All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease. The aim of this study was to comprehensively characterise a novel model of HF with cardiorenal syndrome, i.e. DOXO-induced HFrEF with nephrotic syndrome, in which DOXO was administered to Ren-2 transgenic rats (TGR) via five intravenous injections in a cumulative dose of 10 mg/kg of body weight (BW). Our analysis included survival, echocardiography, as well as histological examination of the heart and kidneys, blood pressure, but also a broad spectrum of biomarkers to evaluate cardiac remodelling, fibrosis, apoptosis, oxidative stress and more. We have shown that the new model adequately mimics the cardiac remodelling described as "eccentric chamber atrophy" and myocardial damage typical for DOXO-related cardiotoxicity, without major damage of the peritoneum, lungs and liver. This pattern corresponds well to a clinical situation of cancer patients receiving anthracyclines, where HF develops with some delay after the anticancer therapy. Therefore, this study may serve as a comprehensive reference for all types of research on DOXO-related cardiotoxicity, proving especially useful in the search for new therapeutic strategies.

• MeSH
• antibiotika antitumorózní škodlivé účinky   MeSH
• doxorubicin * škodlivé účinky   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   patofyziologie   MeSH
• modely nemocí na zvířatech * MeSH
• nefrotický syndrom * chemicky indukované   farmakoterapie   patofyziologie   MeSH
• oxidační stres účinky léků   MeSH
• potkani transgenní * MeSH
• srdeční selhání * chemicky indukované   patofyziologie   MeSH
• tepový objem * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency.

• MeSH
• apoptóza genetika   MeSH
• arterioskleróza genetika   etiologie   imunologie   MeSH
• dítě MeSH
• DNA-helikasy genetika   MeSH
• lidé MeSH
• metabolické nemoci kostí etiologie   genetika   MeSH
• nefrotický syndrom etiologie   genetika   MeSH
• oprava DNA * genetika   MeSH
• osteochondrodysplazie * genetika   imunologie   MeSH
• plicní embolie genetika   etiologie   MeSH
• poruchy růstu genetika   etiologie   MeSH
• primární imunodeficience * genetika   diagnóza   imunologie   MeSH
• syndromy imunologické nedostatečnosti genetika   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Several previous studies have reported a more severe course of nephrotic syndrome in children with low birth weight. PATIENTS: Cohort of 223 children with idiopathic nephrotic syndrome. METHODS: We aimed to investigate the association between course of nephrotic syndrome and low birth weight. Data from seven paediatric nephrology centres were used. RESULTS: Children with low birth weight had 3.84 times higher odds for a more severe course of steroid-sensitive nephrotic syndrome (95% CI 1.20-17.22, P=0.041), and those with low birth weight and remission after 7 days had much higher odds for a more severe course of disease (OR 8.7). Low birth weight children had a longer time to remission (median 12 vs. 10 days, P=0.03). They had a higher need for steroid-sparing agents (OR for the same sex=3.26 [95% CI 1.17-11.62, P=0.039]), and the odds were even higher in females with low birth weight (OR 6.81). There was no evidence of an association either between low birth weight and focal segmental glomerulosclerosis or between low birth weight and steroid-resistant nephrotic syndrome. DISCUSSION: We conducted the first multicentric study confirming the worse outcomes of children with NS and LBW and we found additional risk factors. CONCLUSIONS: Low birth weight is associated with a more severe course of steroid-sensitive nephrotic syndrome, while being female and achieving remission after 7 days are additional risk factors.

• MeSH
• dítě MeSH
• fokálně segmentální glomeruloskleróza farmakoterapie   MeSH
• glukokortikoidy terapeutické užití   škodlivé účinky   MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• nefrotický syndrom * farmakoterapie   MeSH
• novorozenec s nízkou porodní hmotností * MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• rizikové faktory MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie 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

x

x

• MeSH
• cystická onemocnění ledvin * diagnóza   etiologie   klasifikace   MeSH
• lidé MeSH
• nefrotický syndrom klasifikace   patologie   MeSH
• novorozenec MeSH
• postnatální péče MeSH
• prenatální diagnóza MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

Idiopatický steroid senzitivní nefrotický syndrom je nejčastější glomerulopatií dětského věku, která je ve většině případů spojena s dobrou prognózu. U 50 % nemocných dochází ke vzniku častých relapsů nebo k závislosti na kortikoidech. V současné době máme k dispozici několik steroid šetřících léků, které podáváme s cílem navodit trvalou remisi onemocnění a vyhnout se nežádoucím účinkům kortikoidů. V našem přehledovém článku shrnujeme současné poznatky o diagnostice a léčbě steroid senzitivního nefrotického syndromu u dětí.

Idiopathic steroid-sensitive nephrotic syndrome is the most common pediatric glomerulopathy. Most of the patients have favorable outcome, however 50% of children suffer from frequently relapsing course or they are steroid dependent. At present, several steroid sparing agents are available, which are administered to induce sustained remission and to prevent steroid side effects. Here, we review current knowledge in diagnostics and management of steroid-sensitive nephrotic syndrome in children.

• MeSH
• dítě MeSH
• glukokortikoidy MeSH
• imunosupresiva aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• nefrotický syndrom * diagnóza   farmakoterapie   MeSH
• nežádoucí účinky léčiv MeSH
• prednison aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

Nefrotický syndrom (NS) je charakterizován velkou proteinurií (nad 3,5 g/24 h), hypalbuminemií, generalizovanými otoky, hyperlipidemií a poruchami koagulace. Vedle primárních glomerulonefritid se vyskytuje u sekundárních glomerulopatií při diabetu, amyloidóze, systémových zánětlivých chorobách, onkologických onemocněních, u poškození léky a drogami, při alergiích, závažných infekcích a u dětí jsou i formy vrozené. Nejčastější příčinou NS v dospělosti je diabetes mellitus (DM). V současnosti je DM příčinou 40 % selhání ledvin u nemocných na dialýze. Z hlediska prevence je proto věnována velká pozornost gliflozinům (SGLT2 inhibitory), které mají prokazatelně nefroprotektivní účinky. Glifloziny vedou k navození glyko- surie, doprovázené současně natriurézou a osmotickou diurézou. Účinnost gliflozinů na snížení glykemie je proporcionální k úrovni glomerulární filtrace, zatímco efekty vázané na natriurézu jsou zachovány ve všech stadiích renální insuficience.

Nephrotic syndrome (NS) is characterized by high proteinuria (over 3,5g/24 hrs), hypalbuminaemia, general edemas and hypercoagulation. Beside of primary glomerulonephritides this is found in secundary glomerulopaties eg. diabetes, systemic inflammatory diseases, oncology, damage by drugs and poisoning, by alergy, serious infections and in children from hereditary reasons. The most frequent reason for NS in adults patiens is diabetes and diabetes with nephropathy represents almost 40% of dialysed patiens. From this point of view, there is great interest focusing on gliflozins (SGLT2 inhibitors) with positive nephroprotecive effect. It leads do increasing of glycosuria with concomitant natriuresis and osmotic diuresis. The effect is proportional to glomerulal filtration, but the effect on natriuresis stay in all stages of renal insufficiency.

• MeSH
• diabetes mellitus MeSH
• diabetické nefropatie diagnóza   farmakoterapie   prevence a kontrola   MeSH
• glifloziny aplikace a dávkování   terapeutické užití   MeSH
• hypoproteinemie diagnóza   etiologie   MeSH
• lidé MeSH
• metabolismus MeSH
• multimorbidita MeSH
• nefrotický syndrom * diagnóza   etiologie   terapie   MeSH
• proteinurie diagnóza   etiologie   patofyziologie   MeSH
• Check Tag
• lidé MeSH

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

• MeSH
• celogenomová asociační studie * MeSH
• dítě MeSH
• genetická predispozice k nemoci MeSH
• haplotypy MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nefrotický syndrom * genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

• MeSH
• akutní poškození ledvin diagnóza   etiologie   komplikace   terapie   MeSH
• diabetické nefropatie diagnóza   etiologie   farmakoterapie   MeSH
• glifloziny farmakologie   terapeutické užití   MeSH
• hepatorenální syndrom etiologie   patofyziologie   terapie   MeSH
• kardiorenální syndrom epidemiologie   farmakoterapie   patofyziologie   MeSH
• komorbidita MeSH
• komplikace diabetu diagnóza   etiologie   terapie   MeSH
• nefrotický syndrom diagnóza   komplikace   terapie   MeSH
• nemoci ledvin * diagnóza   etiologie   terapie   MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: Schimke immunoosseous dysplasia (SIOD) is an ultra-rare inherited disease affecting many organ systems. Spondyloepiphyseal dysplasia, T-cell immunodeficiency and steroid resistant nephrotic syndrome are the main symptoms of this disease. CASE PRESENTATION: We aimed to characterize the clinical, pathological and genetic features of SIOD patients received at tertiary Pediatric Nephrology Center, University Hospital Motol, Prague, Czech Republic during the period 2001-2021. The mean age at diagnosis was 21 months (range 18-48 months). All patients presented with growth failure, nephropathy and immunodeficiency. Infections and neurologic complications were present in most of the affected children during the course of the disease. CONCLUSIONS: Although SIOD is a disease characterized by specific features, the individual phenotype may differ. Neurologic signs can severely affect the quality of life; the view on the management of SIOD is not uniform. Currently, new therapeutic methods are required.

• MeSH
• centra terciární péče MeSH
• kvalita života MeSH
• lidé MeSH
• nefrotický syndrom * diagnóza   genetika   komplikace   MeSH
• osteochondrodysplazie * diagnóza   genetika   terapie   MeSH
• syndromy imunologické nedostatečnosti * diagnóza   genetika   komplikace   MeSH
• vzácné nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika MeSH