RARE DISEASE
Atypical hemolytic uremic syndrome with anti-factor H antibodies
Atypical hemolytic uremic syndrome with anti-factor H antibodies
Atypical hemolytic uremic syndrome with anti-factor H antibodies
Synonyms: Atypical HUS with anti-factor H antibodies, aHUS with anti-factor H antibodies, aHUS with neutralizing autoantibodies against factor H
Synonyms: Atypical HUS with anti-factor H antibodies, aHUS with anti-factor H antibodies, aHUS with neutralizing autoantibodies against factor H
Synonyms: Atypical HUS with anti-factor H antibodies, aHUS with anti-factor H antibodies, aHUS with neutralizing autoantibodies against factor H
Drug discovery
0
drugs
With orphan designations
Overview
Atypical hemolytic uremic syndrome (aHUS) with anti-factor H (anti-FH) antibodies is a thrombotic microangiopathy characterized by dysregulated complement activation due to autoantibodies targeting the C-terminal domain of factor H. These antibodies impair complement regulation, leading to microvascular thrombosis, acute kidney injury, and multi-organ damage [1][5][9]. Diagnosis requires confirmation of anti-FH antibodies (>100 AU/mL) alongside thrombocytopenia, hemolytic anemia, and renal impairment, excluding Shiga toxin–HUS and ADAMTS13 deficiency [2][6].
Burden
Historical mortality: ~15% in acute episodes; 27% progress to end-stage renal disease (ESRD) [9][16].
Post-eculizumab era: ESRD risk reduced, but 30–40% develop chronic kidney disease or hypertension [4][13].
High relapse risk (40%) without immunosuppression, emphasizing long-term monitoring [6][9].
Therapies
First-line: Plasma exchange (PEX) combined with immunosuppression (steroids, cyclophosphamide, or rituximab) [1][6][9].
Eculizumab (anti-C5 monoclonal antibody) for refractory cases or high-risk patients [4][11].
Antibody titers guide therapy duration; sustained remission correlates with reduced titers [13][16].
Categories: rare genetic diseases, rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
326 drug discovery papers about Atypical hemolytic uremic syndrome with anti-factor H antibodies. Recent publications:
326 drug discovery papers about Atypical hemolytic uremic syndrome with anti-factor H antibodies. Recent publications:
categories:
Small molecules
antibodies
2026-04-16 | [Clinical analysis of eculizumab in the treatment of atypical hemolytic uremic syndrome in children].
Objective: To evaluate the efficacy and safety of eculizumab, a terminal complement inhibitor, in the treatment of pediatric atypical hemolytic uremic syndrome (aHUS), and explore strategies for treatment discontinuation. Methods: This was a case series study. Clinical data of the 10 children diagnosed with aHUS who were hospitalized and treated with eculizumab at Children's Hospital affiliated to Zhengzhou University between March 2024 and September 2025 were retrospectively collected. The data included demographic characteristics, laboratory findings, genetic test results, medication process and drug discontinuation status as well as follow up (till September 2025) after drug withdrawal, etc. The clinical features and prognosis of these patients were summarized. Results: Ten aHUS children included 7 males and 3 females, with an onset age of 61.0 (16.8, 79.8) months. Decreased complement C3 levels were observed in 7 patients, and elevated anti-factor H antibodies in 3. Genetic testing was performed in all patients and identified pathogenic variants in 3 patients: heterozygous CFH mutation, homozygous CFHR1 and CFHR3 deletions, and heterozygous DGKE mutation. The time from symptom onset to eculizumab initiation (defined as delayed administration time) was 7.5 (5.0, 10.5) d. Before treatment, the estimated glomerular filtration rate was 58.0(31.8,64.0)ml/(min·1.73 m²). After 4 weeks of eculizumab therapy, all patients were free from dialysis, and 9 cases achieved normal renal function. Platelet counts normalized after 11.5 (7.5, 17.5) d. Based on physician-patient shared decision-making model, 6 patients discontinued eculizumab, with a treatment duration of 117(53, 155) d. During a follow-up of 139(118, 440) d post-discontinuation, no relapses occurred. Five regained normal renal function, and 1 progressed to stage 2 chronic kidney disease. One patient experienced self-resolved mild limb pain during the treatment, and no other adverse events were observed. None of the children had a history of vaccination with the quadrivalent meningococcal vaccine before treatment. Due to the critical condition, all patients received oral azithromycin for infection prophylaxis, and no case of meningococcal infection occurred. Conclusions: Eculizumab can significantly improve renal function, reduce the incidence of renal failure in the treatment of pediatric atypical hemolytic uremic syndrome and is associated with high safety and few adverse reactions. The decision on treatment discontinuation can be made following the physician-patient shared decision-making model, with the timing reasonably chosen based on the patient's clinical condition and family financial status.
2026-03-24 | Recurrent pancreatitis and atypical hemolytic uremic syndrome (aHUS): an unusual presentation in childhood.
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by the classical triad of acute hemolytic anemia, thrombocytopenia, and kidney impairment. We report a 10-year-old boy with acute pancreatitis presenting simultaneously with atypical HUS (aHUS) with two such episodes occurring 1 year apart. The child presented with abdominal pain, vomiting, oliguria, epigastric tenderness, and had a right undescended testis. During the initial episode, anti-factor H antibodies were mildly elevated while they were normal in the subsequent episode with normal complement components. Whole exome sequencing identified a heterozygous pathogenic CFTR variant, predisposing to recurrent pancreatitis and cryptorchidism, as well as a probable heterozygous CFHR1/CFHR3 deletion, the gene responsible for recurrent aHUS. Treatment of pancreatitis, hemodialysis, and plasma infusions led to complete recovery of acute kidney injury (AKI) and HUS on both occasions.
2026-01-30 | Complement-mediated HUS revisited: evolving insights into pathophysiology, diagnosis, and treatment.
Complement-mediated hemolytic uremic syndrome (CM-HUS), commonly referred to as atypical HUS, is a rare thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway, typically triggered by a "two-hit" mechanism. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage, most commonly affecting the kidneys. While our understanding of the complement system has advanced significantly, CM-HUS remains a complex, heterogeneous disorder influenced by a spectrum of genetic variants, risk haplotypes, and acquired factors such as anti-factor H autoantibodies. This review highlights the current knowledge of CM-HUS pathogenesis, focusing on genetic variants in regulatory and activating proteins of the complement system. We also discuss the diagnostic complexity posed by incomplete penetrance, overlapping phenotypes, and limitations of genetic and functional assays. Emerging ex-vivo assays and complement biomarkers are explored as tools for refining diagnosis and risk stratification. The use of complement inhibitors such as eculizumab and ravulizumab has significantly improved renal outcomes and survival. This review provides a comprehensive, clinically grounded update on the genetics, pathophysiology, diagnostics, and therapeutic considerations in CM-HUS, aiming to provide clinicians and researchers with a deeper understanding of this complex, complement-driven disease.
2025-10-01 | Acute on Chronic Thrombotic Microangiopathy with Evidence of Dense Deposit Disease
Introduction: A 66-year-old Asian male with a background of Raynaud’s disease, dyslipidemia, and hypertension presented with abdominal pain, haematuria, and acute kidney injury (AKI) on chronic kidney disease (CKD). Urine dip revealed +3 proteinuria and +4 haematuria. His history included digital gangrene (2020), treated with Iloprost. Urology investigations were unremarkable. Case Description: Initial exam showed fatigue, shortness of breath, BP 220/110, and bilateral leg edema. Blood tests showed creatinine 354 (eGFR 15), low albumin (20), Hb 69, elevated CRP (74), and LDH (295). Immunology showed low IgG/IgM, presence of IgG lambda paraprotein, but negative ANA, ANCA, anti-GBM, and antiphospholipid antibodies. C3 and C4 were normal. A kidney biopsy revealed mesangiolysis, GBM reduplication, crescent formation, and fibrin deposits—features suggestive of thrombotic microangiopathy (TMA). Anti–Factor H antibody was detected. Diagnosis: paraprotein-driven C3 glomerulopathy (C3G) with overlapping atypical HUS (aHUS). Treatment included Bortezomib (6 cycles) for paraproteinemia and Eculizumab 1.2g biweekly. After 3 months, creatinine improved to 160 then rose to 250, while proteinuria decreased (uPCR from 990 to 129). However, LDH remained elevated, raising concerns about persistent TMA or insufficient treatment of dense deposit disease (DDD). Complement pathways were markedly suppressed. Management involved increasing Eculizumab to 1.5g biweekly and repeating relevant markers and biopsy was considered. After 7 months, the patient improved clinically: no SOB or edema, BP 154/80, stable renal function (creatinine 145, eGFR 43), significantly reduced proteinuria (uPCR 57.2), and normalization of C3/C4. Anti-FH antibodies were no longer detected. Serum immunoglobulins remained low. Kappa/lambda ratio mildly elevated (1.72). Discussion: Was aHUS driven by paraproteinemia or vice versa? Should autologous bone marrow transplant be considered if paraprotein rises? Duration of Eculizumab treatment remains unclear. Ongoing uncertainty between DDD and aHUS as primary pathology.
2025-10-01 | A Case of Postpartum Atypical Hemolytic Uremic Syndrome Caused by CORIN Gene Mutation
Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare disease, characteristics of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, often associated with dysfunction of the alternative pathway of complement. AHUS with CORIN gene mutation have not been described in adult patients. Case Description: A 31-year-old Female patient was presented with severe preeclampsia at 34 weeks of gestation history. A lower segment cesarean section was performed on March 11, 2025. After the operation two days, the patient developed thrombocytopenia and oliguria, hemolytic Anemia, liver dysfunction. The renal biopsy revealed thrombotic microangiopathy (TMA) and Acute tubular injury (ATI)(Figure). The Concentration of Complement Factor H (CFH), Complement Factor I (CFI), Anti-C3 Convertase Antibody, Anti-Human Complement Factor H Antibody and Anti-ADAMTS13 Antibodies were normal. ADAMTS13 Activity is also normal. Clinical picture fit with aHUS as diagnosis. Treatment with plasma exchange, Glucocorticoids, Hemodialysis, Fresh Frozen Plasma were started before admission, but the kidney function was not complete recovery. Treatment with complement inhibitor -Eculizumab was started and patient gradually recovered. Whole exome sequencing identified heterozygous variants in the CORIN in this patient. Discussion: CORIN is a serine protease primarily expressed in cardiomyocytes, responsible for activating atrial natriuretic peptide (ANP) and regulating fluid balance, blood pressure, and renal sodium excretion. Variants in the CORIN gene can lead to reduced or absent function, resulting in impaired ANP activation, which may contribute to pregnancy-related kidney injuries such as preeclampsia and acute kidney injury during pregnancy. Eculizumab is a monoclonal antibody targeting complement protein C5, primarily used to treat complement-mediated disorders such as: Paroxysmal nocturnal hemoglobinuria (PNH), Atypical hemolytic uremic syndrome (aHUS) HELLP syndrome. Corin deficiency-induced kidney injury is primarily associated with ANP deficiency, rather than excessive complement activation. Successful treatment of aHUS with eculizumab in a patient with CORIN gene mutation has not been previously reported.
cell therapies
2026-09-09 | Therapeutic Plasma Exchange for Eculizumab-refractory Peripheral Cyanosis in Pediatric Anti-factor H Atypical Hemolytic Uremic Syndrome: A Rare Case Report
Background/aim: Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated thrombotic microangiopathy characterized by dysregulation of the alternative complement pathway, leading to microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.Anti-complement factor H antibody-associated aHUS represents a distinct subset with potentially severe disease manifestations.Peripheral ischemic complications are rare in pediatric patients and may indicate severe ongoing microvascular injury despite standard therapy.We report a rare pediatric case highlighting the role of therapeutic plasma exchange (TPE) as an adjunctive treatment in refractory disease.Case description: A 3-year-10-month-old boy with anti-complement factor H antibody-mediated aHUS presented with progressive peripheral cyanosis and features of thrombotic microangiopathy.Despite early initiation of eculizumab and renal replacement therapy, the patient developed persistent hemolysis and worsening digital ischemia.Given the ongoing disease activity and severe extrarenal manifestations, therapeutic plasma exchange was initiated.Following TPE, the patient showed marked clinical improvement with resolution of peripheral ischemia and significant biochemical improvement in hemolytic parameters.Conclusion: This case highlights that severe extrarenal manifestations such as peripheral ischemia may occur in anti-factor H antibody-mediated aHUS and can persist despite complement inhibition therapy.In such scenarios, therapeutic plasma exchange may serve as an effective adjunctive treatment to control ongoing hemolysis and improve clinical outcomes.Clinical significance: Early recognition of refractory hemolysis and ischemic complications in pediatric aHUS is essential for timely therapeutic intervention.Adjunctive use of therapeutic plasma exchange may help remove pathogenic antibodies and complement components, thereby stabilizing disease activity and preventing further microvascular injury in selected patients.
2026-06-25 | Long-term outcome of pediatric anti-complement factor H antibody-associated atypical hemolytic uremic syndrome receiving abbreviated plasma exchange: a retrospective study from a single center
BACKGROUND: Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. METHODS: We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. RESULTS: Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. CONCLUSIONS: PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.
2026-05-08 | A systematic review of short-term outcomes in patients with anti-factor H associated atypical HUS managed with plasma exchanges versus eculizumab.
Antibodies to factor H (anti-FH) are a leading cause of atypical hemolytic uremic syndrome (aHUS) in school-going children. While terminal complement blockade with eculizumab (ECZ) is standard of care for all forms of aHUS, anti-FH associated aHUS is uniquely amenable to combination therapy with plasma exchange (PEX) and immunosuppression. There are no controlled comparisons on the relative short- or medium-term efficacy of the two strategies of management. The primary objectives were to compare the time from initiation of therapy to hematological remission and renal recovery between patients managed with PEX versus ECZ, with or without immunosuppression, for anti-FH associated aHUS in native kidneys. We also compared the proportions of patients attaining hematological remission or renal recovery by 7, 14 and 28 days of therapy, and proportion of patients with chronic kidney disease G1-5, dialysis-dependence, or death. PubMed and Embase were searched from January 2004 to April 2025. Studies, in English language, were eligible if they reported the time to hematological remission and renal recovery in individual patients with anti-FH antibody-associated aHUS in native kidneys and treated with either PEX or ECZ with or without additional immunosuppression. Within studies, individual patients were included if they had received either, and not both, PEX or ECZ, and information regarding time to hematological remission and renal recovery was available. The risk of bias for retrospective cohort studies and case reports or series was assessed using the Newcastle-Ottawa Quality Assessment Scale and Joanna Briggs Institute (JBI) tool for systematic reviews, respectively. Individual patient data were combined by therapy group to report time-to-event outcomes as hazard ratios (95% confidence intervals, CI), compared using the log rank test. Other continuous measures were compared between groups using the rank sum test. Fourteen of 57 studies shortlisted from among 403 search results met eligibility criteria, within which 99 patients, including 81 managed with PEX and 18 with ECZ, with/without immunosuppression, were eligible. Patients receiving PEX presented later with more severe anemia and lower eGFR, and more often required dialysis. Median time to hematologic remission was significantly shorter with PEX (9 vs. 20 days; P = 0.0007) while time to renal recovery was similar (16 vs. 20 days; P = 0.36). The proportion with CKD G3-5 and mortality was insignificantly higher with PEX than ECZ (respective P 0.077 and 0.36). Our findings are limited by small numbers of participants and studies, lack of comparative studies, heterogeneity in disease severity, and variations in definitions of outcomes. Patients managed with PEX achieved hematological remission faster than those on ECZ; the time to renal recovery was similar. Given the precautions and vigilance necessary with complement blockade, PEX appears to be a satisfactory initial choice for managing anti-FH associated HUS, particularly in low-resource settings. Prospective trials should compare the efficacy, safety and healthcare costs of these strategies in managing patients with anti-FH associated HUS. PROSPERO ID: CRD420251033150.
2025-11-25 | Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India.
Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare form of thrombotic microangiopathy that results from complement system activation. It represents a significant etiology of acute kidney injury among children. In India, aHUS is predominantly associated with anti-factor H antibodies, presenting unique diagnostic and therapeutic challenges. This study aims to delineate the clinical characteristics, immunological profile, management strategies, and outcomes of pediatric aHUS cases from a tertiary center in Eastern India. Methodology We conducted a retrospective, observational, case series at a tertiary care hospital in Eastern India, including seven pediatric patients diagnosed with aHUS between January 2023 and December 2024. Diagnosis was based on a clinical triad (acute kidney injury, microangiopathic anemia, thrombocytopenia), exclusion of Shiga toxin-associated cases and secondary causes, confirmation with complement/anti-factor H antibody testing, and, where feasible, genetic analysis. Patients received plasma exchange, immunomodulators, and supportive care. Data were analyzed using descriptive statistics. Results A total of seven children (median age = 7 years, six females) were treated for aHUS. CFHR1-CFHR3 deletions and anti-factor H antibodies were each identified in 43% of patients. Plasma exchange and steroids formed the therapeutic mainstay. Hematological remission was achieved in 71% of cases within one week, and 43% attained full renal recovery. However, 29% progressed to chronic kidney disease or remained dialysis-dependent, and the remaining 29% showed only limited renal improvement. Early initiation of plasmapheresis and immunosuppression was associated with better renal outcomes, while lack of access to eculizumab and genetic testing remained significant barriers. Conclusions Pediatric aHUS in Eastern India demonstrates a high burden of anti-factor H antibody-mediated disease and genetic complement abnormalities. Early plasmapheresis and immunomodulator use result in improved hematological and renal outcomes. There is a critical need for enhanced access to complement inhibitors and diagnostic tools to optimize management and prognosis in resource-constrained settings.
2025-10-01 | Evaluating Truncated Plasma Exchange in Anti-Complement Factor H Autoantibody-Associated Hemolytic Uremic Syndrome as a Viable Strategy in Resource-Limited Settings: Evidence from a Clinical Cohort
Background: Anti-complement factor H autoantibody-associated hemolytic uremic syndrome (anti-CFH HUS) accounts for >50% of atypical HUS cases in Indian children. The recommended regimen of 20-22 sessions of plasma exchange (PLEX) combined with immunosuppression is expert-based, however, it imposes severe financial burden in low-resource settings. Thus, we investigated the utility of a truncated PLEX regimen of 5-7 sessions in inducing remission. Methods: Hospital records of children ≤18years with anti-CFH HUS (KDIGO 2021 guidelines; anti-CFH antibody titer>150AU/mL) treated at a tertiary center in a low-resource setting between Jan 2017-Apr 2025, were reviewed following ethical approval. PLEX data, clinical and laboratory parameters at baseline and follow-up were noted. Outcome measures were number of PLEX sessions for hematological remission (platelets>105/mm3 for 2 days) and kidney outcome at 1year. Results: Analysis included 28 episodes in 24 patients with median[IQR] age of 8.4[5.8,9.5]years. The median[IQR] anti-CFH antibody (AU/mL) was 4600[342,10816] and 130[78,220] at onset and last follow-up respectively. The median(range) PLEX sessions were 5(3-20). Patients received immunosuppression with steroids (85.7%), mycophenolate (32.1%), and cyclophosphamide (17.9%). Remission was achieved in 89.3% with truncated PLEX regimen (Figure1). In the median(range) follow-up of 24(1-96)months, only 2(8%) relapsed (both received truncated regimen; 2 episodes each), following an average interval of 9.5 and 44.5months between episodes. At 1year follow-up (N=21), eGFR<60 in 4.7%, hypertension in 57%, and proteinuria in 19% was noted. Conclusion: Truncated PLEX regimen with appropriate immunosuppression achieved remission in a majority of pediatric anti-CFH HUS cases. This is a viable, cost-effective strategy to manage HUS in low-resource settings, where eculizumab is inaccessible.Figure1: Kaplan-Meier Plot for Number of PLEX Sessions to Reach Remission
proteins
2025-07-01 | The four functional segments of Factor H: Role in physiological target recognition and contribution to disease
Factor H controls proximal complement activation, and its dysfunction leads to diseases that often manifest in the kidney. Structural and functional analyses have identified four distinct functional segments: an N-terminal regulatory unit, a cell binding unit, a segment with combined low-affinity C3b and Heparin sites, and a C-terminal recognition or sensor unit with overlapping C3b/C3d and Heparin sites. Three of these segments are associated with diseases. The regulatory segment is implicated in C3 glomerulopathy (C3G) and ANCA-anti neutrophil cytoplasmic antibodies - associated vasculitis (AAV). The second segment includes the Y402H-polymorphism of age relate macular degeneration (AMD), is associated with cancer, and is also targeted by pathogens. The C-terminal sensor segment is involved in atypical hemolytic uremic syndrome (aHUS), in FHR1:FHR3 deficient and autoantibody positive HUS (DEAP-HUS), and is also exploited by pathogens. Factor H functions are modulated by two plasma proteins: Factor H like protein 1 (FHL1) and Factor H related protein 1 (FHR1), both of which share structural segments with Factor H. This interplay is critical for fine-tuning local complement activity. In addition, new noncanonical functions of Factor H and alternative sites of action, including intracellular roles, are being elaborated. A deeper understanding Factor H’s physiological role, as well as the impact of its absence, mutations, or autoantibody targeting, provides valuable insights into disease mechanisms and opens opportunities for therapeutic intervention by using full length Factor H, its fragments, or complement-modulatory compounds.
2024-05-10 | Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity
Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors’ blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro , as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 – the human FH analog expressed in moss – will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.
2023-08-09 | Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation
The complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present in vitro and ex vivo data on the mechanism of action of zilucoplan for the inhibition of C5 activation, including two clinically relevant C5 polymorphisms at R885.The interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers.Zilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the in vitro activation of C5 clinical variants at R885 that have been previously reported to respond poorly to eculizumab treatment. Zilucoplan was further demonstrated to interfere with the formation of C5b6 and inhibit red blood cell (RBC) hemolysis induced by plasmin-mediated non-canonical C5 activation. Zilucoplan demonstrated greater permeability than a monoclonal C5 antibody in a reconstituted basement membrane model, providing a rationale for the rapid onset of action of zilucoplan observed in clinical studies.Our findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.
2021-04-27 | A synthetic protein as efficient multitarget regulator against complement over-activation
Abstract The complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g.COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may present alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH. MFHR13 includes the FH variant I62, which we characterized to induce improved C3b binding and cofactor activity compared to the variant V62. After comparative protein structure modelling, we introduced the SCR FH 13 , which includes an N -glycosylation site for higher protein stability. In summary, the fusion protein MFHR13 comprises SCRs FHR1 1-2 :FH 1-4 :FH 13 :FH 19-20 . It shows an enhanced heparin binding and protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, it also blocks the terminal pathway of complement activation and we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as a therapeutic for complement-associated diseases.
2018-07-04 | Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome
Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.
small molecules
2026-01-01 | Ravulizumab administration for relapse prevention in atypical hemolytic uremic syndrome with a <i>CFH</i> variant: A case report
Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA). When aHUS cannot be excluded, diagnostic treatment with anti-C5 antibody agents should be considered. We report a patient with a novel heterozygous complement factor H (CFH) variant, p.Glu1198Asp (c.3594A>T), who received ravulizumab three months after disease onset. Ravulizumab was administered for relapse prevention in the chronic phase, and no recurrence of thrombotic microangiopathy was observed during the follow-up.
2023-12-04 | ANTI-FACTOR H ANTIBODY ASSOCIATED ATYPICAL HEMOLYTIC-UREMIC SYNDROME IN CHILDREN: CLINICAL PROFILE, DIAGNOSIS AND TREATMENT
Atypical hemolytic uremic syndrome (aHUS) refers to one of the forms of thrombotic microangiopathy occurring with preferred damage to the kidneys. About 10% of all cases of aHUS in children are aHUS associated with antibodies to complement factor H (CFH-Ab-aHUS). In 90% of cases CFH-Ab-aHUS is represented by DEAP-HUS (Deficiency of Complement Factor H Related (CFHR) plasma proteins and Autoantibody Positive Hemolytic Uremic Syndrome) with a predominant deficiency of CFHR1, most often due to a homozygous deletion of CFHR3/CFHR1. CFH-Ab-aHUS is characterized by the age of onset of the disease of 4 to 12 years old; the presence of a prodrome, more often associated with gastrointestinal disorders such as vomiting and abdominal pain, less often diarrhea; relapsing course with a high risk in the first 6 months from the onset of the disease, a high proportion of adverse outcomes: death of the patient or development of end stage chronic kidney disease (CKD). Determination of the CFH-Ab titer should be performed in all children with HUS, and in case of their increase, regularly monitored during treatment. Treatment begins with eculizumab or its biosimilar until a CFH-Ab titer is obtained and, if CFH-Ab-aHUS is confirmed, it is necessary to switch to intensive plasma exchanges in combination with immunosuppressive therapy. If there are contraindications to immunosuppressive therapy or if there is no effect from it, if plasma exchanges are impossible or ineffective, if significant mutations in complement regulator genes are detected, it is necessary to continue or return to complement blocking therapy. After achieving remission of the disease, long-term monitoring of patients is required to control residual effects on the kidneys (hematuria, proteinuria, CKD) and the cardiovascular system (arterial hypertension, left ventricular myocardial hypertrophy). In patients who have reached the end stage of CKD, it is mandatory to determine the anti-CFH titer and conduct a molecular genetic research in order to determine the risks of the disease returning to the kidney graft and the need for prophylactic therapy with eculizumab or its biosimilar before and after the surgical intervention.
2023-04-08 | Heat-inactivated Factor B inhibits alternative pathway fluid-phase activation and convertase formation on endothelial cell-secreted ultra-large von Willebrand factor strings
Abstract Defective regulation of the alternative complement pathway (AP) causes excessive activation and promotes the inflammation and renal injury observed in atypical hemolytic-uremic syndrome (aHUS). The usefulness of heat-inactivated Factor B (HFB) in reducing AP activation was evaluated in: fluid-phase reactions, using purified complement proteins and Factor H (FH)-depleted serum; and in surface-activated reactions using human endothelial cells (ECs). C3a and Ba levels, measured by quantitative Western blots, determined the extent of fluid-phase activation. In reactions using C3, FB, and Factor D proteins, HFB addition (2.5-fold FB levels), reduced C3a levels by 60% and Ba levels by 45%. In reactions using FH-depleted serum (supplemented with FH at 12.5% normal levels), Ba levels were reduced by 40% with HFB added at 3.5-fold FB levels. The effectiveness of HFB in limiting AP convertase formation on activated surfaces was evaluated using stimulated ECs. Fluorescent microscopy was used to quantify endogenously released C3, FB, and C5 attached to EC-secreted ultra-large VWF strings. HFB addition reduced attachment of C3b by 2.7-fold, FB by 1.5-fold and C5 by fourfold. Our data indicate that HFB may be of therapeutic value in preventing AP-mediated generation of C3a and C5a, and the associated inflammation caused by an overactive AP.
2023-01-13 | Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future
Atypical hemolytic uremic syndrome is a thrombotic microangiopathy characterized by hemolysis, thrombocytopenia, and acute kidney injury, usually caused by alternative complement system overactivation due to pathogenic genetic variants or antibodies to components or regulatory factors in this pathway. Previously, a lack of effective treatment for this condition was associated with mortality, end-stage kidney disease, and the risk of disease recurrence after kidney transplantation. Plasma therapy has been used for atypical hemolytic uremic syndrome treatment with inconsistent results. Complement-blocking treatment changed the outcome and prognosis of patients with atypical hemolytic uremic syndrome. Early administration of eculizumab, a monoclonal C5 antibody, leads to improvements in hematologic, kidney, and systemic manifestations in patients with atypical hemolytic uremic syndrome, even with apparent dialysis dependency. Pre- and post-transplant use of eculizumab is effective in the prevention of atypical hemolytic uremic syndrome recurrence. Evidence on eculizumab use in secondary hemolytic uremic syndrome cases is controversial. Recent data favor the restrictive use of eculizumab in carefully selected atypical hemolytic uremic syndrome cases, but close monitoring for relapse after drug discontinuation is emphasized. Prophylaxis for meningococcal infection is important. The long-acting C5 monoclonal antibody ravulizumab is now approved for atypical hemolytic uremic syndrome treatment, enabling a reduction in the dosing frequency and improving the quality of life in patients with atypical hemolytic uremic syndrome. New strategies for additional and novel complement blockage medications in atypical hemolytic uremic syndrome are under investigation.
2022-12-15 | Mycoplasma pneumoniae Infection Associated with Anti-Factor H Autoantibodies in Atypical Hemolytic Uremic Syndrome.
Hemolytic uremic syndrome (HUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia, and renal impairment mostly triggered by strains of Shiga-like toxin-producing Escherichia coli (STEC-HUS). A rarer form of HUS, defined as atypical HUS (aHUS), is associated with genetic or acquired dysregulation of the alternative pathway of the complement system and presents a poorer prognosis than STEC-HUS. Factor H autoantibodies (anti-FHs) have been reported in aHUS in 5-11% of cases and are strongly associated with the homozygous deletion of CFHR3-CFHR1 genes. In the large majority of patients, anti-FH-associated aHUS is commonly preceded by gastrointestinal or respiratory tract infections. Here, we described the clinical case of a 3-year-old boy who was hospitalized for aHUS preceded by Mycoplasma pneumoniae (MP) infection. He resulted positive for anti-FHs and carried the homozygous deletion of CFHR3-CFHR1. Of relevance, he also showed a variant of unknown significance in the C5 gene. The patient was successfully treated with eculizumab and achieved hematological and renal remission. The anti-FH titer decreased, became negative after 6 months of mycophenolate mofetil (MMF) treatment, and remained negative for 21-month follow-up indicating that immunosuppression was effective and could prevent the reappearance of anti-FHs. We hypothesized that MP, likely through an evasion strategy of immunosurveillance based on binding of pathogen to FH, triggers anti-FH antibody generation and aHUS in a subject genetically predisposed. In conclusion, to the best of our knowledge, here, we reported the first case of anti-FH-mediated aHUS after an MP infection who benefited from eculizumab and immunosuppressive therapy based on MMF. Hence, monitoring of anti-FHs in patients with post-MP infection glomerulonephritis could be recommended, especially in those with low C3 plasma levels.
other
2025-07-01 | AAV-mHDM-FH: Safety and expression profile in two murine models of hyper-complement activation
C3 glomerulopathy (C3G) and atypical haemolytic uraemic syndrome (aHUS) are rare kidney disorders characterized by the dysregulation of the alternative pathway (AP). Unlike aHUS, current treatment options for C3G are limited. Factor H (FH) plays a key role in regulating the AP, and mice lacking FH develop a disease similar to C3G. We previously developed mouse homodimeric minimal FH (mHDM-FH) as a gene therapy using an adeno-associated virus (AAV) vector incorporating a liver-specific promoter to rebalance the AP activation. We previously noted that a single dose of AAV-mHDM-FH (1 × 10 11 ) restored complement regulation in Cfh −/− mice by 21 days post inoculation, however this was associated with a strong anti-HDM-FH response, which was markedly reduced in Cfh +/− mice. In the current study, we focussed on long-term evaluation of AAV-mHDM-FH in both Cfh +/− mice and C3 N/N mice (the C3 D1115N gain-of-function mouse model of aHUS). At six months post-inoculation, C3 N/N mice treated with AAV-mHDM-FH showed significantly improved survival compared to AAV-GFP controls. However, the therapeutic effect was partially limited due to reduced binding affinity of mHDM-FH to the mutant C3 D1115N protein. These findings indicate that while AAV-mHDM-FH retains some functionality in C3 mutation-driven disease, its efficacy may not match therapies targeting the terminal complement pathway. In Cfh +/− mice, no signs of disease or safety concerns were observed over the six-month period. Importantly, increased serum levels of both C3 and FH were detected, suggesting improved control of the amplification loop in these mice. AAV transgene expression remained detectable in the liver at six months, an encouraging result for long-term efficacy. Across both experimental time points, anti-AAV antibody responses were detected in Cfh +/− mice. These responses peaked at 21 days post-inoculation but were present at relatively low levels after 6 months. This pattern aligns with observations in patients receiving AAV-based gene therapies. Despite the presence of anti-AAV antibodies, the 6 month data showed transgene expression and no safety concerns, leaving the extent to which these antibodies impact therapeutic efficacy still uncertain. Looking ahead, we aim to enhance long-term vector expression by exploring the use of alternative promoters tailored to different cellular targets. References: 1. Yang Y, Denton H, Davis O R, Smith-Jackson K, Kerr H, Herbert A P, Barlow P N, Pickering M C and Marchbank K J An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy J Am Soc Nephrol 2018 29(6):1649–1661.
antibodies
2026-04-16 | [Clinical analysis of eculizumab in the treatment of atypical hemolytic uremic syndrome in children].
Objective: To evaluate the efficacy and safety of eculizumab, a terminal complement inhibitor, in the treatment of pediatric atypical hemolytic uremic syndrome (aHUS), and explore strategies for treatment discontinuation. Methods: This was a case series study. Clinical data of the 10 children diagnosed with aHUS who were hospitalized and treated with eculizumab at Children's Hospital affiliated to Zhengzhou University between March 2024 and September 2025 were retrospectively collected. The data included demographic characteristics, laboratory findings, genetic test results, medication process and drug discontinuation status as well as follow up (till September 2025) after drug withdrawal, etc. The clinical features and prognosis of these patients were summarized. Results: Ten aHUS children included 7 males and 3 females, with an onset age of 61.0 (16.8, 79.8) months. Decreased complement C3 levels were observed in 7 patients, and elevated anti-factor H antibodies in 3. Genetic testing was performed in all patients and identified pathogenic variants in 3 patients: heterozygous CFH mutation, homozygous CFHR1 and CFHR3 deletions, and heterozygous DGKE mutation. The time from symptom onset to eculizumab initiation (defined as delayed administration time) was 7.5 (5.0, 10.5) d. Before treatment, the estimated glomerular filtration rate was 58.0(31.8,64.0)ml/(min·1.73 m²). After 4 weeks of eculizumab therapy, all patients were free from dialysis, and 9 cases achieved normal renal function. Platelet counts normalized after 11.5 (7.5, 17.5) d. Based on physician-patient shared decision-making model, 6 patients discontinued eculizumab, with a treatment duration of 117(53, 155) d. During a follow-up of 139(118, 440) d post-discontinuation, no relapses occurred. Five regained normal renal function, and 1 progressed to stage 2 chronic kidney disease. One patient experienced self-resolved mild limb pain during the treatment, and no other adverse events were observed. None of the children had a history of vaccination with the quadrivalent meningococcal vaccine before treatment. Due to the critical condition, all patients received oral azithromycin for infection prophylaxis, and no case of meningococcal infection occurred. Conclusions: Eculizumab can significantly improve renal function, reduce the incidence of renal failure in the treatment of pediatric atypical hemolytic uremic syndrome and is associated with high safety and few adverse reactions. The decision on treatment discontinuation can be made following the physician-patient shared decision-making model, with the timing reasonably chosen based on the patient's clinical condition and family financial status.
2026-03-24 | Recurrent pancreatitis and atypical hemolytic uremic syndrome (aHUS): an unusual presentation in childhood.
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by the classical triad of acute hemolytic anemia, thrombocytopenia, and kidney impairment. We report a 10-year-old boy with acute pancreatitis presenting simultaneously with atypical HUS (aHUS) with two such episodes occurring 1 year apart. The child presented with abdominal pain, vomiting, oliguria, epigastric tenderness, and had a right undescended testis. During the initial episode, anti-factor H antibodies were mildly elevated while they were normal in the subsequent episode with normal complement components. Whole exome sequencing identified a heterozygous pathogenic CFTR variant, predisposing to recurrent pancreatitis and cryptorchidism, as well as a probable heterozygous CFHR1/CFHR3 deletion, the gene responsible for recurrent aHUS. Treatment of pancreatitis, hemodialysis, and plasma infusions led to complete recovery of acute kidney injury (AKI) and HUS on both occasions.
2026-01-30 | Complement-mediated HUS revisited: evolving insights into pathophysiology, diagnosis, and treatment.
Complement-mediated hemolytic uremic syndrome (CM-HUS), commonly referred to as atypical HUS, is a rare thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway, typically triggered by a "two-hit" mechanism. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage, most commonly affecting the kidneys. While our understanding of the complement system has advanced significantly, CM-HUS remains a complex, heterogeneous disorder influenced by a spectrum of genetic variants, risk haplotypes, and acquired factors such as anti-factor H autoantibodies. This review highlights the current knowledge of CM-HUS pathogenesis, focusing on genetic variants in regulatory and activating proteins of the complement system. We also discuss the diagnostic complexity posed by incomplete penetrance, overlapping phenotypes, and limitations of genetic and functional assays. Emerging ex-vivo assays and complement biomarkers are explored as tools for refining diagnosis and risk stratification. The use of complement inhibitors such as eculizumab and ravulizumab has significantly improved renal outcomes and survival. This review provides a comprehensive, clinically grounded update on the genetics, pathophysiology, diagnostics, and therapeutic considerations in CM-HUS, aiming to provide clinicians and researchers with a deeper understanding of this complex, complement-driven disease.
2025-10-01 | Acute on Chronic Thrombotic Microangiopathy with Evidence of Dense Deposit Disease
Introduction: A 66-year-old Asian male with a background of Raynaud’s disease, dyslipidemia, and hypertension presented with abdominal pain, haematuria, and acute kidney injury (AKI) on chronic kidney disease (CKD). Urine dip revealed +3 proteinuria and +4 haematuria. His history included digital gangrene (2020), treated with Iloprost. Urology investigations were unremarkable. Case Description: Initial exam showed fatigue, shortness of breath, BP 220/110, and bilateral leg edema. Blood tests showed creatinine 354 (eGFR 15), low albumin (20), Hb 69, elevated CRP (74), and LDH (295). Immunology showed low IgG/IgM, presence of IgG lambda paraprotein, but negative ANA, ANCA, anti-GBM, and antiphospholipid antibodies. C3 and C4 were normal. A kidney biopsy revealed mesangiolysis, GBM reduplication, crescent formation, and fibrin deposits—features suggestive of thrombotic microangiopathy (TMA). Anti–Factor H antibody was detected. Diagnosis: paraprotein-driven C3 glomerulopathy (C3G) with overlapping atypical HUS (aHUS). Treatment included Bortezomib (6 cycles) for paraproteinemia and Eculizumab 1.2g biweekly. After 3 months, creatinine improved to 160 then rose to 250, while proteinuria decreased (uPCR from 990 to 129). However, LDH remained elevated, raising concerns about persistent TMA or insufficient treatment of dense deposit disease (DDD). Complement pathways were markedly suppressed. Management involved increasing Eculizumab to 1.5g biweekly and repeating relevant markers and biopsy was considered. After 7 months, the patient improved clinically: no SOB or edema, BP 154/80, stable renal function (creatinine 145, eGFR 43), significantly reduced proteinuria (uPCR 57.2), and normalization of C3/C4. Anti-FH antibodies were no longer detected. Serum immunoglobulins remained low. Kappa/lambda ratio mildly elevated (1.72). Discussion: Was aHUS driven by paraproteinemia or vice versa? Should autologous bone marrow transplant be considered if paraprotein rises? Duration of Eculizumab treatment remains unclear. Ongoing uncertainty between DDD and aHUS as primary pathology.
2025-10-01 | A Case of Postpartum Atypical Hemolytic Uremic Syndrome Caused by CORIN Gene Mutation
Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare disease, characteristics of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, often associated with dysfunction of the alternative pathway of complement. AHUS with CORIN gene mutation have not been described in adult patients. Case Description: A 31-year-old Female patient was presented with severe preeclampsia at 34 weeks of gestation history. A lower segment cesarean section was performed on March 11, 2025. After the operation two days, the patient developed thrombocytopenia and oliguria, hemolytic Anemia, liver dysfunction. The renal biopsy revealed thrombotic microangiopathy (TMA) and Acute tubular injury (ATI)(Figure). The Concentration of Complement Factor H (CFH), Complement Factor I (CFI), Anti-C3 Convertase Antibody, Anti-Human Complement Factor H Antibody and Anti-ADAMTS13 Antibodies were normal. ADAMTS13 Activity is also normal. Clinical picture fit with aHUS as diagnosis. Treatment with plasma exchange, Glucocorticoids, Hemodialysis, Fresh Frozen Plasma were started before admission, but the kidney function was not complete recovery. Treatment with complement inhibitor -Eculizumab was started and patient gradually recovered. Whole exome sequencing identified heterozygous variants in the CORIN in this patient. Discussion: CORIN is a serine protease primarily expressed in cardiomyocytes, responsible for activating atrial natriuretic peptide (ANP) and regulating fluid balance, blood pressure, and renal sodium excretion. Variants in the CORIN gene can lead to reduced or absent function, resulting in impaired ANP activation, which may contribute to pregnancy-related kidney injuries such as preeclampsia and acute kidney injury during pregnancy. Eculizumab is a monoclonal antibody targeting complement protein C5, primarily used to treat complement-mediated disorders such as: Paroxysmal nocturnal hemoglobinuria (PNH), Atypical hemolytic uremic syndrome (aHUS) HELLP syndrome. Corin deficiency-induced kidney injury is primarily associated with ANP deficiency, rather than excessive complement activation. Successful treatment of aHUS with eculizumab in a patient with CORIN gene mutation has not been previously reported.
cell therapies
2026-09-09 | Therapeutic Plasma Exchange for Eculizumab-refractory Peripheral Cyanosis in Pediatric Anti-factor H Atypical Hemolytic Uremic Syndrome: A Rare Case Report
Background/aim: Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated thrombotic microangiopathy characterized by dysregulation of the alternative complement pathway, leading to microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.Anti-complement factor H antibody-associated aHUS represents a distinct subset with potentially severe disease manifestations.Peripheral ischemic complications are rare in pediatric patients and may indicate severe ongoing microvascular injury despite standard therapy.We report a rare pediatric case highlighting the role of therapeutic plasma exchange (TPE) as an adjunctive treatment in refractory disease.Case description: A 3-year-10-month-old boy with anti-complement factor H antibody-mediated aHUS presented with progressive peripheral cyanosis and features of thrombotic microangiopathy.Despite early initiation of eculizumab and renal replacement therapy, the patient developed persistent hemolysis and worsening digital ischemia.Given the ongoing disease activity and severe extrarenal manifestations, therapeutic plasma exchange was initiated.Following TPE, the patient showed marked clinical improvement with resolution of peripheral ischemia and significant biochemical improvement in hemolytic parameters.Conclusion: This case highlights that severe extrarenal manifestations such as peripheral ischemia may occur in anti-factor H antibody-mediated aHUS and can persist despite complement inhibition therapy.In such scenarios, therapeutic plasma exchange may serve as an effective adjunctive treatment to control ongoing hemolysis and improve clinical outcomes.Clinical significance: Early recognition of refractory hemolysis and ischemic complications in pediatric aHUS is essential for timely therapeutic intervention.Adjunctive use of therapeutic plasma exchange may help remove pathogenic antibodies and complement components, thereby stabilizing disease activity and preventing further microvascular injury in selected patients.
2026-06-25 | Long-term outcome of pediatric anti-complement factor H antibody-associated atypical hemolytic uremic syndrome receiving abbreviated plasma exchange: a retrospective study from a single center
BACKGROUND: Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. METHODS: We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. RESULTS: Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. CONCLUSIONS: PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.
2026-05-08 | A systematic review of short-term outcomes in patients with anti-factor H associated atypical HUS managed with plasma exchanges versus eculizumab.
Antibodies to factor H (anti-FH) are a leading cause of atypical hemolytic uremic syndrome (aHUS) in school-going children. While terminal complement blockade with eculizumab (ECZ) is standard of care for all forms of aHUS, anti-FH associated aHUS is uniquely amenable to combination therapy with plasma exchange (PEX) and immunosuppression. There are no controlled comparisons on the relative short- or medium-term efficacy of the two strategies of management. The primary objectives were to compare the time from initiation of therapy to hematological remission and renal recovery between patients managed with PEX versus ECZ, with or without immunosuppression, for anti-FH associated aHUS in native kidneys. We also compared the proportions of patients attaining hematological remission or renal recovery by 7, 14 and 28 days of therapy, and proportion of patients with chronic kidney disease G1-5, dialysis-dependence, or death. PubMed and Embase were searched from January 2004 to April 2025. Studies, in English language, were eligible if they reported the time to hematological remission and renal recovery in individual patients with anti-FH antibody-associated aHUS in native kidneys and treated with either PEX or ECZ with or without additional immunosuppression. Within studies, individual patients were included if they had received either, and not both, PEX or ECZ, and information regarding time to hematological remission and renal recovery was available. The risk of bias for retrospective cohort studies and case reports or series was assessed using the Newcastle-Ottawa Quality Assessment Scale and Joanna Briggs Institute (JBI) tool for systematic reviews, respectively. Individual patient data were combined by therapy group to report time-to-event outcomes as hazard ratios (95% confidence intervals, CI), compared using the log rank test. Other continuous measures were compared between groups using the rank sum test. Fourteen of 57 studies shortlisted from among 403 search results met eligibility criteria, within which 99 patients, including 81 managed with PEX and 18 with ECZ, with/without immunosuppression, were eligible. Patients receiving PEX presented later with more severe anemia and lower eGFR, and more often required dialysis. Median time to hematologic remission was significantly shorter with PEX (9 vs. 20 days; P = 0.0007) while time to renal recovery was similar (16 vs. 20 days; P = 0.36). The proportion with CKD G3-5 and mortality was insignificantly higher with PEX than ECZ (respective P 0.077 and 0.36). Our findings are limited by small numbers of participants and studies, lack of comparative studies, heterogeneity in disease severity, and variations in definitions of outcomes. Patients managed with PEX achieved hematological remission faster than those on ECZ; the time to renal recovery was similar. Given the precautions and vigilance necessary with complement blockade, PEX appears to be a satisfactory initial choice for managing anti-FH associated HUS, particularly in low-resource settings. Prospective trials should compare the efficacy, safety and healthcare costs of these strategies in managing patients with anti-FH associated HUS. PROSPERO ID: CRD420251033150.
2025-11-25 | Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India.
Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare form of thrombotic microangiopathy that results from complement system activation. It represents a significant etiology of acute kidney injury among children. In India, aHUS is predominantly associated with anti-factor H antibodies, presenting unique diagnostic and therapeutic challenges. This study aims to delineate the clinical characteristics, immunological profile, management strategies, and outcomes of pediatric aHUS cases from a tertiary center in Eastern India. Methodology We conducted a retrospective, observational, case series at a tertiary care hospital in Eastern India, including seven pediatric patients diagnosed with aHUS between January 2023 and December 2024. Diagnosis was based on a clinical triad (acute kidney injury, microangiopathic anemia, thrombocytopenia), exclusion of Shiga toxin-associated cases and secondary causes, confirmation with complement/anti-factor H antibody testing, and, where feasible, genetic analysis. Patients received plasma exchange, immunomodulators, and supportive care. Data were analyzed using descriptive statistics. Results A total of seven children (median age = 7 years, six females) were treated for aHUS. CFHR1-CFHR3 deletions and anti-factor H antibodies were each identified in 43% of patients. Plasma exchange and steroids formed the therapeutic mainstay. Hematological remission was achieved in 71% of cases within one week, and 43% attained full renal recovery. However, 29% progressed to chronic kidney disease or remained dialysis-dependent, and the remaining 29% showed only limited renal improvement. Early initiation of plasmapheresis and immunosuppression was associated with better renal outcomes, while lack of access to eculizumab and genetic testing remained significant barriers. Conclusions Pediatric aHUS in Eastern India demonstrates a high burden of anti-factor H antibody-mediated disease and genetic complement abnormalities. Early plasmapheresis and immunomodulator use result in improved hematological and renal outcomes. There is a critical need for enhanced access to complement inhibitors and diagnostic tools to optimize management and prognosis in resource-constrained settings.
2025-10-01 | Evaluating Truncated Plasma Exchange in Anti-Complement Factor H Autoantibody-Associated Hemolytic Uremic Syndrome as a Viable Strategy in Resource-Limited Settings: Evidence from a Clinical Cohort
Background: Anti-complement factor H autoantibody-associated hemolytic uremic syndrome (anti-CFH HUS) accounts for >50% of atypical HUS cases in Indian children. The recommended regimen of 20-22 sessions of plasma exchange (PLEX) combined with immunosuppression is expert-based, however, it imposes severe financial burden in low-resource settings. Thus, we investigated the utility of a truncated PLEX regimen of 5-7 sessions in inducing remission. Methods: Hospital records of children ≤18years with anti-CFH HUS (KDIGO 2021 guidelines; anti-CFH antibody titer>150AU/mL) treated at a tertiary center in a low-resource setting between Jan 2017-Apr 2025, were reviewed following ethical approval. PLEX data, clinical and laboratory parameters at baseline and follow-up were noted. Outcome measures were number of PLEX sessions for hematological remission (platelets>105/mm3 for 2 days) and kidney outcome at 1year. Results: Analysis included 28 episodes in 24 patients with median[IQR] age of 8.4[5.8,9.5]years. The median[IQR] anti-CFH antibody (AU/mL) was 4600[342,10816] and 130[78,220] at onset and last follow-up respectively. The median(range) PLEX sessions were 5(3-20). Patients received immunosuppression with steroids (85.7%), mycophenolate (32.1%), and cyclophosphamide (17.9%). Remission was achieved in 89.3% with truncated PLEX regimen (Figure1). In the median(range) follow-up of 24(1-96)months, only 2(8%) relapsed (both received truncated regimen; 2 episodes each), following an average interval of 9.5 and 44.5months between episodes. At 1year follow-up (N=21), eGFR<60 in 4.7%, hypertension in 57%, and proteinuria in 19% was noted. Conclusion: Truncated PLEX regimen with appropriate immunosuppression achieved remission in a majority of pediatric anti-CFH HUS cases. This is a viable, cost-effective strategy to manage HUS in low-resource settings, where eculizumab is inaccessible.Figure1: Kaplan-Meier Plot for Number of PLEX Sessions to Reach Remission
proteins
2025-07-01 | The four functional segments of Factor H: Role in physiological target recognition and contribution to disease
Factor H controls proximal complement activation, and its dysfunction leads to diseases that often manifest in the kidney. Structural and functional analyses have identified four distinct functional segments: an N-terminal regulatory unit, a cell binding unit, a segment with combined low-affinity C3b and Heparin sites, and a C-terminal recognition or sensor unit with overlapping C3b/C3d and Heparin sites. Three of these segments are associated with diseases. The regulatory segment is implicated in C3 glomerulopathy (C3G) and ANCA-anti neutrophil cytoplasmic antibodies - associated vasculitis (AAV). The second segment includes the Y402H-polymorphism of age relate macular degeneration (AMD), is associated with cancer, and is also targeted by pathogens. The C-terminal sensor segment is involved in atypical hemolytic uremic syndrome (aHUS), in FHR1:FHR3 deficient and autoantibody positive HUS (DEAP-HUS), and is also exploited by pathogens. Factor H functions are modulated by two plasma proteins: Factor H like protein 1 (FHL1) and Factor H related protein 1 (FHR1), both of which share structural segments with Factor H. This interplay is critical for fine-tuning local complement activity. In addition, new noncanonical functions of Factor H and alternative sites of action, including intracellular roles, are being elaborated. A deeper understanding Factor H’s physiological role, as well as the impact of its absence, mutations, or autoantibody targeting, provides valuable insights into disease mechanisms and opens opportunities for therapeutic intervention by using full length Factor H, its fragments, or complement-modulatory compounds.
2024-05-10 | Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity
Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors’ blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro , as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 – the human FH analog expressed in moss – will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.
2023-08-09 | Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation
The complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present in vitro and ex vivo data on the mechanism of action of zilucoplan for the inhibition of C5 activation, including two clinically relevant C5 polymorphisms at R885.The interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers.Zilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the in vitro activation of C5 clinical variants at R885 that have been previously reported to respond poorly to eculizumab treatment. Zilucoplan was further demonstrated to interfere with the formation of C5b6 and inhibit red blood cell (RBC) hemolysis induced by plasmin-mediated non-canonical C5 activation. Zilucoplan demonstrated greater permeability than a monoclonal C5 antibody in a reconstituted basement membrane model, providing a rationale for the rapid onset of action of zilucoplan observed in clinical studies.Our findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.
2021-04-27 | A synthetic protein as efficient multitarget regulator against complement over-activation
Abstract The complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g.COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may present alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH. MFHR13 includes the FH variant I62, which we characterized to induce improved C3b binding and cofactor activity compared to the variant V62. After comparative protein structure modelling, we introduced the SCR FH 13 , which includes an N -glycosylation site for higher protein stability. In summary, the fusion protein MFHR13 comprises SCRs FHR1 1-2 :FH 1-4 :FH 13 :FH 19-20 . It shows an enhanced heparin binding and protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, it also blocks the terminal pathway of complement activation and we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as a therapeutic for complement-associated diseases.
2018-07-04 | Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome
Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.
small molecules
2026-01-01 | Ravulizumab administration for relapse prevention in atypical hemolytic uremic syndrome with a <i>CFH</i> variant: A case report
Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA). When aHUS cannot be excluded, diagnostic treatment with anti-C5 antibody agents should be considered. We report a patient with a novel heterozygous complement factor H (CFH) variant, p.Glu1198Asp (c.3594A>T), who received ravulizumab three months after disease onset. Ravulizumab was administered for relapse prevention in the chronic phase, and no recurrence of thrombotic microangiopathy was observed during the follow-up.
2023-12-04 | ANTI-FACTOR H ANTIBODY ASSOCIATED ATYPICAL HEMOLYTIC-UREMIC SYNDROME IN CHILDREN: CLINICAL PROFILE, DIAGNOSIS AND TREATMENT
Atypical hemolytic uremic syndrome (aHUS) refers to one of the forms of thrombotic microangiopathy occurring with preferred damage to the kidneys. About 10% of all cases of aHUS in children are aHUS associated with antibodies to complement factor H (CFH-Ab-aHUS). In 90% of cases CFH-Ab-aHUS is represented by DEAP-HUS (Deficiency of Complement Factor H Related (CFHR) plasma proteins and Autoantibody Positive Hemolytic Uremic Syndrome) with a predominant deficiency of CFHR1, most often due to a homozygous deletion of CFHR3/CFHR1. CFH-Ab-aHUS is characterized by the age of onset of the disease of 4 to 12 years old; the presence of a prodrome, more often associated with gastrointestinal disorders such as vomiting and abdominal pain, less often diarrhea; relapsing course with a high risk in the first 6 months from the onset of the disease, a high proportion of adverse outcomes: death of the patient or development of end stage chronic kidney disease (CKD). Determination of the CFH-Ab titer should be performed in all children with HUS, and in case of their increase, regularly monitored during treatment. Treatment begins with eculizumab or its biosimilar until a CFH-Ab titer is obtained and, if CFH-Ab-aHUS is confirmed, it is necessary to switch to intensive plasma exchanges in combination with immunosuppressive therapy. If there are contraindications to immunosuppressive therapy or if there is no effect from it, if plasma exchanges are impossible or ineffective, if significant mutations in complement regulator genes are detected, it is necessary to continue or return to complement blocking therapy. After achieving remission of the disease, long-term monitoring of patients is required to control residual effects on the kidneys (hematuria, proteinuria, CKD) and the cardiovascular system (arterial hypertension, left ventricular myocardial hypertrophy). In patients who have reached the end stage of CKD, it is mandatory to determine the anti-CFH titer and conduct a molecular genetic research in order to determine the risks of the disease returning to the kidney graft and the need for prophylactic therapy with eculizumab or its biosimilar before and after the surgical intervention.
2023-04-08 | Heat-inactivated Factor B inhibits alternative pathway fluid-phase activation and convertase formation on endothelial cell-secreted ultra-large von Willebrand factor strings
Abstract Defective regulation of the alternative complement pathway (AP) causes excessive activation and promotes the inflammation and renal injury observed in atypical hemolytic-uremic syndrome (aHUS). The usefulness of heat-inactivated Factor B (HFB) in reducing AP activation was evaluated in: fluid-phase reactions, using purified complement proteins and Factor H (FH)-depleted serum; and in surface-activated reactions using human endothelial cells (ECs). C3a and Ba levels, measured by quantitative Western blots, determined the extent of fluid-phase activation. In reactions using C3, FB, and Factor D proteins, HFB addition (2.5-fold FB levels), reduced C3a levels by 60% and Ba levels by 45%. In reactions using FH-depleted serum (supplemented with FH at 12.5% normal levels), Ba levels were reduced by 40% with HFB added at 3.5-fold FB levels. The effectiveness of HFB in limiting AP convertase formation on activated surfaces was evaluated using stimulated ECs. Fluorescent microscopy was used to quantify endogenously released C3, FB, and C5 attached to EC-secreted ultra-large VWF strings. HFB addition reduced attachment of C3b by 2.7-fold, FB by 1.5-fold and C5 by fourfold. Our data indicate that HFB may be of therapeutic value in preventing AP-mediated generation of C3a and C5a, and the associated inflammation caused by an overactive AP.
2023-01-13 | Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future
Atypical hemolytic uremic syndrome is a thrombotic microangiopathy characterized by hemolysis, thrombocytopenia, and acute kidney injury, usually caused by alternative complement system overactivation due to pathogenic genetic variants or antibodies to components or regulatory factors in this pathway. Previously, a lack of effective treatment for this condition was associated with mortality, end-stage kidney disease, and the risk of disease recurrence after kidney transplantation. Plasma therapy has been used for atypical hemolytic uremic syndrome treatment with inconsistent results. Complement-blocking treatment changed the outcome and prognosis of patients with atypical hemolytic uremic syndrome. Early administration of eculizumab, a monoclonal C5 antibody, leads to improvements in hematologic, kidney, and systemic manifestations in patients with atypical hemolytic uremic syndrome, even with apparent dialysis dependency. Pre- and post-transplant use of eculizumab is effective in the prevention of atypical hemolytic uremic syndrome recurrence. Evidence on eculizumab use in secondary hemolytic uremic syndrome cases is controversial. Recent data favor the restrictive use of eculizumab in carefully selected atypical hemolytic uremic syndrome cases, but close monitoring for relapse after drug discontinuation is emphasized. Prophylaxis for meningococcal infection is important. The long-acting C5 monoclonal antibody ravulizumab is now approved for atypical hemolytic uremic syndrome treatment, enabling a reduction in the dosing frequency and improving the quality of life in patients with atypical hemolytic uremic syndrome. New strategies for additional and novel complement blockage medications in atypical hemolytic uremic syndrome are under investigation.
2022-12-15 | Mycoplasma pneumoniae Infection Associated with Anti-Factor H Autoantibodies in Atypical Hemolytic Uremic Syndrome.
Hemolytic uremic syndrome (HUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia, and renal impairment mostly triggered by strains of Shiga-like toxin-producing Escherichia coli (STEC-HUS). A rarer form of HUS, defined as atypical HUS (aHUS), is associated with genetic or acquired dysregulation of the alternative pathway of the complement system and presents a poorer prognosis than STEC-HUS. Factor H autoantibodies (anti-FHs) have been reported in aHUS in 5-11% of cases and are strongly associated with the homozygous deletion of CFHR3-CFHR1 genes. In the large majority of patients, anti-FH-associated aHUS is commonly preceded by gastrointestinal or respiratory tract infections. Here, we described the clinical case of a 3-year-old boy who was hospitalized for aHUS preceded by Mycoplasma pneumoniae (MP) infection. He resulted positive for anti-FHs and carried the homozygous deletion of CFHR3-CFHR1. Of relevance, he also showed a variant of unknown significance in the C5 gene. The patient was successfully treated with eculizumab and achieved hematological and renal remission. The anti-FH titer decreased, became negative after 6 months of mycophenolate mofetil (MMF) treatment, and remained negative for 21-month follow-up indicating that immunosuppression was effective and could prevent the reappearance of anti-FHs. We hypothesized that MP, likely through an evasion strategy of immunosurveillance based on binding of pathogen to FH, triggers anti-FH antibody generation and aHUS in a subject genetically predisposed. In conclusion, to the best of our knowledge, here, we reported the first case of anti-FH-mediated aHUS after an MP infection who benefited from eculizumab and immunosuppressive therapy based on MMF. Hence, monitoring of anti-FHs in patients with post-MP infection glomerulonephritis could be recommended, especially in those with low C3 plasma levels.
other
2025-07-01 | AAV-mHDM-FH: Safety and expression profile in two murine models of hyper-complement activation
C3 glomerulopathy (C3G) and atypical haemolytic uraemic syndrome (aHUS) are rare kidney disorders characterized by the dysregulation of the alternative pathway (AP). Unlike aHUS, current treatment options for C3G are limited. Factor H (FH) plays a key role in regulating the AP, and mice lacking FH develop a disease similar to C3G. We previously developed mouse homodimeric minimal FH (mHDM-FH) as a gene therapy using an adeno-associated virus (AAV) vector incorporating a liver-specific promoter to rebalance the AP activation. We previously noted that a single dose of AAV-mHDM-FH (1 × 10 11 ) restored complement regulation in Cfh −/− mice by 21 days post inoculation, however this was associated with a strong anti-HDM-FH response, which was markedly reduced in Cfh +/− mice. In the current study, we focussed on long-term evaluation of AAV-mHDM-FH in both Cfh +/− mice and C3 N/N mice (the C3 D1115N gain-of-function mouse model of aHUS). At six months post-inoculation, C3 N/N mice treated with AAV-mHDM-FH showed significantly improved survival compared to AAV-GFP controls. However, the therapeutic effect was partially limited due to reduced binding affinity of mHDM-FH to the mutant C3 D1115N protein. These findings indicate that while AAV-mHDM-FH retains some functionality in C3 mutation-driven disease, its efficacy may not match therapies targeting the terminal complement pathway. In Cfh +/− mice, no signs of disease or safety concerns were observed over the six-month period. Importantly, increased serum levels of both C3 and FH were detected, suggesting improved control of the amplification loop in these mice. AAV transgene expression remained detectable in the liver at six months, an encouraging result for long-term efficacy. Across both experimental time points, anti-AAV antibody responses were detected in Cfh +/− mice. These responses peaked at 21 days post-inoculation but were present at relatively low levels after 6 months. This pattern aligns with observations in patients receiving AAV-based gene therapies. Despite the presence of anti-AAV antibodies, the 6 month data showed transgene expression and no safety concerns, leaving the extent to which these antibodies impact therapeutic efficacy still uncertain. Looking ahead, we aim to enhance long-term vector expression by exploring the use of alternative promoters tailored to different cellular targets. References: 1. Yang Y, Denton H, Davis O R, Smith-Jackson K, Kerr H, Herbert A P, Barlow P N, Pickering M C and Marchbank K J An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy J Am Soc Nephrol 2018 29(6):1649–1661.
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