International Journal of Molecular Sciences

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20 pages, 9092 KiB

Open AccessArticle

NCKAP1 Inhibits the Progression of Renal Carcinoma via Modulating Immune Responses and the PI3K/AKT/mTOR Signaling Pathway

by Xin Zhang, Jianqing Ye, Lixiang Sun, Wanli Xu, Xiaomeng He, Juan Bao and Jin Wang

Int. J. Mol. Sci. 2025, 26(6), 2813; https://doi.org/10.3390/ijms26062813 - 20 Mar 2025

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Abstract

Nck-associated protein 1 (NCKAP1) is critical for cytoskeletal functions and various cellular activities, and deregulation of NCKAP1 in many cancers significantly influences the outcomes of malignant diseases. However, the functions of NCKAP1 in the progression of renal cancer are yet unknown. To investigate [...] Read more.

Nck-associated protein 1 (NCKAP1) is critical for cytoskeletal functions and various cellular activities, and deregulation of NCKAP1 in many cancers significantly influences the outcomes of malignant diseases. However, the functions of NCKAP1 in the progression of renal cancer are yet unknown. To investigate the specific roles of NCKAP1 in the immune regulation and tumor progression of renal cancer, the expression of NCKAP1 and genetic variations were analyzed across cancer types at different pathological stages via UALCAN and cBioPortal. Immune cell infiltration in renal cancer was also assessed by ssGSEA and single-cell gene expression data from the GEO. RNA sequencing of NCKAP1-overexpressing 769P cells further examined the impact of NCKAP1 on kidney cancer. Our pancancer analyses revealed a complex NCKAP1 expression profile across various cancer types, with reduced levels in renal cancer patients linked to patient prognosis. CIBERSORT and single-cell RNA sequencing revealed the expression patterns of NCKAP1 in different cell lineages in renal cancer and a significant correlation between NCKAP1 and immune cell infiltration in the kidney tumor microenvironment. We further verified that NCKAP1 suppressed cancer cell growth and affected tumor development in renal cancer via the PI3K/AKT/mTOR signaling pathway. Our results indicate that NCKAP1 is a potential predictive marker and treatment target for renal cancer. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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16 pages, 1820 KiB

Open AccessArticle

Induced Genetic Deletion of Cell Division Autoantigen 1 in Adulthood Attenuates Diabetes-Associated Renal Fibrosis

by Pacific Huynh, Yuxin Yang, Hua Tian, Tieqiao Wu, Minling Huang, Jiali Tang, Aozhi Dai, Mark E. Cooper and Zhonglin Chai

Int. J. Mol. Sci. 2025, 26(5), 2022; https://doi.org/10.3390/ijms26052022 - 26 Feb 2025

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Abstract

Cell Division Autoantigen 1 (CDA1) has been shown to play a role in enhancing transforming growth factor beta (TGFβ) signaling, leading to fibrosis in diabetic kidney disease (DKD) using mouse strains with global CDA1 gene deletion. In these models, diabetes has been induced, [...] Read more.

Cell Division Autoantigen 1 (CDA1) has been shown to play a role in enhancing transforming growth factor beta (TGFβ) signaling, leading to fibrosis in diabetic kidney disease (DKD) using mouse strains with global CDA1 gene deletion. In these models, diabetes has been induced, leading to DKD in the absence of CDA1. It is still unknown whether inhibition of CDA1 activity after onset of diabetes in the presence of CDA1 can attenuate renal fibrosis in vivo. Thus, we examined the effect of inducing genetic deletion of CDA1 in adulthood in mice using a tamoxifen-activated estrogen receptor fused cyclization recombinase (ERCre)-Locus of cross-over in P1 (LoxP) system. Male mice at 6–8 weeks of age were rendered diabetic with streptozotocin (STZ) or injected with buffer alone to serve as non-diabetic controls. Five weeks later, genetic deletion of CDA1 was induced by tamoxifen administration in CDA1Flox/ERCre mice, with mice injected with vehicle to serve as CDA1 wildtype controls. Kidney tissues were analyzed 5 weeks after deletion of CDA1. Tamoxifen administration reduced CDA1 gene expression by ~80% in CDA1Flox/ERCre mice. Renal levels of phosphorylated Smad3 and expression of profibrotic genes as well as accumulation of extracellular matrix proteins (ECMs) such as collagens III and IV were increased in diabetic mice, and induced deletion of CDA1 led to attenuation of these parameters. Therefore, targeting CDA1 after onset of diabetes in mice where CDA1 was initially expressed is able to attenuate diabetes-associated renal injury, providing the impetus to target this pathway in order to reduce diabetic kidney disease. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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11 pages, 1074 KiB

Open AccessCommunication

Ezetimibe Enhances Lipid Droplet and Mitochondria Contact Formation, Improving Fatty Acid Transfer and Reducing Lipotoxicity in Alport Syndrome Podocytes

by Jin-Ju Kim, Eun-Jeong Yang, Judith Molina David, Sunjoo Cho, Maria Ficarella, Nils Pape, Josephin Elizabeth Schiffer, Rachel Njeim, Stephanie S. Kim, Claudia Lo Re, Antonio Fontanella, Maria Kaber, Alexis Sloan, Sandra Merscher and Alessia Fornoni

Int. J. Mol. Sci. 2024, 25(23), 13134; https://doi.org/10.3390/ijms252313134 - 6 Dec 2024

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Abstract

Mitochondrial dysfunction is a critical factor in the pathogenesis of Alport syndrome (AS), contributing to podocyte injury and disease progression. Ezetimibe, a lipid-lowering drug, is known to inhibit cholesterol and fatty acid uptake and to reduce triglyceride content in the kidney cortex of [...] Read more.

Mitochondrial dysfunction is a critical factor in the pathogenesis of Alport syndrome (AS), contributing to podocyte injury and disease progression. Ezetimibe, a lipid-lowering drug, is known to inhibit cholesterol and fatty acid uptake and to reduce triglyceride content in the kidney cortex of mice with AS. However, its effects on lipid droplet (LD) utilization by mitochondria have not been explored. Transmission electron microscopy (TEM) and mitochondrial functional assays (ATP production, mitochondrial membrane potential, and citrate synthase activity) were used to investigate the impact of ezetimibe on LD–mitochondria contact formation and mitochondrial function in Col4a3KO (AS) and wildtype (WT) podocytes. TEM analysis revealed significant mitochondrial abnormalities in AS podocytes, including swollen mitochondria and reduced cristae density, while mitochondrial function assays showed decreased ATP production and lowered mitochondrial membrane potential. AS podocytes also demonstrated a higher content of LD but with reduced LD–mitochondria contact sites. Ezetimibe treatment significantly increased the number of LD–mitochondria contact sites, enhanced fatty acid transfer efficiency, and reduced intracellular lipid accumulation. These changes were associated with a marked reduction in the markers of lipotoxicity, such as apoptosis and oxidative stress. Mitochondrial function was significantly improved, evidenced by increased basal respiration, ATP production, maximal respiration capacity, and the restoration of mitochondrial membrane potential. Additionally, mitochondrial swelling was significantly reduced in ezetimibe-treated AS podocytes. Our findings reveal a novel role for ezetimibe in enhancing LD–mitochondria contact formation, leading to more efficient fatty acid transfer, reduced lipotoxicity, and improved mitochondrial function in AS podocytes. These results suggest that ezetimibe could be a promising therapeutic agent for treating mitochondrial dysfunction and lipid metabolism abnormalities in AS. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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24 pages, 8027 KiB

Open AccessArticle

Renal Epithelial Complement C3 Expression Affects Kidney Fibrosis Progression

by Ganna Stepanova, Anna Manzéger, Miklós M. Mózes and Gábor Kökény

Int. J. Mol. Sci. 2024, 25(23), 12551; https://doi.org/10.3390/ijms252312551 - 22 Nov 2024

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Abstract

Kidney fibrosis is a hallmark of chronic kidney diseases. Evidence shows that genetic variability and complement component 3 (C3) might influence tubulointerstitial fibrosis. Still, the role of renal C3 production in the epithelial-to-mesenchymal transition (EMT) and genetically determined fibrosis progression remains undiscovered. The [...] Read more.

Kidney fibrosis is a hallmark of chronic kidney diseases. Evidence shows that genetic variability and complement component 3 (C3) might influence tubulointerstitial fibrosis. Still, the role of renal C3 production in the epithelial-to-mesenchymal transition (EMT) and genetically determined fibrosis progression remains undiscovered. The kidneys of fibrosis-resistant C57Bl/6J (B6) and fibrosis-prone CBA/J (CBA) and BALB/cJ (BalbC) mice (n = 4–8/group) were subjected to unilateral ureteral obstruction (UUO) and analyzed after 1, 3, and 7 days, along with human focal glomerular sclerotic (FSGS) and healthy kidneys. Mouse primary tubular epithelial cells (PTECs) were investigated after 24 h of treatment with transforming growth factor β (TGFβ) or complement anaphylatoxin 3a (C3a) agonist (n = 4/group). UUO resulted in delayed kidney injury in fibrosis-resistant B6 mice, but very early renal C3 messenger RNA (mRNA) induction in fibrosis-prone CBA and BalbC mice, along with collagen I (Col1a1) and collagen III (Col3a1). CBA depicted the fastest fibrosis progression with the highest C3, lipocalin-2 (Lcn2), Tgfb1, and chemokine (C-C motif) ligand 2 (Ccl2) expression. Human FSGS kidneys depicted C3 mRNA over-expression and strong tubular C3 immunostaining. In PTECs, C3a agonist treatment induced pro-fibrotic early growth response protein 1 (EGR1) expression and the EMT, independent of TGFβ signaling. We conclude that de novo renal tubular C3 synthesis is associated with the genetically determined kidney fibrosis progression rate in mice and the pathogenesis of FSGS in humans. This tubular C3 overproduction can, through local pro-fibrotic effects, influence the progression of chronic kidney disease. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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11 pages, 687 KiB

Open AccessArticle

Prediction of Successful Liberation from Continuous Renal Replacement Therapy Using a Novel Biomarker in Patients with Acute Kidney Injury after Cardiac Surgery—An Observational Trial

by Johanna Tichy, Andrea Hausmann, Johannes Lanzerstorfer, Sylvia Ryz, Ludwig Wagner, Andrea Lassnigg and Martin H. Bernardi

Int. J. Mol. Sci. 2024, 25(20), 10873; https://doi.org/10.3390/ijms252010873 - 10 Oct 2024

Cited by 3 | Viewed by 1209

Abstract

An acute kidney injury (AKI) is the most common complication following cardiac surgery, and can lead to the initiation of continuous renal replacement therapy (CRRT). However, there is still insufficient evidence for when patients should be liberated from CRRT. Proenkephalin A 119–159 (PENK) [...] Read more.

An acute kidney injury (AKI) is the most common complication following cardiac surgery, and can lead to the initiation of continuous renal replacement therapy (CRRT). However, there is still insufficient evidence for when patients should be liberated from CRRT. Proenkephalin A 119–159 (PENK) is a novel biomarker that reflects kidney function independently of other factors. This study investigated whether PENK could guide successful liberation from CRRT. Therefore, we performed a prospective, observational, single-center study at the Medical University of Vienna between July 2022 and May 2023, which included adult patients who underwent cardiac surgery for a cardiopulmonary bypass; patients on preoperative RRT were excluded. The PENK levels were measured at the time of AKI diagnosis and at the initiation of and liberation from CRRT, and were subsequently compared to determine whether the patients were successfully liberated from CRRT. We screened 61 patients with postoperative AKI; 20 patients experienced a progression of AKI requiring CRRT. The patients who were successfully liberated from CRRT had mean PENK levels of 113 ± 95.4 pmol/L, while the patients who were unsuccessfully liberated from CRRT had mean PENK levels of 290 ± 175 pmol/L (p = 0.018). For the prediction of the successful liberation from CRRT, we found an area under the curve of 0.798 (95% CI, 0.599–0.997) with an optimal threshold value of 126.7 pmol/L for PENK (Youden Index = 0.53, 95% CI, 0.10–0.76) at the time of CRRT liberation (sensitivity = 0.64, specificity = 0.89). In conclusion, PENK is a novel biomarker that has the potential to predict the successful liberation from CRRT for patients with AKI after cardiac surgery. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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17 pages, 1613 KiB

Open AccessArticle

The Relationship between Vascular Biomarkers (Serum Endocan and Endothelin-1), NT-proBNP, and Renal Function in Chronic Kidney Disease, IgA Nephropathy: A Cross-Sectional Study

by Balázs Sági, Tibor Vas, Csenge Gál, Zoltán Horváth-Szalai, Tamás Kőszegi, Judit Nagy, Botond Csiky and Tibor József Kovács

Int. J. Mol. Sci. 2024, 25(19), 10552; https://doi.org/10.3390/ijms251910552 - 30 Sep 2024

Cited by 1 | Viewed by 1532

Abstract

IgA nephropathy (IgAN) is the most common primary glomerular disease. Endothelin-1 (ET-1) is one of the strongest vasoconstrictor materials in the blood. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is associated with renal function and poor outcomes in chronic kidney disease (CKD). [...] Read more.

IgA nephropathy (IgAN) is the most common primary glomerular disease. Endothelin-1 (ET-1) is one of the strongest vasoconstrictor materials in the blood. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is associated with renal function and poor outcomes in chronic kidney disease (CKD). Serum endocan is a biomarker associated with proinflammatory cytokines, and the increase in the serum level plays a critical role in inflammatory, proliferative, and neovascularization processes and is associated with poor cardiovascular outcomes in patients with CKD too. Identifying high-risk patients using biomarkers could help to optimize their treatment. Ninety patients with biopsy-confirmed IgAN were included in the study (50 males/40 females, mean age: 54.9 ± 14.4 years). Serum endocan, ET-1, and NT-proBNP were measured by enzyme-linked immunosorbent assay kits. Echocardiography was performed, and carotid-femoral pulse wave velocity (cfPWV) was measured by SphygmoCor in this cross-sectional study. Patients were divided into two groups based on serum endocan median level (cut-off: 44 ug/L). There was significantly higher aorta systolic blood pressure (SBPao) (p = 0.013), NT-proBNP (p = 0.028), albumin/creatinine ratio (p = 0.036), and uric acid (p = 0.045) in the case of the higher endocan group compared to the lower. There was also significantly higher SBPao (p = 0.037) and NT-proBNP (p = 0.038) in the case of higher endothelin-1 (ET-1) levels compared to the lower (cut-off: 231 pg/mL) group by the two-sample t-test. Then, we divided the patients into two groups based on the eGFR (CKD 1–2 vs. CKD 3–5). The levels of serum endocan, NT-proBNP, cfPWV, SBPao, left ventricular mass index (LVMI), uric acid, and albuminuria were significantly higher in the CKD 3–5 group compared to the CKD 1–2 group. The serum endocan and NT-proBNP levels were significantly higher in the diastolic dysfunction group (p = 0.047, p = 0.015). There was a significant increase in serum endocan levels (CKD 1 vs. CKD 5; p = 0.008) with decreasing renal function. In IgAN, vascular biomarkers (endocan, ET-1) may play a role in endothelial dysfunction through vascular damage and elevation of SBPao. Serum endocan, ET-1, and NT-proBNP biomarkers may help to identify IgAN patients at high risk. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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13 pages, 3509 KiB

Open AccessArticle

Association between PD-L1 Expression and the Prognosis and Clinicopathologic Features of Non-Clear Cell Renal Cell Carcinoma

by Magdalena Chrabańska, Nikola Szweda-Gandor, Magdalena Rynkiewicz, Dominik Hraboš and Bogna Drozdzowska

Int. J. Mol. Sci. 2024, 25(7), 3916; https://doi.org/10.3390/ijms25073916 - 31 Mar 2024

Cited by 1 | Viewed by 1935

Abstract

PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance [...] Read more.

PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance in non-clear cell renal cell carcinoma (non-ccRCC) patients. A total of 41 papillary (pRCC) and 20 chromophobe (chRCC) RCC tumors were examined for PD-L1 expression by immunohistochemistry in the cancer cells and tumor-infiltrating mononuclear cells (TIMCs). PD-L1 positivity was detected in 36.6% pRCC and 85.0% chRCC cancer cells, while PD-L1 positivity was observed in 73.2% pRCC and 50.0% chRCC TIMCs. PD-L1 positivity in both pRCC and chRCC tumor cells was not correlated with any of the examined clinicopathological features, while PD-L1 positivity in TIMCs was associated with the age of patients with pRCC. During follow-up, the death was documented among 6 patients with pRCC. Papillary RCC patients with PD-L1-positive tumor cells were significantly associated with an increased risk of death compared with patients with PD-L1-negative cancer cells. A similar trend was observed when comparing PD-L1 expression in TIMCs. However, no differences in overall survival for PD-L1-positive pRCC patients with compared to PD-L1-negative patients were observed in tumor cells or TIMCs. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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Review

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28 pages, 2473 KiB

Open AccessReview

High-Density Lipoprotein in Patients with Diabetic Kidney Disease: Friend or Foe?

by Ke Liu, Mark E. Cooper, Zhonglin Chai and Fang Liu

Int. J. Mol. Sci. 2025, 26(4), 1683; https://doi.org/10.3390/ijms26041683 - 16 Feb 2025

Cited by 1 | Viewed by 878

Abstract

High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic [...] Read more.

High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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29 pages, 3330 KiB

Open AccessReview

Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease

by Da-Wei Lin, Tsung-Ming Yang, Cheng Ho, Ya-Hsueh Shih, Chun-Liang Lin and Yung-Chien Hsu

Int. J. Mol. Sci. 2024, 25(8), 4350; https://doi.org/10.3390/ijms25084350 - 15 Apr 2024

Cited by 8 | Viewed by 3750

Abstract

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating [...] Read more.

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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Other

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18 pages, 5008 KiB

Open AccessHypothesis

Hypothetical Pathogenetic Model of Membranous Nephropathy

by Irina Zdravkova, Eduard Tilkiyan, Desislava Bozhkova, Teodor Kuskunov, Yovko Ronchev and Boris Kirilov

Int. J. Mol. Sci. 2025, 26(5), 2206; https://doi.org/10.3390/ijms26052206 - 28 Feb 2025

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Abstract

Membranous nephropathy (MN) is a disease with an etiology and pathogenesis that are still not fully understood, and it represents a great challenge. It is characterized by a variable course, spontaneous remissions and relapses. The inability to rely entirely on antibodies and the [...] Read more.

Membranous nephropathy (MN) is a disease with an etiology and pathogenesis that are still not fully understood, and it represents a great challenge. It is characterized by a variable course, spontaneous remissions and relapses. The inability to rely entirely on antibodies and the continuous threat of a malignant disease make the differentiation of MN types extremely difficult. Data of twelve patients with membranous nephropathy, ranging in age between 28 and 67 years, are presented; in total, seven men and five women were observed for a period of 2 to 10 years. In all patients, the diagnosis was confirmed through kidney biopsy and laboratory tests, including immunological, histopathological, and immunohistochemical tests. Histopathological and immunohistochemical tests were applied on available material from the thyroid gland in two patients and the gallbladder in two patients with MN. Data of 102 patients with MN and their comorbidities are evaluated in order to establish correlations. These and other data are used to build a hypothetical pathogenetic model that explains the etiology and the likely pattern of disease occurrence. We found a connection between chronic cholecystitis, thyroiditis, hepatitis, and other diseases in the occurrence of MN and disease course. From our practice and cases, we drew the conclusion that chronic inflammation in sites that express PLA2R leads to the formation of antibodies against PLA2R. These antibodies occur as a preformed immune complex or separately and are deposited in the subepithelial space, leading to MN appearance. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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15 pages, 7017 KiB

Open AccessCase Report

Fibronectin Glomerulopathy Without Typical Renal Biopsy Features in a 4-Year-Old Girl with Incidentally Discovered Proteinuria and a G417V FN1 Gene Mutation

by Tibor Kalmár, Dániel Jakab, Zoltán Maróti, Gyula Pásztor, Sándor Turkevi-Nagy, Éva Kemény, Helmut Hopfer, Jan Ulrich Becker, Csaba Bereczki and Béla Iványi

Int. J. Mol. Sci. 2025, 26(2), 641; https://doi.org/10.3390/ijms26020641 - 14 Jan 2025

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Abstract

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 (FN1) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 [...] Read more.

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 (FN1) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice. Full article

(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)

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