Atypical hemolytic uremic syndrome (aHUS) is a rare and severe form of thrombotic microangiopathy (TMA) characterized by thrombocytopenia, acute kidney injury, and microangiopathic hemolytic anemia. Our understanding of TMA is evolving, especially regarding its underlying causes. Complement dysregulation plays a pivotal role in the pathogenesis of aHUS, with up to 60% of patients harboring either complement gene variants or testing positive for anti-factor H antibodies. Additionally, non-complement-related hereditary variants, such as those in DGKE, MMACHC, and EXOSC3, can also lead to TMA phenotype.
Secondary HUS encompasses conditions where complement activation occurs alongside other disease processes, including infections, malignant hypertension, autoimmune diseases, malignancies, transplantation, pregnancy, and certain medications. It is essential to note that this classification is not absolute; genetic variants in complement genes have been found in patients with secondary TMA, making it difficult to distinguish between complement-mediated and secondary causes of TMA.
Accurate diagnosis of TMA necessitates specialized laboratory expertise in genetics and immunology. Treatment strategies are contingent upon the underlying cause. While plasma exchange has historically been the standard approach, patients often face high rates of kidney failure and mortality. The advent of complement inhibitors has significantly improved outcomes, yet these therapies remain costly and less accessible in low-resource settings. The optimal dosing and duration of anti-complement therapy are still under investigation. A global research initiative is essential to tackle these challenges and enhance our understanding of aHUS.
