Publications of François JOURET
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See detailIs autosomal dominant polycystic kidney disease an early sweet disease?
DACHY, Angélique ULiege; Decuypère, Jean-Paul; Vennekens, Rudi et al

in Pediatric Nephrology: Journal of the International Pediatric Nephrology Association (2022)

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See detailLe médicament anti-angiogénique Sunitinib contrarie le conditionnement ischémique rénal induit par l’irradiation
Khbouz, Badr ULiege; Pinto Coelho, Tiago ULiege; LALLEMAND, François ULiege et al

Poster (2021, December 08)

Introduction: L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Nous ... [more ▼]

Introduction: L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Nous étudions les voies impliquées dans l'irradiation rénale. Ensuite, nous analysons l'impact fonctionnel sur les reins avant ischémie rénale/reperfusion(IR). Enfin, nous testons si l'inhibition de l'angiogenèse par le Sunitinib empêche le CIR associé à l'irradiation Méthodes: Exp1. Une irradiation rénale(8Gy) est réalisée chez des C57bl/6 mâles(n=10). Un mois plus tard, l'ARN rénal total est extrait pour un RNAseq comparatif. Exp2. À 7-14-28 jours post-irradiation, les reins droits sont néphrectomisés et les reins gauches subissent une ischémie(30min)/reperfusion(48h) (n=8/timing). Exp3. Suivant le même protocole d'I/R à J14, 3 groupes sont comparés(n=8/groupe): 1/irradiation; 2/irradiation et gavage au Sunitinib de J2 à J13; 3/groupe témoin sans irradiation ni gavage Résultats: Exp1. RNAseq montre une up-régulation de l'angiogenèse. L’expression de VEGF et CD31 est augmentée au niveau ARNm et protéique dans les reins irradiés. Exp2. Après IR à J14 post-irradiation, les taux sériques d’urée(BUN) et de créatinine(SCr) sont plus faibles chez les souris irradiées par rapport aux témoins(BUN:86,2±6,8 vs 454,5±27,2 mg/dl; SCr:0,1±0,01 vs 1,7±0,2mg/dl, p<0,01). L'infiltration rénale par les macrophages CD11b(187±32 vs 477±20/mm²) et F4-80(110±22 vs 212±25/mm²) est moindre dans le groupe irradié. L'expression de VEGF et CD31 est majorée dans les reins irradiés à partir de J14. Exp3. Après IR, les taux de BUN et de SCr dans le groupe irradié-exposé au Sunitinib sont similaires aux témoins(BUN 352,2±54,3 vs 408,4±54,9 mg/dl; SCr:1,5±0,3 vs 1±0,2 mg/dl) Conclusion: L'irradiation rénale induit l'activation de l'angiogenèse chez la souris et est associée à un CIR, avec fonction rénale préservée et inflammation atténuée post-IR. L'exposition au Sunitinib post-irradiation empêche ce CIR. [less ▲]

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See detailKidney-targeted radiotherapy triggers renal ischaemic preconditioning in mice
Khbouz, Badr ULiege; LALLEMAND, François ULiege; ROWART, Pascal ULiege et al

Conference (2021, November 26)

INTRODUCTION | Renal ischemia/reperfusion (I/R) is the leading cause of acute kidney injury (AKI). Ischemic preconditioning (IPC) may help to attenuate the severity of I/Rassociated AKI. Whole-body ... [more ▼]

INTRODUCTION | Renal ischemia/reperfusion (I/R) is the leading cause of acute kidney injury (AKI). Ischemic preconditioning (IPC) may help to attenuate the severity of I/Rassociated AKI. Whole-body irradiation induces renal IPC in mice, although the pathways remain largely unknown. Furthermore, the impact of kidney-centred irradiation on renal resistance against I/R has not been studied. First, we comprehensively investigate the pathways involved in renal irradiation. Next, we assess the functional impact of renal irradiation applied I/R injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated IPC. METHODS | Exp1: Renal irradiation (8.5Gy) was performed in male C57bl/6 mice(n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation(n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared(n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage. RESULTS | Exp1: RNAseq showen up-regulation of angiogenesis signalling pathways. Expressions of angiogenesis markers (CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys (p<0.01). Exp2: Following I/R, Blood Urea Nitrogen (BUN) and Creatinine (SCr) levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-(187±32 vs 477±20/mm2) and F4-80-positive cells (110±22 vs 212±25/mm2) was reduced in the irradiated group. VEGF and CD31 expression was increased in irradiated kidneys at both mRNA and protein levels(p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in the irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). CONCLUSION | Renal irradiation induces the activation of angiogenesis in mice. Renal irradiation leads to IPC, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced IPC. [less ▲]

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See detailThe Irradiation-Induced Renal Ischemic Preconditioning Is Blunted by the Oral Administration of the Anti-Angiogenic Agent Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Poster (2021, November 04)

Background: Whole-body irradiation has been suggested to induce renal ischemic preconditioning(RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in renal ... [more ▼]

Background: Whole-body irradiation has been suggested to induce renal ischemic preconditioning(RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in renal irradiation. Next, we assess the functional impact of renal irradiation applied before renal ischemia/reperfusion(I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated RIP. Methods: Exp1: Renal irradiation(8.56 Gy) was performed in male C57bl/6 mice(n=10). One month later, total kidney RNA was extracted from irradiated and control(n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation(n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared(n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage. Results: Exp1: RNAseq showen up-regulation of angiogenesis signalling pathways. Expressions of angiogenesis markers(CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys(p<0.01). Exp2: Following I/R, Blood Urea Nitrogen(BUN) and Creatinine(SCr) levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-(187±32 vs 477±20/mm2) and F4-80-positive cells(110±22 vs 212±25/mm2) was reduced in the irradiated group. VEGF and CD31 expression was increased in irradiated kidneys at both mRNA and protein levels(p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in the irradiated group compared to controls(BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib(BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). Conclusion: Renal irradiation induces the activation of angiogenesis in mice. Renal irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP. [less ▲]

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See detailSerological response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients depends on prior exposure to SARS-CoV-2.
Firket, Louis ULiege; Descy, Julie ULiege; Seidel, Laurence ULiege et al

in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2021), 21(11), 3806-3807

Grupper et al. have reported on a positive humoral response post full vaccination with mRNA SARS-CoV2 BNT162b2 in only 51/136 (37.5%) kidney transplant recipients (KTRs) without prior exposure to the ... [more ▼]

Grupper et al. have reported on a positive humoral response post full vaccination with mRNA SARS-CoV2 BNT162b2 in only 51/136 (37.5%) kidney transplant recipients (KTRs) without prior exposure to the virus(1) . We have conducted an IRB-approved (B707201215598-2021/80) prospective small sample-size study comparing the humoral response to BNT162b2 in 40 consecutive individuals early exposed to the Belgian vaccination program, including 20 KTRs with (n=10, COVID-19(+)) versus without (n=10, COVID-19(-)) history of exposure to SARS-CoV-2 and 20 controls including 10 COVID-19(+) versus 10 COVID-19(-). [less ▲]

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See detailThe genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage following ischemia/reperfusion injury in mouse
Khbouz, Badr ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Acta Physiologica (2021)

Aim: Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ... [more ▼]

Aim: Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ischemia/reperfusion (I/R). We postulate that the functional loss of DUSP3 is associated with kidney resistance to I/R. Methods: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal I/R (30min/48h). Renal injury was assessed based on serum levels of urea (BUN) and Jablonski score. The expression of CD31 and VEGF vascular markers was quantified by RT-qPCR and immuno-staining. Renal resistivity index (RRI) was measured in vivo by Doppler ultrasound. Comparative phosphoproteomics was conducted using IMAC enrichment of phosphopeptides. Inflammatory markers were quantified at both mRNA and protein levels in ischemic vs. non-ischemic kidneys in WT versus Dusp3-/- . Results: At baseline, we located DUSP3 in renal glomeruli and endothelial cells. CD31-positive vascular network was significantly larger in Dusp3-/- kidneys compared to WT, with a lower RRI in Dusp3-/- mice. Following I/R, BUN and Jablonski score were significantly lower in Dusp3-/- vs. WT mice. Phosphoproteomics highlighted a down-regulation of inflammatory pathways and up-regulation of phospho-sites involved in cell metabolism and VEGF-related angiogenesis in Dusp3-/- vs. WT ischemic kidneys. Dusp3-/- ischemic kidneys showed decreased mRNA levels of CD11b, TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b-positive cells were reduced in Dusp3-/- vs. WT kidneys post I/R. Conclusion: Genetic inactivation of Dusp3 is associated with kidney conditioning against I/R, possibly due to attenuated inflammation and improved perfusion. [less ▲]

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See detailLe médicament anti-angiogénique Sunitinib contrarie le conditionnement ischémique rénal induit par l’irradiation
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Pasal, Rowart ULiege et al

Conference (2021, October 06)

Introduction L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Description ... [more ▼]

Introduction L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Description claire et complète de l'expérience Dans cette étude, nous étudions les voies impliquées dans l'irradiation rénale. Ensuite, nous analysons l'impact fonctionnel sur les reins avant ischémie rénale/reperfusion(I/R). Enfin, nous testons si l'inhibition de l'angiogenèse par le Sunitinib empêche le CIR associé à l'irradiation. Méthodes (une explication détaillée de votre analyse est attendue) Exp1. Une irradiation rénale(8Gy) est réalisée chez des C57bl/6 mâles(n=10). Un mois plus tard, l'ARN rénal total est extrait pour un RNAseq comparatif. Exp2. À 7- 14-28 jours post irradiation rénale, les reins droits sont néphrectomisés et les reins gauches subissent une ischémie(30min)/reperfusion(48h) (n=8/timing). Exp3. Suivant le même protocole d'I/R à J14, 3 groupes sont comparés(n=8/groupe) : 1/ irradiation ; 2 /irradiation et gavage au Sunitinib de J2 à J13 ; 3/ groupe témoin sans irradiation ni gavage. Résultats obtenus ou attendus Exp1. RNAseq montre une up-régulation des voies de l'angiogenèse. L’expression de VEGF et CD31 est significativement augmentée au niveau ARNm et protéique dans les reins irradiés. Exp2. Après I/R à J14 post irradiation, les taux sériques d’urée(BUN) et de créatinine(SCr) sont plus faibles chez les souris irradiées par rapport aux témoins(BUN : 86,2±6,8 vs 454,5±27,2 mg/dl ; SCr: 0,1±0,01 vs 1,7±0,2 mg/dl, p<0,01). L'infiltration rénale par les macrophages CD11b(187±32 vs 477±20/mm²) et F4-80(110±22 vs 212±25/mm²) est significativement moindre dans le groupe irradié. L'expression de VEGF et CD31 est majorée dans les reins irradiés à partir de J14. Exp3. Après I/R, les taux sériques de BUN et de SCr dans le groupe irradié-exposé au Sunitinib sont similaires au groupe contrôle(BUN 352,2±54,3 vs. 408,4 ± 54,9 mg/dl ; SCr : 1,5±0,3 vs. 1±0,2 mg/dl). Conclusion L'irradiation rénale induit l'activation de l'angiogenèse chez la souris et est associée à un CIR, avec fonction rénale préservée et inflammation atténuée post I/R. L'exposition au Sunitinib post-irradiation empêche ce CIR. [less ▲]

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See detailRole of the Dual Specificity Phosphatase 3 (DUSP3) in renal ischemia/reperfusion injury
Khbouz, Badr ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

Conference (2021, August 31)

● Background: DUSP3 is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. We study (i) whether and where DUSP3 is expressed in the renal ... [more ▼]

● Background: DUSP3 is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. We study (i) whether and where DUSP3 is expressed in the renal parenchyma, and (ii) whether its genetic deletion in mice (Dusp3-/-) attenuates the ischemic injury. ● Methods: Exp1: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal ischemia(30min)/reperfusion(48h) (I/R). Renal function was assessed upon I/R biomarkers: serum levels of urea (BUN) and creatinine (SCr). The expression of inflammatory markers was quantified at both mRNA and protein levels in ischemic vs. non-ischemic kidneys in WT vs Dusp3-/-. Exp2: Renal resistivity index (RRI) was measured by Doppler ultrasound (n=10 mice). The expression of CD31 and VEGF vascular markers was quantified by qPCR and immuno-staining. ● Results: Exp1: An immuno-reactive signal for DUSP3 was detected in nephrin-positive glomeruli and in Meca-32-positive endothelial cells in both outer and inner medulla, with no immunoreactivity in Dusp3-/- kidneys. Following I/R, the mRNA level of DUSP3 was increased 1.8-fold compared to baseline. Immunoblotting showed a 77-fold increased expression of DUSP3 post I/R. Serum levels of I/R biomarkers were significantly lower in Dusp3-/- compared to WT mice following renal I/R (BUN: 78.4±33.7 vs. 258.9±162.9mg/dL; SCr: 0.1±0.07 vs. 0.8±0.9 mg/dL; p<0.01). At mRNA levels, Dusp3-/- ischemic kidneys showed a significantly decreased expression level of TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to WT. PCNA-, F4-80- and CD11b-positive cells were significantly reduced in Dusp3-/- vs WT renal parenchyma post I/R. Exp2: The RRI was lower in Dusp3-/- compared to WT (0.56±0.03 vs. 0.66±0.02; p<0.001). The Dusp3-/- kidneys were characterized by a 1.8-fold increase of CD31 compared to WT. At mRNA levels, the Dusp3-/- kidneys showed increased basal levels of CD31 and VEGF compared to WT. ● Conclusions: The genetic deletion of DUSP3 is associated with (i) increased renal vascular density, (ii) decreased RRI and (iii) nephroprotection against renal I/R injury. [less ▲]

Detailed reference viewed: 31 (12 ULiège)
See detailThe irradiation-induced renal ischemic preconditioning is blunted by the oral administration of the anti-angiogenic agent, Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Conference (2021, August 30)

Background: Whole-body irradiation induces renal ischemic preconditioning (RIP) in mice, possibly via neoangiogenesis. Here, we test whether Sunitinib-mediated inhibition of angiogenesis prevents the ... [more ▼]

Background: Whole-body irradiation induces renal ischemic preconditioning (RIP) in mice, possibly via neoangiogenesis. Here, we test whether Sunitinib-mediated inhibition of angiogenesis prevents the irradiation-associated RIP. ● Methods: After kidney-centred irradiation (8.56 Gy), the right kidneys were removed and harvested, and the left kidneys underwent ischemia (30min) / reperfusion (48h) (I/R) at Day 14. Three groups were compared (n=8/group): 1/irradiation; 2/irradiation and gavage with Sunitinib (40 mg/kg) from D2 to D13; 3/control group without irradiation or gavage. Renal sections from the 3 groups post-I/R were stained by Periodic Acid Schiff (PAS). I/R-associated acute tubular necrosis was blindly evaluated by a renal pathologist using the histological Jablonski score. The expression of inflammatory markers CD11b and F4/80 was comparatively quantified by immunostaining. The expression of vascular markers CD31 and VEGF in nonischemic kidneys were quantified by real-time qPCR. ● Results: One-way analysis of variance followed by Tukey’s test showed that, following I/R, serum levels of urea (BUN) and creatinine (SCr) were significantly lower in pre-irradiated mice compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), as well as in pre-irradiated mice compared to the irradiated mice fed with Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl). No difference was observed between the Sunitinib group and the control group. Jablonski’s severity score was lower in pre-irradiated mice compared to control group and Sunitinib group (p<0.01). The renal infiltration by CD11b- (560±32 vs. 308±21/mm²) and F4-80 positive cells (430±35 vs. 312±19/mm²) was significantly reduced in the irradiated group compared to controls. At mRNA levels, the renal expression of VEGF and CD31 was increased in the irradiated group but not in the Sunitinib group (p<0.01). ● Conclusions: Renal irradiation before I/R is associated with preserved renal function and attenuated inflammation post I/R. Sunitinib administration prevents the irradiation-induced RIP. [less ▲]

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See detailMesenchymal stromal cells combined with everolimus promote Treg expansion but do not synergize in a rat liver transplant rejection model
VANDERMEULEN, Morgan ULiege; ERPICUM, Pauline ULiege; BLETARD, Noëlla ULiege et al

in Transplant International (2021, August), 34(S1 OP519), 101

Background: Mesenchymal stromal cells (MSCs) have particular properties that can be of interest in organ transplantation, including expansion of regulatory T cells (Tregs), a key factor in graft tolerance ... [more ▼]

Background: Mesenchymal stromal cells (MSCs) have particular properties that can be of interest in organ transplantation, including expansion of regulatory T cells (Tregs), a key factor in graft tolerance induction. The immunosuppression to be associated with MSCs has not yet been defined. Additionally, the impact of the association of everolimus with MSCs on Treg expansion and on induction of liver graft tolerance has never been studied. The aim of this study was to evaluate the effects of MSCs combined, or not, with everolimus, on Treg expansion and in a model of liver transplantation (LT) rejection in the rat. Methods: Firstly, Lewis rats received intravenous MSCs at D9 with/without subcutaneous everolimus from D0 to D14. Analysis of circulating Tregs was performed at D0, D14 and D28. Secondly, 48 h after LT with a Dark Agouti rat liver, 30 Lewis rats were randomized in 3 groups: everolimus (subcutaneous for 14 days), MSCs (intravenous injection at D2 and D9), or both everolimus and MSCs. Rejection of the liver graft was assessed by liver tests, histology and survival. Results: Individually, MSC infusion and everolimus promoted Treg expansion in rats, and everolimus had no negative impact on Treg expansion when combined with MSCs. However, in the LT model, injections of MSCs 2 and 9 days following LT were not effective at preventing acute rejection, and the combination of MSCs with everolimus failed to show any synergistic effect when compared to everolimus alone. Conclusion: Everolimus may be used in association with MSCs. However, in our model of LT in the rat, post-transplant MSC injections did not prevent acute rejection, and the association of MSCs with everolimus did not show any synergistic effect. [less ▲]

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See detailPerioperative risk factors of acute kidney injury post liver transplantation: a monocentric retrospective cohort study of 260 patients
Malisoux, Clarisse ULiege; KOCH, Jean-Noël ULiege; MEURISSE, Nicolas ULiege et al

in Transplant International (2021, August), 34(S1 POS315), 312

Aims and Background: Acute kidney injury (AKI) is a major risk factor of poor outcomes after liver transplantation (LT). AKI is usually attributed to post-LT events and drug toxicity. Peri-operative risk ... [more ▼]

Aims and Background: Acute kidney injury (AKI) is a major risk factor of poor outcomes after liver transplantation (LT). AKI is usually attributed to post-LT events and drug toxicity. Peri-operative risk factors of LT-associated AKI remain poorly documented, which hampers the development of personalized preventive strategies. Methods: AKI was assessed by KDIGO criteria based on creatinine changes from baseline to day 5 post LT. 260 single first full-size LTs without any pre-existing renal replacement therapy (RRT) were performed from 2003 to 2018. Incidence of AKI was assessed. Logistic regression determined the risk factors of KDIGO I and II-III AKI. Results: Incidence of AKI KDIGO I and II-III was 30% (78/260) and 25.7% (67/260), respectively. Preoperatively, patients with AKI had higher lab- MELD and Child-Pugh scores, lower serum fibrinogen and albumin levels. Donor type, donor hepatectomy and cold ischemic time were similar between groups. AKI was more frequent in case of marginal donors. LT surgery was longer in the AKI groups. Needs for per-operative blood transfusions were higher in the AKI groups. Rate of post-reperfusion syndrome was higher in AKI groups. Postoperatively, lower hemoglobin levels and higher INR from day 1-5 were associated with AKI. Peak of transaminases were not different between AKI versus non-AKI groups. AKI was associated with longer length of hospital and ICU stays. After multivariate analysis, blood transfusions and post-reperfusion syndrome were risk factors to develop KDIGO I AKI. Pre-operative serum levels of fibrinogen and albumin were risk factors for KDIGO II-III AKI. Finally, “marginal donors” was the only risk factor for both KDIGO I and II-III AKI. Conclusions: LT-associated AKI occurs in >50% of cases. Per-operative hemorrhage and post-operative reperfusion syndrome represent risk factors, particularly in cases of marginal donors. [less ▲]

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See detailThe genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage following ischemia/reperfusion injury in mouse
Khbouz, Badr ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

Conference (2021, June 05)

BACKGROUND AND AIMS: Dual Specificity Phosphatase 3 (DUSP3) is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. Here, we study (i ... [more ▼]

BACKGROUND AND AIMS: Dual Specificity Phosphatase 3 (DUSP3) is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. Here, we study (i) whether and where DUSP3 is expressed in the renal parenchyma, and (ii) whether its genetic deletion in Dusp3 systemic knock-out (Dusp3-/-) mice attenuates the I/R-associated inflammation and injury. METHOD: Experiment 1: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal ischemia for 30 minutes followed by a reperfusion of 48 hours. Blood and kidneys were collected. Renal function was assessed upon I/R biomarkers, i.e. blood urea nitrogen (BUN) and creatinine (SCr). Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immuno-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in Dusp3 WT vs. KO mice. Experiment 2: Ten C57BL/6 male WT and Dusp3-/- mice were anesthetized. Renal Doppler ultrasound was performed to assess the renal resistivity index (RRI). The expression of CD31 and VEGF vascular markers was quantified by the means of real time qPCR and and immuno-staining (FiJi software). RESULTS: Experiment 1: An immuno-reactive signal for DUSP3 was detected in the glomeruli (in co-localization with nephrin) and in Meca-32-positive endothelial cells of both outer and inner medulla of mouse non-ischemic WT kidneys. No significant immunoreactivity for DUSP3 was detected in Dusp3-/- kidneys. Following renal I/R, the mRNA level of Dusp3 was increased 1.8-fold compared to baseline (p<0.001). Immunoblot quantifications showed a 77-fold increased expression of DUSP3 post renal I/R. Serum levels of I/R biomarkers were significantly lower in Dusp3-/- compared to WT mice following renal I/R (BUN: 78.4633.7 vs. 258.96162.9mg/dL; SCr: 0.160.07 vs. 0.860.9 mg/dL; p<0.01). At mRNA levels, Dusp3-/- ischemic kidneys showed a significantly decreased expression level of CD11b, TNF-a, KIM-1, IL-6, IL-1b and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b positive cells were significantly reduced in Dusp3-/- vs WT renal parenchyma post I/R. Experiment 2: The RRI non-invasively measured by ultrasound was lower in Dusp3-/- group compared to controls (0.566 0.03 vs. 0.6660.02; p<0.001). The Dusp3-/- non ischemic kidneys were characterized by a 1.8-fold increased surface of CD31-positive cells compared to WT kidneys (p<0.001). At mRNA levels, the Dusp3-/- kidneys showed significantly increased basal levels of CD31 and VEGF compared to controls. CONCLUSION: The genetic deletion of DUSP3 is associated with (i) increased renal vascular density, (ii) decreased RRI and (iii) nephroprotection against renal I/R injury. [less ▲]

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See detailEffect of renal irradiation in neo-angiogenesis and ischemic preconditioning
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Conference (2021, June 05)

Background and Aims: Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the ... [more ▼]

Background and Aims: Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method: Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNAs were extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. Fourteen days later, the right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8). Experiment 3: Following the same protocol of renal I/R, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 animals per group): 1/ irradiation 2/ irradiation and gavage with Sunitinib for 14days 3/ control group without irradiation or gavage. All groups undergo an I/R after treatments. Results: Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) shows an increase at both mRNA (real-time qPCR) and protein (immune-staining) levels in irradiated kidneys compared to controls (p<0.01). Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-positive cells (187±32 vs. 477±20/mm²) and F4-80 macrophages (110±22 vs. 212±25/mm²) was significantly reduced in the irradiated group. The real-time qPCR mRNA levels of the angiogenic markers, TGFb1 and CD31, were significantly increased in the irradiated group compared to controls (p<0,01). The CD31-immunostaining was increased in irradiated group compared to controls (p<0.01). Experiment 3: Following I/R, the serum levels of BUN and SCr were lower in pre-irradiated animals compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). No difference observed between the irradiated-exposed mice to Sunitnib and the controls. Conclusion: Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal irradiation causes ischemic preconditioning, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced nephroprotection against I/R. [less ▲]

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See detailThe irradiation-induced renal ischemic preconditioning is blunted by the oral administration of the anti-angiogenic agent, Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Poster (2021, May 27)

● Objective: Irradiation has been suggested to induce renal ischemic preconditioning (RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in kidneys ... [more ▼]

● Objective: Irradiation has been suggested to induce renal ischemic preconditioning (RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in kidneys-centered irradiation. Next, we assess the functional impact of renal irradiation applied before renal ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated RIP. ● Methods: Exp1: Renal irradiation (8.56 Gy) was performed in male C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation (n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared (n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage. ● Results: Exp1: RNA-Seq showed up-regulation of angiogenesis signaling pathways. Expressions of angiogenesis markers (CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys (p<0.01). Exp2: Following I/R, BUN and SCr levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b (187±32 vs. 477±20/mm²) and F4-80 positive cells (110±22 vs.212±25/mm²) was reduced in the irradiated group. VEGF and CD31, were increased in irradiated kidneys at both mRNA and protein levels (p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). ● Conclusions: Kidneys-centered irradiation induces the activation of angiogenesis pathways in mice. Renal irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP. [less ▲]

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See detailHuman Stool Metabolome Differs upon 24 h Blood Pressure Levels and Blood Pressure Dipping Status: A Prospective Longitudinal Study
Cirillo, Arianna ULiege; Huart, Justine ULiege; Taminiau, Bernard ULiege et al

Poster (2021, May 26)

: Dysbiosis of gut microbiota (GM) has been involved in the pathophysiology of arterial hypertension (HT), via a putative role of short chain fatty acids (SCFAs). Its role in the circadian regulation of ... [more ▼]

: Dysbiosis of gut microbiota (GM) has been involved in the pathophysiology of arterial hypertension (HT), via a putative role of short chain fatty acids (SCFAs). Its role in the circadian regulation of blood pressure (BP), also called “the dipping profile”, has been poorly investigated. Sixteen male volunteers and 10 female partners were subjected to 24 h ambulatory BP monitoring and were categorized in normotensive (NT) versus HT, as well as in dippers versus non-dippers. Nuclear magnetic resonance (NMR)-based metabolomics was performed on stool samples. A 5-year comparative follow-up of BP profiles and stool metabolomes was done in men. Significant correlations between stool metabolome and 24 h mean BP levels were found in both male and female cohorts and in the entire cohort (R2 = 0.72, R2 = 0.79, and R2 = 0.45, respectively). Multivariate analysis discriminated dippers versus non-dippers in both male and female cohorts and in the entire cohort (Q2 = 0.87, Q2 = 0.98, and Q2 = 0.68, respectively). Fecal amounts of acetate, propionate, and butyrate were higher in HT versus NT patients (p = 0.027; p = 0.015 and p = 0.015, respectively), as well as in non-dippers versus dippers (p = 0.027, p = 0.038, and p = 0.036, respectively) in the entire cohort. SCFA levels were significantly different in patients changing of dipping status over the 5-year follow-up. In conclusion, stool metabolome changes upon global and circadian BP profiles in both genders [less ▲]

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See detailHuman Stool Metabolome Differs upon 24 h Blood Pressure Levels and Blood Pressure Dipping Status: A Prospective Longitudinal Study
HUART, Justine ULiege; Cirillo, Arianna ULiege; Taminiau, Bernard ULiege et al

in Metabolites (2021), 11(5), 282

Dysbiosis of gut microbiota (GM) has been involved in the pathophysiology of arterial hypertension (HT), via a putative role of short chain fatty acids (SCFAs). Its role in the circadian regulation of ... [more ▼]

Dysbiosis of gut microbiota (GM) has been involved in the pathophysiology of arterial hypertension (HT), via a putative role of short chain fatty acids (SCFAs). Its role in the circadian regulation of blood pressure (BP), also called "the dipping profile", has been poorly investigated. Sixteen male volunteers and 10 female partners were subjected to 24 h ambulatory BP monitoring and were categorized in normotensive (NT) versus HT, as well as in dippers versus non-dippers. Nuclear magnetic resonance (NMR)-based metabolomics was performed on stool samples. A 5-year comparative follow-up of BP profiles and stool metabolomes was done in men. Significant correlations between stool metabolome and 24 h mean BP levels were found in both male and female cohorts and in the entire cohort (R2 = 0.72, R2 = 0.79, and R2 = 0.45, respectively). Multivariate analysis discriminated dippers versus non-dippers in both male and female cohorts and in the entire cohort (Q2 = 0.87, Q2 = 0.98, and Q2 = 0.68, respectively). Fecal amounts of acetate, propionate, and butyrate were higher in HT versus NT patients (p = 0.027; p = 0.015 and p = 0.015, respectively), as well as in non-dippers versus dippers (p = 0.027, p = 0.038, and p = 0.036, respectively) in the entire cohort. SCFA levels were significantly different in patients changing of dipping status over the 5-year follow-up. In conclusion, stool metabolome changes upon global and circadian BP profiles in both genders. [less ▲]

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See detailThe faecal abundance of short chain fatty acids is increased in men with a non-dipping blood pressure profile
HUART, Justine ULiege; Cirillo, Arianna ULiege; SAINT-REMY, Annie ULiege et al

in Acta Cardiologica (2021)

Background and aims: Gut microbiota (GM) has been involved in the pathophysiology of hypertension (HT), notably via short chain fatty acids (SCFAs). Among the clinical manifestations of HT, the absence of ... [more ▼]

Background and aims: Gut microbiota (GM) has been involved in the pathophysiology of hypertension (HT), notably via short chain fatty acids (SCFAs). Among the clinical manifestations of HT, the absence of a significant drop in night-time blood pressure (BP) (also known as the non-dipping BP profile) has been associated with poor renal and cardiovascular outcomes. The putative link between GM-derived metabolites and BP dipping status is still unknown. Methods: Male volunteers (n ¼ 44) were prospectively subjected to 24-hour ambulatory blood pressure monitoring, stool sample collection and a medical questionnaire. Metabolomics analy ses of stool samples were conducted using Nuclear Magnetic Resonance (NMR). Results: Higher amounts of acetate, butyrate and propionate were found in the stools of non dippers (n ¼ 12) versus dippers (n ¼ 26) (p ¼ 0.0252, p ¼ 0.0468, and p ¼ 0.0496, respectively; n ¼ 38 in toto). NMR spectral data were not interpretable in 5 dippers and 1 non-dipper. A simi lar significant association was found when including only patients without anti-HT medications (p ¼ 0.0414, p ¼ 0.0108, and p ¼ 0.0602, respectively; n ¼ 21 in toto). A not significant trend was observed when focussing only on HT patients without anti-HT medications (p ¼ 0.0556; n ¼ 14 in toto). Conclusion: Our pilot study highlights a putative link between GM-derived SCFAs and the BP dipping status, independently of the BP status itself or the anti-hypertensive medications. [less ▲]

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See detailCOVID-19-associated nephropathy includes tubular necrosis and capillarycongestion, with evidence of SARS-CoV-2 in the nephron
BOUQUEGNEAU, Antoine ULiege; ERPICUM, Pauline ULiege; GROSCH, Stéphanie ULiege et al

in Kidney International (2021)

Background: Kidney damage has been reported in patients with COVID-19. Despite numerous reports about COVID-19-associated nephropathy, the factual presence of the SARS-CoV-2 in the renal parenchyma ... [more ▼]

Background: Kidney damage has been reported in patients with COVID-19. Despite numerous reports about COVID-19-associated nephropathy, the factual presence of the SARS-CoV-2 in the renal parenchyma remains controversial. Methods: We consecutively performed 16 immediate (≤3h) post-mortem renal biopsies in patients diagnosed with COVID-19. Kidney samples from 5 patients who died from sepsis not related to COVID-19 were used as controls. Samples were methodically evaluated by 3 pathologists. Virus detection in the renal parenchyma was performed in all samples by bulk RNA RT-PCR (E and N1/N2 genes), immunostaining (nCoV2019 N-Protein), fluorescent in situ hybridization (nCoV2019-S) and electron microscopy. Results: The mean age of our COVID-19 cohort was 68.2±12.8 years, most of whom were males (68.7%). Proteinuria was observed in 53.3% of cases, while acute kidney injury occurred in 60% of cases. Acute tubular necrosis of variable severity was found in all cases, with no tubular or interstitial inflammation. There was no difference in acute tubular necrosis severity between the patients with COVID-19 versus controls. Congestion in glomerular and peri tubular capillaries was respectively observed in 56.3 and 87.5% of patients with COVID-19 compared to 20% of controls, with no evidence of thrombi. The nCoV2019 N-Protein was detected in proximal tubules and also at the basolateral pole of scattered cells of the distal tubules in 9/16 cases. In situ hybridization confirmed these findings in 6/16 cases. RT-PCR of kidney total RNA detected SARS-CoV-2 E and N1/N2 genes in one case. Electron microscopy did not show typical viral inclusions. Conclusions: Our immediate post-mortem kidney samples from patients with COVID-19 highlight a congestive pattern of acute kidney injury, with no significant glomerular or interstitial inflammation. Immunostaining and in situ hybridization suggest that SARS-CoV-2 is present in various segments of the nephron. [less ▲]

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See detailImmunosuppression Withdrawal After Liver Transplantation for Common Variable Immunodeficiency.
Detry, Olivier ULiege; MEURISSE, Nicolas ULiege; Jouret, François ULiege et al

in Liver Transplantation (2021), 27(3), 456-458

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See detailProteinuria in COVID‑19: prevalence, characterization and prognostic role
HUART, Justine ULiege; BOUQUEGNEAU, Antoine ULiege; Lutteri, Laurence ULiege et al

in Journal of Nephrology (2021), 34(3), 355-364

Abstract Background Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantifcation and characterization of ... [more ▼]

Abstract Background Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantifcation and characterization of proteinuria were investigated and their association with mortality was assessed. Methods This retrospective, observational, single center study included 153 patients, hospitalized with COVID-19 between March 28th and April 30th, 2020, in whom total proteinuria and urinary α1-microglobulin (a marker of tubular injury) were measured. Association with mortality was evaluated, with a follow-up until May 7th, 2020. Results According to the Kidney Disease Improving Global Outcomes staging, 14% (n=21) of the patients had category 1 proteinuria (<150 mg/g of urine creatinine), 42% (n=64) had category 2 (between 150 and 500 mg/g) and 44% (n=68) had category 3 proteinuria (over 500 mg/g). Urine α1-microglobulin concentration was higher than 15 mg/g in 89% of patients. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urinary α1-microglobulin were associated with mortality in unadjusted and adjusted models. This association was stronger in subgroups of patients with normal renal function and without a urinary catheter. Conclusions Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin, with increased urinary α1-microglobulin. Tubular proteinuria was associated with mortality in COVID-19 in our restropective, observational study. [less ▲]

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