Long-term outcome and management of complement-mediated thrombotic microangiopathy/aHUS

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Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy characterized by uncontrolled activation of the complement pathway, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The advent of complement inhibitors such as eculizumab and ravulizumab has transformed aHUS management, markedly reducing morbidity and mortality. However, long-term therapy presents challenges, including infection risks, economic burden, and the need for indefinite treatment. Discontinuing complement inhibition is a pivotal clinical decision that requires careful risk assessment to prevent relapse. Pathogenic gene variants in complement- regulating proteins, particularly CFH, CFI, MCP/CD46, and C3, significantly increase the risk of relapse, particularly within the first 3 to 12 months after cessation. Patients with multiple pathogenic variants or variants of uncertain significance exhibit heightened vulnerability, necessitating extended monitoring. Clinical predictors such as young age, prior kidney transplantation, and the presence of extrarenal manifestations further stratify relapse risk. Additionally, dynamic biomarkers such as elevated soluble C5b-9 at the time of discontinuation may signal imminent relapse. Comprehensive postdiscontinuation surveillance, including laboratory assessment of kidney function, hemolysis markers, and complement activity, is crucial for early relapse detection. Emerging strategies for personalized risk assessment, including pharmacogenomic profiling and biomarker-guided monitoring, may optimize therapeutic decision-making in aHUS. This review synthesizes current evidence on the long-term management of aHUS, focusing on strategies for anticomplement therapy discontinuation, relapse prediction, and individualized monitoring.

Learning Objectives

• Provide an update on monitoring atypical hemolytic uremic syndrome (aHUS) and anticomplement therapy

• Provide guidance on the discontinuation of anticomplement therapy and assess the risk of aHUS relapse

Introduction

Complement-mediated thrombotic microangiopathy (CM-TMA), or atypical hemolytic uremic syndrome (aHUS), is a rare, life-threatening thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.^1,2 C5 inhibitors (eculizumab, ravulizumab) have transformed outcomes, cutting kidney failure rates from ∼50% to ∼12% and reducing acute mortality that could reach as high as 25%.³

Long-term management, covering therapy duration, relapse monitoring, and high-risk scenarios (surgery, pregnancy), must be individualized, especially for patients with pathogenic complement variants, who have a higher relapse risk. This review addresses genetic relapse risk, monitoring, diagnosis, and special clinical contexts.

Genetic factors and relapse risk in aHUS

Inherited or acquired complement regulation defects are found in ∼60% of patients with aHUS. Pathogenic variants in complement regulators (CFH, CFI, MCP) or activators (C3, CFB) occur in ∼50% to 60%,¹ with ∼40% to 50% penetrance, typically manifesting after a trigger such as infection or pregnancy.⁴ Anti–factor H (FH) autoantibodies, often linked to CFHR1-3 deletion, occur in ∼10%⁴ and are more common in patients from Africa⁵ or India.⁶

Genetics strongly influences the prognosis of aHUS. Pathogenic variants, especially in CFH, C3, CFI, CFB, and MCP, significantly increase relapse risk after therapy withdrawal. In the French registry, relapse after eculizumab cessation was <5% without genetic variants vs 23% overall.⁷ A meta-analysis found relapse in 42.4% with vs 10.7% without genetic variants, highest for CFH and C3 (>70%).⁸ MCP variants, once considered self-limited, are now linked to frequent relapses.^7,9 The presence of multiple genetic variants may confer a stronger predisposition, though not consistently a higher relapse risk.^7,10 By contrast, “idiopathic” aHUS without detectable variants carries a lower relapse risk, particularly when a one-time trigger can be avoided.

High-risk single-nucleotide polymorphisms (SNPs) in CFH, CFHR3, and MCP are overrepresented in aHUS. CFH C-257T, A2089G, and G2881T¹¹; CFHR3 c.721C>T¹²; and the MCPggaac haplotype¹³ increase susceptibility, with ∼30% penetrance.⁴

Up to 30% of patients harbor a variant of uncertain significance (VUS).⁸ Clinical relevance is more likely if the genetic variant is rare (<0.01%), affects conserved residues or functional domains, is located in a known aHUS hotspot, shows functional impairment in vitro, or segregates with disease.¹⁴ A summary of genetic risk factors for aHUS and their clinical implications is shown in Table 1.

Table 1.

Genetic risk factors for aHUS and relapse

Complement gene variants

○ Found in ∼50%-60% of patients (CFH, CFI, MCP/CD46, C3, and CFB)

○ Penetrance: ∼40-50%

○ Require an environmental “second hit” such as infection, pregnancy, or surgery

○ Additional genes:

▪ DGKE: Associated with infantile-onset aHUS

Acquired factors

○ Approximately 10% of patients have anti-FH antibodies, often associated with CFHR1-3 deletion.

○ Autoantibodies disrupt complement regulation.

Genetic risk and relapse

○ High-risk pathogenic gene variants include CFH, C3, CFI, and CFB.

○ MCP gene variants were historically considered low-risk but shown to have high relapse risk.

○ Multiple complement gene variants may increase predisposition to relapse.

○ Idiopathic aHUS (no genetic variants) generally has a lower relapse rate.

SNPs and haplotypes

○ High-risk SNPs in CFH (C-257T, A2089G, G2881T)

○ CFHR3 pathogenic variant (c.721C>T)

○ MCP promoter haplotype (MCPggacc)

○ Penetrance: ∼30%

Variants of uncertain significance

○ Found in 30%-40% of patients

○ Clinical relevance requires:

▪ Low population frequency (<0.01%)

▪ Location in conserved or functional domains

▪ Functional assays or family segregation studies

Clinical implications

○ Risk-stratified treatment approach:

▪ High-risk patients may require long-term or lifelong therapy.

▪ Low-risk patients may consider therapy discontinuation after 6-12 months.

○ Relapse occurs in 20%-35% of patients postdiscontinuation, often within 3-12 months.

aHUS, atypical hemolytic uremic syndrome; FH, factor H; SNP, single-nucleotide polymorphism.

Many centers use the genetic profile to stratify long-term management of aHUS patients.^7,9,10 High-risk features (eg, pathogenic CFH, C3, CFI, MCP, and CFB variants; strong family history; early onset; or extrarenal involvement) often warrant prolonged and, in some cases, lifelong complement inhibition. Low-risk patients (no pathogenic variants, apparent reversible trigger, complete recovery) may be considered for therapy withdrawal after ≥6 to 12 months,^7,15 with close monitoring.

An emerging consensus is initial treatment for 6 to 12 months, then reassessment. Relapse after eculizumab cessation occurs in 20% to 35%, usually within 3 to 12 months.² Stopping therapy requires a plan for rapid reinstitution if relapse occurs, with patients educated to watch for symptoms (fatigue, pallor, petechiae, jaundice, dark urine, hypertension, edema, oliguria, neurologic signs). Labs typically show proteinuria, rising creatinine, elevated lactate dehydrogenase (LDH), anemia, thrombocytopenia, low haptoglobin, and schistocytes; complement activation markers, such as soluble C5b-9 (sC5b-9), may also increase.

Laboratory monitoring and follow-up evaluations

Long-term follow-up in aHUS requires regular labs to detect relapse and assess therapy. Given the absence of standardized relapse surveillance after discontinuation, patients are followed with close monitoring at the provider's discretion. Core tests include complete blood count (CBC), LDH, haptoglobin, bilirubin, serum creatinine, estimated glomerular filtration rate (eGFR), and urinalysis for proteinuria/hematuria.^1,15 A drop in hemoglobin with elevated LDH/schistocytes or rising creatinine/proteinuria should prompt concern for recurrence.

Anti-C5 therapy should start at aHUS diagnosis, but indefinite treatment is no longer standard. It is generally given for 3 to 6 months, followed by reassessment and individualized continuation.¹⁵ If kidney recovery has not occurred within 6 months and dialysis dependence continues, therapy may be discontinued once extrarenal disease has resolved. Relapses are usually kidney-limited, often indicated by rising creatinine and sometimes requiring a kidney biopsy for confirmation.

In established aHUS, relapse characterized by rising creatinine, thrombocytopenia, hemolysis, and schistocytes generally warrants treatment without biopsy. However, biopsy is valuable after a kidney transplant or when alternative diagnoses (eg, lupus nephritis, vasculitis) must be distinguished from recurrent TMA.

After stopping eculizumab or ravulizumab, close monitoring is advised, with labs checked weekly to biweekly after the first missed dose, for 3 months, and then monthly up to 1 year, since most relapses occur within 6 to 12 months.⁷ Patients should be educated to recognize relapse symptoms and promptly report triggers such as infections.¹⁶

In patients on anticomplement therapy, CH50 testing is used to monitor the adequacy of complement inhibition. CH50 is a pH-sensitive assay and less reliable for ravulizumab.¹⁵ Effective C5 blockade with eculizumab or ravulizumab reduces CH50 to nearly undetectable levels (<10% of normal indicates complete inhibition).^15,17 CH50 should be checked during initiation (eg, before the first ∼4 infusions) to confirm sufficient dosing.¹⁷ CH50 monitoring is also useful when clinical response is lacking. An undetectable CH50 with persistent TMA warrants evaluation for other causes or therapies. The AH50 (alternative pathway assay) can also be used, although it is preferred to CH50 for monitoring of ravulizumab but less clinically available than CH50; however, with effective complement blockade, both CH50 and AH50 should be suppressed.¹⁸

Some centers also measure trough eculizumab (>100-150  µg/mL) or free C5 (<0.5  µg/mL) levels to guide dosing, but these tests are not routinely performed. In settings such as proteinuria, protein-losing enteropathy, or pregnancy, higher doses or shorter dosing intervals may be required. Conversely, fixed dosing often results in supratherapeutic levels (>100  µg/mL), while extending intervals has not reduced efficacy.¹⁹

Pharmacokinetic monitoring may be required in children due to growth and in patients receiving ravulizumab because of its long dosing intervals. For monitoring ravulizumab, unbound C5 (<0.5  µg/mL), trough ravulizumab (>175  µg/mL), sC5b-9, and AH50 are recommended.^20,21 All these tests, except for free C5 level, are available through specialized reference laboratories, although AH50 is less widely available than CH50.

In patients with anti-FH-associated aHUS, monitoring antibody titers is essential.^2,22 Complement inhibition is usually maintained until titers fall (<1000 AU/mL) with immunosuppression,² as relapse risk decreases once antibodies are eliminated.

Emerging biomarkers may improve the monitoring of aHUS. Research assays such as plasma C5b-9, C5a, and Ba reflect complement activation and could signal subclinical TMA,^23,24 but their predictive value for relapse remains unproven. Low C3 or factor B may indicate active disease, but normal levels do not exclude it.¹⁵ Table 2 summarizes lab monitoring tests.

Table 2.

Laboratory Monitoring and Follow-Up in aHUS

Routine monitoring

• CBC, LDH, haptoglobin, bilirubin, creatinine, GFR, urinalysis

• Detect early signs of relapse: hemolysis or kidney injury

Anti-C5 therapy monitoring

• CH50 assay: CH50 < 10% = effective C5 inhibition

• Monitor CH50 before initial doses; adjust dosing if CH50 detectable

• CH50 less useful for ravulizumab; use free C5 (<0.5  µg/mL) or drug trough levels (>175  µg/mL)

High-risk period posttherapy

• Frequent labs (weekly to every other week) in first 3 months, then monthly up to 1 year

• Educate patients on relapse signs and trigger factors (eg, infections)

Autoantibody monitoring

• Monitor anti-FH antibody titers in antibody-associated aHUS

• Continue therapy until titers <1000 AU/mL

Emerging biomarkers

• Ex vivo C5b-9 deposition assays

Modified mHam assay

Human microvascular endothelial cell assay

• Plasma sC5b-9, C5a, Ba: may indicate subclinical complement activation

• Not yet standardized for routine use

aHUS, atypical hemolytic uremic syndrome; CBC, complete blood count; FH, factor H; GFR, glomerular filtration rate; LDH, lactate dehydrogenase; mHam, modified Ham Test; sC5b-9, soluble C5b-9.

Prognostic biomarkers in aHUS

Prediction of relapse after C5 inhibitor withdrawal depends primarily on genetics and certain biomarkers. High-risk features include pathogenic variants in CFH or MCP, persistent sC5b-9 > 300  ng/mL, female sex, extrarenal involvement, and incomplete kidney recovery.⁷ Proteinuria, hemoglobinuria, or new hypertension may precede relapse. The lowest risk is seen in patients without pathogenic variants and with a clear triggering event. Complete renal recovery is associated with favorable outcomes.²⁵ Table 3 summarizes diagnostic and prognostic biomarkers in aHUS.

Table 3.

Diagnostic and Prognostic Biomarkers in aHUS

Diagnostic markers

• ADAMTS13 > 10%: rules out TTP

• Shiga toxin testing: rules out STEC-HUS

• C3 low in ∼50% of active aHUS (supportive, not diagnostic)

• Elevated C5b-9, C5a, Ba/Bb, and C3a reflect complement activation

• CH50/AH50 suppressed in active disease (research use only)

Prognostic biomarkers

• Pathogenic genetic variants (CFH, CFI, MCP, etc) affect severity and relapse risk

• CFH pathogenic variants: ↑ risk of kidney failure; MCP pathogenic variants: ↑ relapse risk

• Anti-FH antibody: diagnostic and requires immunosuppression

Relapse predictors after eculizumab withdrawal

• High sC5b-9 (>300  ng/mL), pathogenic complement gene variants, female sex

• Worsening proteinuria, hemoglobinuria, hypertension: early relapse clues

• Best outcomes in patients with normal kidney recovery and no pathogenic complement gene variants

↑, increase.

ADAMTS13, von Willebrand factor-cleaving protease; aHUS, atypical hemolytic uremic syndrome; MCP, membrane cofactor protein; sC5b-9, soluble C5b-9; STEC-HUS, Shiga toxin-associated hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.

Management of aHUS before major invasive procedures

Major surgery can trigger complement activation and precipitate TMA in patients with aHUS, especially those in remission and off therapy. Stressors include anesthesia, blood loss, tissue injury, and exposure to complement-activating biomaterials (eg, cardiopulmonary bypass) and may act as a “second hit.”

On therapy

In patients receiving eculizumab or ravulizumab, dosing should be scheduled to maintain complete complement blockade perioperatively, by advancing eculizumab if a dose is due or adjusting ravulizumab near the end of its 8-week cycle.

Off therapy

Prophylactic complement inhibition may be warranted in high-risk patients (eg, pathogenic variants, prior severe episodes, cardiovascular surgery, major transplant).^26,27 Strategies include perioperative eculizumab with continuation for 1 to 2 months postoperatively or close monitoring with rapid initiation at the first signs of relapse. In contrast, low-risk patients in long-term remission without variants may be managed with observation alone.

Transplantation and surgical considerations

Kidney transplantation

Before complement inhibitors, chronic advanced kidney disease was common in aHUS, and posttransplant recurrence was frequent, exceeding 80% to 90% with CFH, high with CFI and C3, but lower with MCP (15%-20%) variants.⁴ More than half of transplant recipients experienced recurrence, often leading to graft loss.

Eculizumab has dramatically improved transplant outcomes. Prophylactic C5 inhibition initiated peritransplant and continued for ≥3 to 6 months, or indefinitely in high-risk patients, substantially lowers recurrence and enhances graft survival.²⁷ While some centers discontinue therapy in low-risk cases, most favor long-term maintenance to avert catastrophic relapse.

Posttransplant immune suppression

Calcineurin inhibitors (CNIs), such as tacrolimus and cyclosporine, can induce TMA through complement activation or endothelial injury.²⁸ Distinguishing this from recurrent aHUS in the allograft is difficult; CNI dose reduction or switching may be required, and dual pathology is possible, necessitating close coordination with the transplant team.

Vaccination and infection prophylaxis in patients with aHUS

In long-term complement inhibition, vaccination and infection prophylaxis are essential. All patients should receive meningococcal (Men)ACWY and MenB vaccines ≥2 weeks before therapy when possible²⁹; if urgent treatment is needed, vaccinate promptly and provide interim antibiotics (eg, penicillin or fluoroquinolone) for ≥2 weeks. Breakthrough meningococcal infections have been reported despite vaccination,³⁰ so patients require education, medical alert identification, and immediate evaluation of any fever. Centers for Disease Control and Prevention guidelines also recommend pneumococcal (PCV13/15/20 followed by PPSV23 with 5-year boosters) and Hemophilus influenzae b vaccination, plus routine immunizations (influenza, COVID-19). MenACWY boosters are advised every 5 years and MenB boosters at 1 year, then every 2-3 years. With preventive measures, meningococcal disease is rare,³¹ and the benefits of therapy outweigh infection risks. Table 4 summarizes the recommended vaccination schedule for patients on anticomplement therapy.

Table 4.

Vaccination in patients on anticomplement therapy

≥2 weeks before start

• MenACWY + MenB vaccines (ideal timing)

• Pneumococcal conjugate vaccine (PCV13, PCV15, or PCV20)

• Hemophilus influenzae b

Day 0 (urgent cases)

• Begin C5 inhibitor immediately  • Give vaccines concurrently  • Start antibiotic prophylaxis

Weeks 1-2

• Continue antibiotics for 2 weeks postvaccine to allow immune response

Week 8

• Pneumococcal polysaccharide vaccine (PPSV23)

Ongoing therapy

• Monitor for infection and educate patient on signs/symptoms

• Booster: MenACWY (every 5  y), MenB (1  y, then every 2-3 y)

• Yearly influenza and COVID-19 vaccines

• PPSV23: every 5 years

• Optional antibiotic prophylaxis (individualized)

Discontinuation of anticomplement therapy

• Vaccine protection persists  • Infection risk subsides over weeks

MenACWY, meningococcal ACWY vaccine; MenB, meningococcal B vaccine.

Long-term sequelae of aHUS

Kidney

Chronic kidney disease is the most common long-term outcome; 30% to 50% progress to kidney failure within a year if untreated.^32,33 Even with therapy, proteinuria, hypertension, and reduced kidney function are common.⁷ Chronic endothelial injury may cause arteriolosclerosis or focal segmental glomerulosclerosis, requiring lifelong monitoring and renin-angiotensin system blockade.³⁴

Neurologic

Neurologic complications in acute aHUS, such as seizures, altered consciousness, and posterior reversible encephalopathy syndrome (PRES), may lead to lasting deficits. Long-term sequelae are better documented in Shiga toxin–associated HUS (STEC-HUS),³⁵ likely due to higher case numbers, but aHUS survivors can also show persistent cognitive impairments from microvascular brain injury.³⁶ Children are especially vulnerable to developmental delays during critical neurodevelopmental periods.

Cardiovascular

Hypertension affects over half of aHUS survivors, independent of kidney function,³⁷ driven by parenchymal injury and endothelial dysfunction. Left ventricular hypertrophy is common in both children and adults, while chronic complement dysregulation may promote vascular inflammation and atherosclerosis. Rarely, myocardial TMA causes cardiomyopathy or heart failure. These risks warrant routine cardiovascular monitoring, especially in patients with chronic kidney disease.

Hematologic/complement

Although hematologic parameters usually normalize with treatment, subclinical complement activation may persist, especially in patients with gain-of-function variants,^38,39 predisposing them to relapse after triggers such as infection, surgery, or pregnancy. Relapses often present with kidney dysfunction but can include TMA, cytopenia, or hemolysis; chronic hemolysis may cause iron overload.

Quality of life and special considerations

Fatigue, mood disorders, psychological burden

Many patients report fatigue, anxiety, and depression even after remission, impairing daily function.⁴⁰ Fear of relapse, especially in those with pathogenic variants, affects social life, employment, and family planning.⁴¹

Children and adolescents

aHUS can disrupt schooling and development,⁴² with lasting cognitive/emotional impacts. Parental burden and fear of recurrence during infections highlight the need for psychosocial support.

Management of aHUS during pregnancy and postpartum

Pregnancy and the postpartum period are potential triggers for aHUS; furthermore, pregnancy-associated aHUS (P-aHUS) must be differentiated from other pregnancy-associated TMAs (pregnancy-associated hypertension, preeclampsia/eclampsia, hemolysis, elevated liver enzymes, and low platelets [HELLP], and thrombotic thrombocytopenic purpura [TTP]).^15,43 Table 5 summarizes the clinical and laboratory differences between HELLP, TTP, and P-aHUS. Whereas P-aHUS is complement-mediated, the role of complement in the others remains unproven. P-aHUS, often occurring in the postpartum period, is a well-recognized entity, accounting for a significant subset of adult aHUS cases.⁴⁴

Table 5.

HELLP vs TTP vs P-aHUS in Pregnancy

Feature	HELLP	TTP	P-aHUS
Timing	Third trimester or at delivery	Any trimester (esp. third)	Mostly postpartum
Cause	Placental dysfunction	ADAMTS13 autoantibodies or congenital deficiency	Complement dysregulation
Key labs	↑ AST/ALT, ↓ platelets (<150 K/µL rarely <50 K)	Severe ↓ ADAMTS13 (<10%) ↓↓↓ platelets (frequently <30 K/µL, sometimes <10 K/µL)	ADAMTS13  > 10%, ↑ LDH, ↓ C3 (sometimes) ↓↓ platelets (50-100 K/µL but may be lower)
Kidney involvement	Mild to moderate	Mild or none	Severe AKI common
Neurologic symptoms	Possible (eclampsia)	Very common (80%-90%)	Less common (10%-20%)
Response to delivery	Improves after delivery	No change	Often worsens
Treatment	Delivery, supportive care	Plasma exchange, immunosuppression	Eculizumab, supportive care
Prognosis without treatment	Good	High mortality	High morbidity/mortality

↑, increase; ↓, decrease.

ADAMTS13, von Willebrand factor-cleaving protease; AKI, acute kidney insufficiency; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HELLP, hemolysis, elevated liver enzymes, and low platelet count; LDH, lactate dehydrogenase; P-aHUS, pregnancy-associated atypical hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura. Multiple arrows denote greater magnitudes of increase or decrease.

TTP may occur throughout pregnancy but is most common in the third trimester, as are preeclampsia/eclampsia and HELLP. Differentiation is critical since management differs. Preeclampsia/eclampsia and HELLP require urgent delivery, whereas TTP and P-aHUS are managed medically with plasmapheresis and eculizumab, respectively.⁴³ Without treatment, outcomes are poor, with frequent dialysis and risk of irreversible damage or death, whereas appropriate therapy markedly improves prognosis.⁴⁴

Eculizumab, widely used in pregnant paroxysmal nocturnal hemoglobinuria (PNH)⁴⁵ and smaller numbers of patients with P-aHUS,⁴⁶ crosses the placenta mainly after the second trimester but has not been linked to congenital disabilities.^45,47 It is absent in breast milk, and cord blood levels remain below those affecting complement proteins.⁴⁷ A systematic review of P-aHUS reported that complement inhibition was associated with substantially higher rates of kidney recovery and live birth compared to historical cases managed without eculizumab.⁴⁸ Therefore, the current consensus is that pregnancy is not a contraindication for eculizumab.¹⁵

With limited pregnancy data on ravulizumab, eculizumab is often preferred for its shorter half-life, allowing dose adjustment for complement inhibition and temporary withholding near delivery to reduce neonatal exposure.

Eculizumab dosing may require adjustment during pregnancy. Pregnant patients with aHUS should be monitored closely during gestation and for 4 months postpartum.¹⁵ Those already on therapy should continue it to prevent relapse, with possible dose/frequency increases in late pregnancy if breakthrough activity occurs. Labs should be checked at least biweekly. Prophylactic eculizumab is not recommended for pregnant patients in remission off therapy.

In pregnancy/postpartum TMA, if ADAMTS13 activity >10% and no improvement follows delivery, eculizumab should be initiated promptly. Plasma exchange is often initiated empirically but should be discontinued once aHUS is confirmed, with complement inhibition maintained at full dose. Long-term care requires excluding other TMAs (eg, Shiga toxin–HUS, lupus nephritis), with supportive measures such as dialysis and blood pressure control as needed.

Distinguishing P-aHUS from other pregnancy-related TMAs is critical. Rapid tests (low ADAMTS13 for TTP, high soluble fms-like tyrosine kinase-1 to placental growth factor ratio [sFlt-1/PlGF] ratio for preeclampsia) help differential diagnosis, but persistence or worsening after delivery and plasma exchange strongly indicates aHUS, warranting eculizumab. Eculizumab is generally safe for fetal development but may cross the placenta in late pregnancy, potentially suppressing neonatal complement activity. Complement levels should be monitored and live vaccines deferred until immune function normalizes. Prematurity is common in P-aHUS due to the need for early delivery in the context of maternal illness.

In patients with pathogenic complement variants, relapse risk in future pregnancies is high, and indefinite therapy or prophylactic eculizumab is warranted.

Assessing the risk of aHUS after discontinuation of eculizumab

Discontinuing eculizumab in aHUS is a critical decision, as prolonged therapy lowers relapse risk, but indefinite treatment carries economic, logistical, and infection-related burdens.

Relapse risk after eculizumab withdrawal is highest in the first few months, with a median of ∼20 weeks,⁴⁰ though late relapses can occur.

Pathogenic mutations in complement genes were linked to recurrence.¹⁰ CFH variants conferred a 57% relapse rate, rising to 90% with exon 22 mutations; MCP variants, 51%; and multiple variants, 50%. Variants of uncertain significance raised relapse risk >4-fold and likely pathogenic variants >15-fold compared to benign or absent variants.

A younger age increased relapse risk (each 10-year increment reduced odds by 32%), and prior kidney transplantation markedly elevated recurrence risk.⁸ Soluble C5b-9 levels >300 ng/mL at discontinuation predicted relapse,⁷ with female sex also emerging as a risk factor, while prior dialysis showed no significant effect. A family history of aHUS with progressive renal failure suggests genetic predisposition and may favor continued therapy. In contrast, for patients on dialysis for >3 to 6 months, where kidney recovery is unlikely and extrarenal relapses are rare, discontinuation with close monitoring may be more appropriate than indefinite treatment.

Conflict-of-interest disclosure

Vahid Afshar-Kharghan: no competing financial interests to declare.

Off-label drug use

Vahid Afshar-Kharghan: none to disclose.