Atypical hemolytic uremic syndrome: pathophysiology, clinical presentation, and treatment strategies
Article information
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare and potentially life-threatening thrombotic microangiopathy, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Without timely intervention, it may progress to end-stage kidney disease. The condition is primarily attributed to dysregulation of the alternative complement pathway, with up to 60% of patients exhibiting genetic mutations in complement regulatory proteins such as complement factor H, complement factor I, membrane cofactor protein, and thrombomodulin. The introduction of complement inhibitors, such as eculizumab and ravulizumab, has significantly improved clinical outcomes by reducing recurrence and preserving renal function. These advances have redefined treatment approaches, particularly in pediatric patients and those undergoing kidney transplantation. The prophylactic use of complement inhibitors is now recommended for transplant recipients with moderate to high genetic risk. This review aimed to examine the pathophysiology, clinical manifestations, and treatment strategies of aHUS. Early and targeted complement inhibition is essential for preventing irreversible kidney damage and optimizing outcomes, particularly in children and transplant recipients.
Introduction
Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) [1]. Atypical HUS (aHUS) is a rare and heterogeneous subtype that occurs in the absence of Shiga toxin-producing Escherichia coli infection. The global epidemiology of aHUS remains poorly defined, with an estimated annual incidence ranging from 0.23 to 1.90 cases per million population, varying by age and geographic region. The reported prevalence estimates range from 2.21 to 9.40 cases per million [2]. The pathogenesis of aHUS involves dysregulation of the alternative pathway (AP), resulting in uncontrolled activation and deposition of complement components on endothelial cells, leading to vascular injury and microthrombus formation [3,4]. In approximately 40% to 60% of patients [5-7], aHUS is associated with pathogenic variants in genes encoding complement regulatory proteins, including complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP), thrombomodulin (THBD), complement factor B (CFB), complement component 3 (C3), or the presence of anti-factor H autoantibodies [8,9]. Although the kidneys are primarily affected by aHUS, extrarenal involvement can occur in up to 20% of patients. It may involve the central nervous system (CNS), eyes, cardiovascular system, lungs, and gastrointestinal tract [10]. If not promptly recognized and treated, aHUS can lead to significant morbidity and a high likelihood of progression to end-stage kidney disease (ESKD), especially in children [4]. This review aimed to provide a comprehensive overview of pathophysiology, clinical manifestations, and evolving management strategies for aHUS, with a particular focus on pediatric populations and patients undergoing kidney transplantation (KT).
Pathophysiology
aHUS is primarily driven by the uncontrolled activation of the AP, leading to sustained deposition of complement components on the vascular endothelium. This results in endothelial injury, luminal narrowing, and formation of microvascular thrombi–hallmarks of TMA [4,11]. The complement system, an essential component of innate immunity, is activated via three main pathways: classical, lectin, and alternative. In aHUS, AP is pathologically activated by genetic mutations or acquired autoantibodies that impair complement regulation [11]. In this pathway, C3b binds to foreign surfaces and interacts with factor B to form the C3 convertase (C3bBb), which further amplifies complement activation by generating additional C3b [4,11]. This leads to the formation of C5 convertase and triggers the terminal pathway, generating the membrane attack complex (MAC), also referred to as C5b-9, which induces cell lysis [4,11].
Under physiological conditions, the AP is tightly regulated by CFH, CFI, MCP, and THBD [4,11,12]. CFH and MCP serve as cofactors for CFI-mediated degradation of C3b, while THBD helps neutralize the proinflammatory effects of C3a and C5a [4,11]. In aHUS, loss-of-function mutations in these regulatory proteins (e.g., in CFH, CFI, MCP, and THBD) or gain-of-function mutations (e.g., in C3 and CFB) impair this regulation, resulting in uncontrolled complement activation and subsequent endothelial injury [7]. In addition, autoantibodies targeting CFH can further disrupt regulation and exacerbate vascular damage [7].
Glomerular endothelial cells are particularly vulnerable to complement-mediated injury. One hypothesis suggests that the fenestrated structure of the glomerular endothelium lacks sufficient complement regulatory mechanisms, increasing its susceptibility to damage [13]. Another theory proposes that podocyte injury may indirectly contribute to endothelial dysfunction, as the vascular endothelial growth factor secreted by podocytes is essential for maintaining glomerular endothelial integrity [14].
Fig. 1 illustrates these mechanisms, highlighting the key roles of C3 and C5 convertases, the complement regulatory function of CFH, CFI, MCP, and THBD, and the genetic or acquired factors that contribute to complement dysregulation in aHUS.
Dysregulation of the alternative complement pathway in aHUS. This schematic illustrates the alternative complement pathway and its dysregulation in aHUS. In physiological conditions, spontaneous hydrolysis of complement component (C)3 leads to formation of C3b, which binds to CFB to form the C3 convertase (C3bBb). This complex enzyme amplifies complement activation, generating additional C3b and forming the C5 convertase (C3bBbC3b), which triggers the terminal complement cascade and assembly of MAC. Complement regulatory proteins–CFH, CFI, MCP, and THBD–normally control this process. In aHUS, loss-of-function mutations in these regulators, gain-of-function mutations in C3 or CFB, or the presence of anti-CFH antibodies lead to uncontrolled complement activation, endothelial injury, and thrombotic microangiopathy. aHUS, atypical uremic syndrome; CFB, complement factor B; MAC, membrane attack complex; CFH, complement factor H; CFI, complement factor I; MCP, membrane cofactor protein; THBD, thrombomodulin.
Clinical features
Renal manifestations
Renal involvement is the hallmark of aHUS. Most patients present with AKI, ranging from mild elevation in serum creatinine levels to severe oliguric or anuric renal failure. Proteinuria and hematuria are commonly observed at the time of diagnosis. In a French pediatric cohort [15], 24% of survivors developed ESKD after the first episode, whereas an Italian cohort reported persistent renal dysfunction in 32% of patients [6]. Similarly, data from the Turkish pediatric aHUS registry indicated that although more than 75% of patients had an estimated glomerular filtration (eGFR) of >90 mL/min/1.73 m2, approximately 10% progressed to ESKD during follow-up [16]. In an international prospective cohort study, Johnson et al. [17] reported that 17% of patients with aHUS remained dialysis-dependent until day 33, 46.4% had renal impairment, 11.3% had persistent proteinuria, and 80.3% had renal sequelae.
Extrarenal manifestations
Although renal involvement is predominant, aHUS can also affect other organs with dense endothelial networks. Extrarenal manifestations occur in approximately 20% to 50% of patients with HUS and contribute significantly to morbidity and mortality [18,19]. Beyond the kidneys, the commonly affected systems include the CNS, eyes, cardiovascular system, lungs, and gastrointestinal tract [18,19]. A schematic representation of the extrarenal manifestations of the organ system is shown in Fig. 2.
Extrarenal organ involvement in atypical hemolytic uremic syndrome, including neurological, pulmonary, cardiovascular, and gastrointestinal systems. This schematic illustrates extrarenal organ involvement in atypical hemolytic uremic syndrome, including complications affecting the central nervous, pulmonary, cardiovascular, and gastrointestinal systems. Neurological complications may include seizures and altered consciousness; pulmonary involvement includes respiratory failure and pulmonary edema; cardiovascular complications include cardiomyopathy and heart failure; and gastrointestinal manifestations include pancreatitis, elevated transaminases, and gastrointestinal bleeding.
Central nervous system
CNS involvement is the most frequent extrarenal manifestation of aHUS, reported in 8% to 48% of patients with aHUS [7,16,17,19,20]. Seizures are the most common neurologic symptom, followed by headache, altered consciousness, encephalopathy, vision loss, and hemiparesis [18,19]. In an international cohort study, Johnson et al. [17] observed neurological involvement in 19.7% of patients, including seizures (11.3%) and altered consciousness (8.7%). Similarly, in a Turkish pediatric aHUS cohort, seizures were reported in 20.7% of the patients, and among those with neurological symptoms, 50% also had hypertension [19].
Ocular system
Ocular involvement may present as reduced visual acuity, diplopia, scotomata, ocular pain, and blurred vision. Fundoscopic examination may reveal bilateral flame-shaped intraretinal hemorrhage, optic disc edema, and retinal vessel tortuosity [21,22].
Cardiovascular system
Cardiovascular complications are observed in approximately 3% to 10% of patients with aHUS [23] and include dilated or hypertrophic cardiomyopathy, valve insufficiency, congestive heart failure, myocarditis, and myocardial infarction [23,24].
Pulmonary system
Pulmonary involvement, although often underrecognized, contributes significantly to morbidity in aHUS. Pulmonary complications include pulmonary edema, embolism, and alveolar hemorrhage. Johnson et al. [17] observed that 21% of pediatric patients developed respiratory failure requiring mechanical ventilation, and 1.4% experienced pulmonary effusion.
Gastrointestinal system
Gastrointestinal manifestations are relatively common. In a Turkish study by Besbas et al. [16], 10.9% of pediatric patients exhibited gastrointestinal manifestations such as pancreatitis, cholelithiasis, elevated liver enzyme levels, vomiting, and gastrointestinal bleeding. In an international cohort study, Johnson et al. [17] reported pancreatitis or pancreatic insufficiency (8.5%) and elevated transaminase levels (8.5%) as the most frequent findings, followed by abdominal pain or feeding difficulties (7.0%), intestinal perforation (2.8%), cholestasis or gallstones (2.8%), and gastrointestinal bleeding (1.4%).
Treatment of aHUS
Supportive management
Management of aHUS begins with comprehensive supportive care. Initial supportive care includes correction of anemia with packed red blood cell transfusions when indicated, careful fluid management to maintain euvolemia, and prompt initiation of kidney replacement therapy in patients with severe AKI, presenting with uremic symptoms, fluid overload, or electrolyte imbalance [4,25]. Hypertension should be aggressively managed with antihypertensive agents, and nephrotoxic medications should be avoided whenever possible. Platelet transfusions are typically administered when life-threatening bleeding occurs, or surgical intervention is required [4]. Continuous monitoring of kidney function, blood pressure levels, hemoglobin levels, lactate dehydrogenase (LDH) levels, and complement activity is crucial for assessing disease activity and treatment responses [4,25].
Plasma therapy
Before the introduction of complement inhibitors, plasma therapy, including plasma exchange and plasma infusion, was the mainstay of aHUS management. Plasma exchange removes pathogenic autoantibodies and mutated circulating complement proteins, whereas plasma infusion provides functional complement regulatory proteins [3,6]. Guidelines recommend plasma therapy within 24 hours of symptom onset in patients presenting with microangiopathic hemolytic anemia, thrombocytopenia, or AKI. Plasma infusion (10–20 mL/kg) or plasma exchange (1.5 plasma volumes or 60–75 mL/kg per session) is typically administered daily from 5 days to 2 weeks until the platelet count and hemoglobin and LDH levels have normalized [3,11]. Maintenance therapy may then be tapered, with intervals extending from weekly to every 2–4 weeks, depending on the clinical response [11]. Complete remission is defined as the normalization of both hematological and renal parameters, whereas partial remission refers to hematological recovery with persistent renal dysfunction and sequelae. If no clinical improvement is observed with plasma therapy, the patient is transitioned to complement inhibitor therapy. In a multicenter study, plasma therapy resulted in complete or partial remission in 63% to 97% of patients experiencing episodes, with outcomes varying according to the underlying genetic abnormality. Significantly lower response rates were observed in patients with CFH or CFI mutations [6]. Nonetheless, ESKD develops in 28% to 75% of patients despite plasma therapy [6]. Complications such as catheter-related infections, thrombosis, bleeding, and sensitization to plasma components, may limit the long-term effectiveness of plasma therapy [17].
Eculizumab
Since its introduction in 2009, eculizumab, a recombinant humanized monoclonal antibody that binds to complement component C5, has significantly improved outcomes in patients with aHUS, especially in pediatric populations. Eculizumab binds to C5 and prevents its cleavage into C5a and C5b, thereby inhibiting the formation of the MAC and blocking terminal complement activation [26,27].
Early treatment with eculizumab, ideally within 24 hours of clinical suspicion, is associated with improved renal outcomes and hematological normalization. Genetic testing to identify complement mutations or autoantibodies is important for long-term management but should not delay the initiation of eculizumab. If eculizumab is not immediately available, plasma therapy may be administered temporarily until definitive therapy is initiated. Clinical trials have demonstrated the efficacy of eculizumab in achieving hematological normalization, improving renal outcomes, and reducing the need for dialysis and KT. In a phase II trial by Licht et al. [28], the long-term outcomes of eculizumab therapy were evaluated over 2 years. In trial 1, 82% of the patients showed platelet count normalization at 26 weeks, increasing to 88% at both 1 and 2 years [28]. In trial 2, 80% of the patients were TMA event-free at 26 weeks, which further improved to 85% at 1 year and 95% at 2 years [28]. Notably, dialysis was discontinued in several patients, and none required KT during the 2-year follow-up period [28]. Eculizumab has been proven to be highly effective in pediatric patients. A phase II study involving 22 pediatric patients showed that 64% achieved a complete TMA response by week 25, 82% achieved hematologic normalization, and 95% remained event-free [29]. Moreover, all patients discontinued plasma therapy, and 82% of those who required dialysis at baseline achieved independence during the study period.
In adults, eculizumab is administered intravenously at 900 mg weekly for the first 4 weeks, followed by 1,200 mg at week 5, and subsequently 1,200 mg every 2 weeks thereafter [30]. For pediatric patients weighing less than 40 kg, a weight-based dosing regimen is recommended. Dosing is stratified according to body weight, with patients exhibiting higher body weights receiving proportionally greater maintenance doses. For example, patients weighing 5–10 kg received 300 mg weekly for 4 weeks, followed by 300 mg every 2 weeks, whereas those weighing 30–40 kg received 600 mg weekly for 4 weeks, followed by 1,200 mg every 2 weeks (Table 1).
Weight-based eculizumab dosing regimen for pediatric patients weighing <40 kg
As eculizumab inhibits terminal complement activation, it increases susceptibility to infections caused by encapsulated bacteria, particularly Neisseria meningitidis. To reduce this risk, meningococcal vaccination should be administered at least 2 weeks prior to the first eculizumab dose [31]. In urgent situations where immediate initiation of eculizumab is necessary, prophylactic antibiotics such as ciprofloxacin (500 mg twice daily), rifampin (600 mg twice daily), or penicillin VK (250 mg four times daily) should be administered during the first 2 weeks of therapy [31]. In clinical trials, Legendre et al. [32] and Licht et al. [28] reported that the most commonly observed adverse events associated with eculizumab included hypertension, infections, and infusion-site reactions. Other adverse events, such as peritonitis, influenza, and venous sclerosis at the infusion site, were also noted. Importantly, meningococcal infection did not develop in any of the patients despite the elevated risk of terminal complement blockade. Furthermore, the incidence of adverse events decreased over time, and no cumulative toxicity was observed. These findings support the use of eculizumab as an effective and well-tolerated long-term therapy.
Ravulizumab
Ravulizumab is a long-acting complement C5 inhibitor developed as a next-generation therapy to address the limitations of eculizumab. It was derived by introducing two specific amino acid substitutions into eculizumab, which enabled pH-dependent binding dynamics with C5. These modifications allow ravulizumab to maintain a strong binding affinity at physiological pH (7.4) while facilitating dissociation from C5 in the acidic environment of endosomes (pH 6.0) [33]. This mechanism promotes enhanced recycling through the neonatal Fc receptor pathway, significantly extending the antibody’s half-life to approximately 51.8 days, more than four times longer than eculizumab. As a result, ravulizumab allows for less frequent dosing and is administered every 4–8 weeks depending on the patient’s body weight [33,34]. In a phase III trial evaluating ravulizumab in pediatric patients with aHUS, 77.8% of patients achieved a complete TMA response by week 26. Additional clinical outcomes included platelet normalization in 94.4%, LDH normalization in 88.9%, and a ≥25% improvement in serum creatinine levels in 83.3% of patients [33]. By week 50, 94.4% of patients maintained a complete TMA response [33]. Renal function also showed substantial improvement, with median increases in eGFR of 80.0 mL/min per 1.73 m2 (range, 0–222.0) at week 26 and 94.0 mL/min per 1.73 m2 (range, 10–230) at week 50 [33]. Common adverse events include pyrexia, headache, nasopharyngitis, diarrhea, and vomiting. Serious adverse events occurred in 66.7% of patients, with viral gastroenteritis and abdominal pain being the most frequently reported [33]. Importantly, none of the patients developed meningococcal infection or died during the study period [33]. Overall, ravulizumab provided rapid and sustained improvements in hematological and renal parameters. Its extended dosing interval offers a significant reduction in the treatment burden and may enhance the quality of life, particularly for pediatric patients requiring long-term therapy.
Kidney transplant
Patients with aHUS are at high risk of progressive kidney damage, with up to 50% potentially developing ESKD, often requiring KT. However, KT in aHUS is complicated by a substantial risk of disease recurrence and graft loss, particularly in individuals with underlying complement dysregulation [35]. In addition to recurrence, de novo aHUS can occur in transplant recipients without a prior diagnosis of the disease. Several triggers have been implicated in the development of de novo posttransplant TMA, including antibody-mediated rejection; viral infections such as cytomegalovirus, human immunodeficiency virus, and parvovirus B19; the use of calcineurin inhibitors, mammalian target of rapamycin inhibitors, and valacyclovir; and the presence of prothrombotic conditions such as antiphospholipid syndrome [36]. In a study by Le Quintrec et al. [37], 29% of the patients with de novo posttransplant TMA reported mutations in CFH, CHI, or both, whereas mutations in CFB and/or C3 were found in 25% of patients. The management of aHUS in patients with KT remains challenging. Early recognition of disease recurrence and differentiation from other causes (such as acute antibody-mediated rejection) are critical for preserving graft function. Individualized therapy, guided by genetic risk stratification and early initiation of complement inhibition–most commonly with eculizumab–has markedly improved transplant outcomes in patients with aHUS [37].
KT and aHUS recurrence
The risk of aHUS recurrence following KT varies significantly depending on the underlying genetic abnormality. Patients with mutations in MCP have a lower recurrence risk (up to 15%), whereas those with mutations in circulating complement regulatory proteins such as CFH or CFI have a markedly higher recurrence risk (up to 80%) [38]. A summary of recurrence risk stratification according to specific complement-related genetic mutations is provided in Table 2. To mitigate the risk of recurrence, the Kidney Disease: Improving Global Outcomes guidelines recommend the prophylactic administration of complement inhibitors, particularly eculizumab, in patients identified as having a moderate to high risk of recurrence based on genetic or clinical factors [39]. Prophylactic therapy is particularly emphasized in individuals with CFH or CFI mutations or those with a history of posttransplant aHUS recurrence. Eculizumab is typically initiated prior to transplantation and continued during the peri-transplantation period to prevent early recurrence and graft loss [32].
Genetic risk stratification for aHUS recurrence after KT
Therapeutic strategies for aHUS after KT
The optimal management of aHUS following KT remains incompletely defined, primarily due to the limited availability of prospective clinical trial data. Nonetheless, multiple studies and expert consensus have highlighted the need for an individualized therapeutic approach that incorporates genetic profiles (e.g., mutations in CFH, C3, and CFI), complement dysregulation status, prior transplant history, and clinical presentation. According to recent guidelines and observational data, early recognition and timely initiation of complement inhibition, particularly with eculizumab, can significantly reduce the risk of graft loss and improve long-term outcomes [3,26,32,40]. The comprehensive management of posttransplant aHUS typically involves an integrated strategy that may include therapeutic plasma exchange (when indicated) [26], careful adjustment of immunosuppressive therapy to minimize complement activation [40], and aggressive treatment of concurrent rejection episodes [3,40]. Recently, eculizumab has emerged as a central component of post-transplantation aHUS therapy, particularly in patients with complement gene mutations or evidence of complement overactivation [26,32]. Findings from clinical trials and observational cohorts have consistently demonstrated that eculizumab therapy can substantially lower the risk of recurrent TMA, preserve renal allograft function, and improve graft survival, particularly in patients with mutations in CFH, CFI, C3, or other complement regulatory proteins [26,32,40]. Individualized risk stratification, early diagnosis, and targeted complement inhibition are considered essential strategies for optimizing the outcomes of KT recipients with aHUS.
Conclusions
aHUS is a rare but severe disorder requiring early recognition and prompt intervention to prevent irreversible organ damage. The advent of complement inhibitors, most notably eculizumab and ravulizumab, has significantly improved clinical outcomes in both pediatric patients and kidney transplant recipients. In the context of KT, an individualized therapeutic approach based on genetic and clinical risk assessments is critical to minimizing the risk of disease recurrence and ensuring long-term graft survival. Prophylactic complement inhibition, particularly in high-risk patients, remains an essential component of the current treatment strategies. Continued research efforts and a multidisciplinary approach remain essential for refining individualized treatment approaches and further enhancing long-term outcomes in patients with aHUS.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This study was supported by a 2024 research grant from Pusan National University Yangsan Hospital.
Author contributions
All the work was done by JYS.