Inhibition of terminal complement activation in severe Shiga toxin‐associated HUS – perfect example for a fast track from bench to bedside

Abstract

Typical haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy, leading to severe renal disease as well as life‐threatening extrarenal complications. HUS is primarily caused by infections with enterohaemorrhagic Escherichia coli (EHEC) and 5–20% of EHEC infections result in HUS. EHEC bacteria produce several virulence factors, of which Shiga toxins are believed to play a central role. About 10% of all HUS cases are not caused by E. coli and are thus termed atypical HUS. These are observed as familial or sporadic forms and are most commonly caused by a dysregulation of the alternative pathway of the complement system due to inherited mutations of, or acquired auto‐antibodies against, complement regulator proteins. The, thereby, impaired control of complement, which plays a prominent role in the humoral immune system and in immune homeostasis, leads to a hyperactive state, including activation of endothelial cells and platelets, inflammation of small vessel and eventually to the destruction of the kidney and other organs (summarized in Orth et al, 2009). Lapeyraque et al have published the successful use of the licensed terminal complement C5 inhibitor eculizumab for the treatment of severe Shiga toxin‐associated HUS in three 3‐year‐old children with devastating prognoses (Lapeyraque et al, 2011). The three patients continued to show progression of the HUS despite having received multiple plasma exchanges. Treatment with eculizumab markedly improved their clinical status, in particular their neurological and renal functions, after two to four administrations of this complement inhibitor. Dialysis was reported to be discontinued after 3–16 days in all three patients. Recovery was attributed to eculizumab and absence of mutations of complement proteins …