Atypical Even for Atypical Hemolytic Uremic Syndrome (aHUS)

Introduction: Atypical hemolytic uremic syndrome (aHUS) involves overactivation of the alternative complement pathway leading to complement-mediated acute kidney injury (AKI). This dysregulation occurs in the presence of a genetic predisposition or an acquired loss of regulation, usually resulting in an elevated serum membrane attack complex (sMAC) level. Here we present a case of aHUS where fluid phase levels were normal with indirect evidence of complement activation on the kidney biopsy. Case Description: A 28 year old male with hematuria and flu-like symptoms presented with an AKI (Cr peak 4.4; baseline 1.1), anemia and thrombocytopenia. Thrombotic microangiopathy (TMA) was suspected given low haptoglobin, high lactate dehydrogenase, and schistocytes on peripheral smear. Interestingly, the patient had a similar presentation a year prior following a COVID-19 infection. Empiric plasmapheresis was initiated until ADAMTS13 resulted back normal. Stool Shiga toxin was negative. Empiric terminal complement blockade with eculizumab was started for presumed aHUS. Serologic complement assays including factors I, B, H, factor H antibody, and sMAC were all normal. Only factor Bb level was elevated. After the platelet count improved, a kidney biopsy was obtained demonstrating acute TMA of glomeruli and arterioles. IgG kappa deposition was noted in the vessels, consistent with tissue deposition of eculizumab. Six weeks following hospitalization, Cr was down to 1.4 with normal complete blood count. Genetic testing is pending. Discussion: This patient’s case highlights a severe AKI from TMA due to aHUS and emphasizes that evidence of complement pathway overactivation in aHUS may not always be present in the fluid phase. Despite normal fluid phase assays, the IgG kappa kidney deposition (indicating eculizumab deposition) indirectly reflected tissue level alternative complement activation which was being modulated by the drug. Tissue deposition of eculizumab in this context has been well described previously in the renal pathology literature (Herlitz et al, JASN, 2012, PMID: 22677550). Continued improvement of the patient’s renal and hematologic parameters with eculizumab therapy supports this interpretation. Learning Points: AHUS should remain in the differential even with normal serologic complement assays. Empiric eculizumab therapy is key and its deposition in kidney tissue can provide further diagnostic certainty.