Late Relapse of Atypical Hemolytic Uremic Syndrome 36 Months after Discontinuation of Complement Blockade Therapy

Introduction: Complement-mediated atypical hemolytic uremic syndrome (aHUS) manifests as microangiopathic hemolytic anemia, renal failure, and thrombosis, stemming from dysregulated complement system activation. The outcomes include end-stage kidney disease and death. The advent of complement blockade therapy has improved the prognosis, but with prohibitive costs and the inconvenience of infusions. So, discontinuation is often considered, though there is a 30% risk of relapse, which typically happens within weeks of stopping the treatment. In our case, the relapse occurred years later, raising new questions about this contentious subject. Case Description: In 2020, a five-year-old boy presented with fever, non-bloody diarrhea, and a rash shortly after an influenza infection. He was hypertensive and febrile, along with jaundice and petechiae. Lab results indicated anemia (Hb 10 g/dL) with schistocytes, thrombocytopenia (platelets 17,000/mm3), and acute kidney injury (BUN 44 mg/dL; creatinine 3 mg/dL). Normal ADAMTS-13 activity (99%), and negative stool culture and ELISA for shigella led to the diagnosis of atypical HUS. Along with supportive therapy and plasmapheresis, eculizumab, a complement 5 blocker, was started, inducing remission. Genetic analysis showed a heterozygous mutation of the C3 gene at the binding site for factor H, predisposing to complement dysregulation. Remission was maintained with eculizumab, which was changed to ravulizumab given its longer half-life. During a year of therapy, he was asymptomatic with normal hematological and renal parameters. Ravulizumab was stopped in March 2021. Thirty-six months later, a relapse occurred in March 2024, with another influenza infection. Thus, eculizumab was restarted. Discussion: Prior studies have indicated a median relapse time of 13 weeks after discontinuation of complement blockade. However, our case underscores the potential for delayed relapse, and advocates for extended periods of surveillance. Our decision to discontinue Ravulizumab was guided our patient's negative C3 deposition assay and his mother's asymptomatic status, though she had the same mutation. Secondly, influenza might have been a “second hit”, triggering the relapse. Clinicians must recognize that aHUS can recur despite pre-discontinuation risk assessment. Further research is needed to inform the optimal treatment duration.