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Changing the Outcome of a Pediatric Disease: Part I — Clinical Features of ADpkd

Current Treatment Options in Pediatrics 2022年第3期8卷 65-76页

作者： Cadnapaphornchai, Melissa A. Mekahli, Djalila Rocky Mountain Pediatric Kidney Center Rocky Mountain Hospital for Children at Presbyterian/St. Luke’s Medical Center 2055 N High St #270 Denver 80205 CO United States Department of Pediatric Nephrology and Organ Transplantation University Hospitals Leuven Leuven Belgium PKD Research Group Laboratory of Pediatrics Department of Development and Regeneration KU Leuven Leuven Belgium

Purpose of Review: The goal of this article is to review genetic and clinical features of autosomal dominant polycystic kidney disease (ADpkd) with specific focus on affected children. Recent Findings: Children manifest many of the same features of ADpkd that impact affected adults. Our understanding of how defective regulation and function of polycystin-1 and/or -2 induce kidney cystogenesis in ADpkd forms the rationale for therapeutic interventions. Of critical importance in recent decades is the realization that the primary target of intervention should be structural kidney disease (as measured by total kidney volume (TKV)), rather than the late clinical feature of declining kidney function. Other markers of high risk for disease progression in childhood may include genetic mutation type and presence of hypertension, proteinuria, and/or glomerular hyperfiltration. Summary: ADpkd is a common pediatric disease. Our knowledge of its genetic features and clinical impact in children is growing. We must establish valid and reliable tools to identify children with ADpkd who are at the greatest risk of end-stage kidney disease (ESKD) so that safe and effective treatment options can be timed appropriately to alter the long-term outcome. © 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

关键词： ADpkd Autosomal dominant Cystogenesis Diagnosis Kidney cyst Polycystic kidney disease Prognosis

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Changing the Outcome of a Pediatric Disease: Part II — Current Treatment Options in ADpkd

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Current Treatment Options in Pediatrics 2022年第3期8卷 77-95页

作者： Cadnapaphornchai, Melissa A. Mekahli, Djalila Rocky Mountain Pediatric Kidney Center Rocky Mountain Hospital for Children Presbyterian/St. Luke’s Medical Center 2055 N High St #270 Denver 80205 CO United States Department of Pediatric Nephrology and Organ Transplantation University Hospitals Leuven Leuven Belgium PKD Research Group Laboratory of Pediatrics Department of Development and Regeneration KU Leuven Leuven Belgium

Purpose of Review: The goal of this article is to review appropriate management of autosomal dominant polycystic kidney disease (ADpkd) with specific focus on interventions in childhood. Recent Findings: Enhanced understanding of the pathophysiologic mechanisms of kidney cystogenesis in ADpkd has led to several recent clinical trials in children and adults. The rationale and efficacy of general clinical measures as well as more focused pharmacologic intervention in ADpkd are considered here, including the potential benefit and risk of specific interventions to affected children. Summary: The complex mechanisms of kidney cystogenesis support a variety of potential therapeutic options to slow growth of total kidney volume in ADpkd, thereby altering the long-term outcome of this disease, including risk of end-stage kidney disease (ESKD). It seems likely that a combination of interventions may ultimately prove to be of most clinical benefit, but we need a means to accurately identify children at highest risk of disease progression to address the risk/benefit ratio. More disease-specific therapies are needed in both children and adults with ADpkd. Ultimately, targeted drug delivery to the kidney epithelial cell may play an important role in best outcomes and drug tolerance. © 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

关键词： ADpkd Autosomal dominant Cystogenesis Kidney cyst Polycystic kidney disease Treatment

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Correction to: Is autosomal dominant polycystic kidney disease an early sweet disease?

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Pediatric nephrology (Berlin, Germany) 2022年第9期37卷 2223-2224页

作者： Angélique Dachy Jean-Paul Decuypere Rudi Vennekens François Jouret Djalila Mekahli PKD Research Group GPURE Department of Development and Regeneration KU Leuven Leuven Belgium. Department of Pediatrics ULiège Academic Hospital Liege Belgium. Laboratory of Translational Research in Nephrology (LTRN) GIGA Cardiovascular Sciences ULiège Liege Belgium. Laboratory of Ion Channel Research Department of Cellular and Molecular Medicine VIB Center for Brain and Disease Research KU Leuven Leuven Belgium. Division of Nephrology Department of Internal Medicine ULiège Academic Hospital Liege Belgium. PKD Research Group GPURE Department of Development and Regeneration KU Leuven Leuven Belgium. djalila.mekahli@uzleuven.be. Department of Pediatric Nephrology University Hospitals Leuven Herestraat 49 B-3000 Leuven Belgium. djalila.mekahli@uzleuven.be.

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#2834 Analysis of cyst hetero- and homogeneity to unravel common pathways in autosomal dominant polycystic kidney disease

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Nephrology Dialysis Transplantation 2024年第Supplement_1期39卷 gfae069-0127-2834-gfae069-0127-2834页

作者： Jean-Paul Decuypere Daniel Borras Priyanka Koshy Abhishek Garg Djalila Mekahli Rudi Vennekens KU Leuven PKD Research Group Leuven Belgium KU Leuven Lab of Cell Stress & Immunity Leuven Belgium UZ Leuven Department of Pathology Leuven Belgium UZ Leuven Department of Pediatrics Leuven Belgium KU Leuven Lab of Ion Channel Research Leuven Belgium

Background and Aims Autosomal dominant polycystic kidney disease (ADpkd) is the most common inherited kidney disease, with a prevalence of 1 in ca. 1000 individuals and accounting for 10% of the European dialysis population. It is most frequently (75-80%) caused by mutations in the pkd1 gene encoding Polycystin-1. Besides systemic manifestations such as liver cysts, hypertension and cardiac abnormalities, the most prominent phenotype is the gradual development of kidney cysts, leading to kidney enlargement and a decline in kidney function leading to end-stage kidney disease at an average age of ca. 50 years. The cysts arise from tubular epithelial cells in the nephron that start to dedifferentiate, proliferate and eventually secrete fluid into the cyst lumen promoting its swelling. This process is molecularly regulated by changes in Ca2+, cAMP, PKA and PI3K-Akt-mTOR signaling, among others. The renal cysts are further characterized by ciliary dysfunction, altered signal transduction, loss of polarity, apoptosis, mitochondrial abnormalities, metabolic reprogramming, inflammation, oxidative stress and epigenetic changes. However, the exact sequence of events and their relative importance in the process of cyst formation remains unclear. Therefore, we analyzed the transcriptomic cyst hetero- and homogeneity to identify the pathways that were different, but also shared among individual *** We performed RNA-Seq analysis on 40 individual cystic membranes of nephrectomized kidneys of 4 pkd1 patients. We included 4 samples of macroscopically healthy tissue from 2 ADpkd kidneys (histologically confirmed to have microcysts) and 4 samples from 4 healthy kidneys. Principal component, cluster and trajectory analysis was performed to explore cyst heterogeneity. Adjacent pieces of cystic membrane were analyzed for histology (H&E, Sirius Red) or stained with FITC-tagged Lotus Tetragonolobus Lectin (LTL) or Dolichos Biflorus Agglutinin (DBA), a proximal and distal tubular m

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#2396 The potential of human-derived macrophages to study autosomal dominant polycystic kidney disease (ADpkd)

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Nephrology Dialysis Transplantation 2024年第Supplement_1期39卷 gfae069-0007-2396-gfae069-0007-2396页

作者： Schellekens, Pieter Bammens, Bert Mekahli, Djalila Meyts, Isabelle Vennekens, Rudi KU Leuven Department of Microbiology and Immunology and Transplantation Nephrology and Renal Transplantation Research Group Belgium University Hospitals of Leuven Department of Nephrology Dialysis and Renal Transplantation Leuven Belgium KU Leuven PKD Research Group Belgium University Hospitals of Leuven Department of Pediatric Nephrology Leuven Belgium KU Leuven Department of Microbiology Immunology and Transplantation Inborn Errors of Immunity University Hospitals of Leuven Department of Pediatrics Pediatric Immunology Leuven Belgium KU Leuven Department of Cellular and Molecular Medicine VIB Centre for Brain and Disease Research Laboratory of Ion Channel Research Leuven Belgium

Background and Aims Macrophages are the most prevalent immune cell type in the renal parenchyma in ADpkd. Depletion of macrophages in animal models has shown a dramatic attenuation in cystic burden, suggesting a disease promoting effect of this cell type. So far, studies investigating interaction between epithelial cells and immune cells in the field of ADpkd were performed with mice-derived myeloid cells. We present a new model using human-derived immune cells and tubular epithelial cells for the study of *** We established a technique to isolate CD14+ monocytes from the peripheral blood of young ADpkd patients and healthy controls. Methodology was optimized to create monocyte-derived macrophagesin vitro. Mature macrophages were checked for surface marker expression (CD14, CD11b, CD206, CD163, HLA-DR, D80, and CD86) & cytokine-release after stimulation with LPS, IL-4 and LPS + Nigericin. Co-cultures were performed using human-derived monocytes in combination with double immortalized cystic cells (ciCC) or healthy-kidney derived cell lines (HKT). Differentiation and polarization of macrophages was checked using *** We observed low expression of pkd1 and pkd2 transcripts in primary, human-derived monocytes of ADpkd patients and controls. The expression of pkd1 and pkd2 increased after differentiation into macrophages. There were no clear differences between ADpkd and control-derived macrophages in the differentiation capacity, cell survival nor surface marker expression before and after differentiation. After stimulation with LPS & LPS + Nigericin ADpkd-derived macrophages showed significantly lower expression of pro-inflammatory cytokines (MIP-1α, IP-10, IL-23 and TNFα) as compared to controls. There was no difference in anti-inflammatory cytokine release. Healthy primary monocytes cultured in direct contact with conditionally immortalized cystic cells (ciCC) had a very good survival and showed differentiation into macrophages with high ex

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MO007ANALYSIS OF CALCIUM SIGNALING IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADpkd)

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Nephrology Dialysis Transplantation 2021年第Supplement_1期36卷

作者： Van Giel, Dorien Decuypere, Jean-Paul Mekahli, Djalila Vennekens, Rudi VIB Center for Brain and Disease Research Laboratory of Ion Channel Research Leuven Belgium KU Leuven Department of Development and Regeneration - PKD Research Group Leuven Belgium University Hospitals Leuven Department of Pediatric Nephrology Leuven Belgium

Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADpkd) is an inheritable kidney disease characterized by the development of fluid-filled cysts in all nephron segments, leading to loss of renal function. Mutations in pkd1 or pkd2, which encode polycystin-1 and polycystin-2, are the most common cause of ADpkd. The molecular mechanisms underlying cystogenesis are poorly characterized but it is postulated that disturbed calcium homeostasis is a primary event in cystogenesis. The precise molecular players that cause this disturbance are still a poorly explored area, especially in relevant human cell types. We therefore aim to characterize the profile of calcium-coupled receptors and channels in a human renal epithelial cell model, to identify which receptors and channels are present and whether their function is affected in *** Human urine-derived conditionally immortalized proximal tubule epithelial cells (ciPTECs) of ADpkd patients and healthy controls were screened for calcium-coupled GPCRs, using a GPCR agonist library on Fura-2 loaded cell populations seeded in 96-well format using the Flexstation3 (Molecular Devices). Validation of specific hits was done using single-cell measurements with a fluorescence microscope and built-in perfusion system. The expression of TRP channels and STIM/Orai proteins was determined via *** From a library of 418 GPCR agonists a selective amount of calcium-coupled GPCRs was found functionally active in ciPTECs. ciPTECs from both healthy controls and ADpkd patients were found to functionally express purinergic -, histamine -, serotonin and dopamine receptors. Through qPCR we found expression of various TRP channels, including TRPML1, TRPC1/3, TRPM3/4/7, TRPV4 and TRPA1, as well as high expression of STIM1/2 and Orai1/2/*** We describe the first thorough characterization of molecular players involved in calcium signalling mechanisms in human renal epithelial cells, including the profile of cal

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Correction to: The wind of change in the management of autosomal dominant polycystic kidney disease in childhood

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Pediatric nephrology (Berlin, Germany) 2022年第3期37卷 687-688页

作者： Charlotte Gimpel Carsten Bergmann Djalila Mekahli Department of Internal Medicine IV (Nephrology) Medical Center-University of Freiburg Faculty of Medicine University of Freiburg Hugstetter Str. 55 79106 Freiburg Germany. Charlotte.Gimpel@uniklinik-freiburg.de. Medizinisches Versorgungszentrum des Klinikum Konstanz Constance Germany. Charlotte.Gimpel@uniklinik-freiburg.de. Department of Internal Medicine IV (Nephrology) Medical Center-University of Freiburg Faculty of Medicine University of Freiburg Hugstetter Str. 55 79106 Freiburg Germany. Carsten.Bergmann@medgen-mainz.de. Medizinische Genetik Mainz Limbach Genetics Haifa-Allee 38 55128 Mainz Germany. Carsten.Bergmann@medgen-mainz.de. Department of Pediatric Nephrology University Hospital of Leuven Herestraat 49 3000 Leuven Belgium. Djalila.Mekahli@uzleuven.be. PKD Research Group Pediatric Laboratory Department of Development and Regeneration GPURE KU Leuven Leuven Belgium. Djalila.Mekahli@uzleuven.be.

A Correction to this paper has been published: https://***/10.1007/s00467-021-05207-4

关键词： Pediatrics Nephrology Urology

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#3295 RAPIDLY PROGRESSIVE AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE : RISK FACTORS FOR DISEASE SEVERITY DURING CHILDHOOD AND EARLY ADULTHOOD

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Nephrology Dialysis Transplantation 2023年第SUPPLEMENT_1期38卷

作者： Wigerinck, Stijn Schellekens, Pieter Dachy, Angélique Chedid, Maroun Hanna, Christian Jouret, François Harris, Peter Bammens, Bert Chebib, Fouad Mekahli, Djalila Mayo Clinic Rochester MN Nephrology and Hypertension Rochester United States of America Catholic University of Leuven PKD Research Group Department of Development and Regeneration Leuven Belgium Catholic University of Leuven Department of Nephrology Dialysis and Renal Transplantation Leuven Belgium ULiège Academic Hospital Department of Pediatrics Laboratory of Translational Research in Nephrology (LTRN) Luik Belgium Mayo Clinic Rochester MN Division of Pediatric Nephrology and Hypertension Rochester United States of America ULiège Academic Hospital Department of Internal Medicine Nephrology Luik Belgium Mayo Clinic Jacksonville Fl Nephrology and Hypertension United States of America Catholic University of Leuven Department of Pediatric Nephrology Belgium

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MO011: The Use of a 4-Point Scoring Scale in 18F-FDG-PET/CT Imaging Helps for Diagnosis of Renal and Hepatic CYST Infections in Patients with Autosomal Dominant Polycystic Kidney Disease: A Validation Cohort

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Nephrology Dialysis Transplantation 2022年第Supplement_3期37卷 gfac061.006-gfac061.006页

作者： Demuynck, Selina Lovinfosse, Pierre Seidel, Laurence Mekahli, Djalila Jouret, François Bammens, Bert Goffin, Karolien Departement of Nephrology Dialysis and Renal Transplantation KU Leuven Leuven Belgium Division of Nuclear Medicine and Oncological Imaging Department of Medical Physics Liège Belgium Department of Medico-Economy and Biostatistics University of Liège Hospital Liège Belgium Department of Development and Regeneration KU Leuven PKD Research Group Leuven Belgium Division of Nephrology Department of Internal Medicine University of Liège Hospital Liège Belgium Department of Microbiology Immunology and Transplantation Nephrology and Renal Transplantation Research Group KU Leuven Leuven Belgium Departement of Nuclear Medicine and Molecular Imaging University Hospital Leuven and KU Leuven Leuven Belgium

BACKGROUND AND AIMS Autosomal dominant polycystic kidney disease (ADpkd) is prone to multiple complications, including cyst infection (CyI). 18 F-FDG PET/CT imaging proved useful in the diagnosis of renal and hepatic CyI. A 4-point scale comparing the uptake of 18 F-FDG in the suspected infected cyst versus the hepatic physiological background has been proposed. We performed an independent validation of this semi-quantitative score system. METHOD All ADPDK patients hospitalized between January 2007 and March 2019 who underwent an 18 F-FDG PET/CT for suspected CyI were retrospectively identified using computer-based databases. Medical files were systematically reviewed. CyI was conventionally defined by: fever (>38°C), abdominal pain, increased plasma CRP levels (≥70 mg/dL), absence of any other cause of inflammation and favorable outcomes after ≥21 days of antibiotics. The 18 F-FDG uptake around the suspected CyI was evaluated using the 4-point scale. Stats were performed using SAS version 9.4. RESULTS Our cohort included 51 18 F-FDG PET/CT in 51 patients, including 11 cases of CyI according to the above-detailed definition. The agreement between the 4-point scale and the gold-standard criteria of CyI was significant, with an odds ratio of 6.03 for CyI in case of a score ≥3 ( P, 0.014 ). The corresponding sensitivity and specificity of PET/CT using the 4-point scale were 63.3% and 77.5%, respectively. CONCLUSION Our independent validation cohort confirms that the use of a semi-quantitative 4-point scoring system helps in the diagnosis of CyI by 18 F-FDG PET/CT imaging in patients with ADpkd.

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POS-422 ADPEDKD: A GLOBAL ONLINE PLATFORM TO EXPLORE THE CHILDHOOD PHENOTYPE OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

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Kidney International Reports 2021年第4期6卷 S182-S182页

作者： A. DACHY S. De Rechter L.M. Guay-Woodford A.J. Mallett T. Harris D. Böckenhauer F. Schaefer M.C. Liebau D. Mekahli PKD Research Group KU Leuven Department of Development and Regeneration Leuven Belgium Children's National Research Institute Center for Translational Research Washington United States Townsville HHS QLD Renal Genetics Service Townsville Australia PKD international Chief Executive at Polycystic Kidney Disease Charity UK London United Kingdom Great Ormond Street Hospital NHS Foundation Trust Pediatric Nephrology London United Kingdom Centre for Pediatrics and Adolescent Medicine Heidelberg University Medical Centre Division of Pediatric Nephrology Heidelberg Germany University Hospital of Cologne Department of Pediatrics and Center for Molecular Medicine Cologne Germany

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