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 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.

Clinic-Pathologic Features and Renal Outcome of Fabry Disease: Data from a Chinese Cohort

2018 ◽  
Vol 48 (2) ◽  
pp. 137-146
Author(s):  
Dan Zhang ◽  
Jiong Zhang ◽  
Shaoshan Liang ◽  
Jinquan Wang ◽  
Zhihong Liu
Keyword(s):  
Renal Function ◽  
Survival Rate ◽  
Fabry Disease ◽  
Left Ventricular ◽  
Renal Outcome ◽  
Characteristic Analysis ◽  
Renal Function Deterioration ◽  
Renal Prognosis ◽  
Stable Renal Function ◽  
Fabry Nephropathy

Background: Fabry disease (FD) with life-threatening complications occurs as a result of organ damage in kidneys, heart, and brain. Only a few studies, especially from Asia, report their long-term outcome. Methods: In this monocentric study, patients with Fabry nephropathy confirmed by renal biopsy were clinically investigated in a comprehensive manner. The clinic-pathological features, progression, and risk factors for the outcome were analyzed. Results: Thirty-one patients were recruited, after median 62 months (range 8–156 months) follow-up, 23 of them had stable renal function while 8 underwent renal function deterioration. Frequent presenting symptoms included acroparesthesia (58.1%), edema (51.6%), hypo- or anhidrosis (38.7%), and angiokeratoma (32.3%). Left ventricular hypertrophy was present in 62.5% patients with renal function deterioration and 17.4% patients with stable renal function (p = 0.03). The renal cumulative survival rate of all patients was 64.5% in 10 years. Mainz Severity Score Index (MSSI) and segmental sclerosis are independent predictive factors for a more rapid progression of Fabry nephropathy. The receiver operating characteristic analysis demonstrated that the area under the curve for the prediction of renal function progression on the basis of MSSI and segmental sclerosis levels in patients with FD was 0.845 and 0.780, respectively. MSSI score ≥18 or segmental sclerosis ≥3.9% in patients with FD positively correlated with poor renal prognosis. Conclusions: FD’s clinical manifestations are heterogeneous and nonspecific. The ­10-year cumulative renal survival rate was low in Chinese patients. MSSI score and segmental sclerosis levels predict the renal prognosis of patients with FD sensitively.

scholarly journals Fabry Nephropathy

2017 ◽  
Vol 141 (8) ◽  
pp. 1127-1131 ◽  
Author(s):  
Prudence Colpart ◽  
Sophie Félix
Keyword(s):  
Clinical Signs ◽  
Lysosomal Storage ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Disease Evolution ◽  
Enzyme Replacement ◽  
Life Threatening ◽  
A Cell ◽  
Gla Gene ◽  
Fabry Nephropathy

Fabry disease is a rare X-linked recessive lysosomal storage disease. Multiple mutations of the GLA gene lead to a deficient or absent activity of the lysosomal enzyme α-galactosidase A, resulting in progressive glycotriaosylceramide accumulation in many organs. Low α-galactosidase A activity and mutations in the GLA gene confirm the diagnosis. Clinical signs are multisystemic, heterogeneous, and progressive. Renal, cardiac, and neurovascular involvements are the main life-threatening complications, highlighting the importance of an early initiation of enzyme replacement therapy improving long-term outcome. Fabry nephropathy lesions are characterized by a cell vacuolization of glomeruli, tubules, interstitium, and arteries and by ultrastructural myelin bodies. The main histologic differential diagnoses are toxicity of lysosomal inhibitors and other renal lipidoses. Renal biopsies are not necessary for diagnosis but have an important role in the evaluation of disease evolution and treatment efficiency, which is a major challenge for improving outcome and quality of life.

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 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 SARS-CoV-2 and Fabry nephropathy: potential risks and the pathophysiological perspective

2020 ◽  
Vol 9 (4) ◽  
pp. e36-e36 ◽  
Author(s):  
Hernán Trimarchi
Keyword(s):  
Kidney Disease ◽  
Replacement Therapy ◽  
Mesangial Cells ◽  
Late Onset ◽  
Kidney Injury ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Increased Risk ◽  
Kidney Involvement ◽  
Fabry Nephropathy

Fabry disease is an X-linked disorder due to mutations in alpha-galactosidase A gene. It affects the kidney in virtually all patients with classical and some late onset variants. Podocytes, endothelial cells, vascular smooth muscle, tubular and mesangial cells are involved in different ways. Proteinuria and chronic kidney disease are the result of the progressive accumulation of the enzyme substrates globotriaosylceramide (GB3) and lyso-GB3 in the cytoplasm of these cells (mainly in lysosomes), which leads to cellular and organ dysfunction and eventually renal failure and end-stage kidney disease. Specific enzyme replacement therapy and pharmacological chaperone are at present the main therapeutic approach. After enzyme infusion, the delivered enzyme is differentially uptaken by kidney cells in three different ways: By Mannose-6-phosphate receptor, megalin and sortilin. The delivered enzyme gradually clears cells from the accumulation of the glycosphingolipids and contributes to a cellular healthier status. The recent pandemic caused by SARS-CoV-2 has led to the collapse of health systems around the world and to thousands of deaths. Kidney involvement has been reported to range from proteinuria to acute kidney injury, 30% of which may require renal replacement therapy. In this review the potential causes for which Fabry patients should be at increased risk and the necessity not to discontinue therapy are discussed.

Abstract 532: Effect of 3-hydroxy-3-methylglutaryl-CoA Reductase Inhibitors on Renal Function

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Rishi Sukhija ◽  
Zoran Bursac ◽  
Rajesh Sachdeva ◽  
Jawahar Mehta
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Lipid Lowering ◽  
Channel Blockers ◽  
Converting Enzyme Inhibitors ◽  
Cross Sectional ◽  
Renal Deterioration ◽  
Reductase Inhibitors ◽  
Cardiovascular Morbidity And Mortality ◽  
Coa Reductase

Background : 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol, and cardiovascular morbidity and mortality. The role of lipids in the progression of kidney disease and the potential beneficial effects of statins on renal function is unknown. Oxidative stress and inflammation may be the missing link between CAD and chronic kidney disease. Statins may protect the kidney through both lipid lowering properties and pleiotropic effects. Methods : We analyzed data in 197, 551 patients (mean age 64.8 ± 13.6 years, 95% males, 29.5% (58,332) statin users, and 70.5% (139, 219) non-statin users), who had baseline creatinine less than 3.5 mg/dl, from the cross-sectional data mined from the Veterans Affairs VISN 16 database. Deterioration of renal function was defined as doubling of the baseline or increase in creatinine of 0.5 mg/dl over at least 90 days. Results : Based on this definition, 3.4% of patients developed renal deterioration over 5 year of follow-up. After adjustment for demographics, diabetes mellitus, smoking, and other medications (especially use of angiotensin-converting enzyme inhibitors, calcium channel blockers and aspirin, all of which were confounders of the statin-renal deterioration relationship), use of statins reduced the odds of deterioration in renal function by 15% (OR 0.85, 95% CI = 0.80 – 0.89, p < 0.0001). This effect was independent of cholesterol lowering effect of statins. Impact of other variables was as follows: age (OR = 1.04, CI = 1.03–1.04, p < 0.0001), diabetes (OR = 1.76, CI = 1.67–1.85, p < 0.0001), and smoking (OR = 1.76, CI = 1.05–1.23, p = 0.0014). Conclusion : Statin use may retard the progression of renal disease. Although the precise mechanism is not known, lowering of LDL-cholesterol and improvement in endothelial function by statins may relate to reno-protective effect.

Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study

2018 ◽  
Vol 34 (9) ◽  
pp. 1525-1533 ◽  
Author(s):  
Christoffer V Madsen ◽  
Henrik Granqvist ◽  
Jørgen H Petersen ◽  
Åse K Rasmussen ◽  
Allan M Lund ◽  
...  
Keyword(s):  
Renal Function ◽  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Standard Deviation Score ◽  
Urine Protein ◽  
Enzyme Replacement ◽  
Urine Protein Excretion ◽  
Protein Excretion ◽  
Function Loss

Abstract Background Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. Methods This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. Results In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1–13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of −0.8 ± 0.2 with an annual slope of −0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin–creatinine ratio (UACR) &gt;300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. Conclusions ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.

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.

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