Expert insights on current aHUS diagnosis and management strategies

Atypical haemolytic uraemic syndrome (aHUS) is a group of rare complement dysregulation disorders characterized by haemolytic anaemia, thrombocytopenia and acute kidney injury in both paediatric and adult patients. Prompt management is crucial to avoid life-threatening complications and invasive interventions. However, early detection and treatment remain challenging because aHUS is primarily diagnosed by exclusion. In an interview with MIMS Doctor, experts from Hong Kong shared current practices in the diagnosis and treatment of aHUS as well as their experience with using the complement component 5 (C5) inhibitor, eculizumab, for these patients.

Overcoming aHUS diagnostic and management challenges
In general, all forms of haemolytic uraemic syndrome (HUS) not caused by infections or coexisting medical conditions are classified as aHUS, making it a heterogeneous group of disorders. The common pathology in patients with HUS is thrombotic microangiopathy (TMA) with the classical triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. [Blood 2022;doi:10.1182/blood.2022017860; Pediatr Clin North Am 2022;69:1181-1197]

“aHUS mainly involves dysregulation of the complement alternative pathway,” said Dr Elaine Au, Specialist in Immunology. [Blood 2022;doi:10.1182/blood.2022017860] “Since effective treatments are available and response may be dramatic and life-saving for those with complement-driven disease, accurate and rapid diagnosis of aHUS is crucial to avoid irreversible outcomes.” [Lancet 2022;400:1722-1740]

However, early detection is challenging because there is currently no universally accepted definition or objective diagnostic tool for this group of disorders. [Pediatr Clin North Am 2022;69:1181-1197; J Formos Med Assoc 2022;doi:10.1016/j.jfma.2022.10.006]

aHUS diagnosis: A process of elimination
“Although aHUS is primarily a diagnosis of exclusion, current knowledge of potential differential diagnoses and the number of readily available tests make the process of elimination much easier,” said Au.

“aHUS may manifest at any age, but onset is more common during childhood,” explained Dr Matthew Lee, Specialist in Paediatrics. “Diagnostic workup begins when patients present with nonspecific signs and symptoms such as anorexia, hypertension, lethargy, nausea, pallor, tachycardia and tachypnoea. Documented haematuria may indicate the typical renal involvement of aHUS, leading patients and their family members to seek consultation at the emergency department for further workup.” [Lancet 2022;400:1722-1740; Cells 2021;10:3580]

Diagnosis of aHUS requires initial clinical documentation of TMA (ie, microangiopathic haemolysis in peripheral blood demonstrated by presence of fragmented red blood cells or schistocytes), followed by clinical and laboratory evaluations to establish aetiology. (Figure) For HUS, TMA and laboratory abnormalities must be accompanied by clinical involvement of at least one organ system, usually the kidneys. However, other organ systems may also be involved, and since any tissue may be affected and show clinical signs of microthrombosis and ischaemia, having a multidisciplinary team is critical in the diagnosis and management of these patients. (Figure) [Kidney Int 2017;91:539-551; Clin Adv Hematol Oncol 2016;14(Suppl 11):2-15]

The primary differentials for TMA are disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and infection-associated HUS. Coagulation studies can easily rule out DIC, while TTP can be confirmed with decreased ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) activity (<10 percent). (Figure) [Lancet 2022;400:1722- 1740; Clin Adv Hematol Oncol 2016;14 (Suppl 11):2-15]

“Meanwhile, HUS can be associated with infection, such as that caused by Shiga toxin–producing Escherichia coli and Streptococcus pneumoniae infection, which should be ruled out,” said Lee. (Figure) “This group of patients may have a recent history or present with signs and symptoms of ongoing infection, such as diarrhoea and fever.” [Lancet 2022;400:1722-1740]

Primary aHUS generally includes an underlying complement system defect (eg, mutation in a complement gene or presence of factor H [FH] autoantibodies, with no associated conditions or disorders). Generally, primary aHUS is diagnosed by excluding Shiga toxin–producing enterohaemorrhagic Escherichia coli (STEC)-HUS, TTP and secondary causes of TMA (eg, malignancy, cobalamin C deficiency, and use of drugs such as calcineurin inhibitors, oral contraceptives, and quinine). However, a trigger event or coexisting medical condition, such as infection, transplant and pregnancy, is also possible even in aHUS. [Blood 2022;doi:10.1182/blood.2022017860; Lancet 2022;400:1722-1740] Diagnosis of aHUS should be considered if patient is recurrent or refractory to supportive treatment in secondary TMA. [J Formos Med Assoc 2022;doi:10.1016/j.jfma.2022.10.006]

Role of complement testing and genetic screening
“Although complement and genetic tests for patients with aHUS are ideal, access to these is limited in Hong Kong,” Au commented.“Sometimes, the clinical team may send samples abroad for special tests that are not available locally, and the results may take some time to become available.”

Complement analysis, including CH50, AH50, C3, C4 and sC5b-9, is available within the public sector. “Strict requirements for handling complement testing requests are needed, because samples and reagents are quite labile in test tubes and thus require special care to avoid in vitro complement activation and ensure accurate results,” stressed Dr Crystal Lam, Immunology Fellow.

“aHUS diagnosis is a clinical diagnosis. There is no specific confirmatory test for aHUS. Though they may support diagnosis and prognostication, complement [eg, CH50, AH50, soluble C5b-9] and genetic [eg, C3, CFB, CFH mutations] test results could be inconclusive and delayed,” said Au. (Figure) “There is currently no specific confirmatory test for aHUS. Therefore, results from these investigations should not preclude early use of anticomplement therapy in patients clinically diagnosed with aHUS. Once available, test results may be used to predict patients’ prognosis and guide treatment decision-making in the long term [eg, treatment duration of complement inhibitors in different risk groups].” [J Formos Med Assoc 2022;doi:10.1016/j.jfma.2022.10.006; Lancet 2022;400:1722-1740]

Supportive treatment in aHUS
“We should aim for clinical euvolaemia to maintain tissue perfusion by fluid resuscitation and correction of electrolyte abnormalities and acidosis. In particular, plasma potassium should be closely monitored as ongoing red cell fragmentation is likely. Dialysis should be considered if necessary and the indications are the same as other causes of acute kidney injury. Packed red cell transfusion is considered if haemoglobin is <6 g/dL and should target a level between 8–9 g/dL. Platelet transfusion should be avoided except in situations of clinical bleeding or total platelet count <10 x 10⁹/L. Calcium channel blockers could be used as the initial choice of antihypertensive agent during acute illness,” said Lee.

Role of C5 inhibitors in aHUS management
“Eculizumab is a recombinant humanized monoclonal immunoglobulin G [IgG] antibody that inhibits the cleavage of C5 to C5a and C5b, thus preventing the formation of MAC C5b-9 and inhibiting haemolysis,” said Lee. Eculizumab is an approved first-line treatment for paediatric and adult patients with aHUS, with a maintenance administration schedule of once every 2 weeks in patients with body weight ≥10 kg. [Soliris Hong Kong Prescribing Information; Blood 2022;doi:10.1182/blood.2022017860]

Ravulizumab, a novel long-acting C5 inhibitor with an 8-week dosing interval, demonstrated sustained C5 inhibition, normalization of platelet count and serum lactate dehydrogenase, as well as improvements in haemoglobin, estimated glomerular filtration rate, and patient’ quality of life at a median follow-up of 76.7 weeks. [Kidney Int Rep 2021;6:1603-1613]

Treatment response
“Early treatment with eculizumab is associated with rapid and sustained improvements in haematological and renal parameters in patients with complement-driven aHUS,” said Lee. [Lancet 2022;400:1722-1740; Soliris Hong Kong Prescribing Information] “In our experience, response may be evident after the second dose of eculizumab during the initiation phase [ie, days 14–16], as demonstrated by improvements in renal function and resolution of haemolysis. In prospective studies, estimated median time for platelet count normalization after initiation of eculizumab is about 10 days, suggesting that it may be ideal to evaluate treatment response at this time, along with monitoring for signs and symptoms of TMA recurrence.” (Table) [Blood 2022;doi:10.1182/blood.2022017860; N Engl J Med 2013;368:2169-2181; Am J Kidney Dis 2016;2016:84-93; Soliris Hong Kong Prescribing Information]

“Although not routinely performed in our setting, monitoring of complement activity [eg, CH50, AH50] during eculizumab therapy may also help guide treatment decisions, especially if dose adjustments are needed,” said Lee. (Table) [Kidney Int 2017;91:539-551]

Safety considerations
Vaccinations are recommended to mitigate the risk of meningococcal, Haemophilus influenzae and pneumococcal infections in patients receiving complement inhibitors. In patients aged <18 years, adherence to national recommendations on vaccination against H. influenzae and pneumococcal infections is recommended for each age group before receiving eculizumab. [Soliris Hong Kong Prescribing Information]

“Eculizumab treatment is generally well tolerated,” said Lee. “Absolute contraindications include hypersensitivity to this agent or any of its excipients, unresolved Neisseria meningitidis infection, and patients not vaccinated against meningococcal disease unless they receive appropriate prophylactic antibiotics [methylpenicillin] until 2 weeks after vaccination.” [Soliris Hong Kong Prescribing Information; Blood 2022;doi:10.1182/blood.2022017860]

Challenges and future prospects of aHUS management
“Prompt access to C5 inhibitor therapy and financial support remain important challenges in aHUS management,” said Dr Stella Chim, Specialist in Paediatrics. “Since our understanding of aHUS is constantly evolving, eligibility issues may limit or significantly delay patients’ access to prompt anticomplement therapies.”

“Even with existing medical assistance programmes in Hong Kong, getting financial support, particularly for the crucial first eculizumab dose, is challenging,” she shared. “Early treatment with C5 inhibitors is therefore often only possible with an out-of-pocket expense. Otherwise, treatment initiation is often delayed, which may compromise patient outcomes.”

“We need to constantly review our criteria for providing subsidy for eligible patients to purchase approved and available treatments for aHUS as we gain more knowledge about this disease, and as newer agents such as the longer-acting ravulizumab become accessible,” added Lee. “Subsidy considerations should especially include prompt approval for purchasing the first dose as well as continued support for the succeeding doses, taking into account the expected initial treatment response [ie, after the second dose] and the possibility of extended treatment duration in appropriate patients.”