Genetics and long-term outcome in atypical hemolytic uremic syndrome

Thrombotic microangiopathy (TMA) is a severe multisystem disease involving endothelial cell damage, thrombosis of the microvasculature and organ dysfunction. In patients with atypical hemolytic uremic syndrome (aHUS) mutations in complement proteins and antibodies against regulators cause lack of complement regulation on the endothelium that subsequently leads to TMA. Although several advances have been made in understanding the pathophysiology underlying the expanding spectrum of diseases associated with TMA, there remain significant gaps in knowledge. This work includes lessons we have learned from studying aHUS patient cohorts, biomarkers and in-vitro assays mimicking TMA pathology. In the pediatric cohort reported here, we were able to show some genotype-phenotype correlations for disease manifestation and long-term outcome. Overall, long-term renal sequelae were common (80%) in all patients, except patients with a mutation in MCP. Plasma therapy was not able to prevent disease recurrence and renal sequelae, indicating the need for early and continuous therapeutic complement blockade during the first year after manifestation. Eculizumab therapy has clearly improved long-term outcome in patients with aHUS. Up to now, no reliable and comprehensively studied tool to monitor complement blockade in patients treated with eculizumab is available. We established a novel biomarker that determines therapeutic complement inhibition. The TCC capacity is an easy to perform ELISA, which can indicate successful complement inhibition even in pathophysiological conditions (e.g. infections). Our study indicates that extension of treatment intervals may lead to incomplete complement blockade and patients may be at risk for ongoing organ damage, a sudden TMA episode or progressive decline in renal function. In an in-vitro model, using a microfluidic chamber, complement activation on endothelial cells resulted in neutrophil adhesion. This neutrophil adhesion is complement-mediated, as neutrophil adhesion was not seen when complement inactive serum was used. Furthermore, neutrophil adhesion was terminal pathway dependent and accentuates the important role of C5b-9.by Magdalena RiedlInnsbruck, Med. Univ., Diss., 2015OeBB(VLID)76183