OBJECTIVE: To explore the clinical characteristics and genetic etiology for a child with atypical Hemolytic uremic syndrome (aHUS) in conjunct with nephrotic level proteinuria. METHODS: A child patient who had visited the Affiliated Hospital of Qingdao University on June 25, 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing of the child and his parents. RESULTS: The child, an 8-month-old male, had presented mainly with edema, oliguria, hematuria, nephrotic level proteinuria, anemia, thrombocytopenia, increased creatinine and urea, hypercholesterolemia but normal complement levels. Genetic testing revealed that he has harbored compound heterozygous variants of the DGKE gene, namely c.12_18dupGAGGCGG (p.P7fs*37) and c.1042G>T (p.D348Y), which were respectively inherited from his father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were classified as likely pathogenic and variant of uncertain significance, respectively. By combining his clinical manifestations and results of genetic testing, the child was diagnosed with aHUS with nephrotic level proteinuria. CONCLUSION For infants and young children with aHUS in conjunct with nephrotic level proteinuria, variants of the DGKE gene should be screened. Above finding has expanded the mutational spectrum of the DGKE gene.
Infant ; Female ; Humans ; Child ; Male ; Child, Preschool ; Atypical Hemolytic Uremic Syndrome/diagnosis* ; Mutation ; Genetic Testing ; Thrombocytopenia/genetics* ; Proteinuria/genetics*

Antibodies, Monoclonal, Humanized/therapeutic use* ; Atypical Hemolytic Uremic Syndrome/drug therapy* ; Humans

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. Although these conditions are difficult to differentiate clinically, TTP can be distinguished by low (<10%) ADAMTS13 activity. The aim was to identify the differences in complement activation products between TTP and aHUS and investigate ADAMTS13 activity as a prognostic factor in aHUS. METHODS: We analyzed patients with thrombotic microangiopathy diagnosed as TTP (N=48) or aHUS (N=50), selected from a Korean registry (N=551). Complement activation products in the plasma samples collected from the patients prior to treatment and in 40 healthy controls were measured by ELISA. RESULTS: The levels of generalized (C3a), alternate (factor Bb), and terminal (C5a and C5b-9) markers were significantly higher (all P<0.01) in the patients than in the healthy controls. Only the factor Bb levels significantly differed (P=0.008) between the two disease groups. In aHUS patients, high normal ADAMTS13 activity (≥77%) was associated with improved treatment response (OR, 6.769; 95% CI, 1.605–28.542; P=0.005), remission (OR, 6.000; 95% CI, 1.693–21.262; P=0.004), exacerbation (OR, 0.242; 95% CI, 0.064–0.916; P=0.031), and disease-associated mortality rates (OR, 0.155; 95% CI, 0.029–0.813; P=0.017). CONCLUSION: These data suggest that complement biomarkers, except factor Bb, are similarly activated in TTP and aHUS patients, and ADAMTS13 activity can predict the treatment response and outcome in aHUS patients.
Atypical Hemolytic Uremic Syndrome ; Biomarkers ; Complement Activation ; Complement System Proteins ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mortality ; Plasma ; Purpura, Thrombotic Thrombocytopenic ; Thrombotic Microangiopathies

Atypical hemolytic uremic syndrome (aHUS), a rare form of thrombotic microangiopathy, is distinguished from the typical form by the absence of a preceding verotoxin-producing Escherichia coli infection. Notably, aHUS occurs in association with genetic or acquired disorders causing dysregulation of the alternative complement pathway. Patients with aHUS may show the presence of anti-complement factor H (CFH) autoantibodies. This acquired form of aHUS (anti-CFH-aHUS) primarily affects children aged 9–13 years. We report a case of a 13-year-old Lao girl with clinical features of aHUS (most likely anti-CFH-aHUS). The initial presentation of the patient met the classical clinical triad of thrombotic microangiopathy (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury) without preceding diarrheal illness. Low serum levels of complement 3 and normal levels of complement 4 indicated abnormal activation of the alternative complement pathway. Plasma infusion and high-dose corticosteroid therapy resulted in improvement of the renal function and hematological profile, although the patient subsequently died of infectious complications. This is the first case report that describes aHUS (possibly anti-CFH-aHUS) in Laos.
Adolescent ; Anemia, Hemolytic ; Atypical Hemolytic Uremic Syndrome ; Autoantibodies ; Child ; Complement C3 ; Complement C4 ; Complement Factor H ; Complement Pathway, Alternative ; Female ; Humans ; Immunosuppression ; Kidney ; Laos ; Plasma ; Shiga-Toxigenic Escherichia coli ; Thrombocytopenia ; Thrombotic Microangiopathies

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease that is often associated with genetic defects. Mutations of complement factor H (CFH) are the most common genetic defects that cause aHUS and often result in end-stage renal disease. Since CFH is mainly produced in the liver, liver transplantation (LT) has been performed in patients with defective CFH. METHODS: The clinical courses of four kidney allograft recipients who lost their native kidney functions due to aHUS associated with a CFH mutation were reviewed. RESULTS: Subject A underwent kidney transplantation (KT) twice, aHUS recurred and the allograft kidney failed within a few years. Subject B received a KT and soon experienced a recurrence of aHUS coinciding with infection. Her allograft kidney function has worsened, and she remains on plasma infusion therapy. Subject C underwent LT followed by KT. She is doing well without plasma infusion therapy after combined LT-KT for 3 years. Subject D received KT following LT and is now recurrence-free from aHUS. CONCLUSION: In patients with aHUS associated with a CFH mutation, KT without LT was complicated with a recurrence of aHUS, which might lead to allograft loss. Conversely, LT was successful in preventing the recurrence of aHUS and thus might be another option for a recurrence-free life for aHUS patients associated with CFH mutation.
Allografts ; Atypical Hemolytic Uremic Syndrome ; Complement Factor H ; Complement System Proteins ; Humans ; Kidney Failure, Chronic ; Kidney Transplantation ; Kidney ; Liver Transplantation ; Liver ; Plasma ; Rare Diseases ; Recurrence

Hemolytic uremic syndrome (HUS) is often encountered in children with acute kidney injury. Besides the well-known shiga toxin-producing Escherichia coli-associated HUS, atypical HUS (aHUS) caused by genetic complement dysregulation has been studied recently. aHUS is a rare, chronic, and devastating disorder that progressively damages systemic organs, resulting in stroke, end-stage renal disease, and death. The traditional treatment for aHUS is mainly plasmapheresis or plasma infusion; however, many children with aHUS will progress to chronic kidney disease despite plasma therapy. Eculizumab is a newly developed biologic that blocks the terminal complement pathway and has been successfully used in the treatment of aHUS. Currently, several guidelines for aHUS, including the Korean guideline, recommend eculizumab as the first-line therapy in children with aHUS. Moreover, life-long eculizumab therapy is generally recommended. Further studies on discontinuation of eculizumab are needed.
Acute Kidney Injury ; Atypical Hemolytic Uremic Syndrome ; Child ; Complement System Proteins ; Escherichia ; Hemolytic-Uremic Syndrome ; Humans ; Kidney Failure, Chronic ; Plasma ; Plasmapheresis ; Renal Insufficiency, Chronic ; Stroke

BACKGROUND: Thrombotic microangiopathy (TMA) with non-deficient ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13) outcome is unknown hence the survival analysis correlating with ADAMTS-13 activity is conducted in Malaysia. METHODS: This was a retrospective epidemiological study involving all cases of TMA from 2012–2016. RESULTS: We evaluated 243 patients with a median age of 34.2 years; 57.6% were female. Majority of the patients were Malay (62.5%), followed by Chinese (23.5%) and Indian (8.6%). The proportion of patients with thrombotic thrombocytopenic purpura (TTP) was 20.9%, 72.2% of which were acquired while 27.8% were congenital. Patients with ADAMTS-13 activity ≥5% had a four-fold higher odds of mortality compared to those with ADAMTS-13 activity <5% (odds ratio: 4.133, P=0.0425). The mortality rate was 22.6% (N=55). Most cases had secondary etiologies (42.5%), followed by acquired TTP (16.6%), atypical hemolytic uremic syndrome (HUS) or HUS (12.8%) and congenital TTP (6.4%). Patients with secondary TMA had inferior overall survival (P=0.0387). The secondary causes comprised systemic lupus erythematosus (30%), infection (29%), pregnancy (10%), transplant (8%), malignancy (6%), and drugs (3%). Transplant-associated TMA had the worst OS (P=0.0016) among the secondary causes. Plasma exchange, methylprednisolone and intravenous immunoglobulin were recorded as first-line treatments in 162 patients, while rituximab, bortezomib, vincristine, azathioprine, cyclophosphamide, cyclosporine, and tacrolimus were described in 78 patients as second-line treatment. CONCLUSION: This study showed that TMA without ADAMTS-13 deficiency yielded inferior outcomes compared to TMA with severeADAMTS-13 deficiency, although this difference was not statistically significant.
Asian Continental Ancestry Group ; Atypical Hemolytic Uremic Syndrome ; Azathioprine ; Bortezomib ; Cyclophosphamide ; Cyclosporine ; Epidemiologic Studies ; Female ; Humans ; Immunoglobulins ; Lupus Erythematosus, Systemic ; Malaysia* ; Methylprednisolone ; Mortality ; Plasma Exchange ; Pregnancy ; Purpura, Thrombotic Thrombocytopenic ; Retrospective Studies ; Rituximab ; Tacrolimus ; Thrombospondins ; Thrombotic Microangiopathies* ; Vincristine

Antibodies, Monoclonal, Humanized ; therapeutic use ; Atypical Hemolytic Uremic Syndrome ; drug therapy ; surgery ; China ; Humans ; Kidney Transplantation ; Male

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The major pathogenesis of aHUS involves dysregulation of the complement system. Eculizumab, which blocks complement C5 activation, has recently been proven as an effective agent. Delayed diagnosis and treatment of aHUS can cause death or end-stage renal disease. Therefore, a diagnosis that differentiates aHUS from other forms of thrombotic microangiopathy is very important for appropriate management. These guidelines aim to offer recommendations for the diagnosis and treatment of patients with aHUS in Korea. The guidelines have largely been adopted from the current guidelines due to the lack of evidence concerning the Korean population.
Acute Kidney Injury ; Anemia, Hemolytic ; Atypical Hemolytic Uremic Syndrome* ; Complement C5 ; Complement System Proteins ; Delayed Diagnosis ; Diagnosis ; Humans ; Kidney Failure, Chronic ; Korea* ; Thrombocytopenia ; Thrombotic Microangiopathies

No abstract available.
Atypical Hemolytic Uremic Syndrome* ; Complement C3* ; Complement System Proteins*