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Fabry Disease (FD) is a genetic disease caused by a deficiency in the activity of lysosomal galactosidase A (α-GalA), an enzyme responsible for the catabolism of globotriaosylceramide (Gb3). Since lysosomes are present throughout the body and play a crucial role in catabolism and recycling of cytosolic compounds, FD can affect multiple organs and result in various symptoms, including renal, cardiovascular, neurological, cutaneous, and ophthalmic manifestations. Due to the nonspecific symptoms and the rarity of FD, it is often diagnosed late in life. However, introducing targeted therapies such as enzyme replacement therapy (ERT) and chaperone therapy has significantly improved FD's natural history and prognosis by restoring α-GalA enzyme activity. Despite the advancements, there are limitations to the currently available therapies, which has prompted research into new potential treatments for FD, including alternative forms of enzyme replacement therapy, substrate reduction therapy, mRNA therapy, and genetic therapy. In this review, we analyze the epidemiology, pathophysiology, and treatment of FD, with particular emphasis on promising therapeutic opportunities that could shift the treatment of this rare disease from a standardized to a personalized approach soon. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is a rare X‐linked lysosomal storage disorder caused by variants in GLA gene leading to deficient α‐galactosidase A enzyme activity. This deficiency leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in various tissues and organs, which can result in life‐threatening complications. The clinical presentation of the disease can vary from the "classic" phenotype with pediatric onset and multi‐organ involvement to the "later‐onset" phenotype, which presents with predominantly cardiac symptoms. In recent years, advances in screening studies have led to the identification of an increasing number of variants of unknown significance that have not yet been described, and whose pathogenic role remains undetermined. Methods: In this clinical report, we describe the case of an asymptomatic adult female who was found to have a new variant of unknown significance, p.Met70Val. Given the unknown pathogenic role of this variant, a thorough analysis of the potential organ involvement was conducted. The clinical data were analyzed retrospectively. Results: The analysis revealed that there were no signs of significant organ involvement, and the benignity of the variant was confirmed. Conclusion: This case underscores the importance of a comprehensive evaluation of new variants of unknown significance to establish their pathogenicity accurately. [ABSTRACT FROM AUTHOR]

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature. [ABSTRACT FROM AUTHOR]

Autosomal polycystic kidney disease is the most common inherited kidney disease determining 5% of all end-stage kidney disease. The only therapy approved for this condition is Tolvaptan, which, with its aquaretic effect, has a strong effect on patients' daily life. Recently, the literature has been enriched with new works that analyze possible non-pharmacological therapeutic strategies to slow cysts' enlargement and chronic kidney disease progression. Among them, dietary schemes reducing carbohydrate intake and inducing ketoses have been demonstrated to have efficacy in several pre-clinical and clinical studies. A ketogenic diet, calorie restriction, intermittent fasting, and time-restricted feeding can reduce aerobic glycolysis and inhibit the mTOR pathway, producing a reduction in cyst cell proliferation, a reduction in kidney volume, and helping to preserve kidney function. ADPKD's burden of disease has an impact on patients' quality of life, and the possibility to play sports or carry out physical exercise can help people in everyday life. The multisystemic character of the disease, especially cardiovascular involvement, needs to be carefully evaluated to establish the quality and quantity of physical activity that patients can safely carry out. [ABSTRACT FROM AUTHOR]

Introduction: Proteinuria is a major risk factor for the progression of chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated a nephroprotective and antiproteinuric effect in people with type 2 diabetes (T2DM) and proteinuric CKD. We conducted a retrospective study to evaluate clinical and laboratory variables that can help predict proteinuria reduction with SGLT2i therapy. Materials and methods: Patients affected by T2DM and CKD who started any SGLT2i were included in the study. Patients were stratified into two subgroups, Responder (R) and non-Responder (nR), based upon the response to the therapy with SGLT2i, namely the reduction in a 24 h urine proteins test (uProt) of ≥30% from baseline levels. The aim of the study is to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria reduction. A Kruskal–Wallis test, unpaired t-test and Chi2 test were used to test the difference in means and the percentage (%) between the two groups. Linear and logistic regressions were utilized to analyse the relationship between proteinuria reduction and basal characteristics. Results: A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. R's patients had a significant higher uProt at baseline (1393 vs. 449 mg/24 h, p = 0.010). There was a significant correlation between baseline uProt and proteinuria reduction with SGLT2i in both univariate (β = −0.43, CI −0.55 to −031; p < 0.001) and multivariate analyses (β = −0.46, CI −0.57 to −0.35, p < 0.001). In the multivariate analysis, there was a significant positive correlation between the estimated glomerular filtration rate (eGFR) and proteinuria reduction (β = −17, CI −31 to −3.3, p = 0.016) and a significant negative correlation with body mass index (BMI) (β = 81, CI 13 to 50, p = 0.021). The multivariate logistic regressions show a positive correlation of being in the R group with diabetic retinopathy at baseline (Odds Ratio (OR) 3.65, CI 0.97 to 13.58, p = 0.054), while the presence of cardiovascular disease (CVD) at baseline is associated with being in the nR group (OR 0.34, CI 0.09 to 1.22, p = 0.1), even if these statements did not reach statistical significance. Conclusions: In this real-life experience, following the administration of SGLT2i, a reduction of more than 30% in proteinuria was observed in more than half of the patients, and these patients had a significantly higher baseline proteinuria value. Variables such as eGFR and BMI are variables that, considered in conjunction with proteinuria, can help predict treatment response before therapy initiation. Different phenotypes of diabetic kidney disease may have an impact on the antiproteinuric response. [ABSTRACT FROM AUTHOR]

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) may require specific therapy with vasopressin receptor antagonists to slow the progression of renal disease. Because of its mechanism of action, the most common side effects are polyuria, nocturia, and polydipsia. Elevations of liver enzyme levels can also occur during treatment with Tolvaptan. Temporary drug withdrawal may be indicated if the patient is unable to hydrate adequately or if there are concomitant causes of dehydration, including major infectious events. During the Coronavirus Disease 2019 (COVID-19) pandemic, this should be considered in the management of patients on Tolvaptan therapy. Case Report: We present the clinical case of a 51-year-old male with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and ADPKD receiving Tolvaptan therapy with particular reference to the medical management of the patient during the infectious event. The patient was instructed to discontinue promptly Tolvaptan as soon as symptoms appeared. He was treated with forced hydration and symptomatic therapy. Nevertheless, a transient elevation of liver enzyme levels was detected. The timely discontinuation of Tolvaptan therapy avoided the risk of potential hepatotoxicity in a condition of known susceptibility. Conclusion: Tolvaptan therapy of patients with ADPKD is safe even during SARS-CoV-2 infection. There is need for appropriate and prompt patient counseling to avoid potentially adverse side effects. [ABSTRACT FROM AUTHOR]

Background/Aim: Acute kidney injury is an important cause of mortality in very-low-birth-weight (VLBW) preterm infants. As in the general population, the detection of renal damage cannot rely on the measurement of serum creatinine, since it has been demonstrated to be a weak predictor and a delayed indicator of kidney function deterioration. However, several candidate biomarkers have failed to prove sufficient specificity and sensitivity for a routine clinical use because of the poor awareness of their biological role. This study was aimed to investigate the impact of different maternal and neonatal conditions on several renal biomarkers in VLBW preterm infants during the first week of life. Patients and Methods: Preterm infants<32 weeks' gestation and <1500g were enrolled. We measured urinary biomarkers kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, epidermal growth factor (EGF) and osteopontin (OPN) on the 1st, 3rd, and 7th day after birth. Results: Thirty-tree infants were included. The multivariate analysis showed a significant association between gestational age, the presence of patent ductus arteriosus, antenatal maternal hypertension and the levels of urinary biomarkers. Conclusion: There is a possible relation between early biomarkers of renal injury and antenatal, perinatal and post-natal characteristics in VLBW preterm infants during the first week of life. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury, known as a major trigger for organ fibrosis and independent predictor of chronic kidney disease, is characterized by mesangial cell proliferation, inflammation and unbalance between biosynthesis and degradation of extracellular matrix. Therapeutic approaches targeting the inhibition of mesangial cell proliferation and matrix expansion may represent a promising opportunity for the treatment of kidney injury. An ester of hyaluronic acid and butyric acid (HB) has shown vasculogenic and regenerative properties in renal ischemic-damaged tissues, resulting in enhanced function recovery and minor degree of inflammation in vivo. This study evaluated the effect of HB treatment in mesangial cell cultures exposed to H2O2-induced oxidative stress. Materials and methods: Lactate dehydrogenase release and caspase-3 activation were measured using mesangial cells prepared from rat kidneys to assess necrosis and apoptosis. Akt and p38 phosphorylation was analyzed to identify the possible mechanism underlying cell response to HB treatment. The relative expressions of matrix metallopeptidase 9 (MPP-9) and collagen type 1 alpha genes were also analyzed by quantitative real-time polymerase chain reaction. Cell proliferation rate and viability were measured using thiazolyl blue assay and flow cytometry analysis of cell cycle with propidium iodide. Results: HB treatment promoted apoptosis of mesangial cells after H2O2-induced damage, decreased cellular proliferation and activated p38 pathway, increasing expression of its target gene MPP-9. Conclusion: This in vitro model shows that HB treatment seems to redirect mesangial cells toward apoptosis after oxidative damage and to reduce cell proliferation through p38 MAPK pathway activation and upregulation of MPP-9 gene expression involved in mesangial matrix remodeling. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was the application of complementarity-determining region-3 spectratyping analysis to determine T-cell-repertoire complexity and to detect T-cellclone expansion, as a measure of immune response in nonfunctioning kidney transplants (group hemodialysis-transplant [HD-Tx]), nontransplanted dialysis patients (group hemodialysis [HD]), and normal subjects as controls (group C). Patients and methods: Analysis of T-cell receptor (TCR) diversity by spectratyping was applied to peripheral blood samples collected from 21 subjects: eight in group HD-Tx, seven in group HD, and six in group C. Results: Considering the extent of the skew in TCR variable region repertoires as a measure of clonal T cells, we found that the number of altered spectra showed a progressive increase from normal subjects to dialysis patients and to nonfunctioning kidney transplants, respectively. Healthy subjects had the lowest number of altered spectra, and patients with nonfunctioning kidney transplants the highest. Differences were significant for group HD-Tx vs group C (P=0.017) and group HD vs group C (P=0.015), but not between nonfunctioning kidney-transplant recipients and dialysis patients (group HD-Tx vs group HD). Conclusion: Although dialysis appears to be a weaker trigger for clonal expansion of T cells, our data suggest that the utilization of complementarity-determining region-3 spectratyping analysis of the TCR repertoire might be useful to monitor specific immunoactivation in patients before and after kidney transplantation. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by diffuse mesangial deposition of IgM. IgM nephropathy has been a controversial diagnosis since it was first reported, and there are few data identifying specific pathological features that predict the risk of progression of renal disease. Methods: We identified 57 cases of IgM nephropathy among 3220 adults undergoing renal biopsy at our institution. Biopsies had to satisfy the following three criteria to meet the definition of IgMnephropathy in this study: (i) dominant mesangial staining for IgM, (ii) mesangial deposits on electron microscopy (EM) and (iii) exclusion of systemic disease. Results: The median age was 42 years and 24 patients were male. Thirty-nine per cent of patients presented with the nephrotic syndrome, 49% presented with non-nephrotic proteinuria and 39% had eGFR <60 mL/min. The median post-biopsy follow-up was 40 months and serum creatinine had doubled in 31% by 5 years. Of histological parameters, glomerular sclerosis and tubular atrophy, but not mesangial proliferation, were risk factors for renal insufficiency. Thirty-nine per cent of nephrotic patients achieved complete remission, and outcome was significantly worse in those who did not respond to treatment. Focal segmental glomerulosclerosis was diagnosed in 80% of those undergoing repeat renal biopsy, despite ongoing mesangial IgM deposition. Conclusions: We propose criteria for a consensus definition of IgMnephropathy. [ABSTRACT FROM AUTHOR]