- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06325488
Fibrosis, Inflammation, Oxygenation of Renal Tissue In FabrY Disease (FORTIFY)
The overall objective of this study is to investigate Fabry-associated renal organ involvement by using a novel magnetic resonance imaging (MRI) approach, focusing on changes in renal oxygen levels by blood oxygenation-level dependent (BOLD) imaging. Furthermore, to correlate renal oxygenation to the phenotypic presentation of patients with Fabry-associated nephropathy regarding circulating and imaging-derived biomarkers of kidney inflammation, fibrosis and injury as compared with healthy age- and sex-matched controls.
The study will achieve this by:
1) Using a non-invasive, contrast-free MRI protocol focusing on parameters of oxygenation, inflammation, fibrosis, and injury in the kidney.
2) Using an extensive, in-depth biomarker blood panel to investigate the pathological pathways associated with Fabry disease and Fabry-associated nephropathy.
Study Overview
Status
Conditions
Detailed Description
From attached protocol:
Introduction Fabry disease is a rare X-linked lysosomal disorder caused by mutations in the gene encoding the enzyme alpha-galA, an essential enzyme for normal cellular function. The enzyme deficiency causes progressive accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) in virtually all organs, leading to dysfunction and eventually leading to organ failure. Although, Fabry disease is caused by an X-linked genetic mutation and the clinical implication among men with a classic phenotype are most severe, Fabry disease affects both males and females. Men with a non-classic phenotype and females present with a more heterogenous degree of organ involvement, however, these patients remain at increased risk of multisystem organ involvement and must be attend extensive screening, evaluated repeatedly in order to decide when and who are in need of treatment. However, as evident in patients with the several known genotypes, which presents with no or very low alpha-galA-activity and develop early multi-organ involvement, one of the complication of greatest prognostic impact is an early involvement of the kidney.
Fabry nephropathy Although, the etiology of kidney affection in Fabry disease in general is well established, the actual mechanisms of progression - and thus the targets of therapeutic approach - are largely unknown. Fabry nephropathy is characterized by the accumulation of Gb3 deposition in podocytes, epithelial cells and endothelial cells throughout the tubules, where kidney biopsies suggest healthy, functioning tissue is substituted with reparative diffuse fibrosis. Indeed, evidence shows a direct association between Gb3 accumulation and both a decline in renal glomerular filtration rate and an increase in urinary albumin excretion - both clinically validated biomarkers of kidney injury and decline in function. Given Gb3 accumulation in Fabry disease accounts for less than 5% of the total tissue volume at maximum, the disproportionate and devastating effects observed have led to the proposal of Gb3 having additional effects beyond mere storage. Oxidative stress, endothelial dysfunction, and inflammation have been proposed as important mechanisms induced directly or indirectly by Gb3 accumulation, resulting in increased cell-death of functioning glomeruli with unamenable, reparative fibrosis as a result. Furthermore, certain cells seems more susceptible to injury and less susceptible to the benefits expected from Fabry-specific treatment; an important example being renal podocytes.
Fabry nephropathy and Magnetic Resonance Imaging Renal hypoxia is now considered to play a key role in the development of chronic kidney disease (CKD). Using a novel contrast-free, non-invasive magnetic resonance imaging (MRI), our collaborative partners have reported renal hypoxia in subjects with type I diabetes and pathological urinary albumin/creatinine ratio (UACR) levels. Recent advances in MRI thus, enables us to investigate the pathological mechanisms underlining Fabry nephropathy by non-invasively measurements of oxygenation, inflammation and fibrosis. The kidney's oxidative capacity evaluated by R2*-related blood oxygenation level-dependent (BOLD) MRI has been validated as a parameter of renal cortical and medullar oxygen-partial pressure. Furthermore, changes in dynamic R2*-signaling have been validated as a non-invasive, contrast-free measure of renal oxygenation capacity, which becomes reduced with presence of chronic kidney disease. Concurrently, arterial spin labelling (ASL) is able to provide a reliable measure of total blood flow as well as regional blood flow in the renal artery and the kidney. Finally, the inflammatory and fibrotic burden can be elucidated upon by diffusion-weighted sequences and native T1-mapping. Therefore, this novel method provides information on kidney-specific shift in energetic oxygen-dependent capacity, ongoing inflammation, and accumulation of fibrosis, with changes not only portraying key aspects of kidney physiology, but changes expected to elucidate on the pathophysiology forming the very basis of Fabry nephropathy.
While the recent advances in imaging present a unique possibility for early detection of Fabry nephropathy, there is a need for validation against clinically established biomarkers of risk such as pathologically increased UACR - currently the greatest predictor of progressive loss of glomerular function in regards to end-stage renal disease in general and in Fabry nephropathy. Pathological UACR levels is considered the first clinical sign of Fabry nephropathy, with an estimated prevalence of 50% among men aged 35 years. Even among women, which often less severely afflicted, up to 40% develop proteinuria and 15% experience a clinically significant renal event, thus, the prognostic importance of increased UACR in Fabry disease is evident. Therefore, UACR levels is the key clinical parameter of Fabry nephropathy as recommended in guidelines.
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Caroline M Kistorp, Professor
- Phone Number: 0045 35 45 96 42
- Email: caroline.michaela.kistorp@regionh.dk
Study Contact Backup
- Name: Niels H Brandt-Jacobsen, MD, PhD
- Phone Number: 0045 41 81 30 07
- Email: niels.hoeeg.brandt-jacobsen.01@regionh.dk
Study Locations
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Copenhagen, Denmark, 2100
- Rigshospitalet
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Sampling Method
Study Population
Participants with Fabry disease (n=40) - previously established by genetic testing - are to be grouped according to the presence of renal impairment as defined by the KDIGO criteria.
A group of controls with no renal impairment are to act as healthy controls.
Description
Fabry patients:
Inclusion Criteria:
- Male and female individuals (≥18 years of age)
- Able to give informed consent
Exclusion Criteria:
- Any contraindication for magnetic resonance imaging according to standard checklist used in clinical routine, including claustrophobia or metallic foreign bodies, metallic implants, internal electrical devices, or permanent makeup/tattoos that cannot be declared MR compatible.
- Pregnancy
Control group Inclusion criteria
- Male and female individuals (≥18 years of age)
- Able to give informed consent Exclusion criteria
- A genetically-verified diagnosis of Fabry disease.
- Family member to a patient with a genetically-verified diagnosis of Fabry disease
- Cancer expected to influence life expectancy.
- Known heart failure, previous apoplexia or previously established kidney disease.
- Initiation or change of antihypertensive therapy within 3 months of enrolment
- Renal impairment as depicted by the CKD-EPI classification (≥ CKD G2/A1)
- Any contraindication for MRI according to standard checklist used in clinical routine, including claustrophobia or metallic foreign bodies, metallic implants, internal electrical devices, or permanent makeup/tattoos that cannot be declared MR compatible.
- Pregnancy
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
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Patients with Fabry Disease and impaired kidney function
Participants included in this group
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Patients with Fabry Disease and normal kidney function
Participants included in this group
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Healthy controls
Participants included in this group
Furthermore, healthy controls are excluded
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Renal hypoxia (Fabry patients according to renal impairment)
Time Frame: At baseline
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A between-group difference in renal hypoxia (R*) evaluated by BOLD MRI when comparing the groups of patients with Fabry disease.
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At baseline
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Renal hypoxia (Fabry patient vs controls)
Time Frame: At baseline
|
A between-group difference in renal hypoxia (R*) evaluated by BOLD MRI when comparing patients with Fabry disease irrespective of renal impairment with the control group.
|
At baseline
|
Renal cortical perfusion (Fabry vs. controls)
Time Frame: At baseline
|
A between-group difference in perfusion of the renal medulla (mL/100g/min) when comparing groups with Fabry disease patients with the control group
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At baseline
|
Renal medullar perfusion (Fabry vs. controls)
Time Frame: At baseline
|
A between-group difference in renal blood flow (mL/min) when comparing groups with Fabry disease patients with the control group.
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At baseline
|
Renal inflammation (Fabry vs. controls)
Time Frame: At baseline
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A between-group difference in native T1 (ms) when comparing groups with Fabry disease patients with the control group.
|
At baseline
|
Renal fibrosis (Fabry vs. controls)
Time Frame: At baseline
|
A between-group difference in diffusion-weigthed signaling when comparing groups with Fabry disease patients with the control group.
|
At baseline
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Caroline M Kistorp, Professor, Rigshospitalet, Denmark
Publications and helpful links
General Publications
- Selby NM, Blankestijn PJ, Boor P, Combe C, Eckardt KU, Eikefjord E, Garcia-Fernandez N, Golay X, Gordon I, Grenier N, Hockings PD, Jensen JD, Joles JA, Kalra PA, Kramer BK, Mark PB, Mendichovszky IA, Nikolic O, Odudu A, Ong ACM, Ortiz A, Pruijm M, Remuzzi G, Rorvik J, de Seigneux S, Simms RJ, Slatinska J, Summers P, Taal MW, Thoeny HC, Vallee JP, Wolf M, Caroli A, Sourbron S. Magnetic resonance imaging biomarkers for chronic kidney disease: a position paper from the European Cooperation in Science and Technology Action PARENCHIMA. Nephrol Dial Transplant. 2018 Sep 1;33(suppl_2):ii4-ii14. doi: 10.1093/ndt/gfy152.
- Linhart A, Elliott PM. The heart in Anderson-Fabry disease and other lysosomal storage disorders. Heart. 2007 Apr;93(4):528-35. doi: 10.1136/hrt.2005.063818. No abstract available.
- Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, Feliciani C, Shankar SP, Ezgu F, Amartino H, Bratkovic D, Feldt-Rasmussen U, Nedd K, Sharaf El Din U, Lourenco CM, Banikazemi M, Charrow J, Dasouki M, Finegold D, Giraldo P, Goker-Alpan O, Longo N, Scott CR, Torra R, Tuffaha A, Jovanovic A, Waldek S, Packman S, Ludington E, Viereck C, Kirk J, Yu J, Benjamin ER, Johnson F, Lockhart DJ, Skuban N, Castelli J, Barth J, Barlow C, Schiffmann R. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016 Aug 11;375(6):545-55. doi: 10.1056/NEJMoa1510198.
- Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP; Fabry Registry. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008 Feb;93(2):112-28. doi: 10.1016/j.ymgme.2007.09.013. Epub 2007 Nov 26.
- Inoue T, Kozawa E, Okada H, Inukai K, Watanabe S, Kikuta T, Watanabe Y, Takenaka T, Katayama S, Tanaka J, Suzuki H. Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J Am Soc Nephrol. 2011 Aug;22(8):1429-34. doi: 10.1681/ASN.2010111143. Epub 2011 Jul 14.
- Pruijm M, Mendichovszky IA, Liss P, Van der Niepen P, Textor SC, Lerman LO, Krediet CTP, Caroli A, Burnier M, Prasad PV. Renal blood oxygenation level-dependent magnetic resonance imaging to measure renal tissue oxygenation: a statement paper and systematic review. Nephrol Dial Transplant. 2018 Sep 1;33(suppl_2):ii22-ii28. doi: 10.1093/ndt/gfy243.
- Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009 Nov;11(11):790-6. doi: 10.1097/GIM.0b013e3181bb05bb.
- Wanner C, Germain DP, Hilz MJ, Spada M, Falissard B, Elliott PM. Therapeutic goals in Fabry disease: Recommendations of a European expert panel, based on current clinical evidence with enzyme replacement therapy. Mol Genet Metab. 2019 Mar;126(3):210-211. doi: 10.1016/j.ymgme.2018.04.004. Epub 2018 Apr 11. No abstract available.
- Najafian B, Tondel C, Svarstad E, Gubler MC, Oliveira JP, Mauer M. Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss. J Am Soc Nephrol. 2020 Apr;31(4):865-875. doi: 10.1681/ASN.2019050497. Epub 2020 Mar 3.
- Jehn U, Bayraktar S, Pollmann S, Van Marck V, Weide T, Pavenstadt H, Brand E, Lenders M. alpha-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes. Int J Mol Sci. 2021 Oct 20;22(21):11339. doi: 10.3390/ijms222111339.
- Yogasundaram H, Kim D, Oudit O, Thompson RB, Weidemann F, Oudit GY. Clinical Features, Diagnosis, and Management of Patients With Anderson-Fabry Cardiomyopathy. Can J Cardiol. 2017 Jul;33(7):883-897. doi: 10.1016/j.cjca.2017.04.015. Epub 2017 May 4.
- Eikrem O, Skrunes R, Tondel C, Leh S, Houge G, Svarstad E, Marti HP. Pathomechanisms of renal Fabry disease. Cell Tissue Res. 2017 Jul;369(1):53-62. doi: 10.1007/s00441-017-2609-9. Epub 2017 Apr 12. No abstract available.
- Ravarotto V, Simioni F, Carraro G, Bertoldi G, Pagnin E, Calo LA. Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement? J Clin Med. 2018 Nov 2;7(11):409. doi: 10.3390/jcm7110409.
- Sanchez-Nino MD, Carpio D, Sanz AB, Ruiz-Ortega M, Mezzano S, Ortiz A. Lyso-Gb3 activates Notch1 in human podocytes. Hum Mol Genet. 2015 Oct 15;24(20):5720-32. doi: 10.1093/hmg/ddv291. Epub 2015 Jul 23.
- Ravarotto V, Carraro G, Pagnin E, Bertoldi G, Simioni F, Maiolino G, Martinato M, Landini L, Davis PA, Calo LA. Oxidative stress and the altered reaction to it in Fabry disease: A possible target for cardiovascular-renal remodeling? PLoS One. 2018 Sep 27;13(9):e0204618. doi: 10.1371/journal.pone.0204618. eCollection 2018.
- Fall B, Scott CR, Mauer M, Shankland S, Pippin J, Jefferson JA, Wallace E, Warnock D, Najafian B. Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy. PLoS One. 2016 Dec 16;11(12):e0168346. doi: 10.1371/journal.pone.0168346. eCollection 2016.
- Pruijm M, Milani B, Burnier M. Blood Oxygenation Level-Dependent MRI to Assess Renal Oxygenation in Renal Diseases: Progresses and Challenges. Front Physiol. 2017 Jan 5;7:667. doi: 10.3389/fphys.2016.00667. eCollection 2016.
- Heyman SN, Khamaisi M, Rosen S, Rosenberger C. Renal parenchymal hypoxia, hypoxia response and the progression of chronic kidney disease. Am J Nephrol. 2008;28(6):998-1006. doi: 10.1159/000146075. Epub 2008 Jul 18.
- Laursen JC, Sondergaard-Heinrich N, Haddock B, Rasmussen IKB, Hansen CS, Larsson HBW, Groop PH, Bjornstad P, Frimodt-Moller M, Andersen UB, Rossing P. Kidney oxygenation, perfusion and blood flow in people with and without type 1 diabetes. Clin Kidney J. 2022 May 20;15(11):2072-2080. doi: 10.1093/ckj/sfac145. eCollection 2022 Nov.
- Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M; European FOS Investigators. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006 Apr;43(4):347-52. doi: 10.1136/jmg.2005.036327. Epub 2005 Oct 14.
- Warnock DG, Thomas CP, Vujkovac B, Campbell RC, Charrow J, Laney DA, Jackson LL, Wilcox WR, Wanner C. Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy. J Med Genet. 2015 Dec;52(12):860-6. doi: 10.1136/jmedgenet-2015-103471. Epub 2015 Oct 21.
- Hughes DA, Aguiar P, Deegan PB, Ezgu F, Frustaci A, Lidove O, Linhart A, Lubanda JC, Moon JC, Nicholls K, Niu DM, Nowak A, Ramaswami U, Reisin R, Rozenfeld P, Schiffmann R, Svarstad E, Thomas M, Torra R, Vujkovac B, Warnock DG, West ML, Johnson J, Rolfe MJ, Feriozzi S. Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative. BMJ Open. 2020 Oct 10;10(10):e035182. doi: 10.1136/bmjopen-2019-035182.
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Metabolic Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Urologic Diseases
- Disease Attributes
- Renal Insufficiency
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Metabolism, Inborn Errors
- Lysosomal Storage Diseases
- Lipid Metabolism Disorders
- Brain Diseases, Metabolic
- Brain Diseases, Metabolic, Inborn
- Sphingolipidoses
- Lysosomal Storage Diseases, Nervous System
- Cerebral Small Vessel Diseases
- Lipidoses
- Lipid Metabolism, Inborn Errors
- Chronic Disease
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Fibrosis
- Kidney Diseases
- Renal Insufficiency, Chronic
- Inflammation
- Fabry Disease
Other Study ID Numbers
- H-23035668
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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