1,721,009 research outputs found
Updated evaluation of agalsidase alfa enzyme replacement therapy for patients with fabry disease: insights from real-world data
Get PDFThe clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti -drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD
Pathology and pathogenic pathways in fabry nephropathy
No full textBackground: The pathophysiology of renal damage in Fabry nephropathy involves a complex biological mechanism. The intracellular deposition globotriaosylceramide (Gb3) is just the first step of the mechanism. The glycolipid deposition occurs in all renal cells (endothelial, epithelial and mesangial cells). It stimulates many biological processes, including cytokine release, epithelial-mesenchymal transdifferentiation, oxidative stress and the remodelling of vascular walls, resulting in subtle initial inflammation and eventually tissue fibrosis. It has been hypothesized that the processes activated by Gb3 deposition can subsequently progress independently of cellular deposition and that even Gb3 clearance by specific therapy cannot retard or stop these pathways. Aim: This review aims to gather the reported evidence of these cellular alterations and the resulting histological changes. Our approach is similar to a routine study of kidney biopsy. Results: In the first part of the review, “histology” section, we describe the structures involved (glomeruli, vessels, tubules and interstitium) from a histological point of view. While in the second part, “pathogenesis” section, we present some interpretations about the implicated pathways based on the up-to-date available evidence.Fil: Feriozzi, Sandro. Belcolle Hospital; ItaliaFil: Rozenfeld, Paula Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentin
The role of tubular cells in the pathogenesis of Fabry nephropathy
No full textThe pathophysiology of Fabry nephropathy (FN) is induced by galactosidase Adeficiency with a chronic exposure of glycolipids to every lineage of renalcells. Tissue damage is attributed to the activation of molecular pathways,resulting in tissue fibrosis and chronic kidney disease. Podocytes have beenthe primary focus in clinical pathophysiological research because of thestriking accumulation of large glycolipid deposits observable in histology. Yet,the tubular interstitium makes up a large portion of the whole organ, andtherefore, its role must be further considered in pathogenic processes. In thisreview, we would like to propose Fabry tubulopathy and its ensuing functionaleffects as the first pathological signs and contributing factors to thedevelopment of FN. We will summarize and discuss the current literatureregarding the role of tubular cells in Fabry kidney pathophysiology. Startingfrom clinical and histological evidence, we will highlight the data from animalmodels and cell cultures outlining the pathophysiological pathways associatedwith tubular interstitial injury causing renal fibrosis in Fabry nephropathy.Fil: Rozenfeld, Paula Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Feriozzi, Sandro. Belcolle Hospital; ItaliaFil: Braun, Fabian. University Medical Center Hamburg-Eppendorf; Alemani
The inflammatory pathogenetic pathways of Fabry nephropathy
No full textThe high variability in clinical features and outcomes observed in monogenic diseases like Fabry disease suggeststhe presence of additional pathogenetic pathways beyond the lysosomal deposition of Gb3 and Lyso-GB3.Research indicates that the deposition of Gb3 and Lyso-Gb3 can stimulate the inflammatory processes.Mononuclear immune-competent cells exposed to Gb3 deposition exhibit surface adhesion molecules and releasepro-inflammatory and fibrotic cytokines such as IL β, TNFα, and TGFβ, culminating in the activation ofinflammatory cascades associated with oxidative stress, apoptotic mechanisms maintained by renal residents andinfiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, in another avenue of inquiry(termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alphagalactosidaseA enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response(UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of proinflammatorycytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstratedthat the pathogenetic mechanisms activated by Gb3 and Lyso Gb3 deposition can become independent from theinitial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist posttherapyor gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifestin the absence of Gb3 in the Zebrafish experimental model. This review endeavors to describe the role of theseprocesses in Fabry nephropathy and aims to synthesize the available evidence on the pathogenesis of renaldamage.Fil: Feriozzi. Sandro. Belcolle Hospital; ItaliaFil: Rozenfeld, Paula Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentin
Pathogenesis of Fabry nephropathy: The pathways leading to fibrosis.
No full textBackground: Kidney is one of the main target organs in Fabry disease, a lysosomal X-linked genetic disorder. Renal involvement is characterized by proteinuria and progressive chronic kidney disease leading to end-stage renal disease. Pathogenic mechanisms in the progression of renal damage in Fabry disease are not thoroughly known yet. The lysosomal Gb3 deposition is the first step of complex pathological pathways resulting in renal sclerosis/fibrosis. Our hypothesis is that Fabry disease associated cellular alterations in tubular cells induce the production of TGF-β1, which mediate transdifferentiation of renal cells into myofibroblasts resulting in fibrosis of renal tissue. Objectives: The aim of this work is to study the mechanisms leading to fibrosis in kidney from human Fabry patients. Methods: Fifteen renal biopsies from naïve Fabry patients were included. Histological and immunohistochemical analysis was carried out. Results: Positive staining for TGF-β1 was found in tubular epithelial cells in biopsies from Fabry patients. Apoptosis was determined by active caspase 3 staining in tubular and mesangial glomerular cells. Due to TGF-β1 is the main profibrotic cytokine and induces accumulation of myofibroblasts, we performed a study for its marker α-smooth muscle actin (α-SMA). This study revealed expression of α-SMA on pericytes surrounding peritubular capillaries, smooth muscle cells of blood vessels, mesangial cells and periglomerular zone. TGF-β1 is produced mainly by tubular cells in Fabry kidney biopsies probably inducing cellular trans-differentiation of renal cells into myofibroblasts. A positive staining for a marker of myofibroblasts was present, affirming the presence of those profibrotic cells. Conclusions: These results show for the first time that TGF-β1 is expressed in human renal tissue from Fabry patients, and that this profibrotic cytokine is mainly produced by proximal tubular cells. In addition both, peritubular interstitium and glomeruli, presented cells positive for myofibroblasts markers.Fil: Rozenfeld, Paula Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Bolla, María de los Ángeles. Provincia de Buenos Aires. Hospital Interzonal General de Agudos Gral. San Martín; ArgentinaFil: Quieto, Pedro. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Pisani, Antonio. Università degli Studi di Napoli Federico II; ItaliaFil: Feriozzi, Sandro. Belcolle Hospital; ItaliaFil: Neuman, Pablo. Sanatorio Ipensa; ArgentinaFil: Bondar, Constanza María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentin
Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data
Get PDFThe treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18-66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated
Contribution of inflammatory pathways to Fabry disease pathogenesis
Get PDFLysosomal storage diseases are usually considered to be pathologies in which the passive deposition of unwanted materials leads to functional changes in lysosomes. Lysosomal deposition of unmetabolized glycolipid substrates stimulates the activation of pathogenic cascades, including immunological processes, and particularly the activation of inflammation. In lysosomal storage diseases, the inflammatory response is continuously being activated because the stimulus cannot be eliminated. Consequently, inflammation becomes a chronic process. Lysosomes play a role in many steps of the immune response. Leukocyte perturbation and over-expression of immune molecules have been reported in Fabry disease. Innate immunity is activated by signals originating from dendritic cells via interactions between toll-like receptors and globotriaosylceramide (Gb3) and/or globotriaosylsphingosine (lyso-Gb3). Evidence indicates that these glycolipids can activate toll-like receptors, thus triggering inflammation and fibrosis cascades. In the kidney, Gb3 deposition is associated with the increased release of transforming growth factor beta and with epithelial-to-mesenchymal cell transition, leading to the over-expression of pro-fibrotic molecules and to renal fibrosis. Interstitial fibrosis is also a typical feature of heart involvement in Fabry disease. Endomyocardial biopsies show infiltration of lymphocytes and macrophages, suggesting a role for inflammation in causing tissue damage. Inflammation is present in all tissues and may be associated with other potentially pathologic processes such as apoptosis, impaired autophagy, and increases in pro-oxidative molecules, which could all contribute synergistically to tissue damage. In Fabry disease, the activation of chronic inflammation over time leads to organ damage. Therefore, enzyme replacement therapy must be started early, before this process becomes irreversible.Fil: Rozenfeld, Paula Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Feriozzi, Sandro. Belcolle Hospital; Itali
Identifying Fabry patients in dialysis population: prevalence of GLA mutations by renal clinic screening, 1995-2019
No full textBackground Fabry disease (FD) is a rare X-linked genetic disorder of glycosphingolipid catabolism caused by mutations in the GLA gene. Its heterogeneous presentation, the paucity of specific early markers, and the absence of a genotype-phenotype correlation are associated with a delayed or missed diagnosis. The true prevalence of FD remains so far unknown. Methods A systematic search of FD screening studies in dialysis patients published from January 1995 until January 2019 was performed to reanalyze the prevalence of GLA mutations in this population after assigning their correct phenotype. Results Twenty five screening studies involving 39,621 dialysis patients were included. Of them, 116 [91 males (0.23%) and 25 females (0.06%)] were positive to the GLA sequencing analysis. 56 (48.2%) had benign variant, 52 (44.8%) a pathogenic GLA mutation (39 classic and 13 late onset mutations) and 8 (6.9%) a mutation of uncertain significance. The overall prevalence of GLA variants was 0.24% [CI 95%, 0.17-0.32] while the overall prevalence recalculated on basis of only pathogenetic mutations was 0.14% [CI 95%, 0.08-0.20]. This difference was significant (P = 0.048). Conclusions Although the real prevalence of classic FD is low, the screening in the high-risk renal population remains of primary interest as an early diagnosis is fundamental for a timely specific therapy; moreover, the identification of index cases could allow patients' relatives to be investigated and promptly treated
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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