Atypical hemolytic uremic syndrome: Unique clinical presentation linked to rare CFHR5 mutation

To The Editor, In adults, the diagnosis and the clinical management of atypical hemolytic uremic syndrome is still a challenge for hematologists [1–3]. Here, we report a case of a 40-year-old previously healthy man presented to the emergency department with fever (39.6C) and bilateral persistent foot pain. He has been 2 days earlier by his primary care doctor due to lower extremities pain and a sensation of low body temperature during physical activity. At admission, he was found diaphoretic, apyretic (reported paracetamol intake at home), tachycardic,withmarbled lower limbs and lack of sensitivity in both feet. The patient’s historywas negative for recurrent infections, kidney diseases, immune-rheumatological, or cardiovascular disorders. He smoked 20 cigarettes/day. Chest X-ray showed a small pleural effusion in the lower left lobe, and ECG sinus tachycardia. Several blood test could not be performed due to marker hemolysis. Arterial blood gases were indicative of compensated metabolic acidosis (Table 1; Figure 1A). Therapy consisted of hydration, in conjunction with antibiotic and antifungal therapy (clarithromycin, piperacilline-tazobactam and isavucona-

This was associated with increased total bilirubin 2.4 mg/dl, LDH and reduced haptoglobin (Table 1, Figure 1A). An elevated serum creatinine (3.96 mg/dl) was accompanied by biochemical signs of inflammation (CRP: 127 mg/L, PCT: 64.8 ng/ml) and coagulopathy (Table 1 can be simultaneously present and are of difficult distinction in critically ill patients [4][5][6]. Twelve hours after admission, the patient was tachycardic (135 beats/min) but stable, hemodynamically. He showed a severe compensated lactic metabolic acidosis with hypocapnia with tachypnea, patient became anuric despite intravenous fluid therapy and use of diuretics. A Retiform purpura appeared on the lower limbs, while one with confluent petechiae appeared on the upper limbs and face. Dysaesthesia and paraesthesia were reported in the lower limbs (distal feet and third leg) and hands ( Figure 1A,B). A chest CT showed bilateral pleural effusion with a left > right bi-basal compressive atelectasis, and ground glass lesions bilaterally in the medium and superior fields; an abdomen CT showed swollen kidneys bilaterally with no vascularization of the cortical area and enhancement within the limits of the norm in the medullary area ( Figure 1C).
Repeated CBC and biochemical studies showed severe hemolytic anemia, and thrombocytopenia associated with increased LDH.
Continuous renal replacement therapy (CRRT) was also introduced because of persistent anuria. An OXIRIS filter (Baxter) was used to remove cytokines. The patient was intubated because of the deterioration of the gas exchange and transfused with both packed red cells and platelets ( Figure 1A). A total of four PEX (on day 4, 5, 6, and 8) were performed, and eculizumab was administered on day 4 (300 mg adjusted dose after PEX), day 6 (900 mg), day 8 (300 mg), day 16 (900 mg), and day 28 (1200 mg; Figure 1A)  Figure 1C). Early diagnosis of aHUS with PEX and eculizumab therapies resulted in a rapid hematologic remission, resolution of neurologic symptoms and improvement of the renal function as typically observed [5,8]. Indeed, studies in patients with complementmediated HUS have shown that eculizumab reduces both mortality and acquired end-stage kidney disease [9][10][11].
Four to five months after hospital discharge, patient had recovered to a G4 chronic kidney disease stage (creatinine 3.5 mg/dl, eGFR 20 ml/min/1.73m 2 , K + 5.4 mmol/L), and hemodialysis was discontinued. Bilateral below knee amputations were carried out. Eculizumab they achieved resolution of TMA using eculizumab [9].
The rare missense variant c1541T → G on CFHR5 gene that is characterized by the aminoacid change p.Met514Arg is predicted to be pathogenic from 10 of 11 bioinformatics prediction systems (CADD 22.1). Although the c5141T → G CFHR5 variant has been described in patients with aHUS, it is also present in the healthy control database [12]. Thus, the clinical significance of c1541T → G CFHR5 variant is currently considered uncertain/unknown (VUS). Although VUS-variants are not self-sufficient to determine pathology, they might increase patient susceptibility to aHUS in association with other genetic and/or environmental factors [13]. Different studies have shown that mutations on CFHR genes are related to aHUS as well as to C3 glomerulopathy [1,14]. Noteworthy, growing evidence indicate a role of FHR proteins as modulators/amplifiers of complement activity [1,14]. The mutations on CFHR5 have been reported in patients with aHUS, C3 glomerulopathy, and S. pneumoniae infection [1,14]. In our case, the c1541T → G on CFHR5 mutation might have favored an exaggerated and sustained activation of the alternative complement pathway triggered by S. pneumoniae infection. The excellent clinical recovery after PEX and eculizumab treatment combined with antibiotics reinforces our hypothesis.
Recently, Fakhouri and Fremeaux-Bacchi have reported that aHUS related to rare variants on genes encoding for proteins involved in complement regulation are associated with the increased risk of relapse when eculizumab treatment is withdrawn [1]. However, in patients with aHUS in remission, discontinuation of eculizumab treatment should be considered as a concrete option, requiring a closed follow-up. Indeed, the pros and cons for eculizumab discontinuation in this setting are in favor of discontinuation to limit disease cost and to beneficially impact patient quality of life.