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The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35).

BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.Copyright © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons

Introduction: Cancer after kidney transplantation (KT) is a significant cause of morbidity and mortality. Choice of immunosuppressive regimenmay modify the risk of cancer. Mammalian target of rapamycin inhibitors have been shown to have anti-oncogenic effects in both animal and human studies. A large individual patient data (IPD) meta-analysis showed that sirolimus was associated with a significant reduction in the risk of cancer, but at the cost of an increased risk of death. We aimed to determine the cumulative incidence of cancer in KTrecipients randomised to de novo or early switch to everolimus (EVL)maintenance immunosuppression versus controls on standard calcineurin inhibitor (CNI) based triple therapy. Material(s) and Method(s): We included all de novo or early EVL switch randomised controlled trials (RCTs) conducted in Australia and New Zealand KT recipients between 2001 - 2012 in the IPD meta-analysis (Fig 1). Participants were linked to the Australian and New Zealand Dialysis and Transplantation Registry (ANZDATA) to capture outcomes of incident cancer and all-cause mortality. We compared treatment allocation to EVL or control, with time to first cancer occurrence using Kaplan-Meier estimates. An adjusted Cox proportional hazards model with random effects using pooled individual patient data from all trials was used to determine the overall risks of cancer and death. Results and Discussion: The 279 Australian and New Zealand participants (EVL = 192, control = 87) were followed for a median of 9.0 yrs (IQR 6.8, 9.6). Four RCTs examined EVL immunosuppression using de Novo (n=141) or early (<4 mths) (n=138) strategies in addition to either reduced dose CNI or CNI-withdrawal. The control arm consisted of cyclosporine or tacrolimus with mycophenolic acid or azathioprine and steroid maintenance therapy. The cumulative incidence of any cancer was not significantly different between EVL and control (log-rank test p = 0.8) (Fig 2). 30 (15.6%) EVL patients develope

BACKGROUND: The majority of organ donations in Australia occur in the DonateLife Network of hospitals, but limited monitoring at other sites may allow donation opportunities to be missed. Our aim was to estimate expected donor numbers using routinely collected data from the Australian and New Zealand Intensive Care Society Adult Patient Database and determine whether unrecognized potential donors might exist in non-DonateLife hospitals. METHODS: All deaths at 150 Australian intensive care units (ICUs) contributing to the Australian and New Zealand Intensive Care Society Adult Patient Database were analyzed between January 2010 and December 2015. Donor numbers were extracted from the Australian and New Zealand Organ Donor registry. A univariate linear regression model was developed to estimate expected donor numbers in DonateLife hospitals, then applied to non-DonateLife hospitals. RESULTS: Of 33 614 deaths at 71 DonateLife hospitals, 6835 (20%) met criteria as "ICU deaths potentially suitable to be donors," and 1992 (6%) were actual donors. There was a consistent relationship between these groups (R = 0.626, P < 0.001) allowing the development of a prediction model which adequately estimated expected donors. Of 8077 deaths in 79 non-DonateLife ICUs, 452 (6%) met criteria as potentially suitable donors. Applying the prediction model developed in DonateLife hospitals, the estimated expected donors in non-DonateLife hospitals was 130. However, there were only 75 actual donors. CONCLUSIONS: It is possible to estimate the expected number of Australian organ donors using routinely collected registry data. These findings suggest that there may be a small but significant pool of underutilized potential donors in non-DonateLife hospitals. This may provide an opportunity to increase donation rates.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Background: The A2309 was a 2-year, phase III randomized controlled trial evaluating the effect on graft and patient outcomes of three treatment groups:1.5mg everolimus plus reduced exposure cyclosporin (EVR1.5), 3.0mg everolimus plus reduced exposure cyclosporin (EVR3.0) or 1.44g mycophenolic acid plus standard cyclosporin (MPA). The aim of this study was to evaluate the long-term clinical outcomes of 95 Australia and New Zealand (ANZ) participants in the A2309 study. Method(s): Seven-year data for 95 ANZ A2309 participants were extracted from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Associations between treatment and outcomes, including rejection, estimated glomerular filtration rate (eGFR), graft loss, death and cancer incidence were examined using adjusted generalized linear regression or Cox regression analyses using an intention-to-treat analysis. Adverse events and discontinuation of study drugs (up to 2-years) were compared between treatment groups using data from Novartis. Result(s): Of the 95 participants, 66 (75.2%) were randomized to EVR1.5 or EVR3.0 and 29 (24.8%) to MPA. Compared to MPA, the combined everolimus treatment groups were associated with adjusted hazard ratios of 0.34 (95%CI 0.13, 0.91), 0.35 (0.09, 1.25) and 0.32 (0.15, 0.71) for non-melanoma skin cancers (NMSC), non-skin cancers and any cancers respectively, independent of age, gender and waiting time. The adjusted mean (95%CI) difference in eGFR at 2 and 5-years were numerically (but not statistically significant) higher in the EVR1.5 group compared to MPA group (2 years: 8.66, 95%CI 1.46, 15.85; and 5 years: 4.68, 95%CI -5.37, 14.7mL/min/1.73m2). There were no associations between treatment groups and other clinical outcomes, including rejection, graft loss or death up to 7-years post-transplant. Adverse events and discontinuation rates were similar between treatment groups after 2-years post-transplant. Conclusion(s): Compared to standard-dose cyclospori

A2309 was a 2-year, phase III randomized controlled trial evaluating the effect on graft and patient outcomes of three groups:1.5mg everolimus plus low exposure cyclosporine (EVR1.5), 3.0mg everolimus plus low exposure cyclosporine (EVR3.0) or 1.44g mycophenolic acid plus standard cyclosporine (MPA). 7-year data for 95 ANZ A2309 participants were extracted from the ANZDATA registry. Associations between treatment and outcomes, including rejection, eGFR, graft loss, death and cancer incidence were examined using adjusted generalized linear regression or Cox regression analyses by ITT analysis. Adverse events and discontinuation of study drugs (up to 2-years) were compared between treatment groups using data from Novartis. Randomized to EVR1.5 or EVR3.0 were 66 (75.2%) recipients and to MPA 29 (24.8%. Compared to MPA, everolimus treatment was associated with adjusted hazards of 0.34 (95%CI 0.13, 0.91), 0.35 (0.09, 1.25) and 0.32 (0.15, 0.71) for nonmelanoma skin cancers (NMSC), non-skin cancers and any cancers respectively, independent of age and waiting time. There was no association between treatment groups and graft function, rejection, graft loss or death up to 7-years after transplant. The adjusted mean (95%) difference in EGFR at 2 and 5-years were numerically (but not statistically significant) higher in the EVR1.5 group compared to MPA group (2 years: 8.66, 95%CI 1.46, 15.85; and 5 years: 4.68, 95%CI -5.37, 14.7mL/ min/1.73m2). Adverse events and discontinuation rates were similar between treatment groups. Compared to MPA, treatment with EVR was associated with > 50% reduction in cancer incidence, particularly NMSC. This data supports a class-effect for mTORi in reducing the burden of cancer after transplantation.

Aim: The 2-year, phase III, A2309 trial randomized 833 kidney transplant recipients to receive 1.5 mg everolimus plus low exposure cyclosporine (EVR1.5), 3.0 mg everolimus plus low exposure cyclosporine (EVR3.0) or 1.44 mg mycophenolic acid plus standard cyclosporine (control), all with basiliximab induction and maintenance steroids. Method(s): Follow-up to up to 7 years will be performed by linkage to the ANZDATA Registry assessing patient survival, graft survival, eGFR, and incidence of cancer by ITT analysis. Changes to immunosuppression subsequent to study completion will be examined and sensitivity analyses undertaken. Result(s): At two years follow up there was no difference between arms in regards to the primary endpoint (composite endpoints of tBPAR, graft loss, loss to follow up or death). Australia and New Zealand contributed 95 patients (11%). Analyses restricted to this subgroup revealed superior MDRD eGFR for EVR1.5 versus control (60.7613 ml/min/1.73 m2 v 47.44 (95% CI 4.1, 22.5)). Safety and adverse events were similar with comparable numbers of patients discontinuing in all arms of the study. Total tumour burden was decreased for EVR3.0 versus control (3 v 17 respectively). Everolimus was associated with a hazard ratio for nonmelanoma skin cancers of 0.34 (P = 0.031) and all cancers of 0.35 (P = 0.005). Discussion(s): Medium-term follow-up of the ANZ cohort of participants of this multinational RCT via registry linkage may provide useful data on clinically relevant (eGFR, cancer incidence, retention on therapy) and hard (patient and graft survival) endpoints, with potential to enhance power to differentiate therapies.

Aim: To conduct a pilot trial of diet and exercise to determine feasibility and examine outcomes. Background(s): New Onset Diabetes After Transplantation (NODAT) is common and is predictive of increased mortality. We hypothesised that progressive resistance training (PRT) coupled with dietary advice may improve body composition, decrease insulin resistance and reduce NODAT prevalence. Method(s): Kidney recipients were enrolled 6-8 weeks after transplantation (n = 56) across 4 sites. All received basiliximab, tacrolimus, mycophenolate and steroids. All received dietary assessment/advice plus supervised instruction on PRT, followed by unsupervised PRT for 6 months. Assessments included 3-day food diary, anthropometrics, body composition (DEXA), strength testing, OGTT, kidney function, SF-36. Result(s): Fifty-six patients were enrolled; 9 discontinued prematurely (back pain (2), depression (2), lymphoma (1), non-compliance (1), withdrawal of consent (3)). Intention to treat analysis comparing baseline to study-end demonstrated trends toward less diabetes (24.5% v 11.4%) andinsulin resistance (93.5% v 82.6%). HbA1c (5.6 +/- 0.6 v 5.7 +/- 0.6) was unchanged. Despite reductions in measured caloric intake (8791 +/- 2771 KJ v 7691 +/- 2561) and increased physical activity, BMI (24.6 +/- 3.9 v 25.1 +/- 4.5), WHR (0.89 +/- 0.1 v 0.88 +/- 0.1) and body composition (% body fat (28.7 +/- 8.5 v 29.0 +/- 9.0, lean mass (46.1 +/- 9.3 kg v 47.1 +/- 10.2)) were unchanged. Perceived physical health improved with mean baseline SF-36 PCS scores (41.4 +/- 5.9) becoming similar to population norms at month 6 (50.4 +/- 5.0). Conclusion(s): A program of diet and exercise was generally well tolerated and was associated with trends toward improvement, rather than the usual decline, in metabolic parameters post-transplant. A controlled study is warranted.

Aim: A systematic review of randomized trials where maintenance immunosuppressive regimens containing mammalian target of rapamycin inhibitors (mTOR-I) were compared with regimens containing calcineurin-inhibitors (CNI) for kidney transplant recipients. Background(s): Trials comparing the de novo use of mTOR-I to the use of CNI in kidney transplantation have largely been disappointing. The clinical benefit of the conversion from CNI to mTOR-I remains unclear. Method(s): Databases (2000-2011) and conference proceedings (2009-2011) were searched. Results are expressed as relative risk (RR), and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI). Result(s): Twenty-two trials were included (13 trials of sirolimus and 9 of everolimus). Compared with CNI, mTOR-I was associated with higher mean estimated glomerular filtration rate (eGFR) at 12 months with WMD of 3.68 mL/ min (95%CI 1.67, 5.70; p < 0.01; intention to treat analysis [ITT]), with similar findings for early (<12 months) and late conversion. In the on-treatment analysis up to 5-years post-transplant, mTOR-I was associated with higher mean eGFR compared to CNI with WMD of 14.37 (95%CI 9.69, 19.05; p < 0.01). Biopsy proven acute rejection was higher in the mTOR-I group at 12 months (RR 1.96; 95%CI 1.46, 2.62; p < 0.01), but not beyond 5 years. For graft loss between 2 and 5 years post-conversion, mTOR-I was associated with a lower risk of graft loss (RR 0.45, 95%CI 0.22, 0.95; p = 0.04). For adverse events, there was a greater relative risk of drug discontinuation, oedema, proteinuria, pneumonitis and hyperlipidemia at 12 months with mTOR-I. Conclusion(s): This meta-analysis has demonstrated that surrogate endpoints for graft survival favoured mTOR-I but risk of adverse events and drug discontinuation is higher for mTOR-I.

Introduction: Coronary artery disease (CAD) accounts for half of all deaths in patients with end stage kidney disease (ESKD) who have undergone renal transplantation. In patients with ESKD, "angiographically" significant CAD may be asymptomatic. Identification of these patients, with subsequent revascularisation, may reduce the prevalence of adverse cardiovascular events in the peri-transplant and post-transplant period. Objective(s): We aimed to evaluate the effectiveness of diagnostic (>85% maximum agepredicted heart rate) dobutamine stress cardiac magnetic resonance (DSCMR) imaging in identifying "angiographically" significant CAD in asymptomatic patients. Method(s): Over a five year period, 62 high-risk patients were referred to this program by the nephrology team. All of these subjects had an invasive coronary angiogram (ICA). These subjects had ESKD and were being considered for renal transplantation. 42 (68%) were male. All had at least one traditional cardiovascular risk factor. 58 (94%) were on renal replacement therapy. Of the 62 enrolled patients, 43 (69%) had a diagnostic DSCMR followed by an ICA. ICA reporters were blinded to results of DSCMR and vice-versa. 19 patients (31%) were excluded from the analysis due to non-diagnostic DSCMR scans. The most common reasons for a non-diagnostic DSCMR included insufficient augmentation in heart rate with dobutamine stress (in 8 patients) and claustrophobia (in 5 patients). Significant CAD was defined on ICA as a coronary stenosis of >= 70%. Result(s): Of the 43 included patients, 12 (28%) had significant CAD, and all of these patients had evidence of inducible myocardial ischaemia on DSCMR. 3 (7.0%) patients had false positive DSCMR scans. There were no false negative scans. Of the 19 patients with non-diagnostic CMR scans, 7 subjects had significant angiographic CAD. In this cohort studied with a diagnostic DSCMR: sensitivity = 100%, specificity = 90%, positive predictive value = 80%, negative predictive value =

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m 2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients. © 2013 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

ERDC/CRREL TR-14-16 Engineering for Polar Operations, Logistics, and Research (EPOLAR) Evaluation of a New SnowPaver at McMurdo Station, Antarctica Cold Regions Research and Engineering Laboratory Sally A. Shoop, Russ Alger, Joel Kunnari, and Wendy L. Wieder September 2014 Approved for public release; distribution is unlimited. The U.S. Army Engineer Research and Development Center (ERDC) solves the nation’s toughest engineering and environmental challenges. ERDC develops innovative solutions in civil and military engineering, geospatial sciences, water resources, and environmental sciences for the Army, the Department of Defense, civilian agencies, and our nation’s public good. Find out more at www.erdc.usace.army.mil. To search for other technical reports published by ERDC, visit the ERDC online library at http://acwc.sdp.sirsi.net/client/default.Engineering for Polar Operations, Logistics, and Research (EPOLAR) ERDC/CRREL TR-14-16 September 2014 Evaluation of a New SnowPaver at McMurdo Station, Antarctica Sally A. Shoop Cold Regions Research and Engineering Laboratory (CRREL) U.S. Army Engineer Research and Development Center 72 Lyme Road Hanover, NH 03755-1290 Russ G. Alger and Joel Kunnari Keweenaw Research Center Michigan Technological University 2400 Townsend Drive Houghton, MI 49431 Wendy L. Wieder Science and Technology Corporation 21 Enterprise Parkway, Suite 150 Hampton, VA 23666-6413 Final Report Approved for public release; distribution is unlimited. Prepared for National Science Foundation, Division of Polar Programs 4201 Wilson Boulevard Arlington, VA 22230 Under Engineering for Polar Operations, Logistics, and Research (EPOLAR) EP-ANT-12-15, “Snow Roads and Transportation” ERDC/CRREL TR-14-16 ii Abstract The snow roads at McMurdo Station are the primary transportation corri-dors to the surrounding airfields. However, during warm spells, deterio-rating road conditions can seriously limit payloads for all types of vehicles. The Cold Regions Research an