Pediatric Atypical Hemolytic Uremic Syndrome Advances

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

Keywords: aHUS advancements; pediatric aHUS.

Figure 1

Alternative pathway with key emphasis on interventional drugs and where they act upon. Current therapeutics include Eculizumab, Ravulizumab, Avocapan, Nomacopan, and Cemdisiran. Biosimilars include ABP 959 and Elizaria. Drugs currently being developed include ALXN1720, Poselimab, Tesidolumab, Crovalimab, Avacincaptad Pegol, IFX-1, and Zilucoplan.

Figure 2

Atypical hemolytic uremic syndrome triggers. Novel developing triggers are highlighted in green. SARS-COV-2: severe acute respiratory syndrome coronavirus 2; HIV: human immunodeficiency virus.