Fabry Nephropathy Research Articles

Pharmacological Chaperone Therapy for Fabry Disease

Pharmacological chaperone therapy (PCT) structurally stabilizes mutant enzyme proteins and increases their activity. Although ease of oral administration and effectiveness in patients with central nervous system disorders serve as advantages, PCT is effective only for patients with amenable mutations because its efficacy depends on gene mutations. PCT, which prevents progression of Fabry cardiomyopathy and nephropathy, was approved in Japan in 2018. It is expected that PCT will also be developed for lysosomal diseases that cause central nervous system disorders in the future.

Fabry nephropathy: focus on podocyte damage and therapeutic target

Fabry disease, a rare X-linked lysosomal storage disorder, is marked by a deficiency in the activity of the enzyme α-galactosidase A. This deficiency results in the accumulation of globotriaosylceramide (Gb3) within various tissues and organs, which leads to life-threatening complications and poor prognosis. Clinical manifestations are multisystemic, heterogeneous, and progressive. Early diagnosis and treatment are of great importance. Fabry nephropathy lesions are characterized by a cell vacuolization of glomeruli, tubules, interstitium, and arteries and by ultrastructural myelin bodies. Kidney injury can occur in various structures, with the podocytes being the first to be impacted due to their low regeneration and extensive exposure to Gb3. The accumulation of Gb3 causes injury to podocytes, which are essential components of glomerular cells, responsible for maintaining the integrity of the glomerular filtration barrier. Enzyme replacement therapy, dynamic monitoring of podocyte injury, and research on the repair and regeneration mechanism of podocyte injury will contribute to the overall treatment of kidney damage in Fabry disease and improve the renal prognosis.

Fabry nephropathy. Urinary expression of podocyte proteins mRNA and microRNAs in non-albuminuric patients

Fabry nephropathy. Urinary expression of podocyte proteins mRNA and microRNAs in non-albuminuric patients

Fabry nephropathy: a treatable cause of chronic kidney disease

Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate and thus accumulates Gb3 throughout life. Podocytes are injured by Gb3, leading to their detachment from the glomerular basement membrane and subsequent loss in the urine. Albuminuria starts in childhood and progresses to overt proteinuria in the teens and 20 s. CKD ensues with adults starting dialysis at an average age of 42 years. Patients have a high prevalence of stroke and cardiomyopathy with hypertrophic change, heart failure, and dysrhythmias. Patient survival is limited in both genders. Diagnosis is based on the demonstration of a low α-Gal activity and a pathogenic GLA mutation. Clinical features are highly variable, which makes recognition of this condition difficult. Treatment with intravenous recombinant human enzyme replacement therapy (ERT) and oral pharmacologic chaperone are available. Control of proteinuria to 0.5 g/day or less is of critical importance to limit progression to end-stage renal disease. Early initiation of treatment gives the best results, but the optimal age to start is uncertain. Fabry nephropathy remains a challenge due to its multisystem nature, difficult diagnosis, and complicated management. It is important as a treatable cause of CKD.

The inflammatory pathogenetic pathways of Fabry nephropathy

The high variability in clinical features and outcomes observed in monogenic diseases like Fabry disease suggests the presence of additional pathogenetic pathways beyond the lysosomal deposition of Gb3 and Lyso-GB3. Research indicates that the deposition of Gb3 and Lyso-Gb3 can stimulate the inflammatory processes. Mononuclear immune-competent cells exposed to Gb3 deposition exhibit surface adhesion molecules and release pro-inflammatory and fibrotic cytokines such as IL β, TNFα, and TGFβ, culminating in the activation of inflammatory cascades associated with oxidative stress, apoptotic mechanisms maintained by renal residents and infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, in another avenue of inquiry (termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alpha-galactosidase A enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response (UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of pro-inflammatory cytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstrated that the pathogenetic mechanisms activated by Gb3 and Lyso Gb3 deposition can become independent from the initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-therapy or gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifest in the absence of Gb3 in the Zebrafish experimental model. This review endeavors to describe the role of these processes in Fabry nephropathy and aims to synthesize the available evidence on the pathogenesis of renal damage.

The role of tubular cells in the pathogenesis of Fabry nephropathy.

The pathophysiology of Fabry nephropathy (FN) is induced by galactosidase A deficiency with a chronic exposure of glycolipids to every lineage of renal cells. Tissue damage is attributed to the activation of molecular pathways, resulting in tissue fibrosis and chronic kidney disease. Podocytes have been the primary focus in clinical pathophysiological research because of the striking accumulation of large glycolipid deposits observable in histology. Yet, the tubular interstitium makes up a large portion of the whole organ, and therefore, its role must be further considered in pathogenic processes. In this review, we would like to propose Fabry tubulopathy and its ensuing functional effects as the first pathological signs and contributing factors to the development of FN. We will summarize and discuss the current literature regarding the role of tubular cells in Fabry kidney pathophysiology. Starting from clinical and histological evidence, we will highlight the data from animal models and cell cultures outlining the pathophysiological pathways associated with tubular interstitial injury causing renal fibrosis in Fabry nephropathy.

Pathogenic pathways of renal damage in Fabry nephropathy: interplay between immune cell infiltration, apoptosis and fibrosis.

Fabry nephropathy is a consequence of the deposition of globotriaosylceramide, caused by deficient GLA enzyme activity in all types of kidney cells. These deposits are perceived as damage signals leading to activation of inflammation resulting in renal fibrosis. There are few studies related to immunophenotype characterization of the renal infiltrate in kidneys in patients with Fabry diseaseand its relationship to mechanisms of fibrosis.This work aims to quantify TGF-β1 and active caspase 3 expression and to analyze the profile of cells in inflammatory infiltration in kidney biopsies from Fabry naïve-patients, and to investigate correlations with clinical parameters. Renal biopsies from 15treatment-naïve Fabry patients were included in this study. Immunostaining was performed to analyze active caspase 3, TGF-β1, TNF-α, CD3, CD20, CD68 and CD163.Clinical data were retrospectively gathered at time of kidney biopsy. Our resultssuggest the production of TNFα and TGFβ1 by tubular cells, in Fabry patients. Active caspase 3 staining revealed that tubular cells are in apoptosis, and apoptotic levels correlated with clinical signs of chronic kidney disease, proteinuria, and inversely with glomerular filtration rate. The cell infiltrates consisted of macrophages, T and B cells. CD163 macrophages were found in biopsy specimens and their number correlates with TGFβ1 and active caspase 3 tubular expression. These results suggest that CD163+ cells could be relevant mediators of fibrosis in Fabry nephropathy, playing a role in the induction of TGFβ1 and apoptotic cell death by tubular cells. These cells may represent a new player in the pathogenic mechanisms of Fabry nephropathy.

Switch from enzyme replacement therapy to pharmacologic chaperone: Improvement in advanced Fabry nephropathy

Switch from enzyme replacement therapy to pharmacologic chaperone: Improvement in advanced Fabry nephropathy

The Role of α3β1 Integrin Modulation on Fabry Disease Podocyte Injury and Kidney Impairment.

Podocyte dysfunction plays a crucial role in renal injury and is identified as a key contributor to proteinuria in Fabry disease (FD), primarily impacting glomerular filtration function (GFF). The α3β1 integrins are important for podocyte adhesion to the glomerular basement membrane, and disturbances in these integrins can lead to podocyte injury. Therefore, this study aimed to assess the effects of chloroquine (CQ) on podocytes, as this drug can be used to obtain an in vitro condition analogous to the FD. Murine podocytes were employed in our experiments. The results revealed a dose-dependent reduction in cell viability. CQ at a sub-lethal concentration (1.0 µg/mL) induced lysosomal accumulation significantly (p < 0.0001). Morphological changes were evident through scanning electron microscopy and immunofluorescence, highlighting alterations in F-actin and nucleus morphology. No significant changes were observed in the gene expression of α3β1 integrins via RT-qPCR. Protein expression of α3 integrin was evaluated with Western Blotting and immunofluorescence, demonstrating its lower detection in podocytes exposed to CQ. Our findings propose a novel in vitro model for exploring secondary Fabry nephropathy, indicating a modulation of α3β1 integrin and morphological alterations in podocytes under the influence of CQ.

Renal ANCA+ Vasculitis Concurrent with Fabry Nephropathy: Coincidence or Complication?

Renal ANCA+ Vasculitis Concurrent with Fabry Nephropathy: Coincidence or Complication?

Treatment of Fabry Nephropathy: A Literature Review.

Fabry disease is an X-linked inherited lysosomal storage disorder with a deficiency of α-galactosidase A activity, which results in the intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in various organs. Fabry nephropathy is one of the major complications of Fabry disease, and kidney damage is often related to cardiovascular disease and mortality. The treatment of Fabry nephropathy thus helps prolong life expectancy. Two treatment options for Fabry nephropathy and cardiopathy are now commercially available: enzyme replacement therapy (agalsidase α agalsidase β, and a biosimilar of agalsidase β) and pharmacological chaperone therapy (migalastat). In this review, we summarize the efficacy of these treatment options for Fabry nephropathy with respect to renal function, proteinuria, and renal pathological findings. We also describe the importance of adjunctive therapy for Fabry nephropathy.

A Case Report of Kidney After Heart Transplant in Patient With Fabry Disease

Fabry disease is an X-linked inherited lysosomal storage disorder caused by a mutation in the gene encoding the enzyme α-galactosidase A. It is characterized by the accumulation of globotriaosylceramide in different tissues, resulting in a wide range of clinical presentations. Fabry cardiomyopathy and Fabry nephropathy are the disease's 2 most important life-threatening manifestations and can contribute to higher morbidity and mortality. Heart and kidney transplants can play a major role in patients with Fabry disease who develop end organ damage. We report a case of a successful heart transplant in a male patient with Fabry disease at the age of 62, followed by a kidney transplant later at the age of 69. He has had an uneventful post-transplant course and has been tolerating maintenance immunosuppression and enzyme replacement therapy with recombinant human α-galactosidase A.

Paradoxical Dapagliflozin Effect on Proteinuria in a Female Patient with Classic Fabry Disease First Literatura Report

A 75-year-old female patient, with “classic” Fabry disease (DEL 3&amp;4 EXON, GLA gene) and severe multi-organic compromise (cardiac, brain, renal and peripheral nervous system) is presented. Patient presented treatment initiation criteria, and was a “classic” Fabry phenotype, for this reason, agalsidase-β was indicated. In addition, enalapril, were indicated. After the treatment start and to date, the patient presented: i) LVH stabilization; ii) brain damage stabilization; iii) stable eGFR and sustained improvement in proteinuria and; iv) pain improvement. In September 2022, due to the results of DAPA-CKD study, it was decided to start treatment with dapagliflozin to extend the renal protective effect; patient presented good tolerance to drug and no adverse effects were recorded. A slight decrease in eGFR was observed, but suspension was decided after 8 weeks due to increased proteinuria. Kidney disease is a major Fabry disease complication; it is more severe in the “classic” phenotype and males, although the “non-classic” Fabry phenotype and affected females may also present severe renal disease. Patients with Fabry disease and chronic kidney disease have a high risk of cardiovascular events, SGLT-2 inhibitor drugs have shown favorable effects on cardiovascular events in chronic kidney disease patients, both DBT and non-DBT. Multiple pathophysiological mechanisms have been described in Fabry nephropathy, none of them could explain, the reason why SGLT-2 blockade produced an increase in proteinuria in presented case.

Interpretation of GFR slope in untreated and treated adult Fabry patients.

Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this 'Expert Opinion', that a treatment should be defined effective when eGFR decline is <1ml/min/1.73m2/year and not effective when eGFR loss remains ≥3ml/min/1.73m2/year (≥2.5ml/min/1.73m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18-60years) with an eGFR of 45-90ml/min/1.73m2 and treated with a stable dose of ERT for at least 1year, in which a linear negative slope of eGFR of 3ml/min/1.73m2/year for males (2.5ml/min/1.73m2/year for females) was observed.

Systems analyses of the Fabry kidney transcriptome and its response to enzyme replacement therapy identified and cross-validated enzyme replacement therapy-resistant targets amenable to drug repurposing

Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By understanding the molecular basis of Fabry nephropathy (FN) and ERT's long-term impact, here we aimed to provide a framework for selection of potential disease biomarkers and drug targets. We obtained biopsies from eight control individuals and two independent FN cohorts comprising 16 individuals taken prior to and after up to ten years of ERT, and performed RNAseq analysis. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from four nephron compartments and their integration with existing proteome and drug-target interactome data. Comparing these transcriptional landscapes revealed high inter-cohort heterogeneity. Kidney compartment transcriptional landscapes comprehensively reflected differences in FN cohort characteristics. With exception of a few aspects, in particular arteries, early ERT in patients with classical Fabry could lastingly revert FN gene expression patterns to closely match that of control individuals. Pathways nonetheless consistently altered in both FN cohorts pre-ERT were mostly in glomeruli and arteries and related to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or reemerged despite ERT. Inferring an ERT-resistant genetic module of expressed genes identified 69 drugs for potential repurposing matching the proteins encoded by 12 genes. Thus, we identified and cross-validated ERT-resistant gene product modules that, when leveraged with external data, allowed estimating their suitability as biomarkers to potentially track disease course or treatment efficacy and potential targets for adjunct pharmaceutical treatment.

A questionnaire survey on the diagnosis and treatment of Fabry nephropathy in clinical practice.

Fabry nephropathy is characterized by a deficiency of lysosomal alpha-galactosidase A, which results in proteinuria and kidney disease. The ineffectiveness of enzyme replacement therapy (ERT) for severe kidney failure highlights the need for early detection and meaningful markers. However, because the diagnosis and treatment of Fabry disease can vary according to the expertise of physicians, we evaluated the opinions of Korean specialists. A questionnaire regarding the management of Fabry nephropathy was emailed to healthcare providers with the experience or ability to treat individuals with Fabry nephropathy. Of the 70 experts who responded to the survey, 43 were nephrologists, and 64.3% of the respondents reported having treated patients with Fabry disease. Pediatricians are treating primarily patients with classic types of the disease, while nephrologists and cardiologists are treating more patients with variant types. Only 40.7% of non-nephrologists agreed that a kidney biopsy was required at the time of diagnosis, compared with 81.4% of nephrologists. Thirty-eight of 70 respondents (54.3%) reported measuring globotriaosylsphingosine (lyso-Gb3) as a biomarker. The most common period to measure lyso-Gb3 was at the time of diagnosis, followed by after ERT, before ERT, and at screening. For the stage at which ERT should begin, microalbuminuria and proteinuria were chosen by 51.8% and 28.6% of respondents, respectively. Nephrologists are more likely to treat variant Fabry disease rather than classic cases, and they agree that ERT should be initiated early in Fabry nephropathy, using lyso-Gb3 as a biomarker.

#6896 A SCREENING AND CLINICAL MANIFESTATIONS OF FABRY DISEASE IN PATIENTS ATTENDING DIALYSIS AND NEPHROLOGY CLINICS IN DURBAN, SOUTH AFRICA

Abstract Background and Aims Fabry disease is inherited in an X-linked manner in which the mutated gene inhibits the functioning of the alpha-Galactosidase-A enzyme causing a deficiency or absence of the enzyme, characterizing it as a progressive, lysosomal storage disorder. Subsequently, the accumulation of globotriaosylceramide (Gb3) in the lysosomes causes damage to tissues and major organs. Fabry nephropathy is one of the major organ complications caused by Fabry disease resulting in end-stage kidney disease. The aim of our study is to determine the prevalence of Fabry disease in our patients. Method This study was a prospective, quantitative study. A cohort of 200 male patients with chronic kidney disease (CKD stage 2-5D) was enrolled. A control group of 14 healthy males was also enrolled for this study. The ELISA technique was employed to determine the alpha Gal-A enzyme concentration levels in plasma. A questionnaire using the MSSI scoring system was presented to the participants to identify clinical manifestations. The SPSS Version 27 (IBM, New York, USA) was used to analyse the data. Results A cut-off value for the alpha Gal-A enzyme concentration levels of &amp;lt;500 pg/ml was calculated. A total of 17 participants from the patient group (n=11) and the control group (n=6) displayed alpha-Gal-A enzyme levels &amp;lt;500 pg/ml. Using the univariate regression analysis, statistically significant results were revealed between alpha-Gal levels &amp;lt;500 pg/ml and age (P = .007), heat or cold intolerance (P = .049), hypertension (p &amp;lt; 0.001) and eGFR (p &amp;lt; 0.001). MSSI scores displayed a negative association (P = .001). The multivariate regression analysis showed that age and MSSI scores retained their significance when eGFR was excluded as a variable, however, with the inclusion of eGFR as a variable, none of the variables retained their significance. Conclusion Fabry disease is suspected in 17 participants with alpha-Gal levels of &amp;lt;500 pg/ml. The cause of CKD nephropathy raises interest as conditions such as FSGS have been associated with FD. The low levels of the alpha-Gal enzyme and presentation of the clinical manifestations can be utilized as preliminary findings. Confirmatory tests such as DNA analysis or Gb3 and GL3 analysis are warranted.

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance

Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex. Single-center, case series. Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System. Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age. Retrospective design and inclusion of outpatients partially based on family pedigree. In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Synuclein α accumulation mediates podocyte injury in Fabry nephropathy.

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 α-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.

Is just enzyme replacement therapy enough for Fabry disease treatment? Have we missed a trick?

Background and aimIn Fabry disease (FD), primary factors such as glycosphingolipid deposition that initiate kidney damage and secondary factors that advance kidney damage to fibrosis are different. Periostin is a molecule of proven importance in renal inflammation and fibrosis. It was previously shown that periostin plays an essential role in the process leading to renal fibrosis and its expression is increased in many kidney diseases. In the present study, we aimed to reveal the relationship between periostin and Fabry nephropathy. Material-methodThis cross-sectional study included 18 FD patients (10 males, 8 females) with enzyme replacement therapy (ERT) indications and 22 healthy control patients of similar age and gender. At the time of diagnosis, plasma alpha-galactosidase A (α-gal-A) and globotriaosylsphingosine (lyso-Gb3), proteinuria, and kidney function tests of all FD patients before ERT were scanned from the hospital system. Periostin was studied from serum samples collected and stored before ERT. Parameters related to serum periostin levels in Fabry disease were investigated. ResultsIn FD patients, serum periostin was negatively correlated with age of first symptom and GFR; and positively correlated with proteinuria and lyso-Gb3. In regression analysis, we found that serum periostin was the only independent determinant of proteinuria in patients with Fabry disease. The serum periostin levels were significantly lower in patients with low proteinuria, and the serum periostin levels were correlated with proteinuria. DiscussionPeriostin may be a valuable marker of Fabry nephropathy and proteinuria. Periostin seems to be one of the molecules that may have an important role in the management of the fibrotic process in Fabry nephropathy. We think that the role of periostin among these mechanisms is worth investigating. In addition to standard ERTs, periostin-reducing therapies may contribute to better kidney survival in Fabry disease. Progressive fibrosis processes caused by periostin in patients with Fabry disease are still a hidden issue waiting to be clarified. Progressive fibrosis processes caused by periostin in Fabry patients are still a hidden issue waiting to be clarified.