Publications of François JOURET
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See detailImpact of mesenchymal stroll cells and/or everolimus on T-reg lymphocyte expansion in rats
Vandermeulen, Morgan ULiege; ERPICUM, Pauline ULiege; POMA, Laurence ULiege et al

Conference (2020, March 11)

Background: Mesenchymal stromal cells (MSC) are a promising cell-therapy in solid-organ transplantation, namely because of their immunomodulatory properties and positive impact on the expansion of T ... [more ▼]

Background: Mesenchymal stromal cells (MSC) are a promising cell-therapy in solid-organ transplantation, namely because of their immunomodulatory properties and positive impact on the expansion of T-regulator lymphocytes (Treg). The “optimal” immunosuppressive regimen to be associated with MSC has not been defined. Here, we aimed to evaluate the effects on Treg expansion of a single injection of MSC combined or not with everolimus in rats. Materials and methods: Twenty-four Lewis rats were randomly assigned to 4 groups (n=6 per group): MSC+Evero group, i.e. everolimus (0,25mg/kg/day, SC) from D0 to D14 and iv MSC (±1x106 cells) at D9; MSC group, i.e. placebo from D0 to D14 and iv MSC at D9; Evero group, i.e. everolimus from D0 to D14 and iv saline at D9; control group, i.e. placebo from D0 to D14 and iv saline at D9. T-reg blood levels were measured at D0-14-28 with flow cytometry analysis using anti-CD4,-CD25 and -FoxP3 antibodies. Results: In the two groups infused with MSC, Treg were significantly expanded at D14 and D28 (p<0.01), in comparison to D0. When compared to controls group, the “Evero” group showed a significant expansion of Treg levels at D14 but not at D28. In control, Treg levels did not significantly change compared to D0. Conclusion: A single iv MSC injection was efficient to expand T-reg blood levels. This effect was not altered by everolimus co-administration. Everolimus exposure alone promotes a transient T-reg expansion. Hence, everolimus may be regarded as a co-drug of choice in MSC-based therapy in solid-organ transplantion. [less ▲]

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See detailNouveautés thérapeutiques en Néphrologie : 10 ans d'avancées
BOVY, Christophe ULiege; DELANAYE, Pierre ULiege; JOURET, François ULiege et al

in Revue Médicale de Liège (2020), 75(5-6), 336-343

Chronic kidney disease (CKD) impairs the quality of life and increases the risk for cardiovascular morbimortality. Intensive research is conducted in order to slow down CKD development and progression ... [more ▼]

Chronic kidney disease (CKD) impairs the quality of life and increases the risk for cardiovascular morbimortality. Intensive research is conducted in order to slow down CKD development and progression. During the past decade, a better understanding of the pathophysiological mechanisms of glomerular diseases has highlighted the benefits of rituximab. Progresses have also been made in the understanding of the mechanisms of autosomal polycystic kidney disease, the most frequent inherited kidney disease. These observations led to the discovery and validation of tolvaptan, a blocker of the V2 receptor of the antidiuretic hormone as an innovative treatment. Type 2 diabetic disease is the leading cause worldwide of endstage kidney disease and dialysis. The development of new drugs, such as the gliflozins (inhibiting the sodium glucose reabsorption in the proximal tubule), has contributed to an improvement in the management of the cardiovascular and renal risks especially reducing congestive heart failure rate. Another important progress in nephrology since the beginning of the new century concerns a more precise estimation of the kidney function, which allows to better evaluate the slope of CKD progression and test the influence of different therapeutic approaches aiming at correcting anemia, hyperkalemia, metabolic acidosis and disturbances of calcium and phosphate. The present review summarizes all of these major advances in the field of CKD diagnosis and treatment, and envisions the future of nephrology for the next decade. [less ▲]

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See detailImplications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial.
Janssens, Peter; Jouret, François ULiege; Bammens, Bert et al

in Scientific Reports (2020), 10(1), 4294

It is unknown whether early diagnosis of autosomal dominant polycystic kidney disease (ADPKD) can enable earlier management and improve outcomes. We conducted a post hoc analysis of data from the TEMPO 3 ... [more ▼]

It is unknown whether early diagnosis of autosomal dominant polycystic kidney disease (ADPKD) can enable earlier management and improve outcomes. We conducted a post hoc analysis of data from the TEMPO 3:4 trial. Subjects were stratified by ADPKD diagnosis at age </=18 (childhood diagnosis [CD]) or>18 (adulthood diagnosis [AD]). Groups were compared for baseline characteristics and total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline over 3 years. 294 CD and 1148 AD subjects were analyzed. At inclusion, CD subjects were younger (mean age 34.2 versus 39.8 years; p < 0.0001) and had better eGFR (mean +/- SD 87.4 +/- 23.9 versus 80.1 +/- 20.7 mL/min/1.73 m(2); p < 0.0001), while CD had more severe Mayo risk classification (p < 0.0001) and more PKD1 mutations (p = 0.003). No statistical differences were found in TKV or eGFR change. At study end, placebo-treated CD subjects had better eGFR than projected by a prediction equation (mean difference +/-SD for observed versus predicted eGFR: 2.18 +/- 10.7 mL/min/1.73 m(2); p = 0.0475). However, these results are not confirmed when excluding stage 1 CKD. Whether CD subjects, despite their risk profile, have a slower disease course than predicted remains inconclusive. Future studies are needed to confirm that early diagnosis and management can alter the disease course of ADPKD. [less ▲]

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See detail"Acute kidney dysfunction with no rejection" is associated with poor renal outcomes at 2 years post kidney transplantation.
PAQUOT, Francois ULiege; WEEKERS, Laurent ULiege; BONVOISIN, Catherine ULiege et al

in BMC Nephrology (2019), 20(1), 249

BACKGROUND: "Acute kidney dysfunction with no rejection" (ADNR) corresponds to acute kidney injury without histological evidence of acute rejection (AR) in kidney transplant recipients (KTR). The ... [more ▼]

BACKGROUND: "Acute kidney dysfunction with no rejection" (ADNR) corresponds to acute kidney injury without histological evidence of acute rejection (AR) in kidney transplant recipients (KTR). The prognosis of ADNR is unknown. METHODS: From 2007 to 2015, we categorized KTR with for-cause kidney biopsy within the first 12 months post kidney transplantation (KTx) into ADNR (n = 93) and biopsy-proven AR (n = 22). Controls (C, n = 135) included KTR with no ADNR or AR within the first 24 months post-KTx. A piecewise linear regression with a single fixed-knot at 12 months served to establish intercepts and slopes of MDRD-eGFR variations from 12 to 24 months. The percentage of KTR with >/=30% reduction of eGFR from 12 to 24 months was calculated as a surrogate marker of future graft loss. RESULTS: The median time for for-cause biopsy was 22 [10-70] and 13 [7-43] days for ADNR and AR, respectively. At 12 months, eGFR was significantly higher in C (57.6 +/- 14.9 mL/min/1.73m(2)) vs. ADNR (43.5 +/- 15.4 mL/min/1.73m(2), p < 0.0001) and vs. AR (46.5 +/- 15.2 mL/min/1.73m(2), p < 0.0065). The proportion of KTR with >/=30% reduction in eGFR from 12 to 24 months reached 16.3% in C vs. 29.9% in ADNR (p = 0.02) and vs. 15% in AR (not significant). CONCLUSIONS: ADNR is associated with poor outcomes within 2 years post-KTx. [less ▲]

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See detailOxidative stress in chronic kidney disease
Daenen, K.; Andries, A.; Mekahli, D. et al

in Pediatric Nephrology: Journal of the International Pediatric Nephrology Association (2019)

Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the ... [more ▼]

Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the balance is not disturbed, OS has a role in physiological adaptations and signal transduction. However, an excessive amount of ROS and RNS results in the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease (CKD), increased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients. © 2018, IPNA. [less ▲]

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See detailOxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression?
Andries, Asmin; Daenen, Kristien; Jouret, François ULiege et al

in Pediatric Nephrology: Journal of the International Pediatric Nephrology Association (2019)

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2 genes, is the most common hereditary renal disease. Renal manifestations of ADPKD are gradual cyst development and ... [more ▼]

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2 genes, is the most common hereditary renal disease. Renal manifestations of ADPKD are gradual cyst development and kidney enlargement ultimately leading to end-stage renal disease. ADPKD also causes extrarenal manifestations, including endothelial dysfunction and hypertension. Both of these complications are linked with reduced nitric oxide levels related to excessive oxidative stress (OS). OS, defined as disturbances in the prooxidant/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen and nitrogen free radicals. Next to endothelial dysfunction and hypertension, there is cumulative evidence that OS occurs in the early stages of ADPKD. In the current review, we aim to summarize the cardiovascular complications and the relevance of OS in ADPKD and, more specifically, in the early stages of the disease. First, we will briefly introduce the link between ADPKD and the early cardiovascular complications including hypertension. Secondly, we will describe the potential role of OS in the early stages of ADPKD and its possible importance beyond the chronic kidney disease (CKD) effect. Finally, we will discuss some pharmacological agents capable of reducing reactive oxygen species and OS, which might represent potential treatment targets for ADPKD. [less ▲]

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See detailImplications of AMPK in the Formation of Epithelial Tight Junctions
Rowart, Pascal ULiege; Wu, Jingshing; Caplan, Michael J. et al

in International Journal of Molecular Sciences (2018)

Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial ... [more ▼]

Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of membrane components; and (ii) TJ regulate the selective paracellular permeability. Disruption of TJ is regarded as one of the earliest hallmarks of epithelial injury, leading to the loss of cell polarity and tissue disorganization. Many factors have been identified as modulators of TJ assembly/disassembly. More specifically, in addition to its role as an energy sensor, adenosine monophosphate-activated protein kinase (AMPK) participates in TJ regulation. AMPK is a ubiquitous serine/threonine kinase composed of a catalytic -subunit complexed with regulatory -and -subunits. AMPK activation promotes the early stages of epithelial TJ assembly. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the TJ-associated protein zonula occludens (ZO)-1, thereby facilitating ZO-1 distribution to the plasma membrane. In the present review, we detail the signaling pathways up-and down-stream of AMPK activation at the time of Ca2+-induced TJ assembly. [less ▲]

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See detailGUT MICROBIOTA AND FAECAL LEVELS OF SHORT CHAIN FATTY ACIDS DIFFER UPON BLOOD PRESSURE LEVELS IN MAN
HUART, Justine ULiege; Leenders, Justine ULiege; Taminiau, Bernard ULiege et al

in Nephrology Dialysis Transplantation (2018, May 18), 33(Issue suppl_1), 368369

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailControversies in the management of the haemodialysis-related arteriovenous fistula following kidney transplantation.
Vanderweckene, Pauline ULiege; Weekers, Laurent ULiege; Lancellotti, Patrizio ULiege et al

in Clinical Kidney Journal (2018), 11(3), 406-412

Arteriovenous fistula (AVF) is regarded as the best vascular access for chronic haemodialysis (HD). Still, AVF inherently causes significant haemodynamic changes. Although the necessity for vascular ... [more ▼]

Arteriovenous fistula (AVF) is regarded as the best vascular access for chronic haemodialysis (HD). Still, AVF inherently causes significant haemodynamic changes. Although the necessity for vascular access despite its putative cardiovascular complications favours AVF creation in patients under chronic HD, one may question whether sustaining a functional AVF after successful kidney transplantation extends the haemodynamic threat. Small prospective series suggest that AVF ligation causes rapid and sustained reduction in left ventricular hypertrophy. Still, the benefits of such a cardiac remodelling in long-terms of cardiovascular morbi-mortality still need to be proven. Furthermore, the elevation of diastolic blood pressure and arterial stiffness caused by AVF ligation may blunt the expected cardio-protection. Finally, the closure of a functioning AVF may accelerate the decline of kidney graft function. As a whole, the current management of a functioning AVF in kidney transplant recipients remains controversial and does not rely on strong evidence-based data. The individual risk of graft dysfunction and a return to chronic HD also needs to be balanced. Careful pre-operative functional assessments, including cardio-pulmonary testing and estimated glomerular filtration rate slope estimation, may help better selection of who might benefit the most from AVF closure. Large-scale prospective, ideally multi-centric, trials are essentially needed. [less ▲]

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See detailGenetic susceptibility to delayed graft function following kidney transplantation: a systematic review of the literature.
Huart, Justine; Krzesinski, Jean-Marie ULiege; Jouret, François ULiege

in Clinical Kidney Journal (2018), 11(4), 586-596

Delayed graft function (DGF) is defined as the need for dialysis within 7 days following kidney transplantation (KTx). DGF is associated with increased costs, higher risk for acute rejection and decreased ... [more ▼]

Delayed graft function (DGF) is defined as the need for dialysis within 7 days following kidney transplantation (KTx). DGF is associated with increased costs, higher risk for acute rejection and decreased long-term graft function. Renal ischaemia/reperfusion (I/R) injury plays a major role in DGF occurrence. Single nucleotide polymorphisms (SNPs) in certain genes may aggravate kidney susceptibility to I/R injury, thereby worsening post-transplant outcomes. The present article proposes an extensive review of the literature about the putative impact of donor or recipient SNPs on DGF occurrence in kidney transplant recipients (KTRs). Among 30 relevant PubMed reports, 16 articles identified an association between 18 SNPs and DGF. These polymorphisms concern 14 different well-known genes and one not-yet-identified gene located on chromosome 18. They have been categorized into five groups according to the role of the corresponding proteins in I/R cascade: (i) oxidative stress, (ii) telomere shortening, (iii) chemokines, (iv) T-cell homeostasis and (v) metabolism of anti-inflammatory molecules. The remaining 14 studies failed to demonstrate any association between the studied SNPs and the occurrence of DGF. A better understanding of the genetic susceptibility to renal I/R injury may help prevent DGF and improve clinical outcomes in KTRs. [less ▲]

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See detailLinking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease.
Meijers, Bjorn; Jouret, François ULiege; Evenepoel, Pieter

in Pharmacological Research (2018), 133

Bidirectional interactions exist between the kidneys and the gut. These interactions are commonly referred to as the gut-kidney axis. Chronic kidney disease (CKD) leads to disturbances of the gut ... [more ▼]

Bidirectional interactions exist between the kidneys and the gut. These interactions are commonly referred to as the gut-kidney axis. Chronic kidney disease (CKD) leads to disturbances of the gut ecosystem. Key features include the increase of protein fermentation at the expense of carbohydrate fermentation and a disrupted epithelial barrier. A disturbed gut ecosystem may contribute to the high burden of cardiovascular disease in patients with CKD. The present review discusses the impact of CKD on the gut microenvironment and provides an update as to how gut dysbiosis and a leaky gut may be linked to accelerated cardiovascular disease and hypertension. [less ▲]

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See detailWhat we need to know about lipid-associated injury in case of renal ischemia/reperfusion.
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; Defraigne, Jean-Olivier ULiege et al

in American Journal of Physiology. Renal Physiology (2018)

Renal segmental metabolism is reflected by the complex distribution of the main energy pathways along the nephron, with fatty acid oxidation preferentially used in the cortex area. Ischemia/reperfusion ... [more ▼]

Renal segmental metabolism is reflected by the complex distribution of the main energy pathways along the nephron, with fatty acid oxidation preferentially used in the cortex area. Ischemia/reperfusion injury (IRI) is due to the restriction of renal blood flow, rapidly leading to a metabolic switch towards anaerobic conditions. Subsequent unbalance between energy demand and oxygen/nutrient delivery compromises kidney cell functions, resulting to a complex inflammatory cascade including the production of reactive oxygen species (ROS). Renal IRI especially involves lipid accumulation. Lipid peroxidation is one of the major events of ROS-associated tissue injury. Here, we briefly review the current knowledge of renal cell lipid metabolism in normal and ischemic conditions. Next, we focus on renal lipid-associated injury, with emphasis on its mechanisms and consequences during the course of IRI. Finally, we discuss preclinical observations aiming at preventing and/or attenuating lipid-associated IRI. [less ▲]

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See detailCXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury.
Yakulov, Toma A.; Todkar, Abhijeet P.; Slanchev, Krasimir et al

in Nature Communications (2018), 9(1), 3660

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos ... [more ▼]

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis. [less ▲]

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See detailVps34/PI3KC3 deletion in kidney proximal tubules impairs apical trafficking and blocks autophagic flux, causing a Fanconi-like syndrome and renal insufficiency.
Grieco, Giuseppina; Janssens, Virginie; Gaide Chevronnay, Heloise P. et al

in Scientific Reports (2018), 8(1), 14133

Kidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates ... [more ▼]

Kidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates endosomal dynamics, macroautophagy and lysosomal function. However, its in vivo role in PTCs has not been evaluated. Conditional deletion of Vps34/PI3KC3 in PTCs by Pax8-Cre resulted in early (P7) PTC dysfunction, manifested by Fanconi-like syndrome, followed by kidney failure (P14) and death. By confocal microscopy, Vps34(/) PTCs showed preserved apico-basal specification (brush border, NHERF-1 versus Na(+)/K(+)-ATPase, ankyrin-G) but basal redistribution of late-endosomes/lysosomes (LAMP-1) and mis-localization to lysosomes of apical recycling endocytic receptors (megalin, cubilin) and apical non-recycling solute carriers (NaPi-IIa, SGLT-2). Defective endocytosis was confirmed by Texas-red-ovalbumin tracing and reduced albumin content. Disruption of Rab-11 and perinuclear galectin-3 compartments suggested mechanistic clues for defective receptor recycling and apical biosynthetic trafficking. p62-dependent autophagy was triggered yet abortive (p62 co-localization with LC3 but not LAMP-1) and PTCs became vacuolated. Impaired lysosomal positioning and blocked autophagy are known causes of cell stress. Thus, early trafficking defects show that Vps34 is a key in vivo component of molecular machineries governing apical vesicular trafficking, thus absorptive function in PTCs. Functional defects underline the essential role of Vps34 for PTC homeostasis and kidney survival. [less ▲]

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See detailDO MESENCHYMAL STROMAL CELLS PROMOTE HLA SPECIFIC ANTIBODIES FORMATION AFTER INFUSION IN LIVER TRANSPLANT RECIPIENTS?
VANDERMEULEN, Morgan ULiege; MAGGIPINTO, Gianni ULiege; JOURET, François ULiege et al

in Transplant International (2017, September), 30(S2), 548051

Background: Mesenchymal stromal cells (MSC) immunogenicity is debated. We recently published a prospective, controlled, phase I study evaluating a single administration of third-party MSC in 10 liver ... [more ▼]

Background: Mesenchymal stromal cells (MSC) immunogenicity is debated. We recently published a prospective, controlled, phase I study evaluating a single administration of third-party MSC in 10 liver transplant recipients (LTR). Here, we focus on the development of antibodies (Ab) against MSC-donor HLA (MSCDSA) in LTR following MSC infusion. Methods: Ten LTR under standard immunosuppression received 3rd-party unrelated MSC on postoperative day 3, and were prospectively compared to 10 control LTR. Recipients and donor of either liver or MSC were genotyped for HLA A/B/C/DR/DQ. Recipients were tested for HLA Ab before and 1, 3 and 6 months after transplant by Luminex". Ab were considered as positive in case of MFI >1500 and in accordance with the manufacturer’s recommendations. Results: In MSC-treated group, 2 patients showed pre-transplant MSCDSA. During follow-up, MSCDSA were detected in 6 additional patients who had received multiple red blood cell allo-transfusions before and/or rapidly after transplant. These patients also developed Ab against various MSC-unrelatedHLA. Two patients did not develop any MSCDSA throughout the follow-up, and one of them did not receive any allo-transfusion. MFI of detected MSCDSA were not significantly different from MFI of other detected HLA Ab. In control group, 3 patients were sensitized pre-transplant, and 6 patients developed de novo multiple HLA Ab. Four of these had received multiple allo-transfusions. Conclusion: In the large pool of HLA Ab identified in LTR post transplant, the detection of MSCDSA is most likely caused by allo-transfusions rather than related to MSC infusion. Further studies are required to confirm that MSC are “immune privileged”. [less ▲]

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See detailAdministration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and modulates renal lipid metabolism in rats
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Transplant International (2017, September), 30(S2), 9004

Background: Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodents. The mecha- nisms of such nephroprotection remain unclear. Materials and ... [more ▼]

Background: Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodents. The mecha- nisms of such nephroprotection remain unclear. Materials and Methods: Male Lewis rats aged of 8–10 weeks received tail i.v injection of 1.5x106 MSC in 1 mL saline (MSCD-7, n = 11) or saline alone (SD- 7, n = 6) 7 days before renal I/R. Left renal ischemia (by clamping the renal pedicle) lasted 45 min. Right nephrectomy was simultaneously performed. Blood sample was collected from inferior vena cava 48 h post reperfusion. Renal function was assessed by measuring serum creatinine (SCr) levels. Expressions of inflammatory and apoptotic markers by real-time (RT)-qPCR were comparatively quantified. High-throughput RNA sequencing was applied to MSCD-7 vs. SD-7 non-ischemic right kidneys. Relevant pathways were detected using an Over-Representation Analysis with WebGestalt, and confirmed by RT-qPCR. Results: Scr levels reached 1.4 ` 0.7 vs. 2.4 ` 0.8 mg/dL in MSCD-7 vs. SD-7 group (p < 0.05). MSC infusion significantly reduced mRNA expression of Casp3, Hsp 70, Kim-1, Mcp-1 and Il-6 and increased mRNA expression of Bcl compared to saline. Among 25 908 genes, 748 were identified as significantly differentially expressed (False Discovery Rate (FDR), <0.05) between MSCD-7 and SD-7 non-ischemic kidneys. Among the most affected metabolic pathways, renal lipid metabolism was significantly altered, with down-regulation of fatty acid biosynthesis and an up-regulation of PPARa pathway in MSCD-7 vs. SD-7 groups. By immunoblotting, PPARa and phosphorylated-PPARa were significantly increased in MSCD-7 vs. SD-7 kidneys, in both non-ischemic and ischemic conditions. Moreover, levels of malondialdehyde-derived lipid peroxidation products were decreased in MSCD-7 ischemic kidneys in comparison to SD-7 ischemic kidneys. Conclusion: MSC infusion at day 7 prior injury critically impacts renal lipid metabolism, which may condition kidney parenchyma against I/R. [less ▲]

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See detailAdministration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and may modulate renal lipid metabolism in rats.
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Scientific Reports (2017), 7(1), 8687

Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro-protection remain largely unknown. Furthermore ... [more ▼]

Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro-protection remain largely unknown. Furthermore, the optimal timing of MSC administration has been poorly investigated. Here, we compare the impact of MSC injection 7 days before (MSCD - 7) versus 1 day after (MSCD + 1) renal I/R in rats. Control groups received equivalent volumes of saline at similar time-points (SD - 7 and SD + 1). Right nephrectomy was performed, and left renal ischemia lasted 45 min. After 48-hour reperfusion, we observed significantly improved renal function parameters, reduced apoptotic index and neutrophil/macrophage infiltration in kidney parenchyma, and lower expression of tubular damage markers and pro-inflammatory cytokines in MSCD - 7 in comparison to MSCD + 1 and saline control groups. Next, comparative high-throughput RNA sequencing of MSCD - 7 vs. SD - 7 non-ischemic right kidneys highlighted significant down-regulation of fatty acid biosynthesis and up-regulation of PPAR-alpha pathway. Such a preferential regulation towards lipid catabolism was associated with decreased levels of lipid peroxidation products, i.e. malondialdehyde and 4-hydroxy-2-nonenal, in MSCD - 7 versus SD - 7 ischemic kidneys. Our findings suggest that MSC pretreatment may exert protective effects against renal I/R by modulating lipid metabolism in rats. [less ▲]

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