Exercise intolerance is a common feature of Anderson-Fabry disease (AFD), but its underlying mechanisms remain incompletely understood. We studied eighty-eight patients with classical AFD phenotype and preserved ejection fraction. Patients underwent cardiopulmonary exercise testing (CPET), lactate assessment, and advanced echocardiography including myocardial work and atrial strain analysis. Exercise tolerance was reduced across the cohort, with low peak VO2 measured as percent predicted (VO2

Background/Objectives: The global rise in obesity represents a major public health issue, extending its detrimental impact beyond metabolic complications to encompass renal dysfunction. A key element in this relationship lies in the interaction between visceral obesity and glomerular hyperfiltration—an early, often silent indicator of kidney injury that may precede the onset of chronic kidney disease (CKD). Methods: In this monocentric, retrospective study, we evaluated 43 adults with obesity attending the Outpatient Clinic for Diet Therapy in Transplantation, Renal Failure and Chronic Pathology at the University of Naples Federico II between March 2022 and March 2024. Clinical, anthropometric, biochemical, and 24 h urinary parameters were recorded, along with several validated visceral adiposity indices. Glomerular hyperfiltration was assessed through measured creatinine clearance (mClCr) tertiles, while associations with adiposity indices, proteinuria, and urinary sodium excretion were explored. Results: Higher creatinine clearance values were significantly associated with increased levels of adiposity indices—particularly Lipid Accumulation Product (LAP), New Visceral Adiposity Index (NVAI), and Metabolic Score for Visceral Fat (METS-VF)—as well as greater proteinuria, urinary sodium excretion, and daily salt intake. Subjects with proteinuria ≥ 150 mg/day exhibited higher NVAI values and elevated sodium and potassium urinary excretion compared with those without proteinuria. Significant correlations emerged between LAP and mClCr, sodium excretion, and proteinuria, even after adjustment for age and BMI. Conclusions: Higher visceral adiposity indices were associated with increased creatinine clearance, proteinuria, and urinary sodium excretion in adults with obesity. These findings suggest that visceral adiposity may represent a useful marker of early obesity-related renal alterations. Prospective studies are warranted to determine the causal relationships and mechanisms underlying these associations.

BACKGROUND:Residual proteinuria remains a major determinant of renal disease progression in Fabry disease (FD) despite optimized enzyme replacement or chaperone therapy and maximal renin-angiotensin system (RAS) blockade. Dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonists exert anti-inflammatory, natriuretic, and antifibrotic effects beyond metabolic control. We evaluated the impact of add-on tirzepatide on residual proteinuria in overweight, non-diabetic Fabry patients receiving optimized background therapy. METHODS:In this prospective, proof-of-concept observational study, 15 FD patients with persistent proteinuria ≥ 0.5 g/24 h despite stable disease-specific therapy and maximal tolerated RAS blockade were treated with tirzepatide for 6 months. The primary endpoint was change in 24-hour proteinuria. Secondary endpoints included change in estimated glomerular filtration rate (eGFR), body mass index (BMI), cardiac biomarkers (NT-proBNP, high-sensitivity troponin T), and safety. RESULTS:Tirzepatide is associated with a progressive reduction in proteinuria, which became statistically significant at Month 1 and continued through Month 6 (1.11 ± 0.23 g/24 h at baseline to 0.35 ± 0.19 g/24 h at 6 months; 68.9% reduction; P < 0.001). Two-thirds of patients (66.7%) achieved proteinuria < 0.5 g/24 h. eGFR remained stable throughout the treatment period (P = 0.87). Tirzepatide induced significant weight loss, with BMI decreasing from 29.0 (27.1-29.3) kg/m² at baseline to 24.2 (23.4-25.1) kg/m² at Month 6 (P < 0.001). Beyond the renal effects, cardiac biomarkers also showed significant reductions, with NT-proBNP and high-sensitivity troponin T decreasing by 33.3% (P < 0.01) and 14.3% (P < 0.05), respectively, in the absence of structural echocardiographic changes, that may reflect early modulation of myocardial stress. The drug was well tolerated, with mild gastrointestinal symptoms during initial dose titration and no treatment discontinuations. CONCLUSIONS:Add-on dual GIP/GLP-1 receptor agonism is associated with a reduction in residual proteinuria and showed improvements in cardiac biomarkers in overweight Fabry patients receiving optimized therapy, without affecting eGFR. These findings support a multi-pathway nephroprotective strategy beyond substrate reduction and RAS inhibition.

Heparin-induced thrombocytopenia (HIT) is a life-threatening disorder caused by exposure to heparin and characterized by high morbidity and mortality. It is largely underestimated because of its heterogeneous presentation, ranging from a decrease in platelet count antibody positivity to serious thrombotic complications. Haemodialysis (HD) patients represent a high-risk population due to anticoagulation use during extracorporeal treatments. It usually occurs in the first weeks after the start of HD, although it has been reported in chronic HD patients after surgery procedures. When the diagnosis of HIT is formulated, heparin must be promptly stopped and an alternative anticoagulant has to be started. The aim of this review is to provide a comprehensive overview on the pathogenesis, diagnosis and treatment of HIT in HD in order to increase the awareness of physicians of this important clinical syndrome to promptly start the specific treatment.

BACKGROUND:Fabry disease is a rare X-linked disorder characterized by the accumulation of sphingolipids in various vital systems, leading to multiple organ damage. As previous data showed the association between Fabry disease and parapelvic cysts, the aim of our work was to evaluate the prevalence of GLA variants in patients with parapelvic cysts. METHODS:From November 2022 to September 2024, we conducted a multicenter cohort study on patients referred to 15 Italian Nephrology Units. The prevalence of GLA variants among patients with parapelvic cysts was compared to the prevalence of Fabry disease in newborns and in chronic kidney disease (CKD )patients. RESULTS:Among 306 enrolled patients with parapelvic cysts, we identified seven different variants in the GLA gene in eight patients (4 females, 4 males) (1.3%, 1.3%, respectively): three patients with two different pathogenic variants (2 males, 1 female) (0.65%, 0.32%, respectively), two patients with variants of uncertain significance (VUS) (2 males) (0.65%) and three with benign variants (3 females) (0.98%). The overall prevalence of GLA variants in our population was 2.6%, which is 11-fold higher than in CKD patients not on dialysis (ND) (0.24%), and this difference resulted statistically significant (P <.0001; 11.07, 95%CI: 4.89; 25.06). Our results showed a prevalence of GLA variants 200 times higher compared to Italian newborn screening programs. CONCLUSION:Our study is the first to analyze the prevalence of GLA variants in patients with parapelvic cysts, showing results that are significantly higher compared to CKD-ND patients and the general population. Parapelvic cyst identification, even before clinical manifestations, is crucial for early Fabry disease diagnosis and treatment.

Increased literature support the pathogenetic role of dysfunctional energetic metabolism in the setup and progression of organ damage and failure. Genetic diseases often offer the possibility to investigate pathogenetic mechanisms. In particular, excessive cardiac damage is the most frequent cause of mortality in Fabry disease (FD), a genetic condition caused by deficient α-galactosidase A (GLA) activity, leading to globotriaosylceramide (Gb3) accumulation. Beyond Gb3 storage, metabolic alterations and mitochondrial dysfunction, supported by in vitro evidence or studies in other tissues, may contribute to FD cardiomyopathy. This study investigated, for the first time, the mechanisms of mitochondrial involvement in FD, its role in determining cardiac manifestations, and its potential as a therapeutic target. We used a humanized FD mouse model (R301Q-Tg/GLA knockout), along with derived embryonic fibroblasts and neonatal and adult cardiomyocytes, to assess mitochondrial function across the lifespan. FD cells showed impaired mitophagy, reduced mitochondrial respiration, and increased reactive oxygen species production. Importantly, this mitochondrial dysfunction exacerbated the lysosomal deficit in FD cells, forming a vicious cycle. In cardiomyocytes, these alterations progressed with age, leading to the accumulation of dysfunctional mitochondria, energetic failure, and, in adult hearts, terminal mitochondrial damage and apoptosis. These events ultimately result in cardiac remodeling and dysfunction, including hypertrophy and diastolic impairment. Indeed, L-arginine supplementation, which promotes NO/PGC-1α-dependent mitochondrial rescue, prevented the development of cardiac abnormalities in FD mice. Our findings identify early mitochondrial dysfunction as a key driver of FD cardiomyopathy and support mitochondrial targeting, including L-arginine supplementation, as a promising adjuvant therapeutic strategy. The mechanistic link between lysosomal dysfunction, altered mitochondrial turnover, and energetic collapse emerges as a key targetable pathway in organ damage, extending beyond FD.

OBJECTIVE:Chronic constipation is prevalent in patients undergoing peritoneal dialysis (PD), raising the risk of catheter malfunction and transmural peritonitis. Gut dysbiosis in dialysis patients can worsen constipation. METHODS:A single-arm prospective study was performed to assess the effectiveness of synbiotic (fructo-oligosaccharides and Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus reuteri, and Saccharomyces boulardii) supplementation for 16 weeks in PD patients suffering from chronic constipation. The endpoints were the changes in the constipation scoring system and in laxative use. RESULTS:Out of 106 patients, 76 patients experienced chronic constipation and 70 completed the study. After 16 weeks of synbiotic supplementation, a significant improvement in constipation score was found (-5.3; 95% CI: -5.9/-4.7; P = .001) associated with suspension (36.8%) or reduction (42.1%) of laxatives among baseline users (57/70). The findings were not influenced by age, sex, diabetes, obesity, type of PD, residual diuresis, multidrug therapy, and severe constipation at baseline. CONCLUSIONS:Synbiotic supplementation is associated with constipation relief and reduction in laxatives use.

Background:A treatment for classic Fabry disease (FD) should be defined effective on renal function when it maintains a decline of estimated glomerular filtration rate (eGFR) <1 ml/min/1.73 m2/year, and not effective when the eGFR loss remains ≥3 ml/min/1.73 m2/year. Therefore, considering the evidence of dose-dependent efficacy of the enzyme replacement therapy (ERT) and the data reporting the disease progression after switching form agalsidase beta to migalastat, a switch to higher doses of ERT should be considered in adult Fabry patients who have an eGFR of 45-90 ml/min/1.73 m2, with an eGFR slope ≥3 ml/min/1.73 m2/year. This study aimed to assess the effects of switching to agalsidase beta for renal ineffectiveness of the primary Fabry therapy. Methods:Data retrospectively taken during the pre-switch period were compared with data prospectively collected during the post-switch period. The primary endpoint was the effect on eGFR slope. Secondary endpoints were: changes in clinical events, 24-hour proteinuria, cardiac and neurologic parameters, FD-related symptoms, lyso-Gb3 plasma concentrations, and adverse events. Results:In total, 11 patients (nine males and two females) switched to agalsidase beta from 55.3 ± 31.2 months of primary therapy with agalsidase alfa (eight patients) or migalastat (three patients), were evaluated for a follow-up period of 24 months. After the switch, a significant reduction of the eGFR slope was observed (-4.61 vs -0.45 ml/min/1.73 m2/year, respectively in pre- and post-switch period; P post /pre < .005). After the switch, plasma lyso-Gb3 levels progressively reduced, and the reduction reached the significance vs baseline at T2 (P < .05). Most of FD-related symptoms ameliorated during the primary Fabry therapy and remained stable after the switch. All other parameters were stable over time. Conclusions:Treatment switch from agalsidase alfa or migalastat to agalsidase beta can attenuate eGFR decline and enhance lyso-Gb3 reduction, confirming the dose-dependent effect of agalsidase beta to further slow down FD progression.

Introduction:Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to reduce proteinuria and disease progression in people with chronic kidney disease (CKD), but data in Fabry disease (FD) are scant. This prospective, multicenter study evaluated the 12-month effects of dapagliflozin 10 mg/dL on albuminuria, proteinuria, and renal function in patients with FD and albuminuric CKD. Methods:Adults with FD and albuminuric CKD (estimated glomerular filtration rate [eGFR] ≥ 25 ml/min) despite stable enzyme replacement therapy (ERT) or migalastat and maximally tolerated dose of renin-angiotensin system inhibitors (RAS-i) were included. Proteinuria, urinary albumin-to-creatinine ratio (UACR), eGFR, and blood pressure were assessed 12 months before dapagliflozin initiation (T0), at treatment initiation (T1), and at 12-month follow-up (T2). Results:Sixteen patients were enrolled. After 12 months of dapagliflozin, UACR and 24-hour proteinuria decreased by 47.6% (300.1 [interquartile range, IQR: 106.5-856.1] mg/g [T1] vs. 142.5 [IQR: 60.7-415.7) mg/g [T2]; P = 0.01) and 22.2% (0.45 [IQR: 0.31-1.67] g/d [T1] vs. 0.35 [IQR: 0.18-1.42] g/d [T2]; P < 0.001), respectively. Mixed-effects model analysis confirmed the effect of dapagliflozin on reducing 24-hour proteinuria (P < 0.001), after adjustment for age, sex, eGFR, FD phenotype and ERT/migalastat treatments. eGFR remained stable (63.50 [SD: 25.13] ml/min per 1.73 m2 [T1] vs. 64.31 [SD: 26.40] ml/min per 1.73 m2 [T2]; P = 0.65), contrasting with annual decline (-5.63 [SE: 1.78] ml/min per 1.73 m2) during T0 to T1 period, adjusting for sex, age, FD phenotype, ERT/migalastat treatments and 24-hour proteinuria. Eight out of 9 fast renal progressor patients achieved an annual eGFR slope ≤ 3 ml/min during the T1 to T2 period. Conclusion:this preliminary evidence shows that dapagliflozin was associated with reduction in albuminuria, proteinuria, and eGFR decline in patients with FD and albuminuric CKD receiving ERT or migalastat and RAS-i over 12 months.

INTRODUCTION:Atheroembolic kidney disease (AEKD) is an under-recognized cause of kidney failure, secondary to the obstruction of the renal artery and/or its branches due to the rupture of an unstable atherosclerotic plaque in patients treated with surgical and invasive cardiovascular procedures. The embolization of cholesterol crystals in the renal artery activates the complement and triggers an inflammatory reaction. Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by the hyperactivation of the alternative complement pathway, leading to a prothrombotic and proinflammatory state on the endothelial surface. AEKD and aHUS could share the involvement of the complement in their pathophysiological mechanism and the former could lead to the latter. CASE PRESENTATION:A 72-year-old man was referred to our clinic because of a rapid worsening of renal function after 9 months from an endovascular aortic repair (EVAR). After 4 months from the intervention, his renal function worsened, he developed hypereosinophilia and skin lesions; the renal ultrasound showed increased resistance indexes, strongly suggestive of atheroembolic kidney disease. Successively, we observed thrombocytopenia, anemia, increased LDH, low plasmatic haptoglobin, schistocytes in blood smear, and normal ADAMTS13. We promptly diagnosed an atypical hemolytic uremic syndrome and started ravulizumab. CONCLUSION:To our knowledge, this is the first case of aHUS secondary to a subacute AEKD. Further studies are necessary to fill the gap in the knowledge of the precise mechanism leading to aHUS secondary to AEKD and to confirm that they are two sides of the same coin.