Atypical Hemolytic Uremic Syndrome Research Articles

Postpartum thrombotic microangiopathy with elevated liver enzymes: Distinguishing postpartum HELLP syndromefrom atypical hemolytic uremic syndrome.

Postpartum thrombotic microangiopathy with elevated liver enzymes: Distinguishing postpartum HELLP syndromefrom atypical hemolytic uremic syndrome.

588 Positive predictive value of applying an electronic health record toolkit (deciphEHRTM) in identifying patients with atypical hemolytic uremic syndrome in a searchable data warehouse

588 Positive predictive value of applying an electronic health record toolkit (deciphEHRTM) in identifying patients with atypical hemolytic uremic syndrome in a searchable data warehouse

277 Pregnancy induced atypical hemolytic uremic syndrome

277 Pregnancy induced atypical hemolytic uremic syndrome

Kidney and pregnancy outcomes in pregnancy-associated atypical hemolytic uremic syndrome: A systematic review and meta-analysis.

Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare, life-threatening condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, elevated liver enzymes, and acute kidney injury. Prompt diagnosis and therapy are crucial due to the high risk of progression to chronic kidney disease (CKD), end-stage kidney disease (ESKD), and dialysis dependency, as well as significant maternal and fetal morbidity and mortality. A comprehensive literature search was conducted across EMBASE, MEDLINE, and the Cochrane CENTRAL from January 2000 to March 2024. Studies reporting on pregnancy and kidney outcomes in women diagnosed with p-aHUS were included. Ten studies involving 386 pregnancies in 380 patients met the inclusion criteria for the final analysis. Renal outcomes varied, with mean creatinine levels ranging from 0.72 to 8.734 mg/dL. Dialysis was required in 66.6% of patients, and 25% developed ESKD. Maternal complications included preeclampsia (36.4%) and hemolysis, elevated liver enzymes, and low platelets syndrome (29.7%), with a 5% maternal mortality rate. Fetal complications included intrauterine fetal demise (n = 25), intrauterine growth restriction, low birth weight, and prematurity. Treatment with eculizumab significantly reduced the risk of CKD and ESKD, with a pooled risk ratio of 0.20 (95% confidence interval: 0.09-0.44) and low heterogeneity (I² = 0%, P = .43). This analysis highlights the severe kidney and pregnancy outcomes associated with p-aHUS. Eculizumab treatment is significantly beneficial in reducing the risk of CKD and ESKD.

Atypical hemolytic uremic syndrome: differential diagnosis and therapy - A clinical practice guideline for diagnosis and therapy

Atypical hemolytic uremic syndrome (aHUS) is an important differential diagnosis in thrombotic microangiopathy (TMA). The absence of definitive biomarkers usually allows for aHUS to be diagnosed only through a process of exclusion. Due to the unfavorable prognosis if adequate therapy is delayed or not provided, differential diagnostic considerations and initiation of treatment must occur promptly. The presented guideline is intended to serve as an aid in this process.

Novel immunochromatographic test for rapid detection of anti-factor H autoantibodies with an assessment of its clinical relevance

Factor H (FH) is a crucial complement regulator that prevents complement-mediated injury to healthy cells and tissues. This regulatory function can be disrupted by Factor H autoantibodies (FHAA), which then leads to diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulopathy (C3G). In pediatric aHUS, the FHAA incidence is ~10-15%, although in the Indian population, it rises to ~50%. The specific regions of FH targeted by FHAAs correlate with the pathogenic mechanism of the associated disease. In aHUS, FHAAs target the C-terminus, thereby impacting FH ability to recognize cell surfaces. In C3G, in contrast, FHAAs often target the N-terminus, generating an acquired functional FH deficiency. Detection and monitoring FHAAs are decisive for effectively treating patients. Current FHAA analysis normally identify free FHAAs that bind surface-bound FH using ELISA techniques. These methods require well-equipped laboratories and qualified staff, and do not measure FH-FHAA complexes, which can make it difficult to correlate titers with clinical outcomes. The visually-based immunochromatographic test (ICT) described herein allows for quick detection and quantification of IgG and IgM FH-FHAA complexes in human EDTA-plasma or serum. This ICT offers improved detection of FHAAs compared to ELISA as demonstrated by cases where the ICT identifies FH-FHAA complexes in samples that tested negative with the free FHAA ELISA. Importantly, the ICT indirectly informs on the amount of FH that is complexed with FHAAs, thus assessing the significance of the FHAA in disrupting the regulatory function of FH. Overall, this novel assay offers a simple, fast, cost-effective, and, likely, more clinically relevant alternative for diagnosing FHAAs in at-risk populations.

Targeted Complement Treatments in Glomerulopathies: A Comprehensive Review

The complement system includes soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates proteins with inflammatory and vasoactive activities. Although complement is crucial to host defense and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. Glomerulopathy encompasses a spectrum of diseases with diverse etiologies, clinical presentations, and outcomes. Among the intricate web of factors contributing to glomerulopathies pathogenesis, the role of complement activation has emerged as a focal point of research interest and therapeutic intervention. The pioneer drug was eculizumab, which made it possible to drastically change the prognosis of atypical hemolytic uremic syndrome, an otherwise fatal disease. This comprehensive review aims to elucidate the multifaceted interplay between complement pathways and glomerulopathies, shedding light on potential pathways for targeted therapies and improved patient care.

The membrane attack complex drives thrombotic microangiopathy in complement mediated atypical hemolytic uremic syndrome.

Introduction of complement (C) inhibition into clinical practice has revolutionized the treatment of patients with complement-mediated atypical hemolytic syndrome (aHUS). Our C3D1115N mouse model, engineered around a gain of function point mutation in C3, is associated with complement mediated aHUS in man, allowing us to study the clinical disease in a preclinical model. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled further determination of the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on kidney disease. C7 deficiency completely abolished both clinical and histological evidence of disease. Removing C5aR1 (CD88) attenuated the risk of developing clinical disease, but mice still developed thrombotic microangiopathy. Therapeutic inhibition strengthened our genetic findings showing both anti-C7 therapy and an oral C5aR1 antagonist, when used before evidence of significant kidney injury, prevented mice from succumbing to disease. However, there was ongoing histological disease within mice treated with the C5aR1 antagonist. Our data suggest that both C5aR1 and C7 play a role in the development of the conditions required for thrombotic microangiopathy of the kidney. While disrupting the C5a-C5aR1 axis is beneficial, our genetic and therapeutic studies showed that thrombotic microangiopathy of the kidney can still develop and ultimately our data confirms that the membrane attack complex is required to develop thrombotic microangiopathy of the kidney. Overall, our study shows that in addition to requiring alternative pathway dysregulation, local generation of membrane attack complex within the kidney is also critical to drive disease pathology in complement-mediated aHUS.

Extracorporeal methods of hemocorrection in kidney diseases (literature review)

The literature review is devoted to methods of extracorporeal hemocorrection, such as plasma exchange, cascade plasma filtration and immunosorption in kidney diseases, including glomerulonephritis associated with antibodies to the glomerular basement membrane, antineutrophil cytoplasmic antibodies-associated glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus erythematosus, atypical hemolytic-uremic syndrome in adults

Thrombotic Microangiopathy Associated with Systemic Adeno-Associated Virus Gene Transfer: Review of Reported Cases.

Complement-mediated thrombotic microangiopathy (TMA) in the form of atypical hemolytic uremic syndrome (aHUS) has emerged as an immune complication of systemic adeno-associated virus (AAV) gene transfer that was unforeseen based on nonclinical studies. Understanding this phenomenon in the clinical setting has been limited by incomplete data and a lack of uniform diagnostic and reporting criteria. While apparently rare based on available information, AAV-associated TMA/aHUS can pose a substantial risk to patients including one published fatality. Reported cases were originally limited to pediatric Duchenne muscular dystrophy patients receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently been reported in both pediatric and adult patients across a range of disorders, transgenes, promoters, and AAV capsid types. This article provides an introduction to the complement system, TMA and aHUS, and anticomplement therapies, then presents clinical reviews of AAV-associated TMA/aHUS cases that have been reported publicly. Finally, exploration of risk factors and current and future mitigation approaches are discussed.

Genetic Assessment of Living Kidney Transplant Donors: A Survey of Canadian Practices.

Kidney failure is a prevalent condition with tendency for familial clustering in up to 27% of the affected individuals. Living kidney donor (LKD) transplantation is the optimal treatment option; however, in Canada, more than 45% of LKDs are biologically related to their recipients which subjects recipients to worse graft survival and donors to higher future risk of kidney failure. Although not fully understood, this observation could be partially explained by genetic predisposition to kidney diseases. Genetic testing of potential LKDs may improve risk assessment and inform the safety of donation. The strategies to evaluate these donors are still evolving. In Canada, little is known about the practice of assessing for genetic conditions among LKDs. The aim was to examine the Canadian practices regarding LKDs genetic assessment. Questionnaires were sent to 23 Canadian adult transplant centers to examine their protocols for LKDs genetic assessment. The questionnaire comprised of 10 sections and 21 questions including case scenarios of different LKD encounters. Major domains of the survey addressed general demographics, information sharing practices, effect of mode of inheritance on candidacy decision, having a policy for LKD genetic evaluation, and case scenarios covering the following conditions: autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, Fabry disease, familial focal and segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), autosomal dominant tubulointerstitial kidney disease (ADTKD), sickle cell, and apolipoprotein L1 mutation (APOL1). The questionnaire was sent to the living-donor assessment committee representative (nephrologist) in adult and pediatric kidney transplant centers across Canada. In total, 16 of 23 Canadian centers responded to the survey. Of the 8 surveyed genetic conditions, ADPKD, Alport syndrome, and aHUS were the most frequently encountered. More centers have specific policies for donor evaluation for ADPKD (25%) and aHUS (21.4%) vs none to very few for other genetic conditions. The most cited guidelines are Kidney Disease Improving Global Outcomes (KDIGO), Canadian Society of Nephrology/Canadian Society of Transplantation (CSN/CST), and the Canadian Blood Services' Kidney Paired Donation Protocol. Canadian transplant centers follow a case-by-case approach rather than a standard protocol for genetic assessment of LKDs given that current guideline recommendations are based on expert opinion due to a lack of a reliable body of evidence. With the expected rise in utilization of the increasingly available genetic testing, early multidisciplinary assessment including medical geneticists has the potential to improve personalized management. Studies examining long-term donor and graft outcomes are needed to construct the basis for evidence-based recommendations and inform the safety of donations.

Extrarenal manifestations of atypical hemolytic uremic syndrome: a systematic review and meta-analysis.

Atypical Hemolytic Uremic Syndrome (aHUS) is categorized as a thrombotic microangiopathy (TMA), which arises due to abnormal or unregulated complement pathway activation. While the disease frequently affects renal blood vessels, it can also involve multiple other organ systems. This review examines the prevalence and clinical outcomes of aHUS patients with extrarenal involvement. A comprehensive literature search was performed using PubMed/Medline, Embase, the Web of Science Core Collection, and CINAHL. Search terms included 'aHUS', 'extrarenal', and specific organ systems such as neurological, gastrointestinal, and cardiovascular. Patient data was collected on clinical characteristics, including extrarenal symptoms, lab findings, genetic mutations, and adverse events. Meta-analysis was conducted using R software, version 3.1.0. A total of 47 studies were reviewed, comprising 890 aHUS patients, ranging in age from 3 months to 66 years. Common genetic abnormalities included factor H (CFH) mutations, seen in 12% (84/700 patients) across 19 studies, and anti-FH IgG autoantibodies, identified in 27.1% (102/376 patients) from 10 studies. The central nervous system was the most frequently involved extrarenal site [28% (240/858 patients) from 32 studies], with seizures as the predominant CNS symptom. Gastrointestinal symptoms were next most common [31% (230/741 patients) from 25 studies], followed by cardiovascular involvement [16% (97/607) from 23 studies]. Kidney failure was reported in 13.2% (61/463 patients) from 11 studies, with an overall mortality rate of 8.9% (56/632 patients) reported across 27 studies. Around 20-30% of aHUS patients experience extrarenal manifestations, with neurologic symptoms occurring most frequently. Due to the high costs and limited availability, genetic data is rarely reported, and studies are often small, underscoring the need for larger, multi-center cohort studies. 466915. Approximately 20-30% of patients with atypical Hemolytic Uremic Syndrome (aHUS) experienced extrarenal manifestations, with neurologic involvement being the most common. Current studies in aHUS patients are heterogeneous and inconsistent in reporting complement mutations with extrarenal manifestations. This systematic review highlights the significance of multi-system assessment in aHUS patients and the need for larger, multi-centered cohort studies.

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. Over the past decade, advancements in our understanding of the role of complement in the pathophysiology of aHUS as well as the availability of anticomplement drugs has been a game-changer for our patients. These drugs have revolutionized the clinical course, outcome, and prognosis of this disease. Therefore, all patients in whom aHUS is suspected should undergo testing for complement genetic variants and autoantibodies. In approximately 30% to 40% of patients, a genetic variant of uncertain significance (VUS) may be identified. Such patients should undergo further testing to define the significance of the VUS. A combination of antigenic, functional, and biomarker analyses can assist in establishing the significance of the variants and thereby define the etiology in most patients. These analyses will also help to determine the duration of treatment based on the individual's genetic alteration. This review aims to shed light on the diagnosis and management of aHUS and discusses how to stratify patients to determine who can safely discontinue anticomplement therapy.

Atypical Complement-Mediated Hemolytic Uremic Syndrome Triggered by Molar Pregnancy

Complement-mediated hemolytic uremic syndrome (CM HUS) is a rare but potentially devastating disease that results in intravascular hemolysis and thrombocytopenia, precipitating severe end-organ damage. CM HUS is a specific disorder under the collective group of thrombotic microangiopathies along with thrombotic thrombocytopenic purpura (TTP). Pregnancy itself can be a precipitant of CM HUS, although rare, due to dysregulated complement activation. Typical pregnancy induces elevated complement activation in effect with equal elevation of inhibitory factors to protect the fetus. In a susceptible individual, pregnancy itself may contribute to complement dysregulation resulting in CM HUS. A high index of suspicion is required to differentiate the true cause of the presentation, as there is no specific testing for CM HUS. A devastating result of CM HUS is complete renal failure. Management strategies may include plasma exchange and anti-complement immunotherapies. In this report, we will present a case of postpartum precipitated CM HUS complicated by acute kidney injury requiring hemodialysis and anti-monoclonal therapy.

De Novo C3 Glomerulonephritis of Allograft Associated with Factor H Autoantibody in a Patient with Systemic Lupus Erythematosus: A Case Report

C3 Glomerulonephritis (C3GN) is a rare disease with a challenging diagnosis and poor prognosis. It is characterized by dysregulation of alternate complement pathway and diagnosed by biopsy findings of isolated or predominant C3 deposits on immunofluorescence (IF) staining. Dysregulation of alternate complement pathway (ACP) caused by genetic mutations or autoantibodies leads to C3 glomerulopathy (C3G) and complement-mediated thrombotic microangiopathies (c-TMA), later also referred to as atypical hemolytic uremic syndrome (aHUS). Autoantibodies like C3 nephritic factor and Factor H autoantibodies (FHAA) are frequently seen as acquired abnormalities in C3GN. SLE is a multi-system complex disorder distinguished by the presence of autoantibodies to multiple nuclear antigens, including DNA and ribonucleoprotein leading to complement activation, characterized by low level of C3 and C4 and may present with c-TMA. There are not many cases of C3GN with SLE that have been described, and current literature lacks strong evidence-based treatment options of post-transplant C3GN. Here, we describe a case of de novo C3GN of allograft in a patient with SLE.

Controlling complement in the kidney: Updates on management of aHUS and IgAN from Kidney Week

The complement cascade is a key component of the immune system that plays an important role in recognizing pathogens and mounting an appropriate defence. When activated in the wrong contexts or misdirected against inappropriate tissues, it can lead to various disease pathologies, our understanding of which is continually evolving. In the kidney, complement-mediated injury has long been established as a driver of atypical hemolytic uremic syndrome (aHUS), and more recently, a role for complement has been recognized in IgA nephropathy (IgAN). At the recent Kidney Week meeting of the American Society of Nephrology, several clinical and real-world studies investigated the impact of using complement inhibitors in these two conditions. This report summarizes the most relevant findings and provides perspective from Canadian experts about the implications for clinical practice

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: A Single-Center Experience.

Coronavirus disease 2019 (COVID-19) can lead to various multisystem disorders, including thrombotic microangiopathy (TMA). We present here eight patients with COVID-19-associated TMA who were treated at our center. Our aim was to summarize the demographic and clinical characteristics of the patients and discuss the possible role of COVID-19. One patient presented with thrombotic thrombocytopenic purpura (TTP) and seven with atypical hemolytic-uremic syndrome (aHUS.) Most patients had no obvious symptoms of COVID-19, and TMA occurred after viremia. Two patients had concomitant non-COVID-19-related triggers for TMA: exposure to tacrolimus and everolimus; first presentation of antiphospholipid syndrome. The patient with TTP was treated with therapeutic plasma exchange (TPE), steroids and caplacizumab, resulting in complete hematologic recovery. Six patients with aHUS were treated with TPE with or without steroids, four of whom received a C5 complement inhibitor and one an intravenous immunoglobulin. One patient with aHUS was treated with a C5 complement inhibitor and a steroid. We observed one partial and one complete recovery of renal function, while five patients experienced renal failure. There were no deaths. We believe that COVID-19 may act as a trigger for TMA in patients who have either pre-existing endothelial injury or an underlying predisposition to complement activation, and may also trigger autoimmune diseases. As a consequence of the different underlying pathophysiologies, the treatment of COVID-19-associated TMA requires a specific approach based on the subtype of the syndrome and possible concomitant triggers.

What is proven in the treatment of complement-mediated kidney diseases?

Complement-mediated kidney diseases encompass acomplex group of diseases that are primarily caused by dysregulation of the complement system. The complement system is acrucial component of the innate immune system consisting of soluble and membrane-bound proteins. The complement system is essential for the defence against pathogens and homeostasis but its uncontrolled activation can lead to an exaggerated cellular response to immunogenic, inflammatory and metabolic stimuli. For example, glomerular deposition of immune complexes can activate the complement system and contribute to the progression of kidney diseases. The most well-known complement-mediated kidney diseases are atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, which falls under the group of membranoproliferative glomerulonephritis (MPGN). Diagnosing these diseases requires detailed investigations with respect to triggering factors, including genetic analyses and the measurement of specific complement factors. New therapeutic approaches with drugs targeting complement system activation are now offering promising treatment options. These medications fundamentally differ from other immunosuppressive drugs and specifically target the pathological processes within the complement system. This article provides an overview of the mechanisms of complement regulation, the pathophysiological foundations of complement-mediated kidney diseases and the latest diagnostic and therapeutic advances. The goal is to provide adeeper understanding of these complex conditions and to emphasize the importance of an interdisciplinary approach in treatment and research.

Treatment discontinuation in adults with atypical hemolytic uremic syndrome (aHUS): a qualitative study of international experts’ perspectives with associated cost-consequence analysis

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) related to congenital mutations impeding control of the alternative pathway of complement. Following approval of the complement C5 inhibitor eculizumab by the European Medicines Agency and the US Food and Drug Administration, initial guidelines suggested lifelong therapy. Yet, growing evidence indicates that discontinuation of eculizumab, or its long-acting form ravulizumab, is possible for many patients. This mixed-methods study sought to explore international experts’ perspectives and experiences related to treatment duration in adult patients with aHUS, while also estimating the financial and potential health consequences of early discontinuation.MethodsBetween January and December 2023, we conducted 10 qualitative interviews with experts in the treatment of aHUS, based upon which we constructed a quantitative decision tree, designed to estimate time on treatment and treatment- and disease-related adverse events.ResultsThematic analysis of the interview data identified four main themes: (1) Concerns and prior experience; (2) High-risk vs. low-risk groups; (3) Patient preference and adherence; and (4) Funding for monitoring and re-treatment. Although most interviewees were in favour of considering treatment discontinuation for many patients (citing the high cost, burden, and potential side effects of lifelong treatment as key reasons), a prior negative experience of discontinuation seemed to make others more reluctant to stop. Deciding which patients required lifelong treatment and which not involved consideration of a wide range of factors, including patient- and system-related factors. Cost-consequence analysis demonstrated the financial savings associated with early treatment discontinuation at the expense of increased risk of recurrent TMA events. Close monitoring for these events had the potential to minimise any long-term injury, primarily renal, with an estimated one event per 100 patient years. For patients at high risk of TMA and with poor adherence to monitoring, rates of renal injury rose to three events per 100 patient years.ConclusionsaHUS treatment protocols are changing globally in response to new clinical evidence. Against this backdrop, our mixed-methods study provides compelling evidence on the complexity of factors influencing treatment discontinuation decisions in aHUS, as well as the financial and health consequences of early discontinuation.

Prospective validation of initial eculizumab dosing in adults with atypical hemolytic uremic syndrome.

Prospective validation of initial eculizumab dosing in adults with atypical hemolytic uremic syndrome.