Fibrosis, Inflammation, Oxygenation of Renal Tissue In FabrY Disease

NCT06325488 | Recruiting DMC

• 1 other identifier: H-23035668
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Fabry Disease; Chronic Kidney Diseases

Keywords

Oxygenation; Inflammation; Fibrosis

Outcome Measures

Primary Outcomes (1)

• Renal hypoxia (Fabry patients according to renal impairment)

  A between-group difference in renal hypoxia (R\*) evaluated by BOLD MRI when comparing the groups of patients with Fabry disease.

  At baseline

Secondary Outcomes (5)

• Renal hypoxia (Fabry patient vs controls)

  At baseline

• Renal cortical perfusion (Fabry vs. controls)

  At baseline

• Renal medullar perfusion (Fabry vs. controls)

  At baseline

• Renal inflammation (Fabry vs. controls)

  At baseline

• Renal fibrosis (Fabry vs. controls)

  At baseline

Study Arms (3)

Patients with Fabry Disease and impaired kidney function

Participants included in this group * 18 years of age or above * Fabry Disease as verified by genetic analysis prior to inclusion * Impaired kidney function according to the KDIGO classification (UACR ≥ 30 mg/g and eGFR \< 60 ml/min/1.73m2 \[≥ CKD G3a/A2\])

Patients with Fabry Disease and normal kidney function

Participants included in this group * 18 years of age or above * Fabry Disease as verified by genetic analysis prior to inclusion * Normal kidney function according to the KDIGO classification (UACR \< 30 mg/g and eGFR ≥ 60 will be included \[≤ CKD G2/A1\])

Healthy controls

Participants included in this group * 18 years of age or above * Normal kidney function according to the KDIGO classification (UACR \< 30 mg/g and eGFR ≥ 60 will be included \[≤ CKD G2/A1\]) Furthermore, healthy controls are excluded * Suspected of Fabry Disease or verified by genetic analysis * Related to a patient with Fabry Disease * Have cancer with an expected influence on life expectancy * Known apoplexia cerebri, heart failure or established kidney disease * Recently initiated or have had recent changes in antihypertensive medication (within 3 months)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

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.

You may qualify if:

• Male and female individuals (≥18 years of age)
• Able to give informed consent

You may not qualify if:

• 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
• Male and female individuals (≥18 years of age)
• 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

Sponsors & Collaborators

• Caroline Michaela Kistorp: lead
• Sanofi: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Related Publications (22)

• 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.

  PMID: 19745746 BACKGROUND

• 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.

  PMID: 29724657 BACKGROUND

• 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.

  PMID: 32127409 BACKGROUND

• 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.

  PMID: 27509102 BACKGROUND

• 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.

  PMID: 34768768 BACKGROUND

• 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.

  PMID: 17401074 BACKGROUND

• 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.

  PMID: 28668140 BACKGROUND

• 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.

  PMID: 28401309 BACKGROUND

• 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.

  PMID: 30400144 BACKGROUND

• 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.

  PMID: 26206887 BACKGROUND

• 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.

  PMID: 30261035 BACKGROUND

• 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.

  PMID: 27992580 BACKGROUND

• 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.

  PMID: 30137584 BACKGROUND

• 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.

  PMID: 28105019 BACKGROUND

• 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.

  PMID: 18635927 BACKGROUND

• 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.

  PMID: 21757771 BACKGROUND

• 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.

  PMID: 30137579 BACKGROUND

• 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.

  PMID: 36825032 BACKGROUND

• 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.

  PMID: 18037317 BACKGROUND

• 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.

  PMID: 16227523 BACKGROUND

• 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.

  PMID: 26490103 BACKGROUND

• 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.

  PMID: 33039984 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood and urine samples

MeSH Terms

Conditions

Fabry Disease; Renal Insufficiency, Chronic; Inflammation; Fibrosis

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Caroline M Kistorp, Professor

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Caroline M Kistorp, Professor

CONTACT

35 45 96 42; caroline.michaela.kistorp@regionh.dk

Niels H Brandt-Jacobsen, MD, PhD

CONTACT

41 81 30 07; niels.hoeeg.brandt-jacobsen.01@regionh.dk

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 14, 2024
• First Posted: March 22, 2024
• Study Start: June 1, 2024
• Primary Completion: March 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: April 6, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)