Mesenchymal Stromal Cell Therapy for Solid Organ Transplantation.

Improvement of long term outcome of kidney transplantation has reached its limits, due to consequences of efficient, but nonspecific immunosuppressive drugs. Mesenchymal Stromal Cells (MSC) have been proposed as an alternative strategy for more refined therapy. The interest in MSCs comes from their antiinflammatory properties on the 1 hand and their propensity to ameliorate tissue damage and mediate repair on the other hand. First clinical trials have demonstrated that administration of MSCs in kidney transplant recipients is safe and feasible and follow-up studies have been initiated with the desired clinical efficacy to reduce ischemia reperfusion injury, to prevent/reverse acute transplant rejection, and to improve long-term transplant survival with minimization of immunosuppression. To further promote wider application of MSC in renal transplantation it is of importance to determine efficacy, to increase the understanding of the mechanism of action, and to develop tools to identify eligible patients. In addition, we should overcome challenges particularly at the transition of early phase I studies to more advanced stages of clinical development. In this review, latest insights, first clinical experiences and future challenges of MSC in solid organ transplantation are discussed. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Plasmatic villin 1 is a novel in vivo marker of proximal tubular cell injury during renal ischemia-reperfusion.

Background: Early detection of acute kidney injury (AKI), a common condition with a high mortality risk, can be facilitated by specific and reliable biomarkers. Villin 1, a protein typically found in the brush borders of proximal tubular cells, has been detected in urine of patients with AKI, but its possible release in plasma remains unexplored. Methods: We measured the presence of villin 1 by immunohistochemistry on kidney sections and by Western blotting in plasma samples from rats subjected to renal ischemia-reperfusion injury, pigs subjected to renal transplantation and liver transplantation patients that developed AKI. Moreover, rats were treated with necrostatin-1, an inhibitor of programmed necrosis (necroptosis), which occurs in renal tubular cells during AKI. Villin 1 levels were compared to other renal injury markers (creatinine, aspartate transaminase and heart-type fatty acid binding protein). Results: During AKI, plasmatic villin 1 levels corresponded with the severity of kidney injury and dysfunction. Its detection in plasma was associated with a redistribution in the kidney tissue. Unlike the levels of other markers, plasmatic villin 1 decreased already after a short (3 h) treatment with necrostatin-1 during renal ischemia-reperfusion injury. The presence of plasmatic villin 1 was confirmed in patients who experienced AKI after liver transplantation. Conclusions: Villin 1 is released in plasma during AKI and shows potential as an early marker for proximal tubular injury/necrosis and warrants further investigation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Alleviation of Ischemia-Reperfusion Injury in Liver Steatosis by Augmenter of Liver Regeneration (ALR) Is Attributed to Antioxidation and Preservation of Mitochondria.

Background: Fatty liver is 1 of the major impediments to liver surgery and liver transplantation because steatotic hepatocytes are more susceptible to ischemia-reperfusion injury (IRI). In this study, the effects of augmenter of liver regeneration (ALR) on hepatic IRI in steatotic mice were investigated. Methods: In vivo, liver steatosis of mice was induced by feeding a methionine-choline deficient diet for 2 weeks. Three days prior to hepatic partial warm IRI, mice were transfected with the ALR-containing adenovirus. In an in vitro study, the protective effect of ALR on steatotic HepG2 cells was analyzed after hypoxia/reoxygenation (HR) treatment. Results: The transfection of the ALR gene into steatotic mice attenuated liver injury, inhibiting hepatic oxidative stress, increasing antioxidation capacities, promoting liver regeneration, and consequently suppressing cell apoptosis/death. Furthermore, resistance to HR injury was notably increased in ALR transfected cells compared to the vector transfected cells. The HR induced rise in the mitochondrial ROS was reduced, and cellular antioxidant activities were enhanced. The ALR transfection prevented cells from apoptosis can be attributed to the preservation of the mitochondrial membrane potential, enhancement of oxygen consumption rate (OCR) and production of ATP. Conclusions: ALR protects steatotic hepatocytes from IRI by attenuating oxidative stress and mitochondrial dysfunction, as well as improving antioxidant effect. ALR may be used as a potential therapeutic agent when performing surgery and transplantation of steatotic liver. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors.

Background: Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure. Methods: Single center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR. Patients were evaluated at fixed time points before and after belatacept initiation. Primary outcome was incidence of acute cellular rejection (ACR). Secondary outcomes included incidence of infection, Chronic Lung Allograft Dysfunction (CLAD) progression, death, change in mean arterial pressure (MAP) and estimated glomerular filtration rate (eGFR). Results: Eleven LTRs received belatacept with a mean of 246 (91-1064) days of follow-up after conversion. Four were changed to belatacept for thrombotic thrombocytopenic purpura; 3 for posterior reversible encephalopathy syndrome; 2 for recurrent ACR; 1 for CLAD; and 1 for renal-sparing. ACR was not different before and after belatacpet (p=0.17). Mean eGFR was significantly higher postbelatacept (32.53 vs 45.26, p=0.04). Mean incidence of infections (24.4% vs 16.0%, p=0.55), and MAP (97.5 vs 92.1 p=0.38), were not different. Progression of CLAD occurred in 2 patients. At the end of follow-up, 7/11 patients were alive. Conclusions: Belatacept-based ISR appear to produce reasonable results in LTRs who fail CNI-based ISR. Larger prospective trials appear warranted in lung transplantation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Macromodeling of general linear systems under stochastic variations

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Eventveiligheid, een gedeelde verantwoordeijkheid? Visie van de Vlaamse en Brusselse korpschefs op PPS

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Acoustic positioning telemetry in reflective environments: a practical guidance for error analysis

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