Medication Summary
Supportive care remains the mainstay of therapy for Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) and is very important in atypical hemolytic-uremic syndrome (aHUS) as well. Medications such as antihypertensives, diuretics, anticonvulsants, and analgesics are indicated to treat specific symptoms or complications of hemolytic-uremic syndrome. These medications have not been demonstrated to alter the disease process.
Complement C5 inhibitors
The development of the complement inhibitors eculizumab and ravulizumab has changed dramatically the treatment of aHUS. Both are humanized monoclonal antibodies that bind to complement C5, preventing its cleavage to C5a and C5b. This, in turn, prevents assembly of the membrane attack complex, also referred to as C5b-9 (because it is composed of C5b, C6, C7, C8 and C9.) Eculizumab, approved by the US Food and Drug Administration (FDA) in September 2011, was the first specific, disease-modifying therapy for aHUS. Ravulizumab, approved in 2018, is technically classified as a biosimilar variant of eculizumab. The main difference is that ravulizumab has a longer duration of action, generally requiring less frequent infusions. Dosing in pediatric patients is based on weight. Individualized dosing based on disease measures, biomarkers, and individual pharmacokinetics is being studied. [28] Both drugs specifically state on their labels that they are not indicated for STEC-HUS. In addition, they should not be used for pneumococcal-associated HUS, since they inhibit complement activation, which is of particular importance in fighting infections with encapsulated organisms such as S pneumoniae.
Duration of complement-inhibiting therapy
Complement-inhibiting therapies are generally continued for an extended duration: months, years, or even lifelong, particularly in patients with known complement mutations or inhibitors. When to discontinue these drugs, if at all, has been a subject of much interest. The benefits of cost savings and reduced risk of infections must be balanced against the risk of recurrence of aHUS, with associated complications such as renal failure.
In a retrospective study of 38 adult and pediatric patients who discontinued eculizumab, none of the patients with normal genetic studies relapsed over a median follow-up period of 22 months. Among patients with a known genetic variant in a complement gene, 31% relapsed after discontinuing therapy. [29] In another retrospective study of pediatric patients, eculizumab was withdrawn in 18 patients with no known complement mutations; 4 relapsed, all of whom returned to remission and recovered renal function after restarting eculizumab. [30] A subsequent prospective study of 55 adult and pediatric patients who discontinued eculizumab showed similar results. Eleven of the 13 patients who relapsed after discontinuation had a complement mutation. Importantly, all of the relapsing patients experienced acute kidney injury; one required dialysis; and two had worsening of their preexisting chronic kidney disease, including one who progressed to end-stage renal disease. The remaining patients returned to their baseline level of renal function. [31] The authors conclude that discontinuation of eculizumab is feasible and safe in patients with no known complement mutation. Similar studies regarding ravulizumab withdrawal have not been reported.
In summary, preliminary data suggest that withdrawal of complement inhibition may be reasonable in patients with no known gene mutations and possibly other favorable risk factors, provided that careful monitoring is in place, and therapy can be promptly resumed in the event of a relapse. However, the long-term risk of relapses and other late complications in untreated patients remains unknown. Episodes of acute kidney injury in general (not specifically due to HUS), even if the patient has fully recovered, are associated with a higher risk of chronic kidney disease. These issues should be discussed, and patients should be engaged in decisions regarding withdrawal of therapy.
Neisseria meningitidis prophylaxis while on complement inhibition
Eculizumab and ravulizumab have been associated with life-threatening infections with the encapsulated organism Neisseria meningitidis. Ideally, patients should be vaccinated against meningococcus at least 2 weeks before starting complement inhibitors. Such a delay in therapy would be highly undesirable in acutely ill patients. Therefore, unvaccinated patients may receive initial meningococcal vaccination at the time of starting therapy, with antibiotic prophylaxis for at least 2 weeks to allow time for immunity to develop. Importantly, breakthrough meningococcal infections have been observed in fully vaccinated patients [32] ; a Centers for Disease Control and Prevention publication recommends considering continued meningococcal prophylaxis for the entire duration of treatment with complement inhibition. The Advisory Committee on Immunization Practices (ACIP) recommends that patients treated with complement inhibitors receive both serogroup B meningococcal vaccine (MenB) and quadrivalent meningococcal conjugate vaccine (MenACWY). [33] In the United States, eculizumab and ravulizumab can be prescribed only by providers who are enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program.
Conversion from eculizumab to ravulizumab
Pediatric patients maintained on eculizumab may change to ravulizumab. [34] Conversion is based on the previous dose of eculizumab and is detailed on the ravulizumab product label. The main advantage to conversion is reduced frequency of infusions (depending on patient weight, as often as every 8 weeks versus every 2 weeks for eculizumab). The reduced frequency may also reduce costs. A cost-minimization analysis modeling study showed lifetime cost reductions of 32.4-35.5% for ravulizumab compared with eculizumab. [35]
Other medications
Unfortunately, several other agents that in theory should ameliorate hemolytic-uremic syndrome have failed to do so in clinical trials. These include thrombolytic agents (eg, heparin, urokinase), platelet inhibitors (eg, aspirin, dipyridamole), and a Shiga toxin (Stx)–binding agent (ie, Synsorb-Pk). Current evidence does not support use of these medications.
Corticosteroids are not useful in STEC-HUS. They may be of value in aHUS if the patient has an autoimmune-produced inhibitor of ADAMTS13.
Limited case reports describe using intravenous immune globulin (IVIG) in patients with aHUS associated with organ transplantation. IVIG does not have a role in hereditary aHUS nor in STEC-HUS.
Studies have shown that antibiotics given to patients with diarrhea due to E coli 0157:H7 increase the risk of developing hemolytic-uremic syndrome. [36] A theory proposed to explain this finding is that antibiotic therapy causes rapid large-scale bacterial lysis with massive release of Stx, overwhelming host defense mechanisms. Whether antibiotics affect the course of established hemolytic-uremic syndrome remains unknown. Patients with E coli 0157 colitis usually clear the infection spontaneously.
Most pediatric nephrologists do not routinely use antibiotics in patients with STEC-HUS, based on a theoretical concern it could exacerbate the disease process. [37] However, antibiotics should be used when indicated according to clinical judgment. Examples include patients having suspected or documented bacteremia, urinary tract infection, or sepsis.
Monoclonal Antibodies, Endocrine
Class Summary
Eculizumab and ravulizumab are monoclonal antibodies indicated for atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy; effectiveness is based on the effects on thrombotic microangiopathy and renal function.
Eculizumab (Soliris)
Eculizumab is a monoclonal blocking antibody to complement protein C5; it inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis. It inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy in patients with aHUS.
Ravulizumab (Ravulizumab-cwvz, Ultomiris)
Ravulizumab is a monoclonal blocking antibody to complement protein C5; it inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis. It inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy in patients with aHUS.
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Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.
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Micrograph of a glomerulus in hemolytic-uremic syndrome, showing thrombi and red blood cell fragments in the capillary space. Courtesy of Xin J (Joseph) Zhou, MD, Renal Path Diagnostics, Pathologists BioMedical Labs.
