54 results on '"Nortier JL"'
Search Results
2. Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases
- Author
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UCL - Autre, Norden, AGW, Scheinman, SJ, Deschodt-Lanckman, MM, Lapsley, M, Nortier, JL, Thakker, RV, Unwin, R.J., Wrong, O, 31st Annual Meeting of the American-Society-of-Nephrology, UCL - Autre, Norden, AGW, Scheinman, SJ, Deschodt-Lanckman, MM, Lapsley, M, Nortier, JL, Thakker, RV, Unwin, R.J., Wrong, O, and 31st Annual Meeting of the American-Society-of-Nephrology
- Abstract
Background. The term "tubular proteinuria" is often used interchangeably with "low molecular weight proteinuria" (LMWP), although the former implies a definite etiology. A specific quantitative definition of tubular proteinuria is needed, and we address this by studying five different renal disorders. Methods. Tubular proteinuria was assessed by measuring urinary retinol-binding protein (RBP), beta(2)-microglobulin (beta(2)M), alpha(1)-microglobulin (alpha(1)M), and albumin in 138 patients: 26 affected males and 24 female carriers of the X-linked syndrome "Dent's disease," 6 patients with other Fanconi syndromes, 17 with distal renal tubular acidosis (dRTA), 39 with glomerulonephritis (GN), and 26 with Chinese herbs nephropathy (CHN). Results. REP was better than beta(2)M or alpha(1)M in identifying the tubular proteinuria of Dent's disease. Median urinary REP levels in mg/mmol creatinine were: affected male Dent's, 18.2, N = 26; carrier female Dent's, 0.30, N = 24; dRTA, 0.027, N = 17; GN, 0.077, N = 39; and normal adults, 0.0079, N = 61. Elevated urinary REP (>0.017) and albumin < (10 X REP) + 2 identified all patients with the LMWP of Dent's disease and clearly distinguished their LMWP from that of dRTA and GN. This is a quantitative definition of tubular proteinuria. Consistent with this definition, 80% of those patients with CHN who had an elevated REP had tubular proteinuria. Urinary REP and albumin in carriers of Dent's disease were strikingly correlated over a 100-fold range (R = 0.933). Conclusion. The combination of elevated urinary REP (>0.017) and albumin < (10 x REP) + 2 (mg protein/mmol creatinine) is a quantitative definition of tubular proteinuria. Furthermore, our findings suggest that a shared defect in tubular REP and albumin reuptake causes this form of proteinuria.
- Published
- 2000
3. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)
- Author
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Nortier JL, Martinez MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, Depierreux MF, De Pauw L, Abramowicz D, Vereerstraeten P, Vanherweghem JL, Nortier, J L, Martinez, M C, Schmeiser, H H, Arlt, V M, Bieler, C A, Petein, M, Depierreux, M F, De Pauw, L, and Abramowicz, D
- Abstract
Background: Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic.Methods: The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated.Results: Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma.Conclusions: The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high. [ABSTRACT FROM AUTHOR]- Published
- 2000
4. Experimental Aristolochic Acid Nephropathy: A Relevant Model to Study AKI-to-CKD Transition.
- Author
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Baudoux T, Jadot I, Declèves AE, Antoine MH, Colet JM, Botton O, De Prez E, Pozdzik A, Husson C, Caron N, and Nortier JL
- Abstract
Aristolochic acid nephropathy (AAN) is a progressive tubulointerstitial nephritis caused by the intake of aristolochic acids (AA) contained in Chinese herbal remedies or contaminated food. AAN is characterized by tubular atrophy and interstitial fibrosis, characterizing advanced kidney disease. It is established that sustained or recurrent acute kidney injury (AKI) episodes contribute to the progression of CKD. Therefore, the study of underlying mechanisms of AA-induced nephrotoxicity could be useful in understanding the complex AKI-to-CKD transition. We developed a translational approach of AKI-to-CKD transition by reproducing human AAN in rodent models. Indeed, in such models, an early phase of acute tubular necrosis was rapidly followed by a massive interstitial recruitment of activated monocytes/macrophages followed by cytotoxic T lymphocytes, resulting in a transient AKI episode. A later chronic phase was then observed with progressive tubular atrophy related to dedifferentiation and necrosis of tubular epithelial cells. The accumulation of vimentin and αSMA-positive cells expressing TGFβ in interstitial areas suggested an increase in resident fibroblasts and their activation into myofibroblasts resulting in collagen deposition and CKD. In addition, we identified 4 major actors in the AKI-to-CKD transition: (1) the tubular epithelial cells, (2) the endothelial cells of the interstitial capillary network, (3) the inflammatory infiltrate, and (4) the myofibroblasts. This review provides the most comprehensive and informative data we were able to collect and examines the pending questions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baudoux, Jadot, Declèves, Antoine, Colet, Botton, De Prez, Pozdzik, Husson, Caron and Nortier.)
- Published
- 2022
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5. Antenatal Membranous Nephropathy and Type 2 (Axonal) Charcot-Marie-Tooth With Mutations in the Metallo-Membrane Endopeptidase Gene: A Call for Family Screening and Pharmacovigilance.
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Nortier JL, Remiche G, Delrée P, Nauta J, Notermans NC, Vivarelli M, Diodato D, Solé G, Debiec H, and Ronco P
- Published
- 2021
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6. The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro.
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Sborchia M, De Prez EG, Antoine MH, Bienfait L, Indra R, Valbuena G, Phillips DH, Nortier JL, Stiborová M, Keun HC, and Arlt VM
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- Animals, Aristolochic Acids metabolism, Cells, Cultured, Cytochrome P-450 CYP1A1 genetics, Fibroblasts metabolism, Fibroblasts pathology, Gene Expression drug effects, Kidney Function Tests, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Mutagens metabolism, NAD(P)H Dehydrogenase (Quinone) genetics, Aristolochic Acids toxicity, DNA Damage, Fibroblasts drug effects, Kidney Tubules, Proximal drug effects, Mutagens toxicity, Tumor Suppressor Protein p53 genetics
- Abstract
Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(-/-) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by
32 P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography-mass spectrometry (GC-MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice and exposed them to AAI in vitro (50 µM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(-/-) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(-/-) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.- Published
- 2019
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7. Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.
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Jelaković B, Dika Ž, Arlt VM, Stiborova M, Pavlović NM, Nikolić J, Colet JM, Vanherweghem JL, and Nortier JL
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- Animals, Aristolochia, Balkan Nephropathy diagnosis, Balkan Nephropathy pathology, Balkan Nephropathy therapy, Carcinogens toxicity, DNA Adducts, Humans, Mass Screening, Aristolochic Acids toxicity, Balkan Nephropathy chemically induced, Carcinoma, Transitional Cell chemically induced, Environmental Exposure adverse effects, Kidney Neoplasms chemically induced, Ureteral Neoplasms chemically induced
- Abstract
Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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8. CD4 + and CD8 + T Cells Exert Regulatory Properties During Experimental Acute Aristolochic Acid Nephropathy.
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Baudoux T, Husson C, De Prez E, Jadot I, Antoine MH, Nortier JL, and Hougardy JM
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- Acute Kidney Injury pathology, Animals, Biomarkers, Disease Models, Animal, Immunohistochemistry, Immunophenotyping, Kidney immunology, Kidney metabolism, Kidney pathology, Lymphocyte Depletion, Male, Mice, Spleen immunology, Spleen metabolism, Spleen pathology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Acute Kidney Injury etiology, Acute Kidney Injury metabolism, Aristolochic Acids adverse effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Immunomodulation
- Abstract
Experimental aristolochic acid nephropathy is characterized by transient acute proximal tubule necrosis and inflammatory cell infiltrates followed by interstitial fibrosis and tubular atrophy. The respective role of T-cell subpopulations has never been studied in the acute phase of the mouse model, and was heretofore exclusively investigated by the use of several depletion protocols. As compared to mice injected with aristolochic acids alone, more severe acute kidney injury was observed after CD4
+ or CD8+ T-cells depletion. TNF-alpha and MCP-1 mRNA renal expressions were also increased. In contrast, regulatory T-cells depletion did not modify the severity of the aristolochic acids induced acute kidney injury, suggesting an independent mechanism. Aristolochic acids nephropathy was also associated with an increased proportion of myeloid CD11bhigh F4/80mid and a decreased proportion of their counterpart CD11blow F4/80high population. After CD4+ T-cell depletion the increase in the CD11bhigh F4/80mid population was even higher whereas the decrease in the CD11blow F4/80high population was more marked after CD8+ T cells depletion. Our results suggest that CD4+ and CD8+ T-cells provide protection against AA-induced acute tubular necrosis. Interestingly, T-cell depletion was associated with an imbalance of the CD11bhigh F4/80mid and CD11blow F4/80high populations.- Published
- 2018
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9. Severe myoglobinuric acute kidney injury in a kidney recipient: rapid recovery after hemodialysis with the super high-flux membrane Theralite® .
- Author
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Goubella A, Gankam-Kengne F, Baudoux T, Fagnoul D, Husson C, Delforge ML, Broeders N, and Nortier JL
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- Acute Kidney Injury therapy, Humans, Interleukin-6 blood, Male, Middle Aged, Myoglobinuria therapy, Rhabdomyolysis therapy, Acute Kidney Injury etiology, Kidney Transplantation adverse effects, Myoglobinuria etiology, Renal Dialysis methods
- Abstract
Myoglobinuric acute kidney injury (AKI) is a severe condition requiring early therapeutic strategies. Early recognition and treatment are crucial to reduce morbidity and mortality rate. Here, we report a kidney recipient with severe rhabdomyolysis and AKI secondary to parvovirus B19 infection. Initiation of hemodialysis with the super high-flux filter Theralite
® (Gambro, cut-off 45 kDa, 2.1 m2 ) resulted in the clearance of myoglobin from 61 to 71% after 3 hours. Elimination rates of IL-6 and β2-microglobulin were ~ 30 - 64% and 55 - 71% after 3 hours, respectively. Renal graft function rapidly recovered. The place of this effective but expensive procedure still needs to be defined and validated in high-risk patients. .- Published
- 2017
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10. Early detection of acute cisplatin nephrotoxicity: interest of urinary monitoring of proximal tubular biomarkers.
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Bunel V, Tournay Y, Baudoux T, De Prez E, Marchand M, Mekinda Z, Maréchal R, Roumeguère T, Antoine MH, and Nortier JL
- Abstract
Background: Renal toxicity induced by cisplatin (CisPt) is a clinical issue in patients with or without chronic kidney disease (CKD). Proximal tubular injury can result in acute kidney injury (AKI), which may compromise the course of chemotherapy and the prognosis. The purpose of this study was to investigate the time course of urinary markers of acute tubulotoxicity and to assess the usefulness of such monitoring in a routine clinical setting., Methods: This work is an open prospective pilot study carried out among 23 patients receiving a platinum-based chemotherapy. Individual comorbidities, plasma parameters of kidney function (urea, creatinine) and estimated glomerular filtration rate were registered. Urinary excretion of leucine aminopeptidase, neutrophil gelatinase-associated lipocalin, cystatin C, liver fatty acid-binding protein and interleukin-18 were monitored during successive chemotherapy cycles. Episodes of AKI were identified according to KDIGO (Kidney Disease Improving Global Outcomes) 2012 guidelines., Results: A total of 28 patients were recruited; among them 23 agreed to be part of the study, of whom 18 received CisPt and 5 carbo- or oxaliplatin. Of the 18 CisPt patients, 12 had a preexisting CKD. Sixteen AKI episodes were observed in 13 patients receiving CisPt with a pejorative evolution in seven cases (partial recovery of the renal function); a transient but dramatic increase in urinary biomarkers was observed 3 h after chemotherapy initiation, whereas plasma creatinine rise appeared 72 h after the end of CisPt treatment. Identified precipitating factors included: dehydration due to lack of fluid intake or diuretic use, exposure to high CisPt doses, regular use of nonsteroidal anti-inflammatory drugs and/or iodinated contrast agents and sepsis., Conclusion: Even if numerous precipitating factors could be avoided, the monitoring of urinary markers seemed helpful for the early detection of subclinical AKI induced during CisPt chemotherapy.
- Published
- 2017
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11. Protective Effects of Pistacia lentiscus L. fruit extract against calcium oxalate monohydrate induced proximal tubular injury.
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Cheraft-Bahloul N, Husson C, Ourtioualous M, Sinaeve S, Atmani D, Stévigny C, Nortier JL, and Antoine MH
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- Animals, Cell Adhesion, Cell Line, Cell Survival drug effects, Humans, Kidney Tubules, Proximal pathology, Plant Extracts chemistry, Calcium Oxalate toxicity, Fruit chemistry, Kidney Tubules, Proximal drug effects, Pistacia chemistry, Plant Extracts pharmacology
- Abstract
Ethnopharmacological Relevance: The world prevalence of kidney stones is increasing and plants are frequently used to treat urolithiasis. Pistacia lentiscus L, a plant which freely grows around the Mediterranean basin areas, is widely used for various pathologies. P. lentiscus has an important impact as it has economical value on top of its pharmacological interest. Decoctions of its aerial parts and/or resin are used to treat kidney stones., Aim of the Study: To in vitro assess the potential nephroprotective effect of Pistacia lentiscus ethanolic fruit extract (PLEF) on proximal tubular cells in response to the adhesion of calcium oxalate monohydrate (COM) crystals., Materials and Methods: Human Kidney [HK]-2 cells were incubated with and without COM in the presence or absence of PLEF. Cell viability was measured by the resazurin assay. The expression of E-cadherin was analyzed by PCR. The extracellular production of H
2 O2 was measured by Amplex® Red H2 O2 Assay. The numbers of detached or non-adherent COM crystals in the presence of PLEF were microscopically captured and counted using ImageJ software. The interaction of PLEF with COM and the effect of PLEF on crystal size were analyzed by flow cytometry. The spectrophotometric measurement of turbidity was performed for assessing the COM concentration., Results: PLEF incubated with COM was able to increase the cell viability. The decrease of E-cadherin expression after incubation with COM was counteracted by PLEF. Overproduction of H2 O2 induced by COM was also inhibited by PLEF. Observations using flow cytometry showed that interactions between PLEF and the COM crystals occurred. PLEF was also effective in reducing the particles size and in lowering COM concentration., Conclusion: Our data show that COM tubulotoxicity can be significantly reversed by PLEF -at least in part- via an inhibition of COM crystals adhesion onto the apical membrane. This early beneficial effect of PLEF needs to be further investigated as a useful strategy in nephrolithiasis prevention., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)- Published
- 2017
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12. Donor Cancer Transmission in Kidney Transplantation.
- Author
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Baudoux TER, Gastaldello K, Rorive S, Hamade A, Broeders N, and Nortier JL
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- 2016
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13. Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats.
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Pozdzik AA, Giordano L, Li G, Antoine MH, Quellard N, Godet J, De Prez E, Husson C, Declèves AE, Arlt VM, Goujon JM, Brochériou-Spelle I, Ledbetter SR, Caron N, and Nortier JL
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury prevention & control, Animals, Antibodies, Neutralizing immunology, Antibodies, Neutralizing pharmacology, Aristolochic Acids, Blotting, Western, Cell Line, Cells, Cultured, Endothelial Cells drug effects, Endothelial Cells metabolism, Homeostasis drug effects, Humans, Kidney Tubules, Proximal drug effects, Kidney Tubules, Proximal metabolism, Male, Models, Biological, Myofibroblasts drug effects, Myofibroblasts metabolism, Pericytes drug effects, Rats, Wistar, Signal Transduction drug effects, Smad Proteins metabolism, Time Factors, Transforming Growth Factor beta immunology, Acute Kidney Injury metabolism, Mitochondrial Proteins metabolism, Pericytes metabolism, Receptor, Platelet-Derived Growth Factor beta metabolism, Transforming Growth Factor beta metabolism
- Abstract
Background: The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target., Aims: In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN., Materials and Methods: Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily., Results: At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro., Conclusions: The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation.
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- 2016
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14. Human bone morphogenetic protein-7 does not counteract aristolochic acid-induced renal toxicity.
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Antoine MH, Debelle F, Piccirilli J, El Kaddouri F, Declèves AE, De Prez E, Husson C, Mies F, Bourgeade MF, and Nortier JL
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- Animals, Bone Morphogenetic Protein 7 administration & dosage, Cell Line, Fibronectins metabolism, Fibrosis, Humans, Kidney metabolism, Kidney pathology, Male, Rats, Wistar, Recombinant Proteins administration & dosage, Recombinant Proteins therapeutic use, Renal Insufficiency, Chronic chemically induced, Renal Insufficiency, Chronic metabolism, Renal Insufficiency, Chronic pathology, Transforming Growth Factor beta pharmacology, Transforming Growth Factor beta urine, Treatment Outcome, Vimentin biosynthesis, beta Catenin metabolism, Aristolochic Acids toxicity, Bone Morphogenetic Protein 7 therapeutic use, Kidney drug effects, Renal Insufficiency, Chronic prevention & control
- Abstract
Aristolochic acids (AA) are nephrotoxic and profibrotic agents, leading to chronic kidney disease. As some controversial studies have reported a nephroprotective effect of exogenous recombinant human bone morphogenetic protein (rhBMP)-7 in several models of renal fibrosis, we investigated the putative effect of rhBMP-7 to prevent progressive tubulointerstitial damage after AA intoxication in vitro and in vivo. In vitro, the toxicity of AA on renal tubular cells was demonstrated by an increase in vimentin as well as a decrease in β-catenin expressions, reflecting a dedifferentiation process. Increased fibronectin and interleukin-6 levels were measured in the supernatants. Enhanced α-SMA mRNA levels associated to decreased E-cadherin mRNA levels were also measured. Incubation with rhBMP-7 only prevented the increase in vimentin and the decrease in β-catenin expressions. In vivo, in a rat model of AA nephropathy, severe tubulointerstitial lesions induced by AA after 10 and 35 days (collagen IV deposition and tubular atrophy), were not prevented by the rhBMP-7 treatment. Similarly, rhBMP-7 did not ameliorate the significant increase in urinary concentrations of transforming growth factor-β. In summary, our in vitro data demonstrated a poor beneficial effect of rhBMP-7 to reverse cell toxicity while, in vivo, there was no beneficial effect of rhBMP-7. Therefore, further investigations are needed to confirm the exact role of BMP-7 in progressive chronic kidney disease., (Copyright © 2015 John Wiley & Sons, Ltd.)
- Published
- 2015
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15. Bacillus Calmette-Guerin therapy in non-muscle-invasive bladder carcinoma after renal transplantation for end-stage aristolochic acid nephropathy.
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Roumeguère T, Broeders N, Jayaswal A, Rorive S, Quackels T, Pozdzik A, Arlt VM, Schmeiser HH, and Nortier JL
- Subjects
- Administration, Intravesical, Adult, Aged, Female, Follow-Up Studies, Humans, Kidney Failure, Chronic chemically induced, Middle Aged, Neoplasm Invasiveness, Urinary Bladder Neoplasms pathology, Aristolochic Acids toxicity, BCG Vaccine therapeutic use, Kidney Failure, Chronic surgery, Kidney Transplantation, Urinary Bladder Neoplasms drug therapy
- Abstract
Intravesical instillation of bacillus Calmette-Guerin (BCG) is the treatment of choice for non-muscle-invasive bladder cancer (NMIBC) of high grade and/or carcinoma in situ. This study evaluated the feasibility, efficacy, and tolerance of BCG instillations in eight kidney recipients for end-stage aristolochic acid nephropathy (AAN), a condition at high risk of urothelial carcinoma, and diagnosed for NMIBC. Five of them had relapsed after mitomycin C treatment. Tolerance to BCG was evaluated clinically and regular follow-up with fluorescence cystoscopy was performed along with renal graft function monitoring. Immunosuppression doses were adjusted and prophylactic anti-tuberculous treatment given to reduce risks of graft rejection and infection. After a mean follow-up period of 50 months, seven of the eight patients are free of relapse and kidney graft function remained unchanged. Tolerance was good, except for one episode of fever and one early discontinuation because of subjective discomfort. No systemic tuberculous infection was observed. This is the first clinical observation of successful BCG therapy for NMIBC in patients given transplant for end-stage AAN. Under standardized conditions, immunotherapy based on intravesical BCG is feasible, effective, and well tolerated in renal transplantation., (© 2014 Steunstichting ESOT.)
- Published
- 2015
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16. Morphological Retrospective Study of Peritoneal Biopsies from Patients with Encapsulating Peritoneal Sclerosis: Underestimated Role of Adipocytes as New Fibroblasts Lineage?
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Tooulou M, Demetter P, Hamade A, Keyzer C, Nortier JL, and Pozdzik AA
- Abstract
Background. Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). Besides the endothelial-to-mesenchymal transition (EMT), recently peritoneal adipocytes emerged as a potential source of fibrosis. We performed immunohistochemistry to approach EMT and to localize peritoneal adipocytes in peritoneal biopsies from PD-related EPS patients. Material and Methods. We investigated tissue expression of podoplanin, cytokeratin AE1/AE3 (mesothelium), calretinin (adipocytes), alpha-smooth muscle actin [α-SMA] (mesenchymal cells), interstitial mononuclear cell inflammation, and neoangiogenesis (CD3, CD4, CD8, CD20, CD68, and CD31 immunostainings, resp.). Results. Three patients (1 man/2 women; 17, 64, and 39 years old, resp.) developed EPS after 21, 90, and 164 months of PD therapy. In patients with EPS, we observed (1) loss of AE1/AE3 cytokeratin+ mesothelial cells without any evidence of migration into the interstitium, (2) disappearance of adipose tissue, (3) diffuse infiltration of calretinin+ cells in the areas of submesothelial fibrosis with a huge number of α-SMA and calretinin+ fusiform cells, and (4) increased vascular density. Conclusion. We report that the involvement of EMT in peritoneal fibrosis is difficult to demonstrate and that the calretinin+ adipocytes might be an underestimated component and a new source of myofibroblasts in peritoneal remodeling during PD-related EPS.
- Published
- 2015
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17. Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis.
- Author
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Laville M, Dorval M, Fort Ros J, Fay R, Cridlig J, Nortier JL, Juillard L, Dębska-Ślizień A, Fernández Lorente L, Thibaudin D, Franssen C, Schulz M, Moureau F, Loughraieb N, and Rossignol P
- Subjects
- Aged, Aged, 80 and over, Anticoagulants adverse effects, Coated Materials, Biocompatible, Equipment Failure, Female, Hemorrhage chemically induced, Heparin adverse effects, Humans, Male, Middle Aged, Prospective Studies, Renal Insufficiency therapy, Sodium Chloride administration & dosage, Treatment Outcome, Anticoagulants administration & dosage, Heparin administration & dosage, Membranes, Artificial, Renal Dialysis methods
- Abstract
Heparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standard-of-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standard-of-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.
- Published
- 2014
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18. Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial.
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Massart A, Debelle FD, Racapé J, Gervy C, Husson C, Dhaene M, Wissing KM, and Nortier JL
- Subjects
- Aged, Double-Blind Method, Female, Fibroblast Growth Factor-23, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Vitamin D blood, Cholecalciferol administration & dosage, Cholecalciferol blood, Renal Dialysis methods, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic therapy
- Abstract
Background: The 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol., Study Design: 2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study., Setting & Participants: 55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October 2009., Intervention: Cholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines., Outcomes: Primary end point was the percentage of patients with 25(OH)D levels≥30ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D., Measurements: Blood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and 39., Results: The primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level≥30ng/mL in patients issued from the placebo group., Limitations: Small size of the study population., Conclusions: Oral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2014
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19. Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy.
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Schmeiser HH, Nortier JL, Singh R, Gamboa da Costa G, Sennesael J, Cassuto-Viguier E, Ambrosetti D, Rorive S, Pozdzik A, Phillips DH, Stiborova M, and Arlt VM
- Subjects
- Adult, Aged, Chromatography, Thin Layer, Female, Humans, Kidney chemistry, Kidney pathology, Male, Mass Spectrometry, Middle Aged, Aristolochic Acids adverse effects, Balkan Nephropathy chemically induced, Biomarkers analysis, DNA Adducts analysis, Mutagens adverse effects
- Abstract
Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.
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- 2014
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20. Diffusion-weighted magnetic resonance imaging: a non-nephrotoxic prompt assessment of kidney involvement in IgG4-related disease.
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Pozdzik AA, Matos C, Rorive S, Brocheriou I, Delhaye M, and Nortier JL
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- Animals, Humans, Kidney Diseases diagnosis, Magnetic Resonance Imaging methods, Nephrology trends
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- 2014
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21. Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury.
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Declèves AE, Zolkipli Z, Satriano J, Wang L, Nakayama T, Rogac M, Le TP, Nortier JL, Farquhar MG, Naviaux RK, and Sharma K
- Subjects
- Albuminuria prevention & control, Aminoimidazole Carboxamide analogs & derivatives, Aminoimidazole Carboxamide pharmacology, Animals, Cholesterol metabolism, Diet, High-Fat, Insulin Resistance, Kidney pathology, Mice, Inbred C57BL, Mitochondria physiology, Obesity prevention & control, Ribonucleotides pharmacology, AMP-Activated Protein Kinases physiology, Kidney metabolism, Lipid Metabolism
- Abstract
AMP-activated protein kinase (AMPK) is an important energy sensor that may be critical in regulating renal lipid accumulation. To evaluate the role of AMPK in mediating renal lipid accumulation, C57BL/6J mice were randomized to a standard diet, a high-fat diet, or a high-fat diet plus AICAR (an AMPK activator) for 14 weeks. Renal functional and structural studies along with electron microscopy were performed. Mice given the high-fat diet had proximal tubule injury with the presence of enlarged clear vacuoles, and multilaminar inclusions concurrent with an increase of tissue lipid and overloading of the lysosomal system. The margins of the clear vacuoles were positive for the endolysosomal marker, LAMP1, suggesting lysosome accumulation. Characterization of vesicles by special stains (Oil Red O, Nile Red, Luxol Fast Blue) and by electron microscopy showed they contained onion skin-like accumulations consistent with phospholipids. Moreover, cholesteryl esters and phosphatidylcholine-containing phospholipids were significantly increased in the kidneys of mice on a high-fat diet. AMPK activation with chronic AICAR treatment prevented the clinical and structural effects of high-fat diet. Thus, high-fat diet contributes to a dysfunction of the lysosomal system and altered lipid metabolism characterized by cholesterol and phospholipid accumulation in the kidney. AMPK activation normalizes the changes in renal lipid content despite chronic exposure to lipid challenge.
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- 2014
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22. Chronic kidney disease and upper tract urothelial carcinomas.
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Wang LJ, Nortier JL, Teh BT, Chuang CK, and Lee SY
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- Carcinoma, Transitional Cell complications, Carcinoma, Transitional Cell pathology, Humans, Neoplasm Proteins biosynthesis, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic pathology, Urinary Bladder Neoplasms pathology, Urothelium pathology, Carcinoma, Transitional Cell genetics, Renal Insufficiency, Chronic genetics, Urinary Bladder Neoplasms genetics
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- 2014
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23. Mycobacterium fortuitum and Polymicrobial Peritoneal Dialysis-Related Peritonitis: A Case Report and Review of the Literature.
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Hamade A, Pozdzik A, Denis O, Tooulou M, Keyzer C, Jacobs F, Khabbout J, and Nortier JL
- Abstract
Mycobacterium fortuitum is a ubiquitous, rapidly growing nontuberculous mycobacterium (NTM). It is the most commonly reported NTM in peritoneal dialysis (PD) associated peritonitis. We report a case of a 52-year-old man on PD, who developed refractory polymicrobial peritonitis necessitating PD catheter removal and shift to hemodialysis. Thereafter, M. fortuitum was identified in the PD catheter culture and in successive cultures of initial peritoneal effluent and patient was treated with amikacin and ciprofloxacin for six months with a good and sustained clinical response. Months after completion of the course of antibiotics, the patient successfully returned to PD. To our knowledge, this is the first reported case of M. fortuitum peritonitis in the field of polymicrobial PD peritonitis. It demonstrates the diagnostic yield of pursuing further investigations in cases of refractory PD peritonitis. In a systematic review of the literature, only 20 reports of M. fortuitum PD peritonitis were identified. Similar to our case, a delay in microbiological diagnosis was frequently noted and the Tenckhoff catheter was commonly removed. However, the type and duration of antibiotic therapy varied widely making the optimal treatment unclear.
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- 2014
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24. Evaluation of diagnostic criteria for endemic nephropathy.
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Dika Ž, Antoine MH, Husson C, De Prez EG, Kos J, Mišić M, Fuček M, Čvorišćec D, Bourgeade MF, Nortier JL, and Jelaković B
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- Adolescent, Adult, Aristolochic Acids metabolism, Balkan Nephropathy metabolism, Biomarkers metabolism, Diagnosis, Differential, Female, Humans, Kidney metabolism, Male, Transforming Growth Factor beta metabolism, Young Adult, Balkan Nephropathy diagnosis, Kidney pathology
- Abstract
Diagnosis of endemic nephropathy (EN) is based on the combination of several clinical and laboratory criteria. Despite extensive research no specific diagnostic biomarker for EN has yet been identified. The aim of the study was to evaluate the diagnostic significance of the variables previously proposed as diagnostic criteria, but also new ones. After an extended questionnaire, the clinical and laboratory examination population in EN villages was classified according to the modified WHO criteria. The urinary active form of TGF-β was measured with a bioassay using a cell line which expresses luciferase activity. In the study we used ROC analysis to examine the predictive value of the tested variables. In the study there was no difference in haemoglobin level between the study subgroups. Leucine aminopeptidase (LAP) in urine and active urinary TGF-β levels were increased in the EN diseased group when compared to other subgroups, but they did not fulfil the statistical criteria needed for differentiating a diseased form from other study subgroups. Both kidney length and parenchima thickness, alfa1-microglobulinuria, and kidney function assessed by MDRD formula were the variables that differentiated the study subgroups well. Based on our results the cut-off value of alfa1-microglobulin for screening should be 23.5 mg/g creatinine instead of 15 mg/g creatinine in the present criteria, and for making a diagnosis of EN 31,5 mg/g creatinine. Persons with a positive family history for EN had a 5.8 times greater risk of developing EN when compared to a negative one. Taken together, the above-mentioned variables should be implemented in new uniform diagnostic criteria for EN.
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- 2014
25. Perceptive barriers to peritoneal dialysis implementation: an opinion poll among the French-speaking Belgian nephrologists.
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Desmet JM, Fernandes V, des Grottes JM, Spinogatti N, Collart F, Pochet JM, Dratwa M, Goffin E, and Nortier JL
- Abstract
Although peritoneal dialysis (PD) is recognized as an effective renal replacement therapy (RRT) alternative to haemodialysis (HD), its prevalence is around 15% in most of the industrialized countries. In the French-speaking part of Belgium, PD is clearly underused with a prevalence of 8.7% in 2009. The main objectives of this work were to evaluate the nephrologists' perceived obstacles to PD implementation and reflect on possible actions towards PD development. A computer-based 33-item questionnaire was sent by e-mail to all nephrologists affiliated to the French-speaking association. Among 120 adult nephrologists targeted by this inquiry, 97 completed the online questionnaire (response rate 80.8%). Among them, 29% had little experience with PD (treating less than five patients) and 39% reported no specific training with this modality of RRT. However, 88% of responders claimed PD prevalence should be around 20-25%. Half of the responders would choose PD as a first RRT option if they required RRT for themselves. The three main reasons given to the low prevalence of PD were an easy access to HD, patient refusal and lack of nephrologist motivation. Almost all the nephrologists insisted on the need for a dedicated nursing team delivering an effective educational programme and PD management and care. They believe that PD could and should be implemented in Belgium. Enhanced nephrologist motivation and training in PD were identified as predominant factors to be upgraded, as well as patient education programmes.
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- 2013
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26. Diffusion-weighted magnetic resonance imaging as a new diagnostic tool of subclinical IgG4-related acute tubulointerstitial nephritis.
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Pozdzik AA, Matos C, Rorive S, Brocheriou I, Van Gansbeke D, Delhaye M, Nortier JL, and Neild GH
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- 2013
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27. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review.
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Gökmen MR, Cosyns JP, Arlt VM, Stiborová M, Phillips DH, Schmeiser HH, Simmonds MS, Cook HT, Vanherweghem JL, Nortier JL, and Lord GM
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- Balkan Nephropathy chemically induced, Balkan Nephropathy diagnosis, Balkan Nephropathy epidemiology, Balkan Nephropathy therapy, Humans, Kidney Diseases diagnosis, Kidney Diseases epidemiology, Kidney Diseases physiopathology, Kidney Diseases therapy, Risk Factors, Urologic Neoplasms chemically induced, Urologic Neoplasms diagnosis, Urologic Neoplasms epidemiology, Urologic Neoplasms physiopathology, Urologic Neoplasms therapy, Aristolochic Acids adverse effects, Kidney Diseases chemically induced, Plant Preparations adverse effects
- Abstract
It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.
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- 2013
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28. Prevention of tunneled cuffed hemodialysis catheter-related dysfunction and bacteremia by a neutral-valve closed-system connector: a single-center randomized controlled trial.
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Bonkain F, Racapé J, Goncalvez I, Moerman M, Denis O, Gammar N, Gastaldello K, and Nortier JL
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- Aged, Equipment Design, Equipment Failure, Female, Humans, Male, Middle Aged, Prospective Studies, Bacteremia etiology, Bacteremia prevention & control, Catheter-Related Infections prevention & control, Catheters, Indwelling adverse effects, Renal Dialysis instrumentation
- Abstract
Background: Hemodialysis (HD) tunneled cuffed catheters may be fitted with neutral-valve closed-system connectors. Such connectors, which are flushed with saline solution and used for 3 consecutive HD sessions, provide a mechanically closed positive-pressure barrier and potentially may be useful to prevent catheter-related bacteremia and dysfunction., Study Design: Single-center randomized controlled trial., Setting & Participants: 66 adult HD patients with a tunneled cuffed catheter., Intervention: Neutral-valve closed-system connector (Tego Needlefree Hemodialysis Connector) versus trisodium citrate, 46.7%, locking solution (Citra-Lock; control group)., Outcomes: Primary composite outcome was the incidence rate of catheter-related dysfunction or bacteremia. Secondary outcomes were the separate incidence rates of catheter-related dysfunction and bacteremia and the cost of both procedures., Measurements: Catheter dysfunction was defined as the requirement of urokinase and/or a mean blood flow ≤250 mL/min during 2 consecutive HD sessions. Catheter-related bacteremia was defined as ≥2 positive blood cultures. Time of catheter use was calculated and the incidence rate of complications was expressed per 100 person-years., Results: 66 patients were followed up for a median of 86 (IQR, 29-200) days. The composite primary outcome was not significantly reduced in the closed-system-connector intervention group versus the citrate-locking-solution control group (63.56 vs 71.51 per 100 person-years; P = 0.3). Catheter dysfunction in the intervention group was not decreased versus controls (59.59 vs 51.64 per 100-person-years; P = 0.9). Only 6 catheter-related bacteremia events were identified, one in the intervention group (3.97 vs 19.86 per 100 person-years; P = 0.06)., Limitations: Small size of the patient population and single-center study., Conclusions: Superiority of the closed-system connector in terms of prevention of the primary efficacy end point compared to the standard locking solution was not observed. Further evaluation in a larger study is suggested., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2013
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29. Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy.
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Baudoux TE, Pozdzik AA, Arlt VM, De Prez EG, Antoine MH, Quellard N, Goujon JM, and Nortier JL
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- Animals, Atrophy, Biomarkers blood, Cell Proliferation drug effects, Cell Survival drug effects, Creatinine blood, Cytoprotection, DNA Adducts metabolism, Disease Models, Animal, Fibrosis, Kidney Tubular Necrosis, Acute blood, Kidney Tubular Necrosis, Acute chemically induced, Kidney Tubular Necrosis, Acute pathology, Kidney Tubules metabolism, Kidney Tubules ultrastructure, Male, Mice, Mice, Inbred C57BL, Nephritis, Interstitial blood, Nephritis, Interstitial chemically induced, Nephritis, Interstitial pathology, Organic Anion Transporters antagonists & inhibitors, Organic Anion Transporters metabolism, Proliferating Cell Nuclear Antigen metabolism, Time Factors, Aristolochic Acids, Kidney Tubular Necrosis, Acute prevention & control, Kidney Tubules drug effects, Nephritis, Interstitial prevention & control, Probenecid pharmacology, Protective Agents pharmacology
- Abstract
Experimental aristolochic acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro, probenecid inhibits aristolochic acid entry through organic anion transporters, reduces specific aristolochic acid-DNA adduct formation, and preserves cellular viability. To test this in vivo, we used a mouse model of aristolochic acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by aristolochic acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen-positive cells and total aristolochic acid-DNA adducts were significantly reduced in mice receiving aristolochic acid plus probenecid compared with mice treated with aristolochic acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of aristolochic acid nephropathy.
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- 2012
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30. Sarcoma-like pyogenic granuloma of the thumb and respiratory restrictive syndrome in a non-compliant hemodialysis patient.
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Simon I, Gevenois PA, Del Marmol V, El Kazzi W, Trepant AL, Gastaldello K, and Nortier JL
- Abstract
Pyogenic granuloma is a benign vascular tumor of the skin or mucosae usually observed after irritative processes. We report the case of a non-compliant hemodialysis patient with severe hyperparathyroidism who rapidly developed growing pyogenic granuloma of the distal part of the left thumb. This tumor mimicked sarcoma and caused recurrent bleeding during hemodialysis sessions. Hand radiograph revealed an osteolytic lesion compatible with a brown tumor. Among other brown tumors, several of those found in the ribs were responsible of a severe respiratory restrictive deficit. This report highlights the difficulty to choose the adequate treatment of severe hyperparathyroidism, and discusses the benefit/risk balance of performing parathyroidectomy.
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- 2012
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31. Azathioprine as successful maintenance therapy in IgG4-related tubulointerstitial nephritis.
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Pozdzik AA, Brochériou I, Demetter P, Matos C, Delhaye M, Devière J, and Nortier JL
- Abstract
A 65-year-old man presented with a progressive increase in plasma creatinine (PCr). Two years before, diffusion-weighted magnetic resonance imaging had revealed a relapse of immunoglobulin G4 (IgG4)-related autoimmune pancreatitis (AIP) associated with sclerosing cholangitis. Bilateral hypointense renal cortical nodules were also described. Kidney biopsy showed patchy disappearance of tubules, sparse interstitial fibrosis and IgG4+ plasma cells (>30 per high power field) leading to the diagnosis of IgG4-related tubulointerstitial nephritis (TIN). Despite methylprednisolone, PCr and serum IgG4 levels remained elevated. Starting azathioprine (AZA) normalized IgG4 levels, which elicited corticosteroid withdrawal after 17 months. One year later, renal function remains stable. Our clinical observation underlines the importance of biological and radiological long-term follow-up of patients with previous AIP in order to early detect IgG4-related renal involvement. Corticosteroids are the first choice, but in the case of adverse effects or partial remission, AZA could be a useful and safe alternative therapy.
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- 2012
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32. Hemodiafiltration with online regeneration of ultrafiltrate for severe nevirapine intoxication in a HIV-infected patient.
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Hougardy JM, Husson C, Mackie NE, Van Vooren JP, Gastaldello K, Nortier JL, and Goffard JC
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- Adult, Hemodiafiltration, Humans, Stevens-Johnson Syndrome therapy, Anti-HIV Agents poisoning, HIV Infections drug therapy, Nevirapine poisoning, Stevens-Johnson Syndrome etiology
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- 2012
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33. Risk of urinary tract carcinoma in aristolochic acid nephropathy.
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Pozdzik AA, Baudoux T, Roumeguere T, Vanherweghem JL, and Nortier JL
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- Female, Humans, Male, Aristolochic Acids adverse effects, Kidney Diseases chemically induced, Kidney Diseases diagnosis, Mutagens adverse effects
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- 2012
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34. Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature.
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Simon I, Wissing KM, Del Marmol V, Antinori S, Remmelink M, Nilufer Broeders E, Nortier JL, Corbellino M, Abramowicz D, and Cascio A
- Subjects
- Antibodies, Protozoan blood, Female, Humans, Leg Ulcer parasitology, Leg Ulcer pathology, Leishmania genetics, Leishmania immunology, Leishmania donovani genetics, Leishmania donovani immunology, Leishmaniasis, Cutaneous parasitology, Leishmaniasis, Cutaneous pathology, Leishmaniasis, Mucocutaneous diagnosis, Leishmaniasis, Mucocutaneous parasitology, Leishmaniasis, Mucocutaneous pathology, Leishmaniasis, Visceral parasitology, Leishmaniasis, Visceral pathology, Male, Middle Aged, Polymerase Chain Reaction, Recurrence, Tongue parasitology, Tongue pathology, Kidney Transplantation adverse effects, Leishmania isolation & purification, Leishmania donovani isolation & purification, Leishmaniasis, Cutaneous diagnosis, Leishmaniasis, Visceral diagnosis
- Abstract
The characteristics of 8 episodes of leishmaniasis with atypical manifestations in 2 Italian kidney transplant recipients are analyzed and contextualized among those of 52 other episodes of leishmaniasis observed in 19 transplant recipients found through a systematic review of the international literature. In all the patients, the initial episode was visceral leishmaniasis, which was associated with mucocutaneous involvement in 2 cases. With the exception of 1 case of post kala-azar dermal leishmaniasis, 2 episodes of Leishmania endophthalmitis, and 3 episodes of mucocutaneous leishmaniasis, all the recurrences were characterized by visceral involvement. The potential role of polymerase chain reaction in monitoring the infection, the importance of a long follow-up, the potential benefit of chemoprophylaxis, and the therapeutic challenges are discussed., (© 2011 John Wiley & Sons A/S.)
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- 2011
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35. Gene expression changes induced by the human carcinogen aristolochic acid I in renal and hepatic tissue of mice.
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Arlt VM, Zuo J, Trenz K, Roufosse CA, Lord GM, Nortier JL, Schmeiser HH, Hollstein M, and Phillips DH
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- Animals, Blotting, Western, Carcinogens toxicity, Cell Cycle genetics, Female, Humans, Kidney metabolism, Liver metabolism, Male, Mice, Mice, 129 Strain, Mice, Transgenic, NF-kappa B genetics, NF-kappa B metabolism, Oligonucleotide Array Sequence Analysis, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Aristolochic Acids toxicity, Gene Expression Profiling, Gene Expression Regulation drug effects, Kidney drug effects, Liver drug effects
- Abstract
Aristolochic acid (AA) is the causative agent of urothelial tumors associated with AA nephropathy and is also implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. These tumors contain AA-characteristic TP53 mutations. We examined gene expression changes in Hupki (human TP53 knock-in) mice after treatment with aristolochic acid I (AAI) by gavage (5 mg/kg body weight). After 3, 12 and 21 days of treatment gene expression profiles were investigated using Agilent Whole Mouse 44K Genome Oligo Array. Expression profiles were significantly altered by AAI treatment in both target (kidney) and nontarget (liver) tissue. Renal pathology and DNA adduct analysis confirmed kidney as the target tissue of AAI-induced toxicity. Gene ontology for functional analysis revealed that processes related to apoptosis, cell cycle, stress response, immune system, inflammatory response and kidney development were altered in kidney. Canonical pathway analysis indicated Nfκb, aryl hydrocarbon receptor, Tp53 and cell cycle signaling as the most important pathways modulated in kidney. Expression of Nfκb1 and other Nfκb-target genes was confirmed by quantitative real-time PCR (qRT-PCR) and was consistent with the induction of Nfκb1 protein. Myc oncogene, frequently overexpressed in urothelial tumors, was upregulated by AAI on the microarrays and confirmed by qRT-PCR and protein induction. Collectively we found that microarray gene expression analysis is a useful tool to define tissue-specific responses in AAI-induced toxicity. Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies., (Copyright © 2010 UICC.)
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- 2011
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36. Revisiting nephrogenic systemic fibrosis in 6 kidney transplant recipients: a single-center experience.
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Lemy AA, del Marmol V, Kolivras A, High WA, Matos C, Laporte M, and Nortier JL
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- Adult, Biopsy, Needle, Contrast Media adverse effects, Databases, Factual, Female, Humans, Immunohistochemistry, Incidence, Magnetic Resonance Imaging adverse effects, Magnetic Resonance Imaging methods, Male, Middle Aged, Nephrogenic Fibrosing Dermopathy pathology, Prognosis, Retrospective Studies, Risk Assessment, Gadolinium adverse effects, Kidney Transplantation statistics & numerical data, Nephrogenic Fibrosing Dermopathy epidemiology, Nephrogenic Fibrosing Dermopathy etiology
- Abstract
Background: Nephrogenic systemic fibrosis (NSF) is a fibrotic disorder occurring in patients with renal dysfunction. Exposure to gadolinium (Gd)-based contrast agents (GBCAs) during renal impairment is associated with development of NSF., Methods: A cross-referenced search of kidney transplantation and radiology databases at a single institution revealed the prevalence of NSF in the transplant population. Clinical records and skin biopsy specimens from 6 patients with kidney transplant given a diagnosis of NSF were reviewed to identify contributing factors., Results: Between January 1999 and December 2006, NSF was diagnosed in 6 of 705 patients with kidney transplant (0.9%). Renal function was impaired in all patients. Of 33 patients with kidney transplant exposed to GBCAs, 5 (15.2%) developed NSF. Disease onset ranged from 7 days to 11 months after exposure to GBCAs. All 5 patients exposed to GBCAs who developed NSF were also treated with a beta-blocker and clinical improvement was observed with discontinuation. The sixth case NSF appeared unrelated to Gd, without a known exposure, and testing of tissue via mass spectrometry revealed no Gd. Symptoms of NSF in this patient disappeared after administration of darbepoetin was switched from subcutaneous to intravenous injection. One patient with NSF who manifested the highest Gd level in tissue died 22 months after disease onset., Limitations: The study represents the retrospective experience of only a single center., Conclusions: NSF can develop in kidney transplant recipients with altered graft function. In these patients, exposure to GBCAs appears associated with development of NSF. The role of beta-blockers in the course of the disease merits further investigation., (Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)
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- 2010
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37. Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?
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Pozdzik AA, Berton A, Schmeiser HH, Missoum W, Decaestecker C, Salmon IJ, Vanherweghem JL, and Nortier JL
- Subjects
- Adult, Aged, Case-Control Studies, Disease Progression, Fibrosis immunology, Fibrosis pathology, Humans, Middle Aged, Monocytes immunology, Adaptive Immunity, Aristolochic Acids adverse effects, Drugs, Chinese Herbal adverse effects, Immunity, Innate, Nephritis chemically induced, Nephritis pathology
- Abstract
Aims: The histological features of aristolochic acid nephropathy (AAN) consist of paucicellular interstitial fibrosis, severe tubular atrophy, and almost intact glomeruli with media lesions of interlobular arteries. As an early phase of interstitial inflammation preceded peritubular fibrosis in the rat model of AAN, the aim was to investigate the presence of inflammatory cells in human AAN., Methods and Results: Reports of confirmed cases and case series of AAN were reviewed in terms of interstitial inflammation and found to have very conflicting results. This prompted us to search for and characterize inflammatory cells within the native kidneys provided from four end-stage AAN patients. Prior aristolochic acid exposure was attested by the intrarenal presence of the typical aristolactam I-derived DNA adduct. Besides the tubulointerstitial lesions usually seen in the cortex, a massive infiltration of macrophages, T and B lymphocytes was detected by immunohistochemistry in the medullary rays and in the outer medullae with some extension to the upper cortical labyrinth., Conclusions: In parallel with histological findings reported in the rat model, inflammatory cells are present preferentially in the interstitium of the medullary rays and of the outer medulllae in renal interstitium from human AAN cases, even in the terminal stages. Further studies must be undertaken to determine the respective roles of innate and adaptive immunity in the progression of AAN.
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- 2010
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38. Nephrotic syndrome and renal failure as an unusual presentation of solid tumour.
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Bonkain F, Ena G, Depierreux M, Debelle FD, and Nortier JL
- Abstract
Glomerular diseases may occur as primary manifestation of cancer, especially in patients older than 60 years. Among glomerulopathies, membranous nephropathy is preferentially associated with respiratory and gastrointestinal tract adenocarcinomas, whereas minimal change disease is most often seen in haematological malignancies. Though breast cancer is one of the most frequent malignancies in women, paraneoplastic glomerular disease is rarely observed. We describe the case of a 79-year-old female patient who presented with nephrotic syndrome and renal failure. Breast cancer was found. Pathological studies of kidney and breast biopsy revealed a minimal change disease and an infiltrating ductal carcinoma, respectively.
- Published
- 2010
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39. Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy.
- Author
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Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, Bourgeade MF, Deschodt-Lanckman MM, Vanherweghem JL, and Nortier JL
- Subjects
- Animals, Disease Models, Animal, Fibrosis, Kidney physiopathology, Kidney Failure, Chronic chemically induced, Kidney Failure, Chronic pathology, Kidney Failure, Chronic physiopathology, Macrophages immunology, Macrophages pathology, Male, Monocytes immunology, Monocytes pathology, Rats, Rats, Wistar, Signal Transduction, Smad2 Protein metabolism, Smad3 Protein metabolism, T-Lymphocytes immunology, T-Lymphocytes pathology, Transforming Growth Factor beta metabolism, Aristolochic Acids toxicity, Kidney drug effects, Kidney pathology
- Abstract
Background: Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis., Methods: Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-beta) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-beta signalling pathway., Results: In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-beta significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments., Conclusion: An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-beta is highly suggested, at least via the psmad 2/3 intracellular signalling pathway.
- Published
- 2008
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40. Aristolochic acid nephropathy: a worldwide problem.
- Author
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Debelle FD, Vanherweghem JL, and Nortier JL
- Subjects
- Animals, Aristolochia toxicity, Aristolochic Acids metabolism, Aristolochic Acids toxicity, Balkan Nephropathy chemically induced, Balkan Nephropathy epidemiology, Balkan Nephropathy metabolism, Belgium epidemiology, Cell Transformation, Neoplastic chemically induced, DNA Adducts biosynthesis, Disease Outbreaks, Drugs, Chinese Herbal toxicity, Female, Global Health, Humans, Incidence, Kidney Neoplasms chemically induced, Kidney Neoplasms epidemiology, Kidney Neoplasms metabolism, Nephritis, Interstitial metabolism, Aristolochia adverse effects, Aristolochic Acids adverse effects, Drugs, Chinese Herbal adverse effects, Nephritis, Interstitial chemically induced, Nephritis, Interstitial epidemiology
- Abstract
Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain aristolochic acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines are very popular, the complexity of the pharmacopoeia represents a high risk for AAN because of the frequent substitution of the botanical products by AA-containing herbs. In the Balkan regions, the exposure to AA found in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy. Finally, despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet.
- Published
- 2008
- Full Text
- View/download PDF
41. Clear cell renal carcinoma presenting as a bleeding cyst in pregnancy: inaugural manifestation of a von Hippel-Lindau disease.
- Author
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Simon I, Rorive S, Kirkpatrick C, Roumeguere T, and Nortier JL
- Subjects
- Adult, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell surgery, Diagnosis, Differential, Female, Hematuria diagnosis, Hematuria surgery, Humans, Kidney Neoplasms diagnosis, Kidney Neoplasms surgery, Magnetic Resonance Imaging, Nephrectomy methods, Pregnancy, von Hippel-Lindau Disease diagnosis, Carcinoma, Renal Cell complications, Hematuria etiology, Kidney Diseases, Cystic diagnosis, Kidney Neoplasms complications, Pregnancy Complications, Neoplastic, von Hippel-Lindau Disease complications
- Abstract
Von Hippel-Lindau (VHL) disease is a dominant autosomal disorder inducing the development of many tumors, such as hemangioblastomas in the central nervous system and retina, cysts or tumors (benign or malignant) in the kidneys and/or the pancreas. We report the case of a pregnant woman who presented with a voluminous hemorrhagic cyst of the right kidney with an exophytic lesion detected in the lower median part of the cyst wall. As an anamnestic inquiry resulted in a familial history of VHL disease, a screening imaging was performed and detected three medullary hemangioblastomas. Considering the active bleeding of the renal cyst and its potential malignancy, a unilateral nephrectomy was carried out after pregnancy interruption. Histological analysis confirmed a multilocular clear cell renal carcinoma. This case underlines the importance of screening procedures such as abdominal ultrasonography and medullary magnetic resonance imaging in all pregnant women with a familial history of VHL disease.
- Published
- 2008
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42. Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation.
- Author
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Pozdzik AA, Salmon IJ, Debelle FD, Decaestecker C, Van den Branden C, Verbeelen D, Deschodt-Lanckman MM, Vanherweghem JL, and Nortier JL
- Subjects
- Animals, Cell Proliferation, Chemokine CCL2 urine, Collagen analysis, Collagen metabolism, DNA Damage, DNA Repair, Discoidin Domain Receptor 1, Epithelium drug effects, Epithelium pathology, Fibrosis, Ki-67 Antigen analysis, Kidney Diseases pathology, Kidney Tubules, Proximal chemistry, Kidney Tubules, Proximal pathology, Male, Mesoderm pathology, Mitochondria pathology, Oxidative Stress, Rats, Rats, Wistar, Receptor Protein-Tyrosine Kinases analysis, Apoptosis, Aristolochic Acids toxicity, Kidney Diseases chemically induced, Kidney Tubules, Proximal drug effects, Mutagens toxicity
- Abstract
Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.
- Published
- 2008
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43. Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer.
- Author
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Arlt VM, Stiborová M, vom Brocke J, Simões ML, Lord GM, Nortier JL, Hollstein M, Phillips DH, and Schmeiser HH
- Subjects
- Animals, Balkan Nephropathy complications, Cell Transformation, Neoplastic, DNA Adducts metabolism, Genes, p53, Humans, Mutagenesis, Urinary Bladder Neoplasms metabolism, Aristolochic Acids toxicity, Balkan Nephropathy chemically induced, Mutagens toxicity, Urinary Bladder Neoplasms complications
- Abstract
Balkan endemic nephropathy (BEN) is found in certain rural areas of the Balkans and affects at least 25,000 inhabitants. Of the many hypotheses on BEN, the Aristolochia hypothesis has recently gained ground substantiated by the investigations on aristolochic acid nephropathy (AAN). On both clinical and morphological grounds, AAN is very similar to BEN. That exposure to aristolochic acid (AA) of individuals living in endemic areas through consumption of bread made with flour contaminated with seeds of Aristolochia clematitis is responsible for BEN is an old hypothesis, but one which is fully consistent with the unique epidemiologic features of BEN. Here, we propose an approach to investigate AA-induced mutagenesis in BEN that can provide molecular clues to the aetiology of its associated urothelial cancer. The molecular mechanism of AA-induced carcinogenesis demonstrates a strong association between DNA adduct formation, mutation pattern and tumour development. A clear link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients from different endemic areas becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT --> TA transversion mutations as has already been demonstrated in the human p53 gene of immortalized cells after exposure to AAI and urothelial tumours from BEN patients in Croatia. Moreover, the detection of AA-specific DNA adducts in renal tissue of a number of BEN patients and individuals living in areas endemic for BEN in Croatia provides new evidence that chronic exposure to AA is a risk factor for BEN and its associated cancer.
- Published
- 2007
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- View/download PDF
44. Nephrogenic systemic fibrosis--the need for a multidisciplinary approach.
- Author
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Nortier JL and del Marmol V
- Subjects
- Contrast Media, Dendritic Cells pathology, Fibrosis, Gadolinium DTPA, Glomerular Filtration Rate, Humans, Infant, Kidney Failure, Chronic pathology, Kidney Failure, Chronic physiopathology, Skin Diseases pathology, Skin Diseases physiopathology, Kidney Failure, Chronic therapy, Skin Diseases therapy
- Published
- 2007
- Full Text
- View/download PDF
45. For patients taking herbal therapy--lessons from aristolochic acid nephropathy.
- Author
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Nortier JL and Vanherweghem JL
- Subjects
- Animals, Aristolochic Acids toxicity, Disease Models, Animal, Humans, Kidney Neoplasms chemically induced, Kidney Neoplasms pathology, Aristolochic Acids adverse effects, Kidney Diseases chemically induced, Kidney Diseases pathology, Phytotherapy adverse effects
- Published
- 2007
- Full Text
- View/download PDF
46. Neonatal disease in neutral endopeptidase alloimmunization: lessons for immunological monitoring.
- Author
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Nortier JL, Debiec H, Tournay Y, Mougenot B, Nöel JC, Deschodt-Lanckman MM, Janssen F, and Ronco P
- Subjects
- Antibodies, Anti-Idiotypic immunology, Female, Glomerulonephritis, Membranous etiology, Glomerulonephritis, Membranous immunology, Humans, Immune System Diseases complications, Immunoglobulin G administration & dosage, Immunoglobulin G blood, Immunoglobulin G immunology, Immunoglobulin G therapeutic use, Immunoglobulins, Intravenous therapeutic use, Male, Mutation genetics, Neprilysin genetics, Pedigree, Pregnancy, Pregnancy Complications drug therapy, Syndrome, Immune System Diseases immunology, Infant, Newborn immunology, Isoantigens immunology, Monitoring, Immunologic, Neprilysin immunology, Pregnancy Complications immunology
- Abstract
Neutral endopeptidase (NEP) alloimmunization has recently been determined to cause severe forms of neonatal disease as a result of the transplacental passage of anti-NEP antibodies. However there is a wide spectrum of neonatal disease variability. We present the medical histories of a large family, specifically of two alloimmunized sisters in their second pregnancy in whom we established the basis of immunological surveillance and therapeutic intervention during pregnancy and after delivery. One mother developed dramatically high titers of IgG1 and IgG4, and was treated with IvIg and one plasma exchange, both of which substantially reduced the anti-NEP Ab titer. However, the neonatal syndrome observed in her infant was severe, partly due to treatment delay. Anti-NEP Ab were also found in the mother's milk and the infant's urine. In contrast, the other mother had a normal second pregnancy and delivered a healthy neonate, which was related to the fact that she only produced the non-complement activating IgG4 subclass of anti-NEP antibodies. Thus, anti-NEP Ab (titer and subclass) seem to be highly sensitive biomarkers of neonatal risk. Interventional strategy aimed at reducing anti-NEP titer, should be started early during pregnancy and, possibly, even before pregnancy in those mothers producing anti-NEP IgG1. Careful monitoring of anti-NEP Ab titer and subclass is mandatory in NEP-deficient mothers during their pregnancies.
- Published
- 2006
- Full Text
- View/download PDF
47. Early proximal tubule injury in experimental aristolochic acid nephropathy: functional and histological studies.
- Author
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Lebeau C, Debelle FD, Arlt VM, Pozdzik A, De Prez EG, Phillips DH, Deschodt-Lanckman MM, Vanherweghem JL, and Nortier JL
- Subjects
- Acetylglucosaminidase urine, Albumins metabolism, Animals, Biomarkers metabolism, Chromatography, High Pressure Liquid, DNA Adducts genetics, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Glutathione Transferase urine, Kidney Diseases pathology, Kidney Diseases urine, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Leucyl Aminopeptidase urine, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Male, Neprilysin urine, Rats, Rats, Wistar, Aristolochic Acids toxicity, Carcinogens toxicity, Kidney Diseases chemically induced, Kidney Tubules, Proximal drug effects
- Abstract
Background: Aristolochic acid (AA), the plant extract of Aristolochia species, is involved in the onset of progressive tubulointerstitial renal fibrosis in humans. Clinical and in vitro findings have previously suggested that the proximal tubule was the target of AA., Methods: Using a rat model of AA nephropathy, the proximal tubular lesions induced by daily subcutaneous injections of AA for 35 or 5 days were characterized biochemically and histologically. Urinary excretion of proteins, albumin, low molecular weight proteins, N-acetyl-beta-d-glucosaminidase, alpha-glutathione S-transferase, leucine aminopeptidase and neutral endopeptidase (NEP) was determined and related to histological conventional findings and immunostainings of NEP and megalin., Results: In both protocols, an acute phase of release of urinary markers was observed within the first 3 days of AA treatment in parallel with a significant increase of specific AA-related DNA adducts reflecting early tubular intoxication. A dramatic loss of the proximal tubule brush border was histologically confirmed, while the expression of megalin decreased at the damaged apical epithelium (mainly of the S3 segment)., Conclusion: Proximal tubule injury occurs early after AA intoxication in rats, with a link between specific AA-DNA adduct formation, decreased megalin expression and inhibition of receptor-mediated endocytosis of low molecular weight proteins, bringing in vivo confirmation of previous in vitro studies.
- Published
- 2005
- Full Text
- View/download PDF
48. The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids.
- Author
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Debelle FD, Nortier JL, Husson CP, De Prez EG, Vienne AR, Rombaut K, Salmon IJ, Deschodt-Lanckman MM, and Vanherweghem JL
- Subjects
- Animals, Aristolochic Acids, Biphenyl Compounds, Blood Pressure drug effects, Diet, Sodium-Restricted, Drug Synergism, Fibrosis, Kidney metabolism, Kidney pathology, Kidney Diseases pathology, Kidney Diseases physiopathology, Male, Peptidyl-Dipeptidase A metabolism, Rats, Rats, Wistar, Angiotensin II Type 1 Receptor Blockers pharmacology, Angiotensin-Converting Enzyme Inhibitors pharmacology, Benzimidazoles pharmacology, Enalapril pharmacology, Kidney Diseases chemically induced, Kidney Diseases prevention & control, Renin-Angiotensin System drug effects, Tetrazoles pharmacology
- Abstract
Background: Experimental aristolochic acid nephropathy (AAN), characterized by interstitial fibrosis, tubular atrophy, and chronic renal failure, was reported after 35-day injections of aristolochic acids (AA) to salt-depleted male Wistar rats. The link between renal fibrosis and the renin-angiotensin system (RAS) in this model remains unknown., Methods: We investigated the impact of sodium diets (low and normal), of RAS inhibition with enalapril (ENA) alone, or combined with candesartan (CSN) for 35 days, and ENA + CSN for 65 days on AAN development. At the end of each observation period, blood pressure and renal angiotensin-converting enzyme activity were measured, as well as renal functional impairment (plasma creatinine increase, proteinuria) and histologic lesions (interstitial fibrosis, monocytes/macrophages infiltration, myofibroblasts collagens type I and IV, proliferating cells)., Results: Sodium intake did not modify renal functional and morphologic impairment induced by AA. The RAS blockade by ENA or ENA + CSN in rats receiving AA did not result in any statistical difference in terms of renal failure, proteinuria, and interstitial fibrosis on day 35 or 65. On day 35, the monocytes/macrophages infiltration was significantly decreased by two-fold when ENA (P < 0.01) or ENA + CSN (P < 0.01) was given from day 0., Conclusion: Our data demonstrate that RAS modulation by salt depletion and pharmacologic blockade do not influence renal failure and interstitial fibrosis in the rat model of AAN. We suggest that pathways of interstitial renal fibrosis may be independent of RAS at least in some conditions.
- Published
- 2004
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- View/download PDF
49. Invasive urothelial carcinoma after exposure to Chinese herbal medicine containing aristolochic acid may occur without severe renal failure.
- Author
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Nortier JL, Schmeiser HH, Muniz Martinez MC, Arlt VM, Vervaet C, Garbar CH, Daelemans P, and Vanherweghem JL
- Subjects
- Aged, Carcinoma metabolism, Carcinoma pathology, DNA Adducts metabolism, Fatal Outcome, Female, Humans, Neoplasm Invasiveness, Renal Insufficiency, Tissue Distribution, Urologic Neoplasms metabolism, Urologic Neoplasms pathology, Urothelium, Aristolochic Acids adverse effects, Carcinoma chemically induced, Drugs, Chinese Herbal adverse effects, Urologic Neoplasms chemically induced
- Published
- 2003
- Full Text
- View/download PDF
50. Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi).
- Author
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Nortier JL and Vanherweghem JL
- Subjects
- Animals, Female, Humans, Kidney Function Tests, Kidney Tubules, Proximal pathology, Nephritis, Interstitial pathology, Rats, Urologic Neoplasms pathology, Aristolochia adverse effects, Drugs, Chinese Herbal adverse effects, Nephritis, Interstitial chemically induced, Urologic Neoplasms chemically induced
- Abstract
A new renal disease called 'Chinese-herb nephropathy' (CHN) has been reported to occur in women who have ingested slimming pills containing powdered extracts of the Chinese herb Stephania tetrandra (ST). Moderate to end-stage renal disease developed, requiring renal replacement therapy by dialysis or transplantation. Phytochemical analyses of the pills revealed the presence of aristolochic acids (AA) instead of tetrandrine, suggesting the substitution of ST (Han fang ji) by Aristolochia fangchi containing nephrotoxic and carcinogenic AA. A typical histological feature of CHN is a progressive interstitial fibrosis leading to a severe atrophy of the proximal tubules, as documented by the urinary excretion rates of markers of tubular integrity (reduction of neutral endopeptidase enzymuria and high levels of microproteinurias). Removal of the native kidneys and ureters in end-stage CHN patients provided a high prevalence of urothelial carcinoma (46%). Tissue samples contained AA-related DNA adducts, which are not only specific markers of prior exposure to AA but are also directly involved in tumorigenesis. Exposure to Aristolochia species (spp.) is associated with the development of renal interstitial fibrosis (CHN) and urothelial cancer in humans. Health professionals should be aware that in traditional Chinese medicine, Aristolochia spp. are considered interchangeable with certain other herbal ingredients and are also sometimes mistaken for ST, Akebia, Asarum, Clematis spp. and Cocculus spp. in herbal remedies.
- Published
- 2002
- Full Text
- View/download PDF
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