The C3 p.Ile1157Thr mutation associated with atypical hemolytic uremic syndrome, particularly in Japan, does not lead to disease development in several mouse models.

Eculizumab Successfully Rescues Against de novo Atypical Hemolytic Uremic Syndrome Following Retransplantation.

Ravulizumab is a long-acting C5 complement inhibitor that provides sustained suppression of the complement pathway. It is currently approved by the US Food and Drug Administration (FDA) for the treatment of generalized myasthenia gravis, paroxysmal nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome. With its increasing clinical use, concerns regarding Ravulizumab-associated adverse drug reactions have grown. This study utilized a dataset extracted from the Adverse Event Reporting System (FAERS) database, comprising adverse event reports from the fourth quarter of 2018 to the second quarter of 2025. Four distinct disproportionality analysis methods-the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN)-were applied. Additionally, the time-to-onset profile of adverse events was assessed using the Weibull distribution model. A total of 9,090 adverse event reports associated with ravulizumab were included in this analysis. Commonly reported adverse events included fatigue, asthenia, headache, malaise, dyspnea, back pain, feeling abnormal, and diplopia. Furthermore, potential adverse events not listed on the drug label were identified, such as anemia, dysphagia, urinary tract infection, and somnolence. This investigation identified several adverse events associated with ravulizumab and revealed potential adverse reaction signals that were not previously recognized. Healthcare providers may consider these safety signals to more comprehensively assess potential risks in patients during clinical practice.

Atypical hemolytic-uremic syndrome (aHUS) is a serious problem in pediatrics and pediatric nephrology due to its severe course, tendency to progression, high mortality, and unresolved issues of early diagnosis and therapy. This circumstance dictates the need to improve existing diagnostic approaches and allows timely detection of aHUS and initiation of treatment at an early stage, which will significantly increase the chances of a favorable outcome. This publication presents 2 clinical cases of aHUS associated with antibodies to factor H in patient K., 4 years old, and patient U., 5 years old, who were treated at the state budgetary healthcare institution Children's Regional Clinical Hospital of the Ministry of Health of the Krasnodar Territory. Both children were admitted to the aHUS clinic, but genetic studies have not revealed mutations in specific genes associated with this disease. An increased titer of antibodies to factor H was found, which may indicate an acquired form of thrombotic microangiopathy. Positive dynamics was observed against the background of complement inhibitory therapy

Atypical hemolytic uremic syndrome (aHUS) is an intravascular hemolytic disorder caused by complement dysregulation. A 41-year-old female patient with end-stage kidney disease and a history of glomerulonephritis had been receiving frequent blood transfusions for anemia and thrombocytopenia with hemolytic findings. She came to our hospital for a living donor kidney transplant from her mother, and a preoperative evaluation revealed ABO incompatibility and strong positivity in the T-cell flow cytometry crossmatch (FCXM) due to broad anti-HLA antibodies sensitized by previous blood transfusions. Since her clinical course and genetic testing led to the diagnosis of aHUS, treatment with eculizumab was started prior to kidney transplantation. She received desensitization therapy with intravenous immunoglobulin, plasma exchange, and rituximab along with regular eculizumab treatment, and then underwent living donor kidney transplantation. She achieved stable renal function without developing antibody-mediated rejection (ABMR) or the recurrence of thrombotic microangiopathy (TMA). Kidney graft biopsies 3months and 1year after transplantation showed no ABMR or TMA, with stable renal function. We herein report a positive FCXM case with aHUS that safely underwent living donor kidney transplantation without ABMR or the recurrence of TMA by starting eculizumab and desensitization therapy before surgery.

Skin involvement in haemolytic uremic syndrome (HUS) raises suspicion for atypical HUS; here, we report a child with gangrene and confirmed STEC-HUS. A 3-year-old boy with aggressive HUS presented with leukocytes 33,100/mm3, haemoglobin 7.8g/dL, platelets 93,000/mm3, LDH 6020IU/L, creatinine 2.4mg/dL, sodium 124mEq/L, albumin 1.9g/dL, C-reactive protein 94mg/L. He required peritoneal dialysis, mechanical ventilation for seizures, and milrinone for cardiac dysfunction. On day seven, ischemic lesions on two fingertips developed, prompting plasma infusions. Skin biopsy confirmed thrombotic microangiopathy (TMA). Further investigations confirmed STEC infection (anti-LPS IgM positive) and excluded aHUS and other TMA causes, allowing plasma therapy discontinuation and avoidance of eculizumab. After 21days of dialysis and 13 days of mechanical ventilation, the patient was discharged. Two months later, fingertip auto-amputation occurred. This case highlights the importance of differentiating STEC-HUS from aHUS when skin involvement is present, given the major therapeutic and prognostic implications.

C3 mutation-associated atypical hemolytic uremic syndrome with severe renal dysfunction and hypertensive emergency successfully treated with ravulizumab and sacubitril/valsartan: a case report.

Recurrent Atypical Hemolytic-Uremic Syndrome (aHUS) Associated With CD46 Genetic Mutation: A Report of a Rare Case

Patient: Female, 26-year-oldFinal Diagnosis: Actinomycosis • atypical hemolytic-uremic syndromeSymptoms: Epigastric abdominal painClinical Procedure: CholecystectomySpecialty: Infectious Diseases • General and Internal MedicineObjective: Rare diseaseBackgroundActinomycosis is an uncommon bacterial infection caused by the commensal organism Actinomyces spp., which can become pathogenic upon tissue injury or disruption of the mucosal barrier. While primarily recognized for its cervicofacial and abdominopelvic presentations, actinomycosis can also involve the gallbladder and potentially the pancreas, posing diagnostic and therapeutic challenges due to its ability to mimic other conditions.Case ReportWe present the case of a 26-year-old woman with a history of recurrent acute pancreatitis and cholecystitis, followed by the development of thrombotic microangiopathy. An atypical hemolytic-uremic syndrome panel revealed gene mutations previously associated with the onset of this condition. Computed tomography, endoscopic ultrasound, and abdominal ultrasound revealed focal enlargement of secondary ducts in the head of the pancreas. While no gallbladder wall thickening was observed, imaging demonstrated a substantial amount of heterogeneous, predominantly hypoechoic and amorphous content within the gallbladder, suggestive of biliary sludge. The patient subsequently underwent cholecystectomy, and histopathological examination of the gallbladder specimen confirmed the presence of Actinomyces spp., observed as sulfur granules and Gram-stained bacilli, as well as varying degrees of mucosal hyperplasia, transmural fibrosis, xanthomatous histiocytes, and Rokitansky-Aschoff sinuses.ConclusionsFollowing the procedure and appropriate antimicrobial therapy, the patient experienced resolution of the infection, improvement in overall health status, and no new episodes of pancreatitis during the following year. We propose that underlying CFHR3 and CFI gene mutations and initial systemic inflammation precipitated the thrombotic microangiopathy–atypical hemolytic uremic syndrome, and facilitated Actinomyces colonization of the compromised gallbladder, ultimately leading to chronic gallbladder disease and recurrence.

Overactivation of the complement system plays a role in the pathophysiology of several serious kidney diseases, such as IgA nephropathy, complement 3 glomerulopathy, atypical hemolytic uremic syndrome, and ANCA-associated vasculitis. A key focus of recent research has been developing complement inhibitors to target the underlying disease mechanisms of these diseases and thereby improve patient outcomes. Currently, five complement inhibitors are approved by the US Food and Drug Administration as effective for the treatment of kidney diseases: eculizumab, ravulizumab, avacopan, iptacopan, and pegcetacoplan. However, some of these therapies may increase the risk of serious, potentially life-threatening infections, particularly from encapsulated organisms including Neisseria meningitidis , Streptococcus pneumoniae , and Haemophilus influenzae type b. Health care providers must recognize this risk and implement preventive measures when prescribing complement inhibitors. This review summarizes the infectious risks associated with complement inhibitors and highlights key clinical considerations for their safe and effective use in the treatment of kidney diseases. It is intended to serve as an accessible resource for providers using these agents in clinical practice.

Complement-targeting therapies in hemolytic diseases.

ABSTRACTExtensive hepatic infarction is a rare but potentially fatal complication of HELLP syndrome and is often difficult to recognize because of nonspecific clinical manifestations. A 34‐year‐old woman developed HELLP syndrome shortly after cesarean delivery for severe pre‐eclampsia, presenting with oliguria, marked thrombocytopenia (50 × 109/L), and rapidly rising transaminases (ALT 1077 U/L, AST 1280 U/L). Contrast‐enhanced computed tomography (CT) revealed extensive hepatic infarction. Laboratory findings demonstrated microangiopathic hemolysis, severe coagulopathy, and acute kidney injury. Transient elevation of the terminal complement complex C5b‐9 raised concern for atypical hemolytic uremic syndrome. The patient was treated with plasma exchange, corticosteroids, organ support, and individualized anticoagulation guided by bleeding risk assessment. Serial follow‐up demonstrated sustained hematologic, renal, and hepatic recovery, ultimately excluding atypical hemolytic uremic syndrome. This case highlights the importance of imaging‐guided diagnosis, dynamic laboratory evaluation, and individualized therapeutic decision‐making in HELLP syndrome complicated by severe hepatic injury.

Thrombotic microangiopathy (TMA) is a pathological condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic organ dysfunction due to microvascular endothelial damage and thrombosis. It affects ∼0.8%-14% of kidney transplant recipients, and may manifest as either a recurrent or de novo disease. While systemic manifestations are commonly anticipated, kidney-limited TMA can also occur and is not rare. Histopathologic examination of allograft biopsies shows morphologic features indicating endothelial injury, and repeated episodes of TMA may result in coexisting acute and chronic lesions within the same patient. In transplant recipients, multiple triggers contribute to endothelial damage, including ischemia-reperfusion injury, antibody-mediated rejection, immunosuppressive agents (calcineurin and mTOR inhibitors), and infections. The risk is particularly important in individuals with genetic variants that dysregulate the alternative complement pathway. In de novo TMA, environmental triggers and transplant-related stressors play a central role, whereas genetic predisposition is the primary factor in recurrent cases. Notably, these mechanisms often overlap and may act synergistically. Recurrent atypical hemolytic uremic syndrome can successfully be managed with terminal complement inhibitors, and prophylactic use of eculizumab in the peri-transplant period has significantly reduced recurrence rates. Management of de novo TMA begins with the identification and removal of precipitating factors. In cases where no clear trigger is found, or when the disease proves refractory to conventional therapy, terminal complement inhibition may be an effective therapeutic option. The prognosis of recurrent TMA has improved substantially with the advent of complement targeting therapies but research is still needed to optimize management strategies.

Eculizumab is effective in treating paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Given its high cost and the clinical risks associated with undertreatment or overtreatment, dose individualization is essential. Model-informed precision dosing can optimize therapy using pharmacokinetic (PK) model predictions. This study conducted a primarily internal validation to evaluate the predictive performance of a previously published PK model of eculizumab for model-informed precision dosing. The model's ability to predict future free trough concentrations was assessed using retrospective data from therapeutic drug monitoring. Acceptable bias and precision were defined as mean prediction error and normalized root mean square error less than 25%. Dose adjustments were evaluated based on target trough concentrations of 50 µg/mL for dose escalation and 200 µg/mL for interval extension. The model adequately predicted future trough concentrations. In patients with paroxysmal nocturnal hemoglobinuria, bias and precision were -3.0% and 10.3%, respectively, when using one trough concentration; -8.4% and 24.9%, respectively, when using a trough and a peak concentration; and -4.7% and 16.3%, respectively, when using two trough concentrations. In patients with atypical hemolytic uremic syndrome, bias and precision were 6.1% and 35.5%, respectively, when using one trough concentration; 15.1% and 25.7%, respectively, when using a trough and a peak concentration; and 11.2% and 23.2%, respectively, when using two trough concentrations. The model's predictions led to correct dose recommendations for >80% of patients in most analyses. These results demonstrate that the eculizumab PK model can predict future trough concentrations with acceptable bias and precision.

Rationale:Sepsis can trigger life-threatening atypical hemolytic uremic syndrome (aHUS) through dysregulated complement activation. Diagnosis is challenging due to overlapping features with septic shock, often leading to delayed recognition and high mortality.Patient concerns:A 23-year-old female with chronic kidney disease presented with a 3-day history of productive cough, fever, and progressive dyspnea, which rapidly escalated to respiratory failure, anuria, and coma within 24 hours.Diagnoses:Laboratory findings confirmed thrombotic microangiopathy (hemoglobin 57 g/L, platelets 69 × 109/L, schistocytes 0.3%, lactate dehydrogenase [LDH] 469 U/L) and acute kidney injury (creatinine 535 µmol/L). The diagnosis of complement-mediated aHUS was established by markedly elevated soluble C5b-9 (sC5b-9) (578 ng/mL) with preserved a disintegrin and metalloproteinase with thrombospondin motifs 13 activity (89%).Interventions:Critical care included mechanical ventilation and continuous renal replacement therapy. Specific aHUS therapy comprised plasma exchange (10 sessions) and complement blockade with eculizumab (900 mg weekly for 4 weeks, then 1200 mg every 2 weeks), accompanied by meningococcal prophylaxis.Outcomes:By day 31, hematologic and renal parameters improved (platelets 72 × 109/L, LDH 273 U/L, creatinine 151 µmol/L). By day 51, complement activity normalized (sC5b-9 261 ng/mL, a 54.8% reduction), with full hematologic recovery (platelets 198 × 109/L, LDH 171 U/L), renal function near baseline (creatinine 96 µmol/L), and resolution of hemolysis.Lessons:In sepsis with persistent thrombocytopenia despite infection control, urgent sC5b-9 testing is critical to diagnose aHUS. Eculizumab, combined with supportive continuous renal replacement therapy and plasma exchange, can effectively reverse multi-organ failure even during active bacteremia, with serial sC5b-9 monitoring serving as a key biomarker for guiding therapy.

Treatment of atypical hemolytic uremic syndrome and C3 glomerulopathy in mice by hepatic expression of factor D.

Ravulizumab drug monitoring has not been explored for maintenance therapy in patients with complement-mediated (atypical) hemolytic uremic syndrome (aHUS). Phase III trials suggest the standard dosing regimen provides troughs about threefold higher than needed to suppress complement activity. We describe the use of ravulizumab in pediatric patients with aHUS in remission, exploring potential modified dosing strategies based on serum drug levels and complement markers. This single-center, retrospective cohort study included pediatric patients with aHUS in remission receiving outpatient ravulizumab infusions between June 30, 2023, and March 31, 2024, with at least one ravulizumab trough. Patients received a standard (SR) or a modified (MR) regimen, determined by the nephrologist. The primary outcome was to describe troughs and corresponding AH50 for patients on at least two equal doses. Secondary outcomes included comparison of troughs by regimen, intra-patient variability, possible adverse drug events (pADE), and drug costs. Nine patients were included. The mean ravulizumab trough level was 399.1 (± 107.3) mcg/mL. All patients exceeded the goal of 175 mcg/mL and achieved AH50 < 10%. Four patients (44%) received ravulizumab according to a MR. No difference was observed in ravulizumab trough levels between SR and MR groups (P = 0.67). Patients with multiple troughs showed low intra-patient variability (CV < 25%). pADE rates were similar across regimens, and MR was associated with lower drug costs. Individualized maintenance regimens of ravulizumab based on trough and complement monitoring appear safe and effective while reducing drug costs. Further study is needed to define the optimal ravulizumab maintenance dosing strategy.

The alternative pathway (AP) of the complement system plays a critical role in the pathogenesis of various human diseases, including age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and several glomerular diseases. Although the approved drug Iptacopan is available, it requires twice-daily oral dosing, resulting in suboptimal patient compliance. Using a scaffold-hopping strategy, we identified the clinical candidate (3R,4R)-15, which exhibits potent inhibitory activity against factor B (FB) and the AP, with IC50 values of 10.2 nM and 59.3 nM, respectively. Furthermore, this compound exhibits significantly improved pharmacokinetic properties, including an oral bioavailability of 69.2% in mice. Preliminary clinical studies indicate that (3R,4R)-15 has promising efficacy in patients with PNH. Its once-daily dosing regimen also offers the potential to markedly improve patient compliance. (3R,4R)-15 is currently in Phase 3 trials evaluating its efficacy for the treatment of PNH.

BackgroundWithin 10 months of the declaration of the coronavirus disease 2019 (COVID-19) pandemic, multiple vaccines, including messenger ribonucleic acid, adenoviral vector, and inactivated vaccines, were developed. Adverse events associated with vaccination are closely monitored. Thrombotic microangiopathy after administration of the Pfizer/BioNTech BNT162b2 vaccine is a rare but serious adverse event.Case reportWe report a 28-year-old healthy female who developed fever, arthralgias, myalgias, swelling of the feet, and bilateral loin pain 3 days after receiving the Pfizer/BioNTech BNT162b2 vaccine. She was diagnosed with acute kidney injury with raised creatinine and proteinuria. Kidney biopsy revealed a hilar thrombus, extensive glomerular basement membrane remodelling, and endothelial lesions attributed to vascular injury caused by the BNT162b2 vaccine. She responded well to conservative management and recovered fully from her renal failure.ConclusionOur patient’s favourable outcome of renal-limited thrombotic microangiopathy with little lasting effects is unique compared to other cases leading to end-stage renal disease or death. A high index of suspicion is needed for early diagnosis. The study of vaccine adverse effects is paramount to improve safety and confidence surrounding COVID-19 vaccination.LEARNING POINTSRenal-limited thrombotic microangiopathy is a rare cause of acute kidney injury following vaccination.Renal recovery in renal-limited thrombotic microangiopathy is variable; conservative management with steroids is an initial option.Early comprehensive evaluation to exclude secondary causes of thrombotic microangiopathy, atypical haemolytic uremic syndrome, and autoimmune diseases is recommended.

Patient: Female, 70-year-oldFinal Diagnosis: Atypical hemolytic uremic syndrome triggered by artificial mitral valve dysfunctionSymptoms: Anemia • crepitations • dyspnea • hematuria • malaise • muffled breath sounds • numerous schistocytes in the blood smear • recurrent episodes of bleeding from oral mucosa • significant edema of lower extremities • thrombocytopeniaClinical Procedure: —Specialty: NephrologyObjective: Rare diseaseBackgroundHemolytic uremic syndrome (HUS) is a severe disease classified under thrombotic microangiopathies and characterized by acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. HUS can be divided into 2 subtypes: typical HUS and atypical HUS (aHUS). The standard treatment for aHUS, a complement-mediated thrombotic microangiopathy, as approved in the United States and European Union involves long-term administration of eculizumab or ravulizumab with complement-mediated thrombotic microangiopathy. This report is of a 70-year-old woman with aHUS triggered by artificial mitral valve dysfunction.Case ReportA 70-year-old woman with history of artificial mitral valve replacement was admitted to the nephrology department with suspected HUS. She presented with malaise, dyspnea, anemia, thrombocytopenia, hemolysis, and schistocytes in blood smear. Complement factors were normal, but sC5b-9 was elevated, suggesting complement overactivation. ADAMTS-13 was >10%, ruling out thrombotic thrombocytopenic purpura. Infection with a Shiga toxin–producing bacterium was ruled out. Genetic tests for complement factors revealed no pathogenic variants. The patient was treated with eculizumab, leading to significant clinical improvement. Due to her cardiac history, a comprehensive cardiologic evaluation was performed, revealing perivalvular leakage and severe dysfunction of the mitral valve prosthesis. She subsequently underwent a 2-step intravascular mitral valve repair. The administration of eculizumab resulted in clear improvement in hemolysis, renal function, and platelet count prior to mitral valve surgery, strongly supporting the diagnosis of an aHUS-type thrombotic microangiopathy. Surgical intervention was subsequently performed and contributed to long-term stabilization.ConclusionsThis case underscores the challenges of treating thrombotic microangiopathy in a patient with multiple comorbidities and complicated medical history.