The role of complement in normal pregnancy and preeclampsia.

Preeclampsia affects 3-4% of pregnancies with adverse effects for both mother and child. Minimal therapeutic options are available, and biomarkers are urgently needed to identify those at greatest risk early in the pregnancy. Both the innate and adaptive immune systems are well regulated during normal pregnancy including the complement system.

Management recommendations for kidney transplantation in patients with plasma cell dyscrasia.

Patients with plasma cell dyscrasia, including multiple myeloma, AL amyloidosis, and monoclonal gammopathy of renal significance, face a high burden of end-stage kidney disease, which limits survival and quality of life. Although kidney transplant offers potential benefits, it remains underused because of the high risk of recurrence and historically poor outcomes. A multidisciplinary panel of transplant nephrologists, hematologists/oncologists, and pathologists convened to evaluate contemporary evidence and evolving strategies in kidney transplant for plasma cell dyscrasias and end-stage kidney disease.

Closing Gaps in Chronic Kidney Disease Detection: Evaluating At-Home Targeted Testing in a Safety-Net Population.

Introduction: Chronic Kidney Disease (CKD) affects 1 in 7 adults in the United States, yet 90% of those impacted remain unaware of their condition, and fewer than 20% of at-risk individuals are appropriately tested. Safety-net health care settings are disproportionately burdened by CKD, with a patient population enriched for CKD risk factors, social deprivation, and barriers to diagnostic testing which delay access to diagnosis and lifesaving interventions. The National Kidney Foundation partnered with a Federally Qualified Health Center (FQHC) to evaluate an approach to increase guideline-recommended testing among patients at high-risk for developing CKD.

Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13.

Preeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia.

Gene-Environment Interaction: Lessons From Complement-Mediated Kidney Disease.

Atypical hemolytic uremic syndrome (aHUS) or complement-mediated thrombotic microangiopathy (CM-TMA) and C3 glomerulopathy are two prototypical diseases of complement dysregulation occurring due to genetic variants in complement proteins or acquired factors such as autoantibodies. Despite the presence of an underlying genetic etiology, an environmental trigger is often necessary to manifest disease, a phenomenon known as incomplete penetrance. These triggers could include infections, pregnancy, medication, cancers, or ischemia-reperfusion injury and antibody-mediated rejection in the setting of transplantation and highlight the complex interplay between genetic etiology and environmental factors.

Complement activation in secondary thrombotic microangiopathies.

Secondary thrombotic microangiopathies (TMA) represent a heterogeneous group of diseases associated with a high risk of kidney failure and death despite available therapeutic strategies. Strong evidence implicates complement dysregulation in the pathogenesis of secondary TMA, and emerging data increasingly suggest that pharmacological blockade of the complement improves the outcomes in patients with secondary TMA. Certain forms of secondary TMA, including postpartum TMA, TMA with coexisting hypertensive emergency and de novo TMA after kidney transplantation exhibit a high prevalence of pathogenic variants in complement genes, similar to those observed in primary atypical hemolytic uremic syndrome.

Thrombotic Microangiopathy After Kidney Transplantation: Insights Into Genetic Etiology and Clinical Outcomes.

Introduction: Thrombotic microangiopathy (TMA), characterized by small-vessel thrombosis caused by endothelial injury, presents significant diagnostic and treatment challenges in kidney transplantation.

Methods: To investigate the factors associated with posttransplant TMA, we conducted a retrospective study of 3535 kidney transplant recipients at our center from 2008 to 2023.

Results: Sixty-eight patients were diagnosed with TMA, and 93% (63 of 68) underwent genetic testing.

Post-transplant Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is a challenging and serious complication of kidney transplantation that significantly affects graft and patient survival, occurring in 0.8%-15% of transplant recipients. TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to endothelial damage and microthrombi formation in small vessels.

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.

Atypical hemolytic uremic syndrome: genetically-based insights into pathogenesis through an analysis of the complement regulator CD46.

The complement system is a critical innate immune defense mechanism that also facilitates antigen recognition as well as antibody production through the adaptive immune response. Overall, complement activation contributes to the immune system's recognition and response to foreign pathogens and altered self. Regulating complement activation, particularly its powerful alternative pathway (AP) amplification loop, plays a key role in modulating tissue damage at sites of injury.

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.