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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.

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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:

Easy Bruising
Anemia
  • We hypothesized that atypical neonatal HUS can progress to PA because of the presence of severe anemia and microthrombi formation. [Indexed for MEDLINE] Free full text[ncbi.nlm.nih.gov]
  • From Wikidata Jump to navigation Jump to search complement deficiency that is characterized by mechanical hemolytic anemia, thrombocytopenia, and renal dysfunction atypical hemolytic-uremic syndrome edit English Atypical hemolytic uremic syndrome complement[wikidata.org]
  • PATIENT CONCERNS: A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury.[ncbi.nlm.nih.gov]
  • Monoclonal protein has uncommonly been reported as a cause of microangiopathic hemolytic anemia (MAHA).[ncbi.nlm.nih.gov]
  • BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) results from an inherited dysregulation of the alternative complement pathway leading to thrombotic microangiopathy consisting of hemolytic anemia, thrombocytopenia, and renal injury.[ncbi.nlm.nih.gov]
Pain
  • The allograft preserved good renal function [serum creatinine (sCr) level 110-130 μmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 μmol/L), decreasing platelet count, and hemolytic[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • 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]
  • In clinical trials, 3 out of 222 patients with PNH treated with ULTOMIRIS experienced infusion reactions (lower back pain, drop in blood pressure and infusion-related pain) during ULTOMIRIS administration.[uncommonstrength.com]
Fatigue
  • PATIENT CONCERNS: A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury.[ncbi.nlm.nih.gov]
  • 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. On examination, he was pale with multiple petechiae on his arms and legs.[web.era-edta.org]
  • Symptom onset is usually sudden, and the disease follows a course of apparent remission and recurrence: Parents report feeding difficulties, and the patients themselves suffer from lethargy, fatigue and vomiting.[symptoma.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]
  • They may include: Anemia, causing tiredness, muscle weakness, and fatigue Low platelets in blood, which could lead to uncontrolled and abnormal bleeding Liver dysfunction, potentially resulting in jaundice with pale and yellow skin Kidney dysfunction,[dovemed.com]
Swelling
  • 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]
  • Glomerular thrombosis, intracapillary foamy cells, endocapillary swelling and hypercellularity, mesangiolysis, and double basement membranes are observed in aHUS kidney biopsy. Arterioles have thrombosis, endothelial swelling, or fibrinoid necrosis.[karger.com]
  • Acute oedematous intimal expansion with endothelial swelling and partial occlusion of the lumen without thrombosis (HES, 400). C Activation of complement in heart vessel and myocardium.[doi.org]
  • Thrombotic microangiopathy (TMA) is the term for a histopathologic lesion of small vessels (arterioles and capillaries) characterized by swelling and detachment of the endothelium, subendothelial accumulation of protein and cellular debris, and obstruction[hematology.org]
  • Histologically, the glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling.[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]
  • Severe pallor, as well as icterus, was present. There was no palpable organomegaly. On routine investigation, he was anemic (hemoglobin 4.9 g%) with thrombocytopenia (platelets 97,000). Total leukocyte counts were normal.[ijccm.org]
  • Patient Presentation We report on a 5.5-month-old girl who presented with pallor, fatigue, and nonbloody diarrhea. On admission, she was jaundiced, with elevated lactate dehydrogenase (LDH), progressive anemia, and thrombocytopenia, indicating TMA.[pediatrics.aappublications.org]
  • They can be found as triangular, helmet shaped, or comma shaped with pointed edges, schistocytes are most often found to be microcytic with no area of central pallor.[wikivisually.com]
Dyspnea
  • A 38-year-old Japanese man with a history of central retinal vein occlusion was admitted to our hospital with progressive dyspnea.[ncbi.nlm.nih.gov]
  • Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis.[soliris.net]
  • Presentation A 31-year-old African American female with past medical history significant for type I diabetes, uncontrolled hypertension, chronic kidney disease, venous thrombosis, and cerebral palsy presented with a severe headache, confusion, cough, dyspnea[cureus.com]
  • CASE REPORT Female, 35 years-old, presented complaining with dyspnea, nausea and oliguria initiated 6 days before admission. She referred flu-like symptoms 15 days before. Her past medical history was unremarkable.[jbn.org.br]
  • ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea[uncommonstrength.com]
Pharyngitis
  • Second relapse induced by bacterial pharyngitis was confirmed 4 months after eculizumab discontinuation and prompt eculizumab reinitiation resulted in rapid remission.[ncbi.nlm.nih.gov]
Diarrhea
  • Abstract Atypical Hemolytic Uremic Syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure not associated with diarrhea.[ncbi.nlm.nih.gov]
  • ORPHA:2134 Synonym(s): Atypical HUS D-HUS Hemolytic-uremic syndrome without diarrhea aHUS Prevalence: 1-9 / 1 000 000 Inheritance: Autosomal dominant or Autosomal recessive or Not applicable Age of onset: All ages ICD-10: D58.8 OMIM: 235400 609814 612922[orpha.net]
  • However, it is now evident that atypical HUS actually encompasses a heterogeneous group of disorders, and there are reports suggesting that some cases of atypical HUS have a favorable prognosis, similar to that of diarrhea-associated disease.[ncbi.nlm.nih.gov]
  • METHODS: The current study is aimed at identifying HUS patients with poor outcomes based on the presence or absence of diarrhea (D) or Shiga toxin (S).[ncbi.nlm.nih.gov]
Vomiting
  • A previously healthy 8-month-old boy was referred to our hospital because of onset of fever, vomiting, and a single episode of nonbloody diarrhea.[ncbi.nlm.nih.gov]
  • Four days earlier, she had suffered from gastroenteritis (non-bloody diarrhea and vomiting without fever).[ncbi.nlm.nih.gov]
  • 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]
  • 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. The doctors were stumped.[globalgenes.org]
Nausea
  • He suffered from recurrent episodes of flash edema preceded by nausea and regurgitation that required intubation and dialysis. His condition improved after treatment with eculizumab and IVIG.[thejh.org]
  • 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]
  • 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. She referred flu-like symptoms 15 days before. Her past medical history was unremarkable.[jbn.org.br]
  • […] adults and the prognosis is poor with high morbidity and mortality in acute phase and 50% of progression to chronic kidney disease. 1 The authors describe the case of a 35-year-old man who presented at the emergency department with fever, abdominal pain, nausea[medintensiva.org]
Abdominal Pain
  • The allograft preserved good renal function [serum creatinine (sCr) level 110-130 μmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 μmol/L), decreasing platelet count, and hemolytic[ncbi.nlm.nih.gov]
  • 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]
  • pain, nausea, bilious vomiting and decrease urine output for two weeks.[medintensiva.org]
  • During the prodromal stage, patients may suffer from gastroenteritis with abdominal pain and diarrhea, possibly containing blood.[symptoma.com]
Hypertension
  • She was pyrexial (38 C), tachycardic (110 bpm) and hypertensive (160/110 mmHg). Her fundoscopy revealed grade IV hypertensive retinopathy. She had mild pretibial and periorbital edema, with oliguria (450 mL/day).[ncbi.nlm.nih.gov]
  • In this review, three case reports are presented illustrating the onset and diagnosis of aHUS in the setting of different CACs (pregnancy complications, malignant hypertension, renal transplantation).[ncbi.nlm.nih.gov]
  • The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions.[ncbi.nlm.nih.gov]
  • CASE: We describe a woman with atypical hemolytic uremic syndrome who was given the diagnosis of gestational hypertension during her first pregnancy and preeclampsia and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome followed[ncbi.nlm.nih.gov]
  • BACKGROUND: Severe hypertension (HTN) and acute kidney injury frequently associated with atypical hemolytic uremic syndrome (aHUS) were refractory to various therapies in the pre-eculizumab era.[ncbi.nlm.nih.gov]
Tachycardia
  • Due to anemia, patients often appear pale or cyanotic, and tachycardia may be noted. Thrombocytopenia rarely manifests in form of petechiae, hematoma or spontaneous hemorrhages.[symptoma.com]
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 admission, she was jaundiced, with elevated lactate dehydrogenase (LDH), progressive anemia, and thrombocytopenia, indicating TMA.[pediatrics.aappublications.org]
  • On physical examination, she presented jaundice in sclera, pale mucous membranes and a mild edema in legs bilaterally. The cardiac and pulmonary auscultation were normal. The laboratory tests on admission are illustrated at Table 2. Table 2.[jbn.org.br]
  • High blood pressure, jaundice (a yellow tinge in skin and the whites of the eyes), seizures, and bleeding into the skin can also occur.[en.wikipedia.org]
Petechiae
  • On examination, he was pale with multiple petechiae on his arms and legs. Blood pressure was 175/90.[web.era-edta.org]
  • Thrombocytopenia rarely manifests in form of petechiae, hematoma or spontaneous hemorrhages. Development of peripheral edema is related to renal loss of proteins and subsequent hypoalbuminemia.[symptoma.com]
  • There was no bruises or petechiae. Cardiorespiratory and gastrointestinal examinations were unremarkable. She demonstrated bilateral intention tremor and past pointing with unsteady gait. She had 3 witnessed “dystonic” events in the department.[imj.ie]
Visual Impairment
  • Renal hypertension may cause dizziness, headaches and visual impairment as well as decreased awareness. Other symptoms pointing at compromise of the central nervous system are facial paralysis, hemiparesis, and seizures.[symptoma.com]
Kidney Failure
  • Failure, Chronic/diagnosis Kidney Failure, Chronic/drug therapy Kidney Failure, Chronic/immunology Lactic Acid/blood Long-Term Care Magnetic Resonance Imaging Male Myocardial Ischemia/diagnosis Myocardial Ischemia/drug therapy Myocardial Ischemia/immunology[ncbi.nlm.nih.gov]
  • Failure, Chronic/blood Kidney Failure, Chronic/genetics Kidney Failure, Chronic/immunology* Kidney Failure, Chronic/therapy Kidney Transplantation* Male Plasma Exchange Recurrence Renal Dialysis Retrospective Studies United Kingdom Substances Antibodies[ncbi.nlm.nih.gov]
  • Dialysis: a treatment for kidney failure. Normally, the kidneys work to filter the blood and remove waste, excess salt, and water. Kidney failure, also called “end-stage renal disease,” occurs when the kidneys stop working completely.[ahussource.eu]
  • BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney failure.[ncbi.nlm.nih.gov]
  • Given the lack of response to therapy and the occurrence of kidney failure requiring dialysis, we used eculizumab as rescue therapy, a monoclonal humanized antibody against the complement component C5.[ncbi.nlm.nih.gov]
Oliguria
  • This case report shows that atypical hemolytic uremic syndrome could have unusual presentations such as the absence of oliguria, hypertension, and edema, with rapid recovery and good prognosis.[ncbi.nlm.nih.gov]
  • Although the patient had the typical triad of aHUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), urgent dialysis was not indicated because he had neither oliguria nor severe electrolyte abnormality.[ncbi.nlm.nih.gov]
  • She had mild pretibial and periorbital edema, with oliguria (450 mL/day). She had a pregnancy one year previously, during which she had hypertension, proteinuria and edema, with successful delivery at term.[ncbi.nlm.nih.gov]
  • 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]
  • Oliguria or anuria may occur. Disease progression varies largely and some patients may develop end-stage renal disease as early as during their first bout of aHUS.[symptoma.com]
Anuria
  • CASE PRESENTATION: Here we present a case of a 27-year-old white man with anuria who was hospitalized after being diagnosed as having hemolytic uremic syndrome accompanied by acute renal failure. Renal biopsy results revealed C3 glomerulonephritis.[ncbi.nlm.nih.gov]
  • 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]
  • Oliguria or anuria may occur. Disease progression varies largely and some patients may develop end-stage renal disease as early as during their first bout of aHUS.[symptoma.com]
  • A subsequent aHUS relapse led to anuria. Complement Analyses EDTA-plasma and serum samples were sequentially taken for complement analyses and stored at 70 C until assayed.[doi.org]
Hematuria
  • CASE DIAGNOSIS/TREATMENT: A 28-day-old female presented with gross hematuria and hypertension. aHUS was suspected based on anemia with schistocytes, thrombocytopenia, low C3, and acute kidney injury requiring peritoneal dialysis.[ncbi.nlm.nih.gov]
  • CASE-DIAGNOSIS/TREATMENT: Sudden onset macroscopic hematuria, hypertension, and bruises over the entire body were noted in a 5 day-old newborn.[ncbi.nlm.nih.gov]
  • 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.[symptoma.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]
  • Following three daily PEs, his hematuria, platelet count, serum creatinine, and urine output improved [Figure 1].[indianjnephrol.org]
Headache
  • CASE PRESENTATION: A 32-year-old Caucasian woman presented with pyrexia and headache lasting one week to our Emergency Department. She gave no history of diarrhea or other symptoms to account for her high temperature.[ncbi.nlm.nih.gov]
  • 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. On examination, he was pale with multiple petechiae on his arms and legs.[web.era-edta.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]
  • The combination of MAHA, AKI, and thrombocytopenia in addition to a headache and confusion at the time of the presentation confirmed the diagnosis of aHUS/TTP. In consultation with a hematologist, the patient was placed on daily plasma exchange.[cureus.com]
Seizure
  • The second patient developed cerebral TMA (seizures, vision loss, and nystagmus) 6 days after initial presentation and remained unresponsive to PE/PI.[ncbi.nlm.nih.gov]
  • After 24 months, she was relapse-free and seizure-free, with a normal neurological examination. Copyright 2015 Elsevier Masson SAS. All rights reserved.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: We describe the case of a 23-year-old woman of Hellenic origin who, after a preeclampsia-induced premature delivery, developed thrombotic microangiopathy with renal failure, tonicoclonic seizures, anasarca edema and hypertension.[ncbi.nlm.nih.gov]
  • He later developed sudden onset severe headache followed by loss of vision progressing to generalized tonic–clonic seizures and status epilepticus. Blood pressure was increased at 200/140 mmHg.[ijccm.org]
  • Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis.[soliris.net]
Stroke
  • CASE-DIAGNOSIS/TREATMENT: We present a child with early onset aHUS and a C3 gain-of-function mutation who developed cerebral artery stenoses, leading ultimately to death due to a massive stroke 9 days after successful renal transplantation under prophylactic[ncbi.nlm.nih.gov]
  • Stroke: damage to the brain. Strokes can happen when an artery in the brain becomes clogged or starts bleeding and cuts off the blood supply to that portion of the brain. Syndrome: a set of symptoms that occur together in a pattern.[ahussource.eu]
  • A genetic, chronic, ultra-rare disease that can progressively damage vital organs, potentially leading to stroke, heart attack, kidney failure, and death…. We are coming up on the 3 year mark of his diagnosis.[rareundiagnosed.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]
  • The study data also indicate that earlier intervention with Soliris improves clinical outcomes. 1 aHUS is a chronic and life-threatening condition that can progressively damage vital organs, leading to stroke, heart attack, kidney failure, and death.[news.alexionpharma.com]
Confusion
  • Although initial improvement in renal function was seen in both cases, the first patient showed progressing thrombotic microangiopathy (TMA) despite daily PE, and neurological manifestations (seizures, vision loss, loss of balance, and confusion) developed[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • The combination of MAHA, AKI, and thrombocytopenia in addition to a headache and confusion at the time of the presentation confirmed the diagnosis of aHUS/TTP. In consultation with a hematologist, the patient was placed on daily plasma exchange.[cureus.com]
  • All three of these systemic TMA-causing diseases are characterized by thrombocytopenia and microangiopathic hemolysis, plus one or more of the following: neurological symptoms (e.g., confusion, cerebral convulsions, seizures); renal impairment (e.g.,[en.wikipedia.org]
Lethargy
  • Symptom onset is usually sudden, and the disease follows a course of apparent remission and recurrence: Parents report feeding difficulties, and the patients themselves suffer from lethargy, fatigue and vomiting.[symptoma.com]
  • […] by, last update March 4, 2019 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]
  • Related symptoms and signs include lethargy, decreased urine output, blood in the urine, kidney failure, low platelets, (which are needed for blood clotting), and destruction of red blood cells (microangiopathic hemolytic anemia).[en.wikipedia.org]

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].
Decreased Platelet Count
  • The allograft preserved good renal function [serum creatinine (sCr) level 110-130 μmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 μmol/L), decreasing platelet count, and hemolytic[ncbi.nlm.nih.gov]
  • This leads to platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis, damage to multiple organs, and ultimately, death.[en.wikipedia.org]
Haptoglobin Decreased
Hemoglobin Decreased
  • Her hemoglobin decreased from 13.1 to 4.5 g/dl, and her platelet count fell from 315 to 144 mm 3 during this same time period. At presentation, her C3 was mildly depressed at 81 mg/dl (normal 90 to 180 mg/dl) and the C4 was normal.[doi.org]

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].

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.

References

Article

  1. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol. 2008; 23(10):1749-1760.
  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.
  6. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998; 9(6):1126-1133.
  7. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009; 361(17):1676-1687.
  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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Last updated: 2018-06-21 17:45