Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome

A severely ill 1-year-old Caucasian girl with a several-day history of vomiting and refusal to eat presented on 31 December 2008 with hemolytic anemia, thrombocytopenia, acute renal insufficiency, and intussusception. Schistocytes on peripheral blood film, elevated lactate dehydrogenase (LDH) 2674 U/l (normal range: 216–360 U/l), decreased platelets 108 × 10⁹/l (normal range: 150–350 × 10⁹/l), elevated creatinine 221 μmol/l (normal range: 35–55 μmol/l) and urea 234 mg/dl (normal range: 7–21 mg/dl), and reduced hemoglobin (Hb) 6.5 mg/dl (normal range: 10–14 mg/dl) and albumin 2.76 g/dl (normal range: 3.5–5.5 g/dl) were detected. Activity of ADAMTS-13 (Von Willebrand factor-cleaving protease) was within the normal range (83 %), thus excluding thrombotic thrombocytopenic purpura (TTP) [7]. Complement levels were within the normal range: C3, 94 mg/dl (normal range: 85–120 mg/dl); C4, 16 mg/dl (normal range: 15–40 mg/dl). As stool cultures for Shigella, Salmonella, Yersinia, and Candida were all negative, she was diagnosed with aHUS. Initial management comprised multiple blood transfusions, intensive plasma exchange (2–3 sessions per week), and hemodialysis. These interventions initially improved diuresis, the patient’s creatinine decreasing to a minimum of 94 μmol/l, but she continued to be hospitalized, to need repeated blood transfusions, have severe proteinuria (233 mg/dl), and suffer from hypertension (blood pressure increasing to 128/95 mmHg in the days following presentation) and edema. During the following weeks, she also suffered multiple catheter infections and had to maintain a nasogastric tube for feeding. Overall, the clinical status of the patient further deteriorated, presenting 17 February 2009 with acute renal insufficiency, severe anemia, macroscopic hematuria, proteinuria, arterial hypertension, and dilated cardiomyopathy. Laboratory values showed decreased platelet count (132 × 10⁹/l), an elevated LDH of 1740 U/l and continued anemia (Hb 7.1 mg/dl), and elevated serum creatinine (187 μmol/l). The child also experienced cardiorespiratory arrest requiring cardiopulmonary resuscitation and mechanical ventilation. Genetic analysis revealed a mutation in the C-terminal region of complement factor H (CFH) (a novel heterozygous mutation; 3355 G>A; Asp1119Asn; SCR19), with normal membrane cofactor protein (MCP) and Factor I, and no CFH autoantibodies. PE (fresh–frozen plasma, 2–3 times per week) was continued for the next 3 months, with blood transfusions given as required. The patient’s anti-hypertensive therapy (hydralazine, nifedipine, labetalol, and urapidil) was also continued (Fig. 1). She experienced pulmonary edema in March and again in May. Myocardial dysfunction was diagnosed and an ejection fraction of 32 % (normal values: 56–78 %) was measured in May. Due to concerns that this was caused by fluid overload from PE, PE and hemodialysis were tapered. This led to an improvement in renal function, but she continued to receive antihypertensive treatment and multiple blood transfusions (Fig. 1).

In July, when the patient presented again with cardiac dysfunction and an ejection fraction of 31 %, with moderately controlled blood pressure (100/85) and not managed with PE, the decision was made to initiate treatment with eculizumab; she received one 600-mg eculizumab infusion (at this time, the patient was vaccinated against Neisseria meningococcus serotypes A and Cm, and antibiotic prophylaxis with penicillin was provided). Eculizumab treatment led to normalization of renal and ventricular function, stabilization of hematologic parameters, and blockade of terminal complement activity (Fig. 1).

As the eculizumab dose was not repeated, and terminal complement blockade not maintained, TMA complications were seen again after 8 weeks (mid-September 2009), when the patient presented with renal insufficiency (creatinine, 141 μmol/l) and evidence of hemolysis and platelet consumption (LDH, 760 U/l; platelet count, 151 × 10⁹/l). Chronic eculizumab treatment was initiated following the recommended dosing by weight (5–10 kg) (Soliris® SmPC): initial dose 600 mg, followed by 300 mg every 2–3 weeks. At this time, the patient’s antihypertensive treatment was stopped. Creatinine started to improve prior to eculizumab initiation but levels normalized after 6 days of resuming eculizumab treatment (Fig. 1) and cardiac function improved. LDH levels stabilized but remained elevated (Fig. 1); the complement activity assay showed immediate, sustained blockade of terminal complement activation; and platelet counts remained within the normal range (Fig. 1). The elevated LDH was not the result of anemia, as Hb levels were normal (10 mg/dl) and no schistocytes were seen, with no further need for RBC transfusions.

At last follow-up visit (14 November 2011; >2.5 years since admission), the patient remained on chronic eculizumab treatment; no new clinical complications of TMA have occurred while receiving treatment, and no blood transfusion, plasma exchange, or hemodialysis has been necessary. Serum creatinine is 26.5 μmol/l, and serum protein 34 mg/dl, equivalent to 12 mg/m²/h. No further indication of hypertension or cardiac insufficiency has been noted and her ejection fraction has been normalized (64–70 %). The patient has gained 6 kg of weight and her overall health has improved and normalized entirely. She shows a completely normal development and full recovery of a good quality of life as reported by her parents.

During the >2.5-year period of chronic eculizumab treatment, measurements of complement activity have shown complete terminal complement blockade, which corroborate the clinical data of no manifestations of TMA (Fig. 1).