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Analysis of data from the international Collaborative Transplant Study has revealed striking relationships between human leukocyte antigen mismatching and graft survival, the incidence of death from cardiovascular disease or infection, the occurrence of non-Hodgkin lymphoma, and onset of post-transplant osteoporosis and bone fracture following kidney transplantation from a deceased donor.

Background: The impact and relationship of donor age, human leukocyte antigen (HLA) matching, and posttransplant non-Hodgkin lymphoma in pediatric kidney recipients are not completely understood., Methods: We analyzed Collaborative Transplant Study data from 9209 pediatric kidney transplant recipients to examine the effects of donor age and HLA match on graft survival and the relationship between HLA match and occurrence of non-Hodgkin lymphoma., Results: Survival rates using donors aged 11 to 17, 18 to 34, or 35 to 49 years were similar. Cox regression analysis showed that two HLA-DR mismatches were associated with lower graft survival in transplants performed during 1988 to 1997 (P<0.001) but not during the 1998 to 2007 period (P=0.95). A hierarchical relationship was observed for the effect of increasing numbers of combined HLA-A+B+DR mismatches on graft survival during the 1988 to 1997 (P<0.001) and the 1998 to 2007 period (P<0.001). An association between two HLA-DR mismatches and non-Hodgkin lymphoma was demonstrated by multivariate analysis (hazard ratio for 2 vs. 0-1 DR mismatches 2.04, P=0.021), and the result was consistent during both 10-year periods., Conclusion: We recommend that (1) kidneys from deceased donors up to 49 years be allocated to children, (2) an acceptable HLA-A+B+DR match be attempted in patients with relatively common HLA phenotypes, and (3) transplants with two HLA-DR mismatches be avoided to reduce the risk of posttransplant non-Hodgkin lymphoma.

Posttransplantation non-Hodgkin lymphoma is a life-threatening complication after transplantation. Although pharmacologically suppressed adaptive immunity plays a major role in its development, the role of innate immunity in posttransplantation lymphoma is unknown. We assessed the 158 V/F polymorphism in the Fc-gamma receptor 3A gene (FCGR3A), killer cell immunoglobulin-like receptor (KIR) genotype, KIR ligand status, and a single nucleotide polymorphism affecting the production of interferon-gamma (IFN-gamma; +874 A/T) in 236 patients with posttransplantation lymphoma reported to the Collaborative Transplant Study. In addition, polymorphisms in the interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) genes previously associated with lymphoma development were also typed. Using a split-cohort approach, gene/allele frequency was related to the 5-year patient survival after the diagnosis of lymphoma and compared with 100 control solid organ transplant recipients. FCGR3A and KIR genotype significantly influenced survival after diagnosis of posttransplantation lymphoma: the hazard of dying was reduced in homozygous carriers of the high-affinity V allele (hazard ratio 0.49, 95% confidence interval 0.29-0.82, P = .006), whereas carrying a genotype including KIR2DL2/KIR2DS2 increased the risk of dying (hazard ratio 1.49, 95% confidence interval 1.07-2.05, P = .02). KIR ligands and cytokine polymorphisms had no effect on survival. None of the genetic loci analyzed emerged as risk factors for lymphoma development.

Background: Posttransplant non-Hodgkin lymphoma is a rare complication but associated with high mortality. The extent to which human leukocyte antigen (HLA) mismatching influences the rate of posttransplant lymphoma has not been clarified., Methods: Data on lymphomas occurring in the first 3 years posttransplant were analyzed among first kidney transplants from deceased donors performed between 1985 and 2007 and reported to the Collaborative Transplant Study., Results: Of 152,728 patients included, 593 non-Hodgkin lymphomas were diagnosed. Cox multivariate regression analysis showed that HLA-A mismatches had no influence on the rate of lymphoma. One and two HLA-DR mismatches were associated with a hazard ratio (HR) of 1.21 (95% confidence interval 1.00-1.45, P=0.047) and 1.56 (95% confidence interval 1.21-1.99, P<0.001), respectively. For lymphoma of the kidney and central nervous system, HRs for two HLA-DR mismatches were 2.29 (P=0.007) and 2.17 (P=0.029), respectively. Two HLA-B mismatches were also significantly associated with lymphoma in the kidney (HR 2.82, P=0.009)., Conclusion: Mismatches at the HLA-DR locus are a significant risk factor for posttransplant non-Hodgkin lymphoma, particularly in the kidney and central nervous system, whereas two HLA-B mismatches increase the risk for the development of lymphoma of the kidney.

BACKGROUND.: Despite the importance of non-Hodgkin lymphoma (NHL) as a posttransplant complication, the relationship between NHL and recipient seropositivity for Epstein-Barr virus (EBV) or cytomegalovirus (CMV) is incompletely understood. METHODS.: Kidney, heart, and liver transplant recipients reported to the Collaborative Transplant Study with known pretransplant EBV and CMV serostatus were analyzed in terms of clinically manifest NHL. Cox multivariate regression analysis was performed to account for a wide range of possible confounders. RESULTS.: In total, 18,682 kidney, 2042 heart, and 2616 liver transplant recipients were analyzed. Regardless of age, pretransplant EBV serostatus was significantly associated with risk of NHL in kidney transplant recipients (P<0.001). There was no significant difference in lymphoma rates according to CMV and CMV serostatus among EBV and EBV recipients (log-rank P=0.55 and P=0.57, respectively), but hospitalization for CMV disease during year 1 posttransplant was associated with subsequent NHL (hazard ratio [HR] 6.1; 95% confidence interval [CI] 2.0-18.4; P=0.001). EBV serostatus was also associated with increased risk of NHL in heart transplant patients (HR 3.6; 95% CI 1.1-11.3; P=0.031) but, contrary to expectation, not in liver recipients (HR 0.6; 95% CI 0.1-1.7; P=0.32). CONCLUSIONS.: In view of the striking increase in risk of NHL in EBV kidney transplant recipients of all ages, EBV serostatus should be determined pretransplant in all age groups. CMV serostatus was not independently associated with risk of NHL after kidney transplantation. Surprisingly, in liver transplantation, the risk of NHL was virtually unaffected by EBV serostatus.

Background: Post-transplant non-Hodgkin lymphoma is a feared complication of immunosuppressive treatment and is associated with high mortality. Most post-transplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr-virus (EBV)-infected B lymphocytes. No reliable methods for the prevention of EBV infection and lymphoma are available. We aimed to elucidate the effect of prophylactic treatment for cytomegalovirus (CMV) infection on the incidence of post-transplant lymphomas., Methods: In a multicentre retrospective study, we analysed the incidence of post-transplant non-Hodgkin lymphoma in 44 828 recipients of deceased-donor kidney transplants who were reported to the scientific registry of the Collaborative Transplant Study. Patients had received antiviral drugs (aciclovir or ganciclovir) or anti-CMV immunoglobulin to prevent CMV infection according to the transplant centres' protocols, or no CMV prophylaxis. Standardised incidence ratios (SIR) of lymphoma were calculated and compared by chi(2) analyses, Findings: During the first post-transplantation year, 30 255 patients who did not receive CMV prophylaxis developed lymphomas at SIR 26.4. Lymphoma incidence in 12 470 patients who received antiviral treatment was nearly identical (SIR 24.2, p=0.62) to that in patients who did not receive CMV prophylaxis. However, 2103 patients who received anti-CMV immunoglobulin showed a complete absence of lymphomas in the first after-transplantation year (SIR 0; p=0.012 vs no treatment, p=0.016 vs antivirals). In the subsequent 5 years of follow-up, new cases of lymphoma developed at similar rates in all three groups (p=0.97)., Interpretation: These findings suggest that prophylactic anti-CMV immunoglobulin prevents the development of early post-transplant non-Hodgkin lymphoma in kidney-graft recipients. Prophylactic treatment with antiviral drugs does not reduce the risk of post-transplant lymphoma.

Background: It is widely assumed that the graft-enhancing properties of antilymphocyte induction agents and their lymphoma-inducing potential are intimately related., Methods: The Collaborative Transplant Study (CTS) database was used to evaluate graft survival and non-Hodgkin lymphoma at 3 years according to type of induction in 112,122 patients receiving a deceased-donor renal transplant during 1985 to 2004., Results: The relative risk of 3-year graft loss versus no induction was 1.07 (95% confidence interval [CI], 1.01-1.13; P=0.016) with murine anti-CD3 monoclonal antibody (OKT3), 1.03 (95% CI, 0.95-1.11; NS) with antithymocyte globulin (ATG)-Fresenius, 1.18 (95% CI, 1.02-1.35; P=0.021) with ATGAM, 0.74 (95% CI, 0.68-0.81; P<0.001) with Thymoglobulin, and 0.78 (95% CI, 0.72-0.84; P<0.001) with interleukin (IL)-2RA induction. The standardized incidence ratio of lymphoma compared with a similar nontransplant population was 21.5 (95% CI, 15.7-28.8; P<0.001) with OKT3, 4.9 (95% CI, 1.6-11.5; P=0.008) with ATG-Fresenius, 29.0 (95% CI, 12.5-57.1; P<0.001) with ATGAM, 21.6 (95% CI, 14.3-31.2; P<0.001) with Thymoglobulin, 7.8 (95% CI, 4.4-12.9; P<0.001) with IL-2RAs, and 9.4 (95% CI, 8.3-10.6 P<0.001) with no induction., Conclusions: Those agents that offered the highest rates of graft survival were not necessarily associated with the highest risk of lymphoma. Graft survival was significantly improved with Thymoglobulin and IL-2RA induction, whereas lymphoma rates were highest with ATGAM, OKT3, and Thymoglobulin. IL-2RA agents seem to offer the best risk-to-benefit ratio for this patient population overall in terms of graft survival and lymphoma.

We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200,000 organ transplant recipients. Over a 10-year period, the risk in renal transplant recipients was 11.8-fold higher than that in a matched nontransplanted population (p<0.0001). The majority of lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First-year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post-transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma.