Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, progressive, life-threatening form of thrombotic microangiopathy (TMA) predominantly caused by dysregulation of the alternative pathway of the complement system. Complement-amplifying conditions (CACs), including pregnancy complications [preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome], malignant hypertension, autoimmune diseases, transplantation, and others, are associated with the onset of TMA in up to 69 % of cases of aHUS. CACs activate the alternative pathway of complement and may be comorbid with aHUS or may unmask a previously undiagnosed case. In this review, three case reports are presented illustrating the onset and diagnosis of aHUS in the setting of different CACs (pregnancy complications, malignant hypertension, renal transplantation). The report also reviews the evidence for a variety of CACs, including those mentioned above as well as infections and drug-induced TMA, and the overlap with aHUS. Finally, we introduce an algorithm for diagnosis and treatment of aHUS in the setting of CACs. If TMA persists despite initial management for the specific CAC, aHUS should be considered. The terminal complement inhibitor eculizumab should be initiated for all patients with confirmed diagnosis of aHUS, with or without a comorbid CAC.

Abstract Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, progressive, life-threatening form of thrombotic microangiopathy (TMA) predominantly caused by dysregulation of the alternative pathway of the complement system. Complement-amplifying conditions (CACs), including pregnancy complications [preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome], malignant hypertension, autoimmune diseases, transplantation, and others, are associated with the onset of TMA in up to 69 % of cases of aHUS. CACs activate the alternative pathway of complement and may be comorbid with aHUS or may unmask a previously undiagnosed case. In this review, three case reports are presented illustrating the onset and diagnosis of aHUS in the setting of different CACs (pregnancy complications, malignant hypertension, renal transplantation). The report also reviews the evidence for a variety of CACs, including those mentioned above as well as infections and drug-induced TMA, and the overlap with aHUS. Finally, we introduce an algorithm for diagnosis and treatment of aHUS in the setting of CACs. If TMA persists despite initial management for the specific CAC, Patients with aHUS who are untreated remain at lifelong risk of renal impairment, end-stage renal disease, extrarenal complications, and premature death [4,9]. Management with plasma exchange/plasma infusion (PE/PI) may improve hematologic parameters temporarily [11,12] but not long-term outcomes [4]. The efficacy and safety of eculizumab (Soliris®, Alexion Pharmaceuticals, Inc., Cheshire, CT, USA), a terminal complement inhibitor and the only approved treatment for aHUS [13,14], were first established in two prospective, multicenter clinical studies [15,16], followed by prospective, multicenter studies in pediatric [17] and adult [18] populations. Eculizumab therapy was demonstrated to inhibit complement-mediated TMA and improve hematologic parameters, renal function, and quality of life [15,17,18].
According to the "multiple-hit" hypothesis [19], aHUS is a consequence of both genetic predisposition to alternative complement dysregulation as well as the occurrence of events or conditions that may precipitate TMA by activating complement and/or damaging the endothelium [19,20]. Complement-amplifying conditions (CACs), such as pregnancy complications (preeclampsia, HELLP), autoimmune diseases and others, may be comorbid with aHUS, unmask a previously undiagnosed case, or lead to a misdiagnosis [3,[21][22][23]. Malignant hypertension (MHT) is another CAC that may precipitate aHUS or occur secondary to aHUS [21], potentially confounding the diagnosis. In this review, we describe case reports that demonstrate the onset of aHUS in the setting of CACs. We also review the evidence for a number of CACs, including pregnancy complications, MHT, autoimmune diseases, transplantation, infections, and drugs, and the overlap of these disorders with aHUS. Finally, we present an algorithm for diagnosis and treatment of aHUS in the setting of CACs (Fig. 1) [5].

Case 1
A 33-year-old Hispanic woman developed abruptio placentae leading to fetal death at 33 weeks of gestation. She underwent cesarean section and hysterectomy, and a subsequent exploratory laparotomy. The patient had extensive blood loss and received numerous transfusions. She developed thrombocytopenia [39 × 10 9 /L (normal range 150-350 × 10 9 /L)], microangiopathic hemolytic anemia [hemoglobin level 6.7 g/dL (normal range 14.0-17.5 g/ dL)]; lactate dehydrogenase (LDH) level, 2670 U/L (normal range at institution, 100-200 U/L); haptoglobin level, 5.8 mg/dL (normal range at institution, 26-185 mg/dL); numerous schistocytes on a blood smear, and renal failure [serum creatinine level, 6.0 mg/dL (normal range 0.6-1.2 mg/dL)] necessitating initiation of hemodialysis. The fibrinogen level as well as prothrombin and partial thromboplastin times were normal. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity testing was ordered and PE  1 3 was initiated. The patient showed minimal improvement in hematologic parameters (hemoglobin level, 7.0 g/dL; platelet count, 42 × 10 9 /L) and no improvement in renal function (dialysis dependent) after five daily PEs, and the ADAMTS13 activity level was 56 %. Following diagnosis of aHUS, PE was discontinued. After the discontinuation of PE, the patient was vaccinated against meningococcus, antibiotic prophylaxis was started, and eculizumab therapy was initiated. Two weeks later, dialysis was discontinued. Laboratory tests showed a platelet count of 147 × 10 9 /L, hemoglobin level of 8.8 mg/dL, and serum creatinine level of 3.4 mg/dL. At last follow-up after 27 weeks of eculizumab therapy, platelet count (198 × 10 9 /L), hemoglobin level (13.0 g/dL), and serum creatinine level (0.9 mg/dL) were normal. The patient remains on ongoing eculizumab therapy.

Case 2
A 43-year-old Caucasian woman with a history of migraine headaches since childhood presented with severe headaches and visual impairment lasting for several days. The examination showed a blood pressure of 300/185 mmHg resulting in immediate hospitalization. Fundoscopic examination revealed papilledema, and a subsequent cerebral magnetic resonance tomography showed alterations consistent with posterior reversible encephalopathy syndrome. Laboratory tests including hemoglobin level of 10.8 g/dL, LDH level of 447 U/L (normal range at institution, <250 U/L) and schistocytes on a blood smear revealed microangiopathic hemolytic anemia; the platelet count was normal. Acute kidney injury [serum creatinine level, 3.4 mg/dL (normal range at institution, 0.5-1.0 mg/dL); proteinuria] also was evident. PE was initiated because thrombotic thrombocytopenic purpura (TTP) could not be ruled out initially, but was discontinued after the ADAMTS13 activity was determined to be 64 %. The patient's hypertension was managed with intravenous and oral antihypertensive medications resulting in the resolution of neurological symptoms. Stool examination showed no Shiga toxin-producing Escherichia coli (STEC). A kidney biopsy revealed severe obliterative arteriolosclerosis, ischemic glomerular collapses, and extensive acute tubular injury. Together with typical signs of hypertensive retinopathy and echocardiographic evidence of hypertensive heart disease, the patient was considered to have MHT. However, despite adequate blood pressure control and resolution of hemolysis (LDH, 163 U/L), there was no improvement in anemia (hemoglobin, 10.7 g/ dL) and renal function (serum creatinine level, 3.3 mg/dL) over approximately 5.5 weeks from presentation. Therefore, aHUS was diagnosed with MHT as a presenting sign. No complement gene mutations were identified. After meningococcal vaccination and antibiotic prophylaxis, initiation of eculizumab therapy resulted in gradual improvement of renal function. After 9 months of therapy, the patient's hemoglobin level was 12.2 g/dL and serum creatinine level was stable at 2.1 mg/dL. After 11 months, the hemoglobin and serum creatinine levels were 12.9 g/dL and 2.0 mg/dL, respectively. The patient discontinued from eculizumab therapy after 1 year.

Case 3
A 37-year-old Caucasian female hemodialysis patient with a 14-month history of end-stage renal disease due to recurrent pyelonephritis underwent living-related donor kidney transplantation. Excellent graft function was noted immediately following the surgery, and the serum creatinine level decreased to 0.9 mg/dL. Over the subsequent days, however, urine output gradually decreased and serum creatinine levels increased (1.85 mg/dL on day 5 post-surgery). Humoral rejection was suspected (increasing titer of donor-specific antibodies), and the patient was treated with high-dose corticosteroids and PI. However, the patient developed anuria. Doppler ultrasound showed near-absent graft perfusion. In addition, TMA was suggested by laboratory values including the presence of schistocytes, platelet count of 33 × 10 9 /L, hemoglobin level of 11.7 g/dL, LDH of 675 U/L (normal range at institution, <250 U/L), serum creatinine of 3.5 mg/dL, and heavy proteinuria (6701 mg/g creatinine). The patient was started on hemodialysis because of volume overload and progressive renal dysfunction. On post-transplant day 8, a diagnosis of aHUS was made. Eculizumab therapy, along with antibiotic prophylaxis for meningococcal infection, was initiated, leading to gradual resolution of hemolysis and improved renal function. A renal allograft biopsy revealed TMA consistent with the clinical diagnosis of aHUS. Immunostaining demonstrated C4d staining of peritubular capillaries consistent with humoral rejection. Immunoabsorption was performed for 3 days followed by two doses of intravenous immunoglobulins. Eculizumab treatment was continued with improvement in renal function without the need for further renal replacement therapy. The patient received meningococcal vaccination following discharge. At a follow-up of 6 months, platelet count continues to be stable at 213 × 10 9 /L, hemoglobin level at 11.9 g/dL, LDH level at 273 U/L, and serum creatinine level at 1.7 mg/dL. The patient continues to receive eculizumab therapy. Genetic testing did not reveal any complement gene mutations.

Discussion
These case reports illustrate aHUS in the setting of three CACs: pregnancy complications, MHT, and renal transplantation. In all three cases, a CAC preceded the onset of TMA. Importantly, the standard management of the individual CAC (i.e. cesarean section and subsequent hysterectomy after pregnancy complications, antihypertensive medications for MHT, and corticosteroid therapy for humoral allograft rejection) did not resolve TMA. Each patient had a thorough evaluation for potential underlying causes of TMA. After prompt diagnosis of TMA and recognition of aHUS in each case, treatment with eculizumab was associated with improvement in both hematologic parameters and renal function. Accumulating evidence shows that patients with underlying complement dysregulations are particularly prone to develop TMA when experiencing a CAC. Chronic complement dysregulation, both in aHUS and other disorders, leaves patients predisposed to TMA [24]. When patients are unable to regulate complement, onset or exacerbation of CACs may precipitate aHUS or cause additional manifestations, resulting in persistent TMA despite treatment of CAC symptoms [25]. Findings from a large observational study of patients with aHUS showed that 69 % of the patients had their first TMA manifestations while experiencing a CAC [9].
Proper diagnosis may be particularly challenging in the setting of aHUS and CACs due to overlapping comorbidities [1]. Patients may not necessarily present with the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment [3]; in particular, thrombocytopenia may be absent or mild in MHT [26]. In a large observational study of patients with aHUS, 16 % of patients did not have thrombocytopenia at disease onset [4]. In the described case with MHT, the patient had a normal platelet count at presentation. It is possible that some patients may develop thrombocytopenia relative to earlier laboratory tests, although all values may remain in the normal range. Elevated LDH levels and the presence of schistocytes may also be considered important diagnostic features of microangiopathic hemolytic anemia [5].

Pregnancy complications
TMA occurs in approximately 1 per 25,000 pregnancies [27]. Pregnancy-related aHUS (P-aHUS) may account for approximately 7 % of total aHUS cases [9] and up to 20 % of cases in adult females [4,28]. Complement activation may be augmented during pregnancy, when the placenta may be subject to attack by the complement and immune system [28]. In addition, the complement pathway may be activated postpartum due to maternal circulation of fetal cells, infections, and hemorrhage [28]. Recently, increased complement activation was identified in a subset of women with preeclampsia and HELLP syndrome [29].
In addition to microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency, general signs and symptoms of P-aHUS may include fatigue, headache, nausea, and vomiting. Diagnosis may be difficult because of similarities between P-aHUS and more common pregnancy complications such as preeclampsia and HELLP [27,30]. A recent study of 21 women with P-aHUS showed that most cases occurred postpartum and during second pregnancies [28]. Clinical conditions could rapidly deteriorate, resulting in poor maternal outcomes [27]. Hypertension and chronic kidney disease were frequent long-term complications [27]. End-stage renal disease occurred in 76 % of patients. In severe cases, death may occur within hours to days after the onset of P-aHUS [31]. P-aHUS case reports were first published more than 40 years ago [32]. Delmas et al. [33] were the first to show the beneficial effects of eculizumab on hematologic and renal parameters in a patient with postpartum aHUS. More recent case studies also documented the efficacy of eculizumab in the treatment of P-aHUS, including normalization of hematologic parameters and renal function ( Table 1) [33][34][35][36][37][38][39][40][41].
Emerging evidence shows the safety of eculizumab during pregnancy despite potential placental transfer to the fetus. In a study of 75 pregnancies in 61 women with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab during pregnancy and postpartum, fetal mortality rates were not increased [38]. In these patients, eculizumab was present at low levels in 35 % of cord blood samples, but not in breast milk [42]. Similarly, recently reported case series involving pregnant PNH patients treated with eculizumab demonstrated low levels of the drug in cord blood, but not in breast milk [43,44]. There were no adverse effects on the newborns noted.

Malignant hypertension
MHT can be associated with TMA [45,46]. Many patients with aHUS first present with hypertension, potentially with high severity and/or MHT [7,9,10]. In a retrospective study of 45 children with aHUS, 71 % presented with hypertension [10]. In a large observational study, 8 % of patients with aHUS also had MHT [9].
The role of the endothelium as a pathogenic link between MHT and aHUS was recently reviewed [47]. TMA may occur following fluid shear stress on endothelial cells and subsequent vascular injury (i.e. fibrinoid necrosis, thrombosis, and luminal narrowing), leading to red blood cell fragmentation and platelet consumption [45,46,48]. Aldosterone has been implicated as a potential mediator of vascular endothelial damage in hypertension [21,49,50]. In one study, serum aldosterone levels were found to be higher in MHT patients with TMA versus those without TMA [21]. In addition, hypertensive crises are known to be prothrombotic, leading to platelet aggregation, thrombin generation, and fibrinolysis [51]. Patients with MHT may present with microangiopathic hemolytic anemia, renal impairment, and thrombocytopenia [46], although the latter may be modest and/or resolve quickly [26,52]. Differentiation between MHT-associated TMA and TTP may be particularly difficult because both are associated with neurologic symptoms; however, renal dysfunction may be more common in TMA caused by MHT [26]. Prior history of hypertension and/or relatively high arterial pressure, signs of hypertensive heart disease, relatively high platelet count, and retinopathy are suggestive of MHT-associated TMA [26]. To that end, imaging techniques may be useful in confirming congestive heart disease and/or neurologic involvement due to MHT.
Without proper diagnosis and adequate treatment, patients with aHUS and hypertension and/or MHT may have severe symptoms and poor outcomes, including death [53,54]. Because standard therapies for MHT do not address underlying complement dysregulation, TMA may persist despite such treatment. In a retrospective analysis of 21 patients with TMA and severe/malignant hypertension, 86 % did not recover normal renal function despite antihypertensive therapy [55]. It has been proposed that a diagnosis of aHUS should be suspected in patients with difficult-to-control MHT who demonstrate persistent TMA [52]. In such patients, treatment with eculizumab should be considered. Indeed, case studies have demonstrated the efficacy and safety of eculizumab, with or without antihypertensive agents, in the treatment aHUS in patients with MHT (Table 1) [52,[56][57][58][59][60][61][62].

Renal transplantation
Recurrent and de novo aHUS following renal transplantation have been reviewed in detail previously [5,63]. The availability of eculizumab has substantially changed the landscape of renal transplantation in patients with aHUS [5,63]. In the pre-eculizumab era, renal transplantation in aHUS was associated with poor graft survival and high rates of disease recurrence [64]. In contrast, a large series of 22 patients demonstrated that eculizumab therapy was effective in preventing and treating aHUS recurrence post-transplant [65]. Patients at high risk for recurrence are now candidates for renal transplantation [5]. Additionally, living-non-related donor transplantation may now be considered for certain patients [63]. Expert groups recommend that patients, especially with moderate or high risk for disease recurrence following renal transplantation, receive prophylactic eculizumab therapy [5,63]. Eculizumab should also be considered for patients with de novo aHUS following renal transplantation [5].

Autoimmune diseases
Systemic lupus erythematosus SLE is characterized by the formation of immune complexes that activate complement, leading to cellular injury [66]. Dysregulation of the terminal complement activation has been implicated in the pathogenesis and prognosis of SLE and lupus nephritis [66][67][68]. Complement gene mutations have been identified in patients with SLE and are associated with disease susceptibility [69] and earlier disease onset [69,70]. In patients with SLE, TMA is associated with increased SLE activity, intercurrent infections [71], reduced long-term renal function, and poor overall survival [72][73][74][75][76]. Although TMA is typically Coombs-negative [5], patients with SLE and aHUS may have positive Coombs tests [77].
Recent case studies of SLE comorbid with aHUS have reported varying outcomes with standard SLE therapies (e.g. cyclophosphamide, high-dose steroids, mycophenolate mofetil). Patients may have slow recovery [78], no response [79][80][81], or remain dialysis-dependent [82]. Findings from reports of patients with SLE and aHUS treated with eculizumab have demonstrated the terminal complement inhibitor to be well tolerated and associated with improvement in symptoms, hematologic laboratory values, and renal function (Table 1) [79,80,83].
Scleroderma Progressive scleroderma, or systemic sclerosis, can be complicated by chronic kidney disease associated with hypertension and mild proteinuria as well as by scleroderma renal crisis (SRC). SRC is the most severe form of renal disease in progressive scleroderma and carries a high mortality. SRC manifests as MHT, TMA, and rapid renal failure [84]. Diagnosis can be complicated by the lack of skin changes in some cases making renal histology and serology results the primary basis for appropriate diagnosis [85]. The pathogenesis of progressive scleroderma and its relation to aHUS is not well understood; it is believed that systemic vasoconstriction leads to ischemic injury and organ dysfunction [86].
Several cases of scleroderma-related aHUS have been reported in the literature [86][87][88][89][90]. Overall, outcomes were poor, including death within months of onset in one case [89]. The effects of eculizumab have not been documented in scleroderma-related aHUS. However, in a recent case report of SRC, in which diagnosis of aHUS was not ruled out or substantiated, treatment with eculizumab was associated with improvement in renal function, hypertension, and other symptoms [91].
Ulcerative colitis Diagnosis of aHUS in patients with gastrointestinal symptoms may require differentiation from inflammatory bowel disorders such as ulcerative colitis (UC) [92]. Interestingly, alternative complement activation may also contribute to the pathogenesis of inflammatory bowel disorders. For example, it has been postulated that the upregulation of complement components may contribute to local inflammation and tissue damage in Crohn's disease [93]. Inflammatory bowel disorders have been associated with upregulation of C3, which was strongly correlated with mucosal inflammation [94]. Deposition of C3b and the terminal complement complex have also been demonstrated in mucosal tissue from patients with UC [95].
Only 2 cases of UC-associated aHUS have been reported in the literature (Table 1) [96,97]. In the case reported by Green et al. [96], the patient was found to have complement factor H autoantibodies. Both patients were treated with eculizumab and had favorable outcomes with improvement in renal function and hematologic parameters [96,97].

Drug-induced TMA
aHUS and other TMAs may develop subsequent to the use of certain medications and have been reviewed elsewhere [5]. Data from a recent systematic review showed that nine medications account for 76 % of TMA cases: quinine, tacrolimus, cyclosporine, interferons, gemcitabine, mitomycin, clopidogrel, estrogen/progesterone, and ticlopidine [98]. The pathogenesis of drug-induced TMA involves two distinct mechanisms: immune mediated and direct toxicity. Evidence shows that quinine-, ticlopidine-, and clopidogrel-induced TMAs occur via an immune-mediated reaction, which is typically characterized by severe systemic manifestations including anuric acute kidney injury. TMA caused by cyclosporine, gemcitabine, and mitomycin occurs through a toxicity-mediated mechanism that is dose dependent and may also lead to renal impairment [98,99]. For TMA caused by cancer medications, onset may or may not be dose related and timing can vary from immediately following therapy initiation to a 12-month delay [100]. Gemcitabine-and mitomycin-related TMA occur in <1 and 2-15 % of patients, respectively, and outcomes may be quite poor: renal failure and/or mortality have been reported in up to 70-75 % of cases [101].
It is recommended that patients discontinue the medication if it is suspected to be the cause of TMA [1]. This approach should result in TMA resolution. Patients with TMA caused by immunosuppressants (e.g. cyclosporine, tacrolimus) should receive reduced doses or switch to another agent [102]. However, TMA may continue to progress despite the removal of an offending agent, as has been documented with both mitomycin- [103] and tacrolimusinduced TMA [104]. The optimal management strategy and timing for drug-induced TMA has not been established, but it has been suggested that drug avoidance and supportive care may be the only beneficial options [1]. However, the role for PE/PI is unclear [100], and outcomes have included lack of improvement in or worsening renal function in mitomycin- [104], tacrolimus- [104,105], and gemcitabine-induced TMA [106]. In these example cases, eculizumab therapy, sometimes in addition to anti-inflammatory agents, led to improvements in both hematologic parameters and renal function [103][104][105][106]. More studies are necessary to determine a potential role for eculizumab in drug-induced TMA.

Infection-induced TMA
Infections, particularly of the respiratory and gastrointestinal tract, precede aHUS in approximately half of cases [4,9]. Common bacterial and viral infections associated with TMA have been reviewed elsewhere [5,63] and include Streptococcus pneumoniae, cytomegalovirus, H1N1 influenza, human immunodeficiency virus, and parvovirus. Such infections are thought to activate the alternative pathway of complement and may be associated with increased production of C5 and deposition of C5b-9 [63]. Clinical symptoms of some infections, including diarrhea, may complicate the diagnostic process [3,5].

Diagnosis and management of TMA in patients with CACs
aHUS can be clinically identical to other TMAs, including STEC-HUS and TTP. No testing is available for definitive diagnosis of aHUS [5]. In the setting of CACs and TMA, it may be particularly challenging to rule out other potential causes of TMA, including the existing CAC, to arrive at a diagnosis of aHUS [63]. It is possible that at the onset of aHUS, some patients with existing CACs may not present with all of the classic signs (i.e. thrombocytopenia, microangiopathic hemolytic anemia, acute renal failure) [53].
An algorithm for the management of patients with CACs and TMA is presented in Fig. 1. In a patient presenting with TMA and a specific CAC [9,20,24,28,53], clinicians should first initiate specific management for the identified CAC, in order to treat underlying causes of TMA. If renal or extrarenal TMA arose from the CAC in the absence of complement dysregulation, TMA should resolve rapidly. As the French Study Group for aHUS/C3G (C3 glomerulopathies) has recommended, resolution of renal TMA can be defined as normalization of platelet count and LDH level, and a decrease in serum creatinine by ≥25 % [63].
The persistence of TMA despite specific management for the CAC strongly suggests that the CAC is lowering the threshold for manifestations and unmasking aHUS [5,24,35,53]. In these cases, differential diagnosis of TMA is required [5]. All patients with TMA should have a thorough evaluation for underlying causes [5]. STEC-HUS can be ruled out with a negative stool test for STEC. ADAMTS13 activity <5 % (depending on the assay used) indicates TTP [5]. Genetic investigations may help determine long-term prognosis of aHUS but are not required for diagnosis [5]. Complement gene mutations or factor H autoantibodies are identified in approximately 50-70 % of patients with aHUS [4,9]. The number of mutations characterized has been increasing steadily over recent years [107], and others may be identified in the future.
Overall, clinicians should have a strong suspicion for aHUS in patients with ADAMTS13 activity ≥5 %, negative STEC test, and persistent TMA despite treatment of the CAC. It should be noted that testing results for ADAMTS13 activity level and STEC may not be rapidly available. Thus, some patients may initiate PE during the differential diagnosis period [5] to temporarily maintain hematologic parameters, although it does not inhibit the underlying complement-mediated pathogenesis of aHUS [12] or prevent end-stage renal disease or mortality [9].
For patients with diagnosed aHUS, with or without a comorbid CAC, clinicians should initiate eculizumab therapy immediately according to established guidelines [5,63,108]. Clinical studies have shown that earlier intervention with eculizumab is associated with better renal outcomes for patients with aHUS [15]. The specific effects of eculizumab in aHUS comorbid with individual CACs (e.g. autoimmune diseases) will be demonstrated as evidence accumulates in the literature.
The optimal treatment duration for patients with aHUS and specific CACs has not been established. Expert and regulatory guidance notes that ongoing treatment may prevent risks of potentially life-threatening TMA that may occur following therapy discontinuation [5,13,14].

Conclusions
CACs are increasingly identified in the medical literature as being comorbid with aHUS or unmasking previously undiagnosed cases. The presented case studies illustrate potential complexities in disease onset and differential diagnosis when both a CAC and aHUS are present, as well as the benefits of eculizumab treatment for these patients. Overall, clinicians should consider a diagnosis of aHUS if TMA persists despite specific management for the CAC. Once aHUS is diagnosed, eculizumab should be initiated promptly to halt target organ injury and improve outcomes related to TMA.