Atypical hemolytic uremic syndrome

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.