HUS

Question 1

Features of haemolytic uremic syndrome (HUS)

Answer 1

Triad of:

• AKI
• Microangiopathic haemolytic anaemia
• Thrombocytopenia

Divided into typical HUS (secondary) or atypical HUS (primary)

Microangiopathic haemolytic anaemia: Microangiopathic haemolytic anaemia (MAHA) is a non-immune haemolysis with prominent red cell fragmentation observed on peripheral blood film (schistocytes)

Frequently overlaps clinical presentation with TTP
-­ Can be precipitated by infectious diarrhoeal illnesses,
especially E coli and Shiga toxin producing E coli and pneumococcus

Management: plasma exchange is the standard of care in adults

Atypical HUS

• Not preceded by diarrhoeal illness
• Disorder caused by overwhelming complement activation
• Management: eculizumab (c5)

Question 2

Features of typical HUS

Answer 2

Most cases are secondary (termed ‘typical HUS’):

• Classically Shiga toxin-producing Escherichia coli (STEC) 0157:H7 (‘verotoxigenic’, ‘enterohaemorrhagic’). This is the most common cause in children, accounting for over 90% of cases
• Pneumococcal infection
• HIV
• treatment is supportive e.g. Fluids, blood transfusion and dialysis if required
• there is no role for antibiotics, despite the preceding diarrhoeal illness in many patients
• Rare: systemic lupus erythematosus, drugs, cance

Question 3

Features of atypical HUS

Answer 3

• Primary HUS (‘atypical’) is due to complement dysregulation.
• Causative organisms of atypical HUS include Coxsackie, Streptococcus pneumonia and influenza.
• This condition occurs from a mutation causing complement system activation and has a poorer prognosis where half progress to renal failure. Other causes include HIV, malignancies and SLE.
• Atypical HUS/Complement Induced HUS
• Most common mutation is loss of function mutation in complement factor H.
• Genetic Basis (familial) or autoimmune 70%
• Lead to multiple thrombosis
• Life-threatening catastrophic disease in adults and children
  with a devastating prognosis.

Ongoing disease

• TMA (thrombotic microangiopathy), renal failure, organ failure
• Diagnosis: ADAMTS13 normal (if abnormal means TTP), Shiga toxin -ve (if positive means infection induced HUS)

Treatment:

• Eculizumab C5 inhibitor, prevents cleavage into C5a and C5b
• Eculizumab blocks cleavage of C5 into procoagulant C5a which reduces the inflammation that occurs, allows for therapeutic inhibition of C5 activation
• However as eculizumab deletes C5, there is an infection risk of neisseria - vaccinate pre-treatment

Question 4

Features of microangiopathic haemolytic anaemia

Answer 4

• Schistocytes
• Elevated LDH
• Decreased haptoglobin
• Decreased haemoglobin

Question 5

DDx of thrombotic microangiopathy

Answer 5

Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury.
Thrombotic microangiopathies (TMA) are clinical syndromes defined by the presence of hemolytic anemia (destruction of red blood cells), low platelets, and organ damage due to the formation of microscopic blood clots in capillaries and small arteries.

Criteria
1. Thrombocytopenia <150,000
2. Microangiopathic haemolysis: anaemia, high LDH, low haptoglobin, schistocytes 
Plus 1 or more of the following
- Neurological symptoms
- Renal impairment
- GIT symptoms 

Evaluate ADAMTS13 activity and shiga toxin

• <5% ADAMTS13 activity: TTP
• > 5% ADAMTS13 activity: atypical HUS
• Shiga Toxin: typical HUS

Other ddx

• HELLP
• Malignant HTN
• SLE
• Drug induced TMA
• DIC
• Scleroderma renal crisis

Question 6

aHUS is life threatening condition secondary to complement
dysregulation.
Which is the MOST COMMON mutation in patients with aHUS?
1. Gain of function mutation in MCP.
2. Loss of function mutation in MCP.
3. Gain of function mutation in complement factor H.
4. Loss of function mutation in complement factor H.
5. Loss of function mutation in complement factor I.

Answer 6

4. Loss of function mutation in complement factor H.

Question 7

Historically plasma exchange has been used in the treatment of
aHUS.
Only ONE of the statement is true about plasma exchange, which
one?
1. Plasma exchange improves platelet count.
2. Plasma exchange improves LDH.
3. Plasma exchange improves platelet count and LDH.
4. Plasma exchange improves renal function.
5. Plasma exchange improves extra-renal manifestations of aHUS.

Answer 7

3. Plasma exchange improves platelet count and LDH.

Question 8

Eculizumab, a humanized monoclonal antibody is currently
being used in the treatment of aHUS.
Only ONE of the following is true about eculizumab, which one?
1. It is a humanized monoclonal antibody against C5.
2. In patients with aHUS, it improves GFR but not the platelets.
3. In patients with aHUS, it improves GFR but not the LDH.
4. It protects patients from meningococcal infection.
5. It is only effective in patients with identifiable genetic
mutation.

Answer 8

1. It is a humanized monoclonal antibody against C5.

Question 9

What vaccination is required when on eculizumab

Answer 9

However as eculizumab deletes C5, there is an infection risk of neisseria - vaccinate pre-treatment