Knowledge on rare diseases and orphan drugs

The estimated prevalence in Europe is 1/100,000. Atypical hemolytic uremic syndrome (aHUS) accounts for 5-10% of hemolytic uremic syndrome (HUS) cases in children, and most cases in adults.

Disease onset may occur at any age. Presentation is typically of acute onset, nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The episode is usually preceded by a triggering event such as upper respiratory infection or viral gastroenteritis. In 20% of patients, onset is insidious with relapsing subclinical anemia, thrombocytopenia, decreased or rarely preserved renal function, and nonspecific symptoms (e.g.fatigue, and anorexia). The renal manifestations are variable across patients and can range from acute anuric kidney injury requiring dialysis to chronic kidney disease or chronic proteinuria. Approximately half of the cases progress to end-stage kidney disease. Extra-renal manifestations occur in approximately 20% of patients and include neurological symptoms (10%; e.g. irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, or coma), myocardial infarction (3%), pulmonary hemorrhage, ischemic colitis, pancreatitis, hepatocellular injury, and peripheral vascular disease.

Most of the cases present with uncontrolled complement activation that results in endothelial damage. Pathogenic mutations have been identified in several genes coding proteins and regulators of complement cascade. The most frequent include CFH (1q31.3), CFI (4q25), CD46 (1q32.2), C3 (19p13.3) and CFB (6p21.33). Rearrangements in CFH gene and CFH related genes also cause similar phenotype. An acquired form caused by factor H antibodies exists. Approximately 10% of the aHUS patients have these auto-antibodies identified. There is a possible link to CFHR1 and CFHR3 gene deletions that increase the risk of developing these antibodies in an individual.

Diagnosis is suspected on presentation of thrombotic microangiopathy with renal involvement, and the exclusion of the main differential diagnoses. Diagnosis is confirmed by genetic testing (sequencing and multiplex ligation-dependent probe amplification (MLPA), complement cascade proteins functional tests and screening for factor H auto-antibodies. Tests should evaluate C3, C4, Complement factor H, I and B, membrane cofactor protein, as well as copy number variations by MLPA in CFHR genes and their hybrids with CFH.

The main differential diagnoses includes HUS due to Shiga toxin Escherichia coli, thrombotic thrombocytopenic purpura (both congenital and acquired type) and HUS secondary to immunological or external factors (drugs). Cobalamin C deficiency can present in a similar fashion.

There are no specific anatomical prenatal markers. Genetic prenatal diagnosis is theoretically possible when there is a known familial genetic risk.

Approximately 20-25% of cases are familial, usually with autosomal dominant patterns of predisposition. Autosomal recessive pedigrees can be seen less often. Variable penetrance in autosomal dominant pedigrees is common.

The recommended first line targeted therapy is with eculizumab which blocks complement terminal pathway, thus halting endothelial damage and ensuing thrombotic microangiopathy. Eculizumab should be administered within 24 hours of presentation and is recommended as a lifelong treatment, although trials are ongoing regarding the safe discontinuation. Targeted therapy is accompanied by symptomatic support of acute renal injury by renal replacement therapy (dialysis) and red blood cell transfusions. Plasma exchange (or plasma infusion) is less effective. However, it might still have some relevance in countries with limited resources and no access to eculizumab. For anti-CFH antibody-mediated disease, immunosuppressive regimens (steroids, rituximab and cyclophosphamide) targeting auto-antibody production combined with plasma exchange are also utilized, particularly when eculizumab is unavailable. All patients on eculizumab treatment require prophylactic N. meningitits vaccination and antibiotic prophylaxis.

Prognosis is significantly improved with eculizumab treatment; however, time-to-treatment is a significant factor in recovery of renal function. Without treatment, there is a significant risk of developing end-stage kidney disease.

Last update: July 2021 - Expert reviewer(s): Dr Michal MALINA | ERKNet*

* European Reference Network