Dysregulation of the alternative complement pathway is recognized in 60% of aHUS cases [3, 4]. Uncontrolled activation of the terminal complement leads to the formation of C5b-9 complex (Membrane Attack Complex or MAC), causing endothelial cell damage and leading to the development of pro-coagulant and pro-inflammatory states, which manifest as TMA [2]. Over 100 complement gene mutations predisposing to aHUS have been identified. These include mutations in C3, CD46 (MCP), CFB, CFH, CFI, CFHR1, CFHR3, CFHR4, DGKE, and THBD leading to uncontrolled activation of alternative of complement pathway [4]. Mutations include loss-of-function of complement regulatory proteins, polymorphisms, hybrid gene encoding for a CHFR1/CFH fusion protein, and from gain-of-function mutations of C3 and CFB. Penetrance of these mutations is estimated at 40–60% penetrance with additional complement amplifying conditions needed for disease manifestation in predisposed individuals [2, 3]. These include infection, certain drugs (chemotherapeutic agents, immunotherapeutic agents, antiplatelet agents, oral contraceptives, anti-inflammatory agents), malignancy, post-transplantation, and pregnancy [4].
Although aHUS is a complement mediated disease process, low levels of serum C3 are not specific for aHUS and hence their testing is not of diagnostic value in this setting [5]. Normal C3 values do not exclude mutations or antibodies against the complement system [6]. Recently, Gavriilaki et al. [7] developed an interesting modification of the Ham test (which is used for diagnosis of paroxysmal nocturnal hemoglobinuria (PNH)) to rapidly diagnose aHUS and to differentiate it from other causes of TMA. This test is based on complement-mediated apoptosis and death in glycosylphosphatidylinositol-anchored complement regulatory proteins deficient cells. This will have important clinical implications and also might help in identifying patients at higher risk of developing aHUS [6].
Genetic testing for mutations of the alternative complement pathway are very expensive, take several weeks, and is informative in only 50–60% of the cases [7]. One review article proposed that diagnosing aHUS in a patient with TMA would require demonstration of AP dysregulation biomarkers (for example, by elevation of plasma Ba levels, C4d, and terminal complement activation UC5a/Cr, Uc5b-9/Cr), followed by reassessment of proximal complement activation after specific treatment which targets terminal complement activation (e.g. eculizumab). In patients with aHUS, persistent activation of proximal pathway should still occur despite the treatment, and this can be demonstrated with an indirect Ham test. However, validation of this test in larger cohorts will help in diagnosing aHUS early in the course of the disease instead of waiting to rule out other causes [8].
Our patient had laboratory evidence of TMA with anemia, thrombocytopenia, schistocytes, high LDH, and a reduced haptoglobin level, correlating with the development of AKI. Testing for ADAMTS13 was negative and liver enzyme tests were normal, thus ruling out TTP and HELLP. This initial step is very important because the management varies among different causes of TMA and early initiation of appropriate treatment can have significant effect on morbidity and mortality. The presence of worsening AKI pointed towards aHUS rather than TTP. Typical HUS as alternative diagnosis was considered, but she presented with no gastrointestinal symptoms to our hospital, rendered us questioning the value of Shiga toxin-producing Escherichia coli (STEC) screening test at that time. The fact that the patient’s condition continued to deteriorate after supportive treatment and plasma exchange, makes typical or STEC-HUS unlikely to be the diagnosis.
In a case series published by Fakhouri et al. [9] 21% of aHUS cases were during pregnancy, with the highest reported cases during the second pregnancy and about 80% of the presentations were at the time of delivery or immediately post-partum. Complement activating conditions, such as pregnancy complications (preeclampsia and HELLP), renal transplantation, autoimmune disease, and certain medications have been illustrated as conditions that tend to unmask and precede onset of aHUS in predisposed individuals [10]. Our patient presented with aHUS in the first trimester, a very rare occurrence. This is postulated to be related to the number of pregnancies she had, with each pregnancy causing more robust complement activation secondary to induction of anti-HLA antibodies when fetal cells transverse to the maternal circulation.
It is also worth noting that our patient has a significant medical history of hereditary pancreatitis, which could potentially play a role in subclinical complement activation by a chronic inflammatory process. Hereditary pancreatitis due to R 117 H mutation is a rare genetic disorder, in which Arg-His substitution at residue 117 of trypsinogen gene causes failure to inactivate trypsin, which in turns, results in autodigestion of the pancreas [11].
The high morbidity and mortality of aHUS indicates a severe and unmet medical need. Traditionally, aHUS has been managed by various modalities including anticoagulants, immunosuppressive therapies, and plasma exchange and/or plasma infusion; with a poor prognosis [12]. Plasma exchange or plasma infusion is generally poorly tolerated and has inconsistent results. In patients with a CFH mutation, who developed a TMA, 22% of patients and 30% of patients, treated with plasma exchange progressed to ESRD or death, respectively [12, 13]. The poor outcome on plasma exchange therapy is attributed to directly activated platelets with complement fragments deposited on platelet cell surfaces. Normalization of platelet count and LDH induced by plasma-based therapy had no effect on elevated level of proximal and terminal complement pathway activation, endothelial cell activation, endothelial cell injury, ongoing coagulation pathway activation, systemic inflammation, and ongoing deterioration in renal function [8].
For patients who develop ESRD, kidney transplant is pursued; however, transplant failure occurs in 67–81% of patients with plasma infusion non-MCP mutation aHUS [13]. On the other hand, combined liver–kidney transplantation has been more successful than kidney transplantation alone, possibly curing aHUS [12, 13]. Unfortunately, due to the limited number of organs available and the high risk of the procedure, it is less frequently attempted [13, 14]. Eculizumab is the first treatment to offer a highly specific complement-targeted therapeutic option for patients with TMA.
Eculizumab is a high-affinity humanized monoclonal antibody that binds to and blocks the cleavage of C5 into the inflammatory, prothrombotic, and lytic C5a and C5b-9 terminal complement components, leaving the upstream components, most notably C3a intact. By blocking complement hyper activation and dysregulation, it reduces hemolysis, prothombotic activity, and inflammation associated with aHUS including ESRD and death. It is a pregnancy category C drug, safely used in pregnant women. Limited study by Hallstensen et al. [15] found that very low level eculizumab and eculizumab-C5 complex were detected in the serum of newborns of pregnant women treated with eculizumab, however the newborns still have a fully functional complement activity. Few case reports and series have also demonstrated long-term efficacy and safety of Eculizumab as first line treatment in neonates and infants who suffered from aHUS. Similar to our patient, neonates and infants in the studies also showed complete recovery of the renal function after initiation of Ezulizumab [16, 17].
By inhibiting the late elements of the complement cascade system, patients are predisposed to infection by encapsulated bacteria, including Neisseria meningitidis [18–21]. Therefore, patients who have not been vaccinated against N. meningitidis should receive a quadrivalent meningococcal vaccine at least 2 weeks prior to the first dose of eculizumab [22, 23]. In patients like ours where we need to give the therapy immediately, prophylactic antibiotics can be administered till then. One retrospective study during STEC-mediated HUS outbreak in Germany also reported simultaneous treatment with antibiotic for meningococcal prophylaxis in 98% of patients treated with eculizumab [24, 25]. Rifampin, as one of the antibiotic options, was proven effective at eradicating N. meningitidis up to four weeks after treatment when compared with placebo [26, 27]. This case and the discussion highlight the use of the monoclonal antibody, eculizumab, as a viable option in the treatment of aHUS in pregnant women. It also describes the pathophysiology of aHUS as it relates to the complement pathway.