Data on CFH, CFI, MCP, CFB, and C3 mutation characteristics are reported in Table 1. Data on patient characteristics at presentation, treatment, and clinical outcome for each type of mutation are reported in Tables 2, 3, 4. Due to the small number of patients per mutated complement protein, data were analyzed descriptively without statistical comparisons. Clinical data on the four patients with a combined mutation or a mutation in combination with a homozygous deletion in CFHR1/3 and αFH are given in Table 5. Forty-five patients diagnosed with aHUS from six different university medical centers in The Netherlands and one in Belgium were included. Approximately as many males as females were included in this study.
In 20 of the 45 patients (44%) heterozygous mutations in complement regulating genes and/or autoantibodies against CFH were found, all but one with a homozygous deletion in CFHR1/3 (Table 1). Five patients (overall 11%) carried a mutation in CFH, four (overall 9%) in MCP and also four in C3 (overall 9%). Three patients (overall 7%) had a mutation in CFI and two (overall 4%) in CFB. Six patients (overall 13%) had autoantibodies against CFH. Two of these patients with a genetic anomaly carried a combined mutation (CFI/MCP and CFI/C3). One patient had a CFI mutation and αFH with ∆CFHR1/3, and in one patient αFH were seen in combination with a C3 mutation but without ∆CFHR1/3. Patients with combined mutations are included in both their mutation groups in Tables 2, 3, 4. Characteristics at onset, treatment, and outcome of the four patients with combined genetic anomalies are also summarized separately (Table 5). No mutations in THBD were found in our cohort.
Familial vs sporadic
Eleven patients (24%) had familial aHUS, of whom all except two had an associated mutation. We included one family with three sisters with a CFH mutation and another family with two cousins with a mutation in CFB. Of the other six patients with familial aHUS, only one family member was included in this study because further data were not available. All four patients in this study with a C3 mutation have familial aHUS. Sporadic aHUS was seen in all four patients with MCP mutation and all five patients with αFH and ∆CFHR1/3.
In ten patients (22%), aHUS onset was before 1 year of age, with the youngest patient being only 1 month old. In only one of these patients was a mutation found (C3/αFH), and only two patients had familial aHUS. The majority of aHUS patients (53%) presented between the age of 1 and 7 years, which is also the most common age for children with typical HUS to present with the disease, which suggests that age at onset cannot always help distinguish between typical and aHUS. In 38/45 patients aHUS onset followed a triggering event, such as gastrointestinal symptoms (74%), upper respiratory tract infection (45%), and fever (32%). A combination of triggering events was seen as well; for instance, vomiting and fever were seen in 8/45 patients. Diarrhea was seen in 11 patients, five of whom also had fever. One patient developed aHUS a few days after a hepatitis B vaccination, and one patient was positively tested for a Bordetella pertussis infection a few days before aHUS onset. Other triggers were infection with Haemophilus influenza (n = 1) and a streptococcal infection (n = 1).
Hypertension (blood pressure >95th percentile for age) was present at first presentation in 71% of patients. Six patients had involvement of the central nervous system due to malignant hypertension or cerebral infarction during their first aHUS flare. Two of these patients had a mutation (C3 and CFB) and one patient had αFH with ∆CFHR1/3. These three patients had severe seizures; the other three patients were extremely agitated or had reduced consciousness. One patient had additional visual handicap, and one showed apraxia and aphasia. Pancreas involvement during the first episode was seen in only two patients, both without a genetic defect. In 18 of the 37 patients (49%) for whom data were available, biochemical evaluation showed reduced C3 levels (minimum 210 mg/l, reference range 900–1,800 mg/l). Four of these patients had a mutation (2xCFB, 1xCFI, 1xC3), and four had αFH, of which three also had ∆CFHR1/3. Low C3 levels were always linked with high levels of the activation product C3d. However, we also found elevated levels of C3d in six patients with normal levels of C3. Of the 25 genetically undefined patients, 11 showed reduced C3 levels, and in seven, elevated levels of C3d were found, showing evidence of alternative pathway activation. Remarkably reduced C4 levels were seen in six of the 31 tested patients (19%), with an extreme lowest level of 30 mg/l (reference range 150–400 mg/l). A systemic disease, such as systemic lupus erythamatosis (SLE) or cryoglobulinemia as cause of these low C4 levels was ruled out because of the clinical and laboratory results combined with medical history. One of these patients had a CFH mutation.
Treatment and outcome of first episode
The majority of patients (60%) were treated with plasma therapy, including plasma infusion (PI) and/or plasma exchange (PE) (Table 2). Plasma therapy was applied in 12 patients with a genetic defect vs 15 patients without a known genetic anomaly. In 11 patients, plasma therapy was combined with dialysis. Nine patients were treated conservatively, three of whom had a genetic defect (1xC3, 1xMCP, 1xαFH with ∆CFHR1/3). In only 3/20 patients (15%) with a genetic defect (2xCFH, 1xMCP) was complete remission reached after the first episode, compared with 9/24 patients (38%) in the other group. One of these patients (CFH mutation) was treated with plasma therapy (four infusions with fresh frozen plasma), one with dialysis (CFH mutation), and one patient recovered spontaneously (mutation in MCP). All other patients with a genetic anomaly reached partial remission after the first flare. Of the nine patients without plasma therapy or dialysis, only three reached complete remission (1xMCP, 2xno genetic anomaly).
Chronic plasma therapy and/or dialysis was applied more often in the group with than in the group without a genetic defect (40% vs 30%). One patient died during the first aHUS episode due to consequences of the disease. This was the youngest patient in the study, only 1 month old. A genetic defect in complement proteins was not found in this patient.
Almost half of the aHUS patients (n = 21) had a relapse (Table 3). In the group with a genetic anomaly, 13/20 (65%) of patients relapsed. In the group without known anomalies, relapse occurred in only 8/25 (32%) patients. A total of 43 relapses was seen, of which 29 (67%) occurred in patients with any of the genetic subtypes. A maximum of five relapses was seen in one patient with αFH and ∆CFHR1/3. Of all patients with a relapse, 38% had familial aHUS. Most relapses occurred after a viral infection, usually of the upper respiratory tract. Time between aHUS onset and the first relapse varied widely, from 1 month after remission to a maximum of 8.5 years. In 9/21 patients, aHUS relapsed within 1 year, five had a genetic defect (1xCFH, 1xMCP, 1xC3/CFI, and 2xαFH with ∆CFHR1/3). Ten patients with a relapse were initially treated with plasma therapy, eight of whom received chronic plasma therapy. In most patients, plasma therapy was intensified during the relapse.
In 54% of patients, chronic hypertension was seen after the first flare; in 47%, proteinuria sustained. Most of these patients had to be treated for several months with antihypertensive agents. In four patients, neurological involvement was seen later during the course of disease. Two of these patients presented with seizures due to malignant hypertension (MCP and C3/CFI); one patient without a genetic defect had reduced consciousness [computed tomography (CT) scan showed no abnormalities], and one patient had dysphasia and sensibility disorders due to an arteria cerebralis media stenosis (CFH). Another patient developed necrotizing pancreatitis with transient diabetes mellitus 10 years after first presentation, for which a partial pancreatectomy was performed. No mutation or deletion was found in this patient.
Seven patients (2xCFH, 1xMCP, 1xC3/CFI, and three without a known genetic defect) received a total number of 13 renal transplants, but in 10/13 grafts, aHUS recurred. Three of these patients had familial aHUS. No recurrence was seen in patient with MCP mutation. Time between transplantation and first relapse in renal graft patients varied between 6 days and 4 years. Additionally, one graft was lost due to arteria renalis thrombosis 1 day after transplantation; one graft was lost due to rejection after 4 years. One patient died during the acute phase of aHUS. Three other patients died later during the course of disease. One patient with no genetic defect died 9 years after onset because of massive cerebral bleeding due to malignant hypertension. Another patient with an MCP mutation, who had no recurrence of aHUS in the renal transplant, developed pulmonary veno-occlusive disease (PVOD), which led eventually to the finding of an inborn error of cobalamin metabolism, and he died 7.5 years after his first presentation . The last patient died 12 years after aHUS onset but not due to the consequences of aHUS.