Question 1 of 10

    Atypical Hemolytic Uremic Syndrome (aHUS)

    Hemolytic uremic syndrome refers to the symptom triad of hemolytic anemia, thrombocytopenia and renal insufficiency, with most cases being triggered by bacterial pathogens. A minor share of cases is of unknown etiology and are classified as atypical hemolytic uremic syndrome.

    Presentation

    Both HUS and aHUS are most frequently diagnosed in children aged less than five years, with about 70% of them presenting a first episode of the disease during their first two years of life [5]. Thus, observation of the symptoms detailed below is highly suggestive of either form of the disease if presented by a young child.

    During the prodromal stage, patients may suffer from gastroenteritis with abdominal pain and diarrhea, possibly containing blood. Historically, diarrhea has been assumed to be typical of HUS but not of aHUS, but this distinction no longer holds true [5]. Nevertheless, the prodromal phase may also be characterized by an upper respiratory infection or influenza, or may not be observed at all [11].

    Symptom onset is usually sudden, and the disease follows a course of apparent remission and recurrence:

    Only minor shares of patients present with an incomplete aHUS triad and only show one or two symptoms of the classical symptom complex.

    In advanced stages of the disease, long-term sequelae of renal impairment may manifest:

    Liver, Gall & Pancreas
    Jaundice
    • These might include acute kidney failure, end-stage kidney disease, liver malfunction (leading to jaundice), clot formation leading to damage to the heart (heart attack) and brain (stroke) Lifelong treatment and therapy may be required to manage Atypical[dovemed.com]
    • This condition can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate.[ghr.nlm.nih.gov]
    • On physical examination, she presented jaundice in sclera, pale mucous membranes and a mild edema in legs bilaterally.[jbn.org.br]
    • Her initial presentation included nausea, vomiting, and jaundice.[frontiersin.org]
    • Table 7 Clinical presentation of the various subgroups of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and investigations to confirm diagnosis Neonatal period Severe jaundice Porto colour urine without major hematuria Consanguineous[ojrd.biomedcentral.com]
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  • Entire body system
    Anemia
    • Anemia results if these cells are destroyed faster than the body can replace them.[ghr.nlm.nih.gov]
    • Laboratory tests revealed hemolytic anemia, thrombocytopenia, azotemia, low complement C3 and normal complement C4.[benthamopen.com]
    • Red blood cells are destroyed resulting in in anemia (microangiopathic hemolytic anemia), low platelet count occurs in the blood (thrombocytopenia) and accumulation of platelets and red blood cells (microthrombi) blocks certain blood vessels resulting[library.med.utah.edu]
    • […] hemolytic anemia, thrombocytopenia and acute kidney injury.[ctgt.net]
    • Both are characterized by microangiopathic hemolytic anemia and thrombocytopenia. 2,3 Neurological disorders are dominant in TTP whereas renal failure is dominant in HUS.[medintensiva.org]
    Fatigue
    • Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[en.wikipedia.org]
    • Symptoms Signs and symptoms of HUS can include: Bloody diarrhea Decreased urination or blood in the urine Abdominal pain, vomiting and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion[mayoclinic.org]
    • Test your knowledge A 52 year old man was transferred to the renal unit with a four day history of fatigue, shortness of breath, headache and malaise.[web.era-edta.org]
    • This condition can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate.[ghr.nlm.nih.gov]
    • Instead, the patient starts off ill, fatigue, irritable, and lethargic to a point where hospitalization is needed.[atypicalhus.ning.com]
    Malaise
    • Test your knowledge A 52 year old man was transferred to the renal unit with a four day history of fatigue, shortness of breath, headache and malaise.[web.era-edta.org]
    • Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[en.wikipedia.org]
    Pallor
    • This condition can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate.[ghr.nlm.nih.gov]
    • Symptoms Signs and symptoms of HUS can include: Bloody diarrhea Decreased urination or blood in the urine Abdominal pain, vomiting and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion[mayoclinic.org]
    • Severe pallor, as well as icterus, was present.[ijccm.org]
    • Apart from mild pallor, the remainder of the physical examination was unremarkable.[benthamopen.com]
    • Symptoms in young children are pallor, general distress, poor feeding, vomiting, fatigue, drowsiness and sometimes oedema.[ojrd.biomedcentral.com]
    Weakness
    • However, Idiopathic Atypical Hemolytic-Uremic Syndrome could occur even without genetic mutations in an individual, due to unknown cause(s) The symptoms of Atypical Hemolytic-Uremic Syndrome could include abdominal pain, low urine output, jaundice, weakness[dovemed.com]
    • However, the American Society for Apheresis offers a "weak" recommendation for plasma exchange to treat aHUS, due to the "low" or "very low" quality of evidence supporting its use.[en.wikipedia.org]
    • The patient felt that he had no meaningful life when in hemodialysis 5 times per week, near-constant severe musculoskeletal pain, lethargy, and weakness.[austinpublishinggroup.com]
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  • neurologic
    Confusion
    • However, due to systemic thrombotic microangiopathy, there remains a possibility of failure in 90% of the transplants Additional and Relevant Useful Information for Atypical Hemolytic-Uremic Syndrome: Atypical Hemolytic-Uremic Syndrome should not be confused[dovemed.com]
    • Symptoms Signs and symptoms of HUS can include: Bloody diarrhea Decreased urination or blood in the urine Abdominal pain, vomiting and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion[mayoclinic.org]
    • Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances As with all complement assays, proper sample handling is of utmost importance[mayomedicallaboratories.com]
    • Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[en.wikipedia.org]
    • Her parents reported the onset of unusual posturing episodes overnight after which she appeared confused.[imj.ie]
    Headache
    • Adverse Reactions The most frequently reported adverse reactions in the PNH randomized trial ( 10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea.[soliris.net]
    • Test your knowledge A 52 year old man was transferred to the renal unit with a four day history of fatigue, shortness of breath, headache and malaise.[web.era-edta.org]
    • Computed tomography (CT) scans of the brain done in view of the headache revealed no abnormalities.[sjkdt.org]
    • The ER doctors get my headache and blood pressure under control and discharged me with the instructions to follow up with nephrology the following day because my creatinine was really elevated.[globalgenes.org]
    • Diagnosis of aHUS and Initial Therapy Fourteen months later the donor suffered tiredness and severe headache.[austinpublishinggroup.com]
    Lethargy
    • […] aka Pediatric Perplexity 002 An 18 month-old boy was brought to the ED by his parents with a 5 day history of intermittent vomiting, lethargy, infrequent wet nappies, and decreased oral intake.[lifeinthefastlane.com]
    • The patient felt that he had no meaningful life when in hemodialysis 5 times per week, near-constant severe musculoskeletal pain, lethargy, and weakness.[austinpublishinggroup.com]
    • Symptoms Atypical hemolytic uremic syndrome presents with vague feelings of illness, fatigue, irritability, and lethargy that often lead to hospitalization.[cigna.com]
    Seizure
    • […] control, consider prophylactic phenytoin in patients with neurologic symptoms (20-40% of patients have seizures) Control azotemia Optimize nutrition[emedicine.medscape.com]
    • Seizures are the most common neurological involvement in aHUS.[ijccm.org]
    • Signs and symptoms of HUS can include: Bloody diarrhea Decreased urination or blood in the urine Abdominal pain, vomiting and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion or seizures[mayoclinic.org]
    • Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis.[soliris.net]
    • Aytaç Yaman, Zarife Kuloğlu, Ahmet Kahveci, Ufuk Sayıcı, Arzu Ensari, Aydan Kansu DOI : 10.24953/turkjped.2016.06.002 The seizure semiology consistent with frontal lobe symptomatogenic zone in children.[turkishjournalpediatrics.org]
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  • Skin
    Petechiae
    • On examination, he was pale with multiple petechiae on his arms and legs.[web.era-edta.org]
    • There was no bruises or petechiae.[imj.ie]
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  • respiratoric
    Dyspnea
    • With a suspicion of endocarditis, and with worsening symptoms of dyspnea, fatigue, decreased physical tolerance, and tachycardia, the patient was hospitalized.[hindawi.com]
    • Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis.[soliris.net]
    • CASE REPORT Female, 35 years-old, presented complaining with dyspnea, nausea and oliguria initiated 6 days before admission.[jbn.org.br]
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  • gastrointestinal
    Abdominal Pain
    • However, severe abdominal pain and bloody diarrhea are unusual.[en.wikipedia.org]
    • Symptoms Signs and symptoms of HUS can include: Bloody diarrhea Decreased urination or blood in the urine Abdominal pain, vomiting and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion[mayoclinic.org]
    • The most frequently reported adverse reactions in aHUS single arm prospective trials ( 20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary[soliris.net]
    • In summary, this is a 22 year old female patient who presented with abdominal pain, scleral icterus, and hematuria and was found to have hemolytic anemia, thrombocytopenia, and acute kidney injury with proteinuria.[pubs.sciepub.com]
    Blood in Stool
    • Stool culture was negative for Shiga toxin-producing Escherichia coli , and serum ADAMTS13 activity was normal ( 85%).[benthamopen.com]
    Diarrhea
    Nausea
    • Adverse Reactions The most frequently reported adverse reactions in the PNH randomized trial ( 10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea.[soliris.net]
    • He suffered from recurrent episodes of flash edema preceded by nausea and regurgitation that required intubation and dialysis.[thejh.org]
    • Uraemia: signs and symptoms of kidney failure; signs and symptoms of uraemia can include nausea, vomiting, metallic taste in the mouth, muscle pain, and swelling.[ahussource.eu]
    • CASE REPORT Female, 35 years-old, presented complaining with dyspnea, nausea and oliguria initiated 6 days before admission.[jbn.org.br]
    • Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[en.wikipedia.org]
    Vomiting
    • Uraemia: signs and symptoms of kidney failure; signs and symptoms of uraemia can include nausea, vomiting, metallic taste in the mouth, muscle pain, and swelling.[ahussource.eu]
    • Symptoms Signs and symptoms of HUS can include: Bloody diarrhea Decreased urination or blood in the urine Abdominal pain, vomiting and occasionally fever Pallor Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability Confusion[mayoclinic.org]
    • The most frequently reported adverse reactions in aHUS single arm prospective trials ( 20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary[soliris.net]
    • I started my journey in a small community hospital, dehydrated, where I couldn’t stop vomiting, feverish but freezing cold, and I kept passing out.[globalgenes.org]
    • Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[en.wikipedia.org]
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  • cardiovascular
    Tachycardia
    • With a suspicion of endocarditis, and with worsening symptoms of dyspnea, fatigue, decreased physical tolerance, and tachycardia, the patient was hospitalized.[hindawi.com]
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  • urogenital
    Anuria
    • The patient presented with oliguria soon after the surgery and anuria on the 2 nd day, accompanied by promptly reduced liver and kidney function.[journal-ina.com]
    • At the Intensive Care Unit he presented thrombocytopenia (platelets 98 10 9 ), severe kidney impairment with anuria and started hemodialysis.[medintensiva.org]
    • Some poor prognostic indicators carrying high mortality include duration of illness before onset of HUS 14 days, anuria 3 days, age 18 months and 5 years, non-diarrhea associated HUS, HUS associated with convulsion and hypertension, WBC 30, 000/mm 3 ,[pubs.sciepub.com]
    • However, the patient developed anuria.[link.springer.com]
    • Arterial hypertension is frequent and often severe, due both to volume overload in case of oliguria/anuria and to hyperreninemia secondary to renal TMA.[ojrd.biomedcentral.com]
    Dark Urine
    • The patient also reported noticing dark urine for several days although denied any frank blood and also denied any diarrhea.[pubs.sciepub.com]
    Kidney Failure
    • For example, approximately 1 in 6 patients with aHUS initially will present with proteinuria or hematuria without acute kidney failure.[en.wikipedia.org]
    • Dialysis: a treatment for kidney failure.[ahussource.eu]
    • These abnormalities lead to kidney damage and, in many cases, kidney failure and ESRD.[ghr.nlm.nih.gov]
    • Dialysis (a blood clearance technique) may be needed if the disease progresses to kidney failure.[ema.europa.eu]
    • TTP has a lot of similarities to Atypical HUS, but the symptoms do not show up as kidney failure.[atypicalhus.ning.com]
    Oliguria
    • Case Report Our patient was an Asian female aged 21 who was hospitalized on April 19, 2016, for oliguria and azotemia after her cesarean section.[journal-ina.com]
    • Upon arrival at the nephrology department in Poznan, the patient’s condition was considered severe with dyspnea at rest, tachycardia, hypertension (190/100 mmHg), oliguria, decreased renal function (creatinine 4.69 mg/dL, urea 124 mg/dL), hemolysis (LDH[hindawi.com]
    • CASE REPORT Female, 35 years-old, presented complaining with dyspnea, nausea and oliguria initiated 6 days before admission.[jbn.org.br]
    • Arterial hypertension is frequent and often severe, due both to volume overload in case of oliguria/anuria and to hyperreninemia secondary to renal TMA.[ojrd.biomedcentral.com]
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  • hematological
    Easy Bruising
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  • Eyes
    Visual Impairment
    • Case 2 A 43-year-old Caucasian woman with a history of migraine headaches since childhood presented with severe headaches and visual impairment lasting for several days.[link.springer.com]
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  • Workup

    The aforedescribed symptoms are not specific and usually prompt laboratory analyses of blood samples. These may yield findings consistent with microangiopathic hemolytic anemia, thrombocytopenia and acute kidney impairment, i.e.,

    • Hemoglobin levels <10 g/dl, undetectable haptoglobin and enhanced concentrations of lactate dehydrogenase, reticulocytosis, and schistocytes in blood smears
    • Platelet counts <150*10^9/l, often <60*10^9/l
    • Levels of urea >50 mg/dl and creatinine >1.2 mg/dl

    Furthermore, urine analyses are of major importance for HUS and aHUS diagnosis. Proteinuria and hematuria are the most common findings. While urine parameters may initially normalize between episodes of the disease, proteinuria and hematuria may eventually become chronic. Such findings indicate the progressive worsening of kidney function.

    It may be a major challenge to distinguish HUS from aHUS, and it is strongly advised not to delay the initiation of therapy until the disease etiology can be clarified. However, long-term treatment regimens and the patient's prognosis depend on the specific form of the disease and immediate medical attention should thus be accompanied by further diagnostic measures.

    • Stool samples should be obtained and analyzed; in rare cases, causative pathogens may also originate from the urinary tract [14]. Detection of pathogens or toxins associated with HUS is highly suggestive but not diagnostic of this form of the disease [5] [11]. In turn, negative results don't rule out HUS.
    • Concentrations of complement factors like factors H and I and C3 should be evaluated in serum samples. Reduced levels are indicative of a complement disorder. However, the sensitivity of such measurements is restricted since anomalies may be temporarily restricted to the endothelium.
    • Genetic screens may reveal inherited complement disorders, but a single patient cannot possibly be tested for all possible mutations related to aHUS. A targeted approach is possible only if their familial history or disease course implies a particular defect.
    • Circulating autoantibodies against factor H may be detected by employing immunoassays like ELISA [12].

    Pathology

    Biopsy
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  • Test Results

    Other Test Results
    Schistocytosis
    • Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency.[pagepress.org]
    • Additional work-up revealed schistocytosis on peripheral smear.[frontiersin.org]
    • . • A TMA may be documented in 2 ways: – Clinically, by signs of a microangiopathic hemolytic anemia (schistocytosis on peripheral blood smear, elevated LDH, elevated indirect bilirubin, and low haptoglobin) along with thrombocytopenia and clinical involvement[hematologyandoncology.net]
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  • Laboratory

    Serum
    Decreased Platelet Count
    • This results in platelet activation, damage to endothelial cells (cells that line the blood vessels), and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis (breakdown of red blood cells), damage[en.wikipedia.org]
    • Multivariate analyses identified three predictors of CKD: a high serum creatinine level, a high mean arterial pressure and a mildly decreased platelet count.[journals.plos.org]
    Hemoglobin Decreased
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  • Treatment

    To date, only supportive treatment is available for therapy of aHUS patients. The following measures may be taken to delay disease progression and to relieve affected individuals of symptoms:

    • Plasma therapy and apheresis are indicated as immediate measures, even before the disease underlying aHUS has been identified. This procedure aims at delivering functional complement factors and to remove abnormal molecules. During the first five days after diagnosis, up to 75 ml per kg body weight (approximately 1.5 × plasma volume) should be exchanged in daily sessions [7] [14]. Subsequently, the frequency of treatments is reduced to five per week for two weeks and eventually three per week for two weeks [14]. By this time, hemoglobin levels and platelet counts should have returned to reference ranges. Creatinine levels are not to be used as marker for the patient's response to plasmapheresis. The timely initiation of plasma therapy has a major impact on the patient's prognosis.
    • Non-responders to plasmapheresis may require treatment with eculizumab, which has been approved for use in aHUS in late 2011 [15]. This compound inhibits complement activation by blocking the cleavage of C5 to C5a and C5b, and thus, response to therapy may be assessed by evaluating terminal complement markers. Eculizumab is initially administered weekly with subsequent reduction to bimonthly infusion. Unfortunately, long-term therapy with eculizumab is very expensive.
    • Patients may also be considered for liver or kidney transplantation, particularly if long-term therapy with eculizumab is not an option or the patient does not respond to such treatment: Several complement factors are synthesized in the liver and thus, a healthy liver may provide functional proteins to those individuals diagnosed with determined deficiencies (e.g., factors H and I and C3). As well, there are few alternatives to renal transplantation if a patient develops end-stage renal disease. Recurrence and long-term graft survival rates depend on the precise underlying disorder.
    • Patients suffering from aHUS due to an autoimmune response directed against complement factor H may benefit from immunosuppressive therapy.

    Prognosis

    Morbidity is mainly due to permanent kidney damage resulting in proteinuria, renal hypertension, chronic kidney insufficiency and end-stage renal disease. The overall risk of long-term sequelae is high, with the majority of aHUS patients developing end-stage renal disease within five years after diagnosis [3]. Since aHUS is associated with progressive organ damage, an early diagnosis allows for the initiation of treatment before irreversible lesions occur, and this is the single most important favorable prognostic factor [12].

    aHUS has been reported to be associated with mortality rates of up to 25% [6]. Recent studies offer a more distinctive consideration and reveal that both morbidity and mortality differ largely depending on the underlying disorder. Poorest outcomes have been described for defects of the gene encoding for factor H, with 60% of affected individuals developing end-stage renal disease and dying within one year [13].

    Complications

    Acute Kidney Injury
    • […] hemolytic anemia, thrombocytopenia and acute kidney injury.[ctgt.net]
    • INTRODUCTION Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury [ 1 ].[uptodate.com]
    • Cureus 9(3): e1111. doi:10.7759/cureus.1111 Abstract Hemolytic-uremic syndrome (HUS) is the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI); the main cause of multi-organ failure is related to thrombotic[cureus.com]
    • Atypical hemolytic uremic syndrome Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) characterized by Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.[clinlabnavigator.com]
    • KDIGO clinical practice guideline for acute kidney injury.[pagepress.org]
    Coma
    • […] over 75 People with certain genetic changes that make them more susceptible Complications HUS can cause life-threatening complications, including: Kidney failure, which can be sudden (acute) or develop over time (chronic) High blood pressure Stroke Coma[mayoclinic.org]
    • […] failure, hypertension (high blood pressure), myocardial infarction (heart attack), stroke, lung complications, pancreatitis (inflammation of the pancreas), liver necrosis (death of liver cells or tissue), encephalopathy (brain dysfunction), seizure, or coma[en.wikipedia.org]
    • Half of patients exhibited neurologic impairment, ranging from headache (18%) to seizure (11%) and coma (9%).[journals.plos.org]
    • The most frequent is CNS involvement (10% of patients) manifested by irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, coma.[ojrd.biomedcentral.com]
    Edema
    • He suffered from recurrent episodes of flash edema preceded by nausea and regurgitation that required intubation and dialysis.[thejh.org]
    • However, the patient presented with discernible lower extremities edema in both legs in late gestation with normotension and no signs of urinary protein.[journal-ina.com]
    • The most frequently reported adverse reactions in aHUS single arm prospective trials ( 20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary[soliris.net]
    • Disease remission occurred 3 months after initial presentation with worsening hypertension despite treatment and a 3-week history of lower limb edema.[hindawi.com]
    • Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, confusion, fatigue, edema (swelling), nausea/vomiting and diarrhea. aHUS often presents with malaise and fatigue, as well as microangiopathic anemia.[en.wikipedia.org]
    Hemiparesis
    • The most frequent is CNS involvement (10% of patients) manifested by irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, coma.[ojrd.biomedcentral.com]
    Hypertension
    • Individuals so predisposed could have aHUS episodes precipitated by one of the known disease triggers (e.g., infection, pregnancy, surgery, trauma) as well as by other systemic diseases (e.g., malignant hypertension, SLE, cancer).[en.wikipedia.org]
    • Together with typical signs of hypertensive retinopathy and echocardiographic evidence of hypertensive heart disease, the patient was considered to have MHT.[link.springer.com]
    • The pooled estimate of renal sequelae was 25%, hypertension was 10%, and proteinuria was 15% [ 12 ] .[pubs.sciepub.com]
    • Patient history demonstrated only hypertension of two years duration and a family history of cardiovascular disease.[hindawi.com]
    • He recovered from his acute illness but had persisting renal impairment and hypertension.[lifeinthefastlane.com]
    Hypoalbuminemia
    • […] progressive course, and prior manifestations of nephrotic syndrome, such as swelling from the accumulation of fluid (edema), presence of blood in the urine (hematuria), excessive protein in the urine (proteinuria), and reduced albumin in the serum (hypoalbuminemia[cigna.com]
    Influenza
    • Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenza type b (Hib) infections according to ACIP guidelines.[soliris.net]
    • […] hemolysis (breaking of red blood cells inside of blood vessels), and decreased kidney function Documented meningococcal vaccination not more than 3 years prior to dosing, under 18 also requiring vaccination against Streptococcus pneumoniae and Haemophilus influenzae[renal.wustl.edu]
    • Other triggers have included chicken pox (varicella) or H1N1 influenza.[rarediseases.org]
    • Patients treated with Eculizumab may have increased susceptibility to infections, especially with encapsulated bacteria like Neisseria meningitidis, Streptococcus pneumonia, and Haemophilus influenza type b.[clinlabnavigator.com]
    • We vaccinated our patient against S. pneumoniae , H. influenzae type B, and N. meningitidis .[karger.com]
    Liver Failure
    • However, simultaneous liver and kidney transplantation in two children was complicated by premature liver failure.[emedicine.medscape.com]
    Nephrotic Syndrome
    • A form of hemolytic uremic syndrome, also termed Nephrotic syndrome type 7, is caused by mutations in the DGKE gene.[ctgt.net]
    • The absence of bloody diarrhea, negative stool cultures for Shiga toxin producing-E. coli (most frequently E. coli 0157:H7) associated with HUS, a progressive course, and prior manifestations of nephrotic syndrome, such as swelling from the accumulation[cigna.com]
    • They may go to remission and subsequently have an acute relapse, or they develop progressive hypertension, proteinuria that may induce nephrotic syndrome, and increase of serum creatinine over several weeks or months.[ojrd.biomedcentral.com]
    Proteinuria
    • A unique finding in our patient is the degree of proteinuria she exhibited.[pubs.sciepub.com]
    • For example, approximately 1 in 6 patients with aHUS initially will present with proteinuria or hematuria without acute kidney failure.[en.wikipedia.org]
    • MPGN typically presents with a hematuria and/or proteinuria, acute nephritic syndrome or nephritic syndrome.[sickkids.ca]
    • Mild pretibial edema was accompanied by abnormal urinalysis results (proteinuria 10 g/day).[karger.com]
    • All presented with aHUS before age 1; had persistent hypertension, hematuria, and proteinuria (sometimes in the nephrotic range) between acute episodes; and developed chronic kidney disease with age.[hematology.org]
    Stroke
    • Stroke: damage to the brain.[ahussource.eu]
    • The disease affects both children and adults and is characterized by systemic thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body, which can lead to stroke, heart attack, kidney failure, and death.[en.wikipedia.org]
    • A genetic, chronic, ultra-rare disease that can progressively damage vital organs, potentially leading to stroke, heart attack, kidney failure, and death….[rareundiagnosed.org]
    • Rheumatic Disease Breast Cancer Depression / Anxiety Diabetes GERD / Peptic Ulcers Gynecology Hepatitis Hypertension Lipid Management Nutrition / Obesity Osteoporosis/Bone Disease Pediatric Infections Pregnancy / Infertility Respiratory Infections STDs Stroke[jwatch.org]
    • These might include acute kidney failure, end-stage kidney disease, liver malfunction (leading to jaundice), clot formation leading to damage to the heart (heart attack) and brain (stroke) Lifelong treatment and therapy may be required to manage Atypical[dovemed.com]
    Thrombocytopenia
    • Thrombocytopenia can cause easy bruising and abnormal bleeding.[ghr.nlm.nih.gov]
    • Background: Thrombocytopenia with intravascular hemolysis is a serious complication of pregnancy.[annals.org]
    • […] hemolytic anemia, thrombocytopenia and acute kidney injury.[ctgt.net]
    • Laboratory tests revealed hemolytic anemia, thrombocytopenia, azotemia, low complement C3 and normal complement C4.[benthamopen.com]
    Upper Respiratory Infection
    • The most frequently reported adverse reactions in aHUS single arm prospective trials ( 20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary[soliris.net]
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  • Etiology

    Both congenital and acquired aHUS may be caused by several primary diseases.

    With regards to the former, congenital aHUS may be provoked by gene defects disturbing the balance between pro- and anti-thrombotic processes. aHUS may be induced by hereditary disorders of complement regulation that alter alternative complement pathway activation. Mutations have been identified in those genes encoding for factor H, factor I, C3, membrane cofactor protein (MCP), thrombomodulin and factor B, and are listed here in order of decreasing prevalence [7]. Factors H and I, MCP and thrombomodulin are required for C3b inactivation and thus for the downregulation of C3 convertase production. Deficiencies of these components of the complement system result in excess complement activation and consumption. Gain-of-function mutations affecting factor B may have similar consequences [8]. C3 mutations have been shown to impair factor I and MCP-mediated cleavage of C3b [9]. Complement disorders predisposing for aHUS may be inherited with an autosomal dominant or recessive trait, but mutations may also occur sporadically. The penetrance of mutations is incomplete.

    Similar to the previously mentioned genetic causes of aHUS, dysregulation of the complement system may be triggered by an autoimmune-mediated depletion of complement factors. In this context, anti-factor H autoantibodies have recently been detected in blood samples obtained from aHUS patients [10].

    Acquired aHUS has also been related to pre-existing glomerulopathy caused by autoimmune diseases like systemic lupus erythematosus and anti-phospholipid syndrome, infection with human immunodeficiency virus, solid organ and hematopoietic stem cell transplantation, malignancies and cancer therapy, pregnancy and use of oral contraceptives, application of calcineurin inhibitors, cyclosporin, quinine and other drugs [1] [3]. The causal relation between those entities and aHUS remains largely unknown, but the induction of complement anomalies has been proposed to explain at least some triggers of aHUS [7].

    Of note, hereditary metabolic diseases causing symptoms consistent with HUS have previously been considered subtypes of aHUS. This applies for diacylglycerol kinase ε deficiency and disturbances of cobalamin metabolism [3]. Nowadays, these diseases are treated as own entities.

    Epidemiology

    The annual incidence of HUS has been estimated to be 6 per 100,000 children aged less than five years, whereas less than 2 per 100,000 patients are affected by the disease each year [7]. The incidence of aHUS is not known exactly, but is presumably less than 1 per 100,000 inhabitants per year. While some sources state the overall incidence of aHUS to be as low as 0.2 per 100,000, others claim it to account for the majority of HUS in adults [5] [11]. Literature reviews yield contradictory results owing to the inconsistent use of the term "atypical": Initially, aHUS has been diagnosed when HUS patients did not experience a prodromal period characterized by diarrhea. Only later, the diagnosis of aHUS has been reserved for cases of non-infectious origin. Some experts also recommend to exclude hereditary metabolic diseases from aHUS, and the present article follows that specification [3].

    Sex distribution
    Age distribution

    Pathophysiology

    According to current knowledge, aHUS is mainly triggered by complement disorders: Excess activation of the complement system is induced by deficiencies of inhibitors and gain-of-function mutations of factors that maintain this process. Since many complement factors are expressed by endothelial cells, such anomalies are associated with vascular damage. The latter is most prominent in small vessels, e.g., in capillaries forming glomeruli in the kidneys. Thus, affected individuals suffer from renal impairment. Thrombi easily form within damaged vessels, and thrombus formation may give rise to thromboembolic events. Eventually, platelets are consumed and the patient shows thrombocytopenia. Furthermore, erythrocytes passing through such vessels are subjected to mechanical stress and may be destroyed. This is the pathophysiological equivalent of microangiopathic hemolytic anemia. Consequently, fragments of erythrocytes, so-called schistocytes, may be detected in blood samples.

    Mutations described in the previous paragraphs merely predispose for aHUS, and additional triggers are assumed to be necessary for the induction of an aHUS crisis. Under physiological conditions, the body is able to compensate for certain complement disorders, and only when confronted with pathogens, determined drugs or other challenges do these disorders manifest. Thus, aHUS follows a course of remission and relapse.

    Prevention

    No specific measures can be recommended to prevent aHUS. Because gene defects associated with aHUS merely predispose for the disease, which may or may not be triggered by as-of-yet unknown factors, the benefit of genetic screens of family members of affected individuals is questionable.

    Summary

    Hemolytic uremic syndrome (HUS) is the chosen designation for the symptom triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure [1] and it has first been described by the Swiss pediatrician Conrad von Gasser and colleagues in 1955 [2]. Indeed, it is primarily diagnosed in pediatric patients, especially in young children aged less than five years. Nevertheless, it may affect patients of any age. The vast majority of cases is attributed to an infection with enterohemorrhagic, Shiga-like toxin-producing serotypes of Escherichia coli (i.e., serotype O157:H7 and, less prevalent, non-O157:H7 serotypes). Additionally, HUS may develop secondary to infection with Shigella dysenteriae, Citrobacter spp. and Streptococcus pneumoniae, among others [1]. HUS is associated with an acute mortality rate of 5% in children and frequent long-term sequelae with possible progression to end-stage renal disease [3] [4].

    Cases that cannot be related to an infectious agent are deemed atypical hemolytic uremic syndrome (aHUS). aHUS accounts for less than 10% of all cases diagnosed in pediatric patients, whereas adults diagnosed with HUS are more likely to suffer from the atypical form of the disease [5]. Distinct hypotheses regarding the disease' etiology have been proposed so far, with the theory of aHUS resulting from inherited complement disorders being the one most widely accepted. aHUS is a life-threatening condition ,often with a poor outcome; depending on the precise cause of aHUS. Roughly 38 to 73% develop end-stage renal disease within five years [3]. Mortality exceeds numbers reported for HUS patients and according to older literature, acute and overall mortality approaches 15 and 25%, respectively [6]. Patients remain at high risk for disease recurrence even after kidney transplantation.

    Patient Information

    Hemolytic uremic syndrome (HUS) refers to the symptom triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury, i.e., HUS patients suffer from low levels of hemoglobin, lack of platelets and renal impairment. Their general condition is reduced, they suffer from fatigue, tachycardia and palpitations, are prone to spontaneous bleeding and renal failure. Their damaged kidneys lose protein and are unable to maintain normal blood pressure. Thus, HUS patients develop edema and hypertension.

    In most cases, HUS manifests after an infection with determined serotypes of Escherichia coli, with Shigella dysenteriae, Citrobacter spp. or Streptococcus pneumoniae. Less than 10% of all cases cannot be associated with such an infection and are thus deemed atypical hemolytic uremic syndrome (aHUS). aHUS is often related to gene defects.

    It is of utmost importance to diagnose aHUS during early stages of the disease in order to initiate therapy as soon as possible. This way, the risk of end-stage renal disease, renal failure and death may be reduced. Treatment options comprise plasma exchange, drug therapy and liver and kidney transplantation.

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    References

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    2. Gasser C, Gautier E, Steck A, et al. [Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia]. Schweiz Med Wochenschr. 1955; 85(38-39):905-909.
    3. Kaplan BS, Ruebner RL, Spinale JM, et al. Current treatment of atypical hemolytic uremic syndrome. Intractable Rare Dis Res. 2014; 3(2):34-45.
    4. Spinale JM, Ruebner RL, Copelovitch L, et al. Long-term outcomes of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol. 2013; 28(11):2097-2105.
    5. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011; 6:60.
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    8. Marinozzi MC, Vergoz L, Rybkine T, et al. Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign? J Am Soc Nephrol. 2014; 25(9):2053-2065.
    9. Martínez-Barricarte R, Heurich M, López-Perrote A, et al. The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome. Mol Immunol. 2015; 66(2):263-273.
    10. Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005; 16(2):555-563.
    11. Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004; 43(6):976-982.
    12. Hofer J, Giner T, Jozsi M. Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. Semin Thromb Hemost. 2014; 40(4):431-443.
    13. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007; 18(8):2392-2400.
    14. Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009; 24(4):687-696.
    15. Schmidtko J, Peine S, El-Housseini Y, Pascual M, et al. Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis. 2013; 61(2):289-299.



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