Background: Atypical HUS is a rare disorder caused by uncontrolled activation of the alternative pathway of complement. It presents with thrombotic microangiopathy (TMA), renal insufficiency and in 20% of cases extrarenal manifestations. Most cases of aHUS result from a genetic defect.Methods: We conducted a retrospective chart review of all adult patients with TMA assessed by our apheresis service between January 1, 2010 and December 31, 2013. Complement genetics studies included screening CFI, CFH, CFB, MCP/CD46, CFHR5, C3 and THBD/CD141 genes and were performed at The Hospital for Sick Children, Toronto, Canada. Complement protein and function studies (CH50, AH50, C3d, sC5b-9, C3, factor H, factor I, and anti-CFH antibody) were performed at the University of Heidelberg, Germany.Results: During the study period, 65 patients with TMA were assessed. On clinical and laboratory grounds, 16 patients (25%) were diagnosed with aHUS. 15 patients underwent complement genetics studies and 10/15 (73%) had no disease causing mutations identified.Data on 5 patients with genetic abnormalities are summarized in Table 1. All patients were women, mean age 33 years. 4 patients (80%) had extra-renal manifestations. Mean PLT count nadir during acute episode was 40xE9/L. In most TMA episodes, therapeutic plasma exchange (TPE) resulted in a partial response (normalization/stabilization of thrombocytopenia and/or LD and/or creatinine) (Table 1). Due to limited access to eculizumab, the drug was not consistently used. 3 patients (2, 3 and 5) had low C3 and normal C4, a pattern classically described in aHUS. 4 patients underwent additional complement protein studies during acute episode (Table 2).Abstract 4186. Table 1Age, sexMutationTMA episodesRenal manifestationsExtrarenalmanifestationsOther medical conditionsTreatment of TMA episode and outcome120 Fpolymorphism vs. disease-causing mutation in CFH gene, c.3148A>T (p.Asn1050Tyr)1st and only episodePeak Cr 104Retinal hemorrhages, headache, hypertensive emergency, abdominal pain, elevated liver enzymesDyskeratosis congenita, alloBMTPartial response to TPEResponse to eculizumabDied of sepsis243 Funknown mutation in CFHR5 gene, c.1412G>A (p.Gly471Glu)1st episodeESRD, dialysisLiving related kidney transplant 8 yrs post 1st episodeCardiomyopathy, mitral regurgitationCrohn’s disasePartial response to TPENo renal recovery2nd episodeTMA recurrence in graft, ESRD, dialysisPulmonary hemorrhagePartial response to TPE, steroids, eculizumab (single dose)No renal recoveryMost recent follow-up: TMA free, on dialysis, awaiting 2nd transplant329 Fvariant of unknown significance in C3 gene, c.1685C>T (p.Ser562Leu) predicted to be benign1st and only episodeCr 650, Required hemodialysisCentral retinal artery occlusion, abdominal pain, effusions, seizures, hypertensive emergencyAdult Onset Still’s DiseasePartial response to TPEPartial response to Eculizumab (single dose) Most recent follow-up: TMA free, Cr 95433 Fdisease-causing mutation in CFHR5 gene, c.1135G>C (p.Val379Leu)1st episodeNot availableHypertensive emergencyPulmonary embolus, cardiac arrestBlood pressure control, improved2nd episodePeak Cr 345Hypertensive emergency, headache, small bowel ischemia, pancreatitis, effusionsPartial response to TPE Most recent follow-up: TMA free, Cr 89542 Fdisease-causing mutation in CFI gene, c.949C>T (p.Arg317Trp) and variant of unknown significance in C3 gene (c.193A>C p.Lys65Gln)1st episodePeak Cr 200HypertensionHypo-thyroidismComplete response to TPE, steroids2nd episodePeak Cr 700, dialysis not requiredComplete response to TPE, steroids3rd episodePeak Cr unknown, Dialysis requiredComplete response to TPE, steroids4th episodePeak Cr 533Partial response to TPE, steroidsHematologic response to Rituximab, splenectomyTMA free, Cr 175Started on eculizumab 1 year agoMost recent follow-up: TMA free, Cr 117Table 2CaseComplement protein and function studies1No abnormalities2Elevated AH50, sC5b-9Low C3, fH3Elevated sC5b-9Low C34Elevated AH505Not doneConclusions: 33% of patients diagnosed with aHUS had abnormalities detected on genetic studies. Extrarenal manifestations were common and, in most cases, TPE resulted in only a partial response. Only 3 patients had a classically described pattern of low C3 and normal C4. The utility of extensive complement protein studies requires further study. DisclosuresPavenski:Alexion Pharmaceuticals: Honoraria. Licht:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.