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Fibrosis: a key feature of Fabry disease with potential therapeutic implications.

Weidemann F, Sanchez-Niño MD, Politei J, Oliveira JP, Wanner C, Warnock DG, Ortiz A - Orphanet J Rare Dis (2013)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, The Comprehensive Heart Failure Center at the University of Würzburg.

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.

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Kidney biopsy. A) PAS staining. Histology of the kidney with characteristic changes of advanced Fabry nephropathy. Please note glomerular segmental sclerosis (A), adhesion and Bowman capsule reduplication (B), tubular atrophy and tubular cell related fibrosis (thickened basement membranes) (C) and arteriolar hyalinosis (D). Original magnification 63×. Courtesy of Prof. Justus Müller, Department of Pathology, University Hospital of Würzburg, Würzburg, Germany. B) Sirius red staining of collagen fibers illustrates peri-glomerular fibrosis (E) and interstitial fibrosis (F). Original magnification × 20.
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Figure 2: Kidney biopsy. A) PAS staining. Histology of the kidney with characteristic changes of advanced Fabry nephropathy. Please note glomerular segmental sclerosis (A), adhesion and Bowman capsule reduplication (B), tubular atrophy and tubular cell related fibrosis (thickened basement membranes) (C) and arteriolar hyalinosis (D). Original magnification 63×. Courtesy of Prof. Justus Müller, Department of Pathology, University Hospital of Würzburg, Würzburg, Germany. B) Sirius red staining of collagen fibers illustrates peri-glomerular fibrosis (E) and interstitial fibrosis (F). Original magnification × 20.

Mentions: Fibrosis can be found in histological sections of Fabry disease targets organs. Renal fibrosis is a feature of Fabry nephropathy. The time-course of kidney fibrosis is not as clearly established as in DN, but emerging evidence points to a similar pattern: early podocyte injury and fibrosis generated by epithelial cells that increase as disease progresses[17,21-23] (Figure 2). A grossly thickened GBM was noted in early reports of Fabry nephropathy and GBM duplications and increased glomerular mesangial ECM are also found[21,24-27]. Glomerulosclerosis and interstitial fibrosis are already present in children with early stage tissue injury characterized by preserved renal function and albuminuria <300 mg/g creatinine, along with features of podocyte injury such as segmental foot-process effacement[17,21]. Glomerular sclerosis and interstitial fibrosis may also be observed in females with normal renal function and in the absence of overt proteinuria[23]. In a cross-sectional study of 59 male and female Fabry patients the mean percentage of non-sclerosed glomeruli was 82±19% in 25 patients with well preserved renal function (mean estimated GFR = 113 ml/min/1.73 m2) and 21±14% in 5 patients with severe CKD (eGFR= 16 ml/min/1.73 m2). Mean percentage of interstitial fibrosis area was 8±16% and 66±14%, respectively[22].


Fibrosis: a key feature of Fabry disease with potential therapeutic implications.

Weidemann F, Sanchez-Niño MD, Politei J, Oliveira JP, Wanner C, Warnock DG, Ortiz A - Orphanet J Rare Dis (2013)

Kidney biopsy. A) PAS staining. Histology of the kidney with characteristic changes of advanced Fabry nephropathy. Please note glomerular segmental sclerosis (A), adhesion and Bowman capsule reduplication (B), tubular atrophy and tubular cell related fibrosis (thickened basement membranes) (C) and arteriolar hyalinosis (D). Original magnification 63×. Courtesy of Prof. Justus Müller, Department of Pathology, University Hospital of Würzburg, Würzburg, Germany. B) Sirius red staining of collagen fibers illustrates peri-glomerular fibrosis (E) and interstitial fibrosis (F). Original magnification × 20.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3750297&req=5

Figure 2: Kidney biopsy. A) PAS staining. Histology of the kidney with characteristic changes of advanced Fabry nephropathy. Please note glomerular segmental sclerosis (A), adhesion and Bowman capsule reduplication (B), tubular atrophy and tubular cell related fibrosis (thickened basement membranes) (C) and arteriolar hyalinosis (D). Original magnification 63×. Courtesy of Prof. Justus Müller, Department of Pathology, University Hospital of Würzburg, Würzburg, Germany. B) Sirius red staining of collagen fibers illustrates peri-glomerular fibrosis (E) and interstitial fibrosis (F). Original magnification × 20.
Mentions: Fibrosis can be found in histological sections of Fabry disease targets organs. Renal fibrosis is a feature of Fabry nephropathy. The time-course of kidney fibrosis is not as clearly established as in DN, but emerging evidence points to a similar pattern: early podocyte injury and fibrosis generated by epithelial cells that increase as disease progresses[17,21-23] (Figure 2). A grossly thickened GBM was noted in early reports of Fabry nephropathy and GBM duplications and increased glomerular mesangial ECM are also found[21,24-27]. Glomerulosclerosis and interstitial fibrosis are already present in children with early stage tissue injury characterized by preserved renal function and albuminuria <300 mg/g creatinine, along with features of podocyte injury such as segmental foot-process effacement[17,21]. Glomerular sclerosis and interstitial fibrosis may also be observed in females with normal renal function and in the absence of overt proteinuria[23]. In a cross-sectional study of 59 male and female Fabry patients the mean percentage of non-sclerosed glomeruli was 82±19% in 25 patients with well preserved renal function (mean estimated GFR = 113 ml/min/1.73 m2) and 21±14% in 5 patients with severe CKD (eGFR= 16 ml/min/1.73 m2). Mean percentage of interstitial fibrosis area was 8±16% and 66±14%, respectively[22].

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, The Comprehensive Heart Failure Center at the University of Würzburg.

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.

Show MeSH
Related in: MedlinePlus