Pathomechanisms of renal Fabry disease

Eikrem, Øystein; Skrunes, Rannveig; Tøndel, Camilla; Leh, Sabine; Houge, Gunnar; Svarstad, Einar; Marti, Hanspeter

doi:10.1007/s00441-017-2609-9

Cited by 33 publications

(31 citation statements)

References 69 publications

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“…For HF to develop, the concomitant action of a variety of pathogenic factors are needed, including the activation of the sympathetic nervous system, increased oxidative stress, inflammatory cytokines, and so on, all reported in patients with FD [28][29][30]. In particular, glomerular HF in Fabry patients may be mediated by angiotensin II, which increases to a different extent the vascular tone of both afferent and efferent glo- Data are expressed as mean ± SD or median (IQR) or n (%).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, HF has been associated with peripheral vascular alterations, including low arterial stiffness and endothelial dysfunction, suggesting that it reflects generalized microvascular and macrovascular functional changes [32,33]. Moreover, according to a "tubular hypothesis", in line with the observation of an early distal tubular damage in Fabry nephropathy, the upstream glomeruli of compromised tubules may function poorly, causing other glomeruli to hypertrophy, with subsequent HF [28].…”

Section: Discussionmentioning

confidence: 99%

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Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease

Riccio

Sabbatini²,

Bruzzese³

et al. 2018

Nephron

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Background and objectives: Progressive nephropathy is one of the main features of Fabry disease (FD). It has been supposed that an early phase, clinically silent disease occurs in childhood and adolescence and is characterized by glomerular hyperfiltration (HF). Surprisingly, although HF has been reported in several studies, its prevalence is at present unknown. The focus of our study was to determine the prevalence of HF in a cohort of patients with FD and to identify the factors associated with a high risk of HF. Methods: To address this issue, a retrospective observational study of 87 patients with genetically confirmed FD was performed. HF was defined as an estimated glomerular filtration rate (eGFR) > 130 mL/min/1.73 m² corrected for age (> 40 years: –1 mL/min/1.73 m²/year). Results: HF occurred in 21 patients (24% of our population), and increased to 50% when only young adults were considered. Hyperfiltrating patients were younger and had lower proteinuria levels than those without HF. The prevalence of cardiovascular and other manifestations of FD was significantly lower in hyperfiltering patients. Conclusions: Our study showed a negative correlation between eGFR and age, and with proteinuria levels and the presence of cardiovascular and other manifestations of FD. These data favor the view that HF in Fabry patients could be related predominantly to a predisease state. Even in the absence of a “measured” GFR, HF should be regarded as an early marker of Fabry nephropathy, and its recognition and confirmation by true GFR seems a relevant feature to address the issue of the potential benefit of nephroprotective treatments at the early stage of Fabry nephropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease

Riccio

Sabbatini²,

Bruzzese³

et al. 2018

Nephron

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“…The importance of kidney biopsies in diagnosis of Fabry disease as well as its potential in the assessment of therapeutic effect of enzyme replacement therapy has recently been highlighted [3,4]. Multifactorial mechanisms are involved in progressive Fabry nephropathy affecting glo-merular, vascular and interstitial compartments, many of which are only partly understood [5]. Progressive damage of the glomerular filtration barrier plays an important role in the development of albuminuria/proteinuria and focal and segmental glomerular sclerosis in general, leading to progressive organ failure in kidney diseases, including Fabry disease [1,2,6].…”

Section: Introductionmentioning

confidence: 99%

Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits

Svarstad¹,

Leh²,

Skrunes³

et al. 2017

Nephron

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Background/Aims: A previous case report found stereomicroscopic changes typical for Fabry disease in a kidney biopsy. This case series evaluates an expanded diagnostic capacity of the method. Methods: Bedside stereomicroscopy was performed in a cross-sectional prospective study of 31 consecutive enzyme-treated or treatment-naïve male (n = 14) and female Fabry disease patients. The burden of glomerular storage material was scored semiquantitatively on a visual analog scale (range 0-3) and a blinded comparison was done with a reference histologic method. Results: Significant correlations (p < 0.001) were found between the stereomicroscopic scoring of glomerular characteristic white storage material and the amount of podocyte globotriaosylceramide (Gb3) deposits scored by standardized light microscopy. The bedside method correctly identified the variability of podocyte Gb3 accumulation after 10 years of identical agalsidase therapy in 2 brothers aged 24 and 27 years, and also identified tubular cell deposits. Stereomicroscopy correctly verified the absence of sphingolipid deposits in the biopsy of a female index patient with a genetic variant of unknown significance, and the diagnosis of Fabry disease was finally discarded. Conclusions: Bedside stereomicroscopy of kidney biopsies is an easily available, low-cost microscopy method handled by the clinician. The method carries a high diagnostic sensitivity for Fabry disease, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the grading of the podocyte Gb3 burden and assessment of effectiveness of enzyme replacement therapy. We recommend the method as complementary to current standard histologic evaluation of Fabry kidney biopsies.

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“…(15). The presence of such pathogenic factors has previously been reported in patients with FD (16).…”

Section: Discussionmentioning

confidence: 70%

Variables Associated with Glomerular Hyperfiltration in Fabry Disease Patients

Perretta¹,

Antongiovanni²,

Jaurretche

2020

Nephro-Urol Mon

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Background: Fabry disease is a genetic disorder caused by the deficiency of the lysosomal α-galactosidase A enzyme. This failure generates the storage of globotriaosylceramide in different cells with a progressive multi-organ involvement. Objectives: To report the prevalence of glomerular hyperfiltration in Fabry disease patients and the association with clinical variables. Methods: Adult patients (≥ 18 years) at the moment of FD diagnosis were evaluated. The variables studied were: central and peripheral nervous system compromise, presence of arterial hypertension, cardiac arrhythmia, left ventricular hypertrophy, albuminuria/proteinuria, cornea verticillata, gastrointestinal involvement, treatment with inhibitors of the renin-angiotensin-aldosterone system, deafness, and presence of angiokeratomas. Results: Forty-eight adults with Fabry disease (35.9 ± 11.7 years), 28 women (58.3%), and 20 men (41.7%) were analyzed. Nine (18.8%) patients with glomerular hyperfiltration, including six females and three males (mean age: 28.8 years), were detected. A significant association between and central nervous system (P = 0.021) and peripheral nervous system (P = 0.001) compromise, cardiac arrhythmia (P = 0.001), cornea verticillata (P = 0.009), and gastrointestinal involvement (P = 0.009) was observed. However, no association was found between glomerular hyperfiltration and proteinuria or treatment with inhibitors of the renin-angiotensin-aldosterone system. Conclusions: This research showed a higher prevalence of glomerular hyperfiltration in the younger group and a significant association between glomerular hyperfiltration and some typical manifestations of classic Fabry patients. Although more studies are needed, it is concluded that other mechanisms than glomerular hyperfiltration, like injury by glycosphingolipids deposit into the filtration barrier, might influence the protein loss in Fabry nephropathy.

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Pathomechanisms of renal Fabry disease

Cited by 33 publications

References 69 publications

Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease

Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease

Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits

Variables Associated with Glomerular Hyperfiltration in Fabry Disease Patients

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