Ignite Creation Date:
2024-05-06 @ 8:17 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06325488
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-22
First Post:
2024-02-14
Brief Title:
Fibrosis Inflammation Oxygenation of Renal Tissue In FabrY Disease
Sponsor:
Caroline Michaela Kistorp
Organization:
Rigshospitalet Denmark
Study Overview
Official Title:
Fibrosis Inflammation Oxygenation of Renal Tissue In FabrY Disease
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FORTIFY
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
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
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 albumincreatinine 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 kidneys 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
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 albumincreatinine 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 kidneys 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None