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.

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disease having a prevalence of 1:400–1000 live births. Depending on kidney imaging, patients can be subdivided into Class 1 (typical) and Class 2 (atypical). The present study aims to provide better assessment of Class 2 patients to help define their family history, together with their clinical and radiological characteristics. Methods: One hundred twenty-four PKD patients with abdominal Magnetic Resonance Imaging (MRI) for the staging of ADPKD, were retrospectively analyzed, aiming to focus on Class 2 ADPKD patients. Total kidney volume and total cyst volume were evaluated, while also assessing their clinical and genetic characteristics. Results: Twelve patients fulfilled the Mayo criteria for Class 2 ADPKD (two Class 2B and ten Class 2A). Extrarenal involvement was observed in 66.7% of cases, but only two subjects presented an estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m ² . A positive family history for cystic disease was more frequent compared to other published cohorts. Only 8.3% tested positive for a likely pathogenic mutation in the PKD 1 gene. Class 2B patients showed a lower height-adjusted total kidney volume, with a lower percentage of total cyst volume. Conclusion: Based on our results, atypical ADPKD does not represent an uncommon condition, being present in about 10% of MRI-evaluated patients diagnosed with ADPKD. Genetic tests are frequently negative for PKD1/PKD2 , and total cyst volume and residual tissue volume do not increase the prognostic value of MRI in patients with these radiological characteristics. Other tools are needed to better characterize their kidney prognosis. Graphical

Lupus nephritis (LN) represents one of the most severe manifestations of systemic lupus erythematosus. Despite major advances in the therapeutical armamentarium over the last two decades, the number of patients reaching end-stage kidney disease or dying has not changed significantly. One of the main reasons is that many patients relapse, and with each relapse, further damage is done to the kidney, contributing to the development of progressive chronic kidney disease. This has led to the increased practice of doing protocol biopsies to guide the decision regarding risk of relapses and/or discontinuation of immunosuppression. However, this practice has been based on the assumption that the answer is in the kidney, while in reality the kidney reflects the downstream effect of what is going on upstream, i.e. the immunological milieu. We provide an in-depth review of the use of repeat protocol kidney biopsies in LN with the hope of demonstrating that this practice is based on faulty evidence and is of limited benefit in the management of patients with proliferative class III/IV LN. Rather, physicians treating these patients should focus on markers of immunological activity (anti-dsDNA levels) and clinical activity (C3/C4 complement levels) to better predict risk for relapses and to decide when to reduce/discontinue immunosuppression. As such, this review represents a paradigm shift in the approach of evaluating activity in patients with LN, which is not done by performing protocol kidney biopsies but rather by looking at the serological activity, and as such proposes new insight into the subject that we believe will improve patient care and kidney outcomes.

Background: Sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, has demonstrated antiproteinuric efficacy in randomized trials of IgA nephropathy (IgAN). However, real-world data on treatment response and predictors remain limited. We evaluated longitudinal proteinuria response, kidney function trajectories, and predictors of treatment response over the first year of sparsentan therapy in routine practice. Methods: In this single-center observational study, 38 adults with biopsy-proven IgAN were evaluated at baseline, 3, 6, 9, and 12 months after sparsentan initiation. Predictors of response, defined as ≥50% proteinuria reduction with ≤15% decline in estimated glomerular filtration rate (eGFR), were evaluated at the 9-month landmark analysis using logistic regression. Longitudinal proteinuria and eGFR trajectories were analyzed using linear mixed models. Results: Sparsentan was associated with sustained proteinuria reduction across patient subgroups. In mixed-effects models, proteinuria declined by ∼8% per month, while the annualized eGFR slope was −2.5 ml/min/1.73 m2/year. At the 9-month landmark analysis, baseline hematuria [odds ratio (OR) 10.00; 95% confidence interval (CI) 1.28–78.12; P = .028] and higher systolic blood pressure (sBP) (OR 4.30; 95% CI 1.02–18.10; P = .047) were associated with higher odds of response. Sparsentan was generally well tolerated, with discontinuation in 10.5% of patients, including two cases of reversible liver enzyme elevation. Conclusion: In routine practice, sparsentan was associated with sustained antiproteinuric effects with relatively stable kidney function trajectories despite advanced baseline disease. Exploratory analysis identified baseline hematuria and sBP as potential markers of treatment response; however, these findings require validation in larger prospective cohorts.