|
1
|
Ouyang Y, Zhang W, Zhao Z, Wang C, Ren H, Xie J, Li X, Shen P, Shi H, Xu J, Xu Y, Wang W, Yang L, Yu X, Chen W, Zhao Y, Wang Z, Wu Y, Chen N, Pan X. Globotriaosylsphingosine improves risk stratification of kidney progression in Fabry disease patients. Clin Chim Acta 2024; 556:117851. [PMID: 38438007 DOI: 10.1016/j.cca.2024.117851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 02/22/2024] [Accepted: 03/01/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND Kidney damage is common in patients with Fabry disease (FD), but more accurate information about the risk of progression to kidney failure is needed for clinical decision-making. In particular, FD patients with mild renal involvement often lack timely intervention and treatment. We aimed to utilize a model to predict the risk of renal progression in FD patients. METHODS Between November 2011 and November 2019, ERT-naive patients with FD were recruited from three medical centers in China. To assess the risk of a 50% decline in the estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD), Cox proportional hazards models were utilized. The performance of these models was assessed using discrimination, calibration, and reclassification. RESULTS A total of 117 individuals were enrolled. The mean follow-up time was 4.8 years, during which 35 patients (29.9 %) progressed to the composite renal outcomes. Male sex, baseline proteinuria, eGFR and globotriaosylsphingosine (Lyso-Gb3) were found to be independent risk factors for kidney progression by the Cox model, based on which a combined model containing those clinical variables and Lyso-Gb3 and clinical models including only clinical indicators were constructed. The two prediction models had relatively good performance, with similar model fit measured by R2 (59.8 % vs. 61.1 %) and AIC (51.54 vs. 50.08) and a slight increase in the C statistic (0.949 vs. 0.951). Calibration curves indicated closer alignment between predicted and actual renal outcomes in the combined model. Furthermore, subgroup analysis revealed that Lyso-Gb3 significantly improved the predictive performance of the combined model for kidney prognosis in low-risk patients with a baseline eGFR over 60 ml/min/1.73 m2 or proteinuria levels less than 1 g/d when compared to the clinical model. CONCLUSIONS Lyso-Gb3 improves the prediction of kidney outcomes in FD patients with a low risk of progression, suggesting that these patients may benefit from early intervention to assist in clinical management. These findings need to be externally validated.
Collapse
Affiliation(s)
- Yan Ouyang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Zhang
- Neurology Division, Department of Medicine, Peking University First Hospital, Beijing, China
| | - Zhanzheng Zhao
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chaohui Wang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Ren
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyuan Xie
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Li
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pingyan Shen
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Shi
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yaowen Xu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiming Wang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Yang
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xialian Yu
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weihong Chen
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - YaWen Zhao
- Neurology Division, Department of Medicine, Peking University First Hospital, Beijing, China
| | - Zheng Wang
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - YiFan Wu
- Biomedical and Health Informatics, University of Washington, Seattle, USA
| | - Nan Chen
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - XiaoXia Pan
- Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
2
|
Avarappattu J, Gaspert A, Spartà G, Rohrbach M. Impact of kidney biopsy on deciding when to initiate enzyme replacement therapy in children with Fabry disease. Pediatr Nephrol 2024; 39:131-140. [PMID: 37470867 PMCID: PMC10673963 DOI: 10.1007/s00467-023-06050-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 05/19/2023] [Accepted: 06/04/2023] [Indexed: 07/21/2023]
Abstract
BACKGROUND Recommendations on when to start enzyme replacement therapy (ERT) in children with Fabry disease (FD) differ between guidelines. In this study, kidney biopsies of a cohort of 14 untreated children and one treated child were analyzed for their morphologic changes to determine whether early initiation of ERT is indicated. METHODS All pediatric FD patients (< 18 years old) diagnosed between 2003 and 2021 in our department who received a kidney biopsy were enrolled. Clinical symptoms; laboratory parameters regarding kidney function, such as eGFR, plasma urea, protein-creatinine, and albumin/creatinine ratio; and 14 kidney biopsies prior to ERT and one under treatment were retrospectively analyzed. RESULTS A total of 14 patients were enrolled, including 9 male and 5 female children, aged 3-18 years (median age 11). Seven of the enrolled children were 10 years old or younger. Histological analysis of kidney biopsy samples revealed severe vacuolization and accumulation of inclusions in podocytes and renal tubules. The majority of cases had no FD-specific clinical or laboratory features independent of age, gender, or genotype. The youngest FD patient presenting with isolated abnormal kidney biopsy was 3 years old. CONCLUSIONS We demonstrate that histological lesions, typical for FD, can be observed in kidney biopsies at a very young age in patients without classical clinical symptoms or laboratory abnormalities. Thus, we recommend kidney biopsies as a possible tool for early diagnosis of renal involvement in FD. As a consequence of these early biopsy findings without a clinical correlate, an early initiation of ERT should be considered. A higher resolution version of the Graphical abstract is available as Supplementary information.
Collapse
Affiliation(s)
- Jenny Avarappattu
- Department of Metabolic Medicine and Department of Nephrology, University Children's Hospital Zurich, Zurich, Switzerland
| | - Ariana Gaspert
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Giuseppina Spartà
- Department of Metabolic Medicine and Department of Nephrology, University Children's Hospital Zurich, Zurich, Switzerland
| | - Marianne Rohrbach
- Department of Metabolic Medicine and Department of Nephrology, University Children's Hospital Zurich, Zurich, Switzerland.
| |
Collapse
|
|
3
|
Bichet DG, Torra R, Wallace E, Hughes D, Giugliani R, Skuban N, Krusinska E, Feldt-Rasmussen U, Schiffmann R, Nicholls K. Long-term follow-up of renal function in patients treated with migalastat for Fabry disease. Mol Genet Metab Rep 2021; 28:100786. [PMID: 34401344 PMCID: PMC8353473 DOI: 10.1016/j.ymgmr.2021.100786] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 07/31/2021] [Indexed: 12/14/2022] Open
Abstract
The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were - 1.6 mL/min/1.73 m2 overall and - 1.8 mL/min/1.73 m2 and - 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were - 1.6 mL/min/1.73 m2 overall and - 2.6 mL/min/1.73 m2 and - 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was -1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: -0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.
Collapse
Affiliation(s)
- Daniel G Bichet
- Department of Medicine, Hôpital du Sacré-Coeur, University of Montréal, Montreal, Quebec, Canada
| | - Roser Torra
- Inherited Renal Disorders, Nephrology Department, Fundació Puigvert, REDINREN, IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eric Wallace
- Department of Medicine, University of Alabama, Birmingham, AL, USA
| | - Derralynn Hughes
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, UK
| | - Roberto Giugliani
- Medical Genetics Service, Department of Genetics, Institute of Biosciences, Institute of Basic Health Sciences, Faculty of Medicine, Faculty of Pharmacy (UFRGS) and, National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, Brazil
| | - Nina Skuban
- Amicus Therapeutics, Inc., Cranbury, NJ, USA
| | | | - Ulla Feldt-Rasmussen
- Department of Medical Endocrinology and Metabolism, Rigshospitalet, National University Hospital, Copenhagen University, Copenhagen, Denmark
| | - Raphael Schiffmann
- Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Kathy Nicholls
- Department of Nephrology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| |
Collapse
|
|
4
|
Kim H, Kang MG, Park HW, Park JR, Hwang JY, Kim K. Anderson-Fabry disease presenting with atrial fibrillation as earlier sign in a young patient: A case report. World J Clin Cases 2021; 9:4823-4828. [PMID: 34222454 PMCID: PMC8223842 DOI: 10.12998/wjcc.v9.i18.4823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/03/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder that results from a deficiency of α-galactosidase A enzyme activity in which glycosphingolipids gradually accumulate in multi-organ systems. Cardiac manifestations are the leading cause of mortality in patients with AFD. Among them, arrhythmias comprise a large portion of the heart disease cases in AFD, most of which are characterized by conduction disorders. However, atrial fibrillation as a presenting sign at the young age group diagnosed with AFD is uncommon.
CASE SUMMARY We report a case of a 26-year-old man who was admitted with chest discomfort. Left ventricular hypertrophy was fulfilled in the criteria by the Sokolow-Lyon index and atrial fibrillation on the 12 Leads-electrocardiography (ECG) that was documented in the emergency room. After spontaneously restored to normal sinus rhythm, relationships between P and R waves, including a shorter PR interval on the ECG, were revealed. The echocardiographic findings showed thickened interventricular septal and left posterior ventricular walls. Based on the clues mentioned earlier, we realized the possibility of AFD. Additionally, we noticed the associated symptoms and signs, including bilateral mild hearing loss, neuropathic pain, anhidrosis, and angiokeratoma on the trunk and hands. He was finally diagnosed with classical AFD, which was confirmed by the gene mutation and abnormal enzyme activity of α-galactosidase A.
CONCLUSION This case is a rare case of AFD as a presentation with atrial fibrillation at a young age. Confirming the relationship between P and Q waves on the ECG through sinus rhythm conversion may help in differential diagnosis of the cause of atrial fibrillation and hypertrophic myocardium.
Collapse
Affiliation(s)
- Hangyul Kim
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju 52727, South Korea
| | - Min Gyu Kang
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju 52727, South Korea
| | - Hyun Woong Park
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju 52727, South Korea
| | - Jeong-Rang Park
- Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, South Korea
| | - Jin-Yong Hwang
- Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, South Korea
| | - Kyehwan Kim
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju 52727, South Korea
| |
Collapse
|
|
5
|
Rossi F, L'Imperio V, Marti HP, Svarstad E, Smith A, Bolognesi MM, Magni F, Pagni F, Pieruzzi F. Proteomics for the study of new biomarkers in Fabry disease: State of the art. Mol Genet Metab 2021; 132:86-93. [PMID: 33077353 DOI: 10.1016/j.ymgme.2020.10.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/08/2020] [Accepted: 10/11/2020] [Indexed: 12/25/2022]
Abstract
Nephropathy represents a major complication of Fabry Disease and its accurate characterization is of paramount importance in predicting the disease progression and assessing the therapeutic responses. The diagnostic process still relies on performing renal biopsy, nevertheless many efforts have been made to discover early reliable biomarkers allowing us to avoid invasive procedures. In this field, proteomics offers a sensitive and fast method leading to an accurate detection of specific pathological proteins and the discovery of diagnostic and prognostic biomarkers that reflect disease progression and facilitate the evaluation of therapeutic responses. Here, we report a review of selected literature focusing on the investigation of several proteomic techniques highlighting their advantages, limitations and future perspectives in their application in the routine study of Fabry Nephropathy.
Collapse
Affiliation(s)
- Federica Rossi
- Department of Medicine and Surgery, University of Milano-Bicocca, Nephrology and Dialysis Unit, San Gerardo Hospital, Via G.B. Pergolesi 33, Monza, Italy.
| | - Vincenzo L'Imperio
- Department of Medicine and Surgery, University of Milano-Bicocca, Pathology, San Gerardo Hospital, Via G.B. Pergolesi 33, Monza, Italy.
| | - Hans-Peter Marti
- Department of Medicine, Haukeland University Hospital, Jonas Lies Vei 65, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Jonas Lies Vei 87, Bergen, Norway
| | - Einar Svarstad
- Department of Clinical Medicine, University of Bergen, Jonas Lies Vei 87, Bergen, Norway
| | - Andrew Smith
- Department of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-Bicocca, Via Raoul Follereau 3, Vedano al Lambro, Italy
| | - Maddalena Maria Bolognesi
- Department of Medicine and Surgery, University of Milano-Bicocca, Pathology, San Gerardo Hospital, Via G.B. Pergolesi 33, Monza, Italy
| | - Fulvio Magni
- Department of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-Bicocca, Via Raoul Follereau 3, Vedano al Lambro, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, University of Milano-Bicocca, Pathology, San Gerardo Hospital, Via G.B. Pergolesi 33, Monza, Italy
| | - Federico Pieruzzi
- Department of Medicine and Surgery, University of Milano-Bicocca, Nephrology and Dialysis Unit, San Gerardo Hospital, Via G.B. Pergolesi 33, Monza, Italy
| |
Collapse
|
|
6
|
Levstek T, Vujkovac B, Trebusak Podkrajsek K. Biomarkers of Fabry Nephropathy: Review and Future Perspective. Genes (Basel) 2020; 11:genes11091091. [PMID: 32962051 PMCID: PMC7564978 DOI: 10.3390/genes11091091] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/09/2020] [Accepted: 09/16/2020] [Indexed: 12/22/2022] Open
Abstract
Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. Clinical presentation in individual patients varies widely, even in patients from the same family carrying the same pathogenic GLA variant. Therefore, it is reasonable to anticipate that additional genomic, transcriptomic, proteomic, and metabolomics factors influence the manifestation and progression of the disease. The aim of this article is to provide an overview of nephropathy in Fabry patients and the biomarkers currently used in the diagnosis and follow-up. Current biomarkers are associated with late signs of kidney damage. Therefore, there is a need to identify biomarkers associated with early stages of kidney damage that would enable early diagnosis, which is crucial for effective treatment and prevention of severe irreversible complications. Recent advances in sequencing and -omics technologies have led to several studies investigating new biomarkers. We will provide an overview of the novel biomarkers, critically evaluate their clinical utility, and propose future perspectives, which we believe might be in their integration.
Collapse
Affiliation(s)
- Tina Levstek
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia;
| | - Bojan Vujkovac
- Centre for Fabry Disease, General Hospital Slovenj Gradec, Gosposvetska cesta 1, 2380 Slovenj Gradec, Slovenia;
| | - Katarina Trebusak Podkrajsek
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia;
- Clinical Institute for Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Vrazov trg 1, 1000 Ljubljana, Slovenia
- Correspondence:
| |
Collapse
|
|
7
|
Wu SZ, Liang X, Geng J, Zhang MB, Xie N, Su XY. Hydroxychloroquine-induced renal phospholipidosis resembling Fabry disease in undifferentiated connective tissue disease: A case report. World J Clin Cases 2019; 7:4377-4383. [PMID: 31911921 PMCID: PMC6940343 DOI: 10.12998/wjcc.v7.i24.4377] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/08/2019] [Accepted: 11/23/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Fabry disease is a kind of lysosomal storage disease resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (GLA). A mutation in the GLA gene leads to a loss of activity of alpha-galactosidase A. Some drugs, such as hydroxychloroquine, can cause pathological changes similar to those usually seen in Fabry disease.
CASE SUMMARY We report the case of a 41-year-old female patient who was diagnosed with undifferentiated connective tissue disease in 2008. Hydroxychloroquine treatment started 2 years ago, and proteinuria and hematuria increased. Renal biopsy demonstrated renal phospholipidosis. Zebra bodies and myelin figures were found by renal electron microscopy and were initially thought to be indicators of Fabry disease. A genetic analysis of the patient and her family members did not reveal mutations in the GLA gene, supporting a diagnosis of hydroxychloroquine-induced renal phospholipidosis.
CONCLUSION This report reveals one of the adverse effects of hydroxychloroquine. We should pay more attention to hydroxychloroquine-induced renal phospholipidosis.
Collapse
Affiliation(s)
- Song-Zhao Wu
- Nephrology Department, Tungwah Hospital of Sun Yat-Sen University, Dongguan 523000, Guangdong Province, China
| | - Xiang Liang
- Nephrology Department, Tungwah Hospital of Sun Yat-Sen University, Dongguan 523000, Guangdong Province, China
| | - Jian Geng
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Meng-Bi Zhang
- Nephrology Department, Tungwah Hospital of Sun Yat-Sen University, Dongguan 523000, Guangdong Province, China
| | - Na Xie
- Nephrology Department, Tungwah Hospital of Sun Yat-Sen University, Dongguan 523000, Guangdong Province, China
| | - Xiao-Yan Su
- Nephrology Department, Tungwah Hospital of Sun Yat-Sen University, Dongguan 523000, Guangdong Province, China
| |
Collapse
|
|
8
|
Liern M, Collazo A, Valencia M, Fainboin A, Isse L, Costales-Collaguazo C, Ochoa F, Vallejo G, Zotta E. Podocyturia in paediatric patients with Fabry disease. Nefrologia 2018; 39:177-183. [PMID: 30139698 DOI: 10.1016/j.nefro.2018.05.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/11/2018] [Accepted: 05/14/2018] [Indexed: 01/17/2023] Open
Abstract
INTRODUCTION Fabry disease (FD) is a hereditary disorder caused by a deficiency of α-galactosidase A enzyme activity. The transmission of the disorder is linked to the X chromosome. OBJECTIVES The objectives of the study were: 1. To quantify the presence of podocytes in paediatric patients with FD and compare them with the value of the measured podocyturia in healthy controls. 2. To determine whether a greater podocyturia is related to the onset of pathological albuminuria in patients with FD. 3. To determine the risk factors associated with pathological albuminuria. METHODS We performed an analytical, observational study of Fabry and control subjects, which were separated into 2groups in accordance with the absence of the disease (control group) or the presence of the disease (Fabry group). RESULTS We studied 31 patients, 11 with FD and 20 controls, with a mean age of 11.6 years. The difference between the mean time elapsed from the diagnosis of FD to the measurement of podocyturia (40 months) and the onset of pathological albuminuria (34 months) was not significant (p=0.09). Podocytes were identified by staining for the presence of synaptopodin and the mean quantitative differences between both podocyturias were statistically significant (p=0.001). Albuminuria was physiological in 4 of the patients with FD and the relative risk to develop pathological albuminuria according to podocyturia was 1.1 in the control group and 3.9 in the Fabry group, with a coefficient of correlation between podocyturia and albuminuria in the Fabry group of 0.8354. Finally, the 2 risk factors associated with the development of pathological albuminuria were podocyturia (OR: 14) and being aged over 10 years (OR: 18). We found no significant risk with regard to glomerular filtrate renal (GFR) (OR: 0.5) or gender (OR: 1.3). The mean GFR remained within normal values. CONCLUSION The detection of podocyturia in paediatric patients with FD could be used as an early marker of renal damage, preceding and proportional to the occurrence of pathological albuminuria.
Collapse
Affiliation(s)
- Miguel Liern
- Unidad de Nefrología, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
| | - Anabella Collazo
- Unidad de Nefrología, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Maylin Valencia
- Unidad de Nefrología, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Alejandro Fainboin
- Unidad de Nefrología, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Lorena Isse
- Unidad de Nefrología, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Cristian Costales-Collaguazo
- Departamento de Ciencias Fisiológicas IFIBIO Houssay, CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Cátedra de Fisiopatología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Federico Ochoa
- Departamento de Ciencias Fisiológicas IFIBIO Houssay, CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Graciela Vallejo
- Unidad de Nefrología, Hospital General de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Elsa Zotta
- Departamento de Ciencias Fisiológicas IFIBIO Houssay, CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Cátedra de Fisiopatología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| |
Collapse
|
|
9
|
Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab 2018. [PMID: 29530533 DOI: 10.1016/j.ymgme.2018.02.014] [Citation(s) in RCA: 407] [Impact Index Per Article: 58.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team.
Collapse
Affiliation(s)
- Alberto Ortiz
- Unidad de Dialisis, IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, IRSIN and REDINREN, Madrid, Spain.
| | - Dominique P Germain
- French Referral Center for Fabry disease, Division of Medical Genetics and INSERM U1179, University of Versailles, Paris-Saclay University, Montigny, France
| | - Robert J Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Juan Politei
- Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina
| | - Michael Mauer
- Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | - Christine Eng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Robert J Hopkin
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Dawn Laney
- Division of Medical Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Aleš Linhart
- 2nd Department of Internal - Cardiovascular Medicine, First Medical Faculty, Charles University, Prague, Czech Republic
| | - Stephen Waldek
- School of Pharmacy, University of Sunderland, Sunderland, UK
| | - Eric Wallace
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Frank Weidemann
- Department of Internal Medicine, Katharinen-Hospital Unna, Unna, Germany
| | - William R Wilcox
- Division of Medical Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| |
Collapse
|
|
10
|
Del Pino M, Andrés A, Bernabéu AÁ, de Juan-Rivera J, Fernández E, de Dios García Díaz J, Hernández D, Luño J, Fernández IM, Paniagua J, Posada de la Paz M, Rodríguez-Pérez JC, Santamaría R, Torra R, Ambros JT, Vidau P, Torregrosa JV. Fabry Nephropathy: An Evidence-Based Narrative Review. Kidney Blood Press Res 2018; 43:406-421. [PMID: 29558749 DOI: 10.1159/000488121] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 03/09/2018] [Indexed: 11/19/2022] Open
Abstract
Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options.
Collapse
Affiliation(s)
- María Del Pino
- Nephrology Service, Hospital Torrecardenas, Almeria, Spain
| | - Amado Andrés
- Division of Nephrology, Instituto de Investigación Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain
| | | | | | - Elvira Fernández
- Unit for the Detection and Treatment of Atherothrombotic Diseases (UDETMA), Nephrology Department, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Juan de Dios García Díaz
- Clinical Genetics Unit, Department of Internal Medicine University Hospital Príncipe de Asturias Alcalá de Henares, Madrid, Spain
| | - Domingo Hernández
- Nephrology Department, Carlos Haya Regional University Hospital and University of Málaga, IBIMA, REDinREN (RD16/0009/0006), Málaga, Spain
| | - José Luño
- Nephrology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - José Paniagua
- Nephrology Service, Hospital El Bierzo, Ponferrada, Spain
| | - Manuel Posada de la Paz
- Institute of Rare Diseases Research, SpainRDR and CIBERER, Institute of Health Carlos III, Madrid, Spain
| | - José Carlos Rodríguez-Pérez
- University Hospital of Gran Canaria Dr. Negrin, Universidad de Las Palmas de Gran Canaria (Las Palmas), Las Palmas, Spain
| | - Rafael Santamaría
- Nephrology Department, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba and University of Cordoba, Red de Investigación Renal (RedinRen), Cordoba, Spain
| | - Roser Torra
- Inherited Kidney Disorders, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Joan Torras Ambros
- Nephrology Service, Experimental Nephrology Laboratory, Hospital de Bellvitge, IDIBELL, Barcelona, Spain
| | - Pedro Vidau
- Nephrology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Josep-Vicent Torregrosa
- Nephrology and Renal Transplant Department, Hospital Clinic, University of Barcelona, RedInRen, Barcelona, Spain
| |
Collapse
|
|
11
|
Rozenfeld P, Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab 2017; 122:19-27. [PMID: 28947349 DOI: 10.1016/j.ymgme.2017.09.004] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/11/2017] [Accepted: 09/11/2017] [Indexed: 01/25/2023]
Abstract
Lysosomal 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.
Collapse
Affiliation(s)
- Paula Rozenfeld
- IIFP (Instituto de Estudios Inmunológicos y Fisiopatológicos) UNLP, CONICET, Facultad de Ciencias Exactas, Buenos Aires, Argentina.
| | - Sandro Feriozzi
- Nephrology and Dialysis Unit, Belcolle Hospital, Viterbo, Italy.
| |
Collapse
|
|
12
|
Shimohata H, Maruyama H, Miyamoto Y, Takayasu M, Hirayama K, Kobayashi M. Urinary mulberry cells and mulberry bodies are useful tool to detect late-onset Fabry disease. CEN Case Rep 2017; 6:148-151. [PMID: 28593486 DOI: 10.1007/s13730-017-0262-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 06/04/2017] [Indexed: 01/14/2023] Open
Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by a lack of α-galactosidase A activity, which leads to the accumulation of globotriaosylceramide in various organs. A complete lack of α-galactosidase A activity in a hemizygous male is the classical phenotype, and some hemizygous males show primarily cardiac and/or renal symptoms that appear in adulthood; this is called the variant type or the late-onset type. The kidney and heart are the major target organs, with damage to these organs related to mortality. Thus, in Fabry patients, early detection and early treatment are critical to longevity. Here, we present a 55-year-old Japanese male patient who was diagnosed with late-onset Fabry nephropathy with cardiomyopathy but with no abnormal urinary findings except for urinary mulberry cells and mulberry bodies. In spite of the absence of abnormal urinary findings, the light microscopic and electron microscopic pathological findings showed extensive deposition of globotriaosylceramide to podocytes. In this paper, we propose that the presence of mulberry cells and mulberry bodies can be used for the earlier detection of Fabry nephropathy, especially the late-onset type.
Collapse
Affiliation(s)
- Homare Shimohata
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, 300-0395, Ibaraki, Japan.
| | - Hiroshi Maruyama
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, 300-0395, Ibaraki, Japan
| | - Yasunori Miyamoto
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, 300-0395, Ibaraki, Japan
| | - Mamiko Takayasu
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, 300-0395, Ibaraki, Japan
| | - Kouichi Hirayama
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, 300-0395, Ibaraki, Japan
| | - Masaki Kobayashi
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, 300-0395, Ibaraki, Japan
| |
Collapse
|
|
13
|
Aguiar P, Azevedo O, Pinto R, Marino J, Baker R, Cardoso C, Ducla Soares JL, Hughes D. New biomarkers defining a novel early stage of Fabry nephropathy: A diagnostic test study. Mol Genet Metab 2017; 121:162-169. [PMID: 28526293 DOI: 10.1016/j.ymgme.2017.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/12/2017] [Accepted: 05/12/2017] [Indexed: 11/26/2022]
Abstract
BACKGROUND Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage≥2. METHODS In this multicentre, prospective, cross-sectional and diagnostic test study, a cohort of 78 Fabry patients and 25 healthy controls was consecutively recruited. Patients were grouped by severity of nephropathy: 1) albuminuria<30mg/g; 2) albuminuria 30-299mg/g; 3) albuminuria>300mg/g; 4) glomerular filtration rate (GFR)<60mL/min/1.73m2. Several index tests, namely biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-β-glucosaminidase and alanine aminopeptidase) dysfunction were compared with the reference standard (albuminuria). RESULTS Significant increase of all tested biomarkers in Fabry patients, even in the subgroup of patients without evidence of nephropathy. We also found inverse significant correlations between estimated GFR and collagen type IV (ρ=-0.289; p=0.003) or N-acetyl-β-glucosaminidase (ρ=-0.448; p<0.001), which were stronger than with albumin (ρ=-0.274; p=0.019). There was also better diagnostic accuracy of N-acetyl-β-glucosaminidase to predict CKD stage≥2. CONCLUSIONS These results suggest that studied biomarkers may overcome the limitations of albuminuria as sensitive marker of early renal dysfunction and as marker for CKD progression risk. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage.
Collapse
Affiliation(s)
- Patrício Aguiar
- Medicine 1 Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
| | - Olga Azevedo
- Department of Cardiology, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui Pinto
- JCS. Dr Joaquim Chaves, Lab Análises Clínicas, Miraflores, Portugal
| | - Jacira Marino
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Robert Baker
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Carlos Cardoso
- JCS. Dr Joaquim Chaves, Lab Análises Clínicas, Miraflores, Portugal
| | | | - Derralynn Hughes
- Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| |
Collapse
|
|
14
|
de Menezes Neves PDM, Machado JR, Custódio FB, Dos Reis Monteiro MLG, Iwamoto S, Freire M, Ferreira MF, Dos Reis MA. Ultrastructural deposits appearing as "zebra bodies" in renal biopsy: Fabry disease?- comparative case reports. BMC Nephrol 2017; 18:157. [PMID: 28499424 PMCID: PMC5427530 DOI: 10.1186/s12882-017-0571-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 05/03/2017] [Indexed: 12/12/2022] Open
Abstract
Background Fabry Disease (FD) is a genetic disorder caused by alpha-galactosidase A deficiency. Certain drugs, such as hydroxychloroquine, can produce renal deposits that mimic morphological findings seen in FD, characterizing a type of drug-induced renal phospholipidosis. Case presentation Case 1: A 28-year-old female patient with systemic lupus erythematosus who had been using hydroxychloroquine for 14 months presented subnephrotic proteinuria. Renal biopsy showed deposits compatible with FD. Neither activity analysis of alpha-galactosidase A nor genetic analysis were available and were not performed. These deposits were not detected in a subsequent renal biopsy three years after withdrawal of the medication, characterizing a possible hydroxychloroquine-induced renal phospholipidosis. Case 2: A 29-year-old male patient presented with acroparesthesia, angiokeratomas, cornea verticillata and subnephrotic proteinuria. Deposits compatible with FD were detected upon renal biopsy. The evaluation of alpha-galactosidase A showed no activity in both blood and leukocytes. Genetic analysis identified an M284 T mutation in exon 6, and such mutation was also found in other family members. Conclusion Clinical investigation is necessary in suspected cases of Fabry Disease upon renal biopsy in order to confirm diagnosis. Drug-induced renal phospholipidosis should be considered in differential diagnosis in cases with intracellular osmiophilic, lamellar inclusions in electron microscopy.
Collapse
Affiliation(s)
| | - Juliana Reis Machado
- Nephropathology Service, Federal University of Triângulo Mineiro, Praça Manoel Terra, 330, Uberaba, MG, CEP: 38015-050, Brazil
| | - Fabiano Bichuette Custódio
- Nephropathology Service, Federal University of Triângulo Mineiro, Praça Manoel Terra, 330, Uberaba, MG, CEP: 38015-050, Brazil
| | | | - Shigueo Iwamoto
- Renal Therapy Unit, Federal University of Triângulo Mineiro, Praça Manoel Terra, 330, Uberaba, MG, CEP: 38015-050, Brazil
| | - Marlene Freire
- Rheumatology Service, Federal University of Triângulo Mineiro, Praça Manoel Terra, 330, Uberaba, MG, CEP: 38015-050, Brazil
| | - Marisa França Ferreira
- Nephrology Service, Felício Rocho Hospital, Rua Uberaba, 500, Belo Horizonte, MG, CEP: 30180-080, Brazil
| | - Marlene Antônia Dos Reis
- Nephropathology Service, Federal University of Triângulo Mineiro, Praça Manoel Terra, 330, Uberaba, MG, CEP: 38015-050, Brazil.
| |
Collapse
|
|
15
|
Biancini GB, Morás AM, Reinhardt LS, Busatto FF, de Moura Sperotto ND, Saffi J, Moura DJ, Giugliani R, Vargas CR. Globotriaosylsphingosine induces oxidative DNA damage in cultured kidney cells. Nephrology (Carlton) 2017; 22:490-493. [DOI: 10.1111/nep.12977] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 11/16/2016] [Accepted: 11/30/2016] [Indexed: 01/26/2023]
Affiliation(s)
- Giovana Brondani Biancini
- Graduate Program in Biological Sciences: Biochemistry; Federal University of Rio Grande do Sul (UFRGS); Porto Alegre RS Brazil
- Medical Genetics Service; Clinical Hospital of Porto Alegre (HCPA); Porto Alegre RS Brazil
| | - Ana Moira Morás
- Laboratory of Genetic Toxicology; Federal University of Life Sciences of Porto Alegre (UFSCPA); Porto Alegre RS Brazil
| | - Luiza Steffens Reinhardt
- Laboratory of Genetic Toxicology; Federal University of Life Sciences of Porto Alegre (UFSCPA); Porto Alegre RS Brazil
| | - Franciele Faccio Busatto
- Laboratory of Genetic Toxicology; Federal University of Life Sciences of Porto Alegre (UFSCPA); Porto Alegre RS Brazil
| | | | - Jenifer Saffi
- Laboratory of Genetic Toxicology; Federal University of Life Sciences of Porto Alegre (UFSCPA); Porto Alegre RS Brazil
| | - Dinara Jaqueline Moura
- Laboratory of Genetic Toxicology; Federal University of Life Sciences of Porto Alegre (UFSCPA); Porto Alegre RS Brazil
| | - Roberto Giugliani
- Graduate Program in Biological Sciences: Biochemistry; Federal University of Rio Grande do Sul (UFRGS); Porto Alegre RS Brazil
- Medical Genetics Service; Clinical Hospital of Porto Alegre (HCPA); Porto Alegre RS Brazil
- Department of Genetics; UFRGS; Porto Alegre RS Brazil
| | - Carmen Regla Vargas
- Graduate Program in Biological Sciences: Biochemistry; Federal University of Rio Grande do Sul (UFRGS); Porto Alegre RS Brazil
- Medical Genetics Service; Clinical Hospital of Porto Alegre (HCPA); Porto Alegre RS Brazil
- Graduate Program in Pharmaceutical Sciences; UFRGS; Porto Alegre RS Brazil
| |
Collapse
|
|
16
|
Schiffmann R, Hughes DA, Linthorst GE, Ortiz A, Svarstad E, Warnock DG, West ML, Wanner C, Christensen EI, Correa-Rotter R, Elliott PM, Feriozzi S, Fogo AB, Germain DP, Hollak CE, Hopkin RJ, Johnson J, Kantola I, Kopp JB, Kröner J, Linhart A, Martins AM, Matern D, Mehta AB, Mignani R, Najafian B, Narita I, Nicholls K, Obrador GT, Oliveira JP, Pisani A, Politei J, Ramaswami U, Ries M, Terryn W, Tøndel C, Torra R, Vujkovac B, Waldek S, Walter J. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2016; 91:284-293. [PMID: 27998644 DOI: 10.1016/j.kint.2016.10.004] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 10/08/2016] [Accepted: 10/13/2016] [Indexed: 01/16/2023]
Abstract
Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.
Collapse
Affiliation(s)
- Raphael Schiffmann
- Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.
| | - Derralynn A Hughes
- Department of Haematology, Royal Free London NHS Foundation Trust, & University College London, UK
| | - Gabor E Linthorst
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Alberto Ortiz
- Unidad de Dialisis, IIS-Fundacion Jimenez Diaz/UAM, IRSIN, Madrid, Spain
| | - Einar Svarstad
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - David G Warnock
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Michael L West
- Department of Medicine, Dalhousie University, Halifax, Canada
| | - Christoph Wanner
- Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Sanchez-Niño MD, Ortiz A. Enzyme Replacement Therapy for Fabry Disease. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2016. [DOI: 10.1177/2326409816679428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
| | - Alberto Ortiz
- Dialysis Unit, IIS-Fundación Jiménez Díaz, UAM, REDINREN, FRIAT, Madrid, Spain
| |
Collapse
|
|
18
|
Ortiz A, Sanchez-Niño MD. Diagnosis and treatment of Fabry disease. Med Clin (Barc) 2016; 148:132-138. [PMID: 27912900 DOI: 10.1016/j.medcli.2016.09.047] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 08/30/2016] [Accepted: 09/01/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Alberto Ortiz
- Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, España; Red de Investigación Renal (REDINREN), Madrid, España.
| | - Maria Dolores Sanchez-Niño
- Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, España; Red de Investigación Renal (REDINREN), Madrid, España
| |
Collapse
|
|
19
|
Beirão I, Cabrita A, Torres M, Silva F, Aguiar P, Gomes AM. Anderson-Fabry Disease. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2016. [DOI: 10.1177/2326409816669372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Idalina Beirão
- Centro Hospitalar do Porto, Largo Professor Abel Salazar, Porto, Portugal
| | - Ana Cabrita
- Service of Centro Hospitalar do Algarve, Rua Leao Penedo, Faro, Portugal
| | - Márcia Torres
- Centro Hospitalar do Médio Ave, Largo Domingos Moreira, Santo Tirso, Portugal
| | - Fernando Silva
- Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
| | - Patricio Aguiar
- Hospital de Santa Maria/Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, Portugal
| | - Ana Marta Gomes
- Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
| |
Collapse
|
|
20
|
Abstract
Tenofovir is currently the only commercially available nucleotidic reverse-transcriptase inhibitor of human immunodeficiency virus (HIV). It is overall very well tolerated and is prescribed to millions of patients-without any specific monitoring in developing countries. However a significant nephrotoxicity has been described. Acute nephrotoxicity is well characterized. Tenofovir is excreted in urine by proximal tubular epithelial cells. In case of cytoplasmic accumulation, tenofovir inhibits mitochondrial DNA polymerase γ, which causes a dysfunction of the respiratory chain, and in turn an alteration of the energy-deprived cells. Fanconi syndrome is the clinical expression of tenofovir acute toxicity, with sometimes an associated acute kidney failure. These abnormalities are usually reversible, at least partially, when tenofovir is discontinued. Tenofovir chronic toxicity has been debated but seems now well established by several cohort studies, even though it pathophysiology has yet to be understood. It manifests as an accelerated glomerular filtration rate decline in treated patients with no other renal abnormalities. The identification of this chronic toxicity was probably blurred by multiple cofactors, usually excluded from clinical trials. Simple measures such as dose adaptation to kidney function, identification of risk factors, and plasmatic tenofovir concentration monitoring can help decrease the risk of nephrotoxicity.
Collapse
Affiliation(s)
- Corinne Isnard-Bagnis
- Service d'urologie néphrologie transplantation, groupe hospitalier universitaire Pitié-Salpêtrière-Charles-Foix, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; Université Pierre-et-Marie-Curie, 4, place Jussieu, 75005 Paris, France
| | - Blandine Aloy
- Service d'urologie néphrologie transplantation, groupe hospitalier universitaire Pitié-Salpêtrière-Charles-Foix, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; Service information conseil adaptation rénale (Icar), groupe hospitalier universitaire Pitié-Salpêtrière-Charles-Foix, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France
| | - Gilbert Deray
- Service d'urologie néphrologie transplantation, groupe hospitalier universitaire Pitié-Salpêtrière-Charles-Foix, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; Université Pierre-et-Marie-Curie, 4, place Jussieu, 75005 Paris, France; Service information conseil adaptation rénale (Icar), groupe hospitalier universitaire Pitié-Salpêtrière-Charles-Foix, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France
| | - Jérôme Tourret
- Service d'urologie néphrologie transplantation, groupe hospitalier universitaire Pitié-Salpêtrière-Charles-Foix, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; Université Pierre-et-Marie-Curie, 4, place Jussieu, 75005 Paris, France.
| |
Collapse
|
|
21
|
Cassis L, Cortès-Saladelafont E, Molero-Luis M, Yubero D, González MJ, Herrero AO, Fons C, Jou C, Sierra C, Castejon Ponce E, Ramos F, Armstrong J, O’Callaghan MM, Casado M, Montero R, Olivas SMM, Artuch R, Barić I, Bartoloni F, Bellettato CM, Bonifazi F, Ceci A, Cvitanović-Šojat L, Dali CI, D’Avanzo F, Fumic K, Giannuzzi V, Lampe C, Scarpa M, Cazorla ÁG. Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders. Orphanet J Rare Dis 2015; 10:164. [PMID: 26714856 PMCID: PMC4696316 DOI: 10.1186/s13023-015-0376-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 12/10/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Inherited neurometabolic disorders (iNMDs) represent a group of almost seven hundred rare diseases whose common manifestations are clinical neurologic or cognitive symptoms that can appear at any time, in the first months/years of age or even later in adulthood. Early diagnosis and timely treatments are often pivotal for the favorable course of the disease. Thus, the elaboration of new evidence-based recommendations for iNMD diagnosis and management is increasingly requested by health care professionals and patients, even though the methodological quality of existing guidelines is largely unclear. InNerMeD-I-Network is the first European network on iNMDs that was created with the aim of sharing and increasing validated information about diagnosis and management of neurometabolic disorders. One of the goals of the project was to determine the number and the methodological quality of existing guidelines and recommendations for iNMDs. METHODS We performed a systematic search on PubMed, the National Guideline Clearinghouse (NGC), the Guidelines International Network (G-I-N), the Scottish Intercollegiate Guideline Network (SIGN) and the National Institute for Health and Care Excellence (NICE) to identify all the published guidelines and recommendations for iNMDs from January 2000 to June 2015. The methodological quality of the selected documents was determined using the AGREE II instrument, an appraisal tool composed of 6 domains covering 23 key items. RESULTS A total of 55 records met the inclusion criteria, 11 % were about groups of disorders, whereas the majority encompassed only one disorder. Lysosomal disorders, and in particular Fabry, Gaucher disease and mucopolysaccharidoses where the most studied. The overall methodological quality of the recommendation was acceptable and increased over time, with 25 % of the identified guidelines strongly recommended by the appraisers, 64 % recommended, and 11 % not recommended. However, heterogeneity in the obtained scores for each domain was observed among documents covering different groups of disorders and some domains like 'stakeholder involvement' and 'applicability' were generally scarcely addressed. CONCLUSIONS Greater efforts should be devoted to improve the methodological quality of guidelines and recommendations for iNMDs and AGREE II instrument seems advisable for new guideline development. The elaboration of new guidelines encompassing still uncovered disorders is badly needed.
Collapse
Affiliation(s)
- Linda Cassis
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Elisenda Cortès-Saladelafont
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Marta Molero-Luis
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Delia Yubero
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Maria Julieta González
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Aida Ormazabal Herrero
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Carme Fons
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Cristina Jou
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Cristina Sierra
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Esperanza Castejon Ponce
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Federico Ramos
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Judith Armstrong
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - M. Mar O’Callaghan
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Mercedes Casado
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Raquel Montero
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Silvia Maria Meavilla Olivas
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Rafael Artuch
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| | - Ivo Barić
- />Department of Pediatrics, University Hospital Center Zagreb, Zagreb & University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Franco Bartoloni
- />Gianni Benzi Pharmacological Research Foundation, Valenzano, BA Italy
| | | | - Fedele Bonifazi
- />Gianni Benzi Pharmacological Research Foundation, Valenzano, BA Italy
| | - Adriana Ceci
- />Gianni Benzi Pharmacological Research Foundation, Valenzano, BA Italy
| | - Ljerka Cvitanović-Šojat
- />Department of Pediatrics, University Hospital Center Zagreb, Zagreb & University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Christine I Dali
- />Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Francesca D’Avanzo
- />Department of Women and Children Health, Brains for Brain Foundation, Padova, Italy
| | - Ksenija Fumic
- />Department of Pediatrics, University Hospital Center Zagreb, Zagreb & University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Viviana Giannuzzi
- />Gianni Benzi Pharmacological Research Foundation, Valenzano, BA Italy
| | - Christina Lampe
- />Department of Women and Children Health, Brains for Brain Foundation, Padova, Italy
- />Department of Pediatric and Adolescent Medicine, Centre for Rare Diseases, Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany
| | - Maurizio Scarpa
- />Department of Women and Children Health, Brains for Brain Foundation, Padova, Italy
- />Department of Pediatric and Adolescent Medicine, Centre for Rare Diseases, Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany
- />Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Ángels Garcia- Cazorla
- />Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain
| |
Collapse
|
|
22
|
Epithelial-Mesenchymal Transition in Kidney Tubular Epithelial Cells Induced by Globotriaosylsphingosine and Globotriaosylceramide. PLoS One 2015; 10:e0136442. [PMID: 26291612 PMCID: PMC4546309 DOI: 10.1371/journal.pone.0136442] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 08/04/2015] [Indexed: 11/25/2022] Open
Abstract
Fabry disease is a lysosomal storage disorder caused by deficiency of alpha-galactosidase A (α-gal A), which results in the deposition of globotriaosylceramide (Gb3) in the vascular endothelium. Globotriaosylsphingosine (lyso-Gb3), a deacylated Gb3, is also increased in the plasma of patients with Fabry disease. Renal fibrosis is a key feature of advanced Fabry disease patients. Therefore, we evaluated the association of Gb3 and lyso-Gb3 accumulation and the epithelial–mesenchymal transition (EMT) on tubular epithelial cells of the kidney. In HK2 cells, exogenous treatments of Gb3 and lyso-Gb3 increased the expression of TGF-β, EMT markers (N-cadherin and α-SMA), and phosphorylation of PI3K/AKT, and decreased the expression of E-cadherin. Lyso-Gb3, rather than Gb3, strongly induced EMT in HK2 cells. In the mouse renal mesangial cell line, SV40 MES 13 cells, Gb3 strongly induced phenotype changes. The EMT induced by Gb3 was inhibited by enzyme α-gal A treatment, but EMT induced by lyso-Gb3 was not abrogated by enzyme treatment. However, TGF-β receptor inhibitor (TRI, SB525334) inhibited the activation of TGF-β and EMT markers in HK2 cells with Gb3 and lyso-Gb3 treatments. This study suggested that increased plasma lyso-Gb3 has a crucial role in the development of renal fibrosis through the cell-specific induction of the EMT in Fabry disease, and that TRI treatment, alongside enzyme replacement therapy, could be a potential therapeutic option for patients with Fabry disease.
Collapse
|
|
23
|
Sanchez-Niño MD, Carpio D, Sanz AB, Ruiz-Ortega M, Mezzano S, Ortiz A. Lyso-Gb3 activates Notch1 in human podocytes. Hum Mol Genet 2015. [PMID: 26206887 DOI: 10.1093/hmg/ddv291] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Podocyte injury is an early feature of Fabry nephropathy, but the molecular mechanisms of podocyte injury are poorly understood. Lyso-Gb3 accumulates in serum in Fabry disease and increases extracellular matrix synthesis in podocytes. We explored the contribution of Notch1 signaling, a mediator of podocyte injury, to lyso-Gb3-elicited responses in cultured human podocytes. At clinically relevant concentrations, lyso-Gb3 activates podocyte Notch1 signaling, resulting in increased active Notch1 and HES1, a canonical Notch transcriptional target. A γ-secretase inhibitor or specific Notch1 small interfering RNA (siRNA) inhibited HES1 upregulation in response to lyso-Gb3. Notch1 siRNA or γ-secretase inhibition also prevented the lyso-Gb3-induced upregulation of Notch1, Notch ligand Jagged1 and chemokine (MCP1, RANTES) expression. Notch siRNA prevented the activation of nuclear factor kappa B (NFκB), and NFκB activation contributed to Notch1-mediated inflammatory responses as the NFκB inhibitor, parthenolide, prevented lyso-Gb3-induced chemokine upregulation. Notch1 also mediates fibrogenic responses in podocytes as Notch siRNA prevented lyso-Gb3 upregulation of fibronectin mRNA. Supporting the clinical relevance of cell culture findings, active Notch1, Jagged1 and HES1 were observed in Fabry kidney biopsies. Lyso-Gb3 elicited similar responses in mouse kidney. In conclusion, lyso-Gb3 promotes Notch1-mediated inflammatory and fibrogenic responses in podocytes that may contribute to Fabry nephropathy.
Collapse
Affiliation(s)
- Maria D Sanchez-Niño
- IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and
| | - Daniel Carpio
- Unidad de Nefrología, Instituto de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Ana Belen Sanz
- IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and
| | - Marta Ruiz-Ortega
- IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and
| | - Sergio Mezzano
- Unidad de Nefrología, Instituto de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and
| |
Collapse
|
|
24
|
Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott CR, Waldek S, Warnock DG, Weinreb NJ, Wilcox WR. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet 2015; 52:353-8. [PMID: 25795794 PMCID: PMC4413801 DOI: 10.1136/jmedgenet-2014-102797] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 02/11/2015] [Indexed: 11/24/2022]
Abstract
Background Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. Methods The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. Results 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were −1.89 mL/min/1.73 m2/year and −6.82 mL/min/1.73 m2/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. Conclusions This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.
Collapse
Affiliation(s)
- Dominique P Germain
- Division of Medical Genetics, University of Versailles-St Quentin en Yvelines, Versailles, France; Assistance Publique-Hopitaux de Paris, Garches, France
| | - Joel Charrow
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Robert J Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Nathalie Guffon
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre de Référence des Maladies Héréditaires du Métabolisme, Bron, France
| | - Judy Kempf
- Genzyme, a Sanofi company, Cambridge, Massachusetts, USA
| | - Robin H Lachmann
- Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK
| | - Roberta Lemay
- Genzyme, a Sanofi company, Cambridge, Massachusetts, USA
| | - Gabor E Linthorst
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands
| | - Seymour Packman
- Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, California, USA
| | - C Ronald Scott
- Department of Pediatrics, University of Washington, Seattle, Washington, USA
| | - Stephen Waldek
- Independent Medical Consultant (retired from Salford Royal NHS Trust 2011), Manchester, UK
| | - David G Warnock
- Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Neal J Weinreb
- University Research Foundation for Lysosomal Storage Diseases, Coral Springs, Florida, USA
| | - William R Wilcox
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| |
Collapse
|
|
25
|
Thomas AS, Mehta AB. Difficulties and barriers in diagnosing Fabry disease: what can be learnt from the literature? ACTA ACUST UNITED AC 2013; 7:589-99. [PMID: 24128193 DOI: 10.1517/17530059.2013.846322] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the lysosomal enzyme alpha galactosidase A. Clinical features include neuropathic pain, rash, proteinuria renal failure, stroke and cardiomyopathy accompanied by a reduced life expectancy. Patients report an average delay of > 10 years between symptom onset and diagnosis. Newborn screening studies suggest a much higher prevalence than that found on population studies supporting the notion that FD is under-diagnosed. AREAS COVERED Four key challenges in the diagnosis of FD and strategies to overcome them are discussed. The clinical features of FD are highly heterogeneous resulting in patients presenting to many different specialists, often with non-specific symptoms with a wide differential diagnosis. The pathophysiological mechanisms underlying this are poorly understood and the prediction of pathogenicity on the basis of gene mutation analysis can be problematic. While the availability of treatment adds an impetus to make the correct diagnosis, our understanding of when and if treatment may be required in a specific individual is incomplete. EXPERT OPINION Improving diagnostic rates of FD requires a greater awareness of the disorder among physicians to whom patients may present, new strategies to determine the pathogenicity of novel mutations and a greater understanding of the natural history of FD across the phenotypic spectrum. Collaborative clinical and laboratory research is vital in furthering knowledge of the underlying mechanisms of this disorder and how they may be impacted by current or future therapies.
Collapse
Affiliation(s)
- Alison S Thomas
- Royal Free Hospital and University College London Medical School, Lysosomal Storage Disorders Unit , London NW3 2QG , UK
| | | |
Collapse
|
|
26
|
Tourret J, Deray G, Isnard-Bagnis C. Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? J Am Soc Nephrol 2013; 24:1519-27. [PMID: 24052632 DOI: 10.1681/asn.2012080857] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF), the first nucleotidic inhibitor of HIV reverse transcription, became available in 2001. It has been extensively used worldwide and is now the most prescribed antiretroviral (ARV) drug. Its high antiviral activity and favorable metabolic profile are responsible for its success. Furthermore, TDF has been associated with other ARVs to form new combined antiretroviral treatments in only one tablet once-a-day, which increases treatment adherence. Fears of potential nephrotoxicity that tenofovir would have in common with two other drugs from the same family (adefovir, used to treat hepatitis B, and cidofovir, used to treat cytomegalovirus infections) were alleviated by the early clinical trials. Yet, in 2001, the first case of TDF-induced acute nephrotoxicity was published. Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk. Some facilitating factors have been identified, such as co-prescription of didanosine or boosted protease inhibitor, preexisting CKD, low body weight, and associated diabetes mellitus. Conversely, whether TDF is nephrotoxic in the long term is a highly debated question. Some studies suggest a decreased GFR when TDF is prescribed for a long period, while others indicate that TDF is safe for the kidneys even after many years of use. Here we review the differences in patient characteristics, study designs, and measured outcomes that can possibly explain these conflicting findings. We conclude with rational recommendation for appropriate TDF prescription.
Collapse
Affiliation(s)
- Jérôme Tourret
- Nephrology Department, Groupe Hospitalo-Universitaire Pitié-Salpêtrière and Université Pierre et Marie Curie, Paris, France
| | | | | |
Collapse
|
|
27
|
Weidemann F, Sanchez-Niño MD, Politei J, Oliveira JP, Wanner C, Warnock DG, Ortiz A. Fibrosis: a key feature of Fabry disease with potential therapeutic implications. Orphanet J Rare Dis 2013; 8:116. [PMID: 23915644 PMCID: PMC3750297 DOI: 10.1186/1750-1172-8-116] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 08/01/2013] [Indexed: 12/30/2022] Open
Abstract
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.
Collapse
Affiliation(s)
- Frank Weidemann
- Department of Medicine, Divisions of Cardiology and Nephrology, The Comprehensive Heart Failure Center at the University of Würzburg, Würzburg, Germany
| | | | - Juan Politei
- Trinity Dupuytren Clinic, Neurology department, Buenos Aires, Argentina
| | | | - Christoph Wanner
- Department of Medicine, Divisions of Cardiology and Nephrology, The Comprehensive Heart Failure Center at the University of Würzburg, Würzburg, Germany
| | | | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz-UAM, IRSIN/REDINREN, Madrid, Spain
- Unidad de Dialisis, IIS-Fundacion Jimenez Diaz, Av Reyes católicos 2, Madrid, 28040, Spain
| |
Collapse
|
|
28
|
Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. J Genet Couns 2013; 22:555-64. [DOI: 10.1007/s10897-013-9613-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 05/22/2013] [Indexed: 10/26/2022]
|
|
29
|
|
|
30
|
Pisani A, Visciano B, Roux GD, Sabbatini M, Porto C, Parenti G, Imbriaco M. Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature. Mol Genet Metab 2012; 107:267-75. [PMID: 22963910 DOI: 10.1016/j.ymgme.2012.08.003] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Revised: 08/04/2012] [Accepted: 08/04/2012] [Indexed: 12/25/2022]
Abstract
Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10 years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations.
Collapse
Affiliation(s)
- Antonio Pisani
- Department of Nephrology, University Federico II, Napoli, Italy
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Effects of switching from agalsidase Beta to agalsidase alfa in 10 patients with anderson-fabry disease. JIMD Rep 2012; 9:41-48. [PMID: 23430546 DOI: 10.1007/8904_2012_177] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 09/04/2012] [Accepted: 09/06/2012] [Indexed: 12/29/2022] Open
Abstract
Anderson-Fabry disease (AFD) is a multiorgan X-linked lysosomal storage disease that particularly affects the heart, kidneys, and cerebrovascular system. Current treatment is enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme(®), Genzyme Corporation, Cambridge, MA, USA) or agalsidase alfa (Replagal(®), Shire Human Genetic Therapies AB, Lund, Sweden). It was recommended that patients switch to agalsidase alfa due to a manufacturing shortage of agalsidase beta beginning in June 2009. This study assessed the effect of switching to agalsidase alfa on clinical outcomes in patients with AFD previously treated with agalsidase beta. Ten patients (seven male, three female) with genetically confirmed AFD and at least 48 months' continuous data collected during treatment with agalsidase beta 1 mg/kg every other week were switched to agalsidase alfa 0.2 mg/kg every other week for at least 20 months, with prospective clinical evaluations every 6 months. Pre-switch data was collected retrospectively from patient charts. Cardiac functional parameters were assessed using magnetic resonance imaging. Results showed that renal function was normal (estimated glomerular filtration rate ≥90 mL/min/1.73 m(2)) in 8 of 10 patients prior to agalsidase alfa and generally remained stable after the switch. Cardiac mass decreased significantly (p < 0.05 vs pre-ERT) after agalsidase beta and remained unchanged after switching to agalsidase alfa. Symptoms of pain and health status scores did not deteriorate during agalsidase alfa therapy. Adverse events were mostly mild and infusion related. In conclusion, switching to agalsidase alfa was relatively well tolerated and associated with stable clinical status and preserved renal and cardiac function.
Collapse
|
|
32
|
H Mukdsi J, Gutiérrez S, Barrón B, Novoa P, Fernández S, de Diller AB, I Torres A, Formica RN, Orías M. A renal variant of Fabry disease: A case with a novel Gal A hemizygote mutation. J Nephropathol 2012; 1:194-7. [PMID: 24475416 DOI: 10.5812/nephropathol.8123] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 08/02/2012] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Fabry disease is caused by an X-linked recessive inborn error of glycosphingolipid metabolism with deficient activity of a lysosomal enzyme, alpha-galactosidase A (α-GalA). CASE PRESENTATION A 46 year-old man with progressive kidney disease showed on kidney biopsy electron microscopic evidence of Fabry disease. The patient had no systemic manifestations of Fabry disease, despite residual α-GalA activity, therefore genetic testing was done by direct DNA sequencing, demonstrating a new GAL A gene mutation (C174G-exon 3). After three years of enzyme replacement therapy (agalsidase beta) treatment, a second biopsy was done. Although there was demonstrable clearance of intracellular inclusions, remarkable podocyte activation was evident. CONCLUSIONS This report represents an unusual renal variant of Fabry disease and provides histologic data on long-term follow up after enzyme replacement therapy.
Collapse
Affiliation(s)
- Jorge H Mukdsi
- Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, and Haya de la Torre esquina Enrique Barros, Ciudad Universitaria, Córdoba, Argentina
| | - Silvina Gutiérrez
- Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, and Haya de la Torre esquina Enrique Barros, Ciudad Universitaria, Córdoba, Argentina
| | - Belén Barrón
- Servicio de Nefrología, Sanatorio Allende, Bernardo de Irigoyen 384, Córdoba, Argentina
| | - Pablo Novoa
- Servicio de Nefrología, Sanatorio Allende, Bernardo de Irigoyen 384, Córdoba, Argentina
| | | | - Ana B de Diller
- Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, and Haya de la Torre esquina Enrique Barros, Ciudad Universitaria, Córdoba, Argentina
| | - Alicia I Torres
- Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, and Haya de la Torre esquina Enrique Barros, Ciudad Universitaria, Córdoba, Argentina
| | - Richard N Formica
- Department of Medicine, Section of Nephrology, Yale University School of Medicine, USA
| | - Marcelo Orías
- Servicio de Nefrología, Sanatorio Allende, Bernardo de Irigoyen 384, Córdoba, Argentina
| |
Collapse
|
|
33
|
Ortiz A. Blood Pressure. Clin Ther 2012. [DOI: 10.1016/j.clinthera.2012.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
|
|
34
|
Warnock DG. Managing Patients With Chronic Kidney Disease. Clin Ther 2012. [DOI: 10.1016/j.clinthera.2012.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
|
|
35
|
Alamartine E, Sury A, Roche F, Pichot V, Barthelemy JC. Autonomic nervous system activity in patients with Fabry disease. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/ojim.2012.22021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
36
|
Feriozzi S, Torras J, Cybulla M, Nicholls K, Sunder-Plassmann G, West M. The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. Clin J Am Soc Nephrol 2012; 7:60-9. [PMID: 22246281 PMCID: PMC3265340 DOI: 10.2215/cjn.03130411] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2011] [Accepted: 10/11/2011] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Fabry disease is a rare X-linked disease with multisystemic manifestations. This study investigated the effectiveness of long-term enzyme replacement therapy with agalsidase alfa in Fabry nephropathy treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this observational study, data on patients receiving agalsidase alfa (0.2 mg/kg every other week) were extracted from the Fabry Outcome Survey, an international registry of patients with Fabry disease. Serum creatinine and estimated GFR (eGFR) at baseline and after ≥5 years of treatment were assessed; 24-hour urinary protein excretion and BP measurements were also reviewed. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients with an eGFR <30 ml/min per 1.73 m(2) were excluded. RESULTS Renal function was assessed in 208 patients (mean enzyme replacement therapy, 7.4 years; range, 5.0-11.2 years). Mean yearly change in eGFR was -2.2 ml/min per 1.73 m(2) in men and -0.7 ml/min per 1.73 m(2) in women (95% confidence limits, -2.8; -1.7 and -1.4; 0.0, respectively). Patients with 24-hour protein excretion >1 g/24 h had poorer renal function at baseline and follow-up compared with patients with protein excretion of 500-1000 mg/24 h or with proteinuria <500 mg/24 h. Renal function was worse in patients with baseline arterial hypertension, and there was a more rapid yearly decline compared with normotensive patients. CONCLUSIONS This study suggests that long-term agalsidase alfa therapy is able to stabilize the rate of Fabry nephropathy progression in women and is associated with a mild to moderate decline of renal function in men.
Collapse
Affiliation(s)
- Sandro Feriozzi
- Belcolle Hospital, Nephrology and Dialysis, Strada Sammartinese snc, IT-01100 Viterbo, Italy.
| | | | | | | | | | | |
Collapse
|
|
37
|
Warnock DG, Ortiz A, Mauer M, Linthorst GE, Oliveira JP, Serra AL, Maródi L, Mignani R, Vujkovac B, Beitner-Johnson D, Lemay R, Cole JA, Svarstad E, Waldek S, Germain DP, Wanner C. Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation. Nephrol Dial Transplant 2011; 27:1042-9. [PMID: 21804088 PMCID: PMC3289896 DOI: 10.1093/ndt/gfr420] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. METHODS Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. RESULTS Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). CONCLUSIONS Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
Collapse
|
|
38
|
García de Lorenzo A. Consenso para el estudio y tratamiento de la enfermedad de Fabry. Fundación GETER. Med Clin (Barc) 2011; 137:178-83. [DOI: 10.1016/j.medcli.2011.02.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 02/21/2011] [Accepted: 02/24/2011] [Indexed: 12/13/2022]
|
|
39
|
Abstract
Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study.
Collapse
|
|
40
|
Abstract
Kidney involvement is one of the main manifestations of Fabry's disease. In the absence of enzyme replacement therapy, hemizygous males and some heterozygous females progress to end stage renal failure. In hemizygous males, diffuse glycolipid accumulation is observed in all glomerular and vascular cells whereas distal tubular cells are focally involved. In heterozygous females, the glycolipid storage is irregular in glomeruli and vessels, some cells being massively involved, others being normal. In both sexes, degenerative changes occur, linked to the necrosis of overloaded mesangial and vascular smooth muscle cells. Their progression leads to unspecific arteriopathy and glomerulosclerosis not prone to reverse under enzymotherapy. Kidney biopsy is useful for confirming the diagnosis if clinical presentation of Fabry's disease is atypical. Moreover, histological analysis of renal tissue allows to assess the severity of degenerative changes and to evaluate the beneficial impact of enzyme replacement therapy.
Collapse
Affiliation(s)
- M-C Gubler
- Inserm U574, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Hôpital Necker Enfants Malades, 149 rue de Sèvres 75743 Paris cedex 15, France.
| |
Collapse
|
|
41
|
Patel MR, Cecchi F, Cizmarik M, Kantola I, Linhart A, Nicholls K, Strotmann J, Tallaj J, Tran TC, West ML, Beitner-Johnson D, Abiose A. Cardiovascular Events in Patients With Fabry Disease. J Am Coll Cardiol 2011; 57:1093-9. [DOI: 10.1016/j.jacc.2010.11.018] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 11/15/2010] [Accepted: 11/18/2010] [Indexed: 02/05/2023]
|
|
42
|
Machann W, Breunig F, Weidemann F, Sandstede J, Hahn D, Köstler H, Neubauer S, Wanner C, Beer M. Cardiac energy metabolism is disturbed in Fabry disease and improves with enzyme replacement therapy using recombinant human galactosidase A. Eur J Heart Fail 2010; 13:278-83. [PMID: 21149315 DOI: 10.1093/eurjhf/hfq211] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
AIMS In vitro studies have shown impairment of energy metabolism in cardiac fibroblasts from Fabry patients. A recent in vivo study reported an association between cardiac energy metabolism and increased myocardial mass in Fabry patients. We therefore assessed possible disturbances of cardiac energy metabolism in Fabry patients by in vivo (31)P-MR-spectroscopy. Additionally, the effect of enzyme replacement therapy (ERT) on cardiac energetics was tested. METHODS AND RESULTS Twenty-three patients (41 ± 9 years; 10 females) with genetically proven Fabry disease were examined with a 1.5 T Scanner, and compared with an age-matched healthy control group. Eight patients underwent ERT and had follow-up examinations after 3 and 14 months. The high-energy phosphate molecules phosphocreatine (PCr) and adenosine triphosphate (ATP) were quantified in localized 31P-spectra by SLOOP (spectral localization with optimum point spread function). Cine- and late gadolinium enhancement (LGE) studies were also performed. When compared with healthy controls, Fabry patients demonstrated reduced PCr- (6.1 ± 1.9 vs. 8.8 ± 2.6 mmol/kg; P = 0.003) and ATP concentrations (3.9 ± 1.5 vs. 4.6 ± 1.0 mmol/kg; P = 0.048). During ERT, PCr concentrations increased (7.1 ± 1.5 mmol/kg vs. 6.1 ± 1.9; P < 0.05) and left ventricular mass decreased (215 ± 55 vs. 185 ± 45 g; P = 0.012). Disturbances in cardiac energetics were not correlated to the presence or absence of cardiac fibrosis on LGE. CONCLUSION Cardiac energy metabolism is disturbed in Fabry disease; this may play an important role in the pathogenesis of Fabry cardiomyopathy. Enzyme replacement therapy ameliorates energetic depression.
Collapse
Affiliation(s)
- Wolfram Machann
- Institut für Röntgendiagnostik, Universität Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Wanner C, Oliveira JP, Ortiz A, Mauer M, Germain DP, Linthorst GE, Serra AL, Maródi L, Mignani R, Cianciaruso B, Vujkovac B, Lemay R, Beitner-Johnson D, Waldek S, Warnock DG. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol 2010; 5:2220-8. [PMID: 20813854 DOI: 10.2215/cjn.04340510] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVES These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included. RESULTS Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > -1 ml/min per 1.73 m(2) per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P < 0.0001). Patients were grouped into quartiles based on averaged UP/Cr; renal function in men declined more rapidly with higher UP/Cr, with the steepest declines observed in men with UP/Cr > 1.5 (mean eGFR slope, -5.6 ml/min per 1.73 m(2) per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, -1.3 ml/min per 1.73 m(2) per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function. CONCLUSIONS Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease.
Collapse
Affiliation(s)
- Christoph Wanner
- Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Abstract
The lysosomal storage disorders (LSDs) comprise a heterogeneous group of inborn errors of metabolism characterized by tissue substrate deposits, most often caused by a deficiency of the enzyme normally responsible for catabolism of various byproducts of cellular turnover. Individual entities are typified by involvement of multiple body organs, in a pattern reflecting the sites of substrate storage. It is increasingly recognized that one or more processes, such as aberrant inflammation, dysregulation of apoptosis and/or defects of autophagy, may mediate organ dysfunction or failure. Several therapeutic options for various LSDs have been introduced, including hematopoietic stem cell transplantation, enzyme replacement therapy and substrate reduction therapy. Additional strategies are being explored, including the use of pharmacological chaperones and gene therapy. Most LSDs include a variant characterized by primary central nervous system (CNS) involvement. At present, therapy of the CNS manifestations remains a major challenge because of the inability to deliver therapeutic agents across the intact blood-brain barrier. With improved understanding of underlying disease mechanisms, additional therapeutic options may be developed, complemented by various strategies to deliver the therapeutic agent(s) to recalcitrant sites of pathology such as brain, bones and lungs.
Collapse
Affiliation(s)
- Gregory M. Pastores
- Correspondence to: Gregory M. Pastores, MD Department of Neurology and Pediatrics, NYU School of Medicine, 403 East 34th Street, New York, NY 10016, USA
| |
Collapse
|
|
45
|
Sanchez-Niño MD, Sanz AB, Carrasco S, Saleem MA, Mathieson PW, Valdivielso JM, Ruiz-Ortega M, Egido J, Ortiz A. Globotriaosylsphingosine actions on human glomerular podocytes: implications for Fabry nephropathy. Nephrol Dial Transplant 2010; 26:1797-802. [PMID: 20504837 DOI: 10.1093/ndt/gfq306] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Transforming growth factor-β1 (TGF-β1) and the macrophage inhibitory factor receptor CD74 link the metabolic disorder with tissue injury in diabetic nephropathy. Fabry disease is an X-linked lysosomal glycosphingolipid storage disorder resulting from a deficient activity of α-galactosidase A that leads to proteinuric renal injury. However, the link between the metabolic abnormality and renal injury is poorly characterized. Globotriaosylsphingosine (lyso-Gb3) was recently identified as a bioactive molecule accumulating in Fabry disease. We hypothesized that lyso-Gb3 could modulate the release of secondary mediators of injury in glomerular podocytes and that recently described nephroprotective actions of vitamin D receptor activation in diabetic nephropathy may apply to lyso-Gb3. METHODS Real time RT-PCR, ELISA and Western blot were used to study the biological activity of lyso-Gb3 in cultured human podocytes and potential modulation by vitamin D receptor activation. RESULTS In human podocytes, lyso-Gb3 dose and time dependently increased the expression of TGF-β1, extracellular matrix proteins (fibronectin and type IV collagen) and CD74. TGF-β1 mediated lyso-Gb3 effects on extracellular matrix production. Vitamin D receptor activation with paricalcitol or calcitriol prevented the increase in TGF-β1, CD74 and extracellular matrix induced by lyso-Gb3. CONCLUSIONS Lyso-Gb3 may have a role in glomerular injury in Fabry disease by promoting the release of secondary mediators of glomerular injury common to diabetic nephropathy. These effects are prevented by paricalcitol, raising the issue of vitamin D receptor activation as potential adjunctive therapy in Fabry nephropathy.
Collapse
Affiliation(s)
- Maria D Sanchez-Niño
- Nefrología, Fundación Jiménez Díaz, Universidad Autonoma de Madrid and Instituto Reina Sofia de Investigaciones Nefrológicas-IRSIN, Madrid, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Choi JO, Lee MH, Park HY, Jung SC. Characterization of Fabry mice treated with recombinant adeno-associated virus 2/8-mediated gene transfer. J Biomed Sci 2010; 17:26. [PMID: 20398385 PMCID: PMC2861641 DOI: 10.1186/1423-0127-17-26] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Accepted: 04/16/2010] [Indexed: 12/31/2022] Open
Abstract
Background Enzyme replacement therapy (ERT) with α-galactosidase A (α-Gal A) is currently the most effective therapeutic strategy for patients with Fabry disease, a lysosomal storage disease. However, ERT has limitations of a short half-life, requirement for frequent administration, and limited efficacy for patients with renal failure. Therefore, we investigated the efficacy of recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for a Fabry disease mouse model and compared it with that of ERT. Methods A pseudotyped rAAV2/8 vector encoding α-Gal A cDNA (rAAV2/8-hAGA) was prepared and injected into 18-week-old male Fabry mice through the tail vein. The α-Gal A expression level and globotriaosylceramide (Gb3) levels in the Fabry mice were examined and compared with Fabry mice with ERT. Immunohistochemical and ultrastructural studies were conducted. Results Treatment of Fabry mice with rAAV2/8-hAGA resulted in the clearance of accumulated Gb3 in tissues such as liver, spleen, kidney, heart, and brain with concomitant elevation of α-Gal A enzyme activity. Enzyme activity was elevated for up to 60 weeks. In addition, expression of the α-Gal A protein was identified in the presence of rAAV2/8-hAGA at 6, 12, and 24 weeks after treatment. α-Gal A activity was significantly higher in the mice treated with rAAV2/8-hAGA than in Fabry mice that received ERT. Along with higher α-Gal A activity in the kidney of the Fabry mice treated with gene therapy, immunohistochemical studies showed more α-Gal A expression in the proximal tubules and glomerulus, and less Gb3 deposition in Fabry mice treated with this gene therapy than in mice given ERT. The α-gal A gene transfer significantly reduced the accumulation of Gb3 in the tubules and podocytes of the kidney. Electron microscopic analysis of the kidneys of Fabry mice also showed that gene therapy was more effective than ERT. Conclusions The rAAV2/8-hAGA mediated α-Gal A gene therapy provided improved efficiency over ERT in the Fabry disease mouse model. Furthermore, rAAV2/8-hAGA-mediated expression showed a greater effect in the kidney than ERT.
Collapse
Affiliation(s)
- Jin-Ok Choi
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Korea
| | | | | | | |
Collapse
|
|
47
|
Ortiz A, Cianciaruso B, Cizmarik M, Germain DP, Mignani R, Oliveira JP, Villalobos J, Vujkovac B, Waldek S, Wanner C, Warnock DG. End-stage renal disease in patients with Fabry disease: natural history data from the Fabry Registry. Nephrol Dial Transplant 2010; 25:769-775. [DOI: 10.1093/ndt/gfp554] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
|
|
48
|
|
|
49
|
Warnock DG, Daina E, Remuzzi G, West M. Enzyme replacement therapy and Fabry nephropathy. Clin J Am Soc Nephrol 2009; 5:371-8. [PMID: 20007680 DOI: 10.2215/cjn.06900909] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Involvement of the kidneys in Fabry disease ("nephropathy") occurs in male and female individuals. The majority of patients with progressive nephropathy will have significant proteinuria and develop progressive loss of kidney function, leading to ESRD. All too often, treating physicians may ignore "normal" serum creatinine levels or "minimal" proteinuria and fail to assess properly the severity of kidney involvement and institute appropriate management. Fabry nephropathy is treatable, even in patients with fairly advanced disease. Although the cornerstone of therapy remains enzyme replacement therapy with agalsidase, this treatment alone does not reduce urine protein excretion. Treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors must be added to enzyme replacement therapy to reduce urine protein excretion with the hope that this will stabilize kidney function. Kidney function, with at least estimated GFR based on serum creatinine and measurements of urinary protein, should be measured at every clinic visit, and the rate of change of the estimated GFR should be followed over time. Antiproteinuric therapy can be dosed to a prespecified urine protein target rather than a specific BP goal, with the proviso that successful therapy will usually lower the BP below the goal of 130/80 mmHg that is used for other forms of kidney disease. The overall goal for treating Fabry nephropathy is to reduce the rate of loss of GFR to -1 ml/min per 1.73 m(2)/yr, which is that seen in the normal adult population. A systematic approach is presented for reaching this goal in the individual patient.
Collapse
Affiliation(s)
- David G Warnock
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
| | | | | | | |
Collapse
|
|
50
|
Mignani R, Preda P, Granata A, Maldini L, De Giovanni P, Montevecchi M, Rigotti A, Cagnoli L. Isolated microalbuminuria as the first clinical presentation of Fabry disease in an adult heterozygous female. NDT Plus 2009; 2:455-7. [PMID: 25949379 PMCID: PMC4421328 DOI: 10.1093/ndtplus/sfp104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Accepted: 07/14/2009] [Indexed: 11/23/2022] Open
Abstract
Fabry disease (FD) is a rare X-linked disorder characterized by low or absent activity of the lysosomal enzyme α-glycosidase-A that leads to progressive accumulation of glycosphingolipids in different organs and tissues. Clinical manifestations vary from classic to atypical forms characterized by one prevalent organ involvement, and a renal variant has been described in men but not in women. However, little is known about renal manifestation in females affected by FD. We herein report a case of a 22-year-old female with isolated and persistent microalbuminuria as the only sign of FD. In light of the importance of early recognition and treatment of FD organ damage, this case should call for future studies to determine how to assess organ damage, investigate the existence of a ‘renal variant’ in FD female patients and determine when best to start enzyme replacement therapy (ERT).
Collapse
Affiliation(s)
- Renzo Mignani
- Department of Nephrology and Dialysis , Infermi Hospital , Rimini
| | - Paola Preda
- Institute of Pathology , Bologna University , Policlinico S. Orsola, Bologna
| | - Antonio Granata
- Department of Nephrology, Dialysis and Internal Medicine, A.O. Vittorio Emanuele II, Catania , Italy
| | - Laura Maldini
- Department of Nephrology and Dialysis , Infermi Hospital , Rimini
| | | | | | - Angelo Rigotti
- Department of Nephrology and Dialysis , Infermi Hospital , Rimini
| | - Leonardo Cagnoli
- Department of Nephrology and Dialysis , Infermi Hospital , Rimini
| |
Collapse
|