Complement-driven hemolytic uremic syndrome

Overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Genetically-determined or acquired dysregulation of the complement is frequently identified in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. In contrast, it is still unclear whether self-limited complement activation, which frequently occurs in other forms of HUS, provides key mechanistic clues or results from endothelial damage. Development of novel biomarkers is underway to firmly establish complement-driven pathogenesis. C5 blockade therapy has revolutionized the management of aHUS patients, resulting in a halving of the subpopulation under chronic dialysis over the course of a few years. On the other hand, the efficacy of C5 blockade in secondary forms of HUS, as assessed by small and uncontrolled case series, is less compelling and should be investigated through properly designed prospective clinical trials. The increased risk of meningococcal infection, related to C5 inhibition, must be rigorously addressed with suitable prophylaxis. Treatment duration should be determined based on an individualized benefit/risk assessment.

Automated summary

Overactivation of the complement alternative pathway is the driving factor in the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Dysregulation of the complement is frequently seen in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. It is uncertain whether self-limited complement activation in other forms of HUS provides mechanistic clues or is a result of endothelial damage. Novel biomarkers are being developed to establish complement-driven pathogenesis. C5 blockade therapy has significantly improved the management of aHUS patients, while its efficacy in secondary forms of HUS needs further investigation through prospective clinical trials. The increased risk of meningococcal infection due to C5 inhibition must be addressed with appropriate prophylaxis. Treatment duration should be based on an individualized benefit/risk assessment.