Search Results (24)

Fabry disease (FD) is an X-linked lysosomal disorder caused by GLA mutations, typically associated with glycosphingolipid accumulation and a wide phenotypic spectrum. The p.R112H variant is generally linked to a non-classic predominantly renal phenotype with mild biochemical abnormalities and slow progression. We report the case of a young woman carrying the R112H mutation who exhibited early-onset kidney involvement and unusually rapid progression to end-stage renal disease. Clinical history, serial evaluations, and kidney biopsy findings initially supported a diagnosis of Fabry nephropathy; however, re-evaluation of the native kidney biopsy revealed marked remodeling and multilamellation of the glomerular basement membrane, suggesting Alport-like lesions. Subsequent genetic testing confirmed a heterozygous pathogenic COL4A4 variant (G912R), indicating coexistence of Fabry disease and autosomal dominant Alport syndrome. This dual genetic condition likely accounted for the accelerated decline in kidney function, in contrast with the typically mild phenotype associated with R112H. Our literature review indicates that coexistence of these two inherited nephropathies has not previously been confirmed either histologically or genetically. This case underscores the importance of integrating genetic and ultrastructural assessment in patients with atypical or rapidly progressive renal disease Full article

Background: Fabry disease is a rare X-linked lysosomal storage disorder associated with progressive renal, cardiac, and neurological complications. Enzyme replacement therapy (ERT) has been the standard treatment for more than two decades, but its long-term impact on renal outcomes remains debated. Methods: We conducted a systematic review and meta-analysis of studies reporting renal outcomes in Fabry patients under long-term follow-up, including both ERT-treated and untreated cohorts. Electronic databases were searched up to October 2023. Data were extracted on estimated glomerular filtration rate (eGFR) slope, proteinuria, and clinical events. Random-effects models were used to calculate pooled effect sizes, and subgroup analyses were performed by treatment status and baseline risk factors. Results: Sixteen studies involving 2191 patients were included. Pooled analyses demonstrated a significant decline in eGFR over time across Fabry cohorts. Crucially, baseline proteinuria was identified as a significant prognostic factor; male patients with baseline UPCR > 0.5 g/g experienced a significantly faster decline in eGFR compared to those with UPCR < 0.5 g/g (p = 0.011). While direct comparisons between ERT and non-ERT groups did not consistently reach statistical significance, trends suggested a slower decline in ERT-treated patients, particularly in those with preserved renal function and lower proteinuria. Patients with baseline eGFR < 60 mL/min/1.73 m² had a significantly higher risk of clinical events compared with those with preserved renal function. Conclusions: Fabry patients experience progressive renal decline despite available therapies. Although direct comparisons between ERT and non-ERT groups did not consistently reach statistical significance, our quantitative analysis highlighted baseline proteinuria as a major determinant of renal trajectory. Patients with baseline UPCR > 0.5 g/g exhibited a significantly faster decline in eGFR, emphasizing the importance of early diagnosis and intervention before significant glomerular damage occurs. The limitations of the analysis include the small number of studies, heterogeneity in renal function definitions, exclusion of advanced kidney disease, and methodological constraints related to effect size reporting and risk-of-bias assessment. Full article

Background/Objectives: Fabry nephropathy (FN) is a progressive complication of Fabry disease that significantly affects patient outcomes. However, the molecular mechanisms underlying FN are not yet fully understood. Recent advances in transcriptomics have opened new perspectives for the identification of early changes in gene expression associated with the development and progression of the disease. Methods: This study includes a systematic review of transcriptomic findings in chronic kidney disease, with a particular focus on FN, and presents a proof-of-concept RNA sequencing analysis of peripheral blood samples from six Fabry patients with progressive nephropathy and six age- and sex-matched control subjects. Results: The analysis identified 41 differentially expressed genes (DEGs), all of which were upregulated in Fabry patients. Enrichment analysis revealed significant involvement in immune-related pathways, including neutrophil degranulation, interferon, and cytokine signaling. Cell type enrichment revealed that neutrophils and other immune cells are key players in this process. Conclusions: These results suggest that immune and inflammatory mechanisms play a central role in the pathogenesis of FN. The identified DEGs are involved in pro-fibrotic signaling and immune system activation and shed light on possible mechanisms underlying fibrosis, podocyte injury, and kidney damage. This study contributes to a deeper understanding of FN and may facilitate in the identification of early biomarkers for diagnosis and disease monitoring. Full article

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease and life-threatening complications. FD presents with a broad phenotypic spectrum, ranging from the classic form, with early and severe symptoms, to a later-onset form with variable manifestations. The severity of the disease in females is more variable due to X-chromosome inactivation (XCI). Renal involvement is a key feature, and kidney biopsy remains a valuable tool for diagnosing FD and assessing the extent of nephropathy. Although molecular genetic testing is the gold standard for diagnosis, kidney biopsy aids in confirming renal involvement, detecting coexisting conditions, and determining the pathogenicity of variants of uncertain significance (VUSs). Moreover, kidney biopsy can serve as a prognostic tool by identifying early markers of nephropathy, such as foot process effacement and glomerular sclerosis, which predict disease progression. Emerging technologies, including machine learning, offer the potential to enhance the analysis of renal histology, improving diagnostic accuracy and patient stratification. Despite the challenges posed by overlapping diseases and potential misdiagnoses, kidney biopsy remains an essential component of FD diagnosis and management, facilitating early detection, the monitoring of disease progression, and the evaluation of therapeutic responses. Full article

Fabry nephropathy is a life-threatening complication of Fabry disease characterized by complex and incompletely understood pathophysiological processes possibly linked to premature aging. We aimed to investigate leukocyte telomere length (LTL), oxidative stress, and kidney damage biomarkers in relation to kidney function. The study included 35 Fabry patients and 35 age and sex-matched control subjects. Based on the estimated slope of the glomerular filtration rate, the patients were divided into two groups. Relative LTL was quantified by qPCR, urinary biomarkers 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) by UHPLC-MS/MS, and kidney damage biomarkers by flow cytometry. There was no statistically significant difference in LTL between Fabry patients and controls. However, a significant difference was observed in male patients compared to their matched control subjects (p = 0.013). Oxidative stress biomarkers showed no differences between patients and controls, while significant differences were observed in urinary IGFBP7, EGF, and OPN levels between Fabry patients with stable kidney function and those with progressive nephropathy (FDR = 0.021, 0.002, and 0.013, respectively). Significant differences were also observed in plasma levels of cystatin C, TFF3, and uromodulin between patients with progressive nephropathy and controls (all FDR = 0.039). Along with these biomarkers (FDR = 0.007, 0.017, and 0.010, respectively), NGAL also exhibited a significant difference between the two patient groups (FDR = 0.017). This study indicates accelerated telomere attrition, which may be related to disease burden in males. Furthermore, analyses of urinary oxidative stress markers revealed no notable disparities between the different kidney function groups, indicating their limited utility. However, promising differences were found in some biomarkers of kidney damage in urine and plasma. Full article

Numerous prevalence studies on Fabry disease (FD, OMIM #301500) have been conducted in dialysis populations across the world with variable and controversial results. The FABRYDIAL study aimed to estimate the prevalence of FD in patients aged 18 to 74 years on chronic dialysis in France. This cross-sectional study was conducted in patients undergoing dialysis. One hundred and twenty-four dialysis centers participated. Patients with proven causes of nephropathy unrelated to FD were excluded. Alpha-galactosidase A activity was assayed in men, and both α-galactosidase A and lyso-Gb₃ were assayed in women from dried blood spots. GLA gene sequencing was performed in case of abnormal values. If a variant was identified, a diagnosis validation committee was consulted for adjudication. Among the 6032 targeted patients, 3088 were included (73.6% of the eligible patients). Biochemical results were available for 2815 (1721 men and 1094 women). A genetic variant of GLA was identified in five patients: a benign c.937G>T/p.(Asp313Tyr) variant in two individuals, a likely benign c.427G>A/(p.Ala143Thr) variant, a likely benign c.416A>G/(p.Asn139Ser) variant, and a pathogenic c.1185dupG/p.Phe396Glyfs variant. Among the screened patients, the prevalence was 0.058% [0.010;0.328] in males, 0% [0.000;0.350] in females, and 0.035% [0.006;0.201] when both genders were pooled. Among all patients aged 18–74 years undergoing dialysis without a previously known cause of nephropathy unlinked to FD, the prevalence was 0.028% [0.006;0.121]. The prevalence of FD in a cohort of French dialysis patients was low. However, considering the prognostic impact of earlier diagnosis, signs of FD should be sought in patients with nephropathies of uncertain etiology. Full article

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world’s population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD. Full article

Fabry disease (FD) leads to significant morbidity and mortality, which may indicate accelerated ageing. However, it is still unclear whether there is a relationship between telomere length (TL), a marker of biological ageing, and disease outcome. We aimed to examine the relationship between leukocyte TL (LTL) dynamics and the presence of advanced disease stages and/or late complications of FD, including hypertrophic cardiomyopathy, nephropathy and stroke, both cross-sectionally and longitudinally. DNA was extracted from peripheral blood leukocytes and quantitative PCR was utilized to determine relative LTL in 99 Fabry patients. In the longitudinal analysis, we included 50 patients in whom at least three measurements were performed over a period of 5–10 years. The results showed a significant inverse correlation between LTL and age (ρ = −0.20, p = 0.05). No significant differences in LTL were found between females and males (p = 0.79) or between patients receiving disease-specific therapy and those without (p = 0.34). In a cross-sectional analysis, no association was found between the presence (p = 0.15) or number (p = 0.28) of advanced stages of the disease and/or late complications and LTL. Similarly, in a longitudinal analysis, no difference in LTL dynamics was found regarding the presence (p = 0.16) of advanced stage organ involvement and/or late complications or their number. These findings indicate that LTL dynamics in adulthood may not be a reliable indicator of disease outcomes in Fabry patients. Therefore, LTL may more accurately reflect the disease burden in early life, when TL is primarily determined. Full article

Fabry disease (FD) is caused by mutations in the galactosidase alpha (GLA) gene which lead to the accumulation of globotriaosylceramide (Gb-3). Enzyme replacement therapy (ERT) and oral chaperone therapy are the current pharmacological treatments for this condition. However, in the literature, there is a growing emphasis on exploring non-pharmacological therapeutic strategies to improve the quality of life of patients with FD. In particular, the nutritional approach to FD has been marginally addressed in the scientific literature, although specific dietary interventions may be useful for the management of nephropathy and gastrointestinal complications, which are often present in patients with FD. Especially in cases of confirmed diagnosis of irritable bowel syndrome (IBS), a low-FODMAP diet can represent an effective approach to improving intestinal manifestations. Furthermore, it is known that some food components, such as polyphenols, may be able to modulate some pathogenetic mechanisms underlying the disease, such as inflammation and oxidative stress. Therefore, the use of healthy dietary patterns should be encouraged in this patient group. Sports practice can be useful for patients with multi-organ involvement, particularly in cardiovascular, renal, and neurological aspects. Therefore, the aim of this review is to summarize current knowledge on the role of nutrition and physical activity in FD patients. Full article

Between 15–20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease (PAX2: c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant. Full article

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. Full article

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. Full article

Fabry disease (FD) is a rare genetic disorder caused by a deficiency in the α-galactosidase A enzyme, which results in the globotriaosylceramide accumulation in many organs, including the kidneys. Nephropathy is a major FD complication that can progress to end-stage renal disease if not treated early. Although enzyme replacement therapy and chaperone therapy are effective, other treatments such as ACE inhibitors and angiotensin receptor blockers can also provide nephroprotective effects when renal damage is also established. Recently, SGLT2 inhibitors have been approved as innovative drugs for treating chronic kidney disease. Thus, we plan a multicenter observational prospective cohort study to assess the effect of Dapagliflozin, a SGLT2 inhibitor, in FD patients with chronic kidney disease (CKD) stages 1–3. The objectives are to evaluate the effect of Dapagliflozin primarily on albuminuria and secondarily on kidney disease progression and clinical FD stability. Thirdly, any association between SGT2i and cardiac pathology, exercise capacity, kidney and inflammatory biomarkers, quality of life, and psychosocial factors will also be evaluated. The inclusion criteria are age ≥ 18; CKD stages 1–3; and albuminuria despite stable treatment with ERT/Migalastat and ACEi/ARB. The exclusion criteria are immunosuppressive therapy, type 1 diabetes, eGFR < 30 mL/min/1.73 m², and recurrent UTIs. Baseline, 12-month, and 24-month visits will be scheduled to collect demographic, clinical, biochemical, and urinary data. Additionally, an exercise capacity and psychosocial assessment will be performed. The study could provide new insights into using SGLT2 inhibitors for treating kidney manifestations in Fabry disease. Full article

Although rare, hereditary diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Fabry disease (FD) may significantly progress towards severe nephropathy. It is crucial to characterize it accurately, predict the course of the illness and estimate treatment effectiveness. A huge effort has been undertaken to find reliable biomarkers that might be useful for an early prevention of the disease progression and/or any invasive diagnostic procedures. The study of proteomics, or the small peptide composition of a sample, is a field of study under continuous development. Over the past years, several strategies have been created to study and define the proteome of samples from widely varying origins. However, urinary proteomics has become essential for discovering novel biomarkers in kidney disease. Here, the extracellular vesicles in human urine that contain cell-specific marker proteins from every segment of the nephron, offer a source of potentially valuable urinary biomarkers, and may play an essential role in kidney development and kidney disease. This review summarizes the relevant literature investigating the proteomic approaches and potential applications in the regular studies of ADPKD and FD. Full article

Nephropathy is a major Fabry disease complication. Kidney biopsies reveal glomerulosclerosis even in pediatric patients. The main manifestations of Fabry nephropathy include reduced glomerular filtration rate and proteinuria. In 2016, an oral pharmacological Chaperone was approved to treat Fabry patients with “amenable” mutations. Because (i) Fabry disease is a rare disorder that frequently causes kidney damage, and (ii) a new therapeutic is currently available, it is necessary to review wich biomarkers are useful for nephropathy follow-up among Fabry “amenable” patients receiving migalastat. The literature search was conducted in MEDLINE, EMBASE, SCOPUS, Cochrane, and Google academic. Prospective studies in which renal biomarkers were the dependent variable or criterion, with at least 6 months of follow-up, were included. Finally, we recorded relevant information in an ad hoc database and summarized the main results. To date, the main useful biomarker for nephropathy monitoring among Fabry “amenable” patients receiving migalastat is glomerular filtration rate estimated by equations that include serum creatinine. Full article