Introduction

Driven by chronic, uncontrolled activation of the complement system, atypical haemolytic uremic syndrome (aHUS) is a systemic thrombotic microangiopathy characterised by inflammation, formation of blood clots in small blood vessels, low platelet count, haemolytic anaemia, and renal impairment.^1-4 Though affecting multiple organ systems, the complement attack of endothelial cells is primarily in the glomerulus, where it leads to microthrombi formation in the glomeruli and capillaries and impairs the ability of the kidney to filter blood and produce urine.^1,5

Prevalence

aHUS is classified as an ultra-rare disease, with an annual incidence of 0.23-1.9 cases per million and a global prevalence of 4.9 cases per million.⁶ Disease onset during childhood (<18 years) is observed in 40-50% of patients, with boys and girls affected equally.^6,7 In adulthood, a greater number of patients are female.⁴

Disease Burden

aHUS can cause a range of symptoms and damage various organs if left untreated. Patients with aHUS suffer from a lifelong risk of recurrence, and 25% die from systemic complications.^1,7 The majority of patients suffer from renal damage, including reduced glomerular filtration rate, proteinuria, haematuria, and hypertension.¹ As has been shown, within one year of aHUS diagnosis, 56% of adults die or progress to end-stage renal disease.⁸ Extra-renal damage is observed in 20% of patients.^1,4

In addition to renal injury, patients with aHUS can suffer from gastrointestinal, cardiovascular, respiratory, and central nervous system complications.^1,9-12 Up to 48% of patients are affected by neurological issues including headache, seizure, migraine, epilepsy, and facial paralysis,^1,9 and 30% of patients by gastrointestinal problems like diarrhoea and gastroenteritis.¹⁰ About 10% of patients with aHUS suffer from cardiovascular conditions including cardiomyopathy, myocardial infarction, ischemic attack, embolism, and cardiac arrest,^1,9 and up to 20% of patients experience pulmonary conditions including pulmonary haemorrhage, oedema, and shortness of breath.^11,13 Additional complications may include purpuric rash on the skin and rhabdomyolysis of the skeletal muscles.¹²

Unmet Medical Need

Diagnosis of aHUS is complex and generally driven by nephrology and occasionally haematology specialists. It is a clinical diagnosis, as no specific test is currently available, and must be taken in a stepwise approach. Thrombotic microangiopathy (TMA) is first diagnosed by decreased platelet count, microangiopathic haemolysis, and organ damage.¹² Distinguishing aHUS from other TMAs can be challenging and is done through exclusion of ADAMTS13 deficiency (thrombotic thrombocytopenic purpura – TTP) and a negative STEC (Shiga toxin-producing E. coli) test.^4,12 Testing for complement gene mutations or autoantibodies may be done, although in up to 48% of aHUS patients, no complement mutations or autoantibodies are found.² Additionally, complement-level testing may be considered, however this can be unreliable, complement is also activated in other diseases, and complement levels are normal in many aHUS patients.¹⁴

aHUS requires lifelong multidisciplinary disease management, with renal transplantation indicated for a subset of patients.^1,3,4 Plasma exchange/infusion was the earliest treatment option and still remains the standard of care (SOC) in many regions where alternative treatments are not available.^1,15 It is no longer recommended, however, due to limited efficacy, risk for end-stage renal disease, and premature death.^1,16 As aHUS is driven by dysregulation of the complement system, therapeutics inhibiting the complement system have been developed and are now the SOC.^1,4,8,17 However, despite aHUS treatment improvements, unmet needs remain. The currently approved complement inhibitors can impose a heavy treatment burden on patients and caregivers, with the need for regular, lengthy intravenous infusions, as well as high treatment costs.⁸ Worldwide treatment approval and access also remain limited for these therapies, with reimbursement restrictions in many countries.¹⁸

Ongoing research and development efforts are advancing new therapeutic options that may overcome some of the limitations and address the unmet needs of currently available therapies.¹⁹

Patients’ Needs

The patient journey may begin at the general practitioner’s office with symptoms like fatigue, general distress, and vomiting, or in the emergency room or intensive care unit with severe symptoms including high blood pressure and kidney failure.^4,8 As aHUS diagnosis is challenging, the patient will undergo several tests, including blood panels, platelet counts, evaluation of creatinine levels, and potentially kidney biopsy.^1,12 Once diagnosed with aHUS, complement inhibitor treatment will begin and is recommended to continue indefinitely, with regular monitoring via check-ups and lab tests to ensure no disease relapse.^1,20 Treatment may also be stopped if the patient is stable and the genetic profile is indicative of a lower risk of relapse, but monitoring will need to continue indefinitely, as the risk of relapse remains.^1,20,21

Learn More: Understanding the genetic basis of aHUS

Genetic or acquired defects and immunological predispositions can cause the complement dysregulation observed in aHUS patients, of which approximately 50% have mutations in complement or complement-regulating proteins.^1-4 Familial causes account for approximately 20% of aHUS cases.1 The cause of the remainder of cases remains unidentified,^2,7,22 but it is known that environmental or intrinsic factors can trigger aHUS onset or relapse.²³ The exact mechanism of how stressors induce aHUS, however, remains unknown.²³