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Impact of Hepatitis C Virus Infection on the Risk of Infectious Complications After Kidney Transplantation: Data From the RESITRA/REIPI Cohort

López-Medrano, Francisco1,11; Fernández-Ruiz, Mario1; Morales, José María2; San-Juan, Rafael1; Cervera, Carlos3; Carratalá, Jordi4; Torre-Cisneros, Julián5; Gavaldá, Joan6; Muñoz, Patricia7; Len, Óscar6; Martín-Dávila, Pilar8; Ramos, Antonio9; Montejo, Miguel10; Lumbreras, Carlos1; Moreno, Asunción3; Aguado, José María1the RESITRA/REIPI (Spanish Network for the Research of Infection in Transplantation/Network of Research in Infectious Diseases) Study Group

doi: 10.1097/TP.0b013e318225dbae
Clinical and Translational Research
Free
SDC

Background. There is scarce information regarding the role of hepatitis C virus (HCV) infection in the development of infectious complications after kidney transplantation (KT).

Methods. We prospectively analyzed all KT recipients included in the Spanish Network for the Research of Infection in Transplantation cohort from September 2003 to February 2005 with a posttransplant follow-up of 3 years and compared the incidence of both overall and specific infections according to the pretransplant anti-HCV antibody status.

Results. Of 1302 analyzed recipients, 105 (8.1%) were anti-HCV positive. These patients presented a higher rate of previous transplant (P<0.001), had a lower donor age (P=0.055), higher transfusion requirements (P=0.037), and more frequently received induction therapy with antithymocyte antibodies (P=0.005). We found no differences between anti-HCV-positive and -negative recipients in the overall incidence rate of infection (0.82 vs. 0.74 episodes per 1000 transplant-days, respectively). Nevertheless, anti-HCV-positive recipients had a higher cumulative incidence of bloodstream (P=0.01) and upper urinary tract infections (P=0.037). Anti-HCV status emerged by logistic regression as an independent risk factor only for bloodstream infection (odds ratio, 3.14; 95% confidence interval, 1.19–8.24; P=0.020). Anti-HCV-positive recipients also experimented a higher rate of recurrent acute rejection (P=0.045) and retransplantation (P=0.017), with no differences in overall mortality.

Conclusions. According to the results of the Spanish Network for the Research of Infection in Transplantation cohort, the incidence of some potentially severe posttransplant infections may be increased in anti-HCV-positive KT recipients.

1 Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Avda. de Córdoba, Madrid, Spain.

2 Department of Nephrology, Hospital Universitario 12 de Octubre, Avda. de Córdoba, Madrid, Spain.

3 Department of Infectious Diseases, Hospital Clinic-IDIBAPS, Calle Villarroel, Barcelona, Spain.

4 Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, Feixa Llarga, Hospitalet de Llobregat, Barcelona, Spain.

5 Department of Infectious Diseases, Hospital Universitario Reina Sofía-IMIBIC, Avda. de Menéndez Pidal, Córdoba, Spain.

6 Department of Infectious Diseases, Hospital Universitari Vall d′Hebron, Passeig de la Vall d'Hebron, Barcelona, Spain.

7 Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo, Madrid, Spain.

8 Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Ctra. de Colmenar Viejo, Madrid, Spain.

9 Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Calle Manuel de Falla, Madrid, Spain.

10 Department of Infectious Diseases, Hospital Universitario de Cruces, Plaza Cruces, Barakaldo-Bizkaia, Bilbao, Spain.

This work was supported by the Spanish Ministry of Science and Innovation, the Instituto de Salud Carlos III-FEDER, the Spanish Network of Infection in Transplantation (RESITRA G03/075), and the Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008).

The authors declare no conflicts of interest.

This study was partially presented at the 10th American Transplant Congress (ATC), San Diego, CA (May 1–5, 2010) [poster 1195], and the 14th Congress of the European Society for Organ Transplantation (ESOT), Paris, France (August 30–September 2, 2009) [poster P-316].

11 Address correspondence to: Francisco López-Medrano, M.D., Ph.D., M.Sc., Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Avda. de Córdoba, s/n, Postal code 28041, Madrid, Spain.

E-mail: flmedrano@yahoo.es

F.L.-M., J.M.M., J.C., C.L., A.M., and J.M.A. designed research; F.L.-M., C.C., J.T.-C., R.S.-J., J.G., P.M., Ó.L., P.M.-D., A.R., and M.M. performed research; F.L.-M., M.F.-R., C.C., and J.M.A. analyzed data; F.L.-M., M.F.-R., and R.S.-J. wrote the paper; and J.M.M., J.C., J.G., P.M., Ó.L., P.M.-D., C.L., A.M., and J.M.A. revised and completed the final draft of the manuscript.

Received 28 February 2011. Revision requested 14 March 2011.

Accepted 23 May 2011.

Kidney transplantation (KT) constitutes the best therapeutic option for hepatitis C virus (HCV) patients with end-stage renal disease. The prevalence of HCV seropositivity among hemodialysis patients is higher than in the general population, ranging from 10% to 49% (1, 2). More than 80% of enzyme-linked immunosorbent assay-positive patients have detectable HCV-RNA in serum, leading to a viremic state that usually persists after transplantation (2). Although there is some controversy about the effect of HCV infection on the posttransplant course, several studies have demonstrated its negative impact on both patient survival and graft survival (1–3). A meta-analysis including more than 6300 patients concluded that the presence of anti-HCV antibody was associated with a relative risk of 1.79 and 1.56 for death and graft failure, respectively (4). Some of these series identified posttransplant infection as one of the leading causes of mortality among anti-HCV-positive recipients (4–7), suggesting a reciprocal deleterious effect between HCV infection and the level of immunosuppression achieved after KT. However, most previous studies were not specifically aimed at determining the role of HCV antibody status on the risk of posttransplant infection or did not separately analyze such an effect according to the type of infectious complication or its etiologic agents. Hence, we undertook this study to compare the incidence, type, and etiology of infectious complications between anti-HCV-positive and -negative patients in a multicenter cohort of KT recipients from Spain.

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RESULTS

A total of 1406 KT recipients were included in the Spanish Network for the Research of Infection in Transplantation/Network of Research in Infectious Diseases (RESITRA/REIPI) cohort during the study period. Sixty-nine patients (4.9%) were excluded for the present analysis due to insufficient data. Thirty-five (2.49%) of them had hepatitis B virus (HBV) infection documented in the pretransplant period, so were also excluded. Thus, the final cohort comprised 1302 recipients (761 men) with a mean age of 49.9±15.5 years. Anti-HCV antibodies were present in 105 (8.1%) patients. Table 1 summarizes the demographics and clinical baseline characteristics according to the pretransplant anti-HCV status. Anti-HCV-positive recipients were more likely to have undergone previous solid organ transplantation (P<0.001) and had a lower donor age (P=0.055) and higher transfusion requirements (P=0.037). More than half of anti-HCV-positive recipients had a history of chronic liver disease compared with only 0.9% of those anti-HCV negative (P<0.001). There were also significant differences in the use of induction therapy based on lymphocyte-depleting antibodies (LDA) (either thymoglobulin or OKT3), more frequent among anti-HCV-positive recipients (P=0.005), as well as a statistical trend toward a more frequent administration of monoclonal anti-CD25 antibodies and new investigational drugs. Accordingly, cytomegalovirus (CMV) prophylaxis was also more frequently indicated in this group (P=0.004). The median follow-up period was 35.12 months (range, 0–36 months). Thirty-five patients (2.7%) suffered graft loss (defined by either the need for retransplantation or death) at a median interval of 56 days after KT (range, 0–580 days). As depicted in Table 2, we found a significantly higher rate of recurrent acute rejection episodes in the anti-HCV-positive group (4.8% vs. 1.7%; P=0.045). Although there were no significant differences between anti-HCV-positive and -negative recipients in overall mortality (P=0.67), 3.8% required retransplantation in the first group when compared with 0.8% in the second group (P=0.017).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

We found no significant differences between anti-HCV-positive and -negative patients either in the cumulative incidence of infection at the end of follow-up (45.7% vs. 40.2%; P=0.27) or in the overall incidence rate of any type of infection (0.82 vs. 0.74 episodes per 1000 transplant-days, respectively), as listed in Table 3. The mean number of infections per recipient was 1.88±1.27 in the anti-HCV-positive group compared with 1.97±1.48 in the control group (P=0.59). As also indicated in the Table 3, there were no differences in the distribution of infectious episodes between both groups according to the posttransplant period: early (first month), intermediate (1–6 months), or late (>6 months). The timing of the first episode of bacterial infection was similar regardless the anti-HCV status (median of 16 vs. 19 days from transplant, respectively; P=0.494). Nevertheless, when specific types of infection were examined separately, some significant differences arose between both groups. Anti-HCV-positive recipients exhibited, when compared with the rest of the cohort, a significantly higher cumulative incidence of both bloodstream (8.6% vs. 3.5%; P=0.010) and upper urinary tract infections (12.4% vs. 6.9%, respectively; P=0.037). In the logistic regression analysis for the occurrence of both infectious syndromes, anti-HCV antibody status emerged as an independent risk factor only for bloodstream infection (odds ratio [OR]: 3.14; 95% confidence interval [CI]: 1.19–8.24; P=0.020), along with pretransplant diabetes mellitus and acute rejection (Table 4). On the contrary, anti-HCV status was not retained in the final multivariate model assessing the risk of upper urinary tract infection (Table 5). Finally, there was a trend toward an increased cumulative incidence of infections due to Pseudomonas aeruginosa (8.6% vs. 4.8%; P=0.083) and coagulase-negative staphylococci (2.9% vs. 0.8%; P=0.080) in the anti-HCV-positive group when compared with the remaining cohort.

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

To control the impact of induction therapy based on LDA on the risk of bloodstream infection, we performed an additional analysis by establishing three comparison groups: anti-HCV-positive patients (n=105), anti-HCV-negative patients with induction therapy based on LDA (n=81), and anti-HCV-negative patients without such therapy (n=1116) (considered as the reference category). In the multivariate analysis, only the first group exhibited a significantly increased risk of bloodstream infection when compared with the reference category (OR: 2.89; 95% CI: 1.57–5.32; P=0.028). On the contrary, there were no significant differences between anti-HCV-negative patients with or without induction therapy.

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DISCUSSION

In this large, multicenter, prospective cohort of KT recipients, we found a similar risk of infection or death at 3-year follow-up regardless of the pretransplant anti-HCV antibody status. Such results differ from those from previous studies that reported an increased occurrence of infection (7, 8) or lower patient- and graft-survival rates among HCV-infected recipients (3, 4). This study, through a more detailed analysis, revealed specific associations between anti-HCV seropositivity and the requirement of retransplantion or the cumulative incidence of some infectious syndromes. A major conclusion of our work is the demonstration that anti-HCV-positive KT recipients had more than a 3.0-fold increased risk of bloodstream infection, a finding with potential implications in the clinical management of this population.

It has been reported that HCV infection induces a state of immunodeficiency after solid organ transplantation based on a decrease in the rate of naive T-helper lymphocytes and the T-cell mitogen proliferative response (9), as well as in a severe disturbance of B-cell homeostasis (10). In the same way, our group reported 2 decades ago a lower incidence of acute rejection in anti-HCV-positive recipients (9). In contrast, more recent studies have showed a similar (8) or even a higher incidence of such complication associated with HCV infection (11). A possible explanation lies in the changes experienced by anti-HCV-positive recipients in their immunological risk during the last years. A recent nationwide study performed in our country has demonstrated that the rate of retransplantation among anti-HCV-positive patients was higher in the 1998-2002 period when compared with the 1990-1994 period, as well as their percentages of panel-reactive antibodies positivity (11). Consistent with these data, we have found an increased rate of recurrent acute rejection in the anti-HCV-positive group of our cohort. Of note, these recipients were more likely to have undergone a previous transplant and exhibited higher transfusion requirements, two circumstances previously reported (3, 8) and that seem to be associated with an increased immunological risk (1). Nevertheless, the impact of transfusion practice on the incidence of acute rejection is still controversial, with some authors suggesting better graft survival in transfused recipients, particularly in the presence of two or more HLA mismatches (the so-called “transfusion effect”) (12). In accordance with previous studies in our setting (11), we have also identified significant differences both in donor age and in the use of induction therapy among recipients with and without HCV infection, likely reflecting a higher representation of hyperimmunized recipients in the former group. Although we found a higher use of induction with LDA in the anti-HCV-positive group, this variable did not reach statistical significance in the univariate analysis for the occurrence of bloodstream or upper urinary tract infections, in accordance with a recently published report from the RESITRA/REIPI cohort (13).

Conflicting results have been reported on the long-term natural history of HCV infection after KT (1–4). There are a number of reasons for these discrepancies between series, including the retrospective design of most of them, the different duration of follow-up, and the lack of a homogeneous evaluation of the grade of the underlying liver disease (4). A recent report from Spain has suggested that the use of kidneys from anti-HCV-positive donors into anti-HCV-positive recipients seems to be a safe long-term strategy (14). HCV infection seems not to influence either patient or graft survival in the short term (1, 6). Thus, the relatively short duration of the posttransplant follow-up period for a disease that evolves over decades might explain the negative findings concerning the impact of HCV infection on 3-year mortality in our cohort.

To the best of our knowledge, only one previous study has specifically analyzed the existence of different patterns in the type of infection or the causative microorganisms between anti-HCV-positive and -negative KT recipients. Rao and Ma (7) reported that the mean number of infectious episodes per patient was significantly higher in the hepatitis group both overall and specifically in those potentially fatal (i.e., bloodstream infection or pneumonia). These authors also found a significant increase in the incidence of Gram-negative bacterial infections (7). To explain the discrepancies between both series, it is noteworthy to mention that Rao and Ma included patients with infection by either hepatitis B or C virus, and all of them exhibited clinical evidence of chronic liver disease, when compared with only 52.8% in our cohort. Moreover, the prolonged inclusion period of their study (1969–1995) entails notable differences with the contemporary immunosuppressive and prophylactic regimens.

Interestingly, anti-HCV-positive status exerted an independent impact on the odds of posttransplant bloodstream infection in our multivariate analysis, even after adjustment for other well-known predictive factors such as acute rejection or diabetes mellitus (10). Sepsis-related death had been found to be significantly increased among anti-HCV positive recipients in previous series (5, 15). Reddy et al. (16) recently reported a positive association between anti-HCV status and the incidence of bacteremia in a cohort of hemodialysis patients with tunneled vascular catheters. Forty percent of the patients with detectable circulating virus had a bacteremia episode, in contrast with the absence of such a complication among the patients with undetectable virus. As an explanation for this finding, the authors suggest that chronic HCV infection may lead to a state of relative immunodeficiency by both indirect—through the development of liver dysfunction and chronic liver disease—and the aforementioned direct mechanisms (16). In this regard, it is noteworthy that the impact of anti-HCV serostatus on the risk for bloodstream infection in our cohort was independent of the pretransplant diagnosis of chronic liver disease, as highlighted by multivariate analysis. Finally, we found a numerical trend toward a higher incidence of Pseudomonas aeruginosa infection among the anti-HCV-positive group. Linares et al. (17) have analyzed the epidemiology of multiresistant bacterial infection—including 19% of episodes due to nonfermenting Gram-negative rods—in a large cohort of KT recipients and reported that the pretransplant anti-HCV status had an independent effect on the occurrence of such a complication.

There are some limitations in our study to be considered, the most important of which lies in the lack of information on HCV-RNA status or HCV genotype and on the evolution of liver function tests during follow-up. We were also not able to analyze the impact of interferon-based therapies administered before transplantation. Nevertheless, such limitations are shared by most of previous studies assessing the risk of posttransplant infectious complications (7, 8, 17) or the long-term outcome (5, 11) in HCV infection. On the other hand, the presence of cirrhosis or end-stage liver disease in the pretransplant evaluation is commonly considered an exclusion criterion for KT, so we can assume a relatively mild degree of liver dysfunction among anti-HCV-positive recipients. Although the risk of infection in the late posttransplant period has been reported to be as low as 0.28 episodes/1000 transplant-days (18), the impact of the anti-HCV serostatus could be different in the long-term follow-up, beyond the 3-year limit established in our study. In addition, the low incidence rates observed for certain infectious syndromes and microorganisms (i.e., invasive fungal infections) are prone to type 2 statistical error due to the reduced sample size. Both comparison groups were not homogeneous in their baseline characteristics (rate of previous transplantation) and posttransplant management (use of induction therapy), although we have attempted to control the latter variable by establishing a third comparison group (those anti-HCV-negative patients with induction therapy based on LDA). The lack of details on the immunosuppression regimen, and particularly the cumulative corticosteroid exposure, precludes us from assessing the potential impact of such variable on the risk of infection according to anti-HCV status. Although all data were prospectively collected according to the predefined definitions, we cannot exclude the effect of hidden confounding factors, including differences between participating centers regarding immunosuppression policies, prophylaxis regimens, or posttransplant management.

In conclusion, in the RESITRA/REIPI cohort, the pretransplant anti-HCV serostatus does not seem to impact on the overall incidence of infectious complications considered as a whole nor on the risk of death at 3-year follow-up after KT. However, anti-HCV-positive recipients had a higher rate of retransplantation and recurrent acute rejection and an increased incidence of both bloodstream and upper urinary tract infections. Further studies are needed to clarify the specific role of HCV infection as a risk factor for posttransplant bacteremia. Meanwhile, and given the nonmodifiable nature of such variable, this population should deserve careful attention and prompt treatment in case of bacterial infection, in view of their apparent predisposition to a potentially complicated course.

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MATERIALS AND METHODS

Study Population

RESITRA/REIPI is a research network financed by the Spanish Ministry of Health that comprises 16 transplant centers and three reference laboratories. Its design, definitions, and data collection procedures have been detailed elsewhere (12, 18, 19). Briefly, RESITRA/REIPI was created in April 2003 to evaluate the characteristics of transplantation in our setting, especially focusing on the incidence and features of infectious complications in these patients. Pretransplant, peri-transplant, and follow-up data were prospectively recorded in an online database, as were records of all major events, always according to the predefined definitions published in the RESITRA Web site (www.resitra.retics.net/web/index.asp). Data were extracted through managerial and statistical databases generated from the SQL-server database, after completion of a validating process managed by the coordinator at each hospital. From April to July 2003, research tools were created and implemented, and at the end of July 2003, the first patients were recruited. For this study, we analyzed all KT recipients included in the RESITRA/REIPI cohort from September 2003 to the end of February 2005 who reached a follow-up of 3 years from the time of enrollment (unless death or graft loss were documented earlier). Therefore, the follow-up period comprised the first 3 years posttransplant. As previous studies have demonstrated the impact of HBV infection on the incidence of posttransplant infectious complications (7, 20), we excluded from the analysis those patients with positive HBV surface antigen in the pretransplant evaluation.

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Definitions

HCV infection was defined as detection of HCV antibody in serum by second- or third-generation enzyme-linked immunosorbent assay. Information on anti-HCV antibody status was always assessed before the enrollment in dialysis programs or at the time of transplantation. Routine testing for the presence of viral RNA was not done in all anti-HCV-positive patients. Chronic liver disease was defined biochemically as a raised serum alanine aminotransferase for more than 6 months. No information was available on liver biopsy specimens or previous interferon-based therapies. CMV disease included CMV viral syndrome (temperature of >38°C with a positive antigenemia or polymerase chain reaction result, and one of the following: leukocyte count <4000 cells/mm3, atypical lymphocytes ≥3%, or platelet count <100,000 platelets/mm3) and tissue-invasive disease, the definitive diagnosis of which required the association of compatible symptoms, or signs with histopathological evidence of CMV from an appropriate specimen. We considered bacteremia or fungemia to be significant according to the criteria of the Centers for Disease Control and Prevention (21). The diagnosis of pneumonia was based on clinical, radiographic, and microbiological criteria. Surgical site infection was defined as an infection occurring within 30 days of surgery that involved skin or subcutaneous or deep soft tissues at the surgical wound site, with the isolation of the same microorganism in at least two aseptically obtained cultures. Upper urinary tract infection was defined by the simultaneous presence of fever and an appropriately collected urine culture showing significant bacterial growth of more than 105 colony forming units/mL and/or bacteremia, along with one or more of the following: lumbar pain, graft pain, chills, dysuria, and/or cystitis. Asymptomatic bacteriuria was not considered in the analysis. Invasive fungal infection was defined as proposed by the European Organization on Research and Treatment in Cancer and the Mycoses Study Group (22). Acute rejection was suspected in case of an elevation of the serum creatinine and diagnosed by histological examination if possible. If biopsy was not technically possible, “intended-to-treat” episodes that respond to antirejection therapy were also taken into account. Recurrent acute rejection was defined as rejection diagnosed after clinical and biochemical recovery from the previous episode with a free interval of at least 2 weeks. Other major events were also recorded on a specifically designed data collection form.

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Immunosuppression and Prophylactic Regimens

Immunosuppressive therapy, infection prophylaxis, and posttransplant clinical management were done according to the protocols of each participating center. All patients received intravenous perioperative antibiotic prophylaxis with a first-generation cephalosporin (48.7%), amoxicillin (17.1%), a third-generation cephalosporin (13.1%), or a glycopeptide (4.6%), among other regimens. Prophylaxis against CMV was performed according to the guidelines proposed by Group for the Study of Infection in Transplant Recipients of the Spanish Society of Infectious Diseases and Clinical Microbiology (23). Intravenous ganciclovir was administered for 2 weeks followed by oral valganciclovir during the first 3 months posttransplantation in high-risk patients (CMV mismatch or induction therapy with LDA). In the absence of clear recommendations at the study time, criteria for antifungal prophylaxis (against either Candida spp or filamentous fungi) were not fully homogeneous among participating centers. For maintenance immunosuppressive therapy, most recipients received a double or triple regimen consisting of a calcineurin inhibitor, mofetil mycophenolate, and corticosteroids. Other used regimens included (a) a calcineurin inhibitor, a mammalian target of rapamycin inhibitor, and corticosteroids; or (b) a mammalian target of rapamycin inhibitor, mofetil mycophenolate, and corticosteroids. The treatment of acute rejection consisted on intravenous corticosteroid bolus, followed by a course of OKT3 or antithymocyte globulin in case of corticosteroid resistance.

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Statistical Analysis

Data are shown as mean (or median) ± standard deviation (or range) for quantitative variables and as absolute and relative frequencies for qualitative variables. Continuous variables were compared with the Student's unpaired t test (or U Mann-Whitney test when the assumption of normality did not hold). The χ2 or Wilcoxon tests were used for proportions, as appropriate. We used a backward stepwise logistic regression to specifically assess the role of anti-HCV antibody status on each type of infection. Thus, ORs with 95% CI were calculated for variables with significant differences between patients with or without infectious complications in the univariate analysis. In addition, some clinically relevant factors were forced in the multivariate model to assess their effect. All significance tests were two tailed, and differences were considered to be significant at P value less than 0.05. The statistical analysis was carried out using SPSS, version 16.0 (Statistical Package for the Social Sciences Inc®, Chicago, IL).

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Keywords:

Bloodstream infection; Hepatitis C virus; Infection; Kidney transplantation; RESITRA/REIPI

© 2011 Lippincott Williams & Wilkins, Inc.