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In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m 2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (≥60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nonadherence with immunosuppressive therapy after renal transplantation is a major clinical concern, but longitudinal data are sparse. Adherence data were recorded during the Mycophenolic Acid Observational REnal Transplant (MORE) study to help inform compliance management decisions., Material and Methods: Prospective data were analyzed from the four-year, observational MORE study of de novo adult renal transplant recipients receiving mycophenolic acid (MPA) as enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at 40 US sites under routine management. Adherence was assessed using the Immunosuppressant Therapy Adherence Scale (ITAS): total score 0-12 (12, adherence; <12, nonadherence). A logistic regression model was used to identify factors associated with nonadherence., Results: In total, 808/946 recipients (85.4%) provided ≥1 ITAS score. Nonadherence was reported by 24.8%, 31.5%, 33.0%, 39.8%, 35.4% and 26.4% at months 3, 6, 12, 24, 36 and 48, respectively. Mean ITAS score was higher with EC-MPS vs. MMF at months 24 (11.3[1.0] vs. 10.9[1.4], p=0.001) and 36 (11.4[1.0] vs. 11.1[11.3], p=0.024). The odds ratio for nonadherence was 1.60 (95% CI 1.17, 2.19; p=0.003) for African Americans vs. non-African Americans. The rate of biopsy-proven acute rejection was 12.7% (51/401) in nonadherent recipients vs. 11.3% (46/406) in adherent recipients (p=0.59); graft loss was 4.7% (19/402) vs. 3.0% (12/406) (p=0.20); death was 1.5% (6/402) vs. 4.7% (19/406) (p=0.013)., Conclusions: Adherence to the immunosuppressive regimen decreases over time, highlighting the need to monitor and encourage adherence even in long-term maintenance kidney transplant patients. Other than African American race, demographic factors may be of limited value in predicting nonadherence.

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four-yr data on 904 patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non-AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non-AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC-MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non-AA patients. Biopsy-proven acute rejection was higher in AA vs. non-AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non-AA patients. Kidney allograft survival remains lower for AA vs. non-AA recipients even under the current standard of care., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Everolimus (EVR) has demonstrated good efficacy after renal transplantation. Racial disparities in clinical outcomes after de novo renal transplantation are well documented; whether the efficacy of EVR varies based on recipient ethnicity is unknown. We conducted a comparative risk assessment of EVR by ethnicity., Methods: Data on 2004 renal transplant recipients from three EVR studies were pooled to identify the impact of ethnicity on efficacy outcomes across EVR dosing groups and control groups. Ethnic groups compared were African Americans, non-U.S. blacks, Asians, Hispanics, and Caucasians. EVR groups received either 1.5 or 3 mg per day, with either standard-dose cyclosporine or reduced-dose cyclosporine. Control groups received mycophenolic acid (MPA) with standard-dose cyclosporine. Composite efficacy failure endpoint was graft loss, death, biopsy-proven acute rejection, or lost to follow-up. Adjusted odds ratios were calculated using a logistic regression model., Results: The proportion of renal transplant recipients who met the composite endpoint was African Americans (46%), non-U.S. black (35%), Caucasian (31%), Hispanic (28%), and Asian (25%). The odds of meeting the composite endpoint were significantly (P=0.0001) greater for African Americans versus Caucasians but did not differ among the other ethnic groups (ethnic groups were only compared with Caucasians). EVR and MPA were associated with similar efficacy among each of the ethnic groups., Conclusion: In this pooled data analysis in more than 2000 renal transplant recipients, EVR versus MPA resulted in similar composite endpoint incidence events across ethnicities. Consistent with previously published data, African Americans had poorer clinical outcomes. EVR is efficacious regardless of ethnicity.

Background: Prospective data regarding immunosuppression and rejection in African American patients receiving modern immunosuppressive regimens are sparse., Methods: One-year data were analyzed from 901 tacrolimus-treated de novo kidney transplant patients in the prospective Mycophenolic Acid Observational Renal Transplant registry., Results: Mean tacrolimus dose was significantly higher in African Americans (n=217) versus non-African Americans (n=684), but mean tacrolimus trough concentrations were similar. The proportion of patients receiving mycophenolic acid dose equal to or more than 2000 mg per day (mycophenolate mofetil equivalents) was significantly higher with enteric-coated mycophenolate sodium versus mycophenolate mofetil at month 6 among African Americans and at month 3 in non-African Americans, but rates of acute rejection and adverse events (including gastrointestinal events) were similar. The 1-year incidence of biopsy-proven acute rejection (BPAR) was 14.1% in African Americans versus 7.5% in non-African Americans. On multivariate analysis, African American ethnicity was associated with a higher risk of BPAR (hazard ratio, 1.93; 95% confidence interval, 1.19-3.09; P=0.007). Mean (standard deviation) glomerular filtration rate at month 12 estimated by the Chronic Kidney Disease Epidemiology Collaboration formula was 59.2 (22.2) mL/min/1.73 m in African Americans versus 58.8 (19.9) mL/min/1.73 m in non-African Americans (confidence interval of the difference, -3.4 to 4.3; P=0.83)., Conclusion: This observational study confirms that African Americans require higher doses of tacrolimus to achieve target trough concentrations and are more likely to experience BPAR during the first year after kidney transplantation despite modern immunosuppression regimens. In our 1-year study, this was not associated with significantly inferior graft survival.

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3-8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking., Methods: Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg)., Results: The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p=0.02]; month 12, 47.3% vs. 39.4% [p=0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose>2000 mg (p=0.029) vs. 2000 mg., Conclusions: These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined., (© 2012 John Wiley & Sons A/S.)

Everolimus (EVR) in heart and renal transplant (RTx) recipients may be associated with a decreased incidence of cytomegalovirus (CMV). A detailed analysis of the association between EVR versus mycophenolic acid (MPA) and CMV events has not been reported. CMV data from 2004 de novo RTx recipients from three-randomized, prospective, EVR studies A2309 (N = 833), B201 (N = 588) and B251 (N = 583) were retrospectively analyzed to identify differences between two EVR dosing groups and MPA. EVR groups received 1.5 mg/day, or 3 mg/day with either standard (SD-CsA) or reduced dose cyclosporine (RD-CsA). Controls received MPA with SD-CsA. CMV prophylaxis was as per center practice. CMV incidence (infection/syndrome, disease, viremia) was captured per local center evaluations. Kaplan-Meier analyses demonstrated that freedom from CMV viremia and infection/syndrome was significantly greater for EVR versus MPA for recipients without CMV prophylaxis. Among recipients who received prophylaxis, freedom from viremia was greater for EVR 3.0 mg; freedom from infection/syndrome was greater for EVR 3.0 and 1.5 mg. Although freedom from organ involvement was numerically greater for EVR, it was not statistically significant. This analysis documents significant reductions in the incidence of CMV infection/syndrome and viremia in EVR-treated de novo RTx recipients, especially those who did not receive CMV prophylaxis versus MPA., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Data were pooled from three prospective, multicenter trials in which 1996 de novo kidney transplant recipients were randomized to everolimus 1.5 or 3.0 mg or mycophenolic acid ( MPA), with cyclosporine and steroids. Wound healing complications reported as adverse events were retrospectively reviewed in a blinded manner. The incidence of wound healing adverse events was 17.6% (351 of 1996) by day 90 and was similar for everolimus 1.5 mg (16.6% [110 of 661]) vs. MPA (14.3% [95 of 665]) (p = 0.255), but higher with everolimus 3.0 mg (21.8% [146 of 670]) (p < 0.001 vs. MPA). Similar results were observed for wound healing complications reported as serious adverse events. The 12-month incidence of lymphocele was 11.2% with everolimus 1.5 mg and 8.9% with MPA (p = 0.171), but lymphocele reported as a serious adverse event were more frequent with everolimus 1.5 mg (6.5% vs. 3.5%; p = 0.012). The hazard ratio ( HR) for any wound healing complication vs. MPA was not significantly higher for everolimus <3 ng/mL ( HR 1.33; 95% CI 0.94-1.88; p = 0.104), but increased to 1.46 (95% CI 1.12-1.90; p = 0.005) for 3-8 ng/mL and 1.69 (95% CI 1.20-2.38; p = 0.002) for >8 ng/mL. These results suggest that de novo kidney transplant patients receiving an initial everolimus dose of 1.5 mg do not appear to have a pronounced increased risk of wound healing complications vs. patients receiving MPA. [ABSTRACT FROM AUTHOR]