Establishing the Future Direction of Clinical Outcomes in C3 Glomerulopathy: Perspectives From a Patient and a Physician.

Complement 3 glomerulopathy (C3G) is an ultra-rare glomerulonephritis caused by dysregulation of the alternative complement pathway. C3G has an estimated incidence of 1-3 cases per million people in the United States. Diagnosing C3G based solely on clinical and laboratory features is challenging because it mimics several other glomerular diseases; therefore, diagnosis requires a kidney biopsy.

Atypical hemolytic uremic syndrome: diagnosis, management, and discontinuation of therapy.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy typically characterized by anemia, thrombocytopenia, and end-organ injury. aHUS occurs due to endothelial injury resulting from overactivation of the alternative pathway of the complement system. The etiology of the dysregulated complement system is either a genetic mutation in 1 or more complement proteins or an acquired deficiency due to autoantibodies.

Evaluation for genetic disease in kidney transplant candidates: A practice resource.

The increasing availability of clinically approved genetic tests for kidney disease has spurred the growth in the use of these tests in kidney transplant practice. Neither the testing options nor the patient population where this should be deployed has been defined, and its value in kidney transplant evaluation has not been demonstrated. Transplant providers may not always be aware of the limitations of genetic testing and may need guidance on comprehending test results and providing counsel, as many centers do not have easy access to a renal genetic counselor or a clinical geneticist.

Thrombotic Microangiopathies and the Kidney.

Thrombotic microangiopathy (TMA) is a pathological lesion that occurs due to endothelial injury. It can be seen in a heterogenous group of disorders, typically characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ ischemia. TMA can also be renal limited with no systemic manifestations.

Rare variants in genes coding for components of the terminal pathway of the complement system in preeclampsia.

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of the complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia.

Show Me CKDintercept Initiative: A Collective Impact Approach to Improve Population Health in Missouri.

Ninety percent of people with chronic kidney disease (CKD) remain undiagnosed, most people at risk do not receive guideline-concordant testing, and disparities of care and outcomes exist across all stages of the disease. To improve CKD diagnosis and management across primary care, the National Kidney Foundation launched a collective impact (CI) initiative known as Show Me CKDintercept. The initiative was implemented in Missouri, USA from January 2021 to June 2022, using a data strategy, stakeholder engagement and relationship mapping, learning in action working groups (LAWG), and a virtual leadership summit.

Treatment preference and quality of life impact: ravulizumab vs eculizumab for atypical hemolytic uremic syndrome.

Ravulizumab and eculizumab are complement C5 inhibitors approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Ravulizumab requires less frequent infusions than eculizumab, which may reduce treatment burden. This study investigated patients' treatment preferences and the impact of both treatments on patient and caregiver quality of life.

Mutations in atypical hemolytic uremic syndrome provide evidence for the role of calcium in complement factor I.

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy. Genetic variants in complement proteins are found in ≈60% of patients. Of these patients, ≈15% carry mutations in complement factor I (CFI).

Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study.

Objective: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.

Design: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.

Rare Dysfunctional Genetic Variants and Progression to Advanced Age-Related Macular Degeneration.

Purpose: To evaluate associations between rare dysfunctional () genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV).

Design: Prospective, longitudinal study.

Participants: Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included.

The Role of Complement in Autoimmune Disease-Associated Thrombotic Microangiopathy and the Potential for Therapeutics.

The complement system is a tightly regulated, cascading protein network representing a key component linking the innate and humoral immune systems. However, if misdirected or dysregulated, it can be similarly damaging to host-tissue. The role of complement dysregulation on vascular endothelial cells has been well established in atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and target organ injury.

Functional analysis of rare genetic variants in complement factor I in advanced age-related macular degeneration.

Factor I (FI) is a serine protease inhibitor of the complement system. Heterozygous rare genetic variants in complement factor I (CFI) are associated with advanced age-related macular degeneration (AMD). The clinical impact of these variants is unknown since a majority have not been functionally characterized and are classified as 'variants of uncertain significance' (VUS).

Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation.

Genetic testing has uncovered rare variants in complement proteins associated with thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G). Approximately 50% are classified as variants of uncertain significance (VUS). Clinical risk assessment of patients carrying a VUS remains challenging primarily due to a lack of functional information, especially in the context of multiple confounding factors in the setting of kidney transplantation.

Differentiating Hemolysis, Elevated Liver Enzymes, and Low Platelet Count Syndrome and Atypical Hemolytic Uremic Syndrome in the Postpartum Period.

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Functional Analysis of Rare Genetic Variants in Complement Factor I () using a Serum-Based Assay in Advanced Age-related Macular Degeneration.

Purpose: Factor I (FI) is a serine protease regulator of the complement system. Genetic variants in are associated with advanced age-related macular degeneration (AAMD). However, the clinical and functional impact of these variants is unknown.

The complement system in COVID-19: friend and foe?

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19-related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized.

Peri- and Post-operative Evaluation and Management of Atypical Hemolytic Uremic Syndrome (aHUS) in Kidney Transplantation.

Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by over-activation of the alternative complement pathway. The etiology of the dysregulated complement system is commonly a genetic variant in one or more complement proteins as identified in ∼ 60%-70% patients. The risk of recurrence after a kidney transplantation is high and depends on the underlying complement abnormality.

Complement Dysregulation and Disease: Insights from Contemporary Genetics.

The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation.

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD.

The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants.