aka Pediatric Perplexity 002
An 18 month-old boy was brought to the ED by his parents with a 5 day history of intermittent vomiting, lethargy, infrequent wet nappies, and decreased oral intake. He was afebrile and his parents said that he was pale and that his face was puffy. He had an upper respiratory tract infection about 2 weeks previously but no other significant past medical history.
His laboratory test results included the following:
|White Blood Cells||8.4||(6.0–17.50 x 10E9/L)|
|Platelets||77||(150-400 x 10E9/L)|
The blood film showed schistocytes, microspherocytes and polychromasia.
Q1. Describe the laboratory findings?
Anemia with reticulocytosis and blood film findings consistent with a microangiopathic haemolytic anemia. Thrombocytopenia. Hyperkalemia in the context of an elevated urea and creatinine consistent with renal failure.
Explanation of the blood film findings:
- Polychromasia occurs because red cells of different ages stain differently (young red cells are bluer). It may occur in the context of hemolysis, hemorrhage, treatment with iron or B12 and dyserythropoiesis.
- Shistocytes are fragmented red cells resulting from intravascular hemolysis.
- Spherocytes are spherical cells found in hemolysis, hereditary spherocytosis and burns.
Q2. What is the likely diagnosis?
Atypical hemolytic uremic syndrome (aHUS)
Hemolytic uremic syndrome is the most common cause of pediatric acute renal failure. It is characterized by the triad of:
- Microangiopathic haemolytic anemia
- Acute renal failure
HUS is classified into 2 types:
- Diarrhoea-associated (D+ HUS)
- >90% of HUS cases
- caused by preceding infection with a verocytotoxin-producing bacteria, typically E.coli O157:H7
- Non-diarrhoeal/ atypical (D- or aHUS)
- possibly familial
- poorer prognosis
- often results from complement dysregulation — 50% involve complement regulatory genes: factor H, membrane cofactor protein (MCP) and factor I
aHUS may be difficult to distinguish from thromobotic thrombocytopeinc purpura (TTP), another form of thrombotic microangiopathy.
- TTP has predominantly neurological features, in aHUS renal failure predominates.
- TTP has a distinct molecular pathogenesis – most cases either have inherited ADAMTS13 mutations or acquired antibodies against ADAMST13 (a von Willebrand’s Factor-cleaving metalloproteinase).
- TTP and aHUS can coexist!
Q3. What triggers this condition?
Only about 50% of those with the genetic predisposition develop aHUS.
Triggers of aHUS include:
- Streptococcus pneumoniae (40%) (also known as P-HUS, a subtype of aHUS)
- Pregnancy (term or post-partum)
- Drugs – quinine, mitomycin, ciclosporin, tacrolimus
- Transplantation – renal, haematological stem cell transplantation
- Combined methylmalonic aciduria and homocystinuria (a vitamin B12 metabolism disorder)
P-HUS occurs because S. pneumoniae has a neuraminidase that removes N- acetylneuraminic acid from cell-surface glycoproteins and exposes the normally hidden T antigen (Thomsen-Friedenreich antigen) on red blood cells, platelets, and glomeruli. Anti-T immunoglobulin M (IgM) in the serum reacts with the antigen causing hemolysis, thrombocytopenia and renal damage.
Q4. How is this diagnosis confirmed?
Renal biopsy can confirm the diagnosis but is often not necessary, and may be contraindicated by thrombocytopenia.
Typical histological findings on renal biopsy include:
- Thrombotic microangiopathy with swollen glomerular endothelial cells and red cells and platelets in the capillaries.
- Accumulation of fibrin-like material in the subendothelial space resulting in thickened capillary walls.
- Thrombi in the glomerular capillaries and arterioles.
- There may be acute cortical necrosis involving both glomeruli and convoluted tubules.
Other tests to confirm aHUS and identify the underlying cause include:
- genetic testing
- C3 levels are low in Factor H and I deficiency
- bilirubin and LDH are high due to hemolysis, and haptoglobin is low due to the binding of free hemoglobin.
- FDP is high but the coagulation profile is otherwise normal.
Q5. What is the treatment of this condition?
There are no conclusively proven specific therapies for aHUS. Meticulous supportive care is essential.
- Plasma exchange and plasma infusion
- Efficacy is uncertain given the absence of any randomised controlled trials in aHUS
- Mortality has decreased from 50% to 25% since their introduction to clinical practice
- Avoided in S. pneumoniae-associated HUS (P-HUS) because anti-T IgM in the administered plasma may exacerbate the disease.
- There is no good evidence for:
General treatment of acute renal failure
- Fluid restriction and diuretics
- Avoidance of nephrotoxins where possible
- Dialysis if necessary
Q6. What is the prognosis?
aHUS has a poorer prognosis than D+ HUS.
- 50% develop ESRF and up to 25% die in the acute phase
- Factor H deficiency usually has the worst prognosis of all: >80% suffer a recurrent episode and 65% die or develop ESRF within 1 year.
The patient on whom this case-based question-and-answer scenario was based had Factor H deficiency. He was treated with blood transfusions and had multiple infusions of fresh frozen plasma (FFP). He developed acute pulmonary oedema from fluid overload but with aggressive diuretic and anti-hypertensive treatment he avoided dialysis. He recovered from his acute illness but had persisting renal impairment and hypertension. One of the antihypertensive mediciations used was minoxidil, and he developed hypertrichosis —- profuse thickened dark hair all over his body (this side-effect usually resolves 1-6 months after discontinuation of minoxidil). A few months later he had a relapse, but again managed to avoid dialysis.
- Amirlak I, Amirlak B. Haemolytic uraemic syndrome: an overview. Nephrology(Carlton). 2006 Jun;11(3):213-8. PMID: 16756634.
- Loirat C, Noris M, Fremeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2008 Nov;23(11):1957-72. PMID: 18594873.
- Pickering MC, Cook HT. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin Exp Immunol. 2008 Feb;151(2):210-30. PMID: 18190458; PMCID: PMC2276951