• MeSH
• biologické markery MeSH
• budesonid škodlivé účinky   MeSH
• glomerulus patologie   MeSH
• IgA nefropatie * diagnóza   farmakoterapie   patologie   MeSH
• imunoglobulin A MeSH
• lidé MeSH
• proteinurie patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A proliferation-inducing ligand (APRIL) is a key member of the tumor necrosis factor superfamily of cytokines and plays a central role in B-cell survival, proliferation, and Ig class switching. Recently, there has been increasing interest in the role of APRIL and the related cytokine B-cell activating factor in several glomerular diseases, because of their importance in the above processes. The therapeutic inhibition of APRIL represents a potentially attractive immunomodulatory approach that may abrogate deleterious host immune responses in autoimmune diseases while leaving other important functions of humoral immunity intact, such as memory B-cell function and responses to vaccination, in contrast to B-cell-depleting strategies. In this review, we describe the physiological roles of APRIL in B-cell development and their relevance to glomerular diseases, and outline emerging clinical trial data studying APRIL inhibition, with a focus on IgA nephropathy where the clinical development of APRIL inhibitors is in its most advanced stage.

• MeSH
• B-lymfocyty * imunologie   účinky léků   MeSH
• glomerulus imunologie   patologie   účinky léků   MeSH
• IgA nefropatie * imunologie   farmakoterapie   MeSH
• lidé MeSH
• protein TALL-2 * antagonisté a inhibitory   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Genetic nephrotic syndrome is caused by pathogenic variants in genes encoding proteins necessary for the stability and functionality of the glomerular filtration barrier. To date, more than 70 genes associated with steroid-resistant nephrotic syndrome have been identified. We review the clinical and molecular aspects of genetic nephrotic syndrome with a particular focus on genes associated with slit membrane and podocyte cytoskeleton defects. Sanger sequencing and next-generation sequencing are widely used in the identification of novel gene variants and help us gain a better understanding of the disease. Despite these findings, therapy is mainly supportive and focused on the reduction of proteinuria and management of chronic kidney disease with an unfavorable outcome for a significant proportion of cases. Positive therapeutic effects of immunosuppressive drugs have been reported in some patients; however, their long-time administration cannot be generally recommended. CONCLUSION: Personalized treatment based on understanding the distinct disease pathogenesis is needed. With this, it will be possible to avoid harmful immunosuppressive therapy and improve outcomes and quality of life for pediatric patients suffering from genetic nephrotic syndrome.

• MeSH
• cytoskelet metabolismus   patologie   MeSH
• dítě MeSH
• glomerulus patologie   MeSH
• kvalita života MeSH
• lidé MeSH
• nefrotický syndrom * etiologie   MeSH
• nemoci ledvin * patologie   MeSH
• podocyty * metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.

• MeSH
• aktivace komplementu MeSH
• autoimunitní nemoci * MeSH
• glomerulus patologie   MeSH
• komplement metabolismus   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• nemoci ledvin * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system-particularly the lectin and alternative pathways of complement-has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients.

• MeSH
• glomerulus patologie   MeSH
• IgA nefropatie * patologie   MeSH
• imunoglobulin A metabolismus   MeSH
• ledviny patologie   MeSH
• lektiny metabolismus   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Pathology diagnostics relies on the assessment of morphology by trained experts, which remains subjective and qualitative. Here we developed a framework for large-scale histomorphometry (FLASH) performing deep learning-based semantic segmentation and subsequent large-scale extraction of interpretable, quantitative, morphometric features in non-tumour kidney histology. We use two internal and three external, multi-centre cohorts to analyse over 1000 kidney biopsies and nephrectomies. By associating morphometric features with clinical parameters, we confirm previous concepts and reveal unexpected relations. We show that the extracted features are independent predictors of long-term clinical outcomes in IgA-nephropathy. We introduce single-structure morphometric analysis by applying techniques from single-cell transcriptomics, identifying distinct glomerular populations and morphometric phenotypes along a trajectory of disease progression. Our study provides a concept for Next-generation Morphometry (NGM), enabling comprehensive quantitative pathology data mining, i.e., pathomics.

• MeSH
• glomerulus * patologie   MeSH
• ledviny * patologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes. Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria. This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.

• MeSH
• galaktosa metabolismus   MeSH
• glomerulární mesangium metabolismus   MeSH
• IgA nefropatie * metabolismus   patologie   MeSH
• imunoglobulin A metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Five-sixths nephrectomy is a widely used experimental model of chronic kidney disease (CKD) that is associated with severe mitochondrial dysfunction of the remnant tissue. In this study, we assessed the effect of CKD on mitochondrial respiration separately in the rat kidney cortex and medulla 10 weeks after induction of CKD by subtotal 5/6 nephrectomy (SNX). Mitochondrial oxygen consumption was evaluated on mechanically permeabilized samples of kidney cortex and medulla using high-resolution respirometry and expressed per mg of tissue wet weight or IU citrate synthase (CS) activity. Mitochondrial respiration in the renal cortex of SNX rats was significantly reduced in all measured respiratory states if expressed per unit wet weight and remained lower if recalculated per IU citrate synthase activity, i.e. per mitochondrial mass. In contrast, the profound decrease in the activity of CS in SNX medulla resulted in significantly elevated respiratory states expressing the OXPHOS capacity when Complexes I and II or II only are provided with electrons, LEAK respiration after oligomycin injection, and Complex IV-linked oxygen consumption per unit CS activity suggesting compensatory hypermetabolic state in remaining functional mitochondria that is not sufficient to fully compensate for respiratory deficit expressed per tissue mass. The results document that CKD induced by 5/6 nephrectomy in the rat is likely to cause not only mitochondrial respiratory dysfunction (in the kidney cortex), but also adaptive changes in the medulla that tend to at least partially compensate for mitochondria loss.

• MeSH
• chronická renální insuficience * MeSH
• citrátsynthasa MeSH
• krysa rodu rattus MeSH
• kůra ledviny MeSH
• ledviny * metabolismus   MeSH
• mitochondrie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Akutní poškození ledvin (AKI) léky je relativně častou nežádoucí příhodou, v určitých případech k němu mohou přispět i léky, které z dlouhodobého hlediska mají nefroprotektivní vlastnosti. Tento článek obsahuje základní informace o patogenezi AKI, o rizikových faktorech AKI a příznacích AKI a obsahuje seznam léků, které jsou spojovány se vznikem AKI.

Drug-induced acute kidney injury (AKI) is a relatively common adverse event, and in some cases, drugs that have long-term nephroprotective properties may also contribute to it. This article provides basic information about the pathogenesis of AKI, the risk factors for AKI, and the symptoms of AKI, and contains a list of drugs that are associated with the development of AKI.

• MeSH
• akutní poškození ledvin * chemicky indukované   patofyziologie   MeSH
• antiflogistika nesteroidní škodlivé účinky   MeSH
• diuretika škodlivé účinky   MeSH
• glifloziny škodlivé účinky   MeSH
• glomerulus patofyziologie   účinky léků   MeSH
• inhibitory ACE škodlivé účinky   MeSH
• klinická studie jako téma MeSH
• ledvinové kanálky patofyziologie   účinky léků   MeSH
• lidé MeSH
• nežádoucí účinky léčiv * MeSH
• otrava MeSH
• renin-angiotensin systém MeSH
• rizikové faktory MeSH
• zánět MeSH
• Check Tag
• lidé MeSH

Molecular assessment of renal allografts has already been suggested in antibody-mediated rejection (ABMR), but little is known about the gene transcript patterns in particular renal compartments. We used laser capture microdissection coupled with quantitative RT-PCR to distinguish the transcript patterns in the glomeruli and tubulointerstitium of kidney allografts in sensitized retransplant recipients at high risk of ABMR. The expressions of 13 genes were quantified in biopsies with acute active ABMR, chronic active ABMR, acute tubular necrosis (ATN), and normal findings. The transcripts were either compartment specific (TGFB1 in the glomeruli and HAVCR1 and IGHG1 in the tubulointerstitium), ABMR specific (GNLY), or follow-up specific (CXCL10 and CX3CR1). The transcriptional profiles of early acute ABMR shared similarities with ATN. The transcripts of CXCL10 and TGFB1 increased in the glomeruli in both acute ABMR and chronic active ABMR. Chronic active ABMR was associated with the upregulation of most genes (SH2D1B, CX3CR1, IGHG1, MS4A1, C5, CD46, and TGFB1) in the tubulointerstitium. In this study, we show distinct gene expression patterns in specific renal compartments reflecting cellular infiltration observed by conventional histology. In comparison with active ABMR, chronic active ABMR is associated with increased transcripts of tubulointerstitial origin.

• MeSH
• biopsie MeSH
• chronická nemoc MeSH
• dospělí MeSH
• glomerulus imunologie   metabolismus   patologie   MeSH
• HLA antigeny imunologie   MeSH
• isoprotilátky imunologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• laserová záchytná mikrodisekce MeSH
• ledviny imunologie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• rejekce štěpu genetika   imunologie   metabolismus   patologie   MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• studie případů a kontrol MeSH
• transkriptom * MeSH
• transplantace ledvin škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH