HEREDITARY HEMOLYTIC UREMIC SYNDROME

Atypical HUS — a complement-mediated kidney emergency where eculizumab saves kidneys and lives, but the specific complement gene variant determines whether lifelong therapy is needed or can safely be withdrawn.

Whole genome sequencing evaluates all complement regulatory genes — CFH, CFI, MCP, C3, CFB, THBD, and DGKE — providing the genotype that determines treatment duration, transplant recurrence risk, and family screening priorities.

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About this condition

Hereditary Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy caused by genetic or acquired dysregulation of the alternative complement pathway. Pathogenic variants in complement regulatory genes are identified in approximately 60-70% of aHUS patients: CFH (~25-30%), MCP/CD46 (~10-15%), CFI (~5-10%), C3 (~5-10%), CFB (~1-4%), THBD (~3-5%), and DGKE (~3-5%). These variants produce uncontrolled complement activation on endothelial surfaces, causing thrombotic microangiopathy predominantly affecting the kidney, with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.

aHUS is a medical emergency — without complement inhibitor therapy, approximately 50-65% of patients progress to end-stage renal disease or death within the first year of their initial episode. Eculizumab (Soliris) and ravulizumab (Ultomiris), monoclonal antibodies targeting complement component C5, have transformed aHUS from a frequently fatal condition to a manageable chronic disease. These therapies prevent terminal complement activation, resolving the thrombotic microangiopathy and preserving kidney function when initiated promptly.

The specific complement gene variant determines critical management decisions. MCP (CD46) variants — encoding a membrane-bound complement regulator on endothelial cells — have the best prognosis: ~80% of MCP-variant patients recover kidney function spontaneously, and complement inhibitor therapy can often be discontinued. In contrast, CFH variants carry the highest relapse risk (~50-70% after treatment withdrawal) and the highest post-transplant recurrence risk (~80% without preventive eculizumab). CFI and C3 variants have intermediate risk profiles. This gene-specific risk stratification directly affects the duration of complement inhibitor therapy and the transplant management strategy.

MCP (CD46) variant aHUS has ~80% spontaneous remission rate and complement inhibitor therapy can often be discontinued. CFH variant aHUS has ~70% relapse rate — usually requiring lifelong therapy. Genotype determines the treatment plan.

Gene locus
CFH (1q31.3), MCP/CD46 (1q32.2), CFI (4q25), C3 (19p13.3), CFB (6p21.33), THBD (20p11.21), DGKE (17q22)

Complement inhibitor therapy costs $500,000+/year. Genotype determines whether this therapy is needed lifelong (CFH variants) or can be safely withdrawn (MCP variants) — directly affecting both patient management and healthcare costs.

MCP variants allow eculizumab withdrawal — CFH variants require lifelong therapy. The financial and clinical stakes of this distinction are enormous.

Eculizumab costs approximately $500,000-700,000 per year. For MCP-variant aHUS patients, complement inhibitor therapy can often be discontinued after the acute episode resolves, because the complement dysregulation is limited to the membrane-bound CD46 protein and does not affect circulating complement. For CFH-variant patients, therapy withdrawal carries a 50-70% relapse risk within 12 months — potentially causing irreversible kidney damage. WGS genotyping provides the evidence base for the withdrawal decision, avoiding either unnecessary lifelong therapy (MCP) or dangerous premature withdrawal (CFH).

Kidney transplant in aHUS has up to 80% recurrence risk depending on genotype — molecular testing determines the transplant strategy

CFH-variant aHUS recurs in approximately 80% of kidney transplants performed without prophylactic complement inhibition, because the defective complement factor H circulates systemically. Combined liver-kidney transplantation or prophylactic eculizumab from the time of transplant is required. In contrast, MCP-variant aHUS almost never recurs after transplant (because the donor kidney expresses normal CD46). Without pre-transplant genotyping, the transplant team cannot plan the appropriate complement inhibition strategy, risking graft loss from preventable recurrence.

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