Publications by authors named "Elena Goicoechea de Jorge"
Article Synopsis
- Uncontrolled activation of the complement system can lead to kidney damage in various diseases, notably affecting conditions like atypical hemolytic uremic syndrome and C3 glomerulopathy, with recent evidence linking it to diabetic nephropathy and other glomerulonephritides.
- In 2022, a conference organized by Kidney Diseases: Improving Global Outcomes (KDIGO) focused on the importance of complement dysregulation in kidney diseases, discussing its role in diagnosis and treatment strategies.
- Conference discussions highlighted patient concerns regarding genetic testing and the integration of new therapies, as well as the need for better understanding of biomarkers and the microenvironment of the kidneys to improve monitoring and treatment of these diseases.
Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Laura Lucientes-Continente Gema Fernández-Juárez Bárbara Márquez-Tirado Laura Jiménez-Villegas Mercedes Acevedo Elena Goicoechea de Jorge
Kidney Int
January 2024
Article Synopsis
- The activation of the alternative pathway (AP) of the complement system plays a significant role in the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but the exact mechanisms are not fully understood.
- Researchers analyzed gene variants and plasma levels of different complement components in a Spanish cohort of 102 AAV patients to explore the impact of the AP on the disease.
- The study found that specific genetic variants influence disease susceptibility and kidney damage severity, while high levels of AP activation and certain plasma component ratios correlate with worse outcomes, highlighting FHR-1 as a potential therapeutic target.
Key Points: Kidney survival in C3 glomerulopathy is significantly higher in patients with a disease chronicity score <4 and proteinuria <3.5 g/d, regardless of baseline eGFR. A faster eGFR decline in C3 glomerulopathy is associated with higher probability of kidney failure.
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- - The factor H (FH) protein family plays a crucial role in regulating the complement alternative pathway (AP) and influencing the risk of various diseases, such as infections, autoimmune disorders, and cancer.
- - This family consists of seven proteins in humans, with some inhibiting the AP while others promote its activation, highlighting the complex balance between these roles.
- - Recent research sheds light on the molecular mechanisms of FH proteins, emphasizing their importance in the complement activation process and the resulting implications for diseases caused by AP dysregulation.
Article Synopsis
- - After years of setbacks, complement-targeted therapies are now recognized as effective treatments for various diseases, leading to renewed interest in their potential benefits.
- - The discussion highlights the need for improved diagnostics alongside these therapies, emphasizing the role of complement biomarkers, particularly the human factor H (FH) protein family, in assessing disease risk and treatment responses.
- - The review aims to synthesize current research on circulating levels of FH proteins across different diseases and outlines crucial next steps for integrating these findings into clinical practice.
Article Synopsis
- C3 glomerulopathy is a rare kidney disease that affects how the complement system works, making it hard to predict individual patient outcomes.
- Researchers conducted a study involving 115 patients across 35 nephrology centers to develop a nomogram that forecasts long-term kidney survival using factors like estimated glomerular filtration rate (eGFR), proteinuria, and chronicity score from kidney biopsies.
- The final nomogram showed high accuracy (C-index of 0.860) in predicting kidney failure risk at 1, 2, 5, and 10 years, demonstrating reliable calibration between predicted and actual outcomes.
Article Synopsis
- - The study explores the relationship between thrombotic microangiopathy (TMA) and various causes of malignant hypertension (mHTN) in 199 patients, revealing that TMA is most prevalent in cases related to primary atypical hemolytic uremic syndrome (aHUS) and drug-related hypertension.
- - Findings indicate that patients with TMA are generally younger, predominantly female, and present with poorer kidney function and lower blood pressure levels compared to those without TMA; notably, no cases of renovascular or endocrine-related mHTN exhibited TMA.
- - The results suggest that identifying TMA in mHTN patients should prompt clinicians to consider diagnoses such as primary aHUS and drug-related hypertension,
Article Synopsis
- The article referenced by the DOI discusses a correction related to immunology research.
- It emphasizes the importance of addressing inaccuracies to maintain the integrity of scientific literature.
- The correction may involve changes in data, interpretation, or conclusions drawn from the original findings. *
Background: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.
Methods: Using and assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain.
Article Synopsis
- C3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare kidney condition, and this study examined the clinical and histological characteristics of patients diagnosed with it between 1995 and 2021.
- The study involved 23 patients, with a median age of 63 years, and found that a significant number reached kidney failure (39%) during an average follow-up of 40 months, with transplant recipients faring particularly poorly.
- The researchers concluded that the C3G histologic index is useful for predicting kidney prognosis, noting that clone-targeted therapies improved survival rates in patients who responded to treatment.
Article Synopsis
- Complement activation is critical in causing kidney damage in conditions like glomerulonephritis, with specific roles for complement factor H (FH) and FH-related protein 5 (FHR-5).
- FH serves to inhibit complement C3 activation, while FHR-5 can promote it by competing with FH for binding to C3b, particularly influenced by surface molecules known as glycosaminoglycans (GAGs).
- The study shows that FHR-5 binds to sulfated GAGs and enhances its competitive action against FH on C3b, which improves the understanding of how FHR-5 contributes to kidney diseases related to complement activation.
Article Synopsis
- * This FH family, which includes proteins like Factor H and Factor H-like protein 1, has been associated with various conditions, but the specific functions of some members remain unclear, leading to ongoing questions about their roles in disease.
- * The review highlights challenges such as controversies over the FH proteins’ functions, problems in measuring these proteins accurately, and the limitations of animal models, while also calling for interdisciplinary collaboration among researchers to overcome these obstacles in studying the FH family.
Article Synopsis
- This study investigates how changes in protein levels in urine (proteinuria) over time relate to kidney health in patients with complement component 3 (C3) glomerulopathy.
- Conducted across 35 nephrology departments in Spain, the research analyzed patient data from 1995 to 2020, focusing on the link between proteinuria trends and kidney failure risk.
- Findings reveal that higher proteinuria levels significantly increase the risk of kidney failure, while a reduction of 50% or more in proteinuria is associated with a decreased risk, highlighting proteinuria changes as useful indicators for predicting kidney outcomes.
Article Synopsis
- - Factor H-related proteins, especially FHR-1, play a role in complement activation and are linked to medical conditions like atypical hemolytic uremic syndrome (aHUS) by competing with Factor H for binding with C3b.
- - Researchers studied FHR-1 mutants, finding that aHUS-associated variants can bind sialic acids, enhancing their ability to compete with Factor H, which leads to increased complement activation.
- - The study highlights that higher FHR-1 activity compared to Factor H may lead to uncontrolled complement activation and potential diseases due to an imbalance in their activity ratios.
Article Synopsis
- A study aimed to validate a previously proposed prognostic histologic index for C3 glomerulopathy (C3G) by analyzing kidney biopsy findings in a new patient cohort from Spain.
- The research included 111 patients from various nephrology departments, with assessments focusing on demographic data, clinical parameters, and specific C3G scoring systems.
- Results showed that 43% of patients developed kidney failure, with significant predictors identified, including eGFR, proteinuria, and specific histological features like tubular atrophy and interstitial fibrosis.
Article Synopsis
- - The study investigates C3 glomerulopathy, a kidney disease linked to abnormalities in the complement system, to identify factors influencing treatment outcomes with corticosteroids and mycophenolate mofetil (MMF).
- - Conducted across 35 nephrology departments in Spain, the research analyzed data from 97 patients diagnosed with C3 glomerulopathy or dense deposit disease to evaluate remission rates and kidney survival.
- - Results showed that treatment with corticosteroids plus MMF led to significantly better outcomes (79% remission; 14% kidney failure) compared to other treatments, especially in patients with autoantibody-mediated forms, while those with genetic variants had only partial remissions.
Article Synopsis
- Genetic variability in the complement system has been linked to various diseases for over 50 years, but recent studies have shed light on how these genetic differences actually contribute to disease development.
- Specific genotype-phenotype correlations have been identified, connecting certain genetic variants to alterations in the complement system's activation and regulation, leading to insights on disease mechanisms.
- This research is paving the way for targeted anti-complement therapies and promoting a precision medicine approach that tailors treatment based on patients' complement genetic profiles.
Article Synopsis
- * In a study of 513 aHUS patients, nine showed abnormalities in the FHR-1 gene due to recurrent gene conversions, leading to mutations that hinder the regulation of complement activity in the body.
- * Functional tests revealed that these mutant proteins disrupt normal cellular processes, contributing to severe aHUS symptoms, especially in women post-childbirth, highlighting the need for comprehensive genetic testing methods to uncover these rare mutations.
Article Synopsis
- The complement field has seen significant growth in understanding how complement activators are recognized and how C3 activation occurs over the last decade.
- Advancements in structural biology have been pivotal in revealing the assembly of C3 convertases and the membrane attack complex, as well as the roles of complement regulators.
- This review focuses on new insights into the alternative and terminal complement pathways, shedding light on both confirmed understandings and surprising discoveries.
Article Synopsis
- IgA nephropathy (IgAN) is a common cause of chronic kidney disease, marked by the buildup of immune complexes containing abnormal IgA1 in the kidneys and links to complement factors in disease progression.
- In research involving 112 IgAN patients, 46 with autosomal dominant polycystic kidney disease (ADPKD), and 76 controls, it was found that both patient groups had high levels of FHR-1 protein compared to controls, with elevated levels indicating worsening kidney function.
- The study suggests that increased levels of FHR-1 may disrupt normal regulation of complement activity in IgAN and highlights the potential for further kidney damage as FHR-1 levels rise with declining renal function.
Article Synopsis
- Complement factor H-related proteins (FHRs) are linked to various diseases tied to complement dysregulation, suggesting they play a key role in regulating complement activation.
- Initially thought to be negative regulators like complement inhibitor factor H (FH), recent findings indicate that FHRs may actually enhance complement activation.
- The review proposes that FHRs act as surface recognition molecules that compete with FH, helping to distinguish between self and non-self surfaces, thus influencing complement pathway activation.
Article Synopsis
- The physiological functions of factor H-related proteins, particularly CFHR5, are not well understood, but they are linked to various glomerular diseases.
- CFHR5 has been found to bind with pentraxin 3 (PTX3) more strongly than factor H (FH), inhibiting FH's ability to bind to PTX3 and compete for binding with other proteins.
- CFHR5 appears to promote complement activation by enhancing C1q binding and supporting the formation of C3 convertase, which may contribute to glomerular disease pathology.
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition.
View Article and Find Full Text PDFThe complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins.
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