Incidence Of Biopsy-confirmed Acute Rejection Research Articles

Efficacy of anti-T-lymphocyte globulin-Fresenius as an induction agent in deceased-donor renal transplantation: A cohort study.

Anti-T-lymphocyte globulin (ATG) is frequently used in the induction regimen of renal transplantation, but its dose has not been standardized. In the present study, the efficacy of different ATG-Fresenius (ATG-F) doses was assessed in recipients of renal transplantation. A total of 131 adult recipients of renal transplantation who received ATG-F induction between August 2015 and July 2018 were included. The incidence of biopsy-confirmed acute rejection, graft function, as well as graft and patient survival within 12 months post-transplant, was assessed, and adverse events, including hematologic and infection-associated side effects, were compared between patients receiving a cumulative ATG-F dose of <7 or ≥7 mg/kg. The incidence of biopsy-confirmed acute rejection was similar between patients receiving cumulative doses of <7 and ≥7 mg/kg (7.5 vs. 4.7%, P=0.766). The incidence of infection within 12 months was lower in the ATG-F <7 mg/kg group compared with that in the ≥7 mg/kg group (26.9 vs. 50.0%, P=0.006), but the incidence of pneumonia did not differ between the ATG-F <7 and ≥7 mg/kg groups (10.4 vs. 20.3%, P=0.117). The incidence of urinary infection was higher in the ≥7 mg/kg group than in the <7 mg/kg group (20.4 vs. 7.46%, P=0.033), while the extent and duration of anemia and lymphopenia was similar between groups. There was no difference in graft function, delayed graft function, as well as overall and graft survival between the groups. In conclusion, a moderate reduction in the cumulative ATG-F dose was not associated with an increased risk of acute rejection, while the risk of infection was reduced. Optimization of the ATG-F dose for induction may facilitate the reduction of the risk of infection without compromising the induction efficacy in renal transplant recipients.

Efficacy and safety of prolonged-release versus immediate-release tacrolimus in de novo liver transplant recipients in South Korea: a randomized open-label phase 4 study (MAPLE).

BackgroundProlonged-release tacrolimus is associated with better long-term graft and patient survival than the immediate-release formulation in liver transplant patients. However, no clinical data are available to assess the efficacy and safety of early conversion from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus in de novo liver transplant recipients in Korea.MethodsA 24-week, randomized, open-label study was conducted in 36 liver transplant recipients. All patients received immediate- release tacrolimus (0.1–0.2 mg/kg/day, divided into two doses) for 4 weeks after transplantation, at which time 50% of the patients were converted, at a ratio of 1 mg to 1 mg, to prolonged-release tacrolimus (once-daily). The primary efficacy endpoint was the incidence of biopsy-confirmed acute rejection (BCAR) from weeks 4 to 24 after transplantation (per-protocol set). Medication adherence, adverse event profiles, laboratory tests, vital signs, and physical changes were also recorded.ResultsBCAR frequency at 24 weeks was similar between the two treatment groups; two cases (mean±standard deviation, 0.14±0.53 cases) of BCAR were reported in one patient treated with prolonged-release tacrolimus (n=14), while no such cases were reported among patients treated with immediate-release tacrolimus (n=12). The tacrolimus blood concentration at weeks 12 and 24, medication adherence, and adverse event profiles were also similar between the formulations, with no unusual laboratory test results, vital signs, or physical changes reported.ConclusionsEarly conversion to a simplified, once-daily, prolonged-release tacrolimus regimen may be an effective treatment option for liver transplant recipients in Korea. Larger-scale studies are warranted to confirm non-inferiority to immediate-release tacrolimus formulation in de novo liver transplant recipients.

SAFETY AND EFFICACY OF TWO TACROLIMUS FORMULATIONS (PROGRAF® AND ADVAGRAF®) IN MALAYSIAN RENAL TRANSPLANT PATIENTS: A COMPARATIVE STUDY

Aim: A once-daily formulation of tacrolimus, Advagraf®, is increasingly being used in place of twice-daily tacrolimus, Prograf®, as a standard immunosuppressive agent for transplant patients. In this study, the clinical safety and efficacy of Advagraf® were compared with Prograf®, among multi-ethnic Malaysian renal transplanted population. Method: This retrospective study identified renal transplant patients who were converted from Prograf® to Advagraf® at the University Malaya Medical Centre (UMMC) (n=69). Clinical notes and laboratory records, including tacrolimus daily dose and trough levels, were obtained for one-year, pre-and post-conversion. Causality assessment of suspected adverse events were based on the WHO-Uppsala Monitoring Center criteria. Renal biopsy records were re-evaluated based on the updated Banff 2007 classification for biopsy-confirmed acute rejection (BPAR). Results: Following conversion to Advagraf®, the mean tacrolimus trough level and daily dose decreased significantly (p<0.01) from 6.11±2.15 to 4.91±1.25 ng/mL and 4.08±2.19 to 3.48±1.79 mg/day, respectively. There was no significant difference in serum creatinine and estimated glomerular function. HDL was significantly increased (p=0.005) while triglycerides was significantly decreased following conversion to Advagraf® (p=0.003). The incidence of BPAR was 16% (4 cases in Prograf® and 7 cases in Advagraf®). No patients died or lost their grafts during the study period. There were 34 cases of adverse events which were classified as certain (5%), probable (36%), possible (23%) and unlikely (36%) with no significant difference between groups. Conclusion: Prograf® and Advagraf® tacrolimus formulations have comparable safety and efficacy profiles among Malaysian renal transplant patients. Advagraf® may have an advantage in terms of lipid profile. Keywords: Prograf®, Renal Transplant, Advagraf®, Acute Rejection, Safety

Characteristics and Outcomes of Kidney Transplant Recipients with a Functioning Graft for More than 25 Years

Background: Information regarding the clinical characteristics and outcomes of kidney transplant recipients (KTRs) with > 25 years of graft survival is limited. Methods: In this single-center observational study, we characterized KTRs transplanted between 1973 and 1992 with active follow-up as of July 31, 2017. Results: We identified 112 patients with > 25 years of allograft function. The mean posttransplantation follow-up was 29.8 ± 4.0 years. Glomerulonephritis was the most common cause of end-stage renal disease (ESRD) (52%). The majority received live donor transplants (66%), including 25 patients (22%) with human leukocyte antigen-matched kidneys. The incidence of biopsy-confirmed acute rejection was 21%, ranging from 0 to 26 years post transplantation. Donor-specific antibodies (DSA) were checked in 80% of patients at a mean of 28.4 ± 0.11 years post transplantation. Of these, only 15% were positive. The incidence of malignancy was 44%, with nonmelanoma skin cancers being most common. The incidence of infectious complications was 77%, mostly represented by urinary tract infections. At the time of last follow-up, 63% were on a calcineurin inhibitor (CNI)-free regimen, mean serum creatinine was 1.4 ± 0.6 mg/dL, and the prevalence of hypertension and dyslipidemia was 89 and 88%, respectively. Conclusion: The majority of patients with a long-term functioning graft had glomerulonephritis as cause of ESRD, had received a live donor kidney, were on a CNI-free regimen, and had a low incidence of DSA and opportunistic infections. These characteristics define a unique group of patients requiring specific posttransplantation monitoring and management.

Association of the PPP3CA c.249G>A variant with clinical outcomes of tacrolimus-based therapy in kidney transplant recipients.

BackgroundThe effects of genetic variants related to the pharmacodynamic mechanisms of immunosuppressive drugs on their therapeutic efficacy and safety have been poorly explored. This study was performed to investigate the influence of the PPP3CA c.249G>A variant on the clinical outcomes of kidney transplant recipients.Patients and methodsA total of 148 Brazilian patients received tacrolimus (TAC)-based immunosuppressive therapy for 90 days post-kidney transplantation. The PPP3CA rs3730251 (c.249G>A) polymorphism was determined by real-time polymerase chain reaction. Single-nucleotide polymorphism (SNP) data for CYP3A5 rs776746 (CYP3A5*3C; g.6986A>G) were used to eliminate the confounding effects of this variant.ResultsThe PPP3CA c.249G>A SNP did not influence early TAC exposure, renal function, or other laboratory parameters, including levels of urea, creatinine, glucose, and lipids, and blood counts. This variant also did not account for the cumulative incidence of biopsy-confirmed acute rejection or delayed graft function. Regarding adverse events, PPP3CA c.249A allele carriers initially had a 3.05-fold increased probability of treatment-induced blood and lymphatic system disorders compared with c.249GG genotype individuals (95% confidence interval: 1.10–8.48, p=0.032). However, this result was not maintained after adjusting for body weight and CYP3A5*3C SNP status (p=0.086).ConclusionThe PPP3CA c.249G>A variant does not influence the clinical outcomes of Brazilian patients in the early phase of TAC-based immunosuppressive regimen.

A 6-Month, Open-Label, Multicenter Clinical Study in Korean De Novo Renal Transplant Patients Evaluating the Efficacy, Safety, and Tolerance of Myfortic Concomitantly Used with Tacrolimus

Enteric-coated mycophenolate sodium (Myfortic, Novartis Pharma AG, Basel, Switzerland) is designed to improve the gastrointestinal tolerability of micophenolic acid. This study was designed to evaluate the efficacy and safety of Myfortic in Korean de novo renal transplantation. A total of 65 patients from four transplantation centers received the study drug at least once and were included in the intention-to-treat analysis. This study was an open-label, single-arm, multicenter trial with 6-month patient follow-up. Patients received 360 mg (body weight < 50 kg) or 720 mg (body weight > 50 kg) of Myfortic per day with tacrolimus and steroids. Induction therapy included basiliximab. The incidence of biopsy-confirmed acute rejection (primary endpoint) within 6 months after transplantation was 7/65 (10.8%). There were 2 (3.1%) graft losses due to severe acute rejection and 1 (1.5%) patient-death due to cardiac arrest. Twenty-two (38.8%) patients experienced gastrointestinal discomfort; however, only 3 (4.5%) cases were associated with an apparent drug reaction. Seventeen (25.4%) patients underwent dose adjustment or Myfortic discontinuation during the study period. Patient and graft survival rates at 6 months posttransplantation were 98.1% and 97.0%. Myfortic with tacrolimus-based immunosuppression was efficient and safe after de novo renal transplantation in Korean patients.

Steroid or tacrolimus withdrawal in renal transplant recipients using sirolimus

Calcineurin inhibitor (CNI) and steroid (ST) withdrawal are strategies under investigation to reduce long-term toxicities associated with current immunosuppressive regimens. We conducted a single center, prospective trial comparing the efficacy and safety of CNI or ST withdrawal in kidney transplant recipients receiving sirolimus-based immunosuppressive regimen. Forty-seven recipients of first renal transplant with non-HLA-identical living donors received sirolimus (SRL), tacrolimus (TAC), and ST without induction therapy and were randomized to undergo ST (TAC/SRL group, n = 24) or TAC (SRL/ST group, n = 21) withdrawal 3 months after transplantation. Primary efficacy and safety endpoints were the incidence of biopsy-confirmed acute rejection (BCAR) and renal function at 12 months. No differences were observed in the incidence of BCAR (4.2% vs. 9.5%), graft (95.8% vs. 95.6%), and patient (95.8% vs. 95.6%) survivals or in renal function (60 ± 11.5 vs. 63.4 ± 10.5 ml/min, P = 0.361). Higher mean cholesterol concentration was observed in the SRL/ST group (191.9 ± 63.3 vs. 241.6 ± 61.5 mg/dl, P = 0.019). Treatment discontinuation due to adverse events occurred in 12.5% of patients in TAC/SRL group and 21.7% in SRL/ST group. Within this short period of observation, our study was unable to detect any significant difference in major transplant outcomes comparing CNI and ST elimination strategies.

Comparison of the Safety and Efficacy of Cyclosporine Minimization Versus Cyclosporine Elimination in De Novo Renal Allograft Patients Receiving Sirolimus

The safety and efficacy of concentration-controlled use of sirolimus (SRL) and cyclosporine (CsA) followed by CsA minimization (CsAm) or elimination (CsAe) beginning at week 13 was compared in a phase 4, open-label, randomized (1:1) trial of renal transplant recipients enrolled between March 2004 and November 2005. The primary endpoint was renal function, measured at 12 months using the Nankivell formula, in patients remaining on therapy. Though a total enrollment of 140 patients in each group was planned to provide an 80% power to detect a difference in means, only 207 subjects were enrolled in this study. Demographic characteristics were similar between groups, with 98.1% recipients of first grafts, 69.1% from living donors, and 7.2% diabetics. At 12 months, there were no differences in renal function (61.08 vs 65.24 mL/min, P = .132); incidence of biopsy-confirmed acute rejection (14.3% vs 22.5%, P = .152); and patient (89.5% vs 92.2%, P = .632), graft (87.6% vs 88.2%, P = .999), and death-censored graft (98.1% vs 94.1%, P = .166) survivals between CsAm and CsAe groups, respectively. There were no differences in the overall rate of study-drug discontinuation (32.4% vs 36.3%, P = .562) but more patients discontinued because of lack of efficacy/graft loss in the CsAe group (4.8% vs 14.7%, P = .018). This study was underpowered to demonstrate the superiority of one regimen over the other. In summary, SRL immunotherapy combined with CsA minimization or elimination showed comparative safety and efficacy. Both regimens offer potential treatment options for de novo renal allograft recipients.

Two Years Postconversion From a Prograf-Based Regimen to a Once-Daily Tacrolimus Extended-Release Formulation in Stable Kidney Transplant Recipients

Tacrolimus extended-release (XL) is a once-daily formulation recently developed to reduce the frequency of dosing for patients currently using the twice-a-day formulation of tacrolimus (TAC). As reported previously, 67 kidney transplant recipients were safely converted (1:1 mg basis, total daily dose) from TAC twice-a-day to XL once-daily in the morning and were maintained on an am dosing regimen of XL using the same therapeutic monitoring and patient care techniques currently employed with TAC. The 2-year postconversion patient (100%) and graft (98.5%) survival, incidence of biopsy-confirmed acute rejection (6.0%), incidence of multiple rejections (1.5%), and safety profile (posttransplant diabetes, hyperlipidemia, hypertension, infections, renal dysfunction, hepatic dysfunction, and malignancies) were consistent with or more favorable than those previously reported for TAC twice-a-day.

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.

Impact of initial exposure to calcineurin inhibitors on kidney graft function of patients at high risk to develop delayed graft function

We conducted a retrospective analysis of the influence of full doses of calcineurin inhibitors [8-10 mg kg-1 day-1 cyclosporine (N = 80), or 0.2-0.3 mg kg-1 day-1 tacrolimus (N = 68)] administered from day 1 after transplantation on the transplant outcomes of a high-risk population. Induction therapy was used in 13% of the patients. Patients also received azathioprine (2 mg kg(-1) day(-1), N = 58) or mycophenolate mofetil (2 g/day, N = 90), and prednisone (0.5 mg kg(-1) day(-1), N = 148). Mean time on dialysis was 79 +/- 41 months, 12% of the cases were re-transplants, and 21% had panel reactive antibodies > 10%. In 43% of donors the cause of death was cerebrovascular disease and 27% showed creatinine above 1.5 mg/dL. The incidence of slow graft function (SGF) and delayed graft function (DGF) was 15 and 60%, respectively. Mean time to last dialysis and to nadir creatinine were 18 +/- 15 and 34 +/- 20 days, respectively. Mean creatinine at 1 year after transplantation was 1.48 +/- 0.50 mg/dL (DGF 1.68 +/- 0.65 vs SGF 1.67 +/- 0.66 vs immediate graft function (IGF) 1.41 +/- 0.40 mg/dL, P = 0.089). The incidence of biopsy-confirmed acute rejection was 22% (DGF 31%, SGF 10%, IGF 8%). One-year patient and graft survival was 92.6 and 78.4%, respectively. The incidence of cytomegalovirus disease, post-transplant diabetes mellitus and malignancies was 28, 8.1, and 0%, respectively. Compared to previous studies, the use of initial full doses of calcineurin inhibitors without antibody induction in patients with SGF or DGF had no negative impact on patient and graft survival.

A Prospective, Randomized Trial of Tacrolimus in Combination with Sirolimus or Mycophenolate Mofetil in Kidney Transplantation: Results at 1 Year

This is the 1-year report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Prior to transplantation, recipients were randomized to receive tacrolimus plus corticosteroids with either sirolimus (n=185) or MMF (n=176). The incidence of biopsy-confirmed acute rejection at 6 months was the primary endpoint of the study. Patient and graft survival, renal function, study drug dosing and discontinuations were evaluated at 1 year. At 1 year, there was no difference in patient survival (95.7% sirolimus vs. 97.2% MMF; P=0.45) or graft survival (90.8% sirolimus vs. 94.3% MMF; P=0.22). Patients without delayed graft function (DGF) receiving MMF had significantly better graft survival (99% vs. 93%; P=0.01). Patients receiving a transplant from a live donor had a trend towards better graft survival with MMF as compared to sirolimus (98% vs. 91%; P=0.07). Patients receiving sirolimus had a significantly higher incidence of study drug discontinuation (26.5% vs. 14.8% MMF; P=0.006). Patients receiving MMF had significantly better renal function as shown by median serum creatinine levels (1.3 mg/dL vs. 1.5 mg/dL; P=0.03) and a trend towards higher calculated creatinine clearance (CrCl), (58.4 ml/min vs. 54.3 ml/min; P=0.06). More patients in the sirolimus group had a serum creatinine >2.0 mg/dL, (20.4% vs. 11.0%; P=0.02). Tacrolimus is safe and effective in live and deceased donor kidney transplantation when given in combination with sirolimus or MMF. Patient and graft survival were excellent in both arms. Renal function is superior for patients treated with tacrolimus + MMF combination.

FTY720, A Novel Immunomodulator: Efficacy and Safety Results from the First Phase 2A Study in de novo Renal Transplantation

FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to lymph nodes. This is the first study to evaluate the efficacy and safety of FTY720 in de novo renal transplantation. This phase 2a, multicenter, open-label, dose-finding study compared FTY720 (0.25, 0.5, 1.0, or 2.5 mg) with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids. Patients (n=208) received FTY720 (n=167) or MMF (n=41) for 3 months followed by a 3-month follow-up. The incidence of biopsy-confirmed acute rejection at month 3 was 23.3%, 34.9%, 17.5%, and 9.8%, respectively, with FTY720 at doses of 0.25, 0.5, 1.0, and 2.5 mg, versus 17.1% with MMF. The incidence for the composite endpoint (biopsy-confirmed acute rejection, graft loss, or death) was lowest with FTY720 at a dose of 2.5 mg at month 3 (14.6%) compared with FTY720 at doses of 0.25 mg (25.6%), 0.5 mg (34.9%), and 1.0 mg (17.5%), and MMF (19.5%). Safety was comparable between FTY720 and MMF group. The main difference in tolerability was a mild and transient reduction in heart rate. A decrease in peripheral lymphocytes occurred in patients receiving FTY720, as expected from the mode of action, and this was reversible after treatment cessation. FTY720 at 2.5 mg was found to be as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation. FTY720 was well tolerated and not associated with the side effects commonly observed with immunosuppressant therapies.

Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study

Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study

Steroid withdrawal at 3 months after kidney transplantation: a comparison of two tacrolimus-based regimens

The 6 month prospective, randomized study compared the steroid-sparing potential of two tacrolimus-based regimens after renal transplantation. A total of 489 patients were randomized (1:1) to receive tacrolimus/mycophenolate mofetil (MMF)/steroids (n = 243; group Tac/MMF/S) or tacrolimus/azathioprine/steroids (n = 246; group Tac/Aza/S). At 3 months, steroids were tapered off in 267 (54.6%) patients free from steroid-resistant acute rejection and with serum creatinine concentrations <160 micromol/l. The incidence of biopsy-confirmed acute rejection at month 3 was lower in group Tac/MMF/S compared with group Tac/Aza/S (18.1% vs. 26.0%,P = 0.035). Moreover, more patients in the Tac/MMF/S group met the criteria for steroid withdrawal than in the Tac/Aza/S group (60.5% vs. 48.8%; P < 0.01). The incidence of acute rejection during months 4-6 was low in all groups, both for patients on steroid-free dual therapy (Tac/MMF: 2.7%, Tac/Aza: 0.8%) and for patients who continued steroid maintenance therapy (Tac/MMF/S: 3.5%, Tac/Aza/S: 7.1%). Moreover, kidney function was well preserved in steroid-free patients with month 6 median serum creatinine levels of 119.5 micromol/l (Tac/MMF), and 115.1 micromol/l (Tac/Aza). For patients who continued to receive steroids, month 6 median creatinine levels were 130.5 micromol/l (Tac/MMF/S) and 132.8 micromol/l (Tac/Aza/S). The criteria for the selection of patients to discontinue steroids were adequate. Both tacrolimus-based regimens allowed the safe discontinuation of steroids in low-risk patients at month 3. The Tac/MMF combination was superior in the prevention of acute rejections and more patients met the chosen criteria for steroid withdrawal.

RELATIONSHIP BETWEEN IMMUNOSUPPRESSION AND SUBSEQUENT DEVELOPMENT OF CMV DISEASE

P375 Aims: CMV disease has a significant influence on early and late transplant outcomes. Treatment is costly and associated with side effects, including bone marrow toxicity and nephrotoxicity. The purpose of this study was to identify immunosuppressive regimens with adequate efficacy and associated with lower incidence of CMV disease. Methods: Between 24/06/1998 and 16/08/2003 525 patients were included in prospective clinical trials using different drug combinations (Table 1). IL-2R monoclonal antibodies were used in 20% of patients. CMV disease was diagnosed as a positive antigenemia, clinical symptoms, laboratorial findings associated with CMV infection or tissue analysis. All patients were treated with ganciclovir for 14 to 42 days. Demographic data, biopsy-confirmed acute rejection, and treatment of acute rejection were recorded.FigureResults: Mean age was 37±12 years, 63% males, 50% white. 90% were recipients of living and 10% of cadaveric allografts. Overall incidence of biopsy-confirmed acute rejection was 27% and 1% of them required treatment with antibody. Mean time to acute rejection was 86±199 days. Five-year patient and graft survivals were 96.7% and 89.9%, respectively. Among 506 patients with available pretransplant CMV donor (D) and recipient (R) serologic status (IgG) there were 3% D(-)R(-), 5% D(-)R(+), 11% D(+)R(-) and 81% D(+)R(+). Thirty (5,7%) patients [43% R(-), 57% R(+)] developed CMV infection (21 syndromes; 4 tissue invasive and 5 clinically diagnosed) at a mean time of 109±128 days after transplantation. There were 3 relapses successfully treated with another course of ganciclovir. Among patients who showed CMV infection, 19 (63%) had biopsy-confirmed acute rejection (20% required antibody treatment), 47% was using MMF (6 with CSA, 1 with TAC, 5 with SRL and 2 with prednisone only). Graft loss was more frequent among patients who developed CMV infection (17% vs. 7%). Conclusions: CMV infection was associated with the use of MMF and with higher incidence of graft loss. Table 1. Immunosuppressive regimens CsA: cyclosporine; TAC: tacrolimus; AZA: azathioprine; MMF: mycophenolate mofetil; SRL; sirolimus; EVL: everolimus; FTY: FTY720; PRED: prednisone

Steroid-Withdrawal at 3 Days After Renal Transplantation with Anti-IL-2 Receptor α Therapy: A Prospective, Randomized, Multicenter Study

Steroids have been included in most immunosuppressive regimens after renal transplantation, but are feared for their side-effects. We conducted a prospective multicenter study to investigate whether it is feasible to withdraw steroids early after transplantation with the use of anti-IL-2Rα induction, tacrolimus and mycophenolate mofetil (MMF). A total of 364 patients were randomized to receive either two doses of daclizumab (1 mg/kg) and, for the first 3 days, 100 mg of prednisolone (daclizumab group n = 186), or steroids (tapered to 0 mg at week 16; controls n = 178). All patients received tacrolimus and MMF. The incidence of biopsy-confirmed acute rejection at 12 months was not different between the daclizumab group (15%) and the controls (14%) (95% confidence interval of difference: −6 to + 8%, NS). Graft survival at 12 months was comparable in the two groups (daclizumab group: 91%; controls: 90%). Mean arterial blood pressure, serum lipids, and incidence of patients with hyperglycemia were temporary lower in the daclizumab group compared with controls. The immunosuppressive regimen of the daclizumab group was associated with increased costs. In conclusion, with the use of anti-IL-2Ra induction and daily therapy with tacrolimus and MMF it is feasible to withdraw steroids at 3 days after renal transplantation.

An open‐label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination

The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.

Corticosteroid-free immunosuppression with tacrolimus following induction with daclizumab: A large randomized clinical study

This open, randomized (1 : 1), multicenter, 3-month study compared a dual tacrolimus plus steroids (Tac / steroids) regimen with a steroid-free immunosuppressive regimen of tacrolimus following daclizumab induction therapy (Tac / Dac) in adult liver transplant recipients. The full analysis set comprised 347 patients in the Tac / steroids group and 351 in the Tac / Dac group. Mean tacrolimus dose during month 3 was 0.11 mg/kg/day in both groups; mean whole-blood trough levels during month 3 were 10.9 ng/mL (Tac / steroids) and 10.6 ng/mL (Tac / Dac). The incidence of biopsy-confirmed acute rejection that required treatment was similar in both groups: 26.5% in the Tac / steroids group and 25.4% in the Tac / Dac group (P = .727). However, the incidence of biopsy-confirmed corticosteroid-resistant acute rejection was higher in the Tac / steroids group than in the Tac / Dac group (6.3 vs. 2.8%; P = .027). Kaplan-Meier estimates of graft survival (92.2 vs. 90.5%) and patient survival (94.5 vs. 93.7%) were similar in both groups. While also the overall adverse event profiles were similar, the incidences of diabetes mellitus (15.3 vs. 5.7%, respectively; P < .001) and cytomegalovirus infection (11.5 vs. 5.1%, respectively; P = .002) were higher in the Tac / steroids group compared with the Tac / Dac group. Mean cholesterol levels increased by 16% in the Tac / steroids group, but were unchanged in the Tac / Dac group during the study. In conclusion, tacrolimus monotherapy following daclizumab induction is an effective and safe regimen, with an advantage over concomitant steroid-maintenance therapy in terms of a lower incidence of diabetes and viral infection, and a lower incidence of steroid-resistant acute rejection.

Study 1: an open-label pilot study evaluating the safety and efficacy of converting from calcineurin inhibitors to sirolimus in renal allograft recipients on a regimen of maintenance therapy with moderate renal insufficiency

T he purpose of this study was to determine the safety and efficacy of converting from a calcineurin inhibitor–based to a sirolimus (SRL)–based regimen in established renal transplant recipients who had moderate renal insufficiency. Patients enrolled in the study included 60 renal transplant recipients who were previously treated for a minimum of 3 months with calcineurin inhibitors and who had evidence of moderate renal insufficiency (serum creatinine level of 1.8-3.0 mg/dL and glomerular filtration rate between 30 and 60 mL/ min). SRL therapy was initiated with a loading dose on day 1, and the dose was adjusted to maintain a whole-blood trough concentration of 10 to 20 ng/mL thereafter. The dose of the calcineurin inhibitor was decreased by 50% on day 2 and discontinued when SRL trough concentration was 5 ng/mL. Concomitant therapy with mycophenolate mofetil (MMF) or azathioprine (AZA) and prednisone was continued. The primary efficacy end point included the incidence of biopsy-confirmed acute rejection after conversion. Secondary efficacy end points included patient survival, graft survival, and graft function. Sixty patients (67% male, 27% African American, 57% cadaveric recipients, mean age 45 years) were enrolled. SRL therapy was initiated at a mean of 61 months (range, 7-198 months) after transplantation. The incidence of acute rejection at 12 months after conversion was 3.3%. Patient survival and graft survival were 96.7%. The following values are reported as mean SEM. Trends toward improvement were noted in both mean serum creatinine level (baseline, 2.0 0.06 mg/dL; final, 1.97 0.13 mg/dL) and calculated creatinine clearance (baseline, 51.6 1.8mL/min; final, 54.2 2.31 mL/min). Mean SRL trough concentration was 10 ng/mL in patients with MMF or AZA and 11.7 ng/mL in patients without MMF or AZA. Preconversion and postconversion lipid (in milligrams per deciliter) values were as follows: total cholesterol, 186 4.2 and 208 7.3 (P .05); triglycerides, 177 13.2 and 203 17.7 (P .05), low-density lipoprotein 100 3.1 and 119 6.2 (P .01); high-density lipoprotein, 46 1.9 and 50 2.7 (P .05). After conversion, lipid-lowering therapy was instituted in 21% of patients who had not previously required therapy. Thirteen patients (21.7%) discontinued the study, with the incidence of one or more adverse events being the most commonly cited reason. The most frequently reported adverse events were hyperlipidemia (55%), diarrhea (37%), peripheral edema (35%), rash (31.7%), and anemia (26.7%). Three malignancies (2 skin, 1 renal cell) were reported at days 38, 21, and 82, respectively. Conclusion: At this 12-month interim analysis, conversion of renal transplant recipients with moderate renal insufficiency from a calcineurin inhibitor–based to an SRL-based regimen appears safe, without a significantly increased risk of acute rejection, and results in a trend toward improved renal function. From the Department of Nephrology, University of Cincinnati Medical Center, Cincinnati, OH; and Department of Nephrology, Columbia Presbyterian Medical Center, New York, NY. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.026