Association of immunosuppressive maintenance regimens with posttransplant lymphoproliferative disorder in kidney transplant recipients.
ABSTRACT The association of immunosuppressive regimens (ISRs) with posttransplant lymphoproliferative disorder (PTLD) may be related with the Epstein-Barr virus (EBV) recipient serostatus.
We selected primary kidney transplant recipients from Organ Procurement Transplant Network/United Network for Organ Sharing database (2000-2009) who were discharged with a functioning graft and were receiving an ISR including an antiproliferative drug and a calcineurin inhibitor as follows: mycophenolate mofetil (MMF)/mycophenolate sodium+tacrolimus (TAC), MMF+cyclosporine A (CsA); mammalian target of rapamycin inhibitor (mTORi)+TAC; and mTORi+CsA. Adjusted risks of PTLD, rejection, death, and graft failure were examined in all recipients and compared between EBV+ and EBV- recipients.
Of 114,025 recipients, 754 developed PTLD (5-year incidence of 0.84%). Adjusted hazard ratio for PTLD was 4.39 (95% CI: 3.60-5.37) for EBV- versus EBV+ recipients; and 1.40 (95% CI: 1.03-1.90) for mTORi+TAC, 0.80 (95% CI: 0.65-0.99) for MMF+CsA, and 0.90 (95% CI: 0.57-1.42) for mTORi+CsA, versus MMF+TAC users. In EBV- recipients, hazard ratio for PTLD was 1.98 (95% CI: 1.28-3.07) for mTORi+TAC, 0.45 (95% CI: 0.28-0.72) for MMF+CsA, and 0.84 (95% CI: 0.39-1.80) for mTORi+CsA users versus MMF+TAC. No difference was seen in EBV+ recipient groups. Rejection rates were higher among MMF+CsA recipients in both EBV groups. Death and graft failure risk were increased in all EBV+ISR groups, while in EBV- these risks were only increased in mTORi+TAC group versus MMF+TAC.
In EBV- recipients, immunosuppression with mTORi+TAC was associated with increased risk of PTLD, death, and graft failure, while MMF+CsA use was associated with a trend to increased risk of rejection, lower PTLD risk, and similar risk for graft failure when compared with MMF+TAC.
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ABSTRACT: Lymphoproliferative disease (LPD) after renal transplantation (RT) is an unusual complication but one that impacts greatly on survival. We examined possible predisposing factors and their effect on survival using data from the Andalusian Transplant Co-ordination Information System (SICATA) regional computerized database of patients on renal replacement therapy due to chronic kidney disease (CKD). The study population comprised all RT undertaken at adult centers in Andalusia from January 1, 1990 to December 31, 2009 (N = 5577). We retrospectively analyzed cases at December 31, 2011 (N = 60). A control group comprised the 2 closest RT in time done at the same center and with equal or greater graft survival at the time of diagnosis of LPD in the associated case (N = 120). The basic variables were obtained from the general register (1990-2009) and widened from the specific register (2000-2009). Case-control comparison of survival was done with Kaplan-Meier from diagnosis to death or organ loss censored for death. Cox univariate and multivariate (LPD plus available covariables of demonstrated effect) analyses were done. We found no significant differences between cases and controls regarding the characteristics of the recipient or of the donor/organ, initial immunosuppression by intention to treat, or post-RT course. The impact on recipient survival 5 years after diagnosis was as follows: LPD, 35%; controls, 90% (P < .000). Cox univariate analysis showed the relative risk (RR) of death for LPD was 11.36 (95% confidence interval [CI], 6.2-20.9; P < .000) and the multivariate analysis showed relative risk (RR) = 13.87 (7.45-25.3; P < .000). The impact on death-censored graft survival 5 years after diagnosis was as follows: LPD, 65%; controls, 87% (P = .007). Cox univariate analysis was as follows: RR of failure for LPD, 2.70 (95% CI, 1.3-5.7; P = .009). We found no significant differences between LPD cases and contemporary controls regarding the basic characteristics of the recipient, donor/organ, initial immunosuppression, or initial graft evolution. There was an enormous impact on both patient and graft survival.Transplantation Proceedings 12/2013; 45(10):3624-6. · 0.95 Impact Factor
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ABSTRACT: Patients undergoing renal transplant procedures require multi-agent immunosuppressive regimens both short term (induction phase) and long term (maintenance phase) to minimize the risk of organ rejection. There are several drug classes and agents for immunosuppression. Use of these agents may increase the risk of different harms including not only infections, but also malignancies including post-transplant lymphoproliferative disorder. There is a need to identify which regimens minimize the risk of such outcomes. The objective of this systematic review and network meta-analysis of randomized and observational studies is to explore whether certain modern regimens of immunosuppression used to prevent organ rejection in renal transplant patients are associated with an increased risk of post-transplant lymphoproliferative disorder and other malignancies. 'Modern' regimens were defined to be those evaluated in controlled studies beginning in 1990 or later. An electronic literature search of Medline, Embase and the Cochrane Central Register of Controlled Trials has been designed by an experienced information specialist and peer reviewed by a second information specialist. Study selection and data collection will be performed by two reviewers. The outcomes of interest will include post-transplant lymphoproliferative disorder and other incident forms of malignancy occurring in adult renal transplant patients. Network meta-analyses of data from randomized and observational studies will be performed where judged appropriate based on a review of the clinical and methodological features of included studies. A sequential approach to meta-analysis will be used to combine data from different designs. Our systematic review will include both single-agent and multi-agent modern pharmacotherapy regimens in patients undergoing renal transplantation. It will synthesize malignancy outcomes. Our work will also add to the development of methods for network meta-analysis across study designs to assess treatment safety. PROSPERO Registration Number: CRD42013006951.Systematic reviews. 01/2014; 3(1):16.
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ABSTRACT: Epstein–Barr virus (EBV) DNAemia in the first year posttransplantation has been studied extensively. There is a paucity of information on prevalence and sequelae of EBV infection in adult renal transplantation beyond the first year. This single-center study examines the relationship between EBV DNAemia and demographic, immunosuppressive, hematologic and infection-related parameters in 499 renal transplant recipients between 1 month and 33 years posttransplant. Participants were tested repeatedly for EBV DNAemia detection over 12 months and clinical progress followed for 3 years. Prevalence of DNAemia at recruitment increased significantly with time from transplant. In multivariate adjusted analyses, variables associated with DNAemia included EBV seronegative status at transplant (p = 0.045), non-White ethnicity (p = 0.014) and previous posttransplant lymphoproliferative disease (PTLD) diagnosis (p = 0.006), while low DNAemia rates were associated with mycophenolate mofetil use (p < 0.0001) and EBV viral capsid antigen positive Epstein–Barr nuclear antigen-1 positive serostatus at transplant (p = 0.044). Patient and graft survival, rate of kidney function decline and patient reported symptoms were not significantly different between EBV DNAemia positive and negative groups. EBV DNAemia is common posttransplant and increases with time from transplantation, but EBV DNAemia detection in low-risk (seropositive) patients has poor specificity as a biomarker for future PTLD risk.American Journal of Transplantation 05/2014; · 6.19 Impact Factor