Atypical hemolytic uremic syndrome

Overview

Atypical Hemolytic Uremic Syndrome (aHUS) is a rare, life-threatening disease characterized by a triad of symptoms: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Unlike typical HUS, which is usually triggered by Shiga toxin-producing E. coli infections, aHUS is often caused by dysregulation of the complement system, a part of the immune response that becomes overactive and damages blood vessels.

aHUS can affect both children and adults and may present sporadically or as a chronic, relapsing condition. Without treatment, it can lead to long-term kidney damage or death.

Causes

aHUS is primarily caused by genetic mutations or autoantibodies that affect proteins regulating the complement system. The overactivation of the complement pathway leads to endothelial injury, platelet activation, and thrombotic microangiopathy (TMA).

Known causes include:

• Mutations in complement regulatory genes (e.g., CFH, CFI, MCP/CD46, C3, CFB)

• Anti-factor H autoantibodies

• Secondary triggers such as:

  • Pregnancy

  • Infections

  • Organ transplantation

  • Certain medications (e.g., chemotherapy, immunosuppressants)

Symptoms

The hallmark features of aHUS are related to damage of small blood vessels, especially in the kidneys. Symptoms may develop suddenly or progress over time.

Common symptoms include:

• Fatigue, pallor: Due to hemolytic anemia

• Easy bruising or bleeding: Due to low platelet count (thrombocytopenia)

• Decreased urine output, swelling, or high blood pressure: Due to kidney injury

• Dark or red-colored urine: From hematuria

• Confusion, seizures, or stroke-like symptoms: If the brain is involved

• Gastrointestinal symptoms: Nausea, vomiting, abdominal pain

Diagnosis

Diagnosis of aHUS involves clinical suspicion based on the triad of anemia, thrombocytopenia, and renal dysfunction, combined with laboratory and genetic testing to rule out other causes.

Key diagnostic steps:

• Complete blood count (CBC): Shows anemia and thrombocytopenia

• Peripheral blood smear: Schistocytes (fragmented red cells) indicate microangiopathic hemolysis

• Lactate dehydrogenase (LDH): Elevated due to cell breakdown

• Haptoglobin: Low due to consumption during hemolysis

• Creatinine and BUN: Elevated in kidney injury

• ADAMTS13 activity: Normal or mildly reduced in aHUS (severely reduced in TTP)

• Stool culture: Negative for Shiga toxin-producing E. coli (to rule out typical HUS)

• Complement panel and genetic testing: To identify complement system abnormalities

Treatment

Early recognition and prompt treatment are critical to improve outcomes in aHUS. Treatment focuses on halting complement activation and supporting affected organs.

First-line therapy:

• Eculizumab: A monoclonal antibody that inhibits complement protein C5, preventing further vascular damage. It is the cornerstone of aHUS treatment.

• Ravulizumab: A longer-acting C5 inhibitor used as an alternative to eculizumab

Supportive care:

• Dialysis in cases of kidney failure

• Red blood cell or platelet transfusions if needed

• Control of hypertension

Other therapies:

• Plasma exchange or infusion: Previously standard but now less commonly used in the era of complement inhibitors

• Immunosuppression: If anti-factor H autoantibodies are present

Prognosis

The prognosis of aHUS has improved significantly with the availability of complement inhibitors like eculizumab. However, outcomes depend on the timing of treatment and the presence of irreversible organ damage.

Prognostic considerations:

• Early treatment often prevents permanent kidney damage

• Without therapy, up to 50% of patients may develop end-stage renal disease (ESRD) within a year

• Relapses may occur, especially after discontinuation of treatment

• Lifelong complement inhibition may be needed in some patients

Genetic counseling is recommended for affected individuals and their families to understand the hereditary nature and recurrence risk, especially in transplant or pregnancy scenarios.