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Background/purpose: Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low-dose SRL combined with a CNI could still prevent cancer in renal transplant recipients., Methods: A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271)., Results: The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 ± 37.5 months and 81.7 ± 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation., Conclusion: De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients., (Copyright © 2015. Published by Elsevier B.V.)

Background/purpose: The effect of rituximab on B cell and immunoglobulin production after therapeutic apheresis has not been studied in ABO-incompatible renal transplant patients., Methods: Twenty consecutive ABO-incompatible renal transplant patients receiving rituximab induction and double filtration plasmapheresis were enrolled; one case was excluded because of repeated plasmapheresis and immunoglobulin therapy (Incompatible group). The B cell count of the Incompatible group was compared to another group of 18 ABO-compatible renal transplant patients who were operated on during the same period (Compatible group). In the Incompatible group, the total IgM, IgG, and IgG1-4 subclasses after transplantation were compared to those before desensitization. Tacrolimus, mycophenolate mofetil, and steroids were used for both groups., Results: The B cell count of the Incompatible group was significantly lower than the Compatible group post-transplant from Month 1 to Month 11 only. The B cell count of the Compatible group also decreased for the first 6 months, suggesting that maintenance immunosuppressive agents suppress B cells. Total IgG and IgM levels after transplantation were significantly lower than before desensitization during the 24-month follow-up period. The post-transplant IgG3 level was significantly lower than before desensitization for only 3 months., Conclusion: With the aid of tacrolimus and mycophenolate mofetil, rituximab resulted in sustained suppression of B cell count and total IgG and IgM. Among the IgG subclasses, IgG3 was less sensitive to rituximab., (Copyright © 2013. Published by Elsevier B.V.)

Background: Use of a calcineurin inhibitor (CNI) immunosuppressant following kidney transplantation is associated with development of vasomotor nephrotoxicity. This study was undertaken to evaluate and compare the influences of CNI-based and CNI-free immunosuppressant regimens on two intrarenal vascular resistance parameters, the resistive index (RI) and the pulsatility index (PI), in renal transplant recipients., Methods: Forty-nine renal transplant patients who received ultrasonography examination between January 2007 and December 2007 were enrolled in this case-control study. Thirty-one subjects received a CNI-based regimen, and 18 received a CNI-free (sirolimus-based) regimen. RI and PI were determined by duplex Doppler ultrasonography., Results: Patients receiving a CNI displayed lower cholesterol and triglyceride values and higher RI (mean: 0.7 vs. 0.6, P = 0.002) and PI values (mean: 1.3 vs. 1.1, P = 0.034). Multivariate analyses revealed that advanced age and use of alpha-blockers or diuretics were modestly associated with higher RI and PI values. By multivariate analysis, use of sirolimus was associated with a lower RI by -0.05 [95% confidence interval (CI): -0.085, -0.019; P = 0.003] but not with a lower PI (95% CI: -0.245, 0.001; P = 0.053)., Conclusions: Use of sirolimus is only modestly correlated with a reduced RI and is not associated with a reduced PI. These observations question the superiority of CNI-free over CNI-based regimens with regard to reduction of intrarenal vascular resistance post-transplantation. These findings combined with those regarding recipient factors also cast doubt on the specificity of intrarenal resistance indices for predicting allograft function and/or survival.

Sirolimus is one treatment option in transplant recipients with Kaposi's sarcoma (KS), which involves dysregulation of Akt-mammalian target of rapamycin (mTOR) signaling pathway. Signal modifications after sirolimus therapy in organ recipients with KS are largely unknown and not verified. We reported a case of KS found two yr after liver transplantation in which the immunosuppression was changed from tacrolimus, MMF, and steroid to sirolimus alone. In skin, which was found to have persistent KS after a two-month treatment of sirolimus and was removed completely one yr later, KS was no longer present. The patient went well without graft rejection. Tumor biopsies were performed before, two months, and one yr after the start of sirolimus. Immunohistochemical staining of vascular endothelial growth factor (VEGF), p-Akt, p-mTOR, p-p70 S6 kinase, and Western blot for p-tuberin/ tuberous sclerosis complex (TSC)2 was performed. VEGF was suppressed thoroughly in two-month use of sirolimus. In addition, p-Akt and p-mTOR, which were decreased at two months, could not be detected after one yr of treatment. Moreover, p-p70 S6 kinase, expressed strongly in overlying epidermis initially, was suppressed completely after two months of treatment. However, p-tuberin/TSC2, contrary to suggested theoretically, was not detected through all specimens, implying not to be a significant event. Suppressed expression of VEGF, p-Akt, and p-mTOR was the major event of signaling modification through the long-term use of sirolimus.

Background: Chronic nephrotoxicity of calcineurin inhibitors (CNIs) causes irreversible renal dysfunction and shortens renal transplant survival. We conducted a retrospective cohort study to test a hypothesis that de novo CNI minimization combined with sirolimus (SRL) improves graft survival in renal transplant patients without antibody induction therapy., Methods: Between october 2000 and august 2007, we performed 100 cases of renal transplantation with de novo CNI (either cyclosporine or tacrolimus) minimization combined with sirolimus (SRL group). The initial target trough levels were 100-200 ng/ml for cyclosporine (CSA) and 4-8 ng/mL for tacrolimus (TAC). SRL was given at a loading dose of 6 mg plus 2 mg/day for maintenance. The results for the SRL group were compared to those of 104 transplant recipients given standard CNI- (CsA- or TaC-) based immunosuppressive regimens including mycophenolate mofetil (MMF group) during the same period., Results: The 1-year rejection-free survival (94.8%) and 5-year graft survival (87.7%) rates of the SRL group were significantly better than those of the MMF group (85.5% and 75.2%, respectively). On univariate analyses, 6-month estimated glomerular filtration rate (eGFR), acute rejection and SRL therapy had a significant impact on graft survival, and SRL therapy and tacrolimus therapy had a significant impact on rejection-free survival. Multivariate analyses identified 6-month eGFR as the only prognostic factor for graft survival. Acute rejection and SRL therapy were significant for post-transplant renal function., Conclusions: De novo CNI minimization combined with SRL could decrease acute rejection and improve renal function and graft survival after renal transplantation without the use of antibody induction therapy.

Background/purpose: Combined therapy of sirolimus and cyclosporine has been found to exacerbate cyclosporine-related nephrotoxicity and to imperil graft renal function. We hypothesized that tacrolimus could bring about better renal function than cyclosporine when used in combination with sirolimus and corticosteroids for de novo renal transplantation., Methods: A two-arm randomized study was conducted to test the hypothesis. Patients who gave written informed consent and received renal transplantation were randomized to take sirolimus in combination with either tacrolimus or cyclosporine. The primary endpoint of this study was renal function, and the secondary endpoints were acute rejection, graft and patient survival, metabolic side effects and infectious complications., Results: A total of 41 Taiwanese renal transplant patients were randomized to receive cyclosporine (CsA group, n = 20) or tacrolimus (TAC group, n = 21) in combination with sirolimus and corticosteroids. The average estimated glomerular filtration rate (eGFR) was 52.77 +/- 3.86 mL per minute for the TAC group at 6 months, and 46.42 +/- 3.95 mL per minute for the CsA group (p > 0.05). At 12 months, the average eGFR was 52.04 +/- 4.38 mL per minute for the TAC group, and 46.79 +/- 4.38 mL per minute for the CsA group (p > 0.05). The biopsy-proven acute rejection rate of the TAC group was 4.76% (1/21), and that of the CsA group was 5.00% (1/20) at 12 months. The 12-month graft survival rates for the TAC and CsA groups were 100% and 90% (p = 0.142), respectively., Conclusion: Our study demonstrated that concomitant tacrolimus and sirolimus therapy resulted in a favorable outcome in Taiwanese renal transplant patients at 12 months. Large-scale clinical trials will be needed to further address the issue of which calcineurin inhibitor, cyclosporine or tacrolimus, provides better renal function and graft survival for renal transplant patients.

Background/purpose: Information is needed on renal function improvement after late elimination of calcineurin inhibitors (CNIs) and conversion to combined therapy of sirolimus (SRL) and mycophenolate mofetil (MMF) in Asian renal transplant recipients., Methods: A single-arm prospective study was undertaken to assess the outcome of stable Taiwanese renal transplant recipients who had CNI withdrawn and received combined SRL and MMF therapy. The primary endpoints were acute rejection and renal function. The secondary endpoints were graft and patient survival, side effects and infectious complications. Therapeutic drug monitoring of SRL and MMF was conducted during the study period., Results: Thirty patients were recruited at 9-72 (31.7+/-18.6) months post-transplantation. The graft and patient survival rates were both 100% at 12 months, though one of the 30 patients (3.33%, 1/30) had biopsy-proven acute rejection. On paired t test, the estimated glomerular filtration rates (GFR) from 4 to 12 months were significantly higher than the baseline GFR. The average trough level of SRL was 7.38+/-3.74 ng/mL at 12 months and the average abbreviated area under the concentration curve of mycophenolic acid was 64.86+/-36.62 mg/L*hour at an average MMF dose of 1.56+/-0.45 g/day. However, two patients (6.67%, 2/30) had tuberculosis (TB) reactivation at 3 and 4 months, respectively, after the combined SRL and MMF therapy., Conclusion: Conversion to combined SRL and MMF therapy improved renal function in stable renal transplant recipients, though the risk of TB reactivation should be kept in mind when the combined therapy is employed in the Asian countries with a high prevalence of TB.

Study Objective: To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long-term, staggered administration in kidney transplant recipients. Design. Randomized, open-label, parallel-group trial., Setting: A medical center and one of its teaching hospitals in Taiwan., Patients: Twenty-two de novo kidney transplant recipients., Intervention: Patients received cyclosporine microemulsion or tacrolimus capsules twice/day in combination with once-daily sirolimus solution and corticosteroids. Sirolimus was administered 6 hours after the morning dose of cyclosporine or tacrolimus. After receiving a 6-mg loading dose of sirolimus, participants received sirolimus 2 mg/day for at least 7 days. Neither the cyclosporine nor the tacrolimus dosage was adjusted for at least 3 days before and during blood sampling for pharmacokinetic profiling., Measurements and Main Results: One patient dropped out because of trimethoprim-sulfamethoxazole-related hepatotoxicity. We observed no differences between the two patient groups in terms of their demographic data, renal and liver function, or dosage of sirolimus during the study. During multiple-dose administration, the area under the whole-blood concentration-time curve and the peak and trough concentrations of sirolimus in the cyclosporine group were, respectively, 1.46 (95% confidence interval [CI] 1.21-1.71), 1.42 (95% CI 1.08-1.76), and 1.42 (95% CI 1.09-1.76) times higher than those of the tacrolimus group, even though sirolimus was administered 6 hours after the other agents., Conclusion: Sirolimus pharmacokinetics may change significantly when calcineurin inhibitors are switched, even with staggered administration, which may not completely prevent a drug interaction between cyclosporine and sirolimus solution.

Background and Purpose: Nephrotoxicity caused by calcineurin inhibitors (CNIs) contributes to chronic renal allograft dysfunction (CRAD). This retrospective cohort study evaluated the immunosuppressive and nephrotoxic effects of sirolimus add-on therapy with minimization of CNI in patients with CRAD., Methods: Twenty patients with CRAD were recruited to receive sirolimus add-on rescue (SRL-AR) therapy. The SRL-AR therapy added 6 mg of sirolimus for loading and 2 mg/day for maintenance to CNI-based maintenance immunosuppressive regimens and reduced the dose of CNI, either cyclosporine or tacrolimus, by half at the initiation of sirolimus loading. The primary endpoint of the study was estimated glomerular filtration rate (GFR) determined using the Cockcroft-Gault formula. The efficacy of this SRL-AR therapy was evaluated by comparison to a historic group of 30 patients with CRAD who received a tacrolimus-based rescue therapy., Results: Of the 20 patients receiving sirolimus therapy, 2 had graft failure during the 12-month follow-up. The post-rescue GFR values of the patients receiving sirolimus therapy showed greater improvement than those of the historic group during follow-up except for month 8, with the differences in GFR changes reaching significance at months 1 to 5 (p < 0.05). Multiple regression analysis identified graft age and GFR upon rescue in addition to the SRL-AR therapy as significant factors associated with post-rescue GFR changes., Conclusions: This study demonstrated that SRL-AR therapy combined with reduced CNI doses could effectively improve short-term renal function of patients with CRAD. The long-term outcome of rescuing CRAD is likely to depend on factors including graft age and GFR upon rescue.

Background and Purpose: Sirolimus is a novel immunosuppressive drug with much less nephrotoxicity than cyclosporine. The efficacy and toxicity of the combination of sirolimus and low-dose cyclosporine therapy were compared with data from records of a previous cyclosporine-based regimen used in patients with renal allograft transplantation., Patients and Methods: A prospective study was conducted to assess the clinical effects of a sirolimus (6 mg loading dose over 48 hours plus 2 mg/day maintenance)/cyclosporine (8 mg/kg/day) combination regimen. Three male and 9 female renal transplant recipients were enrolled in the study. The primary endpoint was the incidence of acute rejection. The efficacy and adverse effects of the combined therapy were compared with those recorded in medical records of 24 renal transplant recipients who had received a cyclosporine-based regimen (10 mg/kg/day)., Results: The 12-month acute rejection rate of the study group was 16.67% (2/12), and that of the cyclosporine-based group 29.16% (7/24). One patient in the study group died of complications sustained during a radical operation for recurrent bladder carcinoma during the sixth post-transplant month. The 12-month graft and patient survival rates of the study group were both 91.8%. In the 12 months post-transplant, the mean serum creatinine levels of the study group were significantly lower than those of the historic group at months 1, 3, and 4. The average cyclosporine trough levels of the study group were significantly lower than those of the historic group at months 1, 2, and 12. The average daily doses of prednisolone in the study group were also lower than those of the historic group at months 2, 3, 4, and 12., Conclusions: The sirolimus/cyclosporine combination regimen reduced the incidence of acute renal allograft rejection, did not affect renal function, and reduced the dosage of cyclosporine and steroids compared with the cyclosporine regimen.

Background and Purpose: Mycophenolate mofetil (MMF) in combination with cyclosporine or tacrolimus prevents acute rejection and chronic allograft failure in renal transplantation in Western countries. We began to add low-dose MMF to primary cyclosporine immunosuppressive therapy in renal transplantation at the Department of Surgery of National Taiwan University Hospital in 1998. This study compared low-dose MMF to conventional therapy in Taiwanese renal transplant recipients., Methods: This retrospective cohort study determined the efficacy of low-dose MMF therapy (1 g/day in divided doses). A total of 275 cases with allograft kidney transplants were grouped according to whether they received transplants before or after the adoption of MMF therapy (Period I: 1987-1993; Period II: 1994-1997; Period III: 1998-September 2000). The prognostic significance of MMF therapy and graft and patient survival rate in each time period were assessed., Results: The 18-month graft survival rate was 84.9% in Period I, 86.3% in Period II, and 91.9% in Period III. The 5-year graft survival rates in Periods I and II were 69.3% and 76.6%, respectively. Acute rejection was significantly detrimental to graft survival (p = 0.048), while MMF therapy was significantly advantageous to graft survival (p = 0.015); treatment when MMF was available was also significantly associated with better graft survival (p = 0.043). There was a negative correlation between acute rejection and graft survival (p = 0.035); MMF therapy produced a protective effect on graft survival independent of acute rejection (p = 0.010)., Conclusion: Low-dose MMF therapy significantly improved graft survival after renal transplantation in Taiwanese kidney allograft recipients.

Dn- AIH is a long-term complication after LT. The aim of this study was to analyze the occurrence of autoantibodies in pediatric recipients and the clinical significance. From 1992 to 2008, 96 pediatric LT for non-autoimmune liver diseases were performed in 94 children in our institution. Serum autoantibodies were checked in 68 subjects (73.9%). A positive autoantibody was defined as titers ≥1:40 for ANA, or ≥1:20 for ASMA, anti- LKM, and AMA. Autoantibodies were detectable in 51 of 68 patients (75.0%). There was positivity for ANA in 30 patients, ASMA in 32, and AMA in three, while anti- LKM was all negative. Immunosuppressive treatment with Cs A, more than one episode of rejection, and abnormal ALT were risk factors for the development of autoantibodies. The incidence of the development of autoantibodies was 75.0% in pediatric LT cases in this study. ASMA was the most commonly found autoantibody. Autoantibodies may not play a sentinel role for dn- AIH after LT. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) is an important post-transplant infection. Everolimus has been documented to reduce the risk of cytomegalovirus infection in transplant recipients, but its impact on other infections is less known. The present study aimed to assess immunosuppressive regimens on TB risk in solid-organ transplant (SOT) recipients via a matched case–control study. Methods From May 2005 to December 2018, SOT recipients with TB were retrospectively identified, and those without TB undergoing transplantation at the same university hospital were selected as controls. Controls and cases were matched by age (±5 years), transplant type and year (±5 years) at a ratio of 4:1. Conditional logistic regression was used to analyze the risk factors of TB. Results TB developed in 30 SOT recipients (13 kidney, 7 heart, 6 liver, and 4 lung) after a mean duration of 1,601 days after transplantation, with predominant lung involvement (87%). The diagnosis was made by culture in 70% and pathology in 17%. Rifamycins-based regimens were used in 27 cases, and 4 developed rejection without graft failure. A total of 106 controls were selected. At the time of TB diagnosis, cases were more likely to use everolimus than controls (27% vs. 11%, P < 0.05), but no significant differences were observed in the use of tacrolimus, cyclosporin, sirolimus, prednisolone, or mycophenolate mofetil. The median duration of everolimus use was 585 and 698 days in 8 cases and 12 controls, respectively. Multivariable analysis showed that everolimus use (adjust odds ratio [aOR] 22.3, 95% conference interval [CI] 2.5–203.0) and hemodialysis (aOR 19.6, 95% CI 1.3–287.1) were independently associated with TB. Conclusion TB is more likely to develop in SOT recipients on everolimus and hemodialysis. Further studies to confirm our findings are warranted, and TB risk assessment should be performed for those receiving everolimus and hemodialysis. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]