Key Points: The Mayo clinic imaging classification and the predicting renal outcome in polycystic kidney disease score are used to assess the risk of progression to kidney failure in autosomal dominant polycystic kidney disease. Mayo imaging classification and predicting renal outcome in polycystic kidney disease show little concordance; combined use increased the ability to identify rapid progression especially among intermediate risk patients. Accurate risk prediction is key for determining indication for specific treatment. Background: Autosomal dominant polycystic kidney disease is the most common genetic cause of kidney failure. Specific treatment is indicated on observed or predicted rapid progression. For the latter, risk stratification tools have been developed independently based on either total kidney volume or genotyping as well as clinical variables. This study aimed to improve risk prediction by combining both imaging and clinical-genetic scores. Methods: We conducted a retrospective multicenter cohort study of 468 patients diagnosed with autosomal dominant polycystic kidney disease. Clinical, imaging, and genetic data were analyzed for risk prediction. We defined rapid disease progression as an eGFR slope ≥3 ml/min per 1.73 m² per year over 2 years, Mayo imaging classification (MIC) 1D–1E, or a predicting renal outcome in polycystic kidney disease (PROPKD) score of ≥7 points. Using MIC, PROPKD, and rare exome variant ensemble learner scores, several combined models were designed to develop a new classification with improved risk stratification. Primary endpoints were the development of advanced CKD stages G4–G5, longitudinal changes in eGFR, and clinical variables such as hypertension or urological events. Statistically, logistic regression, survival, receiver operating characteristic analyses, linear mixed models, and Cox proportional hazards models were used. Results: PKD1-genotype (P < 0.001), MIC class 1E (P < 0.001), early-onset hypertension (P < 0.001), and early-onset urological events (P = 0.003) correlated best with rapid progression in multivariable analysis. While the MIC showed satisfactory specificity (77%), the PROPKD was more sensitive (59%). Among individuals with an intermediate risk in one of the scores, integration of the other score (combined scoring) allowed for more accurate stratification. Conclusions: The combined use of both risk scores was associated with higher ability to identify rapid progressors and resulted in a better stratification, notably among intermediate risk patients.

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.

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.

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

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, affecting approximately 1 in 1000 individuals. This genetically heterogeneous condition is primarily caused by monoallelic pathogenic or likely pathogenic variants in the PKD1 and PKD2 genes, accounting for 78% and 15% of typical cases, respectively. Recently, the application of NGS methods has led to the identification of additional genes associated with ADPKD, which have been incorporated into routine diagnostic testing for detecting phenocopies of the disease. Methods: In this study, targeted NGS (tNGS) analysis of the main cystogenes associated with classic and atypical ADPKD was performed in a cohort of 218 patients clinically diagnosed with cystic nephropathies. Results: Genetic testing identified variants in 175 out of 218 cases (80.3%). Among these, 133 probands (76%) harbored likely pathogenic or pathogenic variants in one or more genes of the panel, while 42 individuals (24%) had a variant of unknown significance (VUS). Specifically, one or more class 4/5 variants in PKD1, PKD2, or both were identified in 111 (83.5%) probands. Remarkably, a pathogenic variant in the IFT140 gene was identified in 14 index cases (8% of positive individuals, 6.4% of the global cohort): 10 distinct loss-of-function (LoF) variants were identified (including four frameshift variants, four nonsense variants, and two splice site defects); one individual carried a second IFT140 missense variant classified as VUS. Furthermore, five affected family members were found to carry a P/LP LoF variant in IFT140. Conclusions: Our data support that IFT140 heterozygous IFT140 LoF variants result in an atypical, mild form of ADPKD, consisting of bilateral kidney cysts and renal functional decline at older ages. Furthermore, we describe the second pediatric patient with a mild form of ADPKD due to an IFT140 variant and discuss hyperuricemia as a previously unappreciated feature of this condition.

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