Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome

Abstract

Thrombotic microangiopathy (TMA) is defined by specific clinical characteristics, including microangiopathic hemolytic anemia, thrombocytopenia, and pathologic evidence of endothelial cell damage, as well as the resulting ischemic end-organ injuries. A variety of clinical scenarios have features of TMA, including infection, pregnancy, malignancy, autoimmune disease, and medications. These overlapping manifestations hamper differential diagnosis of the underlying pathogenesis, despite recent advances in understanding the mechanisms of several types of TMA syndrome. Atypical hemolytic uremic syndrome (aHUS) is caused by a genetic or acquired defect in regulation of the alternative complement pathway. It is important to consider the possibility of aHUS in all patients who exhibit TMA with triggering conditions because of the incomplete genetic penetrance of aHUS. Therapeutic strategies for aHUS are based on functional restoration of the complement system. Eculizumab, a monoclonal antibody against the terminal complement component 5 inhibitor, yields good outcomes that include prevention of organ damage and premature death. However, there remain unresolved challenges in terms of treatment duration, cost, and infectious complications. A consensus regarding diagnosis and management of TMA syndrome would enhance understanding of the disease and enable treatment decision-making.

Keywords: Atypical hemolytic uremic syndrome; Complement pathway, alternative; Diagnosis, differential; Eculizumab; Thrombotic microangiopathies.

Figure 1.

Differential diagnosis of thrombotic microangiopathy syndromes. LDH, lactate dehydrogenase; RBC, red blood cell; AKI, acute kidney injury; GI, gastrointestinal; CNS, central nervous system; CV, cardiovascular; STEC HUS, Shiga-toxin producing Escherichia coli hemolytic uremic syndrome; ADAMTS13, metalloproteinase with thrombospondin type 1 motif, member 13; TTP, thrombotic thrombocytopenic purpura; SCr, serum creatinine; BMT, bone marrow transplantation.

Figure 2.

Treatment approach for post-transplant thrombotic microangiopathy. Modified from Campistol et al. [36]. TMA, thrombotic microangiopathy; ADAMTS13, metalloproteinase with thrombospondin type 1 motif, member 13; STEC, Shiga toxin-producing Escherichia coli; DIC, disseminated intravascular coagulation; AMR, antibody mediated rejection; CMV, cytomegalovirus; PE, plasma exchange.

Figure 3.

Preventive strategy for thrombotic microangiopathy in kidney transplant (KT) recipients. Modified from Campistol et al. [36]. Modified from Zuber et al. [34], with permission from Elsevier. TMA, thrombotic microangiopathy; KTR, kidney transplant recipient; ESRD, end-stage renal disease; aHUS, atypical hemolytic uremic syndrome; MCP, membrane cofactor protein gene; CFH, complement factor H gene; CFI, complement factor I gene; CFB, complement factor B; anti-FH, anti-complement factor H antibodies; DSA, donor-specific antibody; CMV, cytomegalovirus; LTBI, latent tuberculosis infection; CNI, calcineurin inhibitors; mTOR, mammalian target of rapamycin.