection with the virus, transmitted through the transplanted organ. CMV-positive recipients receiving an organ from a CMV-positive or -negative donor are at intermediate risk (D+/R+ or D−/R+) of suffering from CMV infection. Several prospective randomized studies have established that in high risk D+/R− patients, prophylaxis is the best option for preventing CMV (2, 4, 9–11). Some of these studies have also suggested that prophylaxis may be of significant benefit in patients with R+ serostatus.

This prospective, randomized clinical trial was performed to determine whether renal transplant recipients with a positive CMV serostatus (both D+/R+ and D−/R+ patients) had a higher rate of CMV infection (i.e., CMV replication) and disease during the first year after transplantation when treated preemptively for CMV infection, compared with recipients treated with primary prophylaxis. In addition, the impact of CMV infection on graft function and rejection was analyzed. Twelve-month data are presented in this article, and patients are in a follow-up phase for a further 4 years to determine any effects of treatment on long-term graft and patient survival.

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RESULTS

Patient Characteristics

Between May 2006 and September 2008, a total of 297 renal graft recipients were randomized. One patient did not receive study medication following randomization and was excluded from the analysis. Hence, the intent-to-treat population consisted of 296 patients: 146 patients receiving prophylaxis and 150 preemptive therapy. A total of 168 recipients were D+/R+ and 128 recipients were D−/R+. Demographic and background characteristics are summarized in Table 1. There were generally only small differences in the demographic and baseline characteristics among the two treatment groups; of note, there were less D−/R+ patients in the prophylaxis group compared with the preemptive therapy group, and patients receiving prophylaxis had the highest proportion of living donors. In addition, differences between groups were evident in the underlying cause of kidney disease; most notably for glomerulonephritis (13.7% of patients receiving prophylaxis vs. 26.0% of patients receiving preemptive therapy). All 296 recipients were analyzed for efficacy and safety.

TABLE 1

TABLE 1

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CMV Infection and Disease

Incidence rates of CMV infection (asymptomatic CMV viral load proven by CMV-polymerase chain reaction [PCR] ≥400 CMV DNA copies/mL) and disease are provided in Table 2, and time to occurrence of first viremia is provided in Figure 1. CMV infection was significantly higher with preemptive therapy (58 patients, 38.7% vs. 16 patients, 11.0%, P<0.0001, preemptive therapy vs. prophylaxis), and most CMV infection was seen for D+/R+ patients receiving preemptive therapy (42 patients, 53.8% vs. 14 patients, 15.6%, P<0.0001, preemptive therapy vs. prophylaxis). Calculated rates of CMV infection after 12 months were 20% for D+/R+ patients receiving prophylaxis (95% confidence interval [CI], 9.5%, 30.5%) and 59.6% (95% CI, 47.5%, 71.8%) for patients receiving preemptive therapy. Similarly for D−/R+ patients, rates were 4.1% (95% CI, 0.0%, 10.1%) and 23.9% (95% CI, 13.2%, 34.6%) for prophylaxis and preemptive therapy, respectively. For the preemptive therapy group, most CMV infection occurred within the first 3 months posttransplantation (48 patients, 32.0% vs. 1 patient, 0.7%, P<0.0001, preemptive therapy vs. prophylaxis). In parallel, D+/R+ patients with preemptive therapy had the greatest rate of CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) (19.2% vs. 4.4%, P=0.003, preemptive therapy vs. prophylaxis). When CMV syndrome was presented separately (Table 2), a similar trend was observed with higher rates in patients receiving preemptive therapy compared with prophylaxis. These were statistically significant for CMV syndrome for all patients (19 patients, 12.7% vs. 7 patients, 4.8%, P=0.0227, preemptive therapy vs. prophylaxis) and for D+/R+ patients (15 patients, 19.2% vs. 5 patients, 5.6%, P=0.0081, preemptive therapy vs. prophylaxis). Only minor differences were observed between treatment groups for the incidence of biopsy-proven tissue-invasive disease without CMV syndrome, but higher rates were observed in recipients receiving preemptive therapy and for D+/R+ patients, although differences to prophylaxis were not statistically significant (P>0.05). Overall rates of late-onset CMV infection after the first 90 days after transplantation were 10.3% in the prophylaxis group and 4.0% in the preemptive group (15 vs. 6 patients); with 6 patients in both groups experiencing late-onset CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven).

TABLE 2

TABLE 2

FIGURE 1.

FIGURE 1.

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CMV Viremia, Creatinine Clearance, Rejection, and Graft Loss

The mean (±standard error) time to occurrence of first viremia was significantly longer in the prophylaxis group (335.7±6.1 days vs. 133.2±5.9 days, P<0.0001, prophylaxis vs. preemptive therapy; accounting for patients who were free of viremia beyond 12 months) (Table 3). In addition, Figure 1 displays the Kaplan-Meier analysis of time to first viremia during the initial 12 months after transplantation. This protective effect was also observed for both R+ groups, although a longer mean time to first viremia was seen in D+/R+ recipients receiving prophylaxis compared with D−/R+ patients (328.8±8.48 days vs. 192.5±4.88 days). For patients who experienced viremia, the viral burden (copies/mL, mean±SD) was similar for both treatment groups, but viral burden was lower in D+/R+ patients receiving prophylaxis (1819.9±1713.9 copies/mL vs. 4904.6±9850.6 copies/mL, P>0.05, prophylaxis vs. preemptive therapy). For patients in both the prophylaxis and preemptive groups, the rate of viremia did not change notably after approximately 200 days posttransplantation (Fig. 1). Creatinine clearance (mL/min, mean±SD) was also similar between treatment groups at 12 months posttransplantation. There was a trend toward more episodes of biopsy-proven acute rejection with prophylaxis (18.5% vs. 12.0%, P>0.05, prophylaxis vs. preemptive therapy), but a significantly higher rate of rejection was only observed in the D−/R+ group (21.4% vs. 8.3%, P=0.042, prophylaxis vs. preemptive therapy), with no difference in the D+/R+ group (16.7% vs. 15.4%, P>0.05, prophylaxis vs. preemptive therapy). Numerically, graft loss occurred more often in preemptive recipients (4 patients, 2.7% vs. 7 patients, 4.7% P>0.05, prophylaxis vs. preemptive therapy) (Table 3).

TABLE 3

TABLE 3

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Tolerability

Safety data are presented in Table 4. The percentage of patients experiencing any serious adverse event was similar for patients receiving prophylaxis or preemptive therapy, with a trend to fewer adverse events in D+/R+ patients receiving prophylaxis (51.1% vs. 59.0%, P>0.05, prophylaxis vs. preemptive therapy). Rates of opportunistic infections were also similar between treatments and by R+ subgroup. There were no statistical differences in the incidence of leukopenia, neutropenia, or the occurrence of posttransplantation diabetes mellitus between groups. CMV infections unresponsive to treatment were higher for patients receiving preemptive therapy for all patients and by R+ subgroup. Two deaths occurred in both treatment groups (1.4% vs. 1.3%, prophylaxis vs. preemptive therapy).

TABLE 4

TABLE 4

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DISCUSSION

In this initial analysis of 12-month data from a long-term outcome study, prophylaxis markedly reduced the incidence of CMV infection and disease (defined as CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) in CMV-positive renal transplant recipients, regardless of donor serostatus. Minor reductions in the incidence of biopsy-proven tissue-invasive disease without CMV syndrome were also observed for D+/R+ patients, but these were not statistically significant. D+/R+ patients experienced an extended time to first viremia and a reduced viral burden, although this was not statistically significant. At this point in time, overall graft function, incidence of rejection, and graft loss did not differ significantly between groups.

There was no evidence for a higher incidence of late-onset CMV disease with valganciclovir prophylaxis as described by Sun et al. (12), although it is feasible that after 29 weeks several episodes of late-onset viremia were undetected as the frequency of regular CMV monitoring was reduced to every 3 months or as clinically indicated. Furthermore, as expected, the majority of CMV viremia occurred in the first 100 days posttransplantation in the preemptive group, whereas most episodes of CMV viremia in the prophylaxis group occurred after 100 days posttransplantation, after treatment had been stopped. It can be postulated that prophylaxis patients did not have the opportunity to develop a specific cellular immune response to CMV due to antiviral therapy and that after treatment was stopped some patients had a rebound response and developed CMV viremia. The possibility of rebound CMV after prophylaxis should be a consideration for physicians when using universal prophylaxis. It remains to be seen whether the benefits observed with prophylaxis treatment may translate into improved long-term graft or patient survival in these patients. In a recent study where a head-to-head comparison of oral ganciclovir prophylaxis versus intravenous preemptive therapy for CMV prevention in renal transplant recipients was performed, it was found that prophylaxis diminished the incidence of CMV infection and exerted a statistically significant benefit on long-term (4-year) graft survival (8). Moreover, a subanalysis also indicated specific benefits for D+/R+ patients, including reduced CMV infection and improved graft survival (13). This previous study was performed with ganciclovir, but as shown in the current analysis valganciclovir, a prodrug of ganciclovir, provides similar benefits in terms of reduced CMV infection; it can be postulated that these may lead to improvements in graft survival. Interestingly, the D−/R+ cohort also experienced a significant reduction in incidence of CMV infection, emphasizing the often underestimated risk of reactivating dormant CMV following the transplantation procedure. Immunocompromised end-stage renal disease patients, undergoing the surgical trauma of kidney engraftment while being initiated on high-dose immunosuppressive therapy, may experience a transient decrease in innate immune surveillance. Thus, even without active reinfection through implantation of a graft from a seropositive donor, preemptive therapy was associated with a more than fivefold increase in breakthrough dormant CMV, compared with prophylaxis.

Within the last few years, evidence has grown that not only CMV disease but also asymptomatic (subclinical) CMV infection correlates with increased long-term morbidity, graft loss, diabetes, atherosclerosis, and mortality following SOT (3–7). Prophylaxis may prevent early organ damage or chronic graft alteration due to asymptomatic CMV infection, whereas patients on a preemptive regimen may experience subclinical CMV infection and CMV viremia (or more intense viremia) for longer periods before therapy is initiated (8). They may also be at higher risk due to the known immunomodulatory effects of CMV (14–16). Prophylaxis has been suggested as beneficial in preventing both the direct and indirect effects of CMV infection in transplant recipients (9, 17). Our results underline the importance of targeted CMV prevention based on CMV serostatus, and improvements in outcomes may also provide significant benefits in terms of overall costs of treatment per patient.

Overall, rejection rates between the two treatment cohorts did not differ; however, in the D−/R+ subgroup, there were significantly fewer rejection episodes (P=0.042) in the preemptive arm. Possibly, the CMV-negative serotype of the donor organ-in concert with the stringent prophylactic study protocol may have prompted investigators to moderate the immunosuppressive regimen, thus increasing the risk for rejection. However, this explanation is only hypothetical and the data available do not provide a definitive explanation for this observation (i.e., mycophenolate mofetil dosing seemed similar in both treatment groups; data not shown). As graft survival at 12 months was similar between treatment groups, the clinical relevance of this difference in rejection rates is unclear.

Overall tolerability was good for both treatments, with the lowest rate of serious adverse events in D+/R+ patients receiving prophylaxis. Rates of opportunistic infections were also similar between regimens, but higher rates of posttransplantation diabetes were observed with prophylaxis. No differences in the rates of any safety assessments by treatment group or R+ status were statistically significant (although the incidence of leukopenia and neutropenia was higher in the prophylaxis group). Graft loss at 12 months posttransplantation occurred more frequently for preemptive patients, but this did not reach statistical significance and no direct evidence of CMV induced chronic graft alteration was available for the current analysis. Patients have entered a long-term follow-up, where graft and patient survival along with a specific urine proteomic pattern of chronic graft alteration will be assessed (18–20).

In conclusion, prophylaxis with valganciclovir provides greater protection against CMV infection and clinically diagnosed CMV disease than preemptive therapy, particularly for D+/R+ patients. This result correlates with the outcomes of our previous head-to-head trial with ganciclovir and with the results of several prospective randomized studies (3, 7–11). Prophylaxis was well tolerated, reduced the incidence of CMV infection and disease, and did not affect overall graft function. However, as this is only an initial analysis of 12-month data, it remains to be seen whether prophylaxis with valganciclovir may improve long-term graft survival as observed for ganciclovir. As the effectiveness of CMV prevention seems to be dependent on the CMV status of the donor, our study supports routine prophylaxis for all D+/R+ recipients.

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MATERIALS AND METHODS

This prospective, randomized, multicenter, open-label clinical trial was performed at 24 transplant centers in Germany and Austria. The study protocol was approved by the ethics committees at Hannover Medical School and was carried out according to the Helsinki Declaration and good clinical practice guidelines. The clinical trial was registered at ClinicalTrials.gov Identifier NCT00372229.

Renal graft recipients were centrally randomized into either study group (1:1 ratio) by phone (ClinIT AG, Freiburg, Germany). Patients were stratified by center and presence of immunosuppression induction therapy with depleting antibodies, such as antithymocyte globulin or OKT 3. All recipients were adults at intermediate risk for CMV disease with a positive CMV IgG serostatus (R+), but currently negative for CMV viral load. Other eligibility criteria were an absolute leukocyte count more than 3500 cells/μL, platelet count more than 100,000 cells/μL, hemoglobin more than 8.0 g/dL, and an estimated creatinine clearance of more than 10 mL/min before randomization, and a standardized immunosuppressive regimen including a calcineurin inhibitor, mycophenolate mofetil, and steroids. All patients had to be able to tolerate oral medication within 14 days posttransplantation. Patients were excluded if they were hypersensitive to acyclovir, valacyclovir, ganciclovir, valganciclovir or had evidence of malabsorption. Women who were pregnant, lactating, or considered at risk of pregnancy were not eligible. Every patient was informed about the nature and aim of the study, and written informed consent was obtained.

The oral prophylaxis group received 900 mg (2×450 mg) per day valganciclovir tablets starting within 14 days after transplantation until day 100 posttransplantation. Patients with impaired renal function below 60 mL/min creatinine clearance received adjusted daily total doses of valganciclovir according to the manufacturer's recommendations. All patients were regularly monitored for CMV viral load in plasma using Cobas Amplicor CMV Monitor (Roche Diagnostics GmbH, Mannheim, Germany), a quantitative CMV-PCR test (21, 22). Monitoring was performed once weekly at weeks 1 to 4; every 3 weeks at weeks 6 to 28; and every 3 months at weeks 29 to 52—or additionally as clinically indicated. All treatment decisions regarding the initiation and finalization of intravenous preemptive therapy were based on CMV-monitor results. Patients in either group who tested positive by CMV-monitor (≥400 CMV DNA copies/mL) at any time after transplantation received 1800 mg (2×900 mg) per day valganciclovir as preemptive therapy for at least 14 days, until CMV DNA was less than 400 copies/mL on two consecutive assessments within 1 week. Thereafter secondary prophylaxis was given using 900 mg (2×450 mg) per day valganciclovir tablets for 28 days. In case of CMV disease or if the patient was unable to take oral medication, intravenous ganciclovir at 2×5 mg/kg body weight per day was permitted. Every reoccurrence of CMV infection was treated with preemptive therapy followed by secondary prophylaxis. In case of CMV disease or no response to valganciclovir, intravenous ganciclovir or additional appropriate therapy could be administered. In the absence of medical contraindications, rejection episodes were biopsy confirmed. Biopsies were assessed histologically using the 1997 Banff criteria (updated in 2003) (23).

The study phase was 12 months posttransplantation, after which patients were treated according to the local site's standard of care. Recipients could complete a further written informed consent to participate in a long-term follow-up program for 4 years. CMV manifestations were defined based on standardized criteria as latent CMV infection (asymptomatic CMV IgG-positive serostatus), CMV infection (asymptomatic CMV viral load proven by CMV-PCR ≥400 CMV DNA copies/mL), CMV syndrome (unspecific clinical symptoms and CMV viral load), and CMV disease (tissue-invasive, proven CMV-related organ dysfunction or failure, and CMV viral load), respectively.

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Statistical Procedures

Sample size was based on the number of patients required to show a difference in graft loss between treatment groups. For the 12-month study phase, the following primary efficacy variables were analyzed: the proportion of patients with CMV infection within 12 months and the proportion of patients with CMV disease (including CMV syndrome and tissue-invasive disease) within 12 months. Secondary efficacy variables were the proportion of patients with CMV syndrome or disease, time to occurrence of first viremia, viral burden at viremia (area under the curve of plasma PCR), creatinine clearance at month 12, and the proportion of patients with treated and biopsy-proven acute rejection episodes within 12 months. For the primary endpoint analysis, the Fisher exact test was used. For the time to occurrence of first viremia Kaplan-Meier methods (24) were used; for all other variables descriptive statistics were prepared. An initial two-step hierarchical test procedure was planned using a global type I error of α=5%; first the difference between the two treatment groups in the proportion of recipients with CMV infection within 12 months was tested, followed by the difference between the two treatment groups in the proportion of patients with CMV disease within 12 months (including CMV syndrome and tissue-invasive disease). The difference in proportions of patients with CMV viremia or disease at 12 months was calculated along with the 95% CI. All analyses were performed by treatment and risk subgroups (donor [D]/recipient [R] CMV serostatus) for the intent-to-treat population (consisting of randomized and treated patients where the primary variable was measured at least once under study medication). Additional analyses of long-term graft and patient survival are planned after the completion of the follow-up phase. Only 12-month data from the initial study phase are presented in this article, and an extended test procedure investigating influence on graft loss and proteomic pattern is planned during follow-up and at study end (25).

Safety analysis was based primarily on the incidence of serious adverse events and the evaluation of hematological parameters (including incidence of leukopenia and neutropenia during the first year), the proportion of patients with opportunistic infections within 12 months, patient and graft survival up to the first year, the proportion of patients with posttransplant diabetes mellitus according to fasting glucose, and the incidence of CMV infection not responding to valganciclovir or ganciclovir treatment. For the comparison of safety variables, the Fisher exact test was used.

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ACKNOWLEDGMENTS

The authors thank Prof., Dr. Volker Kliem (Department of Nephrology, Lower Saxony Center for Nephrology, Transplantation Center, Hann. Muenden, Germany) for critical discussion and review of this manuscript, and Keith Dawes, Ph.D. (PRA International, Reading, UK) for medical writing support.

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APPENDIX

The study group was as follows: Universitätsklinikum Aachen, Medizinische Klinik II, Nephrologie und klinische Immunologie (Eitner, Floege, Mühlfeld, Lepper, Rauen, Dahmen, Michaelis, Kranz); Charité-Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie und Intensivmedizin, Campus Virchow (Reinke, Babel, Schaeffner, Bachmann, Böhnisch, Schweiar, Eibl, Schammann, Hampel, Bold, Hinrichs, Lübeck, Sefrin); Universitätsklinikum Düsseldorf, Klinik für Nephrologie (Voiculescu, Dierkes, Königshauser, Zgoura, Won, Vonend, Siekierka-Harreis, Tiedtke, Dübbers); Universitätsklinikum Erlangen, Medizinische Klinik IV, Nephrologie (Koch, Nonnast-Daniel, Zapf, Pressmar, Buchholz, Opgenoorth, Beck, Teichmann, Jacobi, Hohenstein, Krauss, Streubert, Semprich, Alberth, Weißbrod, Metzeova); Universitätsklinikum Essen, Zentrum für Innere Medizin, Klinik für Nieren- und Hochdruckkrankheiten (Witzke, Pietruck, Kribben, Türk, Schütz, Michell, Nürnberger, Bruck, Feldkamp, Combe, Hörbelt, Tyczynski, Wieneke, Graf, Augustiniak, Schüssler, Behrendt, Huke, Quandt); Klinikum der Johann-Wolfgang-Goethe Universität, Med. Klinik III/Nephrologie (Hauser, Scheuermann, Goßmann, Asbe-Vollkopf, Pliquett, Kachel, Jung, Holzmann, Zimmermann, Henning); Medizinische Hochschule Hannover (Klempnauer, Neipp, Grannas, Schwarz, Haller, Timrott, Merkel, Bode, Scheuer, Erdbrügger, Richter, Emmanouilidis, Wagner, Becker, Kaudel, Beckmann, Reichert, Richter, Kleine, Bittscheidt, Hecker, Kespohl, Müller-Schöner, Koczur, Pfeiffer, Geyer, Mogilevskaja, Ike, Ruggenini, Bahlmann); Nephrologisches ZentrumNiedersachsen, Innere Medizin/Nephrologie (Kliem, Burg, Schocke, Riedel); Universitätsklinikum Jena, Klinik für Innere Medizin III, Abteilung Nephrologie (Wolf, Ott, Gerth, Marx, Traut, Busch, Ulbricht, Sämann, Hartwig, Martin); Universitätsklinikum Leipzig, Zentrum für Chirurgie, Klinik f. Viszeral-, Thorax- u. Gefäßchirurgie (Bartels, Schreiber, Weimann, Quante, Thelen, Jentzsch, Fischer, Linnert, Gnodtke, Reiche); Universitätsklinikum Schleswig-Holstein, Campus Lübeck/Medizinische Klini I, Transplantationszentrum (Nitschke, Kramer, Meier, Derad, Kodal, Schlieter); Klinikum der Universität München, Chirurgische Klinik u. Poliklinik Großhadern, Transplantationschirurgie (Rentsch, Wendler, Eder); Universitätsklinikum Münster, Klinik und Poliklinik für Allgemeine Chirurgie (Wolters, Bahde, Menningen, Pankratious, Kebschull, Irmscher, Utech, Palmes, Anthoni, Eissing, Lamann); Klinikum der Universität Regensburg, Klinik und Poliklinik für Innere Medizin II, Nephrologie (Banas, Kammerl, Böger, Götz, Emmer, Kühn, Müller, Conrad); Universitätsklinikum Tübingen, Klinik für Allgemeine, Viszoral- u. Transplantationschirurgie (Nadalin, Thiel, Knubben, Witte, Wichmann, Templin, Wagner, Walter); Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik I, Abteilung Nephrologie (Lopau, Swoboda, Kirchner); Universitätsklinikum Eppendorf, Zentrum für Innere Medizin, 3. Medizinische Klinik (Stahl, Thaiss, Tenschert, Vernauer, Lange-Hüsingen, Kinzler, Wittenburg, Passoter, Bürgel, Gebhardt); Klinikum Rechts der Isar der, Technischen Universität München (Lutz, Thorban, Valentin, Riediger, Sollinger, Seibel, Schuster, Engelhardt, Schossow); Uniklinikum Köln, Innere Medizin IV, Nephrologie (Teschner, Prenzel, Yavuzyasar, Hörl, Schiffer-Oberländer); Charité-Universitätsmedizin Berlin, Medizinische Klinik IV für Nephrologie, Campus Benjamin Franklin (van der Giet, Straub-Hohenblaicher, Tölle, Westkämper, van der Giet); Klinikum Bremen-Mitte GmbH, Innere Medizin III (Zantvoort, Meyer-Jürgens); Landeskrankenhaus-Universitätskliniken Innsbruck, Universitätsklinik für Chirurgie (Pratschke, Bösmüller, Bergmann, Neyer, Siegele); and Medizinische Universität Wien, Univeritätsklinik für Innere Medizin III, Klein. Abt. f. Nephrologie u. Dialyze (Hörl, Schmaldienst, Plischke).

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Keywords:

Cytomegalovirus; Valganciclovir; Kidney transplantation; Prophylaxis

© 2012 Lippincott Williams & Wilkins, Inc.