Search Results (53)

Background: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy driven by uncontrolled activation of the complement alternative pathway, with pregnancy triggering 10–20% of cases (pregnancy-associated aHUS, p-aHUS). Thalassemia, a chronic hemolytic anemia, creates a state of subclinical complement dysregulation; however, its clinical association with p-aHUS has rarely been reported. Methods: This study presents a 27-year-old primigravida with β-thalassemia intermedia requiring transfusions during pregnancy (CD17 heterozygote) who developed severe postpartum hemorrhage (1760 mL) after vaginal delivery. Over postpartum days 0–4, the patient was monitored for hematological and renal parameters. Laboratory investigations included peripheral smear, ADAMTS13 activity assay, direct Coombs test, and sC5b-9 complement level measurement. Results: Over postpartum days 0–4, the patient developed microangiopathic hemolytic anemia (hemoglobin nadir 46 g/L, lactate dehydrogenase peak 3436 U/L), thrombocytopenia (platelet nadir 31 × 10⁹/L), and acute kidney injury (creatinine peak 663 μmol/L). Peripheral smear showed 4% schistocytes. Subsequent detection revealed normal ADAMTS13 activity (90%), negative direct Coombs test, and elevated sC5b-9 (384.95 ng/mL; normal < 340). The diagnosis of p-aHUS was confirmed, and the patient received hemodialysis and recovered within three months. Conclusions: These findings suggest that chronic complement dysregulation secondary to thalassemia, combined with pregnancy-related complement stress and postpartum hemorrhage, may contribute to the development of p-aHUS. Therefore, thalassemia should be considered a potential sensitizing condition for p-aHUS, warranting close monitoring and complement evaluation in such patients. Full article

Background/Objectives: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy caused by dysregulation of the alternative complement pathway, often related to genetic mutations or autoantibodies. The introduction of complement C5 inhibitors, such as eculizumab and ravulizumab, has significantly improved renal and overall outcomes. However, complement inhibition impairs host defense against encapsulated bacteria, markedly increasing the risk of invasive infections, particularly Neisseria meningitidis. Vaccination against meningococcal groups ACWY and B, along with temporary antibiotic prophylaxis, is therefore recommended before initiating anti-C5 therapy. Methods: We report the clinical course of a 13-year-old boy with aHUS secondary to anti–complement factor H (CFH) autoantibodies and CFHR3–CFHR1 homozygous deletion, treated with C5 inhibitors. Results: Despite complete meningococcal vaccination and a previous course of antibiotic prophylaxis, the patient developed meningitis during ongoing complement inhibitor therapy. Conclusions: This case highlights that breakthrough invasive infections may occur despite adherence to recommended preventive strategies. It underscores the need for sustained clinical vigilance, timely vaccine boosters, and careful reassessment of the risk–benefit balance of continued complement inhibition therapy. Full article

The complement system is the primary defense mechanism against pathogens, acting through opsonization, the membrane attack complex, and classical, lectin, or alternative pathways. These pathways result in the production of key complement components, including C3a (complement component), C5a, and C3b, which recruit inflammatory cells. Complement dysregulation leads to renal disease through the overproduction of anaphylatoxins or inappropriate formation of the membrane attack complex. The levels of complement components have been shown to be useful as predictive markers in acute kidney injury, especially in conditions of alternative pathway activation, and in diseases of immune complex pathology such as lupus nephritis and IgA nephropathy. Genetic defects in complement regulatory proteins result in diseases such as C3 glomerulopathy or atypical hemolytic uremic syndrome, in which uncontrolled C3 convertase activity results in renal failure. Therapeutic interventions targeting complement components, including eculizumab or pegcetacoplan, improve patient outcomes in atypical hemolytic uremic syndrome and C3 glomerulopathy, respectively, while other interventions improve renal function in IgA nephropathy. These findings underscore the dual role of the complement system, which is not only implicated in the progression of renal diseases but also provides the potential for the development of therapeutic interventions for the treatment of various forms of nephropathy. Full article

Therapeutic antibodies have revolutionized hematology, offering targeted and effective treatments for both malignant and non-malignant diseases. In hematologic malignancies, anti-CD20, anti-CD19, anti-CD38, and anti–B-cell maturation antigen (BCMA) antibodies have markedly improved survival outcomes, whereas antibody–drug conjugates and bispecific antibodies continue to expand therapeutic possibilities. Besides cancer, complement inhibitors such as eculizumab, ravulizumab, and the recently approved crovalimab have redefined paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome management, and the bispecific antibody emicizumab has transformed prophylaxis in hemophilia A. Furthermore, novel antibody formats such as the trifunctional anti-CD38 × CD3 antibody (Tri-31C2) exhibit enhanced anti-myeloma activity compared to chimeric CD38 antibodies, underscoring the future potential of T-cell–redirecting designs. This review summarizes key developments in therapeutic antibodies for hematological disorders, their action mechanisms, and emerging strategies to further optimize their efficacy and safety. Full article

Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy primarily affecting the kidneys, can also involve the central nervous system (CNS), often leading to significant morbidity and mortality. Neurologic manifestations are among the most severe extra-renal complications, particularly in children and during outbreaks of Shiga toxin-producing Escherichia coli (STEC)-associated HUS (typical (tHUS)). This review explores the clinical spectrum, pathophysiology, diagnostic workup, and age-specific outcomes of neurologic involvement in both typical (tHUS) and atypical (aHUS). Neurologic complications occur in up to 11% of pediatric and over 40% of adult STEC-HUS cases in outbreak settings. Presentations include seizures, encephalopathy, focal deficits, movement disorders, and posterior reversible encephalopathy syndrome (PRES). Magnetic resonance imaging (MRI) commonly reveals basal ganglia or parieto-occipital lesions, though subtle or delayed findings may occur. Laboratory workup typically confirms microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and kidney damage, with additional markers of inflammation or metabolic dysregulation. Eculizumab is the first-line treatment for aHUS with CNS involvement, while its utility in STEC-HUS remains uncertain. Although many children recover fully, those with early CNS involvement are at greater risk of developing epilepsy, cognitive delays, or fine motor deficits. Adults may experience lingering neurocognitive symptoms despite apparent clinical recovery. Differences in presentation and imaging findings between age groups emphasize the need for tailored diagnostic and therapeutic strategies. Comprehensive neurorehabilitation and long-term follow-up are crucial for identifying residual deficits. Continued research into predictive biomarkers, neuroprotective interventions, and standardized treatment protocols is needed for improving outcomes in HUS patients with neurological complications. Full article

Background/Objectives: The field of nephrology is increasingly embracing advanced treatments and clinical trials that focus on inhibiting specific components of the complement cascade, a key driver in complement-mediated kidney diseases. Materials and Methods: This review aims to summarize innovative therapies targeting various pathways, including the inhibition of the terminal part of the complement pathway (mainly C5), the alternative pathway (factor B inhibitors), and the lectin pathway (MASP inhibitors. C5 inhibitors play a critical role in preventing the formation of the membrane attack complex (MAC), offering effective solutions for conditions like atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH). Meanwhile, avacopan, a C5a receptor antagonist, addresses ANCA-associated vasculitis (AAV) by mitigating inflammation and enabling reduced reliance on corticosteroids. Similarly, narsoplimab, which inhibits MASP-2, targets the lectin pathway implicated in conditions such as aHUS. Iptacopan, a factor B inhibitor, focuses on the alternative pathway and demonstrates efficacy in managing C3 glomerulopathy (C3G). Results: A systematic review of complement-targeted therapies was conducted, analysing studies from 2013 to 2023 that address unmet medical needs in primary and secondary glomerular diseases. Conclusions: Our systematic review of complement-targeted therapies shows that these tailored and innovative treatments may specifically address unmet medical needs in primary and secondary glomerular diseases. Full article

Complement system inhibitors are emerging as promising therapies in nephrology, particularly for diseases where complement dysregulation is central to pathogenesis. This review summarizes the role of complement activation in kidney diseases and current evidence supporting complement-targeted treatments. As the complement system can be involved in the pathogenesis of different diseases to varying degrees, several research works have been conducted. These research efforts aim, firstly, to understand the mechanisms and role of complement cascade components in the most prevalent nephrological diseases and, secondly, to explore the potential of complement system inhibitors in these conditions and their possible clinical applications. Clinical trials demonstrate that complement inhibitors are most effective in conditions with significant complement involvement, such as C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), and immune complex membranoproliferative glomerulonephritis (IC-MPGN). These agents show variable benefits in diseases with partial complement activation, including lupus nephritis and ANCA-associated vasculitis, while their role in disorders like diabetic nephropathy and focal–segmental glomerulosclerosis remains limited. Complement inhibition offers a targeted strategy to prevent disease progression and improve outcomes in selected nephrological disorders. Full article

There is rapidly increasing evidence of the role of complement in different forms of kidney disease and this has broadened the field to involve not only atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), but also a number of other glomerular diseases, mainly ANCA-associated renal vasculitis, immune-complex glomerulonephritis, membranous nephropathy, and IgA nephropathy (IgAN). In parallel, the field of therapeutic agents able to target the three complement pathways at different levels, both proximally and terminally, has grown tremendously in recent years. This has led to the approval of agents targeting complement for ANCA-associated vasculitis, IgA nephropathy, and, very recently, C3 glomerulopathy. The real-world implementation of these agents remains a challenge. This review will attempt, through the presentation of representative clinical vignettes, to provide some practical guidance for the nephrologist in how to navigate these new therapeutic opportunities, focusing on aHUS, C3G, and IgAN. Full article

Background: Atypical hemolytic uremic syndrome (HUS) is a rare form of thrombotic microangiopathy (TMA) characterized by complement dysregulation. Cocaine use has been reported to be a potential trigger of TMA; however, the underlying mechanisms remain poorly elucidated. Proposed hypotheses include direct endothelial injury, activation of the complement cascade, and the unmasking of whether HUS is genetic or acquired. Case Report: We report the case of a 47-year-old man who presented with hypertensive emergency and acute kidney injury following intranasal cocaine use. The laboratory findings were consistent with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and markedly elevated lactate dehydrogenase (LDH) levels. Renal biopsy (RB) revealed classic features of TMA, including glomerular capillary thrombosis, fibrinoid necrosis, and acute tubular injury. Complement studies demonstrated reduced levels of Factor I, indicative of complement dysregulation. The patient was treated with therapeutic plasma exchange and four weekly doses of eculizumab, resulting in hematologic remission and significant improvement in renal function, without the need for dialysis. Genetic testing for known atypical HUS-associated mutations was negative; therefore, maintenance therapy with eculizumab was discontinued without clinical relapses. Discussion: This case underscores cocaine as a rare but important precipitating factor for atypical HUS in predisposed individuals. Early diagnosis, RB, and complement evaluation were essential in determining the etiology and guiding targeted therapy. Complement inhibition with eculizumab was effective in halting disease progression and preventing long-term renal damage. Conclusions: This case highlights the relevance of considering cocaine use as a potential trigger of complement-mediated TMA. Early identification of aHUS features and prompt initiation of complement inhibition therapy may be critical to preventing irreversible kidney injury. Full article

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) characterized by complement dysregulation, leading to microvascular thrombosis and multi-organ injury. TMAs are defined by thrombocytopenia, microangiopathic hemolytic anemia and organ dysfunction caused by small-vessel thrombosis. Unlike thrombotic thrombocytopenic purpura, which results from severe ADAMTS13 deficiency, aHUS is driven by uncontrolled activation of the alternative complement pathway. While the kidneys are most frequently affected, other vital organs can also be involved. Genetic susceptibility contributes significantly to disease risk, but a trigger such as infection, pregnancy or autoimmune disease is usually required. Diagnosis is challenging due to overlapping features with other TMAs and relies on exclusion and complement testing. C5 inhibitors, such as eculizumab and ravulizumab, have revolutionized treatment but necessitate prophylactic vaccination and ongoing clinical surveillance. While these therapies provide effective disease control, discontinuing treatment remains complex, especially in patients with complement gene mutations. New therapies targeting various points in the complement cascade are under investigation and may offer safer, more cost-effective options. Progress in genetic profiling and biomarker discovery is essential for earlier diagnosis, individualized therapy and relapse prevention. This review highlights recent advances in the understanding of aHUS pathophysiology, clinical features and evolving therapeutic strategies aimed at improving patient outcomes. Full article

Case Report: We report a case of a 37-year-old female with kidney transplant, who was admitted at our hospital due to worsening renal function, nephrotic proteinuria, and anemia developed 21 days after the second dose of BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). Laboratory tests revealed hemolytic anemia, thrombocytopenia, and acute kidney injury. Given the clinical picture of Thrombotic Micro-angiopathy (TMA) and severe renal impairment, plasma exchange (PEX) and dialysis were immediately started. Laboratory workup showed low C3 and C4 levels, normal activity of ADAMTS13, and the absence of anti-factor H antibodies. Molecular biology investigations revealed a heterozygous variant in exon 22 (SCR20) of the CFH gene (c.3628C>T; p.Arg1210Cys) described as an atypical Hemolytic Uremic Syndrome (aHUS) causative mutation. Our patient completed two sessions of PEX followed by eculizumab treatment with hematological improvement but no recovery of renal function. This is the first reported case of aHUS triggered by SARS-CoV-2 vaccination in a kidney transplant patient without recovery of renal function. Conclusion: Although rare, clinicians should be aware of possible nephrological complications that may appear after vaccination. Full article

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. Full article

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. Full article

Background/Objectives: Hemolytic uremic syndrome (HUS) is a known cause of acute kidney injury in children, but there are few recent reports on its epidemiology and outcome. We aimed to investigate trends in the incidence and the long-term outcomes of both Shiga toxin-producing Escherichia coli -HUS (STEC-HUS) and atypical HUS (aHUS) in Poland over the last 12 years (2012—2023), based on the Polish Pediatric HUS and Pediatric Renal Replacement Therapy (RRT) Registries. Methods: A total of 436 patients (301 with STEC-HUS and 135 with aHUS) were included. Results: The incidence of STEC-HUS increased during the observation period, with a mean of 3.9 cases per million age-related population (marp). The incidence of aHUS was relatively constant with a mean of 1.8/marp. The majority of patients fully recovered, although kidney sequelae were observed at 5-year follow-ups in 31% of children with STEC-HUS, 57% of aHUS subjects in the pre-eculizumab era, and 37% of aHUS subjects who had received eculizumab. The overall mortality rate was 2% for STEC-HUS and 3.7% for aHUS, with no deaths reported in children on eculizumab and mortality mainly attributed to neurological damage. A decreasing incidence of chronic kidney disease stage 5 (CKD5) due to HUS was observed. Conclusions: Despite an unchanging incidence of aHUS and an increasing incidence of STEC-HUS, the kidney outcomes of both diseases have improved significantly over the last 12 years. Mortality from HUS has dropped due to improved symptomatic treatment and the introduction of anti-C5 therapy. The development of CKD5 in childhood as a consequence of HUS has become exceptional. Full article

Background/Objectives: Eculizumab is a first-line treatment for atypical hemolytic uremic syndrome (aHUS), and patients undergoing eculizumab therapy may become more susceptible to infection caused by Neisseria meningitidis (Nm). While meningococcal vaccination is required for patients undergoing eculizumab therapy, there is limited knowledge about meningococcal carriage in children with aHUS. We aimed to evaluate (1) the prevalence of Nm carriage, (2) serogroup distribution, and (3) the immunization status of children undergoing eculizumab treatment for aHUS. Methods: The Meningo-aHUS study is a prospective, multi-center study evaluating meningococcal carriage in children and adolescents in Türkiye receiving eculizumab for aHUS. We noted the age, gender, daycare, school, or university attendance, passive smoking status, previous infection and antibiotic use, and previous immunization history, including meningococcal vaccines, from the medical records of those children with aHUS. We collected nasopharyngeal samples, tested them for Nm using real-time polymerase chain reaction, and performed a serogroup analysis on the positive samples. Results: We collected nasopharyngeal samples from 62 children with aHUS. Out of 62 children, 61 (98.4%) had received at least one dose of the meningococcal vaccine. The median time since the last meningococcal vaccine dose was 15 months (1–59 months). We detected meningococcal carriage in three (4.8%, 95% CI 1.0–13.5) children, and all three strains were non-groupable (NG). No other serogroups were detected. Conclusions: Almost all the children received their risk-group meningococcal immunization, including booster doses. A 4.8% of children with aHUS carried NG meningococci and, no vaccine serogroups were detected. Patients treated with eculizumab remain profoundly susceptible to IMD due to these NG meningococcal strains. The occurrence of breakthrough cases and carriage of Nm, especially NG strains, highlights the significance of maintaining a state of constant alertness, promptly seeking medical attention, and swiftly treating any symptoms that align with IMD, regardless of their vaccination status or antibiotic prophylaxis. Full article