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  • Ovid Technologies (Wolters Kluwer Health)  (4)
  • Korstanje, Ron  (4)
  • 2020-2024  (4)
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  • Ovid Technologies (Wolters Kluwer Health)  (4)
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  • 2020-2024  (4)
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  • 1
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 1 ( 2021-1), p. 52-68
    Abstract: Nephropathologic analyses provide important outcomes-related data in the animal model studies that are essential to understanding kidney disease pathophysiology. In this work, the authors used a deep learning technique, the convolutional neural network, as a multiclass histology segmentation tool to evaluate kidney disease in animal models. This enabled a rapid, automated, high-performance segmentation of digital whole-slide images of periodic acid–Schiff–stained kidney tissues, allowing high-throughput quantitative and comparative analyses in multiple murine disease models and other species. The convolutional neural network also performed well in evaluating patient samples, providing a translational bridge between preclinical and clinical research. Extracted quantitative morphologic features closely correlated with standard morphometric measurements. Deep learning–based segmentation in experimental renal pathology is a promising step toward reproducible, unbiased, and high-throughput quantitative digital nephropathology. Background Nephropathologic analyses provide important outcomes-related data in experiments with the animal models that are essential for understanding kidney disease pathophysiology. Precision medicine increases the demand for quantitative, unbiased, reproducible, and efficient histopathologic analyses, which will require novel high-throughput tools. A deep learning technique, the convolutional neural network, is increasingly applied in pathology because of its high performance in tasks like histology segmentation. Methods We investigated use of a convolutional neural network architecture for accurate segmentation of periodic acid–Schiff-stained kidney tissue from healthy mice and five murine disease models and from other species used in preclinical research. We trained the convolutional neural network to segment six major renal structures: glomerular tuft, glomerulus including Bowman’s capsule, tubules, arteries, arterial lumina, and veins. To achieve high accuracy, we performed a large number of expert-based annotations, 72,722 in total. Results Multiclass segmentation performance was very high in all disease models. The convolutional neural network allowed high-throughput and large-scale, quantitative and comparative analyses of various models. In disease models, computational feature extraction revealed interstitial expansion, tubular dilation and atrophy, and glomerular size variability. Validation showed a high correlation of findings with current standard morphometric analysis. The convolutional neural network also showed high performance in other species used in research—including rats, pigs, bears, and marmosets—as well as in humans, providing a translational bridge between preclinical and clinical studies. Conclusions We developed a deep learning algorithm for accurate multiclass segmentation of digital whole-slide images of periodic acid–Schiff-stained kidneys from various species and renal disease models. This enables reproducible quantitative histopathologic analyses in preclinical models that also might be applicable to clinical studies.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2029124-3
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  • 2
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 11S ( 2023-11), p. 295-296
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 11S ( 2023-11), p. 295-296
    Type of Medium: Online Resource
    ISSN: 1046-6673
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 3
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 10 ( 2021-10), p. 2634-2651
    Abstract: Genetic differences are possible contributing factors to the substantial unexplained variability in rates of renal function loss in type 1 diabetes. Gene-based testing of protein coding genetic variants in whole-exome scans of individuals with type 1 diabetes with advanced kidney disease, as opposed to genome-wide SNP analyses, revealed that carriers of rarer, disruptive alleles in HSD17B14 experienced net protection against loss of kidney function and development of ESKD. HSD17B14 encodes hydroxysteroid 17- β dehydrogenase 14, which regulates sex steroid hormone metabolism. Paradoxically, proximal tubules from patients and mouse models had high levels of expression of the gene and protein, with downregulation in the presence of kidney injury. Hydroxysteroid 17- β dehydrogenase 14 may therefore be a druggable therapeutic target. Background Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort ( n =2372/1115 events all cohorts) and replicating in two retrospective case-control studies ( n =1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17- β dehydrogenase 14 gene ( HSD17B14 ), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance ( n =4196; P value=3.3 × 10 −7 ). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. Conclusions HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2029124-3
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Journal of the American Society of Nephrology Vol. 32, No. 8 ( 2021-8), p. 1961-1973
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 8 ( 2021-8), p. 1961-1973
    Abstract: Kidney disease severity is partly determined by modifier genes. These genes can be important therapeutic targets but are difficult to identify in patient populations. Our study demonstrates a novel mouse genetic approach using Diversity Outbred mice to identify modifier genes for X-linked Alport Syndrome. We identify several candidate modifier genes and validate the candidacy of Fmn1 . We show that a decrease in Fmn1 expression in Col4a5 knockout mice leads to a decrease in albuminuria and fewer podocyte protrusions in the glomerular basement membrane. Our approach can be easily adapted to identify modifier genes for other forms of kidney disease. Background Mutations in COL4A5 are responsible for 80% of cases of X-linked Alport Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS who have similar genetic mutations present with a wide variation in the extent of kidney impairment and age of onset, suggesting the activities of modifier genes. Methods We created a cohort of genetically diverse XLAS male and female mice using the Diversity Outbred mouse resource and measured albuminuria, GFR, and gene expression. Using a quantitative trait locus approach, we mapped modifier genes that can best explain the underlying phenotypic variation measured in our diverse population. Results Genetic analysis identified several loci associated with the variation in albuminuria and GFR, including a locus on the X chromosome associated with X inactivation and a locus on chromosome 2 containing Fmn1 . Subsequent analysis of genetically reduced Fmn1 expression in Col4a5 knockout mice showed a decrease in albuminuria, podocyte effacement, and podocyte protrusions in the glomerular basement membrane, which support the candidacy of Fmn1 as a modifier gene for AS. Conclusion With this novel approach, we emulated the variability in the severity of kidney phenotypes found in human patients with Alport Syndrome through albuminuria and GFR measurements. This approach can identify modifier genes in kidney disease that can be used as novel therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2029124-3
    Location Call Number Limitation Availability
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