Delayed graft function is a frequent complication following deceased donor renal transplantation, and is closely related to ischemia-reperfusion injury. Experimental and clinical studies have shown protection by remote ischemic conditioning (RIC). We hypothesized that recipient RIC before kidney graft reperfusion reduces the time to graft recovery. This multicenter, blinded, randomized, controlled clinical trial included 225 adult recipients of renal transplants from deceased donors at four transplantation centers in Denmark, Sweden, and the Netherlands. Participants were randomized 1:1 to RIC or sham-RIC. RIC consisted of 4 × 5-min thigh occlusion by an inflatable tourniquet each followed by 5-min deflation, performed during surgery prior to graft reperfusion. The tourniquet remained deflated for sham-RIC. The primary endpoint was the estimated time to a 50% decrease in baseline plasma creatinine (tCr50) calculated from plasma creatinine measurements 30 days posttransplant or 30 days after the last, posttransplant dialysis. No significant differences were observed between RIC and sham-RIC-treated patients in the primary outcome median tCr50 (122 h [95% confidence interval [CI] 98-151] vs. 112 h [95% CI 91-139], p = 0.58), or the number of patients receiving dialysis in the first posttransplant week (33% vs. 35%, p = 0.71). Recipient RIC does not reduce the time to graft recovery in kidney transplantation from deceased donors. ClinicalTrials.gov: NCT01395719.

Summary Delayed graft function (DGF) complicates approximately 25% of kidney allografts donated after brain death (DBD). Remote ischaemic conditioning (rIC) involves brief, repetitive, ischaemia in a distant tissue in connection with ischaemia/reperfusion in the target organ. rIC has been shown to induce systemic protection against ischaemic injuries. Using a porcine kidney transplantation model with donor (63 kg) recipient (15 kg) size mismatch, we investigated the effects of recipient rIC on early renal plasma perfusion and GFR. Brain death was induced in donor pigs (n = 8) and kidneys were removed and kept in cold storage until transplantation. Nephrectomized recipient pigs were randomized to rIC (n = 8) or non‐rIC (n = 8) with one kidney from the same donor in each group. rIC consisted of 4 × 5 min clamping of the abdominal aorta. GFR was significantly higher in the rIC group compared with non‐rIC (7.2 ml/min vs. 3.4 ml/min; ΔGFR = 3.7 ml/min, 95%‐CI: 0.3–7.2 ml/min, P = 0.038). Renal plasma perfusion in both cortex and medulla measured by dynamic contrast‐enhanced magnetic resonance imaging (MRI) was significantly higher over time in the rIC group compared with non‐rIC. This experimental study demonstrated a positive effect of rIC on early graft perfusion and function in a large animal transplantation model.

Normothermic machine perfusion (NMP) of injured kidneys offers the opportunity for interventions to metabolically active organs prior to transplantation. Mesenchymal stromal cells (MSCs) can exert regenerative and anti‐inflammatory effects in ischemia‐reperfusion injury. The aims of this study were to evaluate the safety and feasibility of MSC treatment of kidneys during NMP using a porcine autotransplantation model, and examine potential MSC treatment‐associated kidney improvements up to 14 days posttransplant. After 75 min of kidney warm ischemia, four experimental groups of n = 7 underwent 14 h of oxygenated hypothermic machine perfusion. In three groups this was followed by 240 min of NMP with infusion of vehicle, 10 million porcine, or 10 million human adipose‐derived MSCs. All kidneys were autotransplanted after contralateral nephrectomy. MSC treatment did not affect perfusion hemodynamics during NMP or cause adverse effects at reperfusion, with 100% animal survival. MSCs did not affect plasma creatinine, glomerular filtration rate, neutrophil gelatinase‐associated lipocalin concentrations or kidney damage assessed by histology during the 14 days, and MSCs retention was demonstrated in renal cortex. Infusing MSCs during ex vivo NMP of porcine kidneys was safe and feasible. Within the short posttransplant follow‐up period, no beneficial effects of ex vivo MSC therapy could be demonstrated.

Background.This pilot study aimed to maintain acceptable animal welfare in the development of a porcine autotransplantation model with severe and incremental renal ischemic injury, a model for usage in future intervention studies. Secondary aims were to develop and test methods to collect blood and urine without the need to restrain or use sedative and avoid transportation to optimize welfare of the pig.Methods.Kidneys from 7 female pigs were subjected to incremental durations of warm ischemia (WI) 30, 45, or 75 minutes by left renal artery and vein clamping. After static cold storage, contralateral nephrectomy was performed, and the injured graft was autotransplanted and animals observed for 14 days. Animal welfare was assessed and recorded using a structured scoring sheet before and 4 days after the kidney autotransplantation. Furthermore, blood samples were drawn daily the first week and every second day the following week using a semi-central venous catheter. An ostomy bag around the genitals was tested for urine collection. Measured glomerular filtration rate was calculated using renal clearance of chromium-51-labeled ethylenediamine tetraacetic acid on day 14.Results.None of the 7 animals died during the follow-up. The animal welfare was moderately affected when applying 75 minutes of WI (n = 2), and for that reason WI was not further increased. Pigs with lower WI had no observed welfare issues. With 75 minutes of WI peak, plasma creatinine was 1486 and 1317 µmol/L, reached on day 4. Lowest glomerular filtration rate levels were observed in the pigs with 75 minutes of WI.Conclusions.WI up to 75 minutes caused the intended severely impaired renal function without significantly compromising animal welfare. Blood and urine was collected postoperatively without sedation of the pigs or use of a metabolic cage.

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