Autoantibodies Targeting Nephrin in Podocytopathies.

BACKGROUND: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).

Assessment and Risk Prediction of Chronic Kidney Disease and Kidney Fibrosis Using Non-Invasive Biomarkers.

Effective management of chronic kidney disease (CKD), a major health problem worldwide, requires accurate and timely diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for evaluating specific aspects of CKD have been proposed in the literature, many of which are based on a small number of samples. Based on the evidence presented in relevant studies, a comprehensive overview of the different biomarkers applicable for clinical implementation is lacking. This review aims to compile information on the non-invasive diagnostic, prognostic, and predictive biomarkers currently available for the management of CKD and provide guidance on the application of these biomarkers. We specifically focus on biomarkers that have demonstrated added value in prospective studies or those based on prospectively collected samples including at least 100 subjects. Published data demonstrate that several valid non-invasive biomarkers of potential value in the management of CKD are currently available.

Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review.

Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.

The 14th International Podocyte Conference 2023: from podocyte biology to glomerular medicine.

The 14th International Podocyte Conference took place in Philadelphia, Pennsylvania, USA from May 23 to 26, 2023. It commenced with an early-career researchers' meeting on May 23, providing young scientists with a platform to present and discuss their research findings. Throughout the main conference, 29 speakers across 9 sessions shared their insights on podocyte biology, glomerular medicine, novel technologic advancements, and translational approaches. Additionally, the event featured 3 keynote lectures addressing engineered chimeric antigen receptor T cell- and mRNA-based therapies and the use of biobanks for enhanced disease comprehension. Furthermore, 4 brief oral abstract sessions allowed scientists to present their findings to a broad audience. The program also included a panel discussion addressing the challenges of conducting human research within the American Black community. Remarkably, after a 5-year hiatus from in-person conferences, the 14th International Podocyte Conference successfully convened scientists from around the globe, fostering the presentation and discussion of crucial research findings, as summarized in this review. Furthermore, to ensure continuous and sustainable education, research, translation, and trial medicine related to podocyte and glomerular diseases for the benefit of patients, the International Society of Glomerular Disease was officially launched during the conference.

Mosaic theory revised: inflammation and salt play central roles in arterial hypertension.

The mosaic theory of hypertension was advocated by Irvine Page ~80 years ago and suggested that hypertension resulted from the close interactions of different causes. Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury. Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension. Sodium intake is indispensable for normal body function but can be detrimental when it exceeds dietary requirements. Recent data show that sodium levels also modulate the function of monocytes/macrophages, dendritic cells, and different T-cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome due to high-salt intake. The purpose of this review is to propose a revised and extended version of the mosaic theory by summarizing and integrating recent advances in salt, immunity, and hypertension research. Salt and inflammation are placed in the middle of the mosaic because both factors influence each of the remaining pieces.

[Arterial Hypertension]. / Arterielle Hypertonie ­ Eine Übersicht für den ärztlichen Alltag.

Arterial hypertension affects about one third of the German population with a prevalence increasing with age up to 60 %. Globally, more than a quarter gedoppelt of the population are considered hypertensive, resulting in a total of more than one billion people. Not only due to such high prevalence, but also because of its multiple cardiovascular, renal, ocular, and cognitive complications, arterial hypertension is a leading contributor to the global burden of disease and responsible for up to 10 million deaths worldwide. Contrary to the great importance of arterial hypertension resulting from such high prevalence and immense impact on health worldwide, awareness of disease is low in affected people. Less than every second patient knows about his or her disease status and less than 40 % of patients in Europe show adequate blood pressure control with a treatment target of < 140/90 mmHg despite antihypertensive treatment. This overview of arterial hypertension, its etiology, diagnostic tools, and therapeutic options aims to improve the understanding of arterial hypertension and to facilitate the diagnostic and therapeutic approach, eventually resulting in a better and more successful handling of patients with arterial hypertension.

Measurement of hindered diffusion in complex geometries for high-speed studies of single-molecule forces.

In a high-speed single-molecule experiment with a force probe, a protein is tethered between two substrates that are manipulated to exert force on the system. To avoid nonspecific interactions between the protein and nearby substrates, the protein is usually attached to the substrates through long, flexible linkers. This approach precludes measurements of mechanical properties with high spatial and temporal resolution, for rapidly exerted forces are dissipated into the linkers. Because mammalian hearing operates at frequencies reaching tens to hundreds of kilohertz, the mechanical processes that occur during transduction are of very short duration. Single-molecule experiments on the relevant proteins therefore cannot involve long tethers. We previously characterized the mechanical properties of protocadherin 15 (PCDH15), a protein essential for human hearing, by tethering an individual monomer through very short linkers between a probe bead held in an optical trap and a pedestal bead immobilized on a glass coverslip. Because the two confining surfaces were separated by only the length of the tethered protein, hydrodynamic coupling between those surfaces complicated the interpretation of the data. To facilitate our experiments, we characterize here the anisotropic and position-dependent diffusion coefficient of a probe in the presence of an effectively infinite wall, the coverslip, and of the immobile pedestal.

Elasticity of individual protocadherin 15 molecules implicates tip links as the gating springs for hearing.

Hair cells, the sensory receptors of the inner ear, respond to mechanical forces originating from sounds and accelerations. An essential feature of each hair cell is an array of filamentous tip links, consisting of the proteins protocadherin 15 (PCDH15) and cadherin 23 (CDH23), whose tension is thought to directly gate the cell's transduction channels. These links are considered far too stiff to represent the gating springs that convert hair bundle displacement into forces capable of opening the channels, and no mechanism has been suggested through which tip-link stiffness could be varied to accommodate hair cells of distinct frequency sensitivity in different receptor organs and animals. Consequently, the gating spring's identity and mechanism of operation remain central questions in sensory neuroscience. Using a high-precision optical trap, we show that an individual monomer of PCDH15 acts as an entropic spring that is much softer than its enthalpic stiffness alone would suggest. This low stiffness implies that the protein is a significant part of the gating spring that controls a hair cell's transduction channels. The tip link's entropic nature then allows for stiffness control through modulation of its tension. We find that a PCDH15 molecule is unstable under tension and exhibits a rich variety of reversible unfolding events that are augmented when the Ca2+ concentration is reduced to physiological levels. Therefore, tip link tension and Ca2+ concentration are likely parameters through which nature tunes a gating spring's mechanical properties.