Marginal kidney graft preservation in machine perfusion (MP) is well-established. However, this method requires improvement in order to mitigate oxidative stress during ischemia-reperfusion, by using ...oxygenation or an O
carrier with anti-oxidant capacities (hemoglobin of the marine worm; M101). In our preclinical porcine (pig related) model, kidneys were submitted to 1h-warm ischemia, followed by 23 h hypothermic preservation in Waves
MP before auto-transplantation. Four groups were studied: W (MP without 100%-O2), W-O
(MP with 100%-O2; also called hyperoxia), W-M101 (MP without 100%-O2 + M101 2 g/L), W-O
+ M101 (MP with 100%-O2 + M101 2 g/L) (
= 6/group). Results: Kidneys preserved in the W-M101 group showed lower resistance, compared to our W group. During the first week post-transplantation, W-O
and W-M101 groups showed a lower blood creatinine and better glomerular filtration rate. KIM-1 and IL-18 blood levels were lower in the W-M101 group, while blood levels of AST and NGAL were lower in groups with 100% O2. Three months after transplantation, fractional excretion of sodium and the proteinuria/creatinuria ratio remained higher in the W group, creatininemia was lower in the W-M101 group, and kidney fibrosis was lower in M101 groups. We concluded that supplementation with M101 associated with or without 100% O2 improved the Waves
MP effect upon kidney recovery and late graft outcome.
The use of donors deceased after brain death (DBD) with extended criteria in response to the shortage of grafts leads to the removal of more fragile kidneys. These grafts are at greater risk of not ...being grafted or delayed function. A better knowledge of the pathophysiology of DBDs would improve this situation. There is a difference between the results from animal models of DBD and the clinical data potentially explained by the kinetics of brain death induction. We compared the effect of the induction rate of brain death on the recovery of post-transplant renal function in a pig model of DBD followed by allografts in nephrectomized pigs. Resumption of early function post-transplant was better in the rapidly generated brain death group (RgBD) and graft fibrosis at three months less important. Two groups had identical oxidative stress intensity but a greater response to this oxidative stress by SIRT1, PGC1-α and NRF2 in the RgBD group. Modulation of mechanistic target of rapamycin (mTOR) stimulation by NRF2 would also regulate the survival/apoptosis balance of renal cells. For the first time we have shown that an allostatic response to oxidative stress can explain the impact of the rapidity of brain death induction on the quality of kidney transplants.
The eIF5A hypusination inhibitor GC7 (N1‐guanyl‐1,7‐diaminoheptane) was shown to protect from ischemic injuries. We hypothesized that GC7 could be useful for preconditioning kidneys from donors ...before transplantation. Using a preclinical porcine brain death (BD) donation model, we carried out in vivo evaluation of GC7 pretreatment (3 mg/kg iv, 5 minutes after BD) at the beginning of the 4h‐donor management, after which kidneys were collected and cold‐stored (18h in University of Wisconsin solution) and 1 was allotransplanted. Groups were defined as following (n = 6 per group): healthy (CTL), untreated BD (Vehicle), and GC7‐treated BD (Vehicle + GC7). At the end of 4h‐management, GC7 treatment decreased BD‐induced markers, as radical oxygen species markers. In addition, GC7 increased expression of mitochondrial protective peroxisome proliferator‐activated receptor‐gamma coactivator‐1‐alpha (PGC1α) and antioxidant proteins (superoxyde‐dismutase‐2, heme oxygenase‐1, nuclear factor erythroid‐derived 2‐like 2 NRF2, and sirtuins). At the end of cold storage, GC7 treatment induced an increase of NRF2 and PGC1α mRNA and a better mitochondrial integrity/homeostasis with a decrease of dynamin‐ related protein‐1 activation and increase of mitofusin‐2. Moreover, GC7 treatment significantly improved kidney outcome during 90 days follow‐up after transplantation (fewer creatininemia and fibrosis). Overall, GC7 treatment was shown to be protective for kidneys against BD‐induced injuries during donor management and subsequently appeared to preserve antioxidant defenses and mitochondria homeostasis; these protective effects being accompanied by a better transplantation outcome.
In a porcine kidney transplant model, treatment with an intravenous bolus of a polyamine analog initiated shortly after brain death improved not only antioxidant, mitochondrial, and cellular protective pathways prior to transplantation but also kidney function after transplantation. Schnieke et al.'s editorial is on page 3275.
We describe a 55-year-old woman with extensive digestive resection and recurrent depressive disorder resistant to oral clomipramine tablets but not to an oral solution of amitriptyline. In the light ...of this case report, the potential mechanisms of drug resistance after digestive resection are discussed, including the importance of drug monitoring.
Facing the organizational and technological complexity of nuclear infrastructures (NI), the public reluctance in nuclear technology and the increasing restrictive regulatory environment, improving ...the conceptualization and evaluation of NI architecture is crucial for the successful completion of NI projects. Indeed, many technical engineering difficulties or delays in delivery can be avoided by deepening the design and evaluation of NI architectures. In a context where model‐based systems engineering (MBSE) is becoming more and more relevant, it is interesting to integrate evaluation into this process. Although the architecture evaluation (AE) process is rather well defined in the literature and linked to system analysis practices, it is quite difficult to deploy and pilot within complex NI projects. This article proposes a model‐based method, EVAluation for Critical Infrastructure Model Based System Engineering (EVA‐CIME), to facilitate the deployment of AE processes on a project. The components of this method are described and illustrated in a study of a NI design. The benefits and limitations of EVA‐CIME in its state of development are discussed and lead to the conclusion that the method should be extended to foster an AE culture within the company itself.
Kidneys from donation after circulatory death (DCD) are highly sensitive to ischemia‐reperfusion injury and thus require careful reconditioning, such as normothermic regional perfusion (NRP). ...However, the optimal NRP protocol remains to be characterized. NRP was modeled in a DCD porcine model (30 minutes of cardiac arrest) for 2, 4, or 6 hours compared to a control group (No‐NRP); kidneys were machine‐preserved and allotransplanted. NRP appeared to permit recovery from warm ischemia, possibly due to an increased expression of HIF1α‐dependent survival pathway. At 2 hours, blood levels of ischemic injury biomarkers increased: creatinine, lactate/pyruvate ratio, LDH, AST, NGAL, KIM‐1, CD40 ligand, and soluble‐tissue‐factor. All these markers then decreased with time; however, AST, NGAL, and KIM‐1 increased again at 6 hours. Hemoglobin and platelets decreased at 6 hours, after which the procedure became difficult to maintain. Regarding inflammation, active tissue‐factor, cleaved PAR‐2 and MCP‐1 increased by 4‐6 hours, but not TNF‐α and iNOS. Compared to No‐NRP, NRP kidneys showed lower resistance during hypothermic machine perfusion (HMP), likely associated with pe‐NRP eNOS activation. Kidneys transplanted after 4 and 6 hours of NRP showed better function and outcome, compared to No‐NRP. In conclusion, our results confirm the mechanistic benefits of NRP and highlight 4 hours as its optimal duration, after which injury markers appear.
The authors report a preclinical porcine model for normothermic regional perfusion in the kidney donor used to specify the mechanisms involved and to optimize the duration of the procedure.
Mass flow controllers are complex mechatronic devices, the design of which involves many techniques and skills in various scientific domains. Due to the slow response time of the sensors embedded in ...such devices, it is critically important to control gas flow variations in processes used in semiconductor industry. This paper shows how a digital controller for MFCs can be mathematically computed once the dynamic characteristics of the open-loop system have been identified. The proposed control method goes beyond prior art control methods as it explicitly takes into account the dynamics of the sensor, computes the digital controller appropriate to the order of the open-loop model and imposes a desired closed-loop transient response. The simulations performed and experimental results obtained with this new type of digital controller were very promising.
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