Kidney fibrosis is the hallmark of chronic kidney disease (CKD) and is characterized by an imbalanced extracellular matrix (ECM) remodeling. Collagen type III is one of the main ECM components of the interstitial matrix of the kidney. We hypothesized that measuring three biomarkers of collagen type III reflecting different aspects of this protein turnover (C3M, C3C, and PRO-C3) may provide different information about the fibrotic burden in patients with IgA nephropathy (IgAN). We examined a cohort of 134 patients with IgAN. The three collagen type III biomarkers were measured in serum (S) and in urine (U) samples taken on the same day before kidney biopsy was performed. Biopsies were evaluated for interstitial fibrosis and tubular atrophy, according to the Banff and MEST-C scores. S-PRO-C3 and S-C3C correlated with the degree of fibrosis in the biopsy, whereas U-C3M/Cr had an inverse correlation with fibrosis. U-C3M/Cr had the highest discrimination ability for advanced fibrosis, which was maintained after adjustment for the other collagen type III biomarkers, proteinuria, and serum creatinine. The data presented in this study indicate that measuring the different fragments of the same ECM protein and in different matrices provides a variety of information regarding pathological kidney tissue alterations in patients with IgAN.
- MeSH
- biologické markery MeSH
- fibróza MeSH
- IgA nefropatie * patologie MeSH
- kolagen typ III MeSH
- komplement C3 analýza MeSH
- ledviny patologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR-/-) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR-/- mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.
INTRODUCTION: Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition. METHODS: The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement. RESULTS: Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence. CONCLUSION: Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.
- MeSH
- inhibitory komplementu terapeutické užití metabolismus MeSH
- komplement C3 metabolismus terapeutické užití MeSH
- komplement C5 terapeutické užití MeSH
- lidé MeSH
- paroxysmální hemoglobinurie * farmakoterapie MeSH
- znalecký posudek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- systematický přehled MeSH
- Geografické názvy
- Evropa MeSH
Atypický hemolyticko-uremický syndrom (aHUS) je vzácné, život ohrožující onemocnění řadící se mezi trombotické mikroangiopatie. Je charakterizováno přítomností mikroangiopatické hemolytické anemie, trombocytopenie a akutního poškození ledvin. Příčinou onemocnění je dysregulace aktivity komplementu, přičemž více než polovina případů vzniká v důsledku vrozených či získaných abnormalit alternativní cesty komplementu. Terapie aHUS je obvykle zahajována bez znalosti konkrétní diagnózy; do 24 hodin by měla být započata výměnná plazmaferéza či podávání infuzí plazmy. Léčbou volby u nemocných s prokázaným aHUS je inhibitor C5 složky komplementu ekulizumab, který blokuje štěpení C5 a brání tvorbě membránu atakujícího komplexu, čímž přímo potlačuje mechanismus vzniku onemocnění. Alternativou ekulizumabu je novější inhibitor C5 složky ravulizumab, který se vyznačuje srovnatelnou účinností, má však 4násobně delší biologický poločas, což umožňuje jeho aplikaci v 8týdenních intervalech. Nižší frekvence infuzí je přitom jedním z nejvýznamnějších faktorů, které zlepšují kvalitu života pacientů. V klinických studiích je zkoumána i řada dalších léčiv zaměřených na komplement, která mohou v budoucnu nabídnout další možnosti terapie.
Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease classified as a thrombotic microangiopathy. It is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The cause of the disease is dysregulation of complement activity, with more than half of the cases resulting from congenital or acquired abnormalities of the alternative complement pathway. Therapy for aHUS is usually initiated without knowledge of the specific diagnosis; plasmapheresis or plasma infusions should be started within 24 hours. The treatment of choice for patients with established aHUS is the C5 complement component inhibitor eculizumab, which blocks C5 cleavage and prevents the formation of the membrane-attacking complex, thereby directly suppressing the mechanism of disease. An alternative to eculizumab is the newer C5 inhibitor ravulizumab, which has comparable efficacy but a 4-fold longer biological half-life, allowing it to be administered at 8-week intervals. The lower frequency of infusions is one of the most important factors improving the quality of life of patients. A number of other complement-targeted drugs are also being investigated in clinical trials and may offer additional therapeutic options in the future.
- Klíčová slova
- Ravulizumab, ekulizumab,
- MeSH
- atypický hemolyticko-uremický syndrom * farmakoterapie MeSH
- humanizované monoklonální protilátky farmakologie terapeutické užití MeSH
- inhibitory komplementu * farmakologie terapeutické užití MeSH
- komplement C3 antagonisté a inhibitory účinky léků MeSH
- komplement C5 antagonisté a inhibitory účinky léků MeSH
- lidé MeSH
- plazmaferéza metody MeSH
- Check Tag
- lidé MeSH
Pegcetakoplan (Aspaveli, Sobi) je prvním inhibitorem C3 složky komplementu schváleným pro terapii paroxysmální noční hemoglobinurie. Subkutánně podávaný pegcetakoplan inhibuje štěpení C3 na C3a a C3b a aktivaci dalších částí komplementové kaskády, čímž reguluje intravaskulární i extravaskulární hemolýzu. Jeho účinnost byla demonstrována u dosud neléčených pacientů ve studii PRINCE i u pacientů již léčených inhibitorem C5 ve studii PEGASUS – v této studii byla prokázána superiorita pegcetakoplanu oproti ekulizumabu z hlediska zvýšení hodnoty hemoglobinu a non-inferiorita pegcetakoplanu oproti ekulizumabu z hlediska podílu pacientů bez závislosti na transfuzích a změny absolutního počtu retikulocytů. V obou studiích vedla terapie pegcetakoplanem ke klinicky významnému zmírnění únavy a zlepšení kvality života nemocných. Léčba pegcetakoplanem byla dobře snášena.
Pegcetacoplan (Aspaveli, Sobi) is the first complement component 3 (C3) inhibitor approved for the treatment of paroxysmal noctural haemoglobinuria. Subcutaneous pegcetacoplan inhibits the cleavage of C3 into C3a and C3b and the downstream effectors of complement activation, thereby regulating both intravascular and extravascular haemolysis. Its efficacy has been demonstrated in treatment na�ve patients in the PRINCE trial and in patients formerly treated with C5 inhibitor in the PEGASUS trial – in this study, pegcetacoplan was shown to be superior to eculizumab in terms of increased haemoglobin levels and noninferior to eculizumab in terms of the proportion of transfusion independent patients and change in the absolute reticulocyte count. In both trials, pegcetacoplan therapy led to a clinically meaningful alleviation of fatigue and improvement in the quality of life of the patients. The treatment with pegcetacoplan was well tolerated.
- Klíčová slova
- Pegcetakoplan,
- MeSH
- cyklické peptidy * farmakologie terapeutické užití MeSH
- inhibitory komplementu terapeutické užití MeSH
- komplement C3 antagonisté a inhibitory farmakologie MeSH
- lidé MeSH
- paroxysmální hemoglobinurie * farmakoterapie MeSH
- randomizované kontrolované studie jako téma metody MeSH
- Check Tag
- lidé MeSH
Akutní postinfekční glomerulonefritida představuje akutní glomerulární zánět, který vzniká jako následek proběhlé infekce. Řada infekčních patogenů může vyvolat vznik této glomerulonefritidy, ale nejčastější příčinou zůstává Streptococcus pyogenes. Průběh onemocnění může být různý, někteří jedinci jsou asymptomatičtí, u jiných se rozvine závažný nefritický syndrom či rapidně progredující glomerulonefritida. V laboratoři typicky nacházíme sníženou C3 složku komplementu. Léčba je hlavně symptomatická, důležitá je včasná diagnostika a korekce hypertenze. Prognózu lze obecně považovat za příznivou, nicméně většina pacientů potřebuje dlouhodobé ambulantní sledování.
Acute postinfectious glomerulonephritis is an acute glomerular inflammation that results from the preceding infection. Although multiple infectious agents can cause acute postinfectious glomerulonephritis, Streptococcus pyogenes remains the most common etiology of the disease. The clinical presentation varies from asymptomatic state to severe forms of nephritic syndrome or rapidly progressive glomerulonephritis. Decreased C3 complement level is typically associated with this type of glomerulonephritis. The therapy is mainly supportive, early diagnosis and management of hypertension is important. The prognosis is mostly favourable, however, long-term follow-up is needed in the majority of patients.
Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.
- MeSH
- aktivace komplementu MeSH
- alely MeSH
- biologické markery * MeSH
- dospělí MeSH
- ELISA MeSH
- genetická predispozice k nemoci MeSH
- genetická variace * MeSH
- imunokomplex imunologie MeSH
- jednonukleotidový polymorfismus MeSH
- komplement C3 imunologie MeSH
- komplement genetika metabolismus MeSH
- lidé MeSH
- management nemoci MeSH
- membranoproliferativní glomerulonefritida krev diagnóza etiologie mortalita MeSH
- mladiství MeSH
- mladý dospělý MeSH
- náchylnost k nemoci MeSH
- prognóza MeSH
- ROC křivka MeSH
- studie případů a kontrol MeSH
- určení symptomu MeSH
- vyšetření funkce ledvin MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- autoimunitní hemolytická anemie * diagnóza farmakoterapie krev patologie MeSH
- Coombsův test MeSH
- hematologické testy MeSH
- hemoglobiny analýza účinky léků MeSH
- komplement C3d analýza MeSH
- lidé MeSH
- rituximab aplikace a dávkování MeSH
- senioři MeSH
- Waldenströmova makroglobulinemie diagnóza komplikace MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
PURPOSE: We investigated associations between neovascular age-related macular degeneration (AMD) and rs10490924 polymorphism of ARMS2 gene (age-related maculopathy susceptibility 2), rs1061170 polymorphism of gene for complement factor H (CFH), rs2230199 polymorphism of gene for complement component C3 and rs11200638 polymorphism of gene for serine protease high-temperature requirement A1 (HTRA1) in the Czech population. METHODS: We analysed samples of DNA from 307 patients diagnosed with neovascular form of late AMD (average age: 73.7 ± 7.7 years) and 191 control subjects, recruited from patients awaiting cataract surgery (average age, 73.6 ± 8.7 years). RESULTS: HTRA1, CFH and ARMS2 genes polymorphisms were found to be related to neovascular AMD in the Czech population. All analysed polymorphisms were statistically significantly associated with neovascular AMD, with stronger associations in females than in males. In whole group, CC genotype of CFH gene polymorphism, TT genotype of ARMS2 gene polymorphism and AA genotype of HTRA1 gene polymorphism showed the greatest risk for neovascular AMD with odds ratios equal to 8.43, 10.07, 9.83, respectively (p < 0.0001). Only CG polymorphism of C3 gene showed statistically significant risk for neovascular AMD. In addition, we observed an association between waist circumference and neovascular AMD in both sexes, which further suggests the significance of excessive abdominal fat as a risk factor of AMD. We found a statistically significant association between polymorphisms in HTRA1, CFH and ARMS2 genes and neovascular AMS in the Czech population. The association was stronger in females than in males. CONCLUSION: We demonstrated a relationship between neovascular AMD and genes for HTRA1, CFH, ARMS2 and C3 in Czech population. To our knowledge, the relationship between these polymorphisms and neovascular AMD in Czech population has never been investigated before.
- MeSH
- abdominální obezita komplikace MeSH
- jednonukleotidový polymorfismus MeSH
- komplement - faktor H genetika MeSH
- komplement C3 genetika MeSH
- lidé MeSH
- makulární degenerace genetika MeSH
- proteiny genetika MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- serinová proteasa HTRA1 genetika MeSH
- sexuální faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and a common cause of end-stage renal disease. Evaluation of a kidney biopsy is necessary for diagnosis, with routine immunofluorescence microscopy revealing dominant or co-dominant IgA immunodeposits usually with complement C3 and sometimes IgG and/or IgM. IgA nephropathy reduces life expectancy by more than 10 years and leads to kidney failure in 20-40% of patients within 20 years of diagnosis. There is accumulating clinical, genetic, and biochemical evidence that complement plays an important role in the pathogenesis of IgA nephropathy. The presence of C3 differentiates the diagnosis of IgA nephropathy from the subclinical deposition of glomerular IgA. Markers for the activation of the alternative and mannan-binding lectin (MBL) pathways in renal-biopsy specimens are associated with disease activity and portend a worse renal outcome. Complement proteins in the circulation have also been evaluated in IgA nephropathy and found to be of prognostic value. Recently, genetic studies have identified IgA nephropathy-associated loci. Within these loci are genes encoding products involved in complement regulation and interaction with immune complexes. Put together, these data identify the complement cascade as a rational treatment target for this chronic kidney disease. Recent case reports on the successful use of humanized anti-C5 monoclonal antibody eculizumab are consistent with this hypothesis, but a better understanding of the role of complement in IgA nephropathy is needed to guide future therapeutic interventions.
- MeSH
- chronická renální insuficience imunologie MeSH
- glomerulonefritida imunologie MeSH
- IgA nefropatie imunologie MeSH
- imunoglobulin A imunologie MeSH
- komplement C3 imunologie MeSH
- komplement C5 imunologie MeSH
- ledviny imunologie MeSH
- lidé MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
