Eculizumab for Atypical Hemolytic Uremic Syndrome: Guidance for Developing Countries

Introduction

Hemolytic uremic syndrome (HUS) is an important cause of AKI and the leading cause of thrombotic microangiopathy (TMA) in childhood.^1,2 While Shiga toxin-associated (STEC) HUS is the most common form of the condition globally, the implicated pathogens (enterohemorrhagic Escherichia coli, Shigella dysenteriae) are uncommon in India.³ Atypical HUS (aHUS) is characterized by severe AKI, frequent extrarenal involvement, multiple relapses, and risk of kidney failure. aHUS develops chiefly due to underlying alternate complement pathway dysregulation associated with significant variants in genes encoding factor H (CFH), factor I (CFI), membrane cofactor protein (MCP or CD46), factor B (CFB), or complement C3 (C3). Antibodies against factor H (anti-FH) account for aHUS in 25-55% of pediatric patients (5-15 years).^1,2 Given the predominant role of dysregulation of the alternate complement pathway in aHUS pathogenesis, the term complement-mediated TMA is preferred.

International guidelines recommend that patients with aHUS be treated with eculizumab, a monoclonal antibody against C5, which prevents formation of the membrane attack complex.¹ These recommendations rely on clinical studies that showed that therapy with eculizumab was associated with high rates of hematological remission and recovery of kidney function, with low rates of serious adverse events.⁴ Eculizumab therapy was associated with improved outcomes of aHUS in native kidneys, and risk of transplant recurrences was reduced.^5,6 While the majority of evidence for complement blockade is based on therapy with eculizumab, its long-acting congener ravulizumab is increasingly being used by patients and physicians particularly for maintenance therapy.^1,7 Crovalimab, a C5 inhibitor, targets a different epitope than eculizumab or ravulizumab, enabling C5 blockade in individuals with a rare C5 polymorphism (R885H) that prevents eculizumab binding to C5.^8,9

In the absence of access to C5-blockade in developing countries, intensive plasma exchange (PEX) is an alternative strategy for managing aHUS since it replaces aberrant complement factors and/or removes circulating anti-FH antibodies.² PEX in combination with immunosuppression is associated with satisfactory outcomes in patients with aHUS associated with anti-FH antibodies, the leading cause of TMA in school-going children.¹⁰ However, the role and optimal duration of PEX has not been established for aHUS caused by inherited complement defects who may be refractory to PEX or relapse on its discontinuation.^11,12 Further, the extracorporeal procedure carries a high risk of complications related to vascular access and large plasma infusions.¹³

Until recently, complement blockers were not available in developing countries like India.^2,3 In context of improved access, an update to the consensus guidelines for treatment of HUS (2019) is necessary.² However, the utilization of C5-blocking therapies will be limited by lack of reimbursement for most patients. It also carries risks of serious adverse events such as bacterial infections.

Rational guidance on the use of eculizumab and related therapies is necessary to prevent abuse, improve access, ensure appropriate dosing, and discourage inadequate therapy to improve outcomes and prevent relapses. This document provides the indications for use, dosing schedule, duration of therapy, risk mitigation, and expected adverse events of eculizumab. For guidance on diagnostic evaluation and management of specific entities, readers are referred to guidelines² and recent expert opinions.¹⁴

Indications for use

Table 1 provides the indications for use of eculizumab. Since 2009, international guidelines have recommended prompt therapy with eculizumab, preferably within 24-48 hours of diagnosis, regardless of etiology. This was based on single-limb multicenter prospective trials in patients with aHUS, which showed rapid recovery of kidney functions and hematological remission following C5-blockade.^15–18 A recent comparison of genotype-matched and complement-mediated aHUS cohorts from the United Kingdom showed that therapy with eculizumab resulted in two-fold improved kidney survival (85.5% vs. 39.5%; P <0.0001).⁶ Hence, therapy with eculizumab/ravulizumab is the standard of care for initial management of aHUS, except in low-resource settings with limited access.

While PEX remains effective for patients with aHUS in low-resource settings, there is high risk of relapse and kidney failure.¹² However, complement blockers are likely to remain inaccessible for most patients and related disorders, given their high cost and out-of-pocket expenses. Even if complement blockade is initiated promptly to induce hematological remission or recovery of kidney functions, the feasibility of sustaining this blockade is uncertain given the cost of therapy, need for frequent hospital visits, and risk of severe infections in incompletely immunized patients.

The authors believe that PEX or complement blockade will continue to be used for the initial management of aHUS in south Asia [Table 1]. It is emphasized that either therapy must be provided in adequate doses and for sufficient duration to achieve relapse-free outcomes.

aHUS associated with antibodies to FH (anti-FH associated HUS) is an exception to the above strategy² in being uniquely amenable to management with PEX in combination with immunosuppression. Data from 488 patients, from multicenter studies, indicates that the combination of PEX and immunosuppression induces hematological remission and recovery of kidney functions in patients with this disease.^10,19–29 Therapy with eculizumab, which inhibits the terminal complement pathway and retards formation of the membrane attack complex, is also associated with highly satisfactory outcomes. However, data on the efficacy and safety of eculizumab in anti-FH associated HUS, is limited to 59 patients, chiefly of Caucasian ethnicity.^{23,25,30–41} Further, therapy with eculizumab does not influence anti-FH titers and persistently high anti-FH titers are associated with risk of relapse.^20,42

Intensive PEX is preferred for patients with thrombotic thrombocytopenic purpura (TTP), suspected in individuals with TMA and severe thrombocytopenia (<30,000/mm³) that is out of proportion to AKI severity, or based on clinical prediction tools such as PLASMIC, Bentley, or French scores.⁴³ The diagnosis relies on showing markedly low ADAMTS13 activity (<10%) in freshly drawn plasma. Congenital TTP (cTTP), typically presenting in early childhood or pregnancy, is diagnosed by demonstrating significant biallelic variants in ADAMTS13. Patients with congenital TTP are usually managed with PEX and/or plasma infusions in the long term. Immune-mediated TTP (iTTP), the leading cause of TMA in adolescents and adults, is caused by anti-ADAMTS13 antibodies that neutralize or induce ADAMTS13 clearance. The condition is diagnosed by showing reduced ADAMTS13 activity or the presence of anti-ADAMTS13 antibodies. Most patients with iTTP receive PEX along with brief immunosuppression, including rituximab.⁴⁴ Novel agents, including recombinant ADAMTS13 and caplacizumab are not available in the country.³⁷

Some patients (∼5-8%) with suspected aHUS do not respond to eculizumab therapy. These patients may have pathogenic variants in genes outside the complement pathway, including DGKE (nephrotic-range proteinuria in children <2-yr-old), cobalamin pathway (MTR, MMACHC), nephrotic syndrome (INF2, LMX1B, NPHS2, ACTN4), apparent mineralocorticoid excess (HSD11B2), primary hyperoxaluria type 1 (AGXT), and RNA processing genes, including EXOCS3 (pontocerebellar hypoplasia type 1B), EXOCS5 (cerebellar ataxia, brain abnormalities, cardiac conduction defects; CABAC syndrome), TSEN2 (TSEN2-related aHUS, craniofacial malformations, kidney failure or TSEN2-TRACK syndrome) and POLR3B (Pol III-related leukodystrophy or hypomyelination, hypodontia and hypogonadotropic hypogonadism, 4H, leukodystrophy) [Table 1].⁶

Limited evidence from case series supports complement blockade in patients with STEC-HUS associated with severe neurological involvement and/or myocardial dysfunction.⁴⁵ However, a severity-matched cohort of 54 patients and two randomized controlled trials involving 136 children with STEC-HUS did not demonstrate any benefit with eculizumab in reducing the time to renal or hematological remission or resolution of extra-renal manifestations.^46–48 Unlike the cohort study and ECUSTEC that found no differences in 1-year outcomes, ECULISHU demonstrated favorable kidney outcomes at 1-year in patients treated with eculizumab. Systematic reviews do not indicate a significant impact of eculizumab therapy on medium- to long-term outcomes in patients with STEC-HUS.⁴⁹ Similarly, evidence for benefit of complement blockade in patients with pneumococcal HUS is anecdotal,⁵⁰ indicating that supportive treatment is the cornerstone of management of infection-associated HUS [Table 1].

Eculizumab is useful in complement-mediated TMA associated with pregnancy. However, the diagnosis of this entity requires exclusion of mimics including preeclampsia, cTTP, iTTP, the syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP), puerperal sepsis, and disseminated intravascular coagulation.⁵¹ Complement blockade has variable efficacy in TMA that accompanies 15% of cases of autoimmune diseases. Favorable response to eculizumab therapy was reported for 93% of 30 patients with systematic lupus erythematosus, and 74% of 39 patients with catastrophic antiphospholipid syndrome.^52,53 Variants predisposing to complement dysregulation are uncommon in TMA secondary to medications, infections, malignancies, glomerulopathies, solid organ transplantation, malignant hypertension and pancreatitis; the role of eculizumab in these conditions is uncertain.² C5 blockade should be considered in patients with TMA that persists despite management of malignant hypertension, and refractory cases of TMA associated with hematopoietic stem cell transplantation^54–57 [Table 1].

Dose and schedule

Box 1 summarizes practical guidance for dosing with eculizumab in pediatric and adult patients. While current guidelines advise a fixed dosing schedule, recent studies are exploring the role of monitoring soluble C5b-9 or CH50 levels at onset or during therapy. They use pharmacokinetic-pharmacodynamic models to predict response to therapy or individualize eculizumab dosing for optimal efficacy, to ensure patient-friendly and cost-effective treatment.^58,59

Supplementary Table S1 and Table 2, summarize recommendations on vaccinations before initiating complement blockade, and regimens for antibiotic prophylaxis.^1,2 Guidelines mandate that all patients receive appropriate meningococcal and pneumococcal vaccines, beginning at least 2-weeks prior to the first dose of eculizumab. Acutely ill patients who receive immunization simultaneously with eculizumab should receive antibiotic prophylaxis for the duration of complement blockade and up to 2 months afterwards.^1,2

Patient-level data from clinical trials on eculizumab and ravulizumab, a molecule re-engineered from eculizumab to extend its half-life fourfold, show that the medications show comparable time to recovery of kidney function and hematological remission.^4,60 The convenience of infrequent (8-weekly) administration is important for the long-term in patients in whom discontinuing complement blockade is not appropriate. The COMMUTE studies (NCT04861259, NCT04958265) are expected to provide data on the safety and efficacy of therapy with crovalimab for pediatric and adult patients with TMA.⁶¹ Studies in paroxysmal nocturnal hematuria suggest patient preference for crovalimab given the less frequent dosing and subcutaneous route of administration.⁹ In addition, therapy with crovalimab is effective in the rare patients with non-synonymous single nucleotide polymorphisms of ARG885 (c.2654G>A; c.2653C>T) who are refractory to therapy with eculizumab or ravulizumab.⁶¹ Neither ravulizumab nor crovalimab are currently marketed or licensed for use in TMA in India. Supplementary Table S2 summarizes dosing guidance for these two medications.

Monitoring

Patients with TMA are critically ill and need constant vigilance for severe AKI, thrombocytopenia and anemia, need for kidney support therapy, transfusion of blood products and/or other supportive measures.^1,2 Following initiation of eculizumab therapy, patients require close monitoring for adverse effects, including serious infections, as well as for hematological remission and recovery of kidney function [Table 3]. Once remission is achieved, less frequent monitoring is acceptable. Therapy with eculizumab may be interrupted transiently during serious infections, at physician discretion. In cases of infection-triggered complement-mediated TMA, therapy with eculizumab may be initiated under adequate antibiotic cover, after weighing the risks and benefits.

As many as 50% of patients with significant variants in complement regulatory genes show disease relapses, particularly during the first 12 months and following discontinuation of complement blockade.⁶² While Fakhouri, et al. propose elevated levels of soluble C5b-9 as a marker of relapse, these levels may remain high in a proportion of patients despite sustained remission and adequate eculizumab levels, or increase in response to infections.⁶³ The association between persistently low C3 and relapse risk has not been established. Since eculizumab inhibits C5 without influencing C3 levels, these levels might not indicate the efficacy of the complement blockade.

Careful monitoring must continue for at least 2 years after discontinuing therapy in patients with aHUS [Table 3].⁶² Patients with secondary TMA have lower recurrence risk. Parents and physicians should be vigilant for features of relapse, particularly following minor infections and after complement blockade is discontinued. Urine dipstick monitoring for hemoglobin has been proposed as a useful home-based strategy for detecting relapses but requires validation.³²

Patients and parents should be informed about the risk of serious infections, particularly invasive meningococcemia. Vaccination and prophylactic antibiotics offer partial protection against the disease.⁶⁴ They should be taught about the clinical features of these infections and the need for prompt therapy (‘pill in the pocket’) while awaiting in-hospital review.

Adverse events

Most adverse events reported following eculizumab use are mild to moderate in severity, the most common being nasopharyngitis, diarrhea and abdominal pain [Table 4].^65-69 Invasive meningococcal infections remain the most dreaded complication of complement blockade, with studies indicating a 550-fold increased risk of contracting meningococcal infections compared to the general population.⁶ The risk of contracting other infections, particularly those caused by encapsulated organisms, is also increased several-fold. Hence, patients must be immunized against Neisseria meningitidis before commencing eculizumab therapy, as well as receive appropriate vaccination against Streptococcus pneumoniae, Hemophilus influenzae, and influenza virus.¹⁴ However, humoral and cellular responses to vaccination may vary according to the severity of immunosuppression and kidney disease, and vaccination offers incomplete protection from infections, especially in the early phases of therapy. Careful vigilance and prompt management of infections is imperative for all patients under complement blockade.

Discontinuation of complement blockade

Until recently, guidelines recommended indefinitely prolonged use of eculizumab in patients with aHUS, particularly in those at high risk of disease recurrence [Table 5]. Given the high costs of care, need for frequent hospital visits, high infection risk, and unclear adverse effects of long-term medication use, discontinuation of therapy has been attempted after varying periods of satisfactory response. Studies indicate that safe withdrawal of complement blockade with eculizumab is possible after 3-18 months of the acute episode in most patients.^70–72 Review of data on 171 patients with aHUS indicates about 30% relapse risk after eculizumab discontinuation at a median of 6-months.⁶² While pathogenic variants in CFH and MCP are the most common etiologies in patients with relapses, the latter have favorable long-term outcomes. Experience from the United Kingdom cohort in whom eculizumab was discontinued suggests high risk of relapse in those with pathogenic or likely pathogenic variants in complement regulatory genes (1 in 9.5 person-years), intermediate risk in those with variants of uncertain significance (1 in 10.8 person-years), and negligible risk in those with no variants (none in 67 person-years).⁶

Table 5 summarizes the opinion on indications of discontinuing complement blockade and management of relapse based on genetic screening and testing for anti-FH antibodies. Eculizumab discontinuation appears feasible in patients with MCP (low morbidity despite high relapse rate), CFI variants (most variants have unclear significance and low risk of relapse),^73–75 THBD/CD141 variants (as frequent as in normal population; presence unlikely to influence management),³³ and DGKE, MTR and MMACHC variants (refractory to eculizumab).⁶ In anti-FH-associated HUS, eculizumab discontinuation may be considered once anti-FH levels are <1000 AU/L.^35,76

Physicians and families of patients should be aware of the risk of relapse, especially in the first 6 months following discontinuation. Monitoring with complete blood counts, C3, creatinine, urinalysis, and urine protein-creatinine ratio is advised every 2-3 months for at least 2 years. In case of relapse, eculizumab therapy needs to be restarted within 24-hours, including induction doses followed by maintenance therapy, with a plan to continue for a longer duration.⁶²

Eculizumab use at transplantation

The recurrence risk in the allograft is chiefly determined by etiology [Table 6]. Prophylactic administration of eculizumab beginning within 24 hours after transplantation is recommended in patients at moderate to high recurrence risk,⁷⁷ since the risk of allograft loss is high (40-50%). This strategy is associated with excellent graft outcomes.⁵ While patients at high aHUS risk require long-term therapy, those with moderate risk may discontinue therapy after 6-12 months.^33,78 Factors considered when discontinuing therapy include eGFR >30 mL/min/1.73m² and the lack of acute viral infections or rejections.³³

An alternative strategy of eculizumab administration, as ‘rescue’ therapy within 7 days after aHUS recurrence, appears to be associated with satisfactory allograft survival, comparable to prophylactic therapy.^33,79,80 While the highest risk of recurrence necessitating rescue therapy is within the first year of transplantation, late recurrences are also described that may not always meet the aHUS triad. Patients receiving rescue therapy require long-term complement blockade regardless of etiology.³³

In low-resource settings, where sustained availability of eculizumab is a concern, combined kidney-liver transplantation remains an option for patients with complement-mediated HUS and kidney failure.⁸¹ In such cases, the peri-operative period must be covered with prophylactic eculizumab therapy and complement blockade discontinued after a few weeks of established liver function.⁸²

Table 6 summarizes the recommendations on indications and duration of complement blockade in peri- and post-kidney transplantation period. Eculizumab does not have any drug interactions with immunosuppressants used in kidney transplant recipients. Despite a theoretically increased infection risk, no additional adverse events or infections are ascribed to complement blockade when used post-transplantation, as compared to their use in native kidneys.

aHUS (complement-mediated TMA) is an ultra-rare but severe illness that requires prompt and specific management. While the outcome of aHUS has improved following better evaluation and specific therapies, management with C5 blockers has been limited chiefly to high-income countries. As these therapies are becoming available in India and south Asia, we have summarized available evidence and expert opinion on the indications, prescription and duration of complement blockade, keeping in perspective the cost of care, risks of infections and feasibility of monitoring.