Kidney transplantation with grafts procured after donation-after-cardiac death (DCD) has led to an increase in incidence of delayed graft function (DGF). It is thought that the warm ischemic (WI) insult encountered during DCD procurement is the cause of this finding, although few studies have been designed to definitely demonstrate this causation in a transplantation setting. Here, we use a large animal renal transplantation model to study the effects of prolonged WI during procurement on post-transplantation renal function. Kidneys from 30 kg-Yorkshire pigs were procured following increasing WI times of 0 min (Heart-Beating Donor), 30 min, 60 min, 90 min, and 120 min (n = 3–6 per group) to mimic DCD. Following 8 h of static cold storage and autotransplantation, animals were followed for 7-days. Significant renal dysfunction (SRD), resembling clinical DGF, was defined as the development of oliguria   6.0 mmol/L. Increasing WI times resulted in incremental elevation of post-operative serum creatinine that peaked later. DCD120min grafts had the highest and latest elevation of serum creatinine compared to all groups (POD5: 19.0 ± 1.1 mg/dL, p   500 mL and POD7 serum potassium < 6.0 mmol/L distinguishing this state from primary non-function. In a transplantation survival model, this work demonstrates that prolonging WI time similar to that which occurs in DCD conditions contributes to the development of SRD that resembles clinical DGF.

/pdf/prolonged-warm-ischemia-time-leads-to-severe-renal-11iw8vdow3.pdf

Prolonged warm ischemia time leads to severe renal dysfunction of donation-after-cardiac death kidney grafts.

Therapies that would accelerate recovery from ischemic injury could positively impact the number of kidneys procured from non-heart-beating donors. An acellular warm (32 degrees C) perfusion was used to deliver growth factors to canine kidneys damaged by 2 hours of warm ischemia. Fibroblast growth factors 1 and 2 were selected for activation of the tyrosine kinases because of their known receptor-specific binding in the kidney, metabolic regulation, and mitogenic effect. During 24 hours of ex vivo perfusion at near-normothermia, oxidative metabolism was sufficiently restored to the ischemically damaged tissue to support upregulation of cellular processes dependent on new synthesis. The junctional integrity protein, ZO-1 was used to determine recovery of cytoskeletal integrity. The upregulation of proliferating cell nuclear antigen was used as a marker for recovery of synthetic functions. This modulation of both injury and repair proteins in the damaged kidneys was dependent on new synthesis. The observed modulation resulting in normalization of the cytoskeletal integrity correlated with outcomes in that when the "repaired" kidneys were reimplanted, they provided life-sustaining function. In contrast, when warm ischemically damaged control kidneys without treatment, with subsequent hypothermic perfusion or warm perfused in the absence of growth factors, were reimplanted the result was nonviability. The results of this study suggest that the administration of growth factors during 24 hours of near-normothermic, acellular perfusion, in the absence of concordant inflammation, triggers pathways for new synthesis leading to cellular recovery rather than resulting in cell death.

Potential of repairing ischemically damaged kidneys ex vivo

Background Mesenchymal stromal cell (MSC) therapy may improve renal function after ischemia-reperfusion injury in transplantation. Ex vivo renal intraarterial administration is a targeted delivery method, avoiding the lung vasculature, a known barrier for cellular therapies. In a randomized and blinded study, we tested the feasibility and effectiveness of MSC therapy in a donation after circulatory death autotransplantation model to improve posttransplant kidney function, using an ex vivo MSC delivery method similar to the clinical standard procedure of pretransplant cold graft flush. Methods Kidneys exposed to 75 minutes of warm ischemia and 16 hours of static cold storage were intraarterially infused ex vivo with 10 million male porcine MSCs (Tx-MSC, n = 8) or vehicle (Tx-control, n = 8). Afterwards, the kidneys were autotransplanted after contralateral nephrectomy. Biopsies an hour after reperfusion confirmed the presence of MSCs in the renal cortex. Animals were observed for 14 days. Results Postoperatively, peak plasma creatinine was 1230 and 1274 µmol/L (Tx-controls versus Tx-MSC, P = 0.69). During follow-up, no significant differences over time were detected between groups regarding plasma creatinine, plasma neutrophil gelatinase-associated lipocalin, or urine neutrophil gelatinase-associated lipocalin/creatinine ratio. At day 14, measured glomerular filtration rates were 40 and 44 mL/min, P = 0.66. Renal collagen content and fibrosis-related mRNA expression were increased in both groups but without significant differences between the groups. Conclusions We demonstrated intraarterial MSC infusion to transplant kidneys as a safe and effective method to deliver MSCs to the graft. However, we could not detect any positive effects of this cell treatment within 14 days of observation.

/pdf/ex-vivo-administration-of-mesenchymal-stromal-cells-in-22zx2gniu0.pdf

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

At present, it is widely recognized that machine perfusion allows for a decreased rate of delayed function of the renal graft and of the risk of liver graft early dysfunction. The aim of the review is to present the actual changes of  the donor pool related to prevailing numbers of donors by expanded criteria, to determine the prospects of  expanding of the available donor pool based on their selection, as well as development of functional rehabilitation and modification at tissue, cell and molecular levels with the help of perfusion technologies. The article presents  the state-of-the art view on the mechanisms of ischemic-reperfusion injury of donor organs, delineates the trends  in the maintenance of their viability, and gives the literature data on the role and outlook of perfusion methods in  organ transplantation. The authors provide the rationale for a comprehensive systemic approach to the assessment of the functional status of a donor organ with any baseline parameters and discuss a number of theoretical provisions on the implementation of a personalized perfusion approach to ensure the availability of transplantation care.

/pdf/sokhranenie-i-perfuzionnaia-reabilitatsiia-donorskikh-4ptkvdw0ox.pdf

Сохранение и перфузионная реабилитация донорских органов: достижения последнего десятилетия

La transplantation est la meilleure alternative en cas d'insuffisance renale terminale. Face a la penurie de greffons, les equipes de transplantation se sont tournees notamment vers les donneurs decedes par arret circulatoire (DDAC) non controles. Ces greffons soumis a une periode d'ischemie chaude sont plus fragiles. Des methodes de reconditionnement chez le donneur par refroidissement in situ (RIS) et circulation regionale normothermique (CRN) se sont developpees afin de reduire les lesions d'ischemie-reperfusion. Le choix de la methode est laisse a l'appreciation de chaque equipe et il existe une grande heterogeneite des pratiques. Apres prelevement, l'utilisation des machines de perfusion hypothermique (MPH) est generalement recommandee. L'optimisation de ces phases de reconditionnement chez le donneur et de conservation hypothermique apparait comme un enjeu majeur de sante publique. Concernant l'optimisation du mode de reconditionnement, la mise au point d'un modele preclinique porcin parfaitement reproductible a permis de mettre en evidence une superiorite de la CRN sur le RIS. Une duree de CRN de 4 heures minimum sans depasser 6 heures parait optimale. Concernant la conservation hypothermique, les MPH permettent le maintien du niveau d'expression des genes retrouve en fin de CRN. L'ajout d'une oxygenation active en MPH ou de curcumine en solution statique ameliore le devenir du greffon a court et long termes dans un modele preclinique d'autogreffe. Ce travail pourrait s'etendre a l'etude d'autres organes, d'autres durees d'ischemie chaude et aux DDAC controles afin d'elargir encore le nombre d'organes eligibles a la transplantation.

https://tel.archives-ouvertes.fr/tel-02147081/document

Greffons rénaux issus des donneurs décédés par arrêt circulatoire : optimisation du reconditionnement chez le donneur et de la conservation hypothermique

Donation from uncontrolled circulatory determination of death donors (uDCD) is impractical in United States 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. Nonanticoagulated uDCD sustained 60 min of WIT, and two groups were studied. Rapid recovery (RR)-uDCD renal grafts procured using the standard quick topical cooling and renal flush, and ECS-assisted donation (E-uDCD), 4 hr ECS plus thrombolytics for in situ perfusion before 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 more than 5.0 mg/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 48 hr, but two grafts (16.7%) had DGF at 96 hr. All six recipients from RR-uDCD group had DGF at 48 hr and were killed. Creatinine and blood urea nitrogen (BUN) levels were significantly lower in E-uDCD compared with RR-uDCD group at 24 hr (2.9 ± 0.7 mg/dl vs. 5.2 ± 0.9 mg/dl) and 48 hr (3.2 ± 0.9 mg/dl vs. 7.2 ± 1.0 mg/dl); BUN levels at 24 and 48 hr were 28.3 ± 6.7 mg/dl vs. 39.5 ± 7.5 mg/dl and 23.9 ± 5.0 mg/dl vs. 46 ± 12.9 mg/dl, respectively. Thrombolytics plus ECS precondition organs in situ yielding functional kidneys in a porcine model of uDCD with 60 min of WIT. This procurement method addresses logistical limitations for uDCD use in the United States and could have a major impact on the organ donor pool.

/pdf/successful-porcine-renal-transplantation-after-60-minutes-of-36416bhdi8.pdf

Successful Porcine Renal Transplantation After 60 Minutes of Donor Warm Ischemia: Extracorporeal Perfusion and Thrombolytics

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Successful Porcine Renal Transplantation After 60 Minutes of Donor Warm Ischemia: Extracorporeal Perfusion and Thrombolytics