Once-Daily Tacrolimus Extended-Release Formulation: 1-Year Post-Conversion in Stable Pediatric Liver Transplant Recipients

The pharmacokinetics, safety and tolerability of a once-daily formulation of tacrolimus (tacrolimus extended-release formulation; XL formerly referred to as MR or MR4) were assessed in 18 stable pediatric liver transplant recipients who were converted from the twice-a-day formulation of tacrolimus (TAC) to XL. Patients received their twice-a-day dose of TAC on study days 1 through 7. Beginning on the morning of study day 8, patients were converted to XL on a 1:1 (mg:mg) basis for their total daily dose, and were maintained on a once-daily AM dosing regimen using the same therapeutic monitoring and patient care techniques employed with TAC. Based on pharmacokinetic profiles obtained on study days 7 (TAC) and 14 (XL), steady state exposure (AUC(0-24)) was equivalent between XL and TAC; the mean XL/TAC ratio for lnAUC(0-24) was 100.9% (90% CI: 90.8%, 112.1%). AUC(0-24) and C(min) were strongly correlated at steady state (correlation coefficient: XL 0.90, TAC 0.94). During the first year post-conversion, there were no cases of acute rejection, discontinuation of XL, graft loss or death. The safety profile of XL was consistent with that known for TAC. These results support the safe and convenient conversion of pediatric liver transplant recipients from twice-a-day TAC to once-daily XL.     

Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years

METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years. RESULTS: The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF. CONCLUSION: All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.     

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years

BACKGROUND: A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years. METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years. RESULTS: The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF. CONCLUSIONS: All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.     

Tacrolimus plus mycophenolate mofetil vs. cyclosporine plus everolimus in deceased donor kidney transplant recipients: three‐yr results of a single‐center prospective clinical trial

We compared in kidney transplantation two immunosuppressive regimens: tacrolimus plus mycophenolate mofetil (MMF) (TAC) and everolimus plus low‐dose cyclosporine (EVE). Sixty consecutive patients received TAC (30 patients) or EVE (30 patients) as immunosuppressive regimen; all subjects also received induction with basiliximab and corticosteroids. After three‐yr follow‐up, no difference was found in patient and graft survival (PTS: TAC: 97% vs. EVE: 100%; GS: TAC: 93% vs. EVE: 93%). The incidence of acute rejection was higher in the EVE group but the difference was not statistically significant (17% vs. 23%, p = ns). Patients in EVE showed higher serum cholesterol (205 ± 41 vs. 235 ± 41 mg/dL, p = 0.0012) and lower hemoglobin concentration (13.6 ± 1.4 vs. 12.4 ± 1.9, p = 0.01). Renal function was not significantly different in the two groups (3 Y creatinine: TAC 1.4 ± 0.8 vs. EVE 1.6 ± 0.8 mg/dL, p = ns). Treatment discontinuation was higher in the EVE group (TAC 17 vs. EVE 36%, p = ns). Our data show that in the middle‐term follow‐up, an immunosuppressive regimen with tacrolimus plus MMF has a similar efficacy and safety profile in comparison with the combination of low‐exposure cyclosporine plus everolimus. Further follow up could evidence the benefits related to the anti‐proliferative effects of everolimus.     

达利珠单抗联合环孢素A、霉酚酸酯及糖皮质激素预防肾移植后急性排斥反应

目的 观察达利珠单抗联合环孢素A、霉酚酸酯和糖皮质激素预防肾移植后急性排斥反应的有效性和安全性。方法 由15家肾移植中心参加的开放性临床试验，共纳入72例首次尸肾移植受者为研究对象，在接受环孢素A、霉酚酸酯和糖皮质激素联合应用预防肾移植后急性排斥反应的同时，给予2剂人源化达利珠单抗，首剂给予时间为术前24h内，第2剂在术后第14d给予。对入选患者密切随访，评价肾移植后3个月和6个月时急性排斥反应的发生率、严重程度以及人、肾存活率；评价该治疗方法的安全性。结果 术后3个月内有3例患者发生4次急性排斥反应，3个月及6个月的排斥反应发生率均为5．56％；人／肾6个月和1年的存活率分别为95.8％／95.8％和94．5％／94．5％；仅有1例的腹痛可能与达利珠单抗有关。结论 2剂达利珠单抗联合环孢素A、霉酚酸酯和糖皮质激素预防肾移植后的急性排斥反应安全有效。     

Once-daily tacrolimus extended release formulation: experience at 2 years postconversion from a Prograf-based regimen in stable liver transplant recipients

Compliance with complex immunosuppressant drug therapies in transplant recipients might be improved with regimens that require less frequent dosing. A once-daily extended release (XL) formulation of tacrolimus has been developed that allows a 1:1 conversion from the twice-a-day tacrolimus (TAC) formulation and has a good exposure to trough concentration correlation. In an open-label, multicenter study, stable liver transplant recipients (n=69) were converted from twice-a-day TAC to XL once-daily in the morning, and were maintained for at least 2 years postconversion using the same therapeutic monitoring and patient care techniques employed with TAC. Two years after conversion, the incidence of biopsy-confirmed acute rejection was 5.8% (4 of 69); patient and graft survival was 98.6% (68 of 69). The safety profile of XL was consistent with that previously reported for TAC. Liver transplant recipients can be converted from twice-a-day TAC to once-daily XL and maintained for at least 2 years postconversion with neither unique efficacy nor safety concerns.     

Prospective Clinical Trial Comparing Two Immunosuppressive Regimens, Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine, in De Novo Renal Transplant Recipients: Results at 6 Months Follow-up

Objective

The aim of this study in renal transplant recipients was to compare a tacrolimus plus mycophenolate mofetil (MMF) immunosuppressive regimen with a combination of low dose of cyclosporine and everolimus.

Patients and Methods

Sixty consecutive patients were prospectively assigned to receive tacrolimus and MMF (TAC; n = 30) or everolimus and low-dose cyclosporine (EVL; n = 30). Tacrolimus was dosed seeking a trough blood level of 8 to 10 ng/mL by month 3 and 5 to 8 ng/mL thereafter. Everolimus was dosed seeking a trough blood level of 3 to 8 ng/mL by day 7. Cyclosporine was dosed aiming at a C2 blood level of 350 to 700 ng/mL in the first week and 150 to 400 ng/mL thereafter. All patients received induction with basiliximab and maintenance treatment with corticosteroids.

Results

At 6-months follow-up, patient survival rates (TAC 100% vs EVL 100%) and graft survival rates (TAC 96.7% vs EVL 93.3%) were not significantly different between the groups. Patients in the EVL group showed more acute rejection episodes, but serum creatinine concentrations and creatinine clearances were not significantly different from the TAC group. Among the observed side effects, hypercholesterolemia was significantly higher in the EVL group (total cholesterol: TAC 206 ± 38 vs EVL 250 ± 55 mg/dL; P < .003).

Conclusions

This study showed that the immunosuppressive association of tacrolimus and MMF produced similar acute rejection episodes, graft survivals, and renal function at 6 months after renal transplantation compared with an immunosuppressive combination of everolimus and low-dose cyclosporine. Dyslipidemia was significantly greater among patients who received everolimus.     

Tacrolimus compared with cyclosporine microemulsion in primary simultaneous pancreas-kidney transplantation: the EURO-SPK 3-year results

This 3-year study compared tacrolimus versus cyclosporine (CsA) microemulsion (ME) in conjunction with rATG induction, mycophenolate mofetil (MMF) and short-term corticosteroids in primary simultaneous pancreas-kidney (SPK) transplantation. PATIENTS AND METHODS: This large, prospective, multicenter study was conducted in 10 European centers and one center in Israel. Of the 205 SPK transplants performed from 1998 to 2000, 103 patients were randomly assigned to tacrolimus and 102 to CsA ME. All patients received concomitant rATG induction therapy, MMF, and short-term corticosteroids. RESULTS: In total, 36.9% patients receiving tacrolimus and 57.8% receiving CsA ME discontinued treatment (P = .003). Although 3-year patient and kidney graft survival rates were similar in both groups, pancreas survival was superior with tacrolimus (89.2% versus 72.4%; P = .002). Thrombosis resulted in pancreatic allograft loss in 10 patients receiving CsA ME and in 2 treated with tacrolimus (P = .02). The first episode of biopsy-proven rejection was moderate or severe in 1 of 31 tacrolimus-treated patients and 11 of 39 patients receiving CsA ME (P = .009). Overall adverse event frequency was similar in both groups, but surgical events were lower in the tacrolimus treated group. CONCLUSION: Tacrolimus was more effective than CsA-ME to prevent moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreatic graft survival and reduced the risk of pancreas thrombosis.     

Results of kidney transplantation in patients receiving MMF- or MMF and basiliximab-containing immunosuppression

Mycophenolate mofetil (MMF) is a more potent immunosuppressive drug than azathioprine or mizoribine in combination with cyclosporine (CsA) and steroids. Recently, basiliximab (BA), an interleukin-2 receptor antagonist, has become available in Japan. The purpose of this study was to evaluate the efficacy of an extremely low CsA dose immunosuppressive protocol with MMF versus MMF plus BA after renal transplantation (RTx). PATIENTS: Between September 2001 and March 2003, we performed 79 RTx with CsA-based immunosuppression, including nine from cadavers and 70 from living donors with 15 ABO-incompatible RTx. Immunosuppression consisted of methylprednisolone (MP), CsA and MMF (group 1; n = 24) versus added BA during the induction phase (group 2; n = 55). In group 2, MP was withdrawn on postoperative day 14. Supplementary MP, muromonab-CD3, or gusperimus was administered if rejection was suspected clinically or diagnosed by biopsy. RESULTS: The incidence of biopsy-proven acute rejection (AR) was significantly higher among group 1 than group 2 patients (P < .05). CsA C2 levels in group 1 were significantly higher than group 2 at each time (P < .01). The incidence of infection was comparable. Patient and graft survival rates in group 1 were 100% and 100%; in group 2, they were 98% and 98%, respectively. CONCLUSION: The short-term results of RTx were favorable in both the MMF, and the MMF plus BA immunosuppression. In addition, BA significantly reduced the number of AR episodes. Early steroid withdrawal in recipients receiving BA induction was not associated with an increased risk of AR.     

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.     

Sirolimus in Combination with Tacrolimus Is Associated with Worse Renal Allograft Survival Compared to Mycophenolate Mofetil Combined with Tacrolimus

Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL. We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p<0.001) and death-censored graft survival (p<0.001) as compared to TAC/MMF (N=27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI=1.32, 1.63) and for CsA/SRL 1.38 (95% CI=1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5-12.6%) and not different between groups. In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.     

Delayed Introduction of Reduced-Dose Tacrolimus, and Renal Function in Liver Transplantation: The 'ReSpECT' Study

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels ≤8 ng/mL], and corticosteroids; n = 170); group C (daclizumab induction, MMF, reduced-dose tacrolimus delayed until the fifth day posttransplant and corticosteroids, n = 172). The primary endpoint was change from baseline in estimated glomerular filtration rate (eGFR) at 52 weeks. The eGFR decreased by 23.61, 21.22 and 13.63 mL/min in groups A, B and C, respectively (A vs C, p = 0.012; A vs B, p = 0.199). Renal dialysis was required less frequently in group C versus group A (4.2% vs. 9.9%; p = 0.037). Biopsy-proven acute rejection rates were 27.6%, 29.2% and 19.0%, respectively. Patient and graft survival was similar. In conclusion, daclizumab induction, MMF, corticosteroids and delayed reduced-dose tacrolimus was associated with less nephrotoxicity than therapy with standard-dose tacrolimus and corticosteroids without compromising efficacy or tolerability.     

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.     

他克莫司缓释胶囊对肝移植术后稳定期受者安全性和临床疗效评估

目的通过他克莫司缓释胶囊（MR4）的Ⅲ期临床试验（MR4LTxCN02）评价MR4在肝移植术后稳定期受者中的安全性和临床疗效。方法受试者随机分配入MR4或他克莫司（FK506）组,MR4组药物剂量按1：1进行药物转换,每日口服1次;FK506组维持每12h服药1次至试验结束。在为期3个月的临床试验阶段,随访了受试者生命体征、不良事件、血常规、尿常规、肝功能、血糖、血脂及FK506的谷值浓度。随访结果采用SAS8．0统计软件进行了Fisher精确卡方检验及t检验分析。结果MR4组按1：1药物转换后与FK506组具有同等的安全性和临床疗效。与FK506组比较,MR4组具有感冒、上呼吸道感染症状减少倾向,没有增加不良事件或不良反应的发生率。转换药物后的剂量和血药浓度与换药前未发生显著变化;药代动力学检测结果表明,MR4具备缓释剂型的药代动力学特征,并与FK506具有良好的生物等效性。结论MR4与FK506具有同等的安全性和临床疗效,同时简化了服药次数,在提高受者长期依从性以及术后生活质量方面具有较大的优势。     

Randomized trial of cyclosporine and tacrolimus therapy with steroid withdrawal in living‐donor renal transplantation: 5‐year follow‐up

The aim of this study was to compare the long‐term safety and efficacy of immunosuppressive regimens consisting of cyclosporine (CsA) plus mycophenolate mofetil (MMF) or tacrolimus (TAC) plus MMF after steroid withdrawal 6 months after kidney transplantation in low‐risk patients. One hundred and thirty‐one patients were randomized to receive either CsA (n = 63) or TAC (n = 68). Of these, 117 patients satisfied the criteria for steroid withdrawal (no biopsy‐proven rejection episode and serum creatinine level <2.0 mg/dl 6 months after transplantation). Fifty‐five recipients were of the CsA group, and 62 were of the TAC group. The 5‐year graft survival rate did not differ between groups (90.5% vs. 93.3% respectively; P = 0.55). The cumulative incidence of acute rejection 5 years after transplantation was 16.4% and 8.1% for the CsA and TAC groups respectively (P = 0.15). Post‐transplantation diabetes mellitus was more frequent in the TAC group than in the CsA group (P = 0.05), but the incidence of other side‐effects did not differ between groups. In conclusion, CsA‐ and TAC‐based regimens in conjunction with MMF have similar patient‐ and graft survival rates in low‐risk patients who underwent steroid withdrawal 6 months after kidney transplantation.     

Successful Long-Term Outcomes Using Pediatric En Bloc Kidneys for Transplantation

GOAL: The objective of our study was to determine whether acceptable long-term graft survival and function can be achieved using pediatric en bloc renal transplants by employing specific immunologic and selection strategies. MATERIALS AND METHODS: A retrospective analysis of pediatric en bloc kidney transplants at a single institution was performed. A Kaplan-Meier analysis was used to evaluate graft survival. FINDINGS: Fifty-seven adult recipients with at least a 1-year follow-up period were successfully transplanted using pediatric en bloc kidneys between 1993 and 1998. Complete data regarding immunosuppression were available for 53 patients. All patients had a cyclosporine (CsA)- or tacrolimus (TAC)-based regimen with either azathioprine (Aza) or mycophenolate mofetil (MMF) and corticosteroids. All but two received induction with OKT3. One-, 3-, 4-, 5- and 7-year graft survival was calculated to be 88%, 86%, 83%, 68% and 68%, respectively. The mean serum creatinine value at 3 years was 1.0+/-0.4 mg/dL. Thirteen patients (23%) had biopsy-proven rejection. Ten of 19 (53%) patients treated with CsA/Aza had rejection, whereas 2/15 (13%) on CsA/MMF and 1/19 (5%) of patients on TAC/MMF had rejection. Nine patients (16%) had surgical complications. CONCLUSION: Excellent long-term results can be achieved in pediatric en bloc kidney transplantation using OKT3, TAC and MMF in carefully selected adult recipients.     

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients

Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P = 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.     

Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients

BackgroundThis retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application.MethodsOverall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan–Meier analysis.ResultsThe use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF.ConclusionThe real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.     

Randomized Trial of Basiliximab Induction versus Steroid Therapy in Pediatric Liver Allograft Recipients Under Tacrolimus Immunosuppression

Avoidance of corticosteroids could be beneficial after pediatric liver transplantation (LTx). To test this hypothesis, we performed a randomized prospective study to compare immunosuppression with tacrolimus (TAC) and steroids versus TAC and basiliximab (BAS) after pediatric LTx. Seventy-two patients were recruited, 36 receiving TAC and steroids and 36 TAC and BAS. The primary endpoint was the occurrence of the first rejection episode. Secondary endpoints were the cumulative incidence and severity of rejection, patient and graft survival, and incidence of adverse events. Overall 1-year patient and graft survival rates were 91.4% and 85.5% in the steroid group, and 88.6% and 80% in the BAS group (p = NS). Patients free from rejection were 87.7% in the BAS group and 67.7% in the steroid group (p = 0.036). The use of BAS was associated with a 63.6% reduction in incidence of acute rejection episodes. Overall incidence of infection was 72.3% in the steroid group and 50% in the BAS group (p = 0.035). We conclude that the combination of TAC with BAS is an alternative to TAC and steroid immunosuppression in pediatric LTx, which allows for a significant reduction in the incidence of acute rejection and infectious complications.