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Keywords:

  • EBV;
  • French Registry;
  • HCV;
  • kidney transplantation;
  • post-transplant lymphoproliferative disorders

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Post-transplant lymphoproliferative disorders (PTLD) are a rare but serious complication after organ transplantation. A French Registry of PTLD was set up in a nationwide population of kidney transplant recipients. We prospectively enrolled all adult kidney recipients developing PTLD between January 1, 1998, and December 31, 2003. We analyzed the incidence, risk and prognostic factors of PTLD by Kaplan-Meier and Cox analyses. Totally 230 cases of PTLD were referred to the French Registry. Cumulative incidence was 1.18% after 5 years. Older age (per year, AHR = 2.19, CI = 1.22–3.94) and recipient Epstein-Barr virus seronegativity (AHR = 3.01, CI = 1.57–5.08) were associated with an increased risk of PTLD. Patients with PTLD had a reduced survival rate (61% at 5 years). Graft PTLD had the best prognosis with an 81% survival rate after 5 years. Infection with hepatitis C or B virus (HCV or HBV), late-onset PTLD, multiple sites involvement and high Ann Arbor staging were risk factors for patient death. Use of azathioprine was associated with a poorer survival rate. PTLD incidence and risk factors in French recipients are in line with the international or American PTLD series. We highlighted the role of HBV or HCV in patient mortality and described the relevant prognosis factors for patients with post-transplant lymphoproliferations.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

As long-term survival after organ transplantation has improved, neoplastic complications are increasingly being discovered after transplantation. Immunosuppression clearly exposes patients to a spectrum of malignancies and particularly to post-transplant lymphoproliferative disorders (PTLD). In kidney transplantation, the risk for PTLD was found to be about 40 times greater than in general population with an incidence between 0.4% and 2% in adults (1–3). Moreover, PTLD led to death in more than 50% of patients (4). Lymphoproliferations encompass a heterogeneous group of disorders, which range from a benign self-limited form of cell proliferation to an aggressive widely disseminated disease. These disorders are typically associated with an uncontrolled B-cells proliferation. In rare cases, lymphomas are of T cells, null cells or both T- and B-cell origin. PTLD disclose particular characteristics as compared to immunocompetent patients' lymphomas. The pathophysiology of some PTLD—particularly the earliest ones—seems original. Most of early PTLD are developed from donor lymphocytes, frequently located within the allograft, strongly induced by the amount of immunosuppression and related to Epstein-Barr virus (EBV). They could regress after immunosuppression reduction and host cytotoxic response recovery, leading to a better prognosis (5). The late-onset PTLD are closer to standard lymphomas, since they are developed from host lymphocytes, rarely induced by EBV, are disseminated and have a poor prognosis (6). Nevertheless, the late-onset PTLD show some particularities, such as frequent extra-nodal involvement and common cerebral localization (1). Their occurrence in patients with immunosuppressive treatment may lead to high therapy-related toxicity. The clinical variability of the disease, its frequent extra-nodal involvement, and the wide spectrum of histologic features make the classification of PTLD complex and the management of recipients with PTLD difficult and far from optimal. Moreover, the small number of diseased patients has made the identification of prognostic criteria difficult. The heterogeneity of the therapies reported in the literature has not allowed yet the assessment of a consensual first-line therapy. Most publications report PTLD series from a single institution or multiorgan and multicentric series, which increases the heterogeneity of PTLD presentation and outcome. Furthermore, few multicentric studies have been undertaken in France for reviewing PTLD in adult kidney recipients.

Some risk factors for the development of PTLD have been proposed in the literature, based on pathophysiological concepts or clinical/epidemiological observations. EBV seronegativity (7), chronic antigenic stimulation, the degree of immunosuppression (4,8,9) and viral co-infections like hepatitis C virus (HCV) and cytomegalovirus (10–12) are the most frequent.

The purpose of the present study is to explore the incidence and characteristics of PTLD, and to analyze the risk factors for PTLD occurrence and patients' survival in a nationwide cohort of kidney transplant recipients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Between January 1, 1998, and December 31, 2003, we prospectively enrolled all new diagnosed cases of PTLD occurring after kidney transplantation in adults in 35 transplant centers in France. Inclusion criteria were: recipient age over 18 years at time of transplantation and transplantation of a kidney alone. Extensive data from donors and recipients were collected at time of transplantation, PTLD diagnosis, every 6 months after diagnosis until the second year and then every year. Clinical staging was done according to Ann Arbor Staging System after clinical and radiological evaluations using standard diagnosis procedures. Immunosuppressive drugs were recorded at discharge of the hospital after transplantation and at time of lymphoma diagnosis. Histologic specimens were analyzed by the pathologist of each center. PTLD were classified according to Knowles classification into: plasmatic hyperplasia, polymorphic lymphoproliferative disorder and non-Hodgkin's lymphoma (13). Multiple myelomas and Hodgkin diseases were not included in this analysis. PTLD were classified according to lymphoid cells phenotype. Specimens were studied using monoclonal antibodies directed against kappa and lambda immunoglobulin light chains; and immunoglobulin heavy and light chains rearrangement analyses were assessed to determine the tumor clonality. EBV infection was analyzed according to center protocols using LMP1 and/or EBNA2 immunohistochemistry or EBER in situ hybridization. Treatment was not standardized and conducted according to each center's practice.

Statistical analysis

Three groups of patients were considered for the different analyses:

  • The first group of patients was the whole cohort of recipients with PTLD. This group consisted of 230 patients who developed PTLD after January 1, 1998, whenever was the transplant date. This cohort was used to provide on the one hand the descriptive analysis of lymphomas' presentation and to determine the patients' survival on the other hand. For description of PTLD population, univariate analyses were performed with Chi-square testing for categorical variables and Student's two-sided t-test for continuous variables. Data are given as mean ± SD. A p-value <0.05 was considered to be significant. For survival studies, univariate analyses were performed using Kaplan-Meier plots and prognostic factors were compared using log-rank test. Variables with p < 0.10 in univariate analysis for a relationship with death were entered into Cox regression model as covariates (recipient and sex gender, transplant date, PTLD delay, PTLD localization and immunosuppressive drugs at discharge from the hospital after transplantation). Time to death was considered between PTLD diagnosis and date of death.

  • The second group of patients was limited to the recipients transplanted after January 1, 1998, in order to have a control group to determine the PTLD risk factors. This group consisted in 68 of the 230 PTLD which were compared to the whole cohort of the French transplant patients without PTLD (control group: n = 10 617). This analysis was performed after 1998 because informations in the Transplant French database were not available before 1998 for the patients without PTLD. Univariate analysis was performed using Kaplan-Meier analysis for occurrence of PTLD. Time to PTLD was defined as the time from renal transplant until the date of diagnosis for PTLD, with patients censored at death, loss to follow-up, dialysis or end of the study (which was considered December 31, 2004). Plots were compared by log-rank test after stratification according to different parameters (recipient age and gender, HLA matching, PRA, recipient serological status for CMV and EBV, and immunosuppressive regimen at discharge from the hospital after transplantation). Multivariate analysis was carried out using Cox regression model. Variables with p < 0.10 in univariate analysis for a relationship with development of PTLD were entered into multivariate analysis as covariates.

  • The third group was set up to analyze the PTLD incidence which was calculated by year after transplantation, from the first to the fifth year post-transplantation. For this analysis, we enrolled PTLD occurring in patients transplanted in 1994 for the fifth year analysis only, PTLD occurring in patients grafted in 1995 for the fourth and fifth years' analysis, PTLD occurring in patients grafted in 1996 for the third, fourth and fifth year's analysis, PTLD occurring in patients grafted in 1997 for the second, third, fourth and fifth years' analysis and PTLD occurring in patients grafted after 1998 for the first to fifth years' analysis. The total of this group was 85 PTLD patients. The incidence of PTLD was determined by the ratio between the number of PTLD cases and the number of recipients exposed to the risk of PTLD during this time. Incidence is given by year of follow-up after transplantation and cumulative incidence was determined by the addition of the annual incidences.

All analyses were performed using SPSS 11.0 TM (SPSS, Inc., Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Incidence of PTLD after kidney transplantation

Between January 1, 1998, and December 31, 2003, 230 cases of PTLD occurring after kidney transplantation were referred to the French Registry. Cumulative incidence is shown in Figure 1. Incidence was greater in the first post-transplant year (0.46%, CI 0.32–0.60%) and became stable after the third year (0.13–0.18%). After 5 years, the cumulative incidence was 1.18%.

image

Figure 1. (A) Cumulative incidence of PTLD after kidney transplantation. (B) PTLD incidence by year following kidney transplantation. 95% CI = 95% confidence interval.

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Description of PTLD population

Altogether 156 men and 74 women transplanted between December 1977 and May 2003 developed a PTLD (sex ratio = 2.1). Patients' characteristics are summarized in Table 1. Patients' age at time of transplantation was 46 ± 13 years (18–73 years) and 52 ± 13 years (22–75 years) at time of diagnosis. Among 16 EBV seronegative recipients, 8 were known to be transplanted with a positive donor for EBV. Moreover, 25/186 (14%) recipients were positive for HCV or hepatitis B virus (HBV) before transplantation. Immunosuppressive regimen consisted mostly in a quadruple sequential immunosuppression (Table 1).

Table 1.  Characteristics of patients with PTLD
 n%
  1. Ab = antibody; anti-IL2 = anti-IL2 receptor antibodies; CNI = calcineurin inhibitor; MMF = mycophenolate mofetil; GIT = gastro-intestinal tract; Cr = serum creatinine.

Age (n/230)
 <25 years177
 25–60 years18179
 >60 years3214
Transplant range (n/200)
 1st17688
 2nd2211
 3rd21
Donor (n/200)
 Deceased19698
 Living42
Recipient viral status
 EBV positive152/16691
 EBV negative16/1669
 CMV positive121/19363
 CMV negative109/19356
 CMV disease31/20315
 HCV positive16/1759
 HBV positive9/1865
Immunosuppression after transplantation (n/202)
 Induction16783
  Polyclonal Ab14873
  OKT3105
  Anti-IL294
 CNI19593
  Cyclosporine A17386
  Tacrolimus3216
 MMF7939
 Azathioprine13567
 Steroids19396
Immunosuppression at diagnosis (n/186)
 Cyclosporine A15282
 Tacrolimus2614
 MMF6133
 Azathioprine7038
PTLD localization (n/210)
 Single site12358
 Multiple sites8138
 Graft4320
 Cerebral2813
 GIT4722
 Lymph nodes4823
Ann Arbor classification (n/210)
 Stage I10450
 Stage II199
 Stage III147
 Stage IV7335
Renal insufficiency at presentation (n/192)
 Cr > 150 μmol/L8946
 Cr < 150 μmol/L10454
Histologic features
 B PTLD172/18692
 T PTLD14/1868
 EBV positive103/15168
 EBV negative48/15132
 Polymorphic71/14150
 Monomorphic63/14145
 Polytypic12/6518
 Monotypic50/6577
 Polyclonal12/7516
 Monoclonal50/7567

Considering the whole cohort, the mean delay between transplantation and PTLD was 76 ± 59 months (1–268 months) with a median of 72 months. Nineteen percent of cases occurred in the first year post-transplantation and were classified as early PTLD. Considering only patients transplanted after January 1, 1998, the mean delay between transplantation and PTLD diagnosis was 14 ± 1.4 months (1–51 months) with a median of 10 months. Fifty-seven percent of cases were early-onset PTLD. Delay to PTLD limited near the allograft was shorter than delay for PTLD localized in other sites (32 ± 46 months vs. 86 ± 57 months, p < 0.0001) and 53% of PTLD limited to the graft occurred in the first post-transplantation year.

PTLD localizations and histologic features are depicted in Table 1. Of note, 43/210 PTLD (20%) involved the graft itself, as a unique localization in 32 cases. Mean creatininemia was 192 ± 91 μmol/L (61–722 μmol/L) at PTLD diagnosis. When PTLD involved the graft, 70% of patients (vs. 30%, p = 0.002) displayed a graft dysfunction at diagnosis with a mean creatininemia of 197 ± 97 μmol/L (vs. 162 ± 88 for other localizations, p = 0.03).

Treatment of PTLD was extremely heterogeneous according to each center protocol and specific patient presentation (Table 2). By far, the most common method was to decrease or withdraw at least one of the immunosuppressive drugs. The calcineurin-inhibitors were stopped in 40% of cases and tapered in 32% of cases. The anti-metabolites azathioprine or mycophenolate mofetil were withdrawn in 48% of cases and tapered in 10% of cases. Monoclonal antibody anti-CD20 Rituximab was used in 39% of the cases, alone or in association with chemotherapy. Chemotherapy was used in more than half of the cases, but regimens were not standardized among centers. Twenty-nine patients (of which 18 transplantectomies) restarted dialysis after lymphoma diagnosis (13%).

Table 2.  PTLD treatment (data available for 202 patients)
PTLD treatmentn%
  1. 1Surgery without transplantectomies.

Immunosuppression reduction or withdrawal17285
Anti-viral therapy4522
Monoclonal antibody Rituximab7939
Chemotherapy11456
 Rituximab+chemotherapy4622
Radiotherapy168
Surgery15628
Transplantectomy189

Eighty-nine patients died (39%) after a mean follow-up of 8.3 ± 5 years after transplantation (3 months to 22.5 years) and 10 ± 12.6 months after lymphoma diagnosis (0 month to 4.2 years). Death was related to lymphoma progression in more than half of the cases and to treatment complications in one-third of cases.

One hundred and nine out of 230 patients achieved a complete remission with a mean follow-up of 56 ± 20 months, 6 are in partial remission, and 5 developed a relapse controlled by a recovery of the treatment.

Risk factors for PTLD

In univariate and multivariate analyses, age over 60 years at time of transplantation (p = 0.05 by log-rank test, AHR = 2.19, 95% CI = 1.22–3.94, p = 0.009 in Cox analysis) and recipient EBV seronegativity (p = 0.0004 by log-rank test, AHR = 3.01, 95% CI = 1.57–5.08, p = 0.001) were risk factors for PTLD occurrence.

Patients' survival and prognosis factors

Overall survival after PTLD diagnosis was 73% at 1 year and 61% at 5 years (Figure 2). Survival was different according to transplant era before or after 1996 (56% vs. 67% at 5 years), but this difference did not reach statistical significance. The mean survival for the entire cohort was 4.97 ± 0.2 years (95% CI = 4.5–5.4).

image

Figure 2. Overall patients with PTLD survival by Kaplan-Meier analysis.

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Patients with HCV or HBV at time of transplantation disclosed higher mortality (38% vs. 65% at 5 years, p = 0.005, Figure 3). These deaths occurred mainly in the first 6 months after lymphoma diagnosis. Patient survival was better in patients with early than late lymphomas (80% vs. 58% at 5 years, p = 0.01, Figure 3), in patients with involvement of a single site as compared to multiple sites involvement (74% vs. 49%, p = 0.0002, Figure 3) and in patients with graft lymphoma as compared to all other locations (81% vs. 59% at 5 years, p = 0.02, Figure 3). In patients with allograft PTLD, single site of malignancy was associated with an excellent prognosis (94% vs. 45% survival rates at 1 and 5 years, p = 0.0001). Overall patients' survival is also different according to PTLD localization (graft, lymph nodes, gastro-intestinal tract, central nervous system) and Ann Arbor staging classification (p = 0.05 and p = 0.0005, respectively, Figure 4). Survival was not significantly different with respect to recipient age, gender, serological status for EBV or CMV before transplantation, renal function at lymphoma diagnosis, presence or absence or EBV in tumor, and histological type of the tumor (data not shown). Patient survival was lower in patients treated by azathioprine (55% vs. 76% at 5 years, p = 0.01, data not shown). In multivariate analysis, multiple lymphoma localization and treatment with azathioprine after transplantation remained risk factors for death (AHR = 2.2, CI = 1.3–3.7, p = 0.002 and AHR = 2.2, CI = 1.03–4.9, p = 0.04, respectively).

image

Figure 3. Patient survival from post-transplant lymphoproliferative disorder diagnosis stratified according to different parameters, by Kaplan-Meier analysis. Factors were compared using log-rank test. (A) Survival in patients with early-onset vs. patients with late-onset PTLD. (B) Survival in patients with graft versus patients with other-sites PTLD. (C) Survival in patients with single locations vs. patients with disseminated PTLD. (D) Survival in patients with hepatitis seropositivity vs. patients without hepatitis (HCV and HVB).

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image

Figure 4. Patient survival from post-transplant lymphoproliferative disorder diagnosis stratified according to: (A) PTLD localization: graft (○), lymph nodes (□), gastro-intestinal tract (▵) and central nervous system (×). (B) Ann Arbor classification: stage 1 (○), stage 1E (□), stage 2 (▵), stage 3 (•) and stage 4 (×) by Kaplan-Meier analysis. Factors were compared using log-rank test.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

The present study reports incidence, characteristics, risk factors, management and outcome of 230 cases of PTLD occurring in a prospective French nationwide cohort of adult kidney transplant recipients. The PTLD incidence is higher in the first-post-transplant year (0.46%) and the cumulative 5-years' incidence is around 1.2%. This is close to the incidences reported in large databases such as CTS or USRDS. Opelz and Dohler reported a 0.3% incidence after 1 year and a 1.6% incidence after 10 years (4). A recent study describing PTLD in the American kidney transplant population showed a 1.8% incidence after 3 years (14). In this series, pediatric patients as well as myelomas and Hodgkin diseases were included, explaining the higher incidence.

In our series, the mean delay of PTLD occurrence was 76 months and the median was 72 months. This interval was long because the prolonged follow-up (9.7 ± 5 years) allowed us to include many late-onset lymphomas. If considering only recipients transplanted during the period of enrollment (1998–2003), the mean delay was 10 months and more than half the number of cases occurred during the first year-post-transplantation in accordance with the previous series (4). Time to graft PTLD was shorter than for other localizations. This was reported in kidney, liver or lung transplantation (5,15). Early occurrence of graft PTLD is explained by uncontrolled proliferation of passenger donor lymphocytes which are present in the graft organ at the time of transplantation (5). PTLD arising in immunodeficient patients exhibit features distinct from immunocompetent patients' lymphomas, since PTLD are frequently extra-nodal and localized in the graft itself and the central nervous system (1). The reasons for these particular tropisms are not known even though the role of chronic antigenic stimulation is suspected for graft lymphomas. In our series, graft PTLD accounted for 20% of the localizations and cerebral lymphomas for 13%. This is consistent with the localization of post-transplant lymphomas in other series: 21% to 28% for allograft PTLD (16,17), and 9% for cerebral lymphomas (16).

In terms of risk factors for PTLD development, we found that older age and recipient EBV seronegativity were the main risk factors. Usually, younger age is associated with a higher risk of PTLD because of the high frequency of EBV seronegativity in children. This discrepancy is explained by the exclusion of the pediatric patients in the French Registry. Opelz and Dohler showed an increased risk of PTLD in the youngest and oldest patients (4). Occurrence of PTLD in patients aged above 60 years is in accordance with the greater risk of such proliferations in the general population matched for age. On the other hand, recipient EBV seronegativity is a well-known risk factor of PTLD, as EBV is the main oncogenic virus implicated in lymphomagenesis, especially in immunocompromised patients. Moreover, EBV primo-infection is associated with a 10-fold increase of PTLD frequency (7). We were unable to find any relationship between immunosuppressive drugs and PTLD occurrence, possibly because the studied sample of the risk factors analysis was probably too small for a pertinent analysis.

In contrast, our study highlighted some new prognostic factors in patients with PTLD, which are very consistent since this series is prospective, extensive and includes a large number of cases. After PTLD diagnosis, the 1-year and the 5-year survival rates were 73% and 61%, respectively. These survival rates are better than those reported in other series. Opelz and Dohler reported a 40% survival rate after 5 years for the kidney transplant recipients referred to the CTS, with a 65% survival rate for patients with graft involvement and a 38% survival rate for recipients with CNS lymphomas (4). Overall patients' survival for 402 patients with PTLD enrolled in the Israel Penn International Transplant Tumor Registry between 1968 and 2000 was around 45%, but the mean follow-up was not known (16). As our series enclosed a large number of PTLD, we were able to describe for the first time the specific survival of patients with graft, cerebral, digestive and lymph nodes PTLD. For patients with PTLD localized in the graft, the 5-year survival was good (81%), whereas for recipients with cerebral PTLD, the 5-year survival dropped to 53%. In our study, risk factors for death were late-onset PTLD, disseminated PTLD, localization of lymphomas outside the graft, co-infections with HBV or HCV and immunosuppressive treatment with azathioprine. The poor prognosis of late and disseminated PTLD was underlined in previous studies. In the IPITTR, death rate increased for multiple vs. single sites lymphomas from 53% versus 73%. Leblond et al. showed that EBV-negative lymphomas were of late occurrence, responded poorly to immunosuppression reduction and had poor prognosis (18). Dotti et al. reported a 7-month median survival time in heart and kidney transplant recipients with late PTLD (19). On the contrary, Opelz and Dohler and Trofe et al. showed that patients with lymphoma occurring in the site of transplanted organ had better survival (4,16). This may be explained by more intense monitoring of transplanted organs, leading to early detection of lesions at these sites or easy accessibility for surgical resection, especially for kidney allograft. Of note, infection with HBV or HCV was not yet described as a death-risk factor in patients with PTLD. In the present study, 1-year survival in patients with hepatitis infection was only 48%. Nearly 80% of deaths occurred during the first 6 months after PTLD diagnosis. This high mortality rate might be related to an enhanced vulnerability of these recipients and/or a greater toxicity of PTLD therapies. In our series, 64% of patients with hepatitis died from infectious causes and only 36% from lymphoma progression. The poor prognosis of hepatitis-infected patients was not described in previous literature. This finding leads us to be more careful in these recipients by giving them a less immunosuppressive regimen or by scheduling a more intense monitoring after transplantation. We showed that patients treated with azathioprine were at greater risk of death as compared to patients without azathioprine. Azathioprine-treated patients were older, transplanted in the earlier era (before 1996) and developed more late-onset and disseminated PTLD. Nevertheless, a statistical significance persisted in multivariate analysis after adjusting for all these variables, suggesting a potential deleterious role of azathioprine on lymphoma presentation and patient survival.

The limitations of our study are a lack of statistical power for the analysis of PTLD risk factors, since it investigated 68 cases only. Nevertheless, the study of prognostic factors was done on the whole 230 cases, leading to a relevant analysis of the outcome of kidney recipients with PTLD. On the other hand, the heterogeneity of PTLD treatments makes difficult a pertinent analysis of the outcome of patients according to their treatment, but gives us the opportunity to propose in the future a consensual approach in the management of patients with PTLD.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

The French Registry is the first prospective and nationwide series reported in adult kidney transplant recipients. This Registry allows us to describe the precise incidence of this post-transplant complication in France and to determine various predictive factors for the survival of patients developing PTLD. Among these factors, the prognostic value of hepatitis infection has been underlined for the first time, and caution must be taken in this population by using less aggressive cytotoxic therapies.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

The authors are indebted to Drs. Ph. Lang, Y. Lebranchu and P. Niaudet for their invaluable help for facilitating the study and for their fruitful discussion and suggestions during these 8 years.

This study was supported by a grant of the Agence de Biomedecine.

We wish to also thank gratefully all the collaborating investigators and members of the PTLD French Working Group who contributed to this study including:

P.F. Westeel (CHU Amiens), F. Villemain (CHU Angers), J.M. Rebibou (CHU Besançon), M.C. Morel, P. Merville (CHU Bordeaux), B. Bourbigot (CHU Brest), B. Hurault de Ligny (CHU Caen), A.E. Heng, P. Deteix (CHU Clermont-Ferrand), Y. Tanter, C. Mousson (CHU Dijon), F. Bayle, B. Janbon (CHU Grenoble), F. Provot, C. Noel (CHU Lille), J.P. Szelag, Y. Lemeur (CHU Limoges), R. Purgus, V. Moal (CHU Marseille), G. Mourad (CHU Montpellier), E. Renoult, M. Kessler (CHU Nancy), J. Dantal (CHU Nantes), E. Cassuto (CHU Nice), P. Lang (Créteil, Hôpital Mondor), R. Snanoudj, A. Durrbach, C. Hiesse (Paris, Hôpital Bicêtre), C. Antoine, D. Glotz (Paris, Hôpital Pompidou), M.C. Mamzer-Bruneel, M.N. Peraldi (Paris, Hôpital Necker), B. Viron (Paris, Hôpital Bichat), J. Bedrossian, E. Thervet, C. Legendre (Paris, Hôpital Saint-Louis), E. Rondeau (Hôpital Tenon), M. Pastural, M. Delahousse (Paris, Hôpital Foch), V. Leblond (Paris, Hôpital La Pitié-Salpétrière), G. Touchard, A. Thierry (CHU Poitiers), O. Toupance (CHU Reims), J. Rivalan, P. Le Pogamp (CHU Rennes), I. Etienne (CHU Rouen), B. Bourgeon (CHR St. Denis de la Réunion), E. Alamartine (CHU St. Etienne), B. Ellero (CHU Strasbourg), L. Rostaing, D. Durand (CHU Toulouse), M. Buchler, Y. Lebranchu (CHU Tours).

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References
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