Current therapy of Fabry disease consists of enzyme replacement therapy ERT. Substrate reduction therapy SRT in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney.
Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient. Fibrosis is characterized by an increased accumulation of extracellular matrix ECM [ 8 - 11 ]. Fibrosis or the formation of scar tissue can be the end-result of tissue injury, inflammation and apoptosis and might be considered a final irreversible event with little intrinsic therapeutic interest [ 8 - 11 ].
However, in some clinical conditions fibrosis is an early event, a disease defining-event or a major contributor to clinical manifestations of disease.
Fibrosis: a key feature of Fabry disease with potential therapeutic implications
There is evidence that diabetic nephropathy DN and Fabry disease may be such conditions. Like DN, Fabry nephropathy is a proteinuric nephropathy of metabolic origin characterized by a progressive decrease of renal function to a terminal stage requiring dialysis or transplantation. Although the metabolic environments of the two diseases are considerably different, there is accumulating evidence that they may share common, later-stage pathogenic pathways with other forms of proteinuric CKD. Advances in the understanding of fibrosis regulation in prevalent diseases, such as DN, and their therapeutic implications may be used to develop therapeutic approaches to less common conditions like Fabry disease.
In DN intrinsic renal cells are early contributors to kidney fibrosis. Thus, initial glomerular GBM and tubular basement membrane thickening depends on increased production of ECM by glomerular epithelial podocytes and tubular epithelial cells injured by high ambient glucose concentrations [ 12 - 15 ]. This is followed by recruitment of activated fibroblasts, focal and segmental glomerular fibrosis and sclerosis FSGS and interstitial fibrosis.
Following pancreas transplantation in patients with DN, increased ECM deposition of metabolic origin is reversible following 10 years of continuous correction of the metabolic defect, but not after 5 years [ 16 ]. ERT provides clinically significant, but not complete reversal of the Fabry metabolic defect. Glycolipid deposits may persist for years in certain cell types, such as podocytes, the key cells in glomerulosclerosis and proteinuria [ 6 , 17 ] and circulating levels of deacylated globotriaosylceramide globotriaosylsphingosine, lyso-Gb3 are reduced but not normalized by ERT [ 18 - 20 ].
Depending on dose [ 17 ], ERT provides partial control of the metabolic defect in a manner similar to oral anti-diabetic agents and insulin in diabetes than to the cure offered by pancreas transplantation.
Fibrosis: a key feature of Fabry disease with potential therapeutic implications
ERT may be less effective in controlling the metabolic defect due to pre-existent deposits, sub-optimal dose, and antibodies or due to poor tissue penetration. Furthermore, any potential beneficial effect of ERT to ameliorate or reverse fibrosis is expected to take many years, especially if fibrosis is well established before ERT is started.
Fibrosis can be found in histological sections of Fabry disease targets organs. Renal fibrosis is a feature of Fabry nephropathy.
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The time-course of kidney fibrosis is not as clearly established as in DN, but emerging evidence points to a similar pattern: Glomerular sclerosis and interstitial fibrosis may also be observed in females with normal renal function and in the absence of overt proteinuria [ 23 ]. 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. B Sirius red staining of collagen fibers illustrates peri-glomerular fibrosis E and interstitial fibrosis F.
The typical clinical presentation of Fabry cardiomyopathy is LV hypertrophy. Most patients with a cardiomyopathy exhibit a concentric LV hypertrophy with an end-diastolic wall thickness of up to 16 mm without concomitant LV outflow tract obstruction [ 28 ]. Typical features of Fabry cardiomyopathy include prominence of the papillary muscle [ 29 - 31 ] and development of replacement fibrosis in the basal postero-lateral segments [ 32 - 34 ]. In addition, biopsies have shown interstitial fibrosis at early cardiomyopathy stages.
The fibrotic process starts in the mid-myocardial layers and spreads with disease progression towards transmural fibrosis. Thus, the end-stage of the cardiomyopathy is characterized by the co-existence of LV hypertrophy, myocardial thinning, and the presence of wall motion abnormalities in the fibrotic segments [ 35 , 36 ]. In female Fabry patients, LV hypertrophy and fibrosis seems to be not tightly linked [ 37 ], perhaps reflecting the residual alpha galactosidase A activity in females.
Replacement fibrosis can already be present at a non-hypertrophic disease stage, which is in contrast to males who normally first develop LV hypertrophy and subsequent replacement fibrosis. In addition, in all female patients who develop LV hypertrophy, replacement fibrosis is present.
Thus, despite the delayed development of LV hypertrophy, fibrosis seems to progress continuously and is an integral component of the cardiomyopathy [ 37 ] in female patients with Fabry disease. Much less is known about fibrosis of the CNS in Fabry disease. Indeed the general pathogenesis of fibrosis in the CNS is poorly understood. The term gliosis or glial reaction indicates structural and physiological changes of astrocytes and microglia in response to ischemic, inflammatory or traumatic injuries to the CNS.
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A prominent feature of gliosis is the proliferative response to injury that is followed later by permanent changes, the glial scar [ 38 ]. Gliosis is known to occur in the penumbra area adjacent to the ischemic core during stroke [ 39 ]. In Fabry disease gliosis and fibrosis have been reported at sites of stroke [ 25 ]. Pathological findings secondary to ischemic encephalopathy included fibrillar astrocytosis and proliferation of microglia adjacent to pyknotic neurons in the hippocampus, cerebral cortex and white matter [ 40 ]. In addition, features of a more generalized fibrotic process were also observed in Fabry disease, such as thickening of the pia-arachnoid membranes and an angiopathy of the subarachnoidal arteries characterized by intima and medial thickening and fibrosis and adventitial fibrosis associated with gliosis [ 25 , 41 ].
Improved understanding of fibrosis in Fabry disease will permit development of more effective therapeutic approaches to Fabry disease. The lack of significant end-organ fibrosis may be due to a lower accumulation of glycosphingolipids in mice, differences in lipid metabolism between mice and humans, the potential need for several years of progressive glycolipid accumulation and the genetic background of current Fabry mouse models.
In the absence of an adequate animal model only hypothesis based on human histology or cell culture models are available. Previous reports emphasized that the histological appearance of advanced Fabry nephropathy suggested that kidney fibrosis was a consequence of ischemia [ 24 , 26 ]. Thus, in 25 to 50 year old patients, glomerulosclerosis, often with wrinkled and partially collapsed GBM, tubular atrophy and interstitial fibrosis were thought to result from the also present vascular thickening.
However, these are non-specific features of advanced kidney disease of any etiology. At that time the key importance of podocytes in the maintenance of the glomerular filtration barrier to proteins and the pathogenesis of glomerulosclerosis was unknown. It is now widely accepted that podocyte injury is a key event in the development of proteinuric kidney disease, and that podocyte loss is the main driver of glomerulosclerosis [ 12 ]. More recently it has been recognized that podocytes are among the earliest cells to be loaded with glycolipid deposits.
Moreover, podocyte deposits volume density increased progressively with age unlike endothelial or mesangial inclusion volume densities. Foot process width was greater in male Fabry patients and progressively increased with age compared with the controls, and correlated directly with proteinuria [ 43 ].
Finally, podocyte effacement, a manifestation of podocyte injury, is observed in children with minimal albuminuria [ 21 ]. Hence, podocyte injury has been proposed to play a pivotal role in the development and progression of Fabry nephropathy [ 43 ].
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In this regard, podocyte deposits are the less responsive to ERT in adults and may take up to 5 years of continued ERT to show significant clearing [ 6 , 17 , 44 ]. The clinical correlate is lack of improvement of proteinuria by ERT in adults. In addition to potential direct effects of glycolipids on tubular cells, proteinuria itself may lead to tubular cell activation, inflammatory responses and interstitial fibrosis. In cardiomyocytes, GL-3 storage, trophic factors and other factors e. The elevated lyso-Gb3 in plasma of symptomatic patients might partially explain the finding by Barbey et al.
Of note, a correlation was observed between left ventricular hypertrophy and plasma lyso-Gb3 concentration in heterozygote Fabry patients [ 18 ]. In addition, it was speculated that wall stress may contribute to Fabry cardiomyopathy. Thus, slightly increased blood pressure and the flat curvature of the basal part of the lateral wall may account for an increased wall stress that promotes fibrosis. This scenario would account for fibrosis that starts in the endocardium where wall stress is highest but not at the mid-myocardium as is seen in the cardiac involvement in Fabry disease [ 50 ].
Thus, other unknown factors are contributing to hypertrophy and fibrosis. The relative contribution of cardiomyocytes versus other cell types to myocardial fibrosis in Fabry disease is unclear. It has long been thought that CNS gliosis in Fabry results from ischemia. The anatomical location of white matter lesions also supports an ischemic origin, although the mechanisms of ischemia remain unclear [ 51 , 52 ]. Brain white matter is localized below the cortex and contains axons from neurons. White matter lesions are defined by the presence of bright spots T2 and FLAIR sequences in this region in brain imaging.
Perfusion of the white matter depends on the long penetrating arteries originating from the cortical surface that are perpendicular to the cortex and follow the course of myelinated fibers. Because there are minimal or no anastomoses between sub-ependimal vessels and vessels originating from the cortex, watershed periventricular areas are susceptible to ischemic injury from decreased cerebral blood flow [ 53 ]. However, the decreased blood flow does not result from the involvement of intracerebral vessels by the glycolipid storage process, and other as yet unidentified hemodynamic factors might also be involved.
Khan described massive dilatation of the vertebral and basilar arteries in autopsies, but absence of glycolipid deposits in intracerebral vessels, despite the marked thickening of the media of small arteries and arterioles caused by deposition of the glycolipid observed in almost every tissue, including the leptomeninges of the brainstem and spinal cord [ 25 ]. This was true even in a patient with previous brain infarcts [ 25 ]. Whether other factors contribute to gliosis in the Fabry CNS is unknown. Recent studies suggest that activated astrocytes, marrow-derived fibrocytes and alternatively activated M2 microglia and macrophages contribute to non-Fabry CNS fibrosis [ 54 , 55 ].
These factors should be studied in the context of Fabry disease. The potential role in fibrosis of additional secondary biochemical processes found in Fabry disease has not been addressed [ 56 ]. Compromised energy metabolism has been found both in vitro and in vivo. Low levels of high-energy phosphate molecules phosphocreatine and adenosine triphosphate ATP were observed in Fabry patient hearts and improved with ERT [ 57 ].
Parameters of cardiac energy metabolism negatively correlated with progression of Fabry cardiomyopathy [ 58 ]. Low glucose utilization was observed locally in 18 brain structures in the alpha-galactosidase A gene knockout mouse [ 59 ]. In this regard, low activities of mitochondrial respiratory chain enzymes I, IV, and V were lower in cultured Fabry patient fibroblasts and ATP was marginally reduced [ 60 ]. In addition, altered lipid composition of membranes leading to abnormal trafficking and sorting of rafts-associated proteins was observed in fibroblasts [ 61 ].
Recently, lyso-Gb3 has been proposed as a promoter of fibrosis in Fabry disease [ 62 ]. Having lost a fatty acid, lyso-Gb3 is more water soluble than Gb3 and in some aspects it may behave as an accumulated soluble mediator in a similar manner to glucose and its degradation products that are increased in diabetes. Key differences between lyso-Gb3 and glucose and its degradation products should be recognized; the latter may react with and modify proteins such as type IV collagen in the GBM.
In this regard, the fact that some molecular mechanisms of fibrosis may be similar in Fabry disease and DN cannot be construed as a general equivalence of the underlying pathogenesis. Plasma lyso-Gb3 is dramatically increased in classically affected male Fabry patients, but is also increased in females and is reduced but not normalized following ERT while it is undetectable in normal human plasma [ 18 - 20 ].
These characteristics may contribute to a cross-talk between cells with persistent glycolipid deposits following ERT and may explain observations such a similar mean age at end-stage renal disease for males and for females [ 63 , 64 ].
In this regard, concentrations of lyso-Gb3 observed in plasma of females or ERT-treated Fabry males are biologically active in target cells of Fabry disease in culture even when these cells possess alpha-galactosidase activity [ 18 , 62 ]. Lyso-Gb3 promoted proliferation of vascular smooth muscle cells, but not fibroblasts [ 18 ].
In addition, in cultured human podocytes, lyso-Gb3 recruited secondary mediators of inflammation and fibrosis. The fibrogenic response of podocytes to lyso-Gb3 is similar to podocyte responses to a high glucose extracellular milieu [ 13 ]. Furthermore, lyso-Gb3 stimulated inflammation similar to high glucose levels does, promoting the expression of the cytokine receptor CD74 [ 62 , 65 , 66 ]. Lifetime exposure to lysoGb3 correlated with disease manifestations [ 67 ]. Plasma lysoGb3 concentration correlated with white matter lesions.
In females, plasma lysoGb3 concentration correlated with overall disease severity and LV mass. In addition, lyso-Gb3 reduction on ERT was correlated with LV mass reduction in females and development white matter lesions and stroke [ 68 ]. Imaging techniques in the heart and brain, but not in the kidney can non-invasively assess fibrosis in Fabry disease. In addition, clinical manifestations associated with fibrosis may provide an approximate idea of the extent of underlying fibrosis. Currently, renal biopsy provides the best assessment of the degree of kidney fibrosis.
However, fibrosis may be patchy and the biopsy may not always be fully representative of the whole kidney. Imaging does not yet provide a sensitive assessment and monitoring of kidney fibrosis in humans. Advanced magnetic resonance imaging MRI devices allow quantification of renal fibrosis in experimental animals and clinical advances in the field are expected in the near future. Indeed, proteinuria is a known consequence of glomerulosclerosis.
However, individual variability and the presence of functional factors that impact on albuminuria and proteinuria or GFR makes unreliable the estimation of the degree of kidney fibrosis from biochemical parameters.
Under a Creative Commons license. Recommended articles Citing articles 0. These models will help clinicians in diagnosing, assessing, and treating patients with Fabry disease. As the models can be extrapolated to other diseases, they might contribute to more optimal clinical management of patients with other cardiac disorders. Read more Read less. Enabled Similar books to The Fabry Cardiomyopathy: Kindle Cloud Reader Read instantly in your browser. Product details File Size: Annual Reviews December 12, Publication Date: December 12, Sold by: Related Video Shorts 0 Upload your video. Customer reviews There are no customer reviews yet.
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