Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study.

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2 was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = -0.3, 8.7; P = .006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2 ) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R- high-risk group (P < .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. Clinicaltrials.gov number: NCT01950819.

Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation.

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

Characteristics of compatible pair participants in kidney paired donation at a single center.

Compatible pairs of living kidney donors and their intended recipients can enter into kidney paired donation (KPD) and facilitate additional living donor kidney transplants (LDKTs). We examined 11 compatible pairs (the intended recipients and their intended, compatible donors) who participated in KPD, along with the recipients' 11 matched, exchange donors. The 11 pairs participated in 10 separate exchanges (three were multicenter exchanges) that included 33 total LDKTs (22 additional LDKTs). All the intended donors were blood group O and female, with a mean living kidney donor profile index (LKDPI) of 27.6 (SD 16.8). The matched donors had a mean LKDPI of 9.4 (SD 31.7). Compatible pairs entered KPD for altruistic reasons (N=2) or due to mismatch of age (N=7) or body/kidney size (N=2) between the recipient and intended donor. In four cases, retrospective calculation of the LKDPI revealed that the matched donor had a higher LKDPI than the intended donor. Of the 22 recipients of LDKTs enabled by the compatible pairs, three were highly sensitized, with PRA >80%. In conclusion, most compatible pairs entered into KPD so that the recipient could receive a LDKT transplant from a donor whose age or body/kidney size were more favorable to post-transplant outcomes.

LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups.

African-American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post-transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once-daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak-trough fluctuations vs. tacrolimus twice-daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy-proven acute rejection (BPAR), or lost to follow-up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [-1.48% (-5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [-1.29% (-5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [-13.82% (-27.22%, -0.31%)] and KTR ≥65 [-13.46% (-25.27%, -0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high-risk subgroups, in particular black KTR and KTR ≥65 years old.

Alemtuzumab induction in renal transplantation.

BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).

Conversion from calcineurin inhibitor-based immunosuppression to mammalian target of rapamycin inhibitors or belatacept in renal transplant recipients.

The calcineurin inhibitors (CNIs) remain the standard of care for maintenance immunosuppression following renal transplantation. CNIs have demonstrated their effectiveness in reducing acute cellular rejection; however, some evidence suggests that these compounds negatively affect native renal function and are associated with allograft injury in renal transplant recipients. CNIs have also been linked with hypertension, new-onset diabetes after transplantation, tremor, and thrombotic microangiopathy, which have significant consequences for long-term allograft function and patient health overall. Thus, converting patients to a non-CNI-based regimen may improve renal function and also provide extrarenal benefits. A number of studies have been conducted that explore CNI conversion strategies in renal transplant recipients in an effort to improve long-term allograft function and survival. These include converting to alternative, non-nephrotoxic, maintenance immunosuppressants, such as the mammalian target of rapamycin inhibitors (sirolimus and everolimus) and the costimulation blocker belatacept. In this review of literature, evidence for the potential renal and extrarenal benefits of conversion to these non-CNI-based regimens is evaluated. Clinical challenges, including the adverse event profiles of non-CNI-based regimens and the selection of candidates for conversion, are also examined.

Racial differences in outcomes of the evaluation of potential live kidney donors: a retrospective cohort study.

BACKGROUND: In the USA, the lower rate of live donor kidney transplant among Black transplant candidates may stem from lower rates of donation among potential live donors who are Black. We determined whether outcomes of the evaluation of potential live kidney donors varied according to the potential donors' demographic characteristics. METHODS: We performed a single-center, retrospective observational cohort study of 1,179 potential live kidney donors, who came forward between 2000 and 2007. Potential donors' intended recipients were first-time transplant recipients who were evaluated between 2000 and 2005. RESULTS: There were 268 (22.7%) potential live kidney donors who were Black, of whom 93.7% were recruited by Black transplant candidates. Donor outcomes included actual donation (38.3%), exclusion due to blood group or crossmatch incompatibility (20.4%), exclusion due to medical contraindication to donation (13.7%), and lack of further donor interest (11.2%). Black (vs. non-Black) potential donors were less likely to actually donate (27.2 vs. 41.6%, p < 0.001). Black potential donors were more likely to stop pursuing live donation (p = 0.047) or be excluded from donation for medical reasons (p = 0.008) or blood group or crossmatch incompatibility (p = 0.01). These racial differences persisted in a multivariable multinomial logistic regression model of factors associated with outcomes of the donor evaluation. CONCLUSIONS: Potential live kidney donors who are Black are less likely to actually donate. Future studies should determine whether paired exchange and desensitization programs decrease these racial differences and why Black potential donors appear more likely to stop pursuing live donation.

Health care follow-up by live kidney donors more than three yr post-nephrectomy.

BACKGROUND: Live kidney donors are advised to follow up regularly with healthcare providers to monitor kidney function and to diagnose and treat relevant comorbidities. We sought to determine the frequency and correlates of follow-up care among live kidney donors. METHODS: We sent a mailed questionnaire to 606 live kidney donors from a single center who were at least three yr post-nephrectomy. RESULTS: We received usable responses from 276 (45.5%), at a median of 6.2 yr post-donation. Compared with non-responders, responding donors were more likely to be older (p < 0.001), female (p = 0.002), white (p < 0.001), and married to the recipient (p < 0.001). In the prior year, 87.7% of respondents reported seeing a physician or other healthcare professional, and 79.0% had seen a "general doctor" such as their primary care provider. In univariable analyses of live kidney donors who responded to our survey, lack of medical follow-up in the past year was associated with younger age, current lack of health insurance, and infrequent contact with the transplant recipient. CONCLUSIONS: Most responding live kidney donors had seen a healthcare provider within the past year. To improve donors' follow-up, transplant centers can consider targeting donors who are younger or lack health insurance.

Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial.

As part of the Spare-the-Nephron trial, we evaluated the combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for the preservation of renal function in renal allograft recipients. This 2-year, open-label, multicenter trial randomized 299 patients of which 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine). Baseline characteristics including measured (iothalamate) glomerular filtration rate (GFR) were similar between groups. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Calculated creatinine clearance and GFR were significantly greater with MMF/SRL at 2 years within which biopsy-proven acute rejection (BPAR) occurred in 14 MMF/SRL-treated patients (3 graft losses) and in 17 receiving the MMF/CNI (6 graft losses). Significantly, no patients receiving MMF/SRL but five treated with MMF/CNI died. Thus, compared with MMF/CNI treatment, a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.

YSPSL (rPSGL-Ig) for improvement of early renal allograft function: a double-blind, placebo-controlled, multi-center Phase IIa study.

INTRODUCTION: Recombinant P-selectin glycoprotein ligand IgG fusion protein, rPSGL-Ig (YSPSL), a fusion protein of human P-selectin ligand and IgG1-Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models. PATIENTS AND METHODS: This randomized 15-center, double-blind, 59-patient Ph2a study assessed YSPSL's safety in recipients of deceased-donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated. RESULTS: No drug-specific toxicities or increased adverse event rates were noted. Two YSPSL-treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post-transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post-operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis-delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint. CONCLUSION: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis-DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.

A prospective, randomized, multicenter study evaluating early corticosteroid withdrawal with Thymoglobulin in living-donor kidney transplantation.

BACKGROUND: This study compared the safety and efficacy of early corticosteroid withdrawal (ECSWD) with rabbit anti-thymocyte globulin (rATG) induction to chronic corticosteroid therapy (CCST) without antibody induction in primary, living-donor renal transplant recipients. METHODS: Eligible subjects were randomized 2:1 to receive either an ECSWD (n = 103) or CCST (n = 48) regimen, with all subjects receiving tacrolimus and mycophenolate mofetil (MMF). RESULTS: Results are reported as ECSWD vs. CCST. No significant differences were observed in the primary composite endpoint of freedom from biopsy-proven acute rejection (BPAR), graft loss, and death at six months (85.4% vs. 85.4%) or 12 months (84.4% vs. 74.4%). At 12 months, no difference was observed in BPAR (13.9% vs. 19.4%); however, ECSWD was associated with lower total cholesterol (159.7 +/- 39.2 vs. 196.5 +/- 56.7 mg/dL, p = 0.012), and trends toward significance were noted in serum triglycerides (151.9 +/- 92.0 vs. 181.4 +/- 78.8 mg/dL, p = 0.073) and weight gain (+3.6 +/- 9.4 vs. +6.4 +/- 9.3 kg, p = 0.069). No differences were observed in serious adverse events or infectious complications, with the exception of a higher incidence of leukopenia with ECSWD. CONCLUSIONS: rATG with tacrolimus and MMF therapy may allow early elimination of corticosteroids, is associated with trends toward lower lipid levels, less weight gain, and a safety profile comparable to CCST therapy.

Urologic Complications in 4000 Kidney Transplants Performed at the Saint Barnabas Health Care System.

Renal transplantation is the current standard treatment for end-stage renal disease and is associated with immunologic, vascular, and urologic complications. In this study we report urologic complications following ureteral reimplantation based on 1 urologist's experience at a single high-volume renal transplant institution. METHODS: A retrospective review was performed on all patients who underwent ureteral reimplantation by the transplant urologist at the time of their kidney transplant between July 1, 1993, and December 31, 2016. RESULTS: There was a total of 3951 ureteral reimplantations performed for 3890 renal transplants. The overall complication rate was 7% (276 patients). Vesicoureteral reflux was the most common complication (4.25%), followed by ureteral stricture (1.9%), urine leak (0.6%), and de novo ureteropelvic junction obstruction (0.25%). CONCLUSION: This study is a continuation of our previous case series. Over time, our overall rate of urologic complications has increased. Vesicoureteral reflux has remained the most common complication with increasing incidence compared with our prior reviews. One possible cause for increased incidence is our thorough longitudinal follow-up over more than 2 decades. Some patients who previously had no evidence of reflux eventually did in fact develop reflux. The incidence of ureteral stricture, urine leak, and ureteropelvic junction obstruction has overall remained stable over the past 23 years. In our program, 1 transplant urologist has performed almost all ureteroneocystostomies, leading to consistent management and generalizable results. Review of the literature shows variable rates of complications among different studies with multiple surgeons, disparate techniques, and short follow-up. Our study eliminates many of these confounding factors and provides more reliable, reproducible data.

Oral ganciclovir versus low-dose valganciclovir for prevention of cytomegalovirus disease in recipients of kidney and pancreas transplants.

BACKGROUND: The optimal regimen for prophylaxis of cytomegalovirus (CMV) disease after kidney and/or pancreas transplantation remains unclear. We compared the effectiveness of three months of oral ganciclovir (3 g/day) versus low-dose valganciclovir (450 mg/day) for CMV prophylaxis. METHODS: We performed a retrospective cohort study of patients at our center who received kidney and/or pancreas transplants between January 2000 and April 2003. We used a Cox proportional hazards model to examine the relationship between baseline covariates, including type of CMV prophylaxis, and time to development of CMV disease. RESULTS: Of the 500 patients (295 ganciclovir, 205 valganciclovir), 22 patients (4.4%) developed CMV disease (mean time to CMV disease, 163+/-85 days). Sixteen of the ganciclovir patients (5.4%) and six of the valganciclovir patients (2.9%) developed CMV disease (P=0.18). By CMV serostatus, the incidence of CMV disease during the first posttransplant year was 8.5% among donor-seropositive, recipient-seronegative (D+/R-) patients, 8.6% among D+/R+ patients, 2.9% among D-/R+ patients, 1.0% among D-/R- patients, and 0.9% among patients for whom documentation of CMV serostatus was incomplete. In the unadjusted Cox proportional hazards analysis, race/ethnicity, type of transplant, type of antiviral prophylaxis, CMV serostatus, and use of mycophenolate mofetil were each associated with risk of developing CMV disease. In the adjusted, multivariable model, only CMV serostatus was associated with development of CMV disease. CONCLUSIONS: Three months of low-dose valganciclovir (450 mg/day) was as effective as ganciclovir (3 g/day) for prophylaxis of CMV disease after kidney and/or pancreas transplantation.

Impact of long-term therapy with FTY720 or mycophenolate mofetil on cardiac conduction and rhythm in stable adult renal transplant patients.

The novel immunomodulator FTY720 has been associated with a mild reduction in heart rate (HR) in clinical trials. A total of 421 patients (FTY720, n=94; mycophenolate mofetil [MMF], n=327) underwent 2-day electrocardiogram and 24-h Holter monitoring. Patients had been maintained on cyclosporine plus MMF or FTY720 (2.5 mg and 5.0 mg) for > or =12 months. No significant differences in mean hourly heart rate (HR) over 24 hrs were noted between groups. Bradycardia (HR 35-50 bpm) and sustained bradycardia (HR <50 bpm for >1 min) were more common with MMF than FTY720 (53% vs. 37% and 34% vs. 21%, respectively). Electrocardiogram parameters did not differ significantly between FTY720 and MMF groups, or between FTY720 groups, supporting the absence of a dose-dependent effect. The absence of any clinically significant effect of FTY720 on cardiac rhythm demonstrates that the reduction in HR seen after the first dose does not persist in the maintenance phase.

Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients.

AIMS: To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. METHODS: Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. RESULTS: MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. CONCLUSIONS: Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.

Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.

Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium.

BACKGROUND: The benefit of converting renal transplant recipients with gastrointestinal (GI) complaints from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) has not been evaluated using patient-reported outcomes. METHODS: A multicenter, open-label, prospective study was undertaken in MMF-treated renal transplant patients. Patients experiencing GI complaints were converted to equimolar EC-MPS (Cohort A). Patients without GI complaints remained on MMF (Cohort B). At baseline and Visit 2 (4-6 weeks postbaseline), patients completed the Gastrointestinal Symptom Rating Scale (GSRS), Gastrointestinal Quality of Life Index (GIQLI) and Psychological General Well-being Index (PGWBI). At Visit 2, patients and physicians completed the Overall Treatment Effect (OTE) scale for GI symptoms. Additionally, patients completed the OTE for health-related quality of life (HRQoL). Minimal important difference (MID) was calculated for GSRS and GIQLI based on patients' and physicians' OTE evaluation. RESULTS: Of 328 patients enrolled (i.e. the intent-to-treat and safety populations), 278 formed the per-protocol population (Cohort A, n=177; Cohort B, n=101). At baseline, Cohort A had significantly worse scores on all GSRS, GIQLI and PGWBI subscales compared to Cohort B (all P<0.0001). All GSRS, GIQLI and PGWBI subscale scores improved significantly in Cohort A between baseline and Visit 2 (all P<0.0001). Mean improvements in all GSRS subscales and most GIQLI subscores exceeded the calculated MID. GSRS, GIQLI and PGWBI subscales remained stable in Cohort B. CONCLUSION: This first exploratory study indicates that converting patients with mild, moderate or severe GI complaints from MMF to EC-MPS significantly reduces GI-related symptom burden and improves patient functioning and well-being.

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

BACKGROUND: Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. METHODS: This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. RESULTS: FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. CONCLUSIONS: While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.