Hemolytic and uremic syndrome (HUS) is a clinic-biological syndrome related to thrombotic microangiopathy affecting predominantly the kidney. Atypical HUS (aHUS) has been historically defined as HUS occurring in the absence of infectious event. The role of complement dysregulation in aHUS pathophysiology has been largely demonstrated, since C genetic rare variants are present in 60-70% aHUS patients. In line with the frequency of C dysregulation in aHUS, Eculizumab, an anti-C5 monoclonal antibody, has dramatically improved aHUS patients prognosis.

Numerous conditions have been associated with aHUS, including hypertensive emergency (HE), a syndrome of acute blood pressure flare associated with end-organ damage. In cases of HE-aHUS, whether primary aHUS is complicated by secondary HE, or primary HE leads to secondary aHUS is still debated.

The investigators recently demonstrated that C genetic variants frequency was similar in patients with HE-aHUS and patients with aHUS without HE, suggesting a major role for C dysregulation in HE-aHUS. Consequently, the investigators propose to evaluate, in HE-aHUS patients, the benefit of a strategy with early Eculizumab therapy (used within its marketing authorization and its conditions of refunding by the health insurance in usual care), compared to standard of care including tight blood pressure control.

The hypothesis suggests that C dysregulation may impact renal prognosis of HE-aHUS patients. The investigator's aim to demonstrate that early Eculizumab therapy improves prognosis of HE-aHUS patients.

Method

The HYPERSHU study is a randomized, controlled, open-labelled study including HE-aHUS patients with severe AKI and no evidence of other conditions associated with HUS (infections, autoimmunity, drugs, pregnancy). The investigators plan to include 62 patients. Patients will be randomized in 2 arms:

• Early Eculizumab therapy (for 3 months) added to standard of care (tight blood pressure control).
• Standard of care alone with tight blood pressure control. Renal function after 6 months is the primary evaluation criterium.

HE is a frequently associated with aHUS, and strongly impacts patient renal prognosis. Efficient therapeutic strategies are still lacking for this condition. The HYPERSHU study will allow to evaluate the benefit of early Eculizumab therapy in patients with HE-aHUS and severe renal dysfunction.

Inclusion Criteria:

• ≥ 18years

• Hospitalization for HE-aHUS within prior 10 days:

  • Presume acute renal failure (renal replacement therapy or serum creatinine ≥ 354µM)
  • Mechanical hemolysis including: anemia, thrombopenia, and: low haptoglobin (<LNL), or elevated LDH (>1,5UNL), or presence of schistocytes
  • Severe hypertension with systolic blood pressure >180mmHg or diastolic blood pressure>110mmHg
  • Target organ damage, including neurological involvement (notably hypertensive encephalopathy, headache, confusion, nausea, posterior reversible encephalopathy syndrome), or cardiovascular involvement (notably acute left ventricular failure, acute pulmonary edema, acute cardiac ischemia, chest pain, dyspnea, palpitations), or ophtalmological involvement (notably ischemic retinopathy or blurred vision)

• Effective contraception during the study and for at least 5 months after the last dose of treatment with eculizumab

• Subject affiliated to a social security regimen

• Subject having signed written informed consent.

Exclusion Criteria:

• Atrophic kidneys with maximum length<8cm on recent (<1 month) renal ultrasound, CT scan, or renal MRI
• High clinical suspicion of Complement-mediated aHUS (including familial history of aHUS)
• High clinical suspicion of typical HUS (including Shiga Toxin-producing E. Coli infection) or Thrombotic thrombocytopenic purpura
• High clinical suspicion of secondary HUS related to autoimmune disease (including lupus, scleroderma, antiphospholipid syndrome, ANCA vasculitis), or C3 glomerulopathy.
• High clinical suspicion of recent hemorrhagic or ischemic stroke.
• ADAMTS 13<10%, HIV or HCV infection, positivity of 2 markers among: anticardiolipin IgG/antiBeta2 GP1 IgG/lupus anticoagulant, positivity of ANCA (ELISA PR3 or MPO)
• Active infection
• Subjects with unresolved Neisseria meningitidis infection
• Subjects refusing Neisseria meningitidis vaccination or refusing antibioprophylaxis with oracillin (In case of penicillin allergy, antibioprophylaxis with macrolide couldbeproposed according to ANSM recommendations (azithromycin or roxithromycin)).
• Contra-indication to eculizumab or renin angiotensin system blockers
• Solid organ or haematopoietic transplant
• History (<1year) of active cancer or exposition to drugs associated with aHUS (< 3 months)
• Severe cognitive or psychiatric disorders, patients unable to give an informed consent.
• PCR SARS-CoV2 positive
• Pregnant or breastfeeding woman or ineffective contraception
• Persons deprived of their liberty by judicial or administrative decision,
• Persons under legal protection (guardianship, curatorship)
• Participation in another interventional study involving human participants or being in the exclusion period at the end of a previous study involving human participants.

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