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In this study of three strategies — hypothermia, machine perfusion, or both — for pretransplantation preservation of kidneys from brain-dead donors, hypothermia was found to be inferior to machine perfusion.

In this international randomized, controlled trial, one kidney from each pair from 336 consecutive deceased donors was randomly assigned to machine perfusion and the other to cold storage. All recipients were followed for 1 year. Hypothermic machine perfusion was associated with a reduced risk of the primary end point — delayed graft function — and improved graft survival in the first year after transplantation. In this trial, one kidney from each pair from deceased donors was randomly assigned to machine perfusion and the other to cold storage. Hypothermic machine perfusion was associated with a reduced risk of the primary end point — delayed graft function — and improved graft survival in the first year after transplantation. Two different forms of organ preservation — static cold storage and hypothermic machine perfusion — are used clinically for renal allografts obtained from deceased donors. In static cold storage, the kidney is flushed, cooled with one of several cold preservation solutions, and transported on ice. In hypothermic machine perfusion, after an initial washout of blood, the kidney is connected to a perfusion device, and a solution is pumped continuously through the renal vasculature at temperatures between 1 and 10°C. 1 The typical deceased kidney donor today is older and has been exposed to more concomitant disease than donors were several decades . . .

IntroductionIschaemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively affects patient and graft outcomes. Anaesthetic conditioning (AC) refers to the use of anaesthetic agents to mitigate IRI. AC is particularly associated with volatile anaesthetic (VA) agents and to a lesser extent to intravenous agents like propofol. VA like sevoflurane interferes with many of the processes underlying IRI and exerts renal protective properties in various models of injury and inflammation. We hypothesise that a sevoflurane-based anaesthesia is able to induce AC and thereby reduce post-transplant renal injury, reflected in improved graft and patient outcome, compared with a propofol-based anaesthesia in transplant recipients of a deceased donor kidney.Methods and analysisInvestigator-initiated, multicentre, randomised, controlled and prospective clinical trial with two parallel groups. The study will include 488 kidney transplant recipients from donation after brain death (DBD) or donation after circulatory death (DCD) donors. Participants are randomised in a 1:1 design to a sevoflurane (intervention) or propofol (control) group. The primary endpoint is the incidence of delayed graft function in recipients of DCD and DBD donor kidneys and/or 1-year biopsy-proven and treated acute rejection. Secondary endpoints include functional delayed graft function defined as failure of serum creatinine levels to decrease by at least 10% per day for three consecutive days; primary non-function is defined as a permanent lack of function of the allograft; length of hospital stay and postoperative complications of all kinds, estimated glomerular filtration rate at 1 week and 3 and 12 months calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula; readmissions at 3 and 12 months, graft survival and all-cause mortality at 12 months.Ethics and disseminationThe study is approved by the local ethical committees and national data security agencies. Results are expected to be published in 2025.Trial registration number NCT02727296.

Induction therapy reduces the frequency of acute rejection and delayed graft function. In this study in patients at high risk for acute rejection or delayed graft function who received a cadaveric renal transplant induction therapy with rabbit antithymocyte globulin reduced the incidence and severity of acute rejection, but not the incidence of delayed graft function, as compared with a monoclonal interleukin-2 receptor antibody. Patient and graft survival were similar in the two groups. In patients at high risk for acute rejection or delayed graft function who received a cadaveric renal transplant, induction therapy with rabbit antithymocyte globulin reduced the incidence and severity of acute rejection, but not the incidence of delayed graft function, as compared with basiliximab. Two events occurring early in the post-transplantation period, acute rejection and delayed graft function, negatively affect graft survival. 1 – 3 Patients with delayed graft function have an increased risk of acute rejection, and graft survival is superior in patients who do not have delayed graft function or acute rejection as compared with those who have either or both. 4 – 7 The up-regulation of immunogenic molecules during brain death and during the subsequent procurement of organs predisposes allografts from deceased donors to acute rejection and delayed function. Induction therapy is specific therapy given at the time of transplantation to lower the incidence of . . .

Background Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. Methods/design EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N  = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5–25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. Discussion The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique ‘cytotopic’ property that permits its retention in the organ microvasculature. Trial registration ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.

Hypothermic oxygenated machine perfusion (HOPE) was recently tested in preclinical trials in kidney transplantation (KT). Here we investigate the effects of HOPE on extended-criteria-donation (ECD) kidney allografts (KA). Fifteen ECD-KA were submitted to 152 ± 92 min of end-ischemic HOPE and were compared to a matched group undergoing conventional-cold-storage (CCS) KT (n = 30). Primary (delayed graft function-DGF) and secondary (e.g. postoperative complications, perfusion parameters) endpoints were analyzed within 6-months follow-up. There was no difference in the development of DGF between the HOPE and CCS groups (53% vs. 33%, respectively; p = 0.197). Serum urea was lower following HOPE compared to CCS (p = 0.003), whereas the CCS group displayed lower serum creatinine and higher eGFR rates on postoperative days (POD) 7 and 14. The relative decrease of renal vascular resistance (RR) following HOPE showed a significant inverse association with serum creatinine on POD1 (r = − 0.682; p = 0.006) as well as with serum urea and eGFR. Besides, the relative RR decrease was more prominent in KA with primary function when compared to KA with DGF (p = 0.013). Here we provide clinical evidence on HOPE in ECD-KT after brain death donation. Relative RR may be a useful predictive marker for KA function. Further validation in randomized controlled trials is warranted. Trial registration: clinicaltrials.gov (NCT03378817, Date of first registration: 20/12/2017).

Delayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown. To investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant. This single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population. Patients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 μg/kg/h intraoperatively and 0.1 μg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine. The primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30. Of the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit. This randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants. Chinese Clinical Trial Registry Identifier: ChiCTR1900025493.

BackgroundUp to 50% of kidney transplant patients are diagnosed with delayed graft function (DGF) following transplantation—the majority being linked to ischaemia reperfusion injury (IRI). DGF is traditionally defined as the requirement for dialysis during the first week after transplantation and is associated with inferior graft and patient outcomes. Local synthesis of complement components, largely by the renal tubule, plays a critical role in IRI. We have developed Mirococept, a membrane-targeted complement inhibitor, that can be administered to the donor kidney ex vivo prior to transplantation. After administration, Mirococept is retained in the donor organ, thereby minimising the risk of systemic side effects. We previously launched the EMPIRIKAL study aiming to evaluate the efficacy of Mirococept in reducing DGF in deceased-donor kidney transplantation (KT). The funding body recommended termination of the study to allow a dose-saturating study before the next stage of clinical evaluation. This was carried out in a porcine kidney model and led to a revised dosing regimen for EMPIRIKAL-2 (60–180 mg compared with 5–25 mg in the initial trial). The EMPIRIKAL-2 trial (REC 24/NE/0071) aims to identify the most safe and efficacious dose of Mirococept to reduce DGF rate in deceased-donor KT.Methods and analysisEMPIRIKAL-2 is a Phase IIa multicentre double-blind randomised controlled trial (RCT) with an initial safety run. Participants will be recruited from renal departments at National Health Service tertiary hospital sites in the UK. The purpose of the safety run is to assess the tolerance of each of the three proposed Mirococept doses (60, 120 or 180 mg), before the RCT begins. Three patients will be assigned to each treatment dose, starting from the lower dose. The safety run will be considered successful if at least one dose can be taken forward to the RCT for comparison to placebo.If safety is met, 144 participants (36 per arm excluding drop-outs) will be randomised to all doses meeting the safety criteria or placebo on a 1:1:1:1 basis. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. Enrolment in the RCT is anticipated to take approximately 12 months, and patients will be followed-up for 12 months.Ethics and disseminationThe study has been approved by the Northeast - Newcastle and North Tyneside 2 Research Ethics Service Committee, REC reference 24/NE/0071. The results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals. Once published, a lay summary of the results will be made available to participants who request this information.Trial registration number ISRCTN14279222. Registered on 4 July 2024.Protocol version2.0 dated 9 May 2024.

The use of intraoperative diuretics, such as furosemide or mannitol, during kidney transplantation has been suggested to reduce the rate of delayed graft function (DGF). The evidence base for this is sparse, however, and there is substantial variation in practice. We sought to evaluate whether the use of intraoperative diuretics during kidney transplantation translated into a reduction in DGF. We conducted a cohort study evaluating the use of furosemide or mannitol given intraoperatively before kidney reperfusion compared with control (no diuretic). Adult patients receiving a kidney transplant for end-stage renal disease were allocated to receive furosemide, mannitol, or no diuretic. The primary outcome was DGF; secondary outcomes were graft function at 30 days and perioperative changes in potassium levels. Descriptive and comparative statistics were used where appropriate. A total of 162 patients who received a kidney transplant from a deceased donor (either donation after neurologic determination of death or donation after circulatory death) were included over a 2-year period, with no significant between-group differences. There was no significant difference in DGF rates between the furosemide, mannitol, and control groups. When the furosemide and mannitol groups were pooled (any diuretic use) and compared with the control group, however, there was a significant improvement in the odds that patients would be free of DGF (odds ratio 2.10, 95% confidence interval 1.06-4.16, 26% v. 44%, = 0.03). There were no significant differences noted in any secondary outcomes. This study suggests the use of an intraoperative diuretic (furosemide or mannitol) may result in a reduction in DGF in patients undergoing kidney transplantation. Further study in the form of a randomized controlled trial is warranted.

IntroductionThe introduction of perfusion technologies in kidney transplantation has the potential to improve graft function and survival and increase utilisation. Our previous work demonstrated that kidneys with an enhanced inflammatory and immune response during normothermic machine perfusion (NMP) had significant graft dysfunction after transplantation. The addition of a cytokine filter (CytoSorb) to the NMP circuit dramatically reduces both circulating inflammatory mediators and inflammatory gene expression, but this has not been trialled in clinical practice.Methods and analysisThis is a randomised phase 1 pilot study to evaluate the safety and feasibility of using a CytoSorb filter in clinical NMP to remove inflammatory and immune mediators. Eligible kidney transplant recipients on the waiting list in the East of England will be approached for consent. A total of 20 patients will be recruited and randomised in a 1:1 ratio for the donor kidney to receive either NMP or NMP with a CytoSorb filter pre-transplantation. The kidney will be transplanted according to standard practice after NMP. The primary endpoint is inflammatory and immune gene expression measured in a cortical biopsy from the kidney 60 min post-transplant. Secondary endpoints include rates and duration of delayed graft function and graft function as assessed by change in creatinine clearance and estimated glomerular filtration rate 2 days, 5 days, 1 month and 3 months post-transplant. Additionally, inflammatory mediators and injury markers will be measured in peripheral blood and urine samples taken pre-operatively and on days 2 and 5 after transplant.Ethics and disseminationThis study has been approved by the Health Research Authority Health and Care Research Wales Committee (REC 23/WM/0141) and by National Health Service (NHS) Blood and Transplant (Ref: Study 148). Findings will be published in a peer-reviewed journal and disseminated at scientific conferences. The dataset will be made available on request.Trial registrationThe study is prospectively registered on the ISCRTN registry (ID: 13698207).