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: Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.Transplant Immunology 09/2008; 20(1-2):32-42. · 1.52 Impact Factor
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ABSTRACT: Immunosuppressive therapy is a risk factor for the increased incidence and metastatic progression of malignancies in organ graft recipients. Transforming growth factor (TGF)-beta(1) has been associated with tumor invasion and metastasis, and we have implicated cyclosporine-associated TGF-beta(1) hyperexpression in tumor progression in mice. BALB/c mice or severe combined immunodeficient-beige mice were treated with 2 or 4 mg/kg of tacrolimus, and the effect of treatment on mouse renal cancer cell pulmonary metastasis was investigated. We also determined whether tacrolimus induces TGF-beta(1) expression. Spleens from tacrolimus-treated mice were analyzed for level of expression of TGF-beta(1) mRNA with the use of competitive-quantitative polymerase chain reaction assay, and circulating levels of TGF-beta(1) protein were measured with the use of an enzyme-linked immunosorbent assay. Treatment with tacrolimus resulted in a dose-dependent increase in the number of pulmonary metastases in the BALB/c mice (197+/-16 in untreated mice, 281+/-26 in mice treated with 2 mg/kg of tacrolimus, and 339+/-25 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, Bonferroni's P<0.001) and in the severe combined immunodeficient-beige mice (117+/-18 in untreated mice, 137+/-19 in mice treated with 2 mg/kg of tacrolimus, and 216+/-29 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, P<0.05). Treatment with 4 mg/kg but not 2 mg/kg of tacrolimus resulted in a significant increase in the levels of expression of TGF-beta(1) mRNA and circulating levels of TGF-beta(1) protein. Tacrolimus has a dose-dependent effect on tumor progression and TGF-beta(1) expression, and tacrolimus-induced TGF-beta(1) overexpression may be a pathogenetic mechanism in tumor progression.Transplantation 08/2003; 76(3):597-602. · 3.78 Impact Factor
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ABSTRACT: We have previously documented Caucasian race and cadaver donor source as risk factors for post-transplant lymphoproliferative disorder (PTLD) development in recipients registered in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). We analyzed data from the Scientific Registry of the United Network of Organ Sharing (UNOS) (from January 1988 to December 1999) to determine risk factors for the development of PTLD in all organ systems and its frequency, and we compared these factors to the risk factors in the most recent NAPRTCS database (1987-2000). In the UNOS database, PTLD was reported in 2365 of 205114 organ-transplant recipients (1.2%). PTLD was reported in 3% or more of all intestinal and thoracic organ recipients, but in less than 1% of other abdominal organ recipients. Recipient age < 18 years, Caucasian race and male gender were independent risk factors [Odds Ratios (OR) 2.81, 2.22 and 1.40, respectively, p = 0.0001], but not cadaver donor source. The combination of all three risk factors increased the OR to 8.78. The occurrence of PTLD showed a significant rise per year for heart-lung, kidney, kidney-pancreas and liver transplants, but decreased significantly for heart transplants (p < 0.001). Similar frequencies of PTLD were found in smaller organ-specific registries of heart, intestine, pediatric liver and pediatric kidney transplants. The PTLD incidence per year and incidence density have increased in recent years. Young Caucasian males are at highest risk for PTLD development among solid-organ-transplant recipients. The incidence of PTLD is increasing.American Journal of Transplantation 11/2002; 2(10):993-8. · 6.19 Impact Factor