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  • Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function
    New England Journal of Medicine. 2015;373(5):405-14

    Study Details

    Aims: To test the benefit of targeted hypothermia in organ donors before organ recovery on delayed graft function in kidney recipients.
    Interventions: Deceased organ donors after declaration of death were randomised to undergo either hypothermia (34 to 35⁰C) or normothermia (36.5 to 37.5⁰C).
    Participants: 394 donors aged ≥ 18 years
    Outcomes: The primary outcome measured was delayed graft function (the need for dialysis in the first week posttransplant). Secondary outcomes were the rate of individual organs transplanted in each treatment group and the number of organs transplanted from each enrolled donor.

    CET Conclusion

    Reviewer: Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England, UK.
    This is a fascinating study with significant implications for preservation studies. The authors show that organ donors after brain death subjected to mild cooling had significantly less DGF than donors subjected to conventional normothermia before organ retrieval. In fact the DMC stopped the study on the basis that efficacy had been demonstrated before completion of recruitment. The effect was much more striking in expanded criteria donors. What does this mean in terms of ongoing trials of machine preservation after organ retrieval in kidney transplantation? Would the two approaches be complementary or would ongoing trials need to be repeated in organ donors who have been mildly cooled before retrieval of the kidneys? Certainly this study has provided food for thought in the preservation world!

    Expert Review

    Reviewer: Dr Gabriel C Oniscu, Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★★ (5 of 5)
    This is a significant study in the area of donor management. A simple intervention - mild cooling of the donor from 37°C (±0.5°C) to 34.5°C (±0.5°C) resulted in a significant reduction in the delayed graft function (DGF) in the transplanted kidneys. Overall there was an 11% improvement in DGF with the greatest beneficial effect in the recipients of extended criteria donors (24.5% reduction in DGF). The magnitude of the effect is comparable with that noted in machine preservation studies (compared with cold storage). There is much additional information required prior to generalise these findings (outcome for the other transplanted organs, duration of cooling, optimal cooling temperature, mechanism of action). However, this study could potentially change clinical practice through a simple and low-cost intervention that leads to a significant improvement in the function of the transplanted organs. This study raises many questions for the future practice in transplantation, in particular with regards to the place and role of sophisticated technology for preservation and organ perfusion in the context of simple solutions such as the one implemented in this trial. Therefore there is a clear need for further studies to replicate these findings and understand the mechanisms responsible for these astonishing results.

    Abstract

    BACKGROUND Delayed graft function, which is reported in up to 50% of kidney-transplant recipients, is associated with increased costs and diminished long-term graft function. The effect that targeted mild hypothermia in organ donors before organ recovery has on the rate of delayed graft function is unclear. METHODS We enrolled organ donors (after declaration of death according to neurologic criteria) from two large donation service areas and randomly assigned them to one of two targeted temperature ranges: 34 to 35degreeC (hypothermia) or 36.5 to 37.5degreeC (normothermia). Temperature protocols, which were initiated after authorization was obtained for the organ to be donated and for the donor's participation in the study, ended when organ donors left the intensive care unit for organ recovery in the operating room. The primary outcome was delayed graft function in the kidney recipients, which was defined as the requirement for dialysis during the first week after transplantation. Secondary outcomes were the rates of individual organs transplanted in each treatment group and the total number of organs transplanted from each donor. RESULTS The study was terminated early, on the recommendation of an independent data and safety monitoring board, after the interim analysis showed efficacy of hypothermia. At trial termination, 370 organ donors had been enrolled (180 in the hypothermia group and 190 in the normothermia group). A total of 572 patients received a kidney transplant (285 kidneys from donors in the hypothermia group and 287 kidneys from donors in the normothermia group). Delayed graft function developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and in 112 recipients of kidneys from donors in the normothermia group (39%) (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.92; P=0.02). CONCLUSIONS Mild hypothermia, as compared with normothermia, in organ donors after declaration of death according to neurologic criteria significantly reduced the rate of delayed graft function among recipients. (Funded by the Health Resources and Services Administration; ClinicalTrials.gov number, NCT01680744.).
  • Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial
    Lancet. 2015;385(9987):2577-84

    Study Details

    Aims: To assess the clinical outcomes of the Organ Care System compared with standard cold storage of donor hearts for transplantation.
    Interventions: Patients were randomly assigned to receive donor hearts preserved with either the Organ Care System or standard cold storage.
    Participants: 130 patients aged ≥18 years active on the heart transplant waiting list
    Outcomes: The primary outcome measured was 30 day patient and graft survival. Secondary outcomes were cardiac-related serious adverse events, severe rejection rates, and median length of stay in the intensive-care unit.

    CET Conclusion

    Reviewer: Centre for Evidence in Transplantation
    This is a very interesting study of ex-vivo heart allograft perfusion using the Organ Care System. The study was designed to show non-inferiority to standard cold storage and this was demonstrated with the primary outcome of 30 day patient and graft survival. Significantly the study group had much longer total preservation times on average (324 minutes versus 195 minutes), which was due to the amount of time that it took to adequately install the hearts into the OCS machine. Although the cold ischaemic time was of course less in the study group as the only cold periods were immediately before installing on the machine and after removal immediately prior to transplantation. The next logical step would be to test if systems like this might be better than static cold storage alone and how they might improve preservation times or expand the donor pool. This is crucial given the expense.

    Abstract

    BACKGROUND The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. METHODS We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT00855712. FINDINGS Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 28%, one-sided 95% upper confidence bound 88; p=045). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. INTERPRETATION Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. FUNDING TransMedics.Copyright © 2015 Elsevier Ltd. All rights reserved.
  • Eight-year results of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation
    Transplant international : official journal of the European Society for Organ Transplantation. 2016;29(1):41-50

    Study Details

    Aims: An extension of the Spiesser study to report on outcomes 8 years after kidney transplantation with sirolimus and cyclosporin treatment.
    Interventions: Patients received either a sirolimus-MMF–based regimen (sirolimus group) or cyclosporine-MMF–based regimen (cyclosporin group).
    Participants: 150 kidney transplant recipients aged 18-65 years
    Outcomes: The primary outcomes measured were estimated glomerular filtration rate (eGFR), graft and patient survival, and risk of de novo donor-specific antibody (DSA) appearance. Other outcomes were graft failure and death, serum creatinine level, proteinuria, immunosuppressive regimen, systolic and diastolic arterial pressure, antihypertensive drugs, hemoglobinemia level, erythropoietin use, post-transplant diabetes mellitus (PTDM) and malignancies.

    CET Conclusion

    Reviewer: Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    In this 8 year follow up of a trial comparing de novo sirolimus and cyclosporine in low risk recipients of a renal transplant there was no difference in patient or graft survival but a significant better renal function in the de novo sirolimus group compared to the cyclosporine group. However it should be noted that the analysis only dealt with patients who had a functioning graft at 8 years. Furthermore there was no difference between the groups in the incidence of de novo DSAs. Two earlier reports of the trial have documented the high withdrawal rate in the sirolimus group. Never the less it does appear that patients who can tolerate sirolimus are likely to have better renal function in the long term than patients maintained on cyclosporine.

    Expert Review

    Reviewer: Professor Teun van Gelder, Erasmus Medical Centre, Rotterdam, Netherlands.
    Conflicts of interest: I have been in advisory boards or in speaker buro of Roche, Astellas, Novartis, Chiesi, Teva and Siemens.
    Clinical Impact Rating : ★★☆☆☆ (2 of 5)
    In this paper the 8 year follow-up results of the Spiesser study are reported. In this study low immunological risk de novo renal transplant recipients were randomized for treatment with either sirolimus or cyclosporine based immunosuppression (combined with MMF, and with ATG-induction). The intent-to-treat analysis showed that of the original cohort of 145 patients, there were 99 patients with a functioning graft at 8 years, and that eGFR was significantly better in the patients randomized to sirolimus (62.5 vs 47.8 mL/min). Despite the difference in renal function, the graft and patient survival were similar. In contrast to previous studies suggesting a higher incidence of new DSA in patients on mTOR-inhibitors, in this study there was no difference in the presence of DSA. It is important to note that throughout the years in a large proportion of patients a conversion from the randomized immunosuppression to other regimens had occurred, in both groups. Of the 49 patients who had started on sirolimus at transplant and who still had a functioning graft at 8 years, only 26 were still on sirolimus maintenance treatment.

    Abstract

    INTRODUCTION We present the results at 8 years of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporin in kidney transplant recipients at low immunologic risk. METHODS We assessed estimated glomerular filtration (eGFR), graft, patient and death-censored graft survival (log-rank compared), de novo DSA appearance, risk of malignancy, posttransplant diabetes mellitus (PTDM) and anemia. Intent-to-treat and on- treatment analyses were performed. RESULTS Graft survival was similar in both groups (sirolimus: 73.3%, cyclosporin: 77.7, p=0.574). No difference was observed between treatment groups concerning patient survival (p=0.508) and death-censored graft survival (p=0.858). In conditional intent-to-treat analysis, mean eGFR was greater in sirolimus than cyclosporin group (62.5+/-27.3ml/min vs 47.8+/-17.1ml/min, p=0.004), in particularly because graft function was excellent in patients maintained under sirolimus (eGFR=74.0 ml/min). Importantly, no detrimental impact was observed in patients in whom sirolimus has been withdrawn (eGFR=49.5 ml/min). Overall, 17 patients showed de novo DSAs, with no difference between the 2 groups (p=0.520). Malignancy did not differ by treatment. CONCLUSION An initial maintenance regimen based on sirolimus provides a long-term improvement in renal function for kidney transplant patients, especially for those maintained on sirolimus. This article is protected by copyright. All rights reserved.
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