Review
Urology & Nephrology
Kultigin Turkmen, Ismail Baloglu, Hakan Ozer
Summary: The complement system is crucial in the pathogenesis of C3 glomerulopathy (C3GP) and atypical hemolytic uremic syndrome (aHUS), with recent research suggesting common abnormalities in the control of the alternative complement system between the two diseases. This overlap may impact treatment strategies for both conditions.
INTERNATIONAL UROLOGY AND NEPHROLOGY
(2021)
Article
Immunology
Sigridur Sunna Aradottir, Ann-Charlotte Kristoffersson, Lubka T. Roumenina, Anna Bjerre, Pavlos Kashioulis, Runolfur Palsson, Diana Karpman
Summary: The study indicates that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Yuzhou Zhang, Renee X. Goodfellow, Nicolo Ghiringhelli Borsa, Hannah C. Dunlop, Stephen A. Presti, Nicole C. Meyer, Dingwu Shao, Sarah M. Roberts, Michael B. Jones, Gabriella R. Pitcher, Amanda O. Taylor, Carla M. Nester, Richard J. H. Smith
Summary: C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are rare diseases caused by dysregulated activity of the alternative pathway of complement. This study investigated the functional activity of select CFI missense variants in patients with C3G and aHUS. The researchers found that rare CFI variants were associated with altered FI protein levels and activity, highlighting the complexity and multifactorial nature of these complement-mediated renal diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Medicine, General & Internal
Zhen Ren, Stephen J. Perkins, Latisha Love-Gregory, John P. Atkinson, Anuja Java
Summary: Genetic testing in a kidney transplant cohort revealed rare variants in complement proteins associated with TMA and C3G, with approximately 50% classified as variants of uncertain significance. Structural and functional analysis of identified variants in complement factor H were conducted, determining both deleterious and normal functional activity. The study highlights the importance of functional analysis of genetic variants in complex clinicopathologic scenarios, providing insights for clinical decision making after kidney transplantation.
FRONTIERS IN MEDICINE
(2021)
Article
Immunology
Viktor Rydberg, Sigridur Sunna Aradottir, Ann-Charlotte Kristoffersson, Naila Svitacheva, Diana Karpman
Summary: This study describes genetic variants in the Swedish and Norwegian populations associated with atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G), and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). Genetic screening of patients with these conditions revealed a total of 68 different genetic variants or deletions in aHUS patients, 29 genetic variants or deletions in C3G patients, and 5 genetic variants in IC-MPGN patients, with 26 novel variants identified. The findings highlight the importance of genetic screening for diagnostics and treatment in these patients.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Urology & Nephrology
Gema Ariceta, Bradley P. Dixon, Seong Heon Kim, Gaurav Kapur, Teri Mauch, Stephan Ortiz, Marc Vallee, Andrew E. Denker, Hee Gyung Kang, Larry A. Greenbaum
Summary: Ravulizumab rapidly improved hematologic and kidney parameters in complement inhibitor-naive children with atypical hemolytic uremic syndrome, showing no unexpected safety concerns.
KIDNEY INTERNATIONAL
(2021)
Article
Urology & Nephrology
Marie Sophie Meuleman, Paula Vieira-Martins, Carine El Sissy, Vincent Audard, Veronique Baudouin, Dominique Bertrand, Frank Bridoux, Ferielle Louillet, Claire Dossier, Vincent Esnault, Noemie Jourde-Chiche, Alexandre Karras, Marie-Pascale Morin, Francois Provot, Philippe Remy, David Ribes, Caroline Rousset-Rouviere, Aude Servais, Eric Thervet, Leila Tricot, Mohamad Zaidan, Alain Wynckel, Julien Zuber, Moglie Le Quintrec, Veronique Fremeaux-Bacchi, Sophie Chauvet
Summary: A study found that 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH, CFI, or C3 genes. These variants were linked to poor kidney outcomes.
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
Article
Immunology
Sarah de Jong, Anita de Breuk, Bjorn Bakker, Suresh Katti, Carel B. Hoyng, Sara C. Nilsson, Anna M. Blom, Lambert P. van den Heuvel, Anneke I. den Hollander, Elena B. Volokhina
Summary: Complement factor I (FI) is a key regulator of the complement system, and its dysfunction is associated with increased complement activation and diseases like AMD and aHUS. This study identified CFI gene variants in AMD and aHUS, with more than half leading to reduced FI secretion levels. Functional analysis of 11 rare missense variants revealed 8 variants with impaired C3b degradation, suggesting their likely pathogenicity. Monitoring iC3b in a degradation assay is a useful tool for assessing the functional impact of CFI variants.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Genetics & Heredity
Masafumi Tsuchida, Shin Goto, Hirofumi Watanabe, Sawako Goto, Hiroki Yamaguchi, Ichiei Narita
Summary: Through exome sequence analysis, eight rare variants shared by aHUS patients were identified. Among the prioritized variants, C3 p.W1034R was determined as the most likely candidate gene mutation, despite its classification as a variant of uncertain significance. C3 p.W1034R may result in an inherited form of aHUS that often presents with recurrent episodes, possibly due to impaired interactions between the C3d and C-terminal domains of factor H.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Genetics & Heredity
Ludwig Haydock, Alexandre P. Garneau, Laurence Tremblay, Hai-Yun Yen, Hanlin Gao, Raphael Harrisson, Paul Isenring
Summary: The prevalence of known causative or risk-associated variants in adult-onset aHUS and C3G is lower than 30 to 50%, but extended exome panels and in vitro analyses can identify novel variants of potential clinical significance and candidate genes.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2022)
Article
Urology & Nephrology
Kishor Devalaraja-Narashimha, Karoline Meagher, Yifan Luo, Cong Huang, Theodore Kaplan, Anantharaman Muthuswamy, Gabor Halasz, Sarah Casanova, John O'Brien, Rebecca Peyser Boiarsky, John McWhirter, Hans Gartner, Yu Bai, Scott MacDonnell, Chien Liu, Ying Hu, Adrianna Latuszek, Yi Wei, Srinivasa Prasad, Tammy Huang, George Yancopoulos, Andrew Murphy, William Olson, Brian Zambrowicz, Lynn Macdonald, Lori G. Morton
Summary: A novel murine model of C3G was developed by replacing the mouse C3 gene with the human C3 homolog, leading to rapid disease progression and early mortality. The model demonstrated similar pathological features to human C3G, providing insights into disease mechanisms and potential therapeutic approaches.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2021)
Article
Urology & Nephrology
Magdalena Riedl Khursigara, Mina Matsuda-Abedini, Seetha Radhakrishnan, Michelle A. Hladunewich, Mathieu Lemaire, Chia Wei Teoh, Damien Noone, Christoph Licht
Summary: Transition of clinical care of pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis to adult nephrologists poses challenges. Raising awareness, providing education, and establishing ongoing dialogue are crucial for optimal patient outcomes and safe transition to adulthood.
ADVANCES IN CHRONIC KIDNEY DISEASE
(2022)
Review
Medicine, General & Internal
Ali Jandal, Weixiong Zhong, Deepak Gopal, Vanessa Horner, Leah Frater-Rubsam, Arjang Djamali, Gauri Bhutani
Summary: We present a case of a female patient with mixed nephritic-nephrotic syndrome and recurrent pancreatitis. Kidney biopsy revealed crescentic membranoproliferative glomerulonephritis with dominant C3 staining on immunofluorescence. Genetic testing revealed a rare C3 variant and a deletion of CFHR3CFHR1. The case highlights the challenges of treating complement-mediated kidney disease and suggests the existence of a C3G/aHUS overlap syndrome.
AMERICAN JOURNAL OF THE MEDICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
I-Ru Chen, Chiu-Ching Huang, Siang-Jyun Tu, Guei-Jane Wang, Ping-Chin Lai, Ya-Ting Lee, Ju-Chen Yen, Ya-Sian Chang, Jan-Gowth Chang
Summary: This single-cell sequencing study confirms the importance of immune cell dysregulation in the pathogenesis of aHUS, providing valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Hematology
Vicky Brocklebank, Patrick R. Walsh, Kate Smith-Jackson, Thomas M. Hallam, Kevin J. Marchbank, Valerie Wilson, Theophile Bigirumurame, Tina Dutt, Emma K. Montgomery, Michal Malina, Edwin K. S. Wong, Sally Johnson, Neil S. Sheerin, David Kavanagh
Summary: Our study demonstrates the efficacy of eculizumab in improving ESKD-free survival in patients with complement-mediated atypical hemolytic uremic syndrome. The response to eculizumab treatment is influenced by the underlying genotype and clinical characteristics.
Article
Transplantation
Mendy ter Avest, Romy N. Bouwmeester, Caroline Duineveld, Kioa L. Wijnsma, Elena B. Volokhina, Lambertus P. W. J. van den Heuvel, David M. Burger, Jack F. M. Wetzels, Nicole C. A. J. van de Kar, Rob ter Heine
Summary: This study evaluated the pharmacokinetics and pharmacodynamics of eculizumab in patients with atypical haemolytic uraemic syndrome (aHUS) and proposed improved dosing strategies. The study found that individualized dosing strategy could improve treatment response and reduce treatment costs by prolonging the dosing interval.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Article
Genetics & Heredity
Nzar A. A. Shwan, Eric C. Moise, Paula E. Necsoiu, Amy J. Farr, Daniel P. Gale, Jonathan Barratt, John A. L. Armour
Summary: In this study, the researchers investigated the association between DEFA1A3 copy number variation (CNV) and IgA nephropathy. They measured DEFA1A3 copy number in UK family trios with an affected offspring and used population distributions to infer segregation in trios. The researchers observed some evidence for over- and undertransmission of specific haplotypes, but these effects were not statistically significant after correction for multiple testing.
ANNALS OF HUMAN GENETICS
(2023)
Review
Immunology
Santiago Rodriguez de Cordoba
Summary: The implementation of next-generation sequencing technologies has revealed the association between genetic variability in the components and regulators of the alternative pathway (AP) of the complement system and various diseases. Genetic variants in the AP affect specific aspects of its activation and regulation, providing valuable insights into pathogenic mechanisms and potential diagnostic and therapeutic implications. However, limited data exists on complement expressed quantitative trait loci, and further research is needed to identify and understand their impact on the overall activity of the AP.
IMMUNOLOGICAL REVIEWS
(2023)
Review
Immunology
Marina Noris, Miriam Galbusera
Summary: The complement and hemostatic systems have functional interactions and play important roles in regulating immune response and preventing bleeding. Both systems involve proteins that activate each other and regulate the function of endothelial cells, platelets, and immune cells. Dysregulation of either system can lead to severe thromboinflammatory events.
IMMUNOLOGICAL REVIEWS
(2023)
Correction
Urology & Nephrology
J. Savige, A. Renieri, E. Ars, S. Daga, A. M. Pinto, H. Rothe, D. P. Gale, M. Aksenova, A. Cerkauskaite, O. Bielska, B. Lipska-Zietkiewicz, J. T. Gibson
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
Correction
Biochemistry & Molecular Biology
Sergio Daga, Jie Ding, Constantinos Deltas, Judy Savige, Beata S. Lipska-Zietkiewicz, Julia Hoefele, Frances Flinter, Daniel P. Gale, Marina Aksenova, Hirofumi Kai, Laura Perin, Moumita Barua, Roser Torra, Jeff H. Miner, Laura Massella, Danica Galesic Ljubanovic, Rachel Lennon, Andre B. Weinstock, Bertrand Knebelmann, Agne Cerkauskaite, Susie Gear, Oliver Gross, A. Neil Turner, Margherita Baldassarri, Anna Maria Pinto, Alessandra Renieri
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Dermatology
Jenny Giang, Martijn B. A. van Doorn, Gilles F. H. Diercks, Santiago Rodriguez de Cordoba, Thierry P. P. van den Bosch, Marco W. J. Schreurs, Felix Poppelaars, Jeffrey Damman
Summary: This study investigates complement activation in BP skin biopsies and serum samples. The authors found activation of classical and alternative complement pathways, but not lectin pathway. Inhibition of C1 and factor B selectively reduced complement deposition, while inhibition of C3 and C5 reduced both deposition and release of complement.
EXPERIMENTAL DERMATOLOGY
(2023)
Article
Pediatrics
Mallory L. Downie, Sanjana Gupta, Melanie M. Y. Chan, Omid Sadeghi-Alavijeh, Jingjing Cao, Rulan S. Parekh, Carmen Bugarin Diz, Agnieszka Bierzynska, Adam P. Levine, Ruth J. Pepper, Horia Stanescu, Moin A. Saleem, Robert Kleta, Detlef Bockenhauer, Ania B. Koziell, Daniel P. Gale
Summary: A genetic risk score can help classify patients with INS presenting in different ways when monogenic causes are excluded.
PEDIATRIC NEPHROLOGY
(2023)
Article
Immunology
Emily K. Glover, Kate Smith-Jackson, Vicky Brocklebank, Valerie Wilson, Patrick R. Walsh, Emma K. Montgomery, Edwin K. S. Wong, Sally Johnson, Michal Malina, David Kavanagh, Neil S. Sheerin
Summary: Prophylactic eculizumab treatment dramatically improves graft survival, making transplantation a viable therapeutic option in aHUS.
Article
Urology & Nephrology
Mallory L. Downie, Sanjana Gupta, Catalin Voinescu, Adam P. Levine, Omid Sadeghi-Alavijeh, Stephanie Dufek-Kamperis, Jingjing Cao, Martin Christian, Jameela A. Kari, Shenal Thalgahagoda, Randula Ranawaka, Asiri Abeyagunawardena, Rasheed Gbadegesin, Rulan Parekh, Robert Kleta, Detlef Bockenhauer, Horia C. Stanescu, Daniel P. Gale
Summary: This study aimed to identify additional genetic loci associated with steroid-sensitive nephrotic syndrome (SSNS) in children. Through genome-wide association studies, the researchers found associations between the HLA-DQ/DR and AHI1 genes with SSNS. The AHI1 gene is involved in ciliary protein transport and immune dysregulation.
KIDNEY INTERNATIONAL REPORTS
(2023)
Article
Hematology
Vicky Brocklebank, Patrick R. Walsh, Kate Smith-Jackson, Thomas M. Hallam, Kevin J. Marchbank, Valerie Wilson, Theophile Bigirumurame, Tina Dutt, Emma K. Montgomery, Michal Malina, Edwin K. S. Wong, Sally Johnson, Neil S. Sheerin, David Kavanagh
Summary: Our study demonstrates the efficacy of eculizumab in improving ESKD-free survival in patients with complement-mediated atypical hemolytic uremic syndrome. The response to eculizumab treatment is influenced by the underlying genotype and clinical characteristics.
Article
Hematology
M. Scully, R. Rayment, A. Clark, J. P. Westwood, T. Cranfield, R. Gooding, C. N. Bagot, A. Taylor, V. Sankar, D. Gale, T. Dutt, J. McIntyre, W. Lester, BSH Comm
Summary: The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Genetics & Heredity
Constantinos Deltas, Gregory Papagregoriou, Stavroula F. Louka, Apostolos Malatras, Frances Flinter, Daniel P. Gale, Susie Gear, Oliver Gross, Julia Hoefele, Rachel Lennon, Jeffrey H. Miner, Alessandra Renieri, Judy Savige, A. Neil Turner
Summary: Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, most commonly caused by pathogenic variants in the COL4A3/A4/A5 genes. The disease can lead to kidney failure, but the severity and progression vary among patients. Currently, it is still uncertain how to distinguish patients who require prompt medical intervention.
Article
Multidisciplinary Sciences
Matteo Breno, Marina Noris, Nadia Rubis, Aneliya Ilieva Parvanova, Davide Martinetti, Sara Gamba, Lucia Liguori, Caterina Mele, Rossella Piras, Silvia Orisio, Elisabetta Valoti, Marta Alberti, Olimpia Diadei, Elena Bresin, Miriam Rigoldi, Silvia Prandini, Tiziano Gamba, Nadia Stucchi, Fabiola Carrara, Erica Daina, Ariela Benigni, ORIGIN Study Grp
Summary: This study conducted a genetic association study on the outcome of COVID-19 in a homogeneous population from Bergamo province, which was heavily impacted by the SARS-CoV-2 pandemic in Europe. The results showed an association between the 3p21.31 locus and disease severity, with a stronger effect in severely ill patients. Additionally, transcriptome-wide association study identified eQTLs for LZTFL1 and CCR9, and 17 previously unreported loci were suggestive for an association with COVID-19 severity or susceptibility.
Meeting Abstract
Hematology
David Kavanagh
INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY
(2023)