Individualised therapeutic approach to the patient with atypical haemolytic-uraemic syndrome

Highlights

• •aHUS is a rare complement disease, leading to TMA.
• •eculizumab is a lifelong therapy burdened with high costs and increased infection risk.
• •personalised dosing strategy (PDS) is strongly advised.
• •PDS includes clinical evaluation, genetics, TDM, biomarkers, and literature data.
• •this approach could align effective and optimal treatment with economic factors.

Abstract

Atypical haemolytic-uraemic syndrome (aHUS) is a rare disease associated with uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy (TMA). Early diagnosis and treatment with eculizumab, a monoclonal antibody targeting the complement component C5, are crucial to improve outcomes and prevent renal failure and mortality. Current recommendations include lifelong eculizumab therapy, yet this practice presents challenges including high treatment costs and increased infection risks from prolonged complement inhibition. We hypothesise that a personalised eculizumab dosing strategy tailored to individual patient responses could optimise therapy, reduce costs and improve safety. This hypothesis was evaluated through a presentation of a patient who was managed with a specific eculizumab treatment approach. The patient’s condition improved significantly, allowing for a gradual reduction in eculizumab dosage based on clinical response and drug level monitoring.

Throughout treatment, the patient’s complement activity and eculizumab levels were closely monitored, showing that lower doses maintained therapeutic efficacy without evident TMA recurrence. This case supports the feasibility of transitioning from fixed regimens to personalised dosing strategies in managing aHUS. Such approaches could mitigate the risks and costs associated with lifelong therapy while maintaining disease control, especially considering the variability in relapse risk among different genetic mutations. This personalised treatment model might significantly impact the management of aHUS, aligning clinical care with individual patient needs and economic considerations. Further research should relate drug pharmacokinetics/pharmacodynamics to clinical/genetic setting to identify milestones of individual patient treatment approach.

Introduction

Atypical haemolytic-uraemic syndrome (aHUS) is a rare condition related to the alternative complement pathway activation, frequently due to mutations in various complement components with considerably variable clinical presentation and outcomes.¹ In contrast to typical HUS, which is caused by Shiga toxin-producing Escherichia coli (STEC), aHUS is a disorder of abnormal complement activation causing thrombotic microangiopathy (TMA) and its clinical consequences.² In addition to typical and atypical variants of the disease, secondary HUS involves patients with underlying conditions (autoimmune diseases, specific drug administrations, vitamin B12 metabolism disorder) or infections (influenza, Streptococcus pneumoniae, HIV).³ For aHUS, early diagnosis and treatment are essential to avoid substantial renal morbidity and overall mortality. The primary treatment approach involves the administration of eculizumab as the first-line therapy, followed by plasma exchange as a second-line treatment option.⁴ Eculizumab is a monoclonal antibody against the complement component C5 that inhibits activation of the terminal complement.⁵ It has significantly improved the treatment of aHUS, decreasing the progression to end-stage renal disease (ESRD) or death in children from up to 50% down to 9% and in adults from 60% down to 6–15%.^6,7 According to the summary of product characteristics (SmPCs), the maintenance phase is recommended to continue for the patient’s lifetime and should be discontinued only if clinically justified.⁸ However, many uncertainties still exist, eg the issue of the optimal (dosing, duration) maintenance treatment, especially in patients with ESRD due to the aHUS,² and larger clinical trials are required to address these limitations. There is also a high recurrence rate of aHUS in the transplanted kidney, which further complicates the right strategy for the timing and the duration of prophylactic treatment regimes.³ The burden of treatment costs is substantial, given that the price of 300 mg solution for infusion ranges from €6,500 to €8,500 in the EU.⁹ The usual maintenance dose is 1,200 mg administered intravenously every 14 ± 2 days.⁸ Home infusions performed by a qualified healthcare professional or biweekly hospitalisations during the maintenance phase of treatment further raise the expenses of this costly treatment.¹⁰ Although novel treatment options arise, like ravulizumab, which lessens treatment costs (mainly due to a less frequent dosing schedule),¹¹ this financial burden remains significantly high. A biosimilar product developed after the reference eculizumab product Soliris^Ⓡ is already approved for the treatment of paroxysmal nocturnal haemoglobinuria, but the indication for aHUS is still protected by orphan exclusivity.¹²

Treatment with eculizumab, although currently approved for lifelong administration, should be dynamically tailored to the clinical status of the patient. This approach advocates for a transition from a fixed treatment regimen to a personalised dosing strategy in adult patients, optimising therapy which should be based on individual clinical responses and biomarkers. This individualised treatment emphasises the need for a personalised comprehensive approach that aligns treatment with the specific needs of each patient, potentially improving outcomes and managing the long-term costs and risks associated with lifelong eculizumab therapy. To support that, here we present a clinical case of aHUS and the specific therapeutic scheme based on the clinical response, along with the target and drug level measurements.

Case presentation

A 60-year-old male patient with a history of diabetes mellitus type 2 and controlled hypertension was admitted to the urology department 5 days after prostate biopsy with fever, jaundice, lethargy, leukocytosis (12.9 × 10⁹/L), thrombocytopenia (26 × 10⁹/L), high CRP (127.7 mg/L), PCT-Q (30.62 µg/L), BUN (26 mmol/L) and creatinine (460 µmol/L). Neuroimaging and cerebrospinal fluid analysis ruled out acute cerebrovascular incident and infection, and anuria prompted the commencement of haemodialysis. On day 5, the patient was transferred to ICU. High lactate dehydrogenase (LDH), low haptoglobin, indirect hyperbilirubinaemia, schistocytes, mild anaemia, thrombocytopenia, anuric acute renal injury (Table 1) and neurological symptoms suggested thrombotic microangiopathy (TMA). Plasma exchange therapy (PEX) using fresh frozen plasma as a replacement fluid was started (Table 1). Renal biopsy was considered but was not done because of the anticipated high bleeding risk and urinary tract colonisation with resistant pathogens. ADAMTS13 activity was 42%, the stool was negative for enterohaemorrhagic E. coli, complement C4 and C3 were low, while the terminal complement complex was increased, all supporting the diagnosis of aHUS (Table 1). Fig. 1A depicts the development of platelet count, haemoglobin level, LDH, serum creatinine and haptoglobin during the first 49 ICU days before eculizumab treatment. Additionally, the patient was mechanically ventilated, unconscious, on renal replacement therapy with daily diuresis of 2,000 mL. Genetic testing was in progress. On day 50, eculizumab induction treatment started, although postponed due to superimposed infections associated with artificial medical devices and caused by resistant pathogens. Upon resolution of infections, vaccination against Neisseria meningitidis was administered and prophylaxis with ciprofloxacin was implemented. Four 900 mg doses were given in 7-day intervals. On day 68, the patient regained consciousness. Haemoglobin remained low still requiring red blood cell transfusions, but platelet counts recovered and haptoglobin and LDH indicated that haemolysis was ceasing (Fig. 1B). The first two maintenance eculizumab doses (1,200 mg) were administered 2 weeks apart. Around day 100, the patient’s condition improved, without active TMA and with chronic renal failure (haemodialysis twice weekly) without signs of improvement (Fig. 1C). Since his overall condition had stabilised and improved with inconclusive genetic testing results (Table 2), we decided to continue eculizumab maintenance but with gradual dose reduction and eventual complete withdrawal, if there were no clinical signs of TMA activity. Hence, two 900 mg doses were administered, followed by 600 mg, two times, and the last two doses of 300 mg eculizumab were given, all doses in 2-week intervals. His clinical condition consistently improved, and platelets stably recovered, without TMA activity (Fig. 1C). Finally, after 209 days in ICU, the patient was discharged from the hospital and scheduled for haemodialysis three times/week. Two years after the hospital discharge, he is generally in good condition, without signs of TMA, kept on regular haemodialysis, and waiting for kidney transplantation. The patient gave consent to all analyses and the data presentation.

Table 1.

Patient’s characteristics during the first 20 days in the ICU.

Characteristic	Value	Normal range
Mean of multiple measurements
Diuresis (mL/24 h)	44	>400
Platelet count (× 109/L)	104	158–424
Serum creatinine (µmol/L)	380	79–125
Haemoglobin (g/L)	87	138–175
Lactate dehydrogenase (U/L)	492	0–241
Support TMA/aHUS diagnosis
Haptoglobin (g/L)	<0.0725	0.3–2
ADAMTS13 metalloproteinase activity (%)	42	67–150
Complement C3 (g/L)	0.74	0.9–1.8
Complement C4 (g/L)	0.12	0.15–0.55
sC5b-9 (terminal complement complex) (ng/mL)	323	110–252
Supportive therapeutic procedures
Haemodialysis sessions (days) (CRRT)	18	—
Plasmapheresis (number of procedures)	17	—

CRRT – Continuous renal replacement therapy.

Fig. 1.

Development of platelet counts and haemoglobin, lactate dehydrogenase, serum creatinine, and haptoglobin levels during the entire ICU stay (209 days). A. During the period before eculizumab treatment. B.During the eculizumab induction treatment. C. During eculizumab maintenance. Platelet counts and haemoglobin (upper panel – dashed lines indicate lower limits of normal values; indicated is also the timing of eculizumab dosing) and lactate dehydrogenase and serum creatinine (middle panel – dashed lines indicate upper limits of normal values) are grouped for clarity. Haptoglobin (lower panel) was measured less frequently (the dashed line indicates the lower limit of normal values). Should be noted that platelet counts and haemoglobin levels reflect in part bleeding incidents and transfusions (see textual description).

Table 2.

Genetic analysis.

Gene	Mutation	Type	Protein	Genotype	Interpretation
CFH	c. -331C>T	Promoter	—	Heterozygous	Risk factor for aHUS
CFH	c.184G>A	Coding-missense	p.V62I	Heterozygous	Protective against aHUS
C3	c.941C>T	Coding-missense	p.P314L	Heterozygous	Risk for dense deposit disease

Genetic analysis revealed three mutations (Table 2): (i) a mutation in the promoter region of the CFH gene reportedly associated with HUS¹³ – the c.-331C>T mutation (referred to also as -257T>C) is located within the response element for nuclear factor κB and is suggested to have a role in the regulation of factor H transcription; (ii) the c.184G>A mutation of the CFH gene results in a substitution of valine for isoleucine and is considered to result in increased factor H activity, thus being ‘protective’ against HUS;¹⁴ and (iii) a rare mutation in the C3 gene – c.941C>T was found, reportedly associated with a susceptibility to dense deposit disease.¹⁵

Blood samples for determination of eculizumab concentrations and complement activity were taken immediately before, at the end of infusion, and 7 days after each maintenance dose (Fig. 2A). Eculizumab levels ≥100 µg/mL were attained only immediately after dosing with 1,200 mg and 900 mg, while 300 mg produced no measurable eculizumab concentrations (Fig. 2B). Complement activity (CH50) oscillated from $\le$10% immediately after dosing, even with 600 mg, and then increased; no apparent change in activity was observed with 300 mg (Fig. 2B). At day 7 post-dose, although eculizumab levels were $\le$26 µg/mL, the doses of 1,200 mg and 900 mg kept CH50 at <35% (Fig. 2C).

Fig. 2.

Eculizumab serum concentrations and complement activity during the maintenance dosing. A. Dosing and blood sampling schedule. B. Eculizumab serum concentrations and CH50 values over time. C. Relationship between serum eculizumab concentrations and CH50 values by dose level. Peripheral blood samples were centrifuged for 10 min at 1,500 g, aliquotted (0.5 mL) and frozen at -20 °C within 2 h at the Institution's Central Laboratory. They were shipped on dry ice to the Nephrology Clinical Laboratory Department, where free serum eculizumab (unbound to C5) was quantified using an enzyme-linked immunosorbent assay, and CH50 was determined.

Discussion

In patients with confirmed pathogenic variants, the probability of relapse following the cessation of C5 inhibitor therapy exhibits significant variability depending on the specific genetic mutation involved. For instance, the risk of recurrence is approximately 23% in individuals carrying pathogenic variants in the CFI gene, 37% in those with MCP gene variants, and increases to 64% in carriers of CFH gene mutations.¹⁶ Although precise data for the specific combination of this particular patient’s gene alterations are not well-documented, it is notable that the highest relapse rates are associated with CFH gene variants. This necessitates particular vigilance and more frequent follow-up in affected individuals to manage the heightened risk effectively. Therefore, comprehensive patient evaluation is needed, with genetic testing as important part of the adequate treatment and follow-up.

An individualised therapeutic approach has several implications for the future management of patients with aHUS. Firstly, the prolonged use of C5 inhibitors carries a substantial risk of infections caused by encapsulated pathogens,¹⁷ which can be potentially life-threatening. Discontinuing treatment would mitigate this risk. Moreover, the financial burden of long-term treatment, especially when it does not provide clear benefits, would be significantly reduced. This would enhance treatment accessibility for those indicated for therapy and/or those carrying mutations with a higher risk of disease relapse. Additionally, careful and frequent monitoring of patients who discontinue treatment, including assessments of complement system activity, would provide new insights into the disease and its progression. This opens the possibility of discovering and measuring novel disease biomarkers, enabling a more precise selection of patients who benefit from the treatment. Such findings, combined with blood level monitoring of the drug and related adjustments in dosage and treatment duration, could contribute to more effective management of aHUS patients.

This approach not only addresses the clinical needs but also aligns with the economic and safety concerns, ultimately leading to a more tailored and effective treatment strategy. The disease and the drugs are all in the area of orphan settings (treating a rare medical condition that affects only a small percentage of the population), challenging the expectations of more information from larger-scale randomised studies with longer duration of follow-up.³ Current recommendations in the SmPCs, which allow the decisions at per physician’s discretion, introduce selection bias in future trial designs and decisions.³ Further research is needed also to correlate drug pharmacokinetics/pharmacodynamics with clinical/genetic settings to identify milestones of individual patient treatment approaches.

This patient presented with a severe and rapidly progressing systemic condition, and genetic testing was inconclusive. Recommendations for treatment duration/discontinuation^13,17, 18, 19, 20, 21, 22 are based on relatively sparse data considering the severity of clinical presentations, possible causes, and genetic complement alterations. One pharmacokinetic analysis (nine patients in maintenance treatment) suggested a body weight-based dosing schedule with infusions spaced to 4-week or 6-week intervals.²³ During the literature search, we could not find a case of aHUS with a similar CFH genetic variant and disease severity. Genetic analysis revealed two variants whose carriers have lower alternative pathway activity,¹ but the patient presented with alterations of the classical pathway, shown by quantification of complement components. This fact further increases the complexity of the disease presentation. Considering the complexity of aHUS biology, it seems that an individualised approach to treatment, monitoring and follow-up would be necessary to achieve better outcomes and to keep otherwise considerable treatment costs of lifetime therapy at a reasonable level.

Consent for publication

Consent: Written informed consent was obtained from the patient presented in this case report.

Ethics Approval: This study was approved by the Hospital Ethics Committee (No: KBSD 01-012/16).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Ivana Mikačić: Writing – review & editing, Writing – original draft, Validation, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Nikolina Marić: Writing – review & editing, Investigation, Formal analysis, Data curation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.