Atypical hemolytic-uremic syndrome (aHUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy (TMA). Renal involvement and progression to end-stage renal disease are common in untreated patients. We report a 52-year-old female patient who presented with severe acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. She was managed with steroid, plasma exchange, and dialysis. Kidney biopsy shows TMA and renal cortical necrosis. Genetic analysis reveals heterozygous complement factor I (CFI) mutation. Eculizumab was initiated after 3 mo of presentation, continued for 9 mo, and stopped because of sustained hematologic remission, steady renal function, and cost issues. Despite this, the patient continued to be in hematologic remission and showed signs of renal recovery, and peritoneal dialysis was stopped 32 mo after initiation. We report a case of aHUS due to CFI mutation, which, to the best of our knowledge, has not been reported before in Saudi Arabia. Our case illustrates the challenges related to the diagnosis and management of this condition, in which a high index of suspicion and prompt treatment are usually necessary.

Thrombotic microangiopathy (TMA) is a life-threatening syndrome characterized by systemic microvascular occlusions, thrombocytopenia, microangiopathic hemolytic anemia, and renal or other end-organ damage[1,2]. TMA may complicate several conditions, such as systemic infections, cancer, pregnancy complications, autoimmune diseases, organ transplantation, and severe hypertension[1].

Atypical hemolytic-uremic syndrome (aHUS) is a rare, progressive, life-threatening form of TMA caused by a disorder in complement regulation, predominantly dysregulation of the complement alternative pathway[3,4]. The undelaying pathogenesis is complement gene mutations in the majority of patients and antibodies to complement factor H (CFH) in a smaller subset of patients (approximately 6%)[5-7]. Several cases of aHUS had been reported at different age groups in association with mutations of genes for complement factor H (CFH)[8-10], membrane co-factor protein (MCP)[8,11], and complement factor I (CFI)[8,12,13]. The most frequent mutation detected involves CFH (approximately 30%), then MCP (approximately 10%), and lastly CFI (approximately 5%)[12]. Although approximately 80% of patients present acutely with thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment[14,15], the onset may be more gradual in other patients[16]. Because of systemic vascular involvement[17], extrarenal manifestations occur in up to 48% of patients, with frequent neurologic and cardiovascular involvement[6,18-20].

Untreated aHUS has been linked to high morbidity and mortality, with a 33%-40% risk of progression to end-stage renal disease (ESRD) or death during the first clinical manifestation[6]. Patients treated with plasma exchange remains to have a poor pro-gnosis, with up to 65% experiencing permanent renal damage, ESRD progression, or death within 1 year of diagnosis[8].

The understanding of the disease pathogenesis, which involves activation of alternative complement pathway, resulting in the formation of membrane attack complex (MAC) C5b-9[3], had contributed to the advances in treatment, which is eculizumab, a monoclonal IgG antibody that binds to C5 and prevents subsequent formation of terminal complement[21]. Eculizumab has significantly decreased the risk of ESRD in adult patients with aHUS from 60%-70%[6,14] to approximately 15%-20%[22-24].

Globally, CFI mutation had been rarely reported in association with aHUS, and to our knowledge, this is the first case reported in Saudi Arabia. Our case highlights important challenges related to the diagnosis and treatment of this rare disorder.

We reported a case of a middle-aged woman with aHUS due to rare CFI mutation presenting with severe acute kidney injury. She required dialysis and remained dialysis-dependent for 32 mo. Eculizumab treatment was associated with complete hematologic remission. Interestingly, she is now off dialysis and continues to be in remission despite not taking eculizumab for more than 3 years. There are limitations and difficulties related to the management of this case. Most importantly, the time needed to confirm the diagnosis of complement factor mutation was significant due to lack of a laboratory facility for this test. In addition, eculizumab cost and availability was a limitation against prompt and continued use. Accordingly, these might have delayed the institution of appropriate treatment and impacted the clinical response and renal recovery.

The human complement cascade can be activated through three different pathways: The classical pathway, the lectin pathway, and the alternative pathway. CFH and MCP are regulatory proteins of the alternative pathway[25]. Human CFI is a serine proteinase that cleaves the α chain of C3b and plays a key role in the inhibition of the alternative pathway amplification loop, which generates C3 convertase from C3b[26]. Several familial and sporadic cases of aHUS were linked to mutations in these regulatory proteins of alternative pathway. Initially, the two complement alternative pathway proteins, CFH and MCP (CD46), have been identified to foster the development of aHUS[10,27-30]. More recently, genetic analysis in patients with aHUS with no factor H mutation demonstrated presence of CFI mutations[31]. In their novel description, Fremeaux-Bacchi et al[31] identified two heterozygous CFI mutations leading to a stop codon that are associated with functional deficiency in CFI. Later, more cases had been reported, and currently, CFI mutations account for 4%-10% of all cases of aHUS[32]. The clinical outcomes are characterized by high rate of renal failure, end-stage renal disease (ESRD), post–kidney transplant recurrence, and graft loss.

In a report by Waters and Licht[32,33] in 2010 and a previous cases series by Bell et al[33] in 1991, 33 cases of aHUS with complete or functional deficiency of CFI were described. The age ranges from the time of birth to 57 years, with a mean age of 19 years. Using the varying follow-up data available and before the introduction of eculizumab, the following outcomes were noted among the 33 cases: Two deaths, 74% rate of ESRD, 48% of whom underwent kidney transplantation with a recurrence rate of 82% and very high rate of graft loss after recurrence (up to 100% after first graft). Re-transplantation is associated with recurrence. The response to immunotherapy including FFP infusion with or without plasma exchange was not consistent in cases where it was reported.

Similar to patients described in literature, our patient presented with severe renal failure requiring dialysis and had remained dependent on dialysis for 32 mo. With eculizumab introduction, she developed sustained hematologic remission and later recovered some kidney function and is currently off dialysis for 18 mo, with a serum creatinine level of approximately 200 µmol/L. Because of the unavailability and high cost of eculizumab, it was not provided for the past 3 years, but despite this, she remained in hematologic remission and off dialysis.

Cases with CFI mutation manifest increased susceptibility to infection with encapsulated or-ganisms. Such susceptibility is linked to functional C3 deficiency as a result of uncontrolled activation of the alternative com-plement pathway[34]. Our patient received meningococcal vaccine upon confirmation of the diagnosis of CFI mutation. She developed one episode of hemodialysis catheter–related exit-site Pseudomonas infection and one episode of PD-related staphylococcal peritonitis; however, apart from this, no exceptionally increased rate of infections with encapsulated organisms was noted. The susceptibility to infections in CFI mutations might be more prominent with complete CFI deficiency than with heterozygous mutation. Additionally, the late-age presentation and continued remission despite being off eculizumab in our patient may suggest a less severe genetic defect.

Similar to our patient, several cases of eculizumab discontinuation had been described. The largest case series reported the development of TMA in 5 (31%) of 16 patients following discontinuation[35,36]. Those patients had received eculizumab for a median of 4.3 (range, 0.5-14.4) mo. In those 5 patients, relapse was identified, using regular home urine dipstick testing, within 6 mo of the last eculizumab dose. Eculizumab therapy was restarted, and it resulted in rapid improvement in serum creatinine levels and proteinuria.

In an attempt to address the possibility and safety of eculizumab discontinuation, Macia et al[37] studied the demographics, disease characteristics, and outcomes of aHUS cases in whom eculizumab was discontinued. The post-discontinuation follow-up ranged from few days to 17 mo. According to the data collected from cases reports, TMA developed in 16 (31%) of 52 cases who discontinued the drug after multiple doses and in 4 (80%) of 5 cases who discontinued the drug after a single dose. TMA development was found to be higher with a single dose of eculizumab, and hence, current evidence does not support single-dose eculizumab.

According to the data collected from eculizumab clinical trials, TMA developed in 12 (20%) of 61 patients during a median post-discontinuation follow-up of 24 wk[37]. The median time to TMA development was 13 (range, 4-127) wk. Three patients progressed to ESRD. The authors compared patients who experienced relapse (n = 12) to those who did not (n = 49) post-dis-continuation across several demographic and disease characteristics. No particular trend to predict TMA development was noted with regard to sex, identified complement mutation or antibody, time from diagnosis to start of eculizumab, duration on eculizumab treatment, kidney function and dialysis (at the time of initial treatment and discontinuation), and kidney status (native versus transplant)[37]. However, compared with patients who experienced no relapse, there was a trend to a lower median age (19.5 vs 27 years) and a higher proportion of CFH mutation (42% vs 18%) among those who experienced relapse. It had been noted that the use of functional tests of complement activity and measurement of complement proteins to predict development of TMA is of limited value[37]. The authors concluded that the development of TMA following eculizumab discontinuation is unpredictable.

To our knowledge, this is the first case of aHUS due to heterozygous CFI variant c.944G > A (p.Arg315Lys) reported in Saudi Arabia. Several lessons can be learned from our case and similar cases. Although rarely reported, it is important to keep a high index of suspicion for such severe disease when acute kidney injury presents with unexplained microangiopathic anemia. In such presentations, the severity of renal disease, lack of significant neurologic symptoms, and absence of diarrhea make aHUS the likely clinical diagnosis. In addition, a renal benefit with discontinuation of dialysis was possible in our case despite relatively late initiation of eculizumab and prolonged period of dialysis-dependent kidney disease. Lastly, although eculizumab discontinuation was possible in our patient and seems to be safe in some other reported cases during the reported follow-up periods, predicting the risk of TMA development remains difficult. Therefore, informed decision-making requires a more comprehensive collection of data on eculizumab discontinuation and finding a more sensitive tool to monitor complement activation and disease activity.

The authors acknowledge and thank the staff of the Pathology Laboratory for their contribution in obtaining the renal biopsy slide pictures and the staff of the Laboratory Department for their contribution in tracking the full genetic analysis report, which was done outside the country.