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  • The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine
    Kidney international. 2017;91(4):954-963

    Study Details

    Aims: To compare the risk of cancer incidence among kidney transplant recipients receiving everolimus plus reduced exposure cyclosporine, versus mycophenolate sodium and standard exposure cyclosporine.
    Interventions: Participants were randomised to receive everolimus (1.5mg or 3mg) with reduced cyclosporine, versus mycophenolate sodium and standard exposure cyclosporine. Using data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) and adjusted Cox proportional hazard models, the seven year risk of cancer incidence and other graft outcomes were assessed.
    Participants: 95 living and deceased donor kidney transplant recipients who participated in the A2309 study*.
    Outcomes: The primary outcome measured was the first non-melanoma skin cancer or any non-skin cancers diagnosed after transplantation. Other measured outcomes included delayed graft function, acute rejection, overall graft loss, death, estimated glomerular filtration rate, discontinuation rate, adverse events and a composite endpoint of graft loss and death.

    CET Conclusion

    Reviewer: Centre for Evidence in Transplantation
    This is an interesting study of long-term (7 year) follow up assessing risk of skin and other cancers with two different immune suppression regimens in kidney transplantation. The original study was the A2309 study. Patients were randomized to everolimus plus reduced exposure cyclosporine, versus mycophenolate sodium and standard exposure cyclosporine. The ANZDATA database was used to get these long-term outcomes. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with significantly reduced, unadjusted hazard ratios of 0.28, 0.39 and 0.41, respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Hazard ratios adjusted for non-cancer related deaths and other risk factors were also very favourable towards everolimus (0.34, 0.35 and 0.32 respectively). However, compliance with therapy was inferior for those randomized to everolimus, and more than 50% of participants discontinued everolimus by 2 years after transplantation. The small sample size is a concern, as is the use of a database in which under-reporting or misclassification may have occurred.

    Expert Review

    Reviewer: Professor Hans J. Schlitt, Department of Surgery, University of Regensburg Medical Center, Regensburg, Germany.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★☆ (4 of 5)
    The paper by Lim, W.H. et al presents 7-year follow-up data obtained from a nation-wide registry for Australia and New Zealand on kidney-transplant patients that had been part of a 2-year prospective randomized trial (Novartis, A2309), comparing “standard” cyclosporine/ mycophenolate-based immunosuppression with reduced cyclosporine + everolimus. The impressive difference in de-novo cancers, particularly in non-melanoma skin cancers, is remarkable since: a) the number of patients in this (sub-)study was only 95; b) cyclosporine had not been withdrawn, but only reduced in the everolimus arms; and c) only slightly more than half of the patients in the everolimus arms were actually on assigned treatment. Performing an on-treatment analysis, the hazard ratio for developing de-novo tumors was less than 0.4 for everolimus patients and less than 0.2 for those on high-dose everolimus. This study, gives strong evidence that reducing cyclosporine and adding everolimus in kidney transplant patients leads to an impressive reduction in de-novo cancers (and to improved renal function) in the absence of negative effects on immunologic safety and graft and patient survival. Thus, physicians as well as patients should be aware of these potential benefits of everolimus when they consider stopping the drug because of its specific side effects: in clinical practice, this occurs rather frequently, especially if the treating physician is less experienced with this drug.

    Abstract

    Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.
  • Effects of structured education program on organ donor designation of nursing students and their families: A randomized controlled trial
    Clinical transplantation. 2016;30(11):1513-1519

    Study Details

    Aims: To determine the effect of an education programs designed for nursing students on changing attitudes and behaviours towards deceased organ donation.
    Interventions: Participants were randomly assigned to either receive an education program consisting of a classroom lecture, small group discussion and a brief information booklet (intervention group), or three information booklets (control group).
    Participants: 203 Japanese nursing students from Saku Central Hospital Nursing School who were not previously designated organ donors.
    Outcomes: The primary outcome measured was self-reported organ donor designation. Secondary outcomes measured were proportions of students who discussed deceased organ donation with their family, whose family member provided consent for organ donation, who obtained approval of the family to the student’s consent for organ donation, and who expressed willingness to the following; provide consent for organ donation, donate organs after brain death, donate organs after circulatory death, to approve organ removal from a deceased family donor with organ donor designation, to approve organ removal from a

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This RCT investigates the effect of an education programme on changing attitudes and behaviour towards organ donation. Participants were Japanese nursing students who were allocated according to a computer generated sequence to the education programme or three information booklets. The education programme consisted of a lecture by a transplant nephrologist, small group discussions and an information booklet. No power calculation was conducted and 205 students were allocated of whom 2 were excluded from the analyses. The study found no difference between groups in terms of the number of participants who provided consent for organ donation.

    Expert Review

    Reviewer: Dr Laura A. Taylor, Daniel K. Inouye Graduate School of Nursing, Uniformed Services University, Bethesda, USA.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★☆☆ (3 of 5)
    In attempts to increase organ donor designation registration in Japan, an interprofessional investigative team collaborated to explore the potential impact of education programs on donor designation decision-making and registration. Japanese nursing students (203) were randomly assigned; using computer generated random numbers, to receive an educational program on organ donation in attempts to improve organ donor designation registration in Japan. The control group received a one-day, educational program using booklets. The intervention group received an educational program based on Prochaska’s transtheoretical model on behavioral change. This program included lecture, small group discussion, and booklets. Findings: Well-structured, culturally appropriate educational programs that deliver information in through multiple educational formats generated greater family discussion on organ donor designation and registration as compared to single format educational delivery. No difference in organ donor designation registrations was found between the control and intervention groups. Generalizability is limited to healthcare provider students and participants with a vocational level education. Further research is necessary across educationally diverse participants and family members. Implications for practice: Crafting diverse educational resources can promote organ donor designation discussions across students/participants and their families. Well structured educational resources on organ donation, may influence organ donor designation registration among participants.

    Abstract

    INTRODUCTION Little is known about the effect of education programs on changing attitudes and behaviors of participants and their families towards deceased organ donation. METHODS The subjects of this randomized trial were Japanese nursing students who were not previously designated organ donors. They were randomly assigned to either the education program or information booklet group. The program comprised a lecture followed by group discussion and information booklet. The primary outcome was self-reported organ donor designation. Outcomes were assessed by questionnaire. RESULTS Data of 203 (99.0%) students were analyzed. At study end, 7 of 102 students (6.9%) of the program group and 1 of 101 students (1.0%) of the booklet group consented to donate organs (proportion ratio 6.93 [95% CI 0.87-55.32]). There were significant between-group differences in willingness to consent for donation (54.9% vs. 39.6%; proportion ratio 1.39 [95% CI 1.03-1.87]), family discussion (31.4% vs. 15.9%; 1.98 [1.16-3.38]), and organ donor designation of family members (11.8% vs. 2.0%; 5.94 [1.36-25.88]). No group differences were found in willingness for organ donation by students and family members. CONCLUSION Although there were no significant between-group differences in organ donor designation, the program seems to indirectly promote consent to organ donation by their families. This article is protected by copyright. All rights reserved.
  • Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial
    American Journal of Kidney Diseases. 2016;69(5):587-594

    Study Details

    Aims: To summarise outcomes, specifically the safety and tolerability of belatacept at 36 months post randomization of kidney transplant recipients with low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept.
    Interventions: Participants were randomized to either switch to a belatacept-based immunosuppression (5 mg/kg of belatacept intravenous on days 1, 15, 29, 43, and 57 and every 28 days thereafter) or continue with CNI-based therapy.
    Participants: 173 adult stable kidney transplant recipients who were receiving CNI based maintenance immunosuppression.
    Outcomes: The primary outcome measured was safety, specifically adverse events (AEs) and serious AEs. Secondary outcomes measured were estimated glomerular filtration rate, acute rejection, transplant loss, and death.

    CET Conclusion

    Reviewer: Centre for Evidence in Transplantation
    This manuscript reports the 36-month extension from a phase 2 study randomising stable kidney transplant recipients (6-36 months post-transplant) to either continue CNI or switch to Belatacept. The renal function benefit seen at earlier time-points appears to be maintained, with an acceptable safety profile in both arms. Hazard for acute rejection is increased with Belatacept (HR 2.50), but this does not reach significance due to the small size of the study. In all, these data suggest that a switch to belatacept is safe and may result in small improvements in renal function compared to CNI-based therapy. The results are made difficult to interpret as patients/investigators were given the option to switch to belatacept at month 24. 16 patients (around 18%) in the CNI arm chose to switch, which may lead to an underestimation of any efficacy benefit or additional risk posed by the use of belatacept.

    Expert Review

    Reviewer: Dr Claudio Ponticelli, Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★★ (5 of 5)
    In this multicenter controlled trial, 173 CNI-treated adult kidney transplant recipients with stable graft function were randomly assigned to continue therapy with CNI (89 patients) or to be converted to belatacept (84 patients) at 6-36 months after transplantation. Belatacept-treated patients showed a significantly greater increase in GFR compared to CNI (+1.9 vs 0.07 ml/min). No difference between the two arms was seen in death, graft loss, acute rejection, serious adverse events, serious infection or malignancy. However, viral infection occurred more frequently in belatacept-treated patients. This study confirms that switching patients with stable renal graft function from CNI to belatacept is safe. The fact that the mean GFR at 36 months is better in belatacept-treated patients may represent an important result. However, it is also comforting to note that no attrition of renal function was seen in patients who continued CNI up to 3 years. Of note, the concern that belatacept might increase the risk of posttransplant lymphoproliferative disorder (PTLD) seems to be limited to EBV negative patients. Indeed, no case of PTLD was observed in this trial. In conclusion, the results of this study reinforce the idea that different but equally effective treatments are now available for kidney transplant recipients and that switching from a treatment to another one seems to be feasible and relatively safe, at least in patients with stable renal graft function.

    Abstract

    BACKGROUND In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. STUDY DESIGN 36-month follow-up of the intention-to-treat population. SETTING & PARTICIPANTS CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2). INTERVENTIONS At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). OUTCOMES Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. MEASUREMENTS Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. RESULTS Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). LIMITATIONS Exploratory post hoc analysis with a small sample size. CONCLUSIONS Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.
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