PDGF-D Is Dispensable for the Development and Progression of Murine Alport Syndrome.

Alport syndrome is an inherited kidney disease, which can lead to glomerulosclerosis and fibrosis, as well as end-stage kidney disease in children and adults. Platelet-derived growth factor-D (PDGF-D) mediates glomerulosclerosis and interstitial fibrosis in various models of kidney disease, prompting investigation of its role in a murine model of Alport syndrome. In vitro, PDGF-D induced proliferation and profibrotic activation of conditionally immortalized human parietal epithelial cells.

Kidney fibrosis: Emerging diagnostic and therapeutic strategies.

An increasing number of patients worldwide suffers from chronic kidney disease (CKD). CKD is accompanied by kidney fibrosis, which affects all compartments of the kidney, i.e.

Platelet-instructed SPP1 macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner.

Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation.

Endogenous Modulation of Extracellular Matrix Collagen during Scar Formation after Myocardial Infarction.

Myocardial infarction is remains the leading cause of death in developed countries. Recent data show that the composition of the extracellular matrix might differ despite similar heart function and infarction sizes. Because collagen is the main component of the extracellular matrix, we hypothesized that changes in inflammatory cell recruitment influence the synthesis of different collagen subtypes in myofibroblasts, thus changing the composition of the scar.

The Role of Platelet-Derived Growth Factor in Focal Segmental Glomerulosclerosis.

Background: FSGS is the final common pathway to nephron loss in most forms of severe or progressive glomerular injury. Although podocyte injury initiates FSGS, parietal epithelial cells (PECs) are the main effectors. Because PDGF takes part in fibrotic processes, we hypothesized that the ligand PDGF-B and its receptor PDGFR- β participate in the origin and progression of FSGS.

Stain-Independent Deep Learning-Based Analysis of Digital Kidney Histopathology.

Convolutional neural network (CNN)-based image analysis applications in digital pathology (eg, tissue segmentation) require a large amount of annotated data and are mostly trained and applicable on a single stain. Here, a novel concept based on stain augmentation is proposed to develop stain-independent CNNs requiring only one annotated stain. In this benchmark study on stain independence in digital pathology, this approach is comprehensively compared with state-of-the-art techniques including image registration and stain translation, and several modifications thereof.

Large-scale extraction of interpretable features provides new insights into kidney histopathology - A proof-of-concept study.

Whole slide images contain a magnitude of quantitative information that may not be fully explored in qualitative visual assessments. We propose: (1) a novel pipeline for extracting a comprehensive set of visual features, which are detectable by a pathologist, as well as sub-visual features, which are not discernible by human experts and (2) perform detailed analyses on renal images from mice with experimental unilateral ureteral obstruction. An important criterion for these features is that they are easy to interpret, as opposed to features obtained from neural networks.

Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease.

Aims: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as 'uremic cardiomyopathy'. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD.

Current kidney function parameters overestimate kidney tissue repair in reversible experimental kidney disease.

Although underlying mechanisms and the clinical course of kidney disease progression are well described, less is known about potential disease reversibility. Therefore, to analyze kidney recovery, we adapted a commonly used murine chronic kidney disease (CKD) model of 2,8- dihydroxyadenine (2,8-DHA) crystal-induced nephropathy to study disease recovery and efficacy of disease-modifying interventions. The recovery phase after CKD was characterized by improved kidney function after two weeks which remained stable thereafter.

Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis.

Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3-4 fold; CCL9: 3-5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models.

Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD.

Background: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown.

A Hypercaloric Diet Induces Early Podocyte Damage in Aged, Non-Diabetic Rats.

Background/aims: The number of patients of older age with metabolic syndrome, obesity, and associated kidney disease, which is characterized by podocyte damage, glomerular hypertrophy, and focal segmental glomerulosclerosis (FSGS), is increasing worldwide. Animal models that would reflect the development of such kidney diseases could facilitate the testing of drugs. We investigated the renal effects of a long-term high caloric diet in aged rats and the potential effects of drugs used to treat metabolic syndrome.

State of the Art Cell Detection in Bone Marrow Whole Slide Images.

Context: Diseases of the hematopoietic system such as leukemia is diagnosed using bone marrow samples. The cell type distribution plays a major role but requires manual analysis of different cell types in microscopy images.

Aims: Automated analysis of bone marrow samples requires detection and classification of different cell types.

Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

Background: Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.

Methods: Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage.

Pathology and natural history of organ fibrosis.

Histopathological assessment of fibrosis focusing on morphological patterns provides important information for the management of patients with chronic diseases of the kidney, liver and the lung. This review summarizes key histopathological features of pulmonary, renal and hepatic fibrosis and discusses advances in the understanding of the pathogenesis of pulmonary fibrosis and pathogenetic insights with translational implications for renal fibrosis. The review also tackles new staging approaches based on liver fibrosis dynamics and evaluation of fibrosis regression, digital pathology and second harmonic generation microscopy methods for hepatic fibrosis assessment and critical appraisal of non-invasive tests for liver and renal fibrosis evaluation.

CNN cascades for segmenting sparse objects in gigapixel whole slide images.

Due to the increasing availability of whole slide scanners facilitating digitization of histopathological tissue, large amounts of digital image data are being generated. Accordingly, there is a strong demand for the development of computer based image analysis systems. Here, we address application scenarios in histopathology consisting of sparse, small objects-of-interest occurring in the large gigapixel images.

Glucagon-Like Peptide 1 and Its Cleavage Products Are Renoprotective in Murine Diabetic Nephropathy.

Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, are potent glucose-lowering drugs. Still, only GLP-1 receptor agonists with close peptide homology to GLP-1 (liraglutide and semaglutide) but neither exenatide-based GLP-1 receptor agonists nor DPP-4 inhibitors were found to reduce cardiovascular events. This different response might relate to GLP-1 receptor-independent actions of GLP-1 caused by cleavage products only liberated by GLP-1 receptor agonists with close peptide structure to GLP-1.

PDGF in organ fibrosis.

Fibrosis is part of a tissue repair response to injury, defined as increased deposition of extracellular matrix. In some instances, fibrosis is beneficial; however, in the majority of diseases fibrosis is detrimental. Virtually all chronic progressive diseases are associated with fibrosis, representing a huge number of patients worldwide.

Segmenting renal whole slide images virtually without training data.

Digital pathology is a field of increasing interest and requires automated systems for processing huge amounts of digital data. The development of supervised-learning based automated systems is aggravated by the fact that image properties can change from slide to slide. In this work, the focus is on the segmentation of the glomeruli constituting the most important regions-of-interest in renal histopathology.

Mesenchymal stem cells from rats with chronic kidney disease exhibit premature senescence and loss of regenerative potential.

Mesenchymal stem cell (MSC) transplantation has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g.

Levels of acyl-coenzyme A synthetase 5 in urothelial cells and corresponding neoplasias reflect cellular differentiation.

Metabolic components like fatty acids and acyl-Coenzyme A (acyl-CoA) thioesters have been implicated in the pathogenesis of various tumours. The activation of fatty acids to acyl-CoAs is catalysed by long chain acyl-CoA synthetases (ACSLs), and impairment of ACSL expression levels has been associated with tumourigenesis and progression. Since ACSLs have never been investigated in bladder tissues, the study aims to characterize ACSL expression and acyl-CoA synthesis in normal and neoplastic bladder tissues, as well as cell lines.