HUS and atypical HUS

Abstract

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

When to Stop Eculizumab in Complement-Mediated Thrombotic Microangiopathies

“…While dysregulated complement activity is not the primary driver of typical HUS, infectious pathogens do activate complement to varying degrees [3,5,9], and several case series have shown favorable outcomes with early use of eculizumab, particularly in patients with severe neurologic symptoms [10,11]. Eculizumab has also been increasingly explored for the treatment of sHUS, including in cases associated with drugs, solid organ, and stem cell transplant [12][13][14][15].…”

“…Bacterial Shiga toxin causes direct cytotoxic damage to vascular endothelial, renal mesangial and epithelial cells, as well as platelets and red blood cells. The complement pathway is activated in typical HUS to varying degrees due to stimulation by infectious pathogens [3,5]. Treatment is generally supportive, as more aggressive interventions have not been shown to improve outcomes [6].…”

“…Disease TTP [4] Typical HUS [2] Atypical HUS [2,3] Secondary HUS [3] Prevalence/incidence -1 case/million annually -Usual onset: adulthood (acquired) cleavage of circulating large von Willebrand factor multimers, excessive platelet adhesion, activation and aggregation, and finally microthrombi formation. The majority of adult cases of TTP are acquired via the production of anti-ADAMTS13 antibodies, and thus this disease can be effectively treated with therapeutic plasma exchange (PEX) and immune suppression [4].…”

“…These disorders are further subdivided into atypical HUS (aHUS) and secondary HUS (sHUS). aHUS is caused by congenital or acquired defects in alternative complement pathway regulatory proteins [1][2][3]. sHUS is the least well-defined group of complement-mediated TMAs, with a list of precipitating causes including drugs, solid-organ or stem cell transplant, and systemic illnesses such as sepsis, auto-immune disorders, and malignancy.…”

“…The latter pathologic findings can manifest as varying degrees of end-organ damage, most commonly renal failure or neurologic deficits. TMAs can be further subdivided into 3 categories: thrombotic thrombocytopenic purpura (TTP), typical hemolytic uremic syndrome (typical hemolytic uremic syndrome [HUS]), and the group of disorders known as complement-mediated TMAs (Table 1) [1][2][3].…”