scholarly journals Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss

2020 ◽  
Vol 31 (4) ◽  
pp. 865-875 ◽  
Author(s):  
Behzad Najafian ◽  
Camilla Tøndel ◽  
Einar Svarstad ◽  
Marie-Claire Gubler ◽  
João-Paulo Oliveira ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Volume Fraction ◽  
Structural Parameters ◽  
Clinical Information ◽  
Electron Microscopic ◽  
Podocyte Injury ◽  
Enzyme Replacement ◽  
Podocyte Loss ◽  
Foot Process ◽  
Fabry Nephropathy

BackgroundIn males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α-galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss.MethodsIn this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases.ResultsPodocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion—a strong prognosticator of adverse renal outcomes in Fabry disease—as well as with decreasing GFR.ConclusionsGiven the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.

scholarly journals Kidney Transplant in Fabry Disease: A Revision of the Literature

Medicina ◽  
2020 ◽  
Vol 56 (6) ◽  
pp. 284 ◽  
Author(s):  
Irene Capelli ◽  
Valeria Aiello ◽  
Lorenzo Gasperoni ◽  
Giorgia Comai ◽  
Valeria Corradetti ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Transplantation ◽  
Fabry Disease ◽  
Therapeutic Option ◽  
Gene Mutations ◽  
Disease Recurrence ◽  
Long Term Effects ◽  
Enzyme Replacement ◽  
Fabry Nephropathy

Fabry disease is classified as a rare X-linked disease caused by a complete or partial defect of enzyme alpha-galactosidase, due to GLA gene mutations. This disorder leads to intracellular globotriaosylceramide (Gb3) deposition associated with increased Gb3 plasma levels. Most of the symptoms of the disease, involving kidneys, heart and nervous system, result from this progressive Gb3 deposition. The incidence is estimated in 1/50,000 to 1/117,000 in males. Fabry nephropathy begins with microalbuminuria and/or proteinuria, which, in the classic form, appear from childhood. Thus, a progressive decline of renal function can start at a young age, and evolve to kidney failure, requiring dialysis or renal transplantation. Enzyme replacement therapy (ERT), available since 2001 for Fabry disease, has been increasingly introduced into the clinical practice, with overall positive short-term and long-term effects in terms of ventricular hypertrophy and renal function. Kidney transplantation represents a relevant therapeutic option for Fabry nephropathy management, for patients reaching end-stage renal disease, but little is known about long-term outcomes, overall patient survival or the possible role of ERT after transplant. The purpose of this review is to analyze the literature on every aspect related to kidney transplantation in patients with Fabry nephropathy: from the analysis of transplant outcomes, to the likelihood of disease recurrence, up to the effects of ERT and its possible interference with immunosuppression.

scholarly journals Synuclein alpha accumulation mediates podocyte injury in Fabry nephropathy

2021 ◽  
Author(s):  
Ahmed Abed ◽  
Fabian Braun ◽  
Dominik Sellung ◽  
Mathias Woidy ◽  
Oystein Solberg Eikrem ◽  
...  
Keyword(s):  
Cell Injury ◽  
Kidney Injury ◽  
Human Kidney ◽  
Organ Damage ◽  
Alpha Synuclein ◽  
Podocyte Injury ◽  
Enzyme Replacement ◽  
Alpha Galactosidase ◽  
Fabry Nephropathy ◽  
And Function

Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosome dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease remains unclear. First, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/CAS9-mediated alpha-Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.

Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy

2020 ◽  
Author(s):  
Hiroaki Yonishi ◽  
Tomoko Namba-Hamano ◽  
Takayuki Hamano ◽  
Masaki Hotta ◽  
Jun Nakamura ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Podocyte Injury ◽  
Enzyme Replacement ◽  
Average Area ◽  
Potential Biomarker ◽  
Efficacy Assessment ◽  
Novel Biomarkers ◽  
Fabry Nephropathy

Abstract Background The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of >1 g/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN. Methods Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion. Results Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocytes. We observed more severe podocyte vacuolation with increased uMB excretion (P = 0.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P = 0.018). Eighteen-month-long ERT reduced uMB excretion (P = 0.03) without affecting proteinuria. Conclusions uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.

scholarly journals The Management of Fabry Nephropathy

2016 ◽  
Vol 2 (1) ◽  
pp. pocj.5000203 ◽  
Author(s):  
Renzo Mignani
Keyword(s):  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Kidney Biopsy ◽  
Supportive Therapy ◽  
Organ Damage ◽  
Enzyme Replacement ◽  
History Of ◽  
Fabry Nephropathy ◽  
Key Questions

A case of an adult female with Fabry disease is described with discussion based on the following key questions: 1. What is the natural history of Fabry nephropathy? 2. What are the indications to perform kidney biopsy in Fabry disease? 3. How to perform the workout of the patient in recognition of systemic organ damage? 4. Is the missed recognition of Fabry disease frequent in dialysis patients? 5. When and which patients are eligible to start enzyme replacement therapy? 6. Is enzyme replacement therapy effective in Fabry nephropathy? 7. What is the outcome of the patient who underwent a kidney transplantation? 8. Is the supportive therapy important in Fabry disease nephropathy? 9. What are the future therapeutic perspectives?

scholarly journals Variables Associated with a Urinary MicroRNAs Excretion Profile Indicative of Renal Fibrosis in Fabry Disease Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Sebastián Jaurretche ◽  
Germán Perez ◽  
Norberto Antongiovanni ◽  
Fernando Perretta ◽  
Graciela Venera
Keyword(s):  
Urinary Excretion ◽  
Fabry Disease ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Statistical Significance ◽  
Clinical Manifestations ◽  
Kidney Fibrosis ◽  
Enzyme Replacement ◽  
Urine Albumin ◽  
Fabry Nephropathy

Introduction. In advanced Fabry nephropathy stages, enzyme replacement theraphy (ERT) efficacy decreases, due to its impossibility to reverse renal fibrosis. Therefore, the finding of early kidney fibrosis biomarkers in affected patients is of interest. During renal fibrosis miR-21, miR-192 and miR-433 (fibrosis promotors) are activated by transforming growth factor-β (TGF-β), and miR-29 and miR-200 family (fibrosis supressors) are inhibited by TGF-β. The aim of this study is to analyze the probability that Fabry disease (FD) patients with some clinical variables can present an urinary microRNAs excretion profile indicative of renal fibrosis through a logistic regression analysis. Results. A population of 34 participants was included: 24 FD patients and 10 controls. 16/24 (66.66%) FD patients presented microRNAs urinary excretion profile indicative of renal fibrosis. This profile was observed by decrease of fibrosis suppresors miR-29 and miR-200 and not by increase of fibrosis promotors miR-21, miR192, and miR-433. Hypohidrosis, angiokeratomas, neuropathic pain, hearing loss, cardiac involvement, male gender, reduced αGalA activity, and renin-angiotensin-aldosterone system inhibitors treatment are associated with the appearance of amicroRNAs urinary excretion profile indicative of renal fibrosis. A probable beneficial effect on urinary microRNAs excretion profile was observed in patients receiving ERT with agalsidase beta. The correlation between parameters of renal function with each family of microRNAs was studied. The only association with statistical significance was found between miR-21 and urine albumin-creatinine ratio (p =0.021). Conclusions. A probable microRNAs regulation not mediated by TGF-β should be considered or TGF-β has a different effect in FD than in other nephropathies on microRNAs regulation. Typical clinical manifestations of classic FD are associated with appearance of urinary microRNAs profile indicative of renal fibrosis. FD patients express renal fibrosis biomarkers in urine prior to onset of pathological albuminuria. A direct correlation between urinary miR-21 and degree of albuminuria was observed.

scholarly journals Expression of uPAR in Urinary Podocytes of Patients with Fabry Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Hernán Trimarchi ◽  
Romina Canzonieri ◽  
Amalia Schiel ◽  
Juan Politei ◽  
Cristian Costales-Collaguazo ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Cross Sectional Study ◽  
Urinary Protein ◽  
Potential Contribution ◽  
Creatinine Ratio ◽  
Cross Sectional ◽  
Enzyme Replacement ◽  
Upar Expression ◽  
Podocyte Detachment ◽  
Fabry Nephropathy

Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia is an irreversible event that antedates proteinuria and leads to chronic renal failure. We evaluated a potential mechanism of podocyte detachment via the expression of the urokinase-type Plasminogen Activator Receptor (uPAR) in urinary podocytes of Fabry patients.Methods. This is a cross-sectional study that included controls (n=20) and Fabry patients (n=44) either untreated (n=23) or treated with agalsidase-β(n=21).Variables. Variables are estimated glomerular filtration rate (eGFR), urinary protein : creatinine ratio, and urinary uPAR+ podocyte : creatinine ratio. uPAR mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes.Results. Controls and Fabry patients had similar age, gender, and renal function. Urinary uPAR+ podocytes were higher in patients than in controls. Untreated patients were significantly younger; had more females, and presented lower urinary protein : creatinine ratios and significantly higher urinary uPAR+ podocytes than treated subjects. In treated patients, urinary uPAR+ podocytes correlated with urinary protein : creatinine ratio (ρ=0.5;p=0.02). Lyso-Gb3 at concentrations found in the circulation of Fabry patients increased uPAR expression in cultured podocytes.Conclusions. Urinary podocytes expressing uPAR are increased in Fabry patients, especially in untreated patients. The potential contribution of uPAR expression to podocyte detachment merits further studies.

scholarly journals Copious Podocyturia without Proteinuria and with Normal Renal Function in a Young Adult with Fabry Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
H. Trimarchi ◽  
R. Canzonieri ◽  
A. Muryan ◽  
A. Schiel ◽  
A. Araoz ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Fabry Disease ◽  
Renal Damage ◽  
Dual Problem ◽  
Clinical Signs ◽  
Enzyme Replacement ◽  
Cardiovascular Morbidity And Mortality ◽  
Initiation Of Therapy ◽  
Fabry Nephropathy

The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matter of debate, particularly when no overt classical clinical signs or symptoms are present. With respect to Fabry nephropathy, a dual problem coexists: the reluctance of many nephrologists to start enzyme replacement infusion until signs of renal disease appear as the appearance of proteinuria or an elevation in serum creatinine and the lack of validated biomarkers of early renal damage. In this regard, proteinuria is nowadays considered as an early and appropriate marker of kidney disease and of cardiovascular morbidity and mortality. However, in this report we demonstrate that podocyturia antedates the classical appearance of proteinuria and could be considered as an even earlier biomarker of kidney damage. Podocyturia may be a novel indication for the initiation of therapy in Fabry disease.

scholarly journals Podocyte Structural Parameters Do Not Predict Progression to Diabetic Nephropathy in Normoalbuminuric Type 1 Diabetic Patients

2015 ◽  
Vol 41 (4-5) ◽  
pp. 277-283 ◽  
Author(s):  
Tasma Harindhanavudhi ◽  
Alicia Parks ◽  
Michael Mauer ◽  
M. Luiza Caramori
Keyword(s):  
Diabetic Nephropathy ◽  
Structural Changes ◽  
Structural Parameters ◽  
Diabetic Patients ◽  
Numerical Density ◽  
Podocyte Injury ◽  
Foot Process ◽  
Nested Case Control ◽  
Type 1 Diabetic Patients

Background: Podocyte injury has been implicated in diabetic nephropathy (DN) ranging from normoalbuminuria to proteinuria in both type 1 and type 2 diabetes. Methods: To determine whether podocyte structural parameters predict DN risk in initially normoalbuminuric long-standing type 1 diabetic patients, we performed a nested case-control study in sex and diabetes duration-matched progressors (progression to proteinuria or ESRD, n = 10), non-progressors (normoalbuminuric at follow-up, n = 10), and non-diabetic controls (n = 10). Results: HbA1c and diastolic blood pressure were higher in progressors versus non-progressors. Podocyte number per glomerulus, numerical density of podocyte per glomerulus, and foot process width were not different among groups. The glomerular basement membrane width was greater in progressors versus non-progressors or controls, and in non-progressors versus controls. As expected, the mesangial fractional volume was greater in progressors and non-progressors versus controls, with no differences between progressors and non-progressors. Conclusion: This study does not indicate that podocyte structural changes are preconditions for later DN progression in initially normoalbuminuric type 1 diabetic patients. However, this does not preclude an important role for podocyte injury at a later stage of DN.

scholarly journals A Case Study of Fabry Nephropathy and Its Progression: The First Reported Case in Malaysia

2021 ◽  
Author(s):  
Ingrid Ting Pao Lin ◽  
Andy Tang Sing Ong ◽  
Fam Tem Lom ◽  
Clare Tan Hui Hong
Keyword(s):  
Fabry Disease ◽  
Disease Progression ◽  
Incidental Finding ◽  
Disease Diagnosis ◽  
Progression Rate ◽  
Renal Disease Progression ◽  
Timely Initiation ◽  
Enzyme Replacement ◽  
First Case ◽  
Fabry Nephropathy

Abstract IntroductionFabry disease (FD) is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, causing common and serious kidney complications. We report the first case of Fabry disease detected in Malaysia. Clinical ScenarioA 35-year-old man had an incidental finding of proteinuria during routine health screening. His symptoms included frothy urine and intermittent lower limb swelling. Renal biopsy showed features of Fabry’s disease which was confirmed with genetic testing. He had classical hemizygous Fabry disease of c.610 C>T with Fabry nephropathy, cardiomyopathy, and cornea verticillata. He was then started on be Enzyme Replacement Therapy (ERT) with agalsidase till date. ConclusionProteinuria is the predominant factor in Fabry nephropathy predicting renal disease progression rate. Early Fabry Disease diagnosis could prevent kidney disease progression through the timely initiation of treatment which will help enhance the quality of life of the patient, as the disease progresses.

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