Pediatric Atypical Hemolytic Uremic Syndrome

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1		Amrit Khooblall	+ 4059 word(s)	4059	2021-12-20 02:58:14	\|
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This entry is adapted from the peer-reviewed paper 10.3390/cells10123580

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework.

pediatric aHUS aHUS advancements aHUS COVID-19 SARS-CoV-2 DGKE C3 aHUS Triggers aHUS Manifestations aHUS Therapeutics

1. Introduction

Atypical hemolytic uremic syndrome (aHUS), characterized by a triad of thrombocytopenia, acute kidney injury (AKI), and microangiopathic hemolytic anemia, is a rare form of thrombotic microangiopathy (TMA) caused by dysregulation of the alternative pathway (AP) ^[1]. Clinical diagnosis of aHUS can be challenging as it relies on the symptomatic recognition of TMAs, yet it requires excluding all other causes of TMAs and HUSs. Thus, the precise incidence of aHUS in pediatric and young adult populations (<20 years of age) is fluid in nature. Typically diagnosed at 2 years of age, aHUS is associated with a mortality rate of 20–25% and a morbidity of 48%, as pediatric patients typically progress to end stage renal disease (ESRD) ^[1]^[2].

Genetic variants in complement regulatory proteins (CRPs) account for 50% to 60% of all aHUS cases, with approximately 30–50% having no known identifiable mutation ^[3]. Underlying triggers, such as infections, malignancy, or pregnancy, can also induce the clinical manifestation of aHUS. As more data from aHUS patients is reported, such principles are subject to change. Assessing the pathogenesis, triggers, manifestations, and treatment options for aHUS is vital for early diagnosis and management; however, recognizing previously unknown mechanisms, causations, and symptoms is equally as important.

2. The Complement System

The complement system serves a critical role in the innate immune system with respect to three major physiological outcomes: membrane attack complex (MAC) formation, propagation of anaphylatoxins, and opsonization of pathogens. The three distinct pathways that launch the propagation of the complement system are the classical pathway (activated by a microbial-bound immunoglobulin G dimer), the lectin pathway (recognition of foreign particles via mannose binding lectin and ficolin), and the AP (continuously expressed and activated in the serum).

In aHUS, the AP is continuously active via hydrolytic activation of C3 into C3b by the ubiquitous water molecule and is regulated to prevent AP activated complement system attack on host cells. Regulatory factors found both in the serum and on the host cell surface function to inactivate C3b if not in the presence of a pathogen.

AP activated C3 protein is enzymatically divided into two parts: C3a and C3b. C3a serves as an anaphylatoxin while C3b further integrates into the complement pathway. C3b merges with activated complement factor B (Bb) to serve as a C3 convertase to further amplify inactivated C3 and can also recruit synthesized C3b to form the integral C5 convertase (schematically written as C3bBbC3b). The C5 convertase cleaves complement 5 (C5) into an anaphylatoxin (C5a) and the activated complement pathway mediator C5b. C5a increases the permeability of blood vessels and attracts inflammatory cells via chemotaxis. C5b further recruits complement factors 6, 7, 8, and multiple complement factor 9s to form the MAC, denoted as C5–9, ultimately killing the microorganism.

Atypical HUS, and the broader category of TMAs, are brought about by an imbalance of AP activated C3 protein and the regulatory factors deactivating it. Eculizumab, the typical course of treatment for aHUS, targets complement C5 by inhibiting the cleavage of C5, thus inhibiting MAC formation ^[3]^[4] (Figure 1).

Figure 1. Alternative pathway with key emphasis on interventional drugs and where they act upon. Current therapeutics include Eculizumab, Ravulizumab, Avocapan, Nomacopan, and Cemdisiran. Biosimilars include ABP 959 and Elizaria. Drugs currently being developed include ALXN1720, Poselimab, Tesidolumab, Crovalimab, Avacincaptad Pegol, IFX-1, and Zilucoplan.

3. Genetics

Since genetic abnormalities affecting the complement system are present in roughly 60% of patients diagnosed with aHUS, genetic testing is recommended for all potential aHUS patients under at least one of the following categories: tested negative for Shiga toxin-producing Escherichia coli, HUS after reporting prodromal diarrhea, have persistent thrombocytopenia, or reported ADAMTS13 activity levels <50% ^[1]^[2]^[3]. Genetic testing for heterozygous pathogenic mutations or polygenic mutations is primarily centered on C3, CD46, CFB, CFH, CFI, or thrombomodulin (THBD). A complete gene panel test should also include heterozygous or homozygous pathogenic variants of diacylglycerol kinase epsilon (DGKE), methylmalonic aciduria and homocystinuria, cobalamin C (MMACHC), C3, CD46, CFB, CFH, CFD, and CFI as well as homozygous deletions of the CFHR genes (typically CFHR1–3 and 5) ^[1]^[2]^[3]. An additional element to CFH and aHUS includes spontaneous mutations that lead to anti-complement factor H autoantibodies (anti-CFH) ^[5]. Homozygous deletions in CFHR1 and CFHR3 have been associated with the formation of anti-CFH antibodies, although the exact mechanism responsible is not yet known ^[6].

These guidelines for genetic testing are affirmed by a number of studies that have analyzed the data on complement system dysfunction mediated by genetic mutations and autoantibodies. Our meta-analysis over 12 studies (n = 2317) show 54.21% (n = 1256) of cases having at least one functional mutation in a complement gene (Table 1). The pooled proportion of CFH mutations was the highest at 21.41% (95% Confidence Interval (CI); 16.60–26.64%; p = 0.5189) and CFB was the lowest at 1.55% (95% CI; 0.99–2.32%; p = 0.7374). Other notable complement mutations also include C3 (5.29%), CFI (6.89%), THBD (1.74%), and CD46 (9.98%).

Table 1. Pooled proportion of different mutations in aHUS patients.

Mutation	No. of Studies	Total aHUS Patients	Pooled Estimate	I² (95% CI); p Value	Egger’s Test
Mutation	No. of Studies	Total aHUS Patients	(95% CI)	I² (95% CI); p Value	Egger’s Test
CFH	12	2295	21.41%	85.84% (76.97–91.29%);	p = 0.5189
CFH	12	2295	(16.60–26.64%)	p < 0.0001	p = 0.5189
CD46	11	2177	9.98%	76.84% (58.58–87.05%);	p = 0.2614
CD46	11	2177	(7.15–13.22%)	p < 0.0001	p = 0.2614
CFI	12	2295	6.89%	64.69% (34.6–80.93%);	p = 0.2206
CFI	12	2295	(5.01–9.05%)	p = 0.0010	p = 0.2206
DGKE	4	558	6.57%	90.06% (77.48–95.61%);	p = 0.1619
DGKE	4	558	(0.93–16.76%)	p < 0.0001	p = 0.1619
C3	9	2193	5.29%	61.37% (20.05–81.34%);	p = 0.8866
C3	9	2193	(3.74–7.09%)	p = 0.0080	p = 0.8866
THBD	6	1176	1.74%	77.9% (51.11–90.01%);	p = 0.6401
THBD	6	1176	(0.47–3.8%)	p = 0.0004	p = 0.6401
CFB	5	1469	1.55%	26.03% (0.00–70.5%);	p = 0.7374
CFB	5	1469	(0.99–2.32%) *	p = 0.2480	p = 0.7374
Others	4	691	19.29%	98.7% (97.98–99.16%);	p = 0.7916
Others	4	691	(1.34–50.78%)	p < 0.0001	p = 0.7916
Combined	7	1922	3.06%	84.36% (69.48–91.98%);	p = 0.0566

* Random effect model; for others the fixed effect model was used. ^ Data based on a single study, pooled estimate is not possible. Pooled estimate of proportion of aHUS patients was calculated with random effects model for high heterogeneity and fixed effects model for low heterogeneity. I² test assessed the degree of between-study heterogeneity, where I² ≥ 50% indicated high heterogeneity. Egger’s test for publication bias, where p < 0.05 indicted the presence of publication bias.

4. Triggers

Heterozygous mutations predisposing children to aHUS are often not sufficient to clinically manifest the disease due to poor penetrance—a trigger is often required. Tomazos et al. conducted a retrospective study (n = 147) identifying the primary triggers of adult aHUS as infection (63%, n = 92), chemotherapy (16%, n = 28), and systemic lupus erythematosus (15%, n = 26). Bacterial infections, primarily of the upper respiratory tract, predominated the infection subgroup at 42% (n = 75) ^[7]. More than one-third of all aHUS cases have unidentified triggers, which makes its sporadic presentation, especially in pediatrics, even more confounding. However, research identifying known causes, as well as novel ones, is rapidly developing (Figure 2) ^[8].

Figure 2. Atypical hemolytic uremic syndrome triggers. Novel developing triggers are highlighted in green. SARS-COV-2: severe acute respiratory syndrome coronavirus 2; HIV: human immunodeficiency virus.

5. Manifestations

As a TMA characterized by thrombocytopenia and microangiopathic hemolytic anemia, aHUS can induce organ damage due to ischemia downstream of occluded blood vessels ^[9]^[10]. Resulting extrarenal complications can present in aHUS patients and often affect the central nervous system (seizures, cortical blindness, encephalopathy, and drowsiness), pulmonary system (pulmonary hemorrhage), cardiovascular system (myocardial infarction, heart failure, and cardiomyopathy), gastrointestinal system (intestinal bleeding, pancreatitis), and the skeletal system (rhabdomyolysis). A list of clinical manifestations of aHUS based on organ system can be found in Table 2, with individual reports in Table 3.

Table 2. Clinical manifestations of aHUS based on organ system.

Organ System	Clinical Manifestations		Reported Efficacy of Eculizumab
Renal	Glomerular thrombotic microangiopathy, Arterial TMA, and Cortical necrosis		Yes
Neurological	Seizures, Headache, Altered consciousness, Hemiparesis, Vision loss, Hallucinations, Encephalopathy	Agitation, Confusion, Reduced reflexes, Hemiplegia, Nystagmus, Diplopia, Focal neurologic deficits, Coma	Yes
Pulmonary	Pulmonary embolism, Hemorrhage, Edema, Respiratory failure		N/A
Dermatologic	Peripheral gangrene, Ischemia, Cutaneous rashes		Yes
Cardiovascular	Hypertrophic cardiomyopathy, Left ventricular hypertrophy, Elevated CK-MB level, Dilated cardiomyopathy, Valve insufficiency	Tachycardia, Intracardiac thrombus, Steno-occlusive arterial disease in large arterial vessels (i.e., middle and anterior cerebral artery stenosis)	Yes
Ocular	Reduced visual acuity, Ocular pain, Visual scotomas, Diplopia, Blurred vision	Optic disc edema, Bilateral flame-shaped intraretinal hemorrhage, Tortuosity, Venous stasis retinopathy	Yes
Gastrointestinal	Vomiting, Cholelithiasis, Transaminitis, Pancreatitis,	Hepatitis, Gastrointestinal bleeding, Abdominal pain	Yes

Clinical manifestations of aHUS based on organ system and documented effectiveness of Eculizumab.

Table 3. Reports of organ system complications in aHUS.

Organ System Complications Due to aHUS
Organ System	Authors	Year	Sample Size	Age	Outcome
Neurological	Gulleroglu et al.	2013	2	14	Neurologic symptoms and irregular cerebral MRI results
Neurological	Diamante et al.	2014	1	<18	Multifocal hyperintensities and altered consciousness
Cardiovascular	Hu et al.	2015	1	0.75	Cardiomyopathy and altered cardiac function
	Vilalta et al.	2012	1	1
	Neuhaus et al.	1997		23
	Davin et al.	2010	1	15	Middle and anterior cerebral artery stenosis
Pulmonary	Johnson et al.	2014	71	-	21% of aHUS patients developed respiratory failure
Ocular	Zheng et al.	2014	1	11	Decreased visual acuity (20/100 in the right eye, 20/200 in the left eye) Intraretinal hemorrhages, Venous stasis retinopathy, and Vein occlusions
Gastrointestinal	Besbas et al.	2017	146	-	10% displayed vomiting, cholelithiasis, transaminitis, pancreatitis, hepatitis, and GI bleeding
	Dragon-Durey et al.	2010	45	-	<80% of patients with anti-CFH antibodies had GI symptoms
	Roman-Ortiz et al.	2014	1	9	Abdominal pain

Reports of organ system complications in atypical hemolytic uremic syndrome patients/cohorts. MRI: magnetic resonance imaging; GI: gastrointestinal; CFH: complement factor H.

6. Selected Mutations and Anti-Complement Factor Antibodies

6.1. Complement Factor H and Anti-Complement Factor H Antibodies

Preliminary reports have observed anti-CFH immunoglobulin G antibodies in 25–50% of pediatric aHUS cases ^[11]. aHUS mediated by anti-CFH antibodies has a 16% mortality rate and can cause kidney sequelae in around 50% of surviving patients ^[12]. This is observed through elevated anti-CFH antibody titers, which can rise to 1000–50,000 AU/mL ^[13]. CFH binding to platelets is a well-established mechanism, but information about the binding of platelets to anti-CFH antibodies requires further examination ^[14].

CFH regulates the AP of the complement system by directly binding to polyanions and compounds that activate C3. CFH, located near CFHR1 and CRFH5 genes, is composed of 20 short consensus repeat (SCR) domains, four of which are involved in the complement regulatory functions. Recent reports have demonstrated that the homozygous deletion of CFHR1 produces anti-CFH antibodies ^[15]. These antibodies bind to the N and C terminus of the CFH protein, decreasing CFHs ability to bind to C3b, C3c, and C3, resulting in the abnormal hemolysis associated with aHUS. In vitro binding of anti-CFH antibodies to CFH also causes lysis of platelets, which subsequently over-activates the complement system ^[14]^[15]^[16]^[17]. Anti-CFH antibodies have also been shown to interfere with the binding of CFH to glomeruli endothelial cells ^[17] and have been recently identified as a prognostic factor for aHUS in pediatric patients.

aHUS due to anti-CFH antibodies was identified in a pediatric aHUS cohort (n = 436), with two cases of homozygous deletions of CFHR1-CFHR3 and anti-CFH autoantibodies in pediatric aHUS patients ^[16]. Both patients were successfully treated with Eculizumab and mycophenolic acid (MPA), as identified by stable anti-CFH antibody titer levels below <1000 UA. Notably, Matrat et al. is the first to report successful treatment of anti-CFH aHUS in pediatric patients with Eculizumab and MPA ^[12]. Previously, plasma exchange (PE), Rituximab, and cyclophosphamide have been widely used despite significant side effects, including cardiotoxicity, osteoporosis, decreased fertility, and an increased risk for tumors.

The exact site of anti-CFH binding to SCR has been debated, where Norris et al. and Wuo et al. report its binding at SCR 19–20, while Pursawani et al. reports its binding to the C-terminus of CFH at SCR 17–20 and SCR 5–8 ^[11]^[16]^[17]. Geographical differences have also been observed in the frequency of anti-CFH aHUS. These antibodies affect 5–25% of aHUS patients in Europe, but over 50% of aHUS patients in South Asia. Its prominence and prevalence in South Asia is thought to be due to higher rates of exposure to respiratory and GI pathogens, with the majority of anti-CFH antibody aHUS cases in South Asia among children ages 4–11 years old. Future research should seek to clearly define the true binding mechanism, which may explain the regional variations and contribute to the potential management and treatment of anti-CFH aHUS.

6.2. Complement Factor I and Anti-Complement Factor I Autoantibodies

CFI is a serum serine protease which cleaves C3b and C4b and prevents the formation of C3 and C5 convertase. Mutated forms make up 4–8% of aHUS cases, obstructing the secretion of proteins or altering CFI’s ability to cleave C3b and C4b, resulting in cleavage into abnormal products. This mutation affects both the cell surface and fluid phase, and in 20–30% of cases is associated with lower C3 levels ^[11].

Novel reports of CFI autoantibodies have recently emerged in a small subset of aHUS cohorts. Genetic testing of affected individuals revealed that all individuals with CFI autoantibodies have two copies of CFHR1 and CFHR3 genes, suggesting that CFI autoantibodies affect the development of CFH since low CFH levels were observed in all three patients. Govindarajan et al. reported CFI autoantibodies identified in 31% of a sample pediatric aHUS population in India ^[18]. Age notably affected which antibodies were the most common, where aHUS patients under 2 years old mainly had CFI autoantibodies and children over 2 years old had anti-CFH antibodies.

6.3. Diacylglycerol Kinase Epsilon

The first non-complement system gene associated with aHUS was identified as DGKE and has been detected in 27% of all aHUS patients ^[19]. DGKE phosphorylates diacylglycerol to phosphatidic acid, which ultimately activates protein kinase C. The exact mechanism by which mutations in DGKE manifest in aHUS has not yet been identified; however, Zhu et al. hypothesized that the absence of DGKE may result in modifications of the vascular tone actin cytoskeleton, secretion of prothrombotic and antithrombotic factors, and the activation of platelets. These changes were confirmed when DGKE knockout mice showed irregularities in the extracellular matrix basement membrane and glomerular endothelium, occluded glomerular capillaries upon exposure to nephrotoxic serum, and impaired synthesis of prostaglandin E2 and cyclooxygenase 2 ^[20]. Lemaire et al. reinforced Zhu et al.’s reports of DGKE mutations clinically manifesting as chronic TMA characterized by glomerular cellularity, split glomerular basement membranes, swelling of endothelial cells, and widening of the glomerular basement membrane (GBM) internal lamina rara in the absence of electron-dense deposition ^[19].

7. Current Therapeutics

7.1. Immunotherapy

Plasma exchange (PE) and plasma infusions (PI) were once the generally accepted method of treating aHUS, despite little to no supportive clinical trials. PE allows for the relatively rapid removal of antibodies in autoimmune TMA and other malignant proteins, and can eliminate vWF multimers or autoantibodies. PE and PI function to alleviate the symptoms of TMAs or TPPs; however, they fail to accurately solve the root problem. After 2010, the guidelines were re-examined after unremarkable and even negative effects from PE and PI plagued many patients ^[21]. As the understanding and diagnostic capabilities regarding aHUS as grown within the last few decades, so have advances in therapeutics. However, it should be noted that less developed countries still rely on PE and PI due to costs and availability. Currently, there are three medications that are potentially usable for treating aHUS: Eculizumab, Ravulizumab, and Avacopan, all targeting and reducing the C5/C5a axis.

Fremeaux-Bacchi et al. and Loirat et al. observed aHUS patients with CFH mutations and found that those who received high-intensity plasma therapy had similar outcomes regarding the progression of ESRD compared to those who did not ^[13]^[22]. In institutions where the anti-C5 inhibitor Eculizumab is not readily available, PE continues to be the first line of treatment ^[23]. Within 24 h of presentation, PE is typically initiated and encompasses daily infusions (1.5 times the plasma volume; 660–75 mL/kg) until platelet count, LDH, and hemoglobin levels are normalized ^[24]. If a patient’s hematological and renal functions are unresponsive to PE, Eculizumab is then required. The combination of PE and immunosuppressive agents, especially in patients with anti-factor H antibodies, has shown positive results primarily in adults in the literature ^[25]^[26]^[27]. However, its combined efficacy in the pediatric population is largely unknown due to the lack of randomized controlled trials.

7.2. Eculizumab

Eculizumab, a monoclonal antibody, was the first successful terminal complement inhibitor available to pediatric aHUS patients ^[28]. Eculizumab targets the complement system by binding to C5 and preventing its cleavage into C5a and C5b. This mitigates the proinflammatory effects of C5a, prevents the formation of C5b-9, and protects the functionality of upstream innate immune complement factors, such as C3a and C3b. ^[4]^[29].

Ariceta et al. contrarily observed 90.9% and 59% of children on eculizumab experience adverse side effects (cough, fever, abdominal pain, respiratory tract infections, and diarrhea) and serious complications (elevated severity of the aforementioned), respectively ^[30]. Eculizumab is ineffective in patients with polymorphic forms of C5, as it is unable to bind to C5 variants; hence, it is unable to block the cleavage of C5 in patients. Due to a greater risk of infection from encapsulated bacteria, such as meningococcal infections, pediatric aHUS patients require prophylactic vaccinations ^[29]^[31]. Eculizumab is commonly used today for the treatment of aHUS, and has paved the way for the development of other aHUS therapeutics such as Ravulizumab.

7.3. Ravulizumab

Ravulizumab is a humanized monoclonal antibody developed by the same manufacturer as Eculizumab. Similarly, it acts as a C5 inhibitor by binding with greater specificity and affinity to C5 to prevent the terminal complement complex formation. This second-generation drug was developed by modifying Eculizumab to create a novel, longer-acting antibody which would require less frequent infusions than its predecessor. The drug was developed through the Xencor antibody half-life prolongation technology Xtend; a technology that increases half-life through Fc variants ^[32]. Through modifications in amino acids, this drug enhances the rate at which the mAb:C5 complex dissociates in the acidic early endosome at pH 6.0 and increases antibody recycling of the neonatal Fc receptor, both of which increase the life of terminal complement inhibition. Ravulizumab has a half-life 4-fold greater than that of Eculizumab, allowing patients to receive infusions every 2–8 weeks rather than bi-monthly, as with Eculizumab ^[29].

Ravulizumab has also been analyzed in pediatric aHUS patients who have not been treated with complement inhibition therapy. Ariceta et al. described the first prospective phase III trial which demonstrated that Ravulizumab is safe and successful in treating complement inhibitor-naïve pediatric patients ^[30]. Patients less than 20 kg were given infusions every 4 weeks and patients more than 20 kg were given infusions every 8 weeks. This trial led to complete inhibition of C5, causing normalization of hematological parameters and repaired renal function. A complete TMA response was characterized by the normalization of platelet count and LDH, and a ≥25% increase in serum creatinine levels. Of the total participants, 77.8% attained this response by 26 weeks, and a total of 94.4% patients reached a full TMA response by week 50. Platelets normalized faster than other TMA response components, 8 days after the first infusion. All participants had either discontinued or were never started on dialysis by week 50, and each patient had improved renal function by week 50 (measured via eGFR). More importantly, all participants had improved FACIT-fatigue scores at 26 and 50 weeks, which is suggestive of an improved risk-benefit ratio for Ravulizumab treatment.

The major limitation to using Ravulizumab is that its affinity for C5 is 17-fold greater than Eculizumab, which ultimately stunts the immune system and makes patients susceptible to infection ^[29]. Tanaka et al. observed recurring oropharyngeal pain (30%) and upper respiratory tract infections (40%) in pediatric participants in their study ^[33]. Ariceta et al. reported that 47.6% of participants in their study had drug induced complications, including pyrexia, nasopharyngitis, vomiting, diarrhea, and headaches ^[30]. However, both studies concluded that the benefits outweighed these risks. Ariceta et al. reported no cases of meningococcal infections and less frequent infusions (decreasing from 26 to 7–13 infusions per year). Additionally, aHUS patients may not need a port to access the vasculature, preventing related comorbidities from infections or clots. Patients on Ravulizumab require less appointments, which may decrease potential exposure to nosocomial infections. Children may also experience less fear, pain, and illness from the venipuncture. These potential benefits are indicative of higher quality of life for pediatric aHUS patients on Ravulizumab. The improved efficiency of Ravulizumab allows for 60% and 73% lower productivity costs in the clinic and at home, respectively, also demonstrating decreased societal and healthcare-associated costs of therapy.

Similar in effect, Nomacopan, Cemdisiran, and Avacopan are three novel drugs that are currently being investigated in aHUS patients; however, they have yet to be established as primary treatments for aHUS, such as Eculizumab and Ravulizumab. Avacopan is an antagonist to C5aR1 that inhibits the functions of the C3a, C4a, and C5a protein ^[34]. It has demonstrated positive results in mice with glomerulonephritis, monkeys with neutropenia, and in Phase II and III trials of patients with AAV. A phase III adeno-associated virus (AAV) trial revealed Avacopan had significantly improved outcomes, including renal function, compared to other medications which have been studied after 26 and 52 weeks. Unfortunately, a different phase II trial initiated on six aHUS patients was terminated without a reported reason ^[29]. Nomacopan is a recombinant protein derived from a tick C5 inhibitor that binds to and inhibits C5 and leukotriene B4. It has been studied in aHUS patients, yet due to its 10 h half-life, daily subcutaneous injections would be required ^[29]. Kuhn et al. and Miles et al. suggest that an N-terminal fusion tag (PASylation) could perhaps increase the half-life of Nomacopan without reducing the efficacy of C5 inhibition, reducing the number of injections to once per week ^[35]. Cemdisiran consists of short sequences of interfering RNA, which match the mRNA for the C5 protein, with N-acetylgalactosamine. Upon its weekly or biweekly administration to monkeys, Cemdisiran stopped C5 production and decreased hemolytic activity to 80% ^[36]. This drug is now being studied in aHUS patients.

7.4. Kidney Transplant Setting

In patients with aHUS and a mutation in the complement factor H gene (CFH), there is an 80% risk of renal allograft failure within the first two years following the transplant ^[37]^[38]. Despite prophylactic PE, patients carrying the CFH or CFH/CFHR1 hybrid genes have shown an increased risk of recurrences. Preemptive therapy in the form of Eculizumab has been positively associated with a decreased risk of recurrence, as reinforced by several case reports and controlled trials ^[39]^[40]^[41]^[42]^[43]^[44]. Multiple reports regarding the pediatric population have emphasized this anti-C5 drug’s efficacy in preventing post-transplant aHUS recurrence, especially for those at high risk ^[45]^[46]^[47]^[48]. Zuber assessed nine aHUS renal transplant patients all carrying a genetic abnormality associated with a high risk of recurrence and reported that 8/9 patients experienced a successful recurrence-free posttransplant course with the use of Eculizumab ^[42].

7.5. Biosimilars

A biosimilar is a drug that is not significantly different from an established FDA approved drug with regards to its structure, pharmacokinetics (PK), pharmacodynamics (PD), purity, mechanism, safety, potency, and immunogenicity.

ABP 959, a biosimilar to FDA-licensed Eculizumab, was tested in healthy adult male subjects in a Phase III trial by Chow et al. for its safety and efficacy ^[49]. Participants aged 18–45 were given 300-mg intravenous (IV) infusions of the drug. The results of this study showed PK similarity between ABP 959 and Eculizumab, as measured by the PK parameters AUC0, AUClast, and Cmax. Measured by ABEC for CH50, PD between Eculizumab and ABP 959 were also similar. The ABP 959 infusions were deemed safe, as the occurrences of infections were similar in both groups; the reported grade 3 viral infection was concluded to be unrelated to the drug. Additionally, no participants developed neutralizing antibodies and the anti-drug antibody binding was similar in both ABP 959 and Eculizumab. Overall, Chow et al. demonstrated the safety and efficacy of the biosimilar ABP 959, as shown by similar PK and PD parameters and immunogenicity and safety profiles.

Elizaria is the first Russian biosimilar to Eculizumab. It is used today in clinical practice, as phase III trials demonstrated similar safety, efficacy, PK/PD parameters to treat paroxysmal nocturnal hemoglobinuria, and immunogenicity as Soliris. The authorization of Elizaria in the market led to a 25% reduction in the cost of aHUS treatment, which expanded access to complement-inhibiting therapies for aHUS patients. Lavrishcheva et al. reported a case of a 46-year-old aHUS patient who was initially taking traditional Eculizumab and switched to Elizaria ^[50]. The drug demonstrated efficacy, as this patient had improved renal function, decreased proteinuria, and normalized blood pressure levels. This case also demonstrated drug safety, as no serious adverse events were noted in the follow-up period, and discontinuation of the trial was not necessary. Although this study describes the case report of an adult, it points to future studies which could potentially show the safety and efficacy of Elizaria in pediatric aHUS patients as well.

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