Atypical Hemolytic Uremic syndrome (aHUS) is a rare thrombotic microangiopathy that results from dysregulation of the complement system . We describe an adult patient, with plasma-exchange refractory aHUS and advanced renal failure, who was treated with eculizumab.
A 47-year-old female presented with several days of nausea, vomiting, and malaise. Her evaluation revealed acute renal failure, anemia, thrombocytopenia, elevated LDH, and schistocytes on peripheral blood smear. Renal biopsy demonstrated findings consistent with thrombotic microangiopathy. ADAMTS13 activity level was greater than 50%. After several days of therapeutic plasma exchange (TPE), her creatinine stabilized, and her LDH and platelet count improved. However, 2 weeks later, she developed a worsening thrombocytopenia that did not improve with the resumption of daily TPE. Her renal failure progressed; her creatinine rose to 6.9 mg/dL, and she developed volume overload and hypertension. Her microangiopathic findings, thrombocytopenia, normal ADAMTS13 activity level, and isolated renal pathology were clinically consistent with aHUS, so a genetic analysis to evaluate the mutational status of the commonly-implicated complement was ordered.
After the presumptive diagnosis of aHUS, the patient was treated with eculizumab. Shortly after her first infusion of 900 mg, her renal function stabilized, and she avoided hemodialysis (Table I). Treatment was well tolerated, with no infusion-related or infectious complications. She was discharged home and continued receiving weekly infusions of eculizumab (900 mg). After her fourth weekly infusion, she was transitioned to a maintenance dose of 1200 mg every 2 weeks. Her creatinine has continued to trend down to 2.7 mg/dL on this treatment. Three months after starting eculizumab, her complement studies confirmed a mutant allele for complement Factor I consistent with the diagnosis of aHUS. 108:
|Days relative to first eculizumab infusion||−18||−7||−1||0||1||2||3||7||14||21||35||49|
|Platelet Count K/uL||181||70||114||144||170||163||129||84||100||99||116||221|
Patients with aHUS have deficiencies of regulatory complement proteins that allow constitutive activation of the complement cascade within the glomerular capillary bed, leading to thrombotic microangiopathy and renal failure . The glomerular capillary bed is particularly susceptible to complement attack and thrombotic microangiopathy, possibly due to its fenestrated endothelium that continually exposes the subendothelial matrix to circulating complement proteins .
While many patients present in infancy or childhood, some become symptomatic in adulthood . This variable age of onset relates to incomplete penetrance of the genetic abnormalities, likely due to a complex interaction between genetic factors, environment, medications, and potential infectious triggers . The prognosis is poor, with 60–80% of patients progressing to end-stage renal disease or death . Additionally, the disease frequently relapses following renal transplantation , so strategies to improve outcome in patients with aHUS are needed. Eculizumab, a monoclonal antibody specific for the C5 complement protein , is FDA-approved for the treatment of PNH and has been reported to slow the progression of aHUS [3, 4]. It blocks activation of C5 , thereby preventing the production of the terminal membrane attack complex that ultimately leads to a thrombotic microangiopathy.
Thus far, there are few accounts documenting the efficacy of eculizumab in aHUS [3, 4]. Two case reports describe favorable outcomes [3, 4]. In each of these cases, the disease was identified early, and treatment was initiated, whereas creatinine was only mildly elevated at 1 and 1.5 mg/dL, respectively [3, 4].
Our patient was treated further into her disease course after she had already sustained severe renal damage. The outcome of this case is important because it demonstrates that complement inhibition with eculizumab may still be effective even if severe renal dysfunction is already present. Additionally, to our knowledge, this is the first reported case of an adult with plasma exchange-refractory aHUS that was managed successfully with eculizumab.
In patients with a high clinical suspicion for aHUS, therapy should not be withheld pending the results of genetic studies to confirm the diagnosis of aHUS given the potential for eculizumab to improve outcome. This case suggests that eculizumab may prevent progression to ESRD in patients with a presumed diagnosis of aHUS. A study of eculizumab in adult patients with aHUS has been completed, and we await the results of this trial. Future studies will also be required to determine if successfully treated patients will require indefinite prophylactic therapy to prevent recurrences of aHUS and progression to ESRD.