Publications of Pauline ERPICUM
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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 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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See detailImpact of mesenchymal stromal 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 detailAtteintes rénales de la COVID-19
ERPICUM, Pauline ULiege; GROSCH, Stéphanie ULiege; BOUQUEGNEAU, Antoine ULiege et al

in Revue Médicale de Liège. Supplément (2020), 75(supplément 1), 109-114

The SARS-CoV-2 virus causes a respiratory distress syndrome, the main symptom of COVID-19 (for “COronaVIrus Disease 2019”). This infectious disease has been causing a major health and socio-economic ... [more ▼]

The SARS-CoV-2 virus causes a respiratory distress syndrome, the main symptom of COVID-19 (for “COronaVIrus Disease 2019”). This infectious disease has been causing a major health and socio-economic pandemic since December 2019. The pulmonary alveolus is regarded as the main target of SARS-CoV-2. However, this coronavirus is capable of directly or indirectly affecting other organs, including the kidneys. Here, we summarize the presumed pathophysiology of COVID-19 renal disease. The incidence of acute kidney injury ranges from 0,5 to 22 % of all patients infected with SARS-CoV-2. The need for renal replacement therapy is reported in 5-9 % of patients in intensive care. Histological analysis of renal biopsies mainly shows acute tubular necrosis of varying severity, as well as the congestion of glomerular and peri-tubular capillaries. Endothelitis has been described in few cases. Evidence for a factual inflammation of the glomerulus remains controversial. The medium/long term consequences of COVID-19 nephropathy are unknown and will deserve a tight follow-up. [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 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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See detailMesenchymal Stromal Cells Accelerate Epithelial Tight Junction Assembly via the AMP-Activated Protein Kinase Pathway, Independently of Liver Kinase B1
Rowart, Pascal ULiege; ERPICUM, Pauline ULiege; KRZESINSKI, Jean-Marie ULiege et al

in Stem Cells International (2017)

Background. Mesenchymal stromal cells (MSC) are fibroblast-like multipotent cells capable of tissue-repair properties. Given the essentiality of tight junctions (TJ) in epithelial integrity, we ... [more ▼]

Background. Mesenchymal stromal cells (MSC) are fibroblast-like multipotent cells capable of tissue-repair properties. Given the essentiality of tight junctions (TJ) in epithelial integrity, we hypothesized that MSC modulate TJ formation, via the AMP-activated kinase (AMPK) pathway. Liver kinase-β1 (LKB1) and Ca2+-calmodulin-dependent protein kinase kinase (CaMKK) represent the main kinases that activate AMPK. Methods. The in vitro Ca2+ switch from 5 μM to 1.8 mM was performed using epithelial Madin-Darby canine kidney (MDCK) cells cultured alone or cocultured with rat bone marrow-derived MSC or preexposed to MSC-conditioned medium. TJ assembly was measured by assessing ZO-1 relocation to cell-cell contacts. Experiments were conducted using MDCK stably expressing short-hairpin-RNA (shRNA) against LKB1 or luciferase (LUC, as controls). Compound STO-609 (50 μM) was used as CaMKK inhibitor. Results. Following Ca2+ switch, ZO-1 relocation and phosphorylation/activation of AMPK were significantly higher in MDCK/MSC compared to MDCK. No difference in AMPK phosphorylation was observed between LKB1-shRNA and Luc-shRNA MDCK following Ca2+ switch. Conversely, incubation with STO-609 prior to Ca2+ switch prevented AMPK phosphorylation and ZO-1 relocation. MSC-conditioned medium slightly but significantly increased AMPK activation and accelerated TJ-associated distribution of ZO-1 post Ca2+ switch in comparison to regular medium. Conclusions. MSC modulate the assembly of epithelial TJ, via the CaMKK/AMPK pathway independently of LKB1. [less ▲]

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See detailintravenous administration of mesenchymal stream cells modulates renal lipid metabolism in rats
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

Conference (2017, March 16)

Mesenchymal stromal cells (MSC) have been shown to attenuate renal ischemia/reperfusion (I/R) injury in rodents. Still, the mechanisms of such a nephroprotection remain unclear. Here, rats were ... [more ▼]

Mesenchymal stromal cells (MSC) have been shown to attenuate renal ischemia/reperfusion (I/R) injury in rodents. Still, the mechanisms of such a nephroprotection remain unclear. Here, rats were intravenously infused with MSC (1.5x10^6 cells in 1 ml saline; MSCD-7 group, n=6) or equivalent volume of saline (SD-7 group, n=6) 7 days before kidney sampling. High-throughput RNA sequencing technology was used to compare transcriptomic renal profiles, using TopHat and Cufflinks open-source software tools. A total of 494 and 256 genes were found to be significantly (q-value <.05) down- and up-regulated in mscd-7 versus sd-7 groups, respectively. Hierarchical cluster analysis by “david” “webgestalt” softwares highlighted that the metabolic pathways mostly affected msc included adipogenesis, insulin signalling, fatty acid (fa) biosynthesis, il-6 b-cell receptor il-3 pathway nuclear receptors involved lipid me- tabolism. Real-time qpcr immunoblotting analyses confirmed pivotal enzymes of fa biosynthesis were significantly downregulated group, whereas expression ppar alpha, a transcription factor oxidation, was induced msc. Additional- ly, fat />CD36 – a key regulator of membrane uptake of FA – was increased in MSCD-7 kidneys, with a preferential localization in proximal tubules (PT). As a whole, our data suggest that MSC infusion causes critical modifications of lipid metabolism, including (i) down-regulation of FA biosynthesis; (ii) activation of PPAR alpha pathway, and (iii) prioritization of FA as sources of energy in PT cells, which may eventually prevent lipid peroxidation and attenuate renal I/R damage. [less ▲]

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See detailAdministration of Third-Party Mesenchymal Stromal Cells at the Time of Kidney Transplantation: Interim Safety Analysis at One-Year Follow-Up
WEEKERS, Laurent ULiege; ERPICUM, Pauline ULiege; DETRY, Olivier ULiege et al

Conference (2017, March 16)

Mesenchymal stromal cells (MSC)-based therapy has been proposed in kidney transplantation (KTx). We report on the 1-year follow-up of an open-label phase I trial using MSC in KTx. On postoperative day 3 ... [more ▼]

Mesenchymal stromal cells (MSC)-based therapy has been proposed in kidney transplantation (KTx). We report on the 1-year follow-up of an open-label phase I trial using MSC in KTx. On postoperative day 3, third-party MSC (~2.0x106/kg) were administered to 7 non-immunized first-transplant recip- ients from deceased donors, under standard immunosuppression (Basiliximab, Tacrolimus, MMF and steroids). No HLA matching was required for MSC donors. Seven comparable KTx recipients were included as controls. Informed consent was obtained. No side-effect was noted at the time of MSC injection. Still, 1 patient with a history of ischemic heart disease had a NSTEMI ~3h after MSC infusion. Ten months after KTx, 1 MSC patient had type B aortic dissection and STEMI. Four MSC patients had at least 1 opportunistic infection, whereas 3 controls had polyoma-BK viremia. At day 14, eGFR in MSC and control groups was 47.1 ± 6.8 and 39.7 ± 5.9 ml/min, respectively (p, 0.05). At 1 year, eGFR in MSC and control groups was 46.5 ± 18.6 and 54.2 ± 16.3 ml/min, respectively (p, 0.42). Per-cause biopsies evidenced 1 bor- derline and 1 acute rejections in MSC group, whereas no AR was biopsy-proven in controls. Three patients developed anti-HLA antibodies against MSC (n=1) or shared kidney/MSC (n=2) mismatches.MSC infusion was safe in all patients except one. Incidence of opportunist infections was similar in both groups. No difference in eGFR was found at 1-year post KTx. Putative immunization against MSC was observed in 3 patients. [less ▲]

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See detailNon-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients, part II: omics analyses of urine and blood samples
Erpicum, Pauline ULiege; HANSSEN, Oriane ULiege; WEEKERS, Laurent ULiege et al

in NDT Plus (2017)

Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, the full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ... [more ▼]

Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, the full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene-expression profiling and omics analyses of blood and urine samples. Most imaging techniques, such as contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leucocytes may be detectable by 18F-fluorodeoxyglucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3ε, CXCL10 and 18S RNA levels, have been identified. None of these approaches has yet been adopted in the clinical follow-up of KTRs, but standardization of analysis procedures may help assess reproducibility and comparative diagnostic yield in large, prospective, multicentre trials. [less ▲]

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See detailNon-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients. Part I. In vivo imaging methods.
HANSSEN, Oriane ULiege; Erpicum, Pauline ULiege; LOVINFOSSE, Pierre ULiege et al

in Clinical Kidney Journal (2017), 10(1), 97-105

Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ... [more ▼]

Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene expression profiling and omics analyses of blood and urine samples. Most imaging techniques, like contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leukocytes may be detectable by 18F-fluoro-deoxy-glucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3epsilon, IP-10 and 18S RNA levels, have been identified. None of these approaches has been adopted yet in the clinical follow-up of KTRs, but standardization of procedures may help assess reproducibility and compare diagnostic yields in large prospective multicentric trials. [less ▲]

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See detailAdministration of Third-Party Mesenchymal Stromal Cells at the Time of Kidney Transplantation: Interim Safety Analysis at One-Year Follow-Up
Erpicum, Pauline ULiege; WEEKERS, Laurent ULiege; DETRY, Olivier ULiege et al

Conference (2016, April 28)

Objective. Mesenchymal stromal cells (MSC) therapy has been suggested in kidney transplantation (KTx). We report on the 1-year follow-up of an open-label phase I trial using MSC at the time of KTx ... [more ▼]

Objective. Mesenchymal stromal cells (MSC) therapy has been suggested in kidney transplantation (KTx). We report on the 1-year follow-up of an open-label phase I trial using MSC at the time of KTx. Methods. On postoperative day 3 (D3), third-party MSC (~2.0x106/kg) were administered to 7 non-immunized first-transplant recipients from deceased donors, under standard immunosuppression (Basiliximab, Tacrolimus, MMF and steroids). No HLA matching was required for MSC donors. In parallel, 7 comparable KTx recipients were included as controls. Written informed consent was obtained from all participants. Results. No hemodynamic or immune-allergic side-effect was noted at the time of MSC injection. Still, 1 patient with a history of ischemic heart disease had a NSTEMI ~3h after MSC infusion. Four MSC patients presented with CMV reactivation within 165 ± 96 days post KTx, whereas 3 controls had positive polyoma-BK viremia within 92 ± 4d post KTx. Three MSC patients were affected by pneumonia within 269 ± 98d post KTx, whereas 3 controls had urinary infection within 48 ± 43d post KTx. No MSC engraftment syndrome was observed. At D14, eGFR in MSC and control groups was 47.1 ± 6.8 and 39.7 ± 5.9 ml/min, respectively (p, 0.05). At 1 year, eGFR in MSC and control groups was 43.1 ± 17.8 and 53.9 ± 13.4 ml/min, respectively (p, 0.25). At 3-month protocol biopsy, no rejection was evidenced in MSC or control patients. Later on, 1 acute rejection was diagnosed at D330 in 1 MSC patient. No biopsy-proven AR was noted in controls. Three patients developed anti-HLA antibodies against MSC (n=1) or shared kidney/MSC (n=2) mismatches. Conclusions. MSC infusion was safe in all patients except one. Incidence of opportunist and non-opportunist infections was similar in both MSC and control groups. No MSC engraftment syndrome was documented. No difference in eGFR was found at 1 year post KTx. Putative immunization against MSC was observed in 3 patients. [less ▲]

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See detailadministration of Third-Party Mesenchymal Stromal Cells at the Time of Kidney Transplantation: Interim Safety Analysis at One-Year Follow-Up
WEEKERS, Laurent ULiege; Erpicum, Pauline ULiege; DETRY, Olivier ULiege et al

in Transplant International (2016), 29(Suppl 2), 13-6

Objective. Mesenchymal stromal cells (MSC) therapy has been suggested in kidney transplantation (KTx). We report on the 1-year follow-up of an open-label phase I trial using MSC at the time of KTx ... [more ▼]

Objective. Mesenchymal stromal cells (MSC) therapy has been suggested in kidney transplantation (KTx). We report on the 1-year follow-up of an open-label phase I trial using MSC at the time of KTx. Methods. On postoperative day 3 (D3), third-party MSC (~2.0x106/kg) were administered to 7 non-immunized first-transplant recipients from deceased donors, under standard immunosuppression (Basiliximab, Tacrolimus, MMF and steroids). No HLA matching was required for MSC donors. In parallel, 7 comparable KTx recipients were included as controls. Written informed consent was obtained from all participants. Results. No hemodynamic or immune-allergic side-effect was noted at the time of MSC injection. Still, 1 patient with a history of ischemic heart disease had a NSTEMI ~3h after MSC infusion. Four MSC patients presented with CMV reactivation within 165 ± 96 days post KTx, whereas 3 controls had positive polyoma-BK viremia within 92 ± 4d post KTx. Three MSC patients were affected by pneumonia within 269 ± 98d post KTx, whereas 3 controls had urinary infection within 48 ± 43d post KTx. No MSC engraftment syndrome was observed. At D14, eGFR in MSC and control groups was 47.1 ± 6.8 and 39.7 ± 5.9 ml/min, respectively (p, 0.05). At 1 year, eGFR in MSC and control groups was 43.1 ± 17.8 and 53.9 ± 13.4 ml/min, respectively (p, 0.25). At 3-month protocol biopsy, no rejection was evidenced in MSC or control patients. Later on, 1 acute rejection was diagnosed at D330 in 1 MSC patient. No biopsy-proven AR was noted in controls. Three patients developed anti-HLA antibodies against MSC (n=1) or shared kidney/MSC (n=2) mismatches. Conclusions. MSC infusion was safe in all patients except one. Incidence of opportunist and non-opportunist infections was similar in both MSC and control groups. No MSC engraftment syndrome was documented. No difference in eGFR was found at 1 year post KTx. Putative immunization against MSC was observed in 3 patients. [less ▲]

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See detailImpact of timing administration of mesenchymal stromal cells on serum creatinine following renal ischemia/ reperfusion in rats
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Transplant International (2015, November), 28(S4), 1129

Experimental models of renal ischemia/reperfusion (I/R) have suggested protective effects of mesenchymal stromal cells (MSC) therapy. Still, param- eters of MSC injection, including volume, route and ... [more ▼]

Experimental models of renal ischemia/reperfusion (I/R) have suggested protective effects of mesenchymal stromal cells (MSC) therapy. Still, param- eters of MSC injection, including volume, route and timing of cell administration, remain largely debated. Particularly, MSC infusion in mouse has been shown to be beneficial “a priori” but deleterious “a posteriori” of renal I/R injury. In order to further investigate the influence of the timing of MSC administration, we used 10-week-old Lewis rats categorized in 4 groups. Groups 1 (MSC D-7, n = 10) and 2 (MSC D + 1, n = 7) received caudal i.v. injection of MSC (1.5 9 106 in 1 ml of saline) 7 days before or 1 day after renal I/R, respectively. Control groups 3 (saline D-7, n = 6) and 4 (saline D + 1, n = 6) received equal volume of saline at similar time points. Left renal ischemia (by clamping of the renal pedicle) lasted 45 min. Right nephrectomy was simultaneously performed. Blood sample was collected from inferior vena cava at 48 h post reperfusion. MSC phenotype was confirmed by FACS analysis. In groups 1 and 3, serum creatinine (SCr) reached 1.4 ` 0.7 versus 2.4 ` 0.8 mg/dl, respectively (p < 0.05). In groups 2 and 4, SCr was 4.9 ` 0.7 versus 3.3 ` 0.9 mg/dl, respectively (p < 0.001). Furthermore, SCr levels were statistically worse when MSC were administered after renal I/R in comparison to a priori infusion (p < 0.0001). In conclusion, MSC administration 7 days prior to renal I/R attenuates kidney injury in comparison to (i) saline infusion or (ii) MSC infusion 1 day after renal I/R. Conversely, on the basis of SCr levels, MSC therapy performed after renal I/R worsens kidney injury in rats. [less ▲]

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See detailThird-party mesenchymal stem cell infusion in kidney transplant recipient: 6-month safety interim analysis
WEEKERS, Laurent ULiege; ERPICUM, Pauline ULiege; DETRY, Olivier ULiege et al

in Transplant International (2015, November), 28(S4), 223-224278

Background: Mesenchymal stromal cell (MSC) have immunomodulating properties and could be used as immunosuppressive agents. We report the 6- month safety results for the 5 first patients treated with MSC ... [more ▼]

Background: Mesenchymal stromal cell (MSC) have immunomodulating properties and could be used as immunosuppressive agents. We report the 6- month safety results for the 5 first patients treated with MSC after kidney transplantation (KTx). Here, we address 3 specific safety issues: immunization against MSC and engraftment syndrome defined as acute graft dysfunction not related to rejection and over-immunosuppression. Patients and method: MSC production was carried out locally. MSC were not matched with kidney recipients’ HLA. Included patients were non-immunized, first transplant recipients from deceased donors. MSC (1.5–3.0 9 106/kg) infusion was planned 3 to 5 days post KTx. Patients with cardiovascular instability post KTx were excluded. All patients were treated with Basiliximab induction, Tacrolimus, Mycophenolate Mofetil and Steroid. We prospectively screened for anti-HLA antibodies at month 1, 3 and 6. Informed consent was obtained from all participants. The local ethical committee approved the protocol. Results: Collectively there were 23/50 and 29/50 HLA mismatches (MM) with kidney and MSC donor respectively, out of which 5 were shared MM. One patient developed de novo DSA, 2 patients anti-HLA antibodies against shared kidney/MSC MM and 1 patient developed 2 specific antibodies against MSC (MSCSA) at month 6. All antibodies were anti HLA class I except for 1. We did not observe any “engraftment” syndrome. Three patients experienced non- severe opportunistic infections: 1 CMV reactivation and 2 polyoma-BK virus viremia.Conclusion: We did not observe any strong safety signal. We did however observe some degree of immunization in 3 patients: 2 developed antibodies against shared kidney/MSC donor HLA MM and 1 MSCSA. [less ▲]

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