Search Results (88)

Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS. Full article

Steroid-resistant nephrotic syndrome (SRNS) in childhood frequently reflects monogenic podocytopathies in which immunosuppression is ineffective. Biallelic variants in MYO1E, encoding the class I myosin Myo1E, cause a distinctive form of focal segmental glomerulosclerosis (FSGS) often accompanied by “Alport-like” multilamination of the glomerular basement membrane (GBM). Early recognition has therapeutic and prognostic implications. A previously healthy 4-year-old boy presented with generalized edema and nephrotic-range proteinuria. Glucocorticoids induced no remission; sequential calcineurin inhibition (cyclosporine, then tacrolimus) and a single dose of ofatumumab yielded only transient, partial reductions in proteinuria. A first biopsy elsewhere showed FSGS with nonspecific IgM/C3 trapping; electron microscopy (EM) was not performed. At age 10, repeat biopsy with EM revealed ~30% segmental foot-process effacement, focal GBM thickening (to 1740 nm), irregular lamina densa multilamination, and lamellar duplications without immune-complex deposits—features highly suggestive of hereditary GBM disease. Targeted sequencing identified compound-heterozygous MYO1E variants segregating in trans: a canonical splice-donor change (c.2785+1G>A) and a frameshift (c.3094_3097del; p.Thr1032Profs*73). Each parent was an unaffected heterozygous carrier; the sibling was negative. Supportive therapy with ramipril was continued. At last follow-up (January 2025), renal function was normal (serum creatinine 0.5 mg/dL; creatinine clearance 122 mL/min) with stable sub-nephrotic proteinuria (0.52 g/day; 16 mg/m² per hour) and normotension. This case broadens clinicopathologic recognition of MYO1E-associated nephropathy and highlights the teaching point that Alport-like GBM changes are not pathognomonic for type IV collagen disorders but may signal defects in podocyte cytoskeletal anchoring. Full article

One of the key pathological features of Diabetic Kidney Disease (DKD) progression is the accumulation of extracellular matrix (ECM) proteins in kidneys, leading to thickening of the glomerular and tubular basement membranes, subsequently resulting in mesangial expansion, sclerosis, and tubulointerstitial fibrosis. Given the high prevalence of DKD among both T2DM and T1DM patients, as well as the complexity of its underlying molecular mechanisms, this study provides a comparative analysis of published urinary proteomics datasets in DKD (n = 4). By integrating these data with published tissue proteomics (n = 2) and published transcriptomics datasets (n = 5), the study further aims to link urinary findings to tissue pathophysiology. Through integrative proteomic and transcriptomic analysis, DKD was associated with distinct alterations in the urinary proteome, particularly involving proteins related to ECM turnover. Using multiple validation datasets, several upregulated proteins with potential biological significance were identified, including annexins, collagens, cathepsins, and glycoproteins. Overall, our findings underscore the critical role of ECM remodeling in DKD progression and further validation could open new avenues for biomarker development and targeted therapy in early stages of DKD. Full article

Kidney toxicity remains a major dose-limiting complication of radiation therapy and platinum-based chemotherapy, yet the molecular determinants of renal susceptibility and resilience to these genotoxic treatments are incompletely understood. Podocytes are particularly vulnerable to such insults, and emerging evidence implicates lipid dysregulation in podocyte injury. This study investigated the role of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a podocyte-enriched lipid-modulating enzyme, in radiation- and cisplatin-induced nephrotoxicity. Using a doxycycline-inducible, podocyte-specific SMPDL3B transgenic mouse model, renal injury was assessed following focal kidney irradiation, cisplatin administration, or their combination through functional assays, histopathology, ultrastructural analysis, immunofluorescence, and targeted lipidomics. Combined radiation and cisplatin exposure markedly reduced podocyte SMPDL3B expression, accompanied by podocyte depletion, glomerular basement membrane remodeling, proteinuria, and impaired renal function. These structural and functional abnormalities were associated with the selective accumulation of long-chain ceramide-1-phosphate species. In contrast, podocyte-specific induction of SMPDL3B preserved glomerular architecture, maintained renal function, and prevented pathological ceramide-1-phosphate elevation. Collectively, these findings identify SMPDL3B as a key regulator of podocyte stability and lipid homeostasis during chemoradiation stress. Enhancing SMPDL3B activity may represent a mechanistically grounded strategy to mitigate treatment-induced kidney injury while preserving anticancer efficacy. Full article

Background/Objectives: Transmission electron microscopy (TEM) is an essential tool for diagnosing renal diseases. It produces high-resolution visualization of glomerular and mesangial ultrastructural features. However, manual interpretation of TEM images is labor-intensive and prone to interobserver variability. In this study, we introduced and evaluated deep learning architectures based on YOLOv8-OBB for automated detection of six ultrastructural features in kidney biopsy TEM images: glomerular basement membrane, mesangial folds, mesangial deposits, normal podocytes, podocytopathy, and subepithelial deposits. Methods: Building on our previous work, we propose a modified YOLOv8-OBB architecture that incorporates three major refinements: a grayscale input channel, a high-resolution P2 feature pyramid with refinement blocks (FPRbl), and a four-branch oriented detection head designed to detect small-to-large structures at multiple image scales (feature-map strides of 4, 8, 16, and 32 pixels). We compared two pretrained variants: our previous YOLOv8-OBB model developed with a grayscale input channel (GSch) and four additional feature-extraction layers (4FExL) (Pretrained + GSch + 4FExL) and the newly developed (Pretrained + FPRbl). Results: Quantitative assessment showed that our previously developed model (Pretrained + GSch + 4FExL) achieved an F1-score of 0.93 and mAP@0.5 of 0.953, while the (Pretrained + FPRbl) model developed in this study achieved an F1-score of 0.92 and mAP@0.5 of 0.941, demonstrating strong and clinically meaningful performance for both approaches. Qualitative assessment based on expert visual inspection of predicted bounding boxes revealed complementary strengths: (Pretrained + GSch + 4FExL) exhibited higher recall for subtle or infrequent findings, whereas (Pretrained + FPRbl) produced cleaner bounding boxes with higher-confidence predictions. Conclusions: This study presents how targeted architectural refinements in YOLOv8-OBB can enhance the detection of small, low-contrast, and variably oriented ultrastructural features in renal TEM images. Evaluating these refinements and translating them into a web-based platform (Renal-AI) showed the clinical applicability of deep learning-based tools for improving diagnostic efficiency and reducing interpretive variability in kidney pathology. Full article

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

Τargeted genetic sequencing in a 6-year-old with steroid-resistant nephrotic syndrome and biopsy findings of focal segmental glomerulosclerosis (FSGS) revealed a novel COL4A3 pathogenic variant (p.Arg341His). Combined with electron microscopy findings of glomerular basement membrane abnormality, this led to a diagnosis of type IV collagen-related nephropathy. This case underscores the benefit of early genetic testing in presumed FSGS for prognosis and avoiding unnecessary immunosuppression in pediatric nephrotic syndrome. Full article

The cause of nephrotic–nephritic syndrome and elevated blood pressure values was investigated by renal biopsy in a 72-year-old Caucasian male with B-cell chronic lymphocytic leukemia (B-CLL) and a low level of IgG/lambda paraprotein. Double-contoured glomerular capillaries, glomerular thrombi, interstitial B-CLL infiltrates, and normal-looking arteries and arterioles were observed histologically. The glomerular capillaries displayed nonspecific entrapment of IgM and C3 and pseudolinear C4d positivity immunohistochemically. With electron microscopy, diffusely effaced foot processes, widened and duplicated glomerular basement membrane (BM), mesangial cell interposition, and thickened, non-fenestrated, and serrated endothelial cells located on subendothelial BM layer(s) were seen. The peritubular capillaries lacked any significant BM multilayering. Chronic glomerular thrombotic microangiopathy (TMA) was diagnosed; the C4d positivity result indicated structural remodeling of glomerular capillary walls. Laboratory features of microangiopathic hemolytic anemia were absent. The functional complement assay found selective classical pathway activation and the consumption of early complement components. The components of the alternative pathway were not consumed. A disease-causing variant in the coding region of the complement C2 gene was screened, with negative results. The kidney function gradually deteriorated to stage 4 chronic kidney disease over a period of six months. Second-line treatment with ibrutinib markedly decreased the leukemic symptoms, stopped the production of paraprotein, and eliminated the nephrotic syndrome; the kidney function improved. The decreased activity of the classical pathway remained unchanged. The culprit of glomerular anomalies seemed to be the paraprotein, which acted as a nephrotoxic mediator and triggered glomerular TMA. A hypothetical pathophysiologic explanation of TMA is presented. The paraneoplastic classical pathway activation of complement did not play any role in the development of glomerular TMA. Full article

Recurrence of the original glomerular disease (GN) poses a significant threat to kidney transplant function and longevity. The probability and severity of this recurrence vary, with C3 glomerulopathy and certain forms of FSGS exhibiting particularly high rates. Kidney transplant GN recurrence risk hinges on the characteristics of the initial GN, recipient/donor genetics, recipient age, donor type, end-stage kidney disease (ESRD) progression rate, and proteinuria levels. Standard immunosuppression has limited efficacy in preventing primary disease recurrence; however, agent selection and induction therapy can influence the risk for specific GNs. Diagnosing recurrent GN involves a comprehensive approach, including clinical evaluation, laboratory tests (such as proteinuria, hematuria, and specific biomarkers like anti-PLA2R for membranous nephropathy or complement for C3G), and, critically, an allograft biopsy analyzed with light, immunofluorescence, and electron microscopy. Treatment strategies are evolving towards targeted therapies, such as rituximab for antibody-mediated GN and complement inhibitors for C3G, moving away from broad immunosuppression. This narrative literature review provides practical monitoring algorithms for post-transplant settings, synthesizing information on the incidence, predictors, diagnostic strategies, and therapeutic options for various glomerular disease subtypes. The methodology involved searching MEDLINE, Embase, and Cochrane databases from 1996 to 2025, prioritizing systematic reviews, cohort studies, registries, and interventional reports. Eligibility criteria included adult transplant recipients and English-language reports on recurrent glomerular disease outcomes, excluding most single-patient case reports. Limitations include potential selection bias, omission of relevant studies, and the absence of a formal risk-of-bias assessment or meta-analysis. The evidence base is heterogeneous, with inconsistent outcome reporting and scarce randomized controlled trials. Future efforts should focus on developing predictive biomarkers, standardizing diagnostic and response criteria, conducting multicenter prospective cohorts and pragmatic trials, and creating shared registries with harmonized data. Full article

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus that is associated with long-term morbidity and mortality. Pathomorphological findings of LN are broadly divided into proliferative lupus nephritis (PLN) and membranous lupus nephritis (MLN). PLN is characterized by diffuse global or segmental proliferative glomerulonephritis with significant infiltration of inflammatory cells. Type 1 T-helper (Th1) cells, which predominate under inflammatory conditions, and NETosis, as the process of forming neutrophil extracellular traps (NETs), are key factors in the development of PLN. Meanwhile, MLN is characterized by diffuse membranous nephropathy (MN) with global granular subepithelial immune deposits. MLN patients usually experience massive proteinuria, and occasionally show an unfavorable renal prognosis despite aggressive treatment, similar to PLN patients. Intriguingly, in some instances, MLN patients do not show the general immunoserological characteristics of SLE, such as low serum complement and elevated anti-DNA antibody titers. Several reports have indicated an association between Th2 cell dominance and the development of MLN. Moreover, exostosin 1 (EXT1) and exostosin 2 (EXT2) on the glomerular basement membrane have recently been discovered as novel putative antigens for secondary MN, and have been shown to be up-regulated in patients with MLN. To date, many studies have focused on the dissimilarities between PLN and MLN. However, the reason for two polar morphological forms existing within the same disease is not completely clear. The present review addresses published observations on this topic in addition to providing our assertion regarding characteristic NETosis and glomerular EXT1/EXT2 expressions between PLN and MLN. Full article

Background/Objectives: Although essential for oxygen transport and DNA synthesis, excess iron is toxic and can damage organs such as the kidneys. Research has shown that iron overload induces kidney injury, and aging contributes to kidney dysfunction through functional and structural changes. The interaction between iron overload and aging remains poorly understood. Therefore, this study investigated their combined effects on renal microstructure and function using an iron-dextran-injected mouse model. Methods: Young and old mice were divided into control and iron overload groups, renal function was evaluated by serum creatinine and albuminuria, and urinary iron excretion was also measured to assess iron handling. The structural changes were assessed using histological analysis and electron microscopy. Results: Although the iron overload groups had similar blood iron levels, the old iron overload group exhibited significantly higher levels of albuminuria, urinary iron excretion, and serum creatinine compared with the young group. In the iron overload model, histological and ultrastructural analyses demonstrated iron accumulation in mesangial and endothelial cells, glomerular basement membrane thickening, and foot process widening, which were more pronounced in aged mice, suggesting that aging exacerbates iron-induced kidney injury. Conclusions: These findings demonstrate that aging increases susceptibility to iron-induced kidney injury, as shown by the accelerated glomerular injury observed in iron-overloaded aged mice. Therefore, elucidating the effects of aging on iron metabolism may contribute to identifying approaches for reducing age-associated renal injury. Full article

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransferase deficiency with two clinical variants (fish-eye Disease and the p.Leu364Pro mutation), lead to NS through mechanisms involving podocyte and lipid metabolism dysfunction. Congenital disorders of glycosylation and Nail–Patella Syndrome emphasize the role of deranged protein processing and transcriptional regulation in glomerular injury. The link of NS with type 1 diabetes, though rare, suggests an etiology on the basis of common HLA loci and immune dysregulation. Histopathological analysis, particularly electron microscopy, shows mainly podocyte damage, mesangial sclerosis, and alteration of the basement membrane, which aids in differentiating rare forms. Prompt recognition of these novel etiologies by genetic analysis, renal biopsy, and an interdisciplinary panel is essential to avoid delays in diagnosis and tailored treatment. Full article

Pathogenic variants in type IV collagen genes (COL4A3, COL4A4, COL4A5) are classically associated with Alport syndrome (AS), a hereditary nephropathy primarily affecting the glomerular basement membrane (GBM). Recent findings, however, suggest a broader phenotypic spectrum that includes renal cyst formation, raising questions about overlapping mechanisms with other cystic kidney diseases. Clinically, renal cysts have been increasingly reported in patients with autosomal dominant and X-linked forms of Alport syndrome, particularly in association with glycine missense variants. The most recent studies focusing on the cystic phenotype in Alport syndrome provide growing support for the idea that variants in type IV collagen genes are associated with an increased likelihood of developing renal cysts, likely through mechanisms involving the structural integrity of renal basement membranes. In this review, we explore evidence from murine models and human studies indicating defects in collagen IV and discuss their contribution to cystogenesis. These observations underscore the need for broader genetic screening strategies and further investigation into the molecular mechanisms underlying this emerging phenotype. Full article

Primary membranous nephropathy is a leading cause of nephrotic syndrome in adults, characterized by immune complex deposition in the glomerular basement membrane. Predicting proteinuria remission is essential for guiding treatment decisions, optimizing immunosuppressive therapy, and improving renal outcomes. Traditional prognostic markers, such as anti-PLA2R antibody status and baseline proteinuria levels, offer valuable insights into disease progression. However, recent research has identified additional biomarkers that may enhance risk stratification and refine individualized treatment strategies. Serum-based markers, such as uric acid and inflammatory indices, may indicate systemic changes that impact disease progression. Urinary biomarkers, including microhematuria, α1-microglobulin, and CXCL13, have been proposed as potential predictors of disease activity and remission likelihood. Furthermore, histopathological features, such as glomerular basement membrane thickness, tubulointerstitial injury, and acute kidney injury, provide structural correlates that may inform prognosis. This review explores both established and emerging prognostic indicators across various biological domains. Understanding these predictors can aid in developing personalized therapeutic strategies, optimizing disease management, and improving patient outcomes in primary membranous nephropathy. Full article

Background: Anti-glomerular basement membrane (anti-GBM) nephritis is mediated by autoantibodies and may progress to end-stage renal disease. Although its pathogenesis is not completely understood, dendritic cells (DCs) have been reported to play an important role in this process. Hypoxia-inducible factor-2α (HIF-2α) has been reported to have a regulatory effect on DCs under hypoxic conditions, while no research has investigated its role in autoimmune nephritis. Methods: Anti-GBM nephritis was induced in CD11c-specific HIF-2α-deficient and WT mice using nephrotoxic serum (NTS). All mice were divided into four groups: (i) WT+PBS, (ii) CD11c-Cre⁺ Hif2α^fl/fl+PBS, (iii) WT+NTS and (iv) CD11c-Cre⁺ Hif2α^fl/fl+NTS. Seven days after induction, renal function, immune cell infiltration and the expression levels of genes in the renal cortex were assessed in each group. Results: On day 7, the levels of serum creatinine and blood urea nitrogen and the urine albumin-to-creatinine ratio were lower for mice with DC-specific deletion of HIF-2α compared with their WT counterparts (p < 0.05). Histopathological analysis showed that there was less crescent formation in the renal cortex with conditional HIF-2α knockout, and the infiltration of DCs and macrophages was also suppressed (p < 0.05). Genes related to antigen processing and presentation were found to be expressed differentially between the two groups, and the activation of the MAPK pathway was affected (p < 0.05). Western blot analysis validated that HIF-2α knockout inhibited the phosphorylation of p38 MAPK (p < 0.05). Conclusions: In this study, we observed a pro-inflammatory effect of HIF-2α in DCs in early anti-GBM nephritis, and the results suggested a regulating effect of HIF-2α on p38 MAPK pathways. Full article