De Novo Renal Transplant Recipients Research Articles

Everolimus With Reduced-Dose Cyclosporine in De Novo Renal Transplant Recipients: Philippine Experience

Objective The objective of this study was to describe the appropriate dose of everolimus to achieve target trough concentrations in standard-risk Filipino kidney transplant recipients. Methodology We reviewed all kidney transplant recipients from December 1, 2006 to June 15, 2007 who were given everolimus (1.5 mg/d) in combination with low-dose cyclosporine (5 mg/kg/d) and prednisone but without induction therapy for their immunosuppressive doses, trough levels, as well as hematologic and blood chemistry profiles. Target everolimus trough concentration was 3–8 ng/mL and C2 level was 1000–1400 ng/mL for the first 3 months. Results Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but only 15 patients completed the 3-month follow-up and are the subject of this report. Their mean age was 33 years, average PRA 2%, and mean HLA mismatches 3. All were from living donors. At 7 days posttransplantation, all patients achieved or exceeded the target everolimus trough and cyclosporine C2 level. At 1 and 3 months posttransplantation the mean everolimus dose was 1.17 and 0.78 mg/d, respectively, whereas the cyclosporine dose was 195 and 148 mg/d, respectively. Three patients showed elevated alanine aminotransferase (ALT) and all patients had hypercholesterolemia after 1 month, which improved with everolimus dose reduction (half required statins). One patient experienced a Banff Grade IA acute rejection episode at 2 months posttransplantation with a serum creatinine value of 2 mg/dL after steroid pulsing. Conclusions Most standard-risk Filipino kidney transplant recipients required a maintenance everolimus dose of 1 mg/d at 1 month. The cyclosporine dose requirement was also lower. A larger sample size is needed to provide a level of significance compared with other populations.

Excellent Long-Term Results in De Novo Renal Transplant Recipients Treated With Proliferation Signal Inhibitors and Reduced Calcineurin Inhibitors Exposure

Background A new class of immunosuppressants, proliferation signal inhibitors (PSI)—sirolimus and everolimus—has the potential to prevent chronic allograft nephropathy (CAN). This retrospective analysis reports a 6-year practice using PSI at a single center, comparing a regimen based on reduced-dose calcineurin inhibitors (CNI) and PSI versus full-dose CNI and mycophenolic acid (MPA). Methods The study population included 70 patients (group A) who received de novo PSI therapy in combination with reduced dose of CNI, standard steroids, and basiliximab induction, and 216 patients (group B) with full-dose CNI, MPA, steroids, and basiliximab induction. Results No statistically significant differences were recorded in the baseline donor and recipient characteristics. A difference was observed in cold ischemia time, which could represent a bias for the analysis. No differences were recorded in actuarial patient survival, delayed graft function, biopsy-proven acute rejection rates, and renal function analysis. A significant difference was recorded in the actuarial graft survival rate at years 2, 3, and 4 ( P < .01), as well as overall graft survival rates ( P = .025). Discussion The reduction of cold preservation time seemed to be an important factor to improve both short- and long-term renal function. This regimen revealed a long-term trend toward better renal function and graft survival. The use of PSI with reduced doses of CNI seems to be indicated for suboptimal grafts, especially when a reduced quality of the kidney is associated with prolonged cold ischemia time.

Does Reduction in Immunosuppression in Viremic Patients Prevent BK Virus Nephropathy in De Novo Renal Transplant Recipients? A Prospective Study

BK virus nephropathy (BKVN) is a severe complication of renal transplantation, resulting in graft loss in >50% of cases. Because patients with BKV viremia are at high risk for developing BKVN, the aim of our study was to analyze whether early reduction of immunosuppression (IS) could prevent BKVN in viremic patients. BKV viruria was prospectively screened every 3 months by real-time polymerase chain reaction during the first year after transplantation in 123 consecutive renal transplant recipients. Plasma viral load was measured by polymerase chain reaction whenever viruria was positive; in viremic patients a graft biopsy was systematically performed and IS was reduced. Viruria, viremia, and BKVN occurred in 48.8%, 10.5%, and 2.4% of patients, respectively. In the 13 patients with positive viremia, initial graft biopsy showed BKVN in two. After reduction of IS in patients without BKVN, viremia disappeared in 8 of 11, decreased in 2 of 11, and increased in one patient who eventually developed BKVN. In contrast, viremia remained positive in one patient with BKVN and disappeared in the second but renal function deteriorated in both of them. Initial viral load was higher in patients who developed BKVN. Reduction of IS is probably an effective therapeutic option to clear viremia and prevent BKVN in viremic renal transplant patients.

Efficacy and Safety of Enteric-Coated Mycophenolate Sodium in De Novo Renal Transplant Recipients: Pooled Data From Three 12-Month Multicenter, Open-Label, Prospective Studies

Background The myfortic Prospective Multicenter Study ( myPROMS) utilizes a core protocol in which renal transplant patients receive enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine microemulsion. Substudies investigate specific aspects of the immunosuppressive regimen. Methods A pooled analysis of three 12-month myPROMS substudies in de novo renal transplant patients was undertaken. Patients in the US01 and DE01 substudies were randomized to higher or lower cyclosporine C 2 target ranges; patients in FR01 were randomized to early or delayed introduction of cyclosporine. All patients received steroids and interleukin-2 receptor antagonist induction. Results In total, 456 patients were included in the pooled analysis. Treatment failure (biopsy-proven acute rejection, graft loss, or death) occurred in 118 patients (25.9%) by month 12, with biopsy-proven acute rejection reported in 101 patients (22.1%). Fourteen patients (3.1%) lost their graft, and six patients died (1.3%). Median calculated creatinine clearance was 62.9 mL/min at month 12 (median serum creatinine, 138 ± 51 μmol/L). Gastrointestinal (GI) adverse events were reported in 354 patients (77.6%); these were mild or moderate in 323 patients. Within 12 months, 16.2% of patients required EC-MPS dose changes for GI adverse events. GI disorders led to EC-MPS discontinuation in only 10 patients (2.2%). Over the 12-month study, mean EC-MPS dose was 1352 ± 230 mg/d (94% of recommended dose). Conclusion Cyclosporine, EC-MPS, and steroids with interleukin-2 antagonist induction offers effective and well-tolerated immunosuppression following renal transplantation. Graft survival was excellent and renal function was stable. High EC-MPS dosing was sustained throughout (>90% recommended dose) and dose modifications due to EC-MPS–related adverse events or infections were infrequent.

Comparison of Generic Cyclosporine Microemulsion versus Neoral in de Novo Renal Transplant Recipients Managed By 2-Hour Postdose Monitoring

Introduction The bioequivalence of generic formulations is established by measuring pharmacokinetic parameters in healthy volunteers. Cyclosporine (CsA) absorption and exposure is known to differ between healthy volunteers and transplant recipients. Therefore bioequivalence testing may be inadequate to ensure therapeutic equivalence. We sought to compare the efficacy of generic cyclosporine (ArpimuneME, RPG Life Sciences) versus Sandimmune Neoral in de novo renal transplant recipients. Methods A prospective single-center, open-label study enrolled 20 de novo renal transplant patients (group 1: mean age 30.55 ± 9.81 years, M:F 19:1, mean donor age 43.4 ± 10.8). All patients received ArpimuneME along with azathioprine and prednisolone. The results were compared with 17 matched controls (group 2: mean age 28.1 ± 9.5 years, M:F 13:4, mean donor age 47.8 ± 6.8) who received Neoral and were transplanted during the same period. C 2 levels were monitored by the cloned enzyme donor immunoassay (CEDIA). Results Patient and graft survivals were 100% and 100% and 100% and 92.8% in groups 1 and 2, respectively ( P = NS). Six patients (30%) experienced rejection in group 1 as compared eight patients (47.1%) in group 2. Mean CsA levels (ng/mL) during the first month were 1419.1 ± 213.6 and 1460.5 ± 290.7 and at 3 months, 1296.3 ± 227.8 and 1342.4 ± 303.4 in the two groups, respectively ( P = NS). The mean serum creatinine levels (mg%) in group 1 and group 2 were 1.6 ± 0.8 and 2.0 ± 1.4 at discharge and 1.5 ± 0.4 and 1.5 ± 0.8 at 6 months, respectively ( P = NS). Conclusion Use of a generic microemulsion form of CsA provided safe and effective immunosuppression compared with Sandimmune Neoral when drug monitoring was performed by C 2 levels.

Efficacy and Safety of Enteric-Coated Mycophenolate Sodium ( myfortic) in De Novo Renal Transplant Recipients: Results of a 12-Month Multicenter, Open-Label, Prospective Study

Enteric-coated mycophenolate sodium (EC-MPS) has been developed as an alternative formulation of mycophenolate acid aiming for improved gastrointestinal (GI) tolerability. This 12-month, open-label, multicenter, prospective study investigated the efficacy and tolerability of EC-MPS (720 mg twice a day) given in combination with cyclosporine microemulsion (CsA-ME) in de novo renal transplant recipients ( n = 140). The efficacy evaluation was the incidence of treatment failure (defined as biopsy-proven acute rejection [BPAR], graft loss, or death) after 6 and 12 months of treatment. The incidences of treatment failure, BPAR, and graft loss were comparable at 6 and 12 months (18.6% vs 22.1%, 15.7% vs 19.3%, and 1.4% vs 2.1%, respectively). Renal function at 6 and 12 months (creatinine clearance) was 60.6 ± 19.8 mL/min and 63.2 ± 27.1 mL/min, respectively. EC-MPS was generally well tolerated; 95.9% of the reported GI adverse events (AEs) were rated as mild or moderate. The rate of EC-MPS dose reduction was 26.4%; 4.3% were due to GI AEs. The rate of EC-MPS dose interruption was 10%; 2.1% were due to GI AEs. In summary, EC-MPS given in combination with CsA-ME demonstrates good efficacy and tolerability in de novo renal transplant recipients.

Use of Enteric-Coated Mycophenolate Sodium in De Novo Renal Transplant Recipients With High Incidence of Delayed Graft Function

Patients with delayed graft function (DGF) are at risk of increased incidence for acute rejection episodes (ARE). Mycophenolate mofetil or induction therapy has produced a reduction in ARE incidence. An open, prospective, 3-month trial was performed in a group of Argentinian renal transplant recipients. We recruited 46 patients, 71.7% men, aged 41.7 ± 13.8 years; including 36 (78.3%) recipients of cadaveric donors (CD) who were aged 43.4 ± 15.5 years with a cold ischemia time of 19.4 hours ± 5.4 minutes, and 10 (27.7%) recipients of living donors (LD) aged 37.8 ± 12.9 years. HLA mismatches ≥ 3 were observed in 58.4% of CD and in 7% of LD. All patients received two doses of basiliximab (20 mg each, days 0 and 4), cyclosporine microemulsion (CsA-ME) monitored by the second-hour concentrations (C 2), enterio-coated mycophenolate sodium (EC-MPS; 720 mg twice a day, and steroids. A 58% incidence of DGF was observed. At the end of the third month the incidence of biopsy-proven ARE was 15%, with a median serum creatinine of was 1.54 ± 0.42 mg/dL, including three grafts lost. Two patients died. No patient required EC-MPS dose discontinuation but 20% of patients required dose adjustments. The absence of discontinuations and the low incidence of dose adjustments of EC-MPS in this high-risk de novo population provided support of a suitable tolerability profile for this EC-MPS, and the possibility to impact efficacy results.

A Multicenter, Prospective Study of C2-Monitored Cyclosporine Microemulsion in a U.S. Population of De Novo Renal Transplant Recipients

Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/1.73 m. Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.

Everolimus versus Mycophenolate Mofetil in the Prevention of Rejection in De Novo Renal Transplant Recipients: A 3-Year Randomized, Multicenter, Phase III Study

This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 micromol/L or greater with everolimus and 7 micromol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin-inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.

Efficacy and Safety Outcomes Among De Novo Renal Transplant Recipients Managed by C2 Monitoring of Cyclosporine A Microemulsion: Results of a 12-Month, Randomized, Multicenter Study

The clinical benefits of C2 monitoring of cyclosporine microemulsion have been demonstrated, but C2 targets in renal transplant recipients during the first year require validation. MO2ART was a prospective, multicenter study of renal transplant recipients managed by C2 monitoring of cyclosporine microemulsion with steroids and mycophenolate mofetil or azathioprine. Patients were randomized on day 3 to two groups, which were managed from month 3 with higher or lower C2 target ranges (months 4-6, 1,000-1,200 ng/mL vs. 800-1,000 ng/mL; months 7-12, 800-1,000 ng/mL vs. 600-800 ng/mL, respectively). The primary endpoint was the glomerular filtration rate (GFR) at month 12. A total of 296 patients were recruited, of whom 250 remained in the study at 3 months (higher-C2, n=131; lower-C2, n=119). GFR at 12 months did not differ between the higher- and lower-C2 groups (65+/-17 mL/min vs. 66+/-14 mL/min). When patients were regrouped according to C2 achieved by months 8 to 12, those with the lowest C2 (<700 ng/mL) showed the lowest GFR at month 3 and the most pronounced increase in GFR between month 3 and month 12 (P=0.04). Five episodes of biopsy-proven acute rejection occurred after month 3 (higher-C2 group, n=2; lower-C2 group, n=3). The overall 12-month Kaplan-Meier incidence of biopsy-proven acute rejection was 13.7%. Patient and graft survival were 93% and 89%, respectively, at 12 months. Both C2 target ranges investigated showed excellent and nearly equivalent outcomes at 12 months. The decision to target the higher or lower end of these C2 ranges should be made on an individual basis, taking into account patient and graft characteristics, and co-medication.

A Double Absorption-Phase Model Adequately Describes Mycophenolic Acid Plasma Profiles in De Novo Renal Transplant Recipients Given Oral Mycophenolate Mofetil

Mycophenolic acid (MPA) shows complex plasma concentration-time profiles, particularly in the immediate (first month) post-transplantation phase for which no relevant pharmacokinetic model has been proposed thus far. The aim of this study was to develop a model to accurately describe the time profile of plasma MPA concentrations after oral administration of mycophenolate mofetil in adult kidney transplant patients, in any post-transplantation period. Full interdose pharmacokinetic profiles were collected in 45 adult renal transplant patients who were orally administered mycophenolate mofetil and ciclosporin; 25 patients were de novo transplant patients for whom individual pharmacokinetics were assessed at three post-transplantation periods (days 3, 7 and 30) and 20 patients were stable transplant patients (>3 months post-transplantation). MPA was determined in plasma by liquid chromatography-mass spectrometry. Models combining a single- or double-input (described as single or double gamma distributions) with one- or two-compartments were developed using in-house software and fitted to the individual profiles by nonlinear regression. Visual inspection of the pharmacokinetic profiles showed highly variable absorption profiles and secondary peaks of various intensity. The pharmacokinetic models including a double gamma distribution best fitted these various profiles in the immediate post-transplantation period (mean bias and precision of -0.92% and 20.19%; -1.5% and 18.02%, on day 7 and day 30, respectively), while in the stable post-grafting phase (beyond 3 months), the single- and double-absorption models performed similarly (mean bias and precision of -3.37% and 17.64%; -3.12% and 18.44%, on day 7 and day 30, respectively). The proposed pharmacokinetic models adequately describe the concentration-time profiles of MPA in renal transplant patients and could be helpful in the development of tools for MPA monitoring.