Turkish pediatric atypical hemolytic uremic syndrome registry: initial analysis of 146 patients

Here, we introduce one of the largest pediatric aHUS registries in the world. However, it is very well known that registries have its own limitations. In aHUS, many factors such as STEC, genetics, anti-factor H antibodies and follow-up data of the patients have to be taken into consideration to draw a certain conclusion. In this study, we performed longitudinal follow-ups of pediatric patients with aHUS to evaluate their clinical and genetic characteristics in order to better understand the diversity of this rare disease in the Turkish population. Owing to the low incidence of aHUS, majority of the previous series on aHUS have included both adult and pediatric patients [2, 16‐18] However, pediatric aHUS cases have different disease characteristics than those of adult cases. A study by Fremeaux-Bacchi et al. consisted of 214 patients, 89 of whom were pediatric patients. In this study, the characteristics of adult and pediatric patients were compared [2]. Another analysis of aHUS was from the global aHUS registry, which was supported by an industry sponsor. In that study, the baseline demographic and clinical characteristics of 516 patients with aHUS from 195 clinical centers in 16 countries were described. In that series, 201 patients were in the pediatric age group [16]. When compared with other established series, the Turkish aHUS registry has several distinctive features, namely its homogenous nature (i.e. it involves only Turkish patients with aHUS); availability of detailed data on patient demographics, initial clinical presentation, and the different treatments employed at the clinical centers; and availability of long-term follow-up and outcome data.

In our study, there were more female patients than male patients. While the mean patient age at diagnosis was comparable to the mean age of the population of the global aHUS registry, it was higher than the mean age of the population in the French registry (4.8 years vs. 1.5 years). Patients aged younger than 2 years accounted for 36.3% of the population in our study, which was significantly lower than the corresponding percentages reported in the global and French registries (43.9% and 56%, respectively) [2, 16]. A total of 28 patients (19.1%) in our study were aged under 1 year; the corresponding data are not available in the other registries. In our study, patients aged older than 12 years constituted 10.3% of all patients, whereas this figure was 6.5% in the global registry. All these discrepancies could be attributed to the different genetic abnormalities and/or environmental factors that the patients in the different populations were exposed to. It is well known that some genetic abnormalities are associated with early-onset aHUS whereas others can cause adolescent- or even adult-onset aHUS. One of the most striking findings in our study was the rather low percentage of patients with a family history of aHUS when compared to the global registry (4.8% vs 20.4%) despite a high rate of consanguinity in the Turkish population [16]. This was an unexpected finding and may be due to the fact that family history was not examined thoroughly by the reporting clinicians in our study. Alternatively, since the diagnosis of aHUS requires specific knowledge and expertise, aHUS among family members of the Turkish registry patients may not have been recognized if they did not undergo a specialist evaluation.

Extra-renal involvement in aHUS can significantly impact patient prognosis. Neurologic involvement is the most frequent complication, which can occur in 8–30% of the patients [10]. In our study, neurologic involvement was observed in 28.1% of the patients, which is consistent with the literature. The involvement of other organ systems is reported to be much lower than that of the central nervous system. Johnson et al. reported that the most common gastrointestinal manifestations were pancreatitis/pancreatic insufficiency and elevated transaminases, and they observed respiratory and cardiac involvement (i.e. heart failure/cardiomyopathy and pericardial effusion) in 21% and 5.6% of pediatric patients with aHUS, respectively [12]. In the current study, we observed that pancreatitis was one of the most common gastrointestinal system complications and that cardiac involvement occurred at a similar rate (6.1%), whereas respiratory involvement was slightly lower (6.8%).

Although we have limited data on genetics, the results of our study might provide a general idea of the underlying genetic abnormalities in Turkish patients with aHUS. It has recently been reported that 60–70% of patients with aHUS carry identifiable mutations in complement genes or anti-CFH antibodies, which result in TMA lesions [11]. In a multicenter audit analysis comprising 71 patients, 61% of the patients with results available for both complement genetic testing and anti CFH-autoantibody testing had evidence of alternative complement pathway dysregulation [12]. In our study population, genetic analyses were completed for the corresponding genes in 42 patients (37.1%). In this subset of patients, disease-causing mutations, 17 of which were novel, were identified in 34 patients (80.9%). This figure might indicate that the probability of detecting any mutation in already known genes is high in Turkish patients and, thereby, justifies the necessity of genetic screening for a long-term therapeutic plan. In previous studies, CFH mutations were the most commonly identified abnormalities [2, 18]. In contrast, we found that MCP mutations and C3 mutations were the most common genetic abnormalities whereas CFH mutations were detected in less than 10% of the genetically studied population. These initial results may confirm the racial differences between Turks and other populations. One of the limitations of our study was that we did not screen for thrombomodulin mutations, which have a minor role in aHUS [11].

Before the introduction of eculizumab, plasma therapy was the mainstay of treatment for aHUS, based on the premise that it was beneficial by supplying normal complement proteins and/or removing mutant proteins or autoantibodies [11, 12]. After the study published by Bell et al. in 1991, plasma-based therapies became the initial treatment for most patients with aHUS [19]. Noris et al. reported that two-third of adult patients with aHUS had a poor outcome after 3 years of follow-up [3]. In a study by Johnson et al. on aHUS treatment outcomes in 71 patients, 59 patients received plasma therapy and the other 12 patients received other types of treatment. Their results revealed that 17% of the patients remained dependent on dialysis and 80.3% of the patients had persistent renal sequelae at day 33 of treatment. The long-term results of plasma therapy were unavailable [12]. In our study, 12.1% of the patients were on dialysis at the time of discharge; after a median follow-up period of 1.7 years, 1 patient was still on dialysis and 1 patient had undergone renal transplantation. These differences in findings between our study and other studies may be attributed to the different genetic backgrounds of the studied populations. Plasma therapy (i.e. plasma infusions and/or plasma exchange) still appears to be a valid therapeutic option for Turkish patients with aHUS.

The introduction of eculizumab has profoundly changed the management of aHUS. The efficacy of eculizumab has been demonstrated in three prospective clinical trials performed primarily in adult patients with TMA [14, 20, 21]. In these trials, it was demonstrated that eculizumab resulted in a time-dependent improvement in patients with aHUS, and the beneficial effects were maintained after 2 years of follow-up. In children, the evidence for the efficacy of eculizumab came from case reports and retrospective studies [11, 22, 23]. Recently, Greenbaum et al. published the first pediatric prospective study that assessed the efficacy and safety of eculizumab in patients with aHUS who were aged <18 years. Mutations in the genes of the alternative complement pathway were identified in 50% of the patients [15]. MCP mutations were the most common; the mean duration of eculizumab treatment was 5.5 months, and hematological remission occurred in 82% of the patients. The authors reported that the mean improvement in eGFR from baseline to week 27 was 64 mL/min/1.73 m², and discontinuation of dialysis was possible in 82% of the patients who initially required renal replacement therapy [15]. In our study, 16 patients (15.5%) received eculizumab as a first-line therapy. Complete hematologic and renal remission was achieved in 82.2% and 76.3% of the patients, respectively. Our study as well as the study by Greenbaum et al. supported the efficacy of eculizumab in the acute period. However, there is ongoing debate on the appropriate duration and intervals for eculizumab treatment. Ardissino et al. reported findings from 10 patients who received eculizumab treatment, which was discontinued later. All of these patients had complement system dysregulation, and showed beneficial effects after being treated with eculizumab. After the eculizumab treatment was stopped, 3 patients relapsed within 6 weeks [24]. Later, the authors published results from a longer follow-up period. During a cumulative time off treatment of 243 months, 5 of the patients experienced relapse within 6 months of their last eculizumab dose [25]. In our patient cohort, eculizumab was discontinued in 52 patients for various reasons. The analyses of the genetic backgrounds and clinical outcomes of the patients are still underway and will be reported in detail in another manuscript.

Another noteworthy feature of our study is that we completed almost 2 years of patient follow-up. It has been previously reported that the mortality rate in children with aHUS was higher than that in adults, but the renal outcomes were worse in adults than in children [2]. In our study on pediatric patients, the mortality rate was 2% (3 out of 146 patients) during the acute stage, and 77.7% of the patients had a GFR >90 mL/min/1.73 m² during the follow-up period. Our results suggest that aHUS is a treatable disease and that progression to ESKD can be prevented with early diagnosis, and meticulous treatment and follow-up. However, it should be noted that in our patient cohort, high frequency of MCP mutations, lack of information on completed genetic data and early initiation of treatment may explain favorable outcome.