RARE DISEASE
Atypical hemolytic uremic syndrome with complement gene abnormality
Atypical hemolytic uremic syndrome with complement gene abnormality
Atypical hemolytic uremic syndrome with complement gene abnormality
Synonyms: Atypical HUS with complement gene abnormality, aHUS with complement gene abnormality
Synonyms: Atypical HUS with complement gene abnormality, aHUS with complement gene abnormality
Synonyms: Atypical HUS with complement gene abnormality, aHUS with complement gene abnormality
Drug discovery
1
drug
With orphan designation
Overview
Atypical hemolytic uremic syndrome (aHUS) is a rare, genetically driven thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. Mutations in genes such as CFH, CFI, CD46, C3, and CFB result in uncontrolled complement activation, leading to endothelial injury, microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Up to 50% progress to end-stage renal disease (ESRD), with extrarenal complications (e.g., neurological, cardiovascular) in 20% of cases. Diagnosis relies on clinical criteria, complement testing, and genetic analysis, while targeted anti-C5 therapies (eculizumab/ravulizumab) are first-line treatments [1][4][14][19].
Burden
Morbidity: ~50% progress to ESRD; 20% experience life-threatening extrarenal complications [4][10][14].
Mortality: Historically 33–40% within a year pre-eculizumab; improved with anti-C5 therapies [19].
Cost: High due to lifelong biologic therapy (eculizumab: ~$500,000/year) and renal replacement therapies [6][19].
Therapies
C5 inhibitors (eculizumab/ravulizumab): Block terminal complement activation, reducing thrombotic events and improving renal outcomes [4][5][19].
Plasma exchange: Limited utility, primarily used in acute settings or anti-CFH antibody–positive cases [4][12].
Genetic testing: Guides long-term therapy duration and transplant decisions (e.g., high recurrence risk with CFH mutations) [5][14].
Categories: rare genetic diseases, rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
298 drug discovery papers about Atypical hemolytic uremic syndrome with complement gene abnormality, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
298 drug discovery papers about Atypical hemolytic uremic syndrome with complement gene abnormality, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2022-12-02 | Case report: Novel FHR2 variants in atypical Hemolytic Uremic Syndrome: A case study of a translational medicine approach in renal transplantation.
Atypical hemolytic-uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 (FHR2) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient's serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient's serum could induce complement activation, as well as C5b-9 deposition on human endothelial cells, and affected cell morphology. As C5b-9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b-9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation.
2020-07-31 | Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation
Hemopexin is the main plasmatic scavenger of cell-free heme, released in the context of intravascular hemolysis or major cell injury. Heme is indispensable for the oxygen transport by hemoglobin but when released outside of the erythrocytes it becomes a danger-associated molecular pattern, contributing to tissue injury. One of the mechanisms of pro-inflammatory action of heme is to activate the innate immune complement cascade. Therefore, we hypothesized that injection of hemopexin will prevent hemolysis-induced complement activation. Human plasma-derived hemopexin is compatible with the heme clearance machinery of the mice. 100 or 500 mg/kg of hemopexin was injected in C57Bl/6 mice before treatment with phenylhydrazine (inducer of erythrocytes lysis) or with PBS as a control. Blood was taken at different timepoints to determine the pharmacokinetic of injected hemopexin in presence and absence of hemolysis. Complement activation was determined in plasma, by the C3 cleavage (western blot) and in the kidneys (immunofluorescence). Kidney injury was evaluated by urea and creatinine in plasma and renal NGAL and HO-1 gene expression were measured. The pharmacokinetic properties of hemopexin (mass spectrometry) in the hemolytic mice were affected by the target-mediated drug disposition phenomenon due to the high affinity of binding of hemopexin to heme. Hemolysis induced complement overactivation and signs of mild renal dysfunction at 6h, which were prevented by hemopexin, except for the NGAL upregulation. The heme-degrading capacity of the kidney, measured by the HO-1 expression, was not affected by the treatment. These results encourage further studies of hemopexin as a therapeutic agent in models of diseases with heme overload.
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.
2018-01-15 | The MFHR1 Fusion Protein Is a Novel Synthetic Multitarget Complement Inhibitor with Therapeutic Potential
The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1. In vitro , MFHR1 showed cofactor and decay acceleration activity and inhibited C5 convertase activation and C5b-9 assembly, which prevented C3b deposition and reduced C3a/C5a and C5b-9 generation. Furthermore, this fusion protein showed the ability to escape deregulation by FH-related proteins and form multimeric complexes with increased inhibitory activity. In addition to substantially inhibiting alternative and classic pathway activation, MFHR1 blocked hemolysis mediated by serum from a patient with aHUS expressing truncated FH. In FH−/− mice, MFHR1 administration augmented serum C3 levels, reduced abnormal glomerular C3 deposition, and ameliorated C3 glomerulopathy. Taking the unique design of MFHR1 into account, we suggest that the combination of proximal and terminal cascade inhibition together with the ability to form multimeric complexes explain the strong inhibitory capacity of MFHR1, which offers a novel basis for complement therapeutics.
2017-11-13 | Genetic predisposition to infection in a case of atypical hemolytic uremic syndrome
Most cases of hemolytic uremic syndrome (HUS) are caused by infection with enterohemorrhagic Escherichia coli (EHEC). Genetic defects causing uncontrolled complement activation are associated with the more severe atypical HUS (aHUS). Non-EHEC infections can trigger the disease, however, complement defects predisposing to such infections have not yet been studied. We describe a 2-month-old patient infected with different Gram-negative bacterial species resulting in aHUS. Serum analysis revealed slow complement activation kinetics. Rare variant R229C was found in complement inhibitor vitronectin. Recombinant mutated vitronectin showed enhanced complement inhibition in vitro and may have been a predisposing factor for infection. Our work indicates that genetic changes in aHUS can not only result in uncontrolled complement activation but also increase vulnerability to infections contributing to aHUS.
cell therapies
2024-01-03 | Atypical hemolytic-uremic syndrome in pregnancy: a case report
Introduction: The diagnosis of Atypical hemolytic-uremic syndrome (aHUS) is largely imprecise. Improving outcomes requires accurate diagnosis and timely management. Acute kidney damage, thrombocytopenia, and microangiopathic hemolytic anemia are all signs of aHUS. The condition is brought on by pregnancy, and in genetically susceptible women, it progresses to a terrible hemolytic illness marked by widespread endothelium damage and platelet consumption. The sickness is a potentially fatal ailment that demands quick identification and treatment.Case Presentation: Our facility provided treatment for severe anemia, thrombocytopenia, and acute renal damage in a 24-year-old G1P1A0 postpartum lady with Caesarean sectio and a HELLP syndrome suspicion. An aHUS diagnosis was later verified. The condition of the patient failed to improve in the first 24 hours after birth. Inside this presence of TMA, the patient began on daily TPE and ran in parallel prednisone medication (1 mg/kg/day). After six TPE cycles, the laboratory values began to rise.Conclusion: AHUS can be challenging to diagnose early since it frequently mimics other illnesses. To enhance results, proper diagnosis and prompt management are essential. The management strategy includes a multidisciplinary team, early plasmapheresis, and complement inhibition. To lessen the effects of aHUS, TPE should be carried out as soon as feasible on a daily basis.
2023-07-03 | Profile and Post-Kidney Retrieval Outcomes in Asymptomatic Kidney Donors With Genetic Mutations in Complement Factors-Related Genes.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder triggered by various stressors. Most of the time, stressors may not be identified in patients with aHUS. The disease may remain quiescent without manifestation throughout life. To assess the outcome of an asymptomatic carrier of genetic mutations of patients with aHUS who had undergone donor kidney retrieval surgery. We retrospectively included the patients diagnosed with a genetic abnormality in complement factor H (CHF) or CHF-related (CFHR) genes without manifestation of the aHUS and who had undergone donor kidney retrieval surgery. The data were analyzed with descriptive statistics. Among patients who were the kidney recipients from the prospective donors, 6 donors were screened for genetic mutations in CFH and CFHR genes. Four donors showed positive mutation for CFH and CFHR. The mean age was 54.5 years (range, 50-64 years). After over a year since donor kidney retrieval surgery, all prospective mother donors are alive without aHUS activation and with a normal kidney function on a single kidney. Asymptomatic carriers of genetic mutations in CFH and CFHR can be the prospective donors for their first-degree family member who have active aHUS. A genetic mutation in an asymptomatic donor should not be a contraindication for refuting the prospective donor.
2019-06-07 | Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database
Background: Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury, is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required. Methods: Of 781 patients <18-year-old of aHUS in the nationwide database from 2007-2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-yr (n=317) were compared to before (n=119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity (n=8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH) and proteinuria were evaluated in a subset. Results: Patients presented with markedly elevated anti-FH titers (10633.2±998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-yr showed better renal survival at mean 28.5±27.3 months (log rank P=0.022). Mean anti-FH titers stayed 700-1164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission (Generalized estimating equations, P=0.001); anti-FH levels ≥1330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; P=0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8000 AU/ml (HR 2.23; P=0.024), time to PEX ≥14 days (HR 2.09; P=0.071) and PEX for <14 days (HR 2.60; P=0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; P=0.026); maintenance therapy reduced risk of relapses (HR 0.11; P<0.001). At 4.4±2.5 yr, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38%, 30% and 18%, respectively. Proteinuria and LVH occurred in 58% and 28% patients, respectively. Conclusion: Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.
2019-06-07 | Membrane‐filtration based plasma exchanges for atypical hemolytic uremic syndrome: Audit of efficacy and safety
ABSTRACT Background While complement blockade with eculizumab is recommended as first‐line therapy of atypical hemolytic uremic syndrome (aHUS), plasma exchanges (PEX) remain the chief option for anti‐factor H (FH) antibody associated disease and when access to eculizumab is limited. Methods We reviewed adverse events (AEs) and adverse outcomes (eGFR <30 mL/min/1.73 m 2 or death), in all patients with aHUS managed with membrane‐filtration based PEX at one tertiary care center over 5.5 years. Results During January 2013 to June 2018, 109 patients with aHUS (74 with antibodies to FH), aged median (range) 7.6 (0.5‐18) year weighing 22.1 (6‐90) kg, underwent 2024 sessions of PEX. AE, in 12.1% patients, were usually self‐limiting and included chills (5.5%), vomiting/abdominal pain (3.3%), hypotension (1.6%), urticaria (1.5%), seizures (0.2%), hypocalcemia (0.2%), and hemorrhage (0.1%); plasma hypersensitivity and severe reactions were rare. Rate of catheter‐related infections was 1.45/1000 catheter‐days. Filter reuse (OR 1.69; 95% CI 1.26‐2.26; P < .001) and >20 sessions of PEX/patient (OR 1.99; 95% CI 1.27‐3.10; P = .002) were independently associated with adverse events; infusion of IV calcium gluconate during PEX was protective (OR 0.26; 95% CI 0.16‐0.43; P < .001). Hematological remission was achieved in 96.3% patients after 6 (5‐8) PEX sessions; 80.8% and 89.6% patients were dialysis independent by one and 3 months, respectively. Conclusions PEX is safe and associated with satisfactory short‐term outcomes in children with aHUS. Prolonged PEX and filter‐reuse are associated with complications.
2015-04-27 | Posttransplant outcome of atypical haemolytic uraemic syndrome in a patient with thrombomodulin mutation: a case without recurrence
Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ∼50% of the cases. Thrombomodulin (THBD) gene mutations occur in ∼3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation.
small molecules
2024-03-08 | The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases, and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
2023-09-21 | Immunosuppressive Therapy of Antibody-Mediated aHUS and TTP
The recent classification of pediatric thrombotic microangiopathies (TMA) takes into consideration mechanisms of disease for guidance to targeted therapies. We present our experience with seven patients with antibody mediated atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). Five children had aHUS with antibodies against complement factor H (CFH-ab) and two with TTP with antibodies against metalloproteinase ADAMTS13. In the aHUS cases diagnosed and treated before the eculizumab era, CFH-ab was detected using the ELISA assay. Mutational analysis of selected complement genes was performed. TTP was diagnosed if, in addition to microangiopathic hemolytic anemia and thrombocytopenia, ischemic organ involvement and severe deficiency in ADAMTS13 activity were present. Treatment protocol consisted of plasma exchanges (PE) and steroid pulses, followed by the combination of cyclophosphamide and rituximab to achieve long-term immunosuppression. Four patients with CFH-ab and the TTP patients with ADAMTS13 antibodies came into sustained remission. After a median follow-up of 11.7 (range 7.7-12.9) years without maintenance therapy, no disease recurrence was observed; nevertheless, six patients, two had hypertension and two had proteinuria as a late consequence. One patient, with late diagnosis of CFH-ab and additional genetic risk factors who was treated only with PE and plasma substitution, reached end-stage renal disease and was later successfully transplanted using eculizumab prophylaxis. In the cases of antibody-mediated TMAs, PE and early immunosuppressive treatment may result in sustained remission with preserved kidney function. Further data are needed to establish optimal treatment of anti-FH antibody-associated HUS.
2021-06-10 | Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.
2021-05-09 | Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling
Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.
2020-04-02 | Prophylactic amoxicillin for the prevention of meningococcal infection in infants with atypical hemolytic uremic syndrome under treatment with eculizumab: a report of two cases
Eculizumab, a humanized monoclonal antibody to complement C5, is a therapeutic drug for atypical hemolytic–uremic syndrome (aHUS) that inhibits the terminal pathway of complement. Patients on eculizumab therapy may become more susceptible to infection with capsule-forming bacteria, including meningococci. Therefore, meningococcal vaccination is required for patients who are on eculizumab therapy. However, the means to prevent meningococcal infection in infants who cannot be vaccinated with the available meningococcal vaccine have not yet been established internationally. In two infants with aHUS at 4–5 months after birth, prophylactic oral amoxicillin was administered, and meningococcal infection was not detected during the period between the initiation of eculizumab therapy and the administration of meningococcal vaccine. Neither adverse events related to amoxicillin nor thrombotic microangiopathy occurred during the treatment. Thus, oral administration of amoxicillin may be effective for preventing meningococcal infection under treatment with eculizumab in infants who have not received meningococcal vaccination.
antibodies
2024-10-01 | Influenza B Triggering Atypical Hemolytic Uremic Syndrome (aHUS) in a Patient with Cobalamin C (CblC) Disease Carrier State and a Complement Factor H (CFH) Mutation
Introduction: AHUS is driven by abnormalities in genes coding for alternative complement pathway regulators triggering increased activity of the membrane attack complex. This causes endothelial damage, platelet adhesion and formation of microthrombi with subsequent thrombocytopenia, intravascular destruction of erythrocytes and acute kidney injury; termed thrombotic microangiopathy (TMA). We report a rare environmental trigger for aHUS in a patient with rare mutations in cobalamin uptake and CFH gene. Case Description: A 59-year-old woman presented with upper respiratory symptoms and tested positive for Influenza B. Laboratory showed AKI, thrombocytopenia, hemolytic anemia with schistocytes and nephrotic range proteinuria. Creatinine at admission was 2.14mg/dL (from a normal baseline) and peaked at 8.67mg/dL with hyperkalemia requiring hemodialysis. C3 was low. C4, ADAMTS13 activity and Vitamin B12 were normal and methylmalonic acid level was mildly elevated. Acute kidney injury progressed and patient required initiation of hemodialysis. Kidney biopsy showed lobular accentuation of glomeruli, increased matrix deposition, karyorrhectic debris and red blood cell fragments in the mesangium and fibrinoid necrosis of an arteriole. Eculizumab was initiated and six days later renal function recovered, and dialysis was discontinued. Genetic testing revealed heterozygous p. Arg161Gly missense variant in the metabolism of cobalamin associated C (MMACHC gene) and heterozygous p. Thr724Lys missense variant in the CFH gene classified as a variant of unknown significance. Discussion: MMACHC gene mutations cause autosomal recessive methylmalonic aciduria and homocystinuria (CblC disease) which rarely presents as aHUS. CblC disease is usually reported in children and none in the carrier state. Additional CFH high-risk haplotype and environmental factors increased the risk for aHUS in this case, with influenza being a known trigger but influenza B being very rare. This case highlights the importance of suspecting aHUS in older adults with identifiable triggers and low threshold to initiate complement blockade.
2024-05-15 | An unusual case of adult-onset still's disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome.
Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.
2024-01-11 | Rational use of eculizumab in secondary atypical hemolytic uremic syndrome
Background Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS. Methods Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort). Conclusion Early and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.
2023-10-19 | C5 inhibition in aHUS
C5 inhibition in aHUSTo obtain credit, you should first read the journal article.After reading the article, you should be able to answer the following, related, multiplechoice questions.To complete the questions (with a minimum 75% passing score) and earn continuing medical education (CME) credit,
2023-09-01 | Pregnancy-Associated Atypical Hemolytic Uremic Syndrome: A Case Report with a rare MCP Gene Mutation and Successful Eculizumab Treatment
Abstract Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare condition characterized by microangiopathic hemolytic anemia and kidney injury from thrombotic microangiopathy. P-aHUS occurs in approximately 1 in 25,000 pregnancies and is strongly related to complement dysregulation and pregnancy-related disorders, such as preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome, resulting in adverse perinatal and fetal outcomes. Complement dysregulation in P-aHUS is commonly attributed to genetic mutations or autoantibodies affecting complement factors, including CFH, CFI, and MCP. We present a case of a 25-year-old primigravida who experienced severe preeclampsia and HELLP syndrome followed by the development of complicated P-aHUS during the early postpartum period. The patient exhibited severe clinical manifestations, including hypertensive emergency, central nervous system involvement, renal impairment, and microangiopathic hemolytic anemia. Timely initiation of eculizumab therapy resulted in successful disease remission. Further genetic analysis revealed a likely rare pathogenic MCP gene variant.
other
2025-05-20 | RNA Splicing Analysis of the CFI Mutation Site in the Causative Gene for Atypical Hemolytic Uremic Syndrome
目的：CFI基因编码的补体因子I (FI)是补体系统调节过程中重要的丝氨酸蛋白酶，其功能缺陷与多种疾病相关，然而许多突变的致病机制并未完全阐明。本实验旨在通过迷你基因实验验证CFI基因突变对mRNA剪接的影响，为解释致病机制、发现治疗靶点提供新思路。方法：本研究首先通过生物信息学软件，从人类基因数据库中筛选出目标突变，并将包含该突变位点的基因片段导入载体中。随后将构建好的含有野生型和突变型的质粒分别转染至人胚肾细胞(HEK293T)中，并利用RT-PCR和测序技术分析其mRNA产物的变化。结果：与野生型5号外显子相比，c.772G>A突变导致外显子完全跳变，产生了异常剪接产物。这一异常剪接可能导致产生的FI蛋白功能域缺陷，从而影响其蛋白酶活性或与其他补体因子的结合。结论：本研究成功构建了CFI基因的迷你基因实验体系，证实了c.772G>A突变可导致mRNA剪接异常。这为深入理解CFI基因突变的致病机制提供了重要的实验依据，也为aHUS疾病的基因诊断和治疗提供了新的靶点。 Objective: Complement factor I (FI), encoded by the CFI gene, is an important serine protease regulating the complement system, and its functional defects have been associated with a wide range of diseases. However, the pathogenic mechanisms of many mutations have not been fully elucidated. This experiment aims to verify the effect of CFI gene mutation on mRNA splicing through minigene experiments, which will provide new ideas to explain the pathogenic mechanism and discover therapeutic targets. Methods: In this study, the target mutation was first screened out from the human gene database by bioinformatics software, and the gene fragment containing the mutation site was introduced into the vector. Subsequently, the constructed plasmids containing wild-type and mutant were transfected into human embryonic kidney cells (HEK293T) respectively, and the changes in their mRNA products were analyzed by RT-PCR and sequencing. Results: Compared with wild-type exon 5, the c.772G>A mutation resulted in a complete exon skipping, producing an aberrant splicing product. This aberrant splicing may lead to defects in the functional domains of the resulting FI proteins, thus affecting their protease activity or binding to other complement factors. Conclusion: In this study, we successfully constructed a minigene experimental system for the CFI gene and confirmed that the c.772G>A mutation could lead to abnormal mRNA splicing. This provides an essential experimental basis for the in-depth understanding of the pathogenic mechanism of CFI gene mutation and also provides a new target for the genetic diagnosis and treatment of aHUS disease.
2014-06-06 | A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation
Genomic aberrations affecting the genes encoding factor H (FH) and the five FH-related proteins (FHRs) have been described in patients with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ARF. These genomic rearrangements occur through nonallelic homologous recombinations caused by the presence of repeated homologous sequences in CFH and CFHR1-R5 genes. In this study, we found heterozygous genomic rearrangements among CFH and CFHR genes in 4.5% of patients with aHUS. CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. Five patients carried known CFH/CFHR1 genes, but we found a duplication leading to a novel CFHR1/CFH hybrid gene in a family with two affected subjects. The resulting fusion protein contains the first four short consensus repeats of FHR1 and the terminal short consensus repeat 20 of FH. In an FH-dependent hemolysis assay, we showed that the hybrid protein causes sheep erythrocyte lysis. Functional analysis of the FHR1 fraction purified from serum of heterozygous carriers of the CFHR1/CFH hybrid gene indicated that the FHR1/FH hybrid protein acts as a competitive antagonist of FH. Furthermore, sera from carriers of the hybrid CFHR1/CFH gene induced more C5b-9 deposition on endothelial cells than control serum. These results suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of complement at the endothelial cell surface. We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, particularly before a kidney transplant.
2011-06-24 | Soluble CD59 Expressed from an Adenovirus In Vivo Is a Potent Inhibitor of Complement Deposition on Murine Liver Vascular Endothelium
Inappropriate activation of complement on the vascular endothelium of specific organs, or systemically, underlies the etiology of a number of diseases. These disorders include atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, and transplant rejection. Inhibition of the terminal step of complement activation, i.e. formation of the membrane attack complex, using CD59 has the advantage of retaining the upstream processes of the complement cascade necessary for fighting pathogens and retaining complement's crucial role in tissue homeostasis. Previous studies have shown the necessity of membrane targeting of soluble CD59 in order for it to prove an effective inhibitor of complement deposition both in vitro and in vivo. In this study we have generated an in vivo model of human complement activation on murine liver vascular endothelium. This model should prove useful for the development of anti-complement therapies for complement-induced pathologies of vascular endothelium. Using this model, we have demonstrated the viability of a non membrane-targeted soluble CD59 to significantly inhibit complement deposition on the endothelium of murine liver vasculature when expressed in vivo from an adenovirus. This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited.
proteins
2022-12-02 | Case report: Novel FHR2 variants in atypical Hemolytic Uremic Syndrome: A case study of a translational medicine approach in renal transplantation.
Atypical hemolytic-uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 (FHR2) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient's serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient's serum could induce complement activation, as well as C5b-9 deposition on human endothelial cells, and affected cell morphology. As C5b-9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b-9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation.
2020-07-31 | Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation
Hemopexin is the main plasmatic scavenger of cell-free heme, released in the context of intravascular hemolysis or major cell injury. Heme is indispensable for the oxygen transport by hemoglobin but when released outside of the erythrocytes it becomes a danger-associated molecular pattern, contributing to tissue injury. One of the mechanisms of pro-inflammatory action of heme is to activate the innate immune complement cascade. Therefore, we hypothesized that injection of hemopexin will prevent hemolysis-induced complement activation. Human plasma-derived hemopexin is compatible with the heme clearance machinery of the mice. 100 or 500 mg/kg of hemopexin was injected in C57Bl/6 mice before treatment with phenylhydrazine (inducer of erythrocytes lysis) or with PBS as a control. Blood was taken at different timepoints to determine the pharmacokinetic of injected hemopexin in presence and absence of hemolysis. Complement activation was determined in plasma, by the C3 cleavage (western blot) and in the kidneys (immunofluorescence). Kidney injury was evaluated by urea and creatinine in plasma and renal NGAL and HO-1 gene expression were measured. The pharmacokinetic properties of hemopexin (mass spectrometry) in the hemolytic mice were affected by the target-mediated drug disposition phenomenon due to the high affinity of binding of hemopexin to heme. Hemolysis induced complement overactivation and signs of mild renal dysfunction at 6h, which were prevented by hemopexin, except for the NGAL upregulation. The heme-degrading capacity of the kidney, measured by the HO-1 expression, was not affected by the treatment. These results encourage further studies of hemopexin as a therapeutic agent in models of diseases with heme overload.
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.
2018-01-15 | The MFHR1 Fusion Protein Is a Novel Synthetic Multitarget Complement Inhibitor with Therapeutic Potential
The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1. In vitro , MFHR1 showed cofactor and decay acceleration activity and inhibited C5 convertase activation and C5b-9 assembly, which prevented C3b deposition and reduced C3a/C5a and C5b-9 generation. Furthermore, this fusion protein showed the ability to escape deregulation by FH-related proteins and form multimeric complexes with increased inhibitory activity. In addition to substantially inhibiting alternative and classic pathway activation, MFHR1 blocked hemolysis mediated by serum from a patient with aHUS expressing truncated FH. In FH−/− mice, MFHR1 administration augmented serum C3 levels, reduced abnormal glomerular C3 deposition, and ameliorated C3 glomerulopathy. Taking the unique design of MFHR1 into account, we suggest that the combination of proximal and terminal cascade inhibition together with the ability to form multimeric complexes explain the strong inhibitory capacity of MFHR1, which offers a novel basis for complement therapeutics.
2017-11-13 | Genetic predisposition to infection in a case of atypical hemolytic uremic syndrome
Most cases of hemolytic uremic syndrome (HUS) are caused by infection with enterohemorrhagic Escherichia coli (EHEC). Genetic defects causing uncontrolled complement activation are associated with the more severe atypical HUS (aHUS). Non-EHEC infections can trigger the disease, however, complement defects predisposing to such infections have not yet been studied. We describe a 2-month-old patient infected with different Gram-negative bacterial species resulting in aHUS. Serum analysis revealed slow complement activation kinetics. Rare variant R229C was found in complement inhibitor vitronectin. Recombinant mutated vitronectin showed enhanced complement inhibition in vitro and may have been a predisposing factor for infection. Our work indicates that genetic changes in aHUS can not only result in uncontrolled complement activation but also increase vulnerability to infections contributing to aHUS.
cell therapies
2024-01-03 | Atypical hemolytic-uremic syndrome in pregnancy: a case report
Introduction: The diagnosis of Atypical hemolytic-uremic syndrome (aHUS) is largely imprecise. Improving outcomes requires accurate diagnosis and timely management. Acute kidney damage, thrombocytopenia, and microangiopathic hemolytic anemia are all signs of aHUS. The condition is brought on by pregnancy, and in genetically susceptible women, it progresses to a terrible hemolytic illness marked by widespread endothelium damage and platelet consumption. The sickness is a potentially fatal ailment that demands quick identification and treatment.Case Presentation: Our facility provided treatment for severe anemia, thrombocytopenia, and acute renal damage in a 24-year-old G1P1A0 postpartum lady with Caesarean sectio and a HELLP syndrome suspicion. An aHUS diagnosis was later verified. The condition of the patient failed to improve in the first 24 hours after birth. Inside this presence of TMA, the patient began on daily TPE and ran in parallel prednisone medication (1 mg/kg/day). After six TPE cycles, the laboratory values began to rise.Conclusion: AHUS can be challenging to diagnose early since it frequently mimics other illnesses. To enhance results, proper diagnosis and prompt management are essential. The management strategy includes a multidisciplinary team, early plasmapheresis, and complement inhibition. To lessen the effects of aHUS, TPE should be carried out as soon as feasible on a daily basis.
2023-07-03 | Profile and Post-Kidney Retrieval Outcomes in Asymptomatic Kidney Donors With Genetic Mutations in Complement Factors-Related Genes.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder triggered by various stressors. Most of the time, stressors may not be identified in patients with aHUS. The disease may remain quiescent without manifestation throughout life. To assess the outcome of an asymptomatic carrier of genetic mutations of patients with aHUS who had undergone donor kidney retrieval surgery. We retrospectively included the patients diagnosed with a genetic abnormality in complement factor H (CHF) or CHF-related (CFHR) genes without manifestation of the aHUS and who had undergone donor kidney retrieval surgery. The data were analyzed with descriptive statistics. Among patients who were the kidney recipients from the prospective donors, 6 donors were screened for genetic mutations in CFH and CFHR genes. Four donors showed positive mutation for CFH and CFHR. The mean age was 54.5 years (range, 50-64 years). After over a year since donor kidney retrieval surgery, all prospective mother donors are alive without aHUS activation and with a normal kidney function on a single kidney. Asymptomatic carriers of genetic mutations in CFH and CFHR can be the prospective donors for their first-degree family member who have active aHUS. A genetic mutation in an asymptomatic donor should not be a contraindication for refuting the prospective donor.
2019-06-07 | Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database
Background: Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury, is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required. Methods: Of 781 patients <18-year-old of aHUS in the nationwide database from 2007-2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-yr (n=317) were compared to before (n=119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity (n=8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH) and proteinuria were evaluated in a subset. Results: Patients presented with markedly elevated anti-FH titers (10633.2±998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-yr showed better renal survival at mean 28.5±27.3 months (log rank P=0.022). Mean anti-FH titers stayed 700-1164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission (Generalized estimating equations, P=0.001); anti-FH levels ≥1330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; P=0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8000 AU/ml (HR 2.23; P=0.024), time to PEX ≥14 days (HR 2.09; P=0.071) and PEX for <14 days (HR 2.60; P=0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; P=0.026); maintenance therapy reduced risk of relapses (HR 0.11; P<0.001). At 4.4±2.5 yr, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38%, 30% and 18%, respectively. Proteinuria and LVH occurred in 58% and 28% patients, respectively. Conclusion: Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.
2019-06-07 | Membrane‐filtration based plasma exchanges for atypical hemolytic uremic syndrome: Audit of efficacy and safety
ABSTRACT Background While complement blockade with eculizumab is recommended as first‐line therapy of atypical hemolytic uremic syndrome (aHUS), plasma exchanges (PEX) remain the chief option for anti‐factor H (FH) antibody associated disease and when access to eculizumab is limited. Methods We reviewed adverse events (AEs) and adverse outcomes (eGFR <30 mL/min/1.73 m 2 or death), in all patients with aHUS managed with membrane‐filtration based PEX at one tertiary care center over 5.5 years. Results During January 2013 to June 2018, 109 patients with aHUS (74 with antibodies to FH), aged median (range) 7.6 (0.5‐18) year weighing 22.1 (6‐90) kg, underwent 2024 sessions of PEX. AE, in 12.1% patients, were usually self‐limiting and included chills (5.5%), vomiting/abdominal pain (3.3%), hypotension (1.6%), urticaria (1.5%), seizures (0.2%), hypocalcemia (0.2%), and hemorrhage (0.1%); plasma hypersensitivity and severe reactions were rare. Rate of catheter‐related infections was 1.45/1000 catheter‐days. Filter reuse (OR 1.69; 95% CI 1.26‐2.26; P < .001) and >20 sessions of PEX/patient (OR 1.99; 95% CI 1.27‐3.10; P = .002) were independently associated with adverse events; infusion of IV calcium gluconate during PEX was protective (OR 0.26; 95% CI 0.16‐0.43; P < .001). Hematological remission was achieved in 96.3% patients after 6 (5‐8) PEX sessions; 80.8% and 89.6% patients were dialysis independent by one and 3 months, respectively. Conclusions PEX is safe and associated with satisfactory short‐term outcomes in children with aHUS. Prolonged PEX and filter‐reuse are associated with complications.
2015-04-27 | Posttransplant outcome of atypical haemolytic uraemic syndrome in a patient with thrombomodulin mutation: a case without recurrence
Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ∼50% of the cases. Thrombomodulin (THBD) gene mutations occur in ∼3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation.
small molecules
2024-03-08 | The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases, and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
2023-09-21 | Immunosuppressive Therapy of Antibody-Mediated aHUS and TTP
The recent classification of pediatric thrombotic microangiopathies (TMA) takes into consideration mechanisms of disease for guidance to targeted therapies. We present our experience with seven patients with antibody mediated atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). Five children had aHUS with antibodies against complement factor H (CFH-ab) and two with TTP with antibodies against metalloproteinase ADAMTS13. In the aHUS cases diagnosed and treated before the eculizumab era, CFH-ab was detected using the ELISA assay. Mutational analysis of selected complement genes was performed. TTP was diagnosed if, in addition to microangiopathic hemolytic anemia and thrombocytopenia, ischemic organ involvement and severe deficiency in ADAMTS13 activity were present. Treatment protocol consisted of plasma exchanges (PE) and steroid pulses, followed by the combination of cyclophosphamide and rituximab to achieve long-term immunosuppression. Four patients with CFH-ab and the TTP patients with ADAMTS13 antibodies came into sustained remission. After a median follow-up of 11.7 (range 7.7-12.9) years without maintenance therapy, no disease recurrence was observed; nevertheless, six patients, two had hypertension and two had proteinuria as a late consequence. One patient, with late diagnosis of CFH-ab and additional genetic risk factors who was treated only with PE and plasma substitution, reached end-stage renal disease and was later successfully transplanted using eculizumab prophylaxis. In the cases of antibody-mediated TMAs, PE and early immunosuppressive treatment may result in sustained remission with preserved kidney function. Further data are needed to establish optimal treatment of anti-FH antibody-associated HUS.
2021-06-10 | Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.
2021-05-09 | Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling
Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.
2020-04-02 | Prophylactic amoxicillin for the prevention of meningococcal infection in infants with atypical hemolytic uremic syndrome under treatment with eculizumab: a report of two cases
Eculizumab, a humanized monoclonal antibody to complement C5, is a therapeutic drug for atypical hemolytic–uremic syndrome (aHUS) that inhibits the terminal pathway of complement. Patients on eculizumab therapy may become more susceptible to infection with capsule-forming bacteria, including meningococci. Therefore, meningococcal vaccination is required for patients who are on eculizumab therapy. However, the means to prevent meningococcal infection in infants who cannot be vaccinated with the available meningococcal vaccine have not yet been established internationally. In two infants with aHUS at 4–5 months after birth, prophylactic oral amoxicillin was administered, and meningococcal infection was not detected during the period between the initiation of eculizumab therapy and the administration of meningococcal vaccine. Neither adverse events related to amoxicillin nor thrombotic microangiopathy occurred during the treatment. Thus, oral administration of amoxicillin may be effective for preventing meningococcal infection under treatment with eculizumab in infants who have not received meningococcal vaccination.
antibodies
2024-10-01 | Influenza B Triggering Atypical Hemolytic Uremic Syndrome (aHUS) in a Patient with Cobalamin C (CblC) Disease Carrier State and a Complement Factor H (CFH) Mutation
Introduction: AHUS is driven by abnormalities in genes coding for alternative complement pathway regulators triggering increased activity of the membrane attack complex. This causes endothelial damage, platelet adhesion and formation of microthrombi with subsequent thrombocytopenia, intravascular destruction of erythrocytes and acute kidney injury; termed thrombotic microangiopathy (TMA). We report a rare environmental trigger for aHUS in a patient with rare mutations in cobalamin uptake and CFH gene. Case Description: A 59-year-old woman presented with upper respiratory symptoms and tested positive for Influenza B. Laboratory showed AKI, thrombocytopenia, hemolytic anemia with schistocytes and nephrotic range proteinuria. Creatinine at admission was 2.14mg/dL (from a normal baseline) and peaked at 8.67mg/dL with hyperkalemia requiring hemodialysis. C3 was low. C4, ADAMTS13 activity and Vitamin B12 were normal and methylmalonic acid level was mildly elevated. Acute kidney injury progressed and patient required initiation of hemodialysis. Kidney biopsy showed lobular accentuation of glomeruli, increased matrix deposition, karyorrhectic debris and red blood cell fragments in the mesangium and fibrinoid necrosis of an arteriole. Eculizumab was initiated and six days later renal function recovered, and dialysis was discontinued. Genetic testing revealed heterozygous p. Arg161Gly missense variant in the metabolism of cobalamin associated C (MMACHC gene) and heterozygous p. Thr724Lys missense variant in the CFH gene classified as a variant of unknown significance. Discussion: MMACHC gene mutations cause autosomal recessive methylmalonic aciduria and homocystinuria (CblC disease) which rarely presents as aHUS. CblC disease is usually reported in children and none in the carrier state. Additional CFH high-risk haplotype and environmental factors increased the risk for aHUS in this case, with influenza being a known trigger but influenza B being very rare. This case highlights the importance of suspecting aHUS in older adults with identifiable triggers and low threshold to initiate complement blockade.
2024-05-15 | An unusual case of adult-onset still's disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome.
Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.
2024-01-11 | Rational use of eculizumab in secondary atypical hemolytic uremic syndrome
Background Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS. Methods Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort). Conclusion Early and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.
2023-10-19 | C5 inhibition in aHUS
C5 inhibition in aHUSTo obtain credit, you should first read the journal article.After reading the article, you should be able to answer the following, related, multiplechoice questions.To complete the questions (with a minimum 75% passing score) and earn continuing medical education (CME) credit,
2023-09-01 | Pregnancy-Associated Atypical Hemolytic Uremic Syndrome: A Case Report with a rare MCP Gene Mutation and Successful Eculizumab Treatment
Abstract Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare condition characterized by microangiopathic hemolytic anemia and kidney injury from thrombotic microangiopathy. P-aHUS occurs in approximately 1 in 25,000 pregnancies and is strongly related to complement dysregulation and pregnancy-related disorders, such as preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome, resulting in adverse perinatal and fetal outcomes. Complement dysregulation in P-aHUS is commonly attributed to genetic mutations or autoantibodies affecting complement factors, including CFH, CFI, and MCP. We present a case of a 25-year-old primigravida who experienced severe preeclampsia and HELLP syndrome followed by the development of complicated P-aHUS during the early postpartum period. The patient exhibited severe clinical manifestations, including hypertensive emergency, central nervous system involvement, renal impairment, and microangiopathic hemolytic anemia. Timely initiation of eculizumab therapy resulted in successful disease remission. Further genetic analysis revealed a likely rare pathogenic MCP gene variant.
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2025-05-20 | RNA Splicing Analysis of the CFI Mutation Site in the Causative Gene for Atypical Hemolytic Uremic Syndrome
目的：CFI基因编码的补体因子I (FI)是补体系统调节过程中重要的丝氨酸蛋白酶，其功能缺陷与多种疾病相关，然而许多突变的致病机制并未完全阐明。本实验旨在通过迷你基因实验验证CFI基因突变对mRNA剪接的影响，为解释致病机制、发现治疗靶点提供新思路。方法：本研究首先通过生物信息学软件，从人类基因数据库中筛选出目标突变，并将包含该突变位点的基因片段导入载体中。随后将构建好的含有野生型和突变型的质粒分别转染至人胚肾细胞(HEK293T)中，并利用RT-PCR和测序技术分析其mRNA产物的变化。结果：与野生型5号外显子相比，c.772G>A突变导致外显子完全跳变，产生了异常剪接产物。这一异常剪接可能导致产生的FI蛋白功能域缺陷，从而影响其蛋白酶活性或与其他补体因子的结合。结论：本研究成功构建了CFI基因的迷你基因实验体系，证实了c.772G>A突变可导致mRNA剪接异常。这为深入理解CFI基因突变的致病机制提供了重要的实验依据，也为aHUS疾病的基因诊断和治疗提供了新的靶点。 Objective: Complement factor I (FI), encoded by the CFI gene, is an important serine protease regulating the complement system, and its functional defects have been associated with a wide range of diseases. However, the pathogenic mechanisms of many mutations have not been fully elucidated. This experiment aims to verify the effect of CFI gene mutation on mRNA splicing through minigene experiments, which will provide new ideas to explain the pathogenic mechanism and discover therapeutic targets. Methods: In this study, the target mutation was first screened out from the human gene database by bioinformatics software, and the gene fragment containing the mutation site was introduced into the vector. Subsequently, the constructed plasmids containing wild-type and mutant were transfected into human embryonic kidney cells (HEK293T) respectively, and the changes in their mRNA products were analyzed by RT-PCR and sequencing. Results: Compared with wild-type exon 5, the c.772G>A mutation resulted in a complete exon skipping, producing an aberrant splicing product. This aberrant splicing may lead to defects in the functional domains of the resulting FI proteins, thus affecting their protease activity or binding to other complement factors. Conclusion: In this study, we successfully constructed a minigene experimental system for the CFI gene and confirmed that the c.772G>A mutation could lead to abnormal mRNA splicing. This provides an essential experimental basis for the in-depth understanding of the pathogenic mechanism of CFI gene mutation and also provides a new target for the genetic diagnosis and treatment of aHUS disease.
2014-06-06 | A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation
Genomic aberrations affecting the genes encoding factor H (FH) and the five FH-related proteins (FHRs) have been described in patients with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ARF. These genomic rearrangements occur through nonallelic homologous recombinations caused by the presence of repeated homologous sequences in CFH and CFHR1-R5 genes. In this study, we found heterozygous genomic rearrangements among CFH and CFHR genes in 4.5% of patients with aHUS. CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. Five patients carried known CFH/CFHR1 genes, but we found a duplication leading to a novel CFHR1/CFH hybrid gene in a family with two affected subjects. The resulting fusion protein contains the first four short consensus repeats of FHR1 and the terminal short consensus repeat 20 of FH. In an FH-dependent hemolysis assay, we showed that the hybrid protein causes sheep erythrocyte lysis. Functional analysis of the FHR1 fraction purified from serum of heterozygous carriers of the CFHR1/CFH hybrid gene indicated that the FHR1/FH hybrid protein acts as a competitive antagonist of FH. Furthermore, sera from carriers of the hybrid CFHR1/CFH gene induced more C5b-9 deposition on endothelial cells than control serum. These results suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of complement at the endothelial cell surface. We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, particularly before a kidney transplant.
2011-06-24 | Soluble CD59 Expressed from an Adenovirus In Vivo Is a Potent Inhibitor of Complement Deposition on Murine Liver Vascular Endothelium
Inappropriate activation of complement on the vascular endothelium of specific organs, or systemically, underlies the etiology of a number of diseases. These disorders include atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, and transplant rejection. Inhibition of the terminal step of complement activation, i.e. formation of the membrane attack complex, using CD59 has the advantage of retaining the upstream processes of the complement cascade necessary for fighting pathogens and retaining complement's crucial role in tissue homeostasis. Previous studies have shown the necessity of membrane targeting of soluble CD59 in order for it to prove an effective inhibitor of complement deposition both in vitro and in vivo. In this study we have generated an in vivo model of human complement activation on murine liver vascular endothelium. This model should prove useful for the development of anti-complement therapies for complement-induced pathologies of vascular endothelium. Using this model, we have demonstrated the viability of a non membrane-targeted soluble CD59 to significantly inhibit complement deposition on the endothelium of murine liver vasculature when expressed in vivo from an adenovirus. This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited.
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Drug Discovery Landscape
1 orphan drug designation for Atypical hemolytic uremic syndrome with complement gene abnormality.
1 orphan drug designation for Atypical hemolytic uremic syndrome with complement gene abnormality.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Human IgG1 minibody against Complement C5 [MUBODINA] | antibodies | EMA | — | Adienne S.r.l. |
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