Ex vivo normothermic perfusion (EVNP) is a novel method of preservation that restores circulation and allows an organ to regain function prior to transplantation. The aim of this study was to assess the effects of EVNP in kidneys from marginal donors. Eighteen kidneys from extended criteria donors (ECD) underwent a period of EVNP immediately before transplantation. Kidneys were perfused with a plasma free redcell based solution at a mean temperature of 34.6• C. The outcome of these kidneys was compared to a control group of 47 ECD kidneys that underwent static cold storage (CS). The mean donor age was 61 ± 1 years in the EVNP and 62 ± 6 years in the CS group (p = 0.520). EVNP kidneys were perfused for an average of 63 ± 16 min and all were transplanted successfully. The delayed graft function rate (DGF), defined as the requirement for dialysis within the first 7 days was 1/18 patients (5.6%) in the EVNP group versus 17/47 (36.2%) in the CS group (p = 0.014). There was no difference in graft or patient survival at 12 months (p = 0.510, 1.000). This first series of EVNP in renal transplantation demonstrates that this technique is both feasible and safe. Our preliminary data suggests that EVNP offers promise as a new technique of kidney preservation.

IntroductionEx vivo normothermic perfusion (EVNP) is a novel technique that reconditions the kidney and restores renal function prior to transplantation. Phase I data from a series of EVNP in extended criteria donor kidneys have established the safety and feasibility of the technique in clinical practice.Methods and analysisThis is a UK-based phase II multicentre randomised controlled trial to assess the efficacy of EVNP compared with the conventional static cold storage technique in donation after circulatory death (DCD) kidney transplantation. 400 patients receiving a kidney from a DCD donor (categories III and IV, controlled) will be recruited into the study. On arrival at the transplant centre, kidneys will be randomised to receive either EVNP (n=200) or remain in static cold storage (n=200). Kidneys undergoing EVNP will be perfused with an oxygenated packed red cell solution at near body temperature for 60 min prior to transplantation. The primary outcome measure will be determined by rates of delayed graft function (DGF) defined as the need for dialysis in the first week post-transplant. Secondary outcome measures include incidences of primary non-function, the duration of DGF, functional DGF defined as <10% fall in serum creatinine for 3 consecutive days in the first week post-transplant, creatinine reduction ratio days 2 and 5, length of hospital stay, rates of biopsy-proven acute rejection, serum creatinine and estimated glomerular filtration rate at 1, 3, 6 and 12 months post-transplant and patient and allograft survival. The EVNP assessment score will be recorded and the level of fibrosis and inflammation will also be measured using tissue, blood and urine samples. Ethics and dissemination. The study has been approved by the National Health Service (NHS) Health Research Authority Research Ethics Committee. The results are expected to be published in 2020.Trial registration numberISRCTN15821205; Pre-results.

We conclude that ex vivo normothermic kidney perfusion with a plasma-free red cell-based solution is a feasible method of preservation. This first case was performed without compromising the transplant kidney.

BackgroundA significant proportion of donation after circulatory death (DCD) kidneys are declined for transplantation because of concerns over their quality. Ex vivo normothermic machine perfusion (NMP) provides a unique opportunity to assess the quality of a kidney and determine its suitability for transplantation.MethodsIn phase 1 of this study, declined human DCD kidneys underwent NMP assessment for 60 min. Kidneys were graded 1–5 using a quality assessment score (QAS) based on macroscopic perfusion, renal blood flow and urine output during NMP. In phase 2 of the study, declined DCD kidneys were assessed by NMP with an intention to transplant them.ResultsIn phase 1, 18 of 42 DCD kidneys were declined owing to poor in situ perfusion. After NMP, 28 kidneys had a QAS of 1–3, and were considered suitable for transplantation. In phase 2, ten of 55 declined DCD kidneys underwent assessment by NMP. Eight kidneys had been declined because of poor in situ flushing in the donor and five of these were transplanted successfully. Four of the five kidneys had initial graft function.ConclusionNMP technology can be used to increase the number of DCD kidney transplants by assessing their quality before transplantation.

Ex vivo normothermic machine perfusion (NMP) is a new clinical strategy to assess and resuscitate organs likely to be declined for transplantation, thereby increasing the number of viable organs available. Short periods of NMP provide a window of opportunity to deliver therapeutics directly to the organ and, in particular, to the vascular endothelial cells (ECs) that constitute the first point of contact with the recipient’s immune system. ECs are the primary targets of both ischemia-reperfusion injury and damage from preformed antidonor antibodies, and reduction of perioperative EC injury could have long-term benefits by reducing the intensity of the host’s alloimmune response. Using NMP to administer therapeutics directly to the graft avoids many of the limitations associated with systemic drug delivery. We have previously shown that polymeric nanoparticles (NPs) can serve as depots for long-term drug release, but ensuring robust NP accumulation within a target cell type (graft ECs in this case) remains a fundamental challenge of nanomedicine. We show that surface conjugation of an anti-CD31 antibody enhances targeting of NPs to graft ECs of human kidneys undergoing NMP. Using a two-color quantitative microscopy approach, we demonstrate that targeting can enhance EC accumulation by about 5-to 10-fold or higher in discrete regions of the renal vasculature. In addition, our studies reveal that NPs can also non-specifically accumulate within obstructed regions of the vasculature that are poorly perfused. These quantitative preclinical human studies demonstrate the therapeutic potential for targeted nanomedicines delivered during ex vivo NMP.

Summary Kidney transplantation is limited by hypothermic preservation techniques. Prolonged periods of cold ischaemia increase the risk of early graft dysfunction and reduce long‐term survival. To extend the boundaries of transplantation and utilize kidneys from more marginal donors, improved methods of preservation are required. Normothermic perfusion restores energy levels in the kidney allowing renal function to be restored ex vivo. This has several advantages: cold ischaemic injury can be avoided or minimized, the kidney can be maintained in a stable state allowing close observation and assessment of viability and lastly, it provides the ideal opportunity to add therapies to directly manipulate and improve the condition of the kidney. This review explores the experimental and clinical evidence for ex vivo normothermic perfusion in kidney transplantation and its role in conditioning and repair.

The TAP block procedure is beneficial in reducing postoperative pain and early morphine requirements in laparoscopic live-donor nephrectomy.

EVNP combined with a simple scoring system is an innovative technology for pretransplant assessment of kidney quality and acceptability for transplantation. This study suggests that a high percentage of retrieved kidneys are being discarded unnecessarily.