Management of hemolytic uremic syndrome

Abstract

Hemolytic uremic syndrome (HUS) is a disease characterized by hemolysis, thrombocytopenia, and acute kidney injury, although other organs may be involved. Most cases are due to infection with Shiga toxin-producing Escherichia coli (STEC). Early identification and initiation of best supportive care, with microbiological input to identify the pathogen, result in a favorable outcome in most patients. The remaining 10% of HUS cases are classed together as atypical HUS and have a diverse etiology. The majority are due to inherited or acquired abnormalities that lead to a failure to control complement activation. Atypical HUS occurring in other situations (for example, related to pregnancy or kidney transplantation) may also involve excessive complement activation. Plasma therapies can reverse defective complement control, and it is now possible to specifically target complement activation. This has led to improved outcomes in patients with atypical forms of HUS. We will review our current understanding of the pathogenesis of HUS and how this has led to advances in patient care.

Figure 1.. Glomerular pathology in hemolytic uremic syndrome

(A) In the normal glomerulus, patent capillary lumina containing erythrocytes stain yellow (arrowhead). (B) In hemolytic uremic syndrome, the glomerular capillary loops contain fibrin thrombi and microthrombi that stain bright red (black arrow). There is endothelial cell swelling with obliteration of some of the capillary lumina (arrowhead) and red cell fragmentation (red arrow). Stain: Martius scarlet blue trichrome; magnification: 400×.

Figure 2.. Algorithm for the diagnosis of the main types of thrombotic microangiopathy

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; STEC, Shiga toxin-producing Escherichia coli; TTP, thrombotic thrombocytopenic purpura.

Figure 3.. Complement activation in atypical hemolytic uremic syndrome

The complement system, through the alternative pathway, is in a state of continuous low-level activation with generation of a fluid phase C3 convertase (C3H₂OBb). This generates the fragment of C3, C3b, which can bind to cell membranes, which leads to cell-bound C3 convertase. If unchecked, this process leads to rapid amplification of complement activation and generation of the effector proteins of the system: C5b-9, C3a, C5a, and more C3b. To prevent this, there are cell surface (or membrane co-factor protein [MCP]) and fluid phase—complement factor H and complement factor I (CFI)—inhibitors of complement activation. Failure to adequately control activation leads to endothelial injury, with thrombus formation, red cell fragmentation, and platelet consumption.