Atypical hemolytic uremic syndrome

A rare, chronic, life-threatening, systemic disease with genetic defects regulating the alternative complement pathway.

A thrombotic microangiopathy that can lead to renal failure in over 50% of patients within one year.

It is a hereditary condition caused by genetic mutations of complement factors or by the formation of antibodies to the complement proteins, resulting in complement dysregulation.

Germline variance in genes that regulate the alternative pathway or sometimes autoantibodies against factor H, are found in up to 60% of patients.

Penetrance is variable since conditions such as surgery, auto immunity, infection, or pregnancy that amplify complement are often required to trigger disease.

It is most commonly seen in children with an estimated prevalence of seven per 1,000,000 children.

The prevalence is not well-established in adults.

A family history of hereditary uremic syndrome of hemolytic uremic syndrome is present in 20 to 30% of patients.

The penetrance of disease is approximately 50%, such that have a family members with the affected gene will suffer from the condition.

An ultra-rare and life-threatening disorder caused by uncontrolled activation of the terminal complement pathway manifesting as thrombotic microangiopathy (TMA) characterized by thrombocytopenia, hemolysis, and renal impairment.

A thrombotic microangiopathy driven by uncontrolled activation of the alternative complement pathway in context with a genetic or autoimmune complement abnormality.

Atypical hemolytic uremic syndrome is frequently unrecognized.

Originally referred to the triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia in children without a prodrome of hemorrhagic diarrhea, in contrast to the typical hemolytic uremic syndrome with such a prodrome.

Shiga toxins play a central role in the pathogenesis of typical hemolytic uremic syndrome: in contrast atypical hemolytic uremic syndrome is a disease caused by defective regulation of the alternative complement pathway.

Strongly associated with molecular effects causing overactivity of the complement cascade.

aHUS requires two processes for development: pre-existing susceptibility factors, either congenital or acquired, that interfere with the ability to regulate activation of the alternate complement pathway and modulating factors that promote endothelial cells and platelets activation and injure endothelium in the context of complement activation.

The most common site of complement activation via the alternative pathway is in the kidney.

The kidney damage in the form of thrombotic microangiopathy accounts for hemolysis and thrombocytopenia, as well as activation of the renin-angiotensin-aldosterone system and uncontrolled hypertension.

Thrombotic microangiopathy affects preglomerular arterioles or small arteries causing hypertension by disrupting the renin homeostasis in the juxtaglomerular apparatus.

Uncontrolled intravascular activation of the complement system generates injury swelling of endothelial cells, often accompanied by intimal edema, myofibroblast proliferation, or fibrosis.

Patients presents with five pathophysiological abnormalities or complications including: renal injury, hypertension, extra renal organ dysfunction, microangiopathic hemolytic anemia, and thrombocytopenia.

The most common extra renal tissue pathological findings are interstitial edema and fluid accumulation, as a result of abnormal vascular permeability.

Abnormal vascular permeability is induced by histamine and other vasoactive mediators released from basofils and mast cells by C3 and C5 generated in the kidney and released in the circulation.

Fibrin-platelet thrombosis may occur at sites of endothelial cell necrosis and disruption and can constitute the pathology of thrombotic microangiopathy.

At autopsy thrombotic microangiopathy is found primarily in the kidney, although C5b-9 also has been detected on cutaneous endothelial cells.

Approximately 2/3 of a HUS cases are associated with complement activating conditions which include: infection as H1N1, influenza virus, Adenovirus, cytomegalovirus, HIV, streptococcal pneumonia, and Shigatoxin producing E. coli, pregnancy, malignant hypertension, autoimmune disorder is particularly SLE and systemic sclerosis, organ and tissue transplant, malignancy, Immunosuppressive immunosuppressive drugs, such as,  calcineurin Inhibitors and mammalian target rapamycin Inhibitors, cancer chemotherapy agents such as gemcitabine, mitomycin C, cis-platinum, and vascular endothelial growth factor Inhibitors, platelet antagonists such as ticopidine and clopidogrel and extended form of oxymorphone.
Thrombotic thrombocytopenic purpura or hemolytic crises related to sickle cell anemia and cold agglutinin disease may unmask aHUS.
The consequences of uncontrolled complement activation with the generation of C5a and sC5b-9  include inflammation, platelet activation and aggregation, erythrocyte lysis, and endothelial cell injury, leading to the formation of fibrin microthrombi throughout the microvasculature.

The release of histamine another vasoactive mediators from complement activation causes capillary leak in various organs, accounting for extra renal manifestations.

The degree of complement activation can be variable.

Associated with a high degree of morbidity and mortality in the first year of presentation, unless appropriately treated.

Patients with aHUS can present is malignant hypertension and preeclampsia.

79% of patients with aHUS die, require dialysis, or have permanent renal damage within three years (Noris M et al).

The annual incidence of STEC-HUS is about 2 per hundred thousand in adults and 6.1 per 100 thousand in children younger than five years, while the incidence of aHUS is about 2 per million for adults and 3.3 per million in children younger than 18 years.

The first clinical manifestations may not be recognized until adulthood, despite genetic predisposition present at birth.

Patients with aHUS are susceptible to thrombotic microangiopathy complications when experiencing complement amplifying condition.

69% of patients with aHUS manifested first clinical processes when experiencing one of the compliment amplifying conditions which include: diarrhea, gastroenteritis, upper respiratory tract infections, pregnancy, malignant hypertension, glomerulopathy, and malignancy.

Patients with SLE with an underlying complement mutation for aHUS are at higher risk for thrombotic microangiopathy.

Genes identified as causing atypical hemolytic syndrome include regulators and activators of alternative pathway of complement activation, but a phenotypic correlation is not apparent.

Similar mutations have been reported in patients with C3 glomerulopathy.

Mutations of the regulators such as complement factor H, complement factor I, CD46 or activators such as C3 will complement factor B of the alternative complement pathway are detected in approximately half of the patients with clinical diagnosis of atypical hemolytic uremic syndrome.

C5  inhibition is the most effective therapy and results in complete remission with normalization of kidney function, platelet count, and lactate dehydrogenase levels in the majority of patients.

Treatment is with eculizumab to inhibit complement mediated thrombotic microangiopathy.

((Eculizumab)) is a monoclonal antibody to C5 that blocks the generation of C5a and C5-9, complement activation fragments with proinflammatory and cytotoxic effects.

20-35% of patients treated with eculizumab relapse after median of three months.
Rates of off treatment recurrence after eculizumab is higher for children and adults, and elevated in those with the personal family history of atypical hemolytic uremic syndrome.

The duration of maintenance treatment with the humanized anti-C5 monoclonal antibody 

eculizumab in aHUS, a complement mediated thrombotic microangiopathy is unresolved.


Some advocate for discontinuing treatment within six months after remission induction. 


The duration of maintenance treatment with the humanized anti-C5 monoclonal antibody eculolizumab in aHUS, a complement mediated thrombotic microangiopathy is unresolved.

Some advocate for discontinuing treatment within six months after remission induction. 

It is associated with a risk for infection, particularly meningococcal meningitis, secondary to blockade of terminal complement components required for the control of  Neisseria meningitis and Neisseria gonorrhoeae in adults, and several other encapsulated micro organisms in children.


Amino acid modifications of eculizumab led to the development of ravulizumab with the half-life of at least eight weeks.

Ravulizumab-cwvz is approved for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome(atypical-HUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

C5 inhibition can be discontinued in most patients if they achieve a complete remission with the control of the inflammatory trigger.

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