Successful Porcine Renal Transplantation After 60 Minutes of Donor Warm Ischemia

Abstract

Donation from uncontrolled circulatory determination of death donors (uDCD) is impractical in America because of the time needed to organize procurement before irreversible organ damage. Salvaging organs after prolonged warm ischemic time (WIT) may address this limitation. We evaluated the combination of extracorporeal support (ECS) and thrombolytics in a porcine uDCD renal transplant model. Non anti-coagulated uDCD sustained 60min of WIT, and two groups were studied. Rapid recovery (RR-uDCD), kidneys procured using rapid topical cooling; and ECS assisted donation (E-uDCD), 4hr ECS plus thrombolytics for in-situ perfusion prior to procurement. All kidneys were flushed and cold stored, followed by transplantation into healthy nephrectomized recipients without immunosuppression. Delayed graft function (DGF) was defined as creatinine>5.0mg/dL on any postoperative day. Twelve kidneys in E-uDCD and 6 in RR-uDCD group were transplanted. All 12 E-uDCD recipients had urine production and adequate function in the first 48hr, but two grafts (16.7%) had DGF at 96hr. All 6 recipients from RR-uDCD group had DGF at 48hr and were euthanized. Creatinine and BUN levels were significantly lower in E-uDCD compared to RR-uDCD group at 24hr (2.9±0.7mg/dL vs. 5.2±0.9mg/dL), and 48hr (3.2±0.9mg/dL vs. 7.2±1.0mg/dl); BUN levels at 24hr, (28.3±6.7mg/dL vs. 39.5±7.5mg/dL), and 48hr (23.9±5.0mg/dL vs. 46±12.9mg/dL) respectively. ECS plus thrombolytics precondition organs in-situ yielding functional kidneys in a porcine model of uDCD with 60 minutes of WIT. This procurement method addresses logistical limitations for uDCD use in the US, and could have a major impact on the organ donor pool.

A Pilot Study of Postoperative Animal Welfare as a Guidance Tool in the Development of a Kidney Autotransplantation Model With Extended Warm Ischemia

“…This pilot optimization study was not powered to get significant results, but the expected trend toward increasing plasma creatinine and decreased GFR was seen with prolonged WI duration. In some previous studies using ischemically injured grafts, the WI has been shorter, mainly between 20 and 60 minutes, resulting in a lower peak plasma creatinine, 2,13,14,16,17 whereas other experimental transplantation studies have applied >75 minutes of WI, which on the other hand had mortality rates of 17% 46 and 50% 47 (90-minute WI), and 67% 46 (120-minute WI) in their untreated control groups. It is a delicate balance to ensure adequate injury while ensuring acceptable animal welfare and avoiding high mortality.…”

“…Our decline of plasma creatinine after 9–14 days is a limitation of the porcine model in general and is consistent with previous studies. 2,11,13-17 In addition, it is well known that removal of 1 kidney will stimulate an increase of renal perfusion and GFR with compensatory growth of the remaining kidney. 48 A 1-kidney GFR of 38 and 40 mL/min is below normal range for this size of pigs and represents a state of renal damage when compared with older studies.…”

First Russian experience in liver and kidney transplantation from donors with out-of-hospital cardiac arrest: 3 years’ results

“…Несмотря на неоднократные эксперименты на животных, в которых была показана эффективность использования тромболитиков, а также наш клинический опыт применения тромболитиков (Стрептокиназы, Альтеплазы) при абдоминальной нормотермической перфузии in situ, в настоящее время отсутствуют сообщения о включении данной группы препаратов в протоколы работы с «внегоспитальными» донорами [6,49,50]. Такая же ситуация наблюдается и с применением механической и фармакологической лейкоредукции в организме донора.…”

Ex Vivo Administration of Mesenchymal Stromal Cells in Kidney Grafts Against Ischemia-reperfusion Injury—Effective Delivery Without Kidney Function Improvement Posttransplant

“…40 The pigs studied were younger and more healthy than most human DCD donors with better healing potential. Like in other studies, [44][45][46][47] we intended to cure serious IRI with a maximum of translationality. 27 Similar to the present study, several preclinical and clinical studies make use of allogeneic MSCs.…”