What is haemolytic uraemic syndrome or HUS?

Other renal conditions
What is haemolytic uraemic syndrome or HUS?

Haemolytic uraemic syndrome (HUS) is a medical emergency. It is a rare but serious condition, often due to infection (especially bacteria such as subgroups of E Coli), and less commonly to genetic predisposition or other underlying conditions.

It affects blood vessels (causing inflammation and small blood clots) all over the body, particularly in the kidneys. This is called a thrombotic microangiopathy (TMA).

It can cause AKI, with some patients requiring dialysis. It can be due to infection (especially E Coli), and outbreaks occur.

So. What is haemolytic uraemic syndrome or HUS? Let’s start with the basics.

1. Definition

HUS is characterised by a triad of symptoms:

  • Microangiopathic haemolytic anaemia (MAHA) = destruction of red blood cells due to damaged blood vessels, and blood clots. Red blood cells break apart as they squeeze past clots within small blood vessels
  • Thrombocytopenia = low platelet count
  • Acute kidney injury (AKI).
2. Epidemiology

HUS is more common in children under the age of 5 years, but it can occur in people of any age. It has a higher incidence in certain regions and countries (e.g. Argentina); and during the warmer months, correlating with outbreaks of STEC infection.

3. Causes
Primary (10%)

Atypical HUS (aHUS). It is more common in adults (responsible for 60% of this group) but can occur in children – and is due to abnormalities in the alternative complement regulatory pathway.

It is a genetic/immune disease, and genetic mutations cluster in families. Less than 20% of cases run in families. When the disorder is familial, it can have an autosomal dominant or an autosomal recessive pattern of inheritance. Some patients get recurrent episodes.

Atypical HUS can also present with bloody diarrhoea (in up to 30% of cases); making it sometimes hard to distinguish from secondary diarrhoea-associated causes (see below).

Secondary (90%)
  • Diarrhoea-associated HUS (D+ HUS). It is the most common cause in children; and usually caused by Shiga toxin-producing Escherichia colis (STEC; including o157 and 0145 subgroups) and other bacteria (Shigella, Salmonella, Camplyobacter, Clostridium butyricum). D+ HUS generally appears about seven days after the onset of the diarrhoea (range 2-14 days).
  • Other infections: HIV, pneumococcus
  • Malignancy
  • Solid organ and bone marrow transplants
  • Other autoimmune disorders – eg, systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome
  • Certain medication – e.g. ciclosporin/tacrolimus, chemotherapy agents (e.g. mitomycin C, gemcitabine), quinine, oral contraceptive pill
  • Pregnancy.

Notes

  1. Post-partum HUS can occur upto 6 months after delivery.
  2. Secondary HUS is sometimes called ‘typical HUS’, to distinguish it from atypical HUS (aHUS)
4. Risk factors
  • Ingestion of contaminated food or water
  • Exposure to infected individuals in institutional settings
  • Genetic predisposition (for atypical HUS).
5. Symptoms

The brain, heart, and kidneys are particularly likely to be affected. Neurological manifestations occur in about 25% of patients and include confusion, mini-strokes, and seizures. Eye involvement includes damage top the retina.

Cardiac involvement may cause arrhythmias. Heart failure can occur particularly in women who have recently had a baby. Large-vessel thrombi are uncommon.

  • Diarrhoea (especially bloody diarrhoea)
  • Abdominal pain
  • High blood pressure
  • Low urine output
  • Fluid overload
  • Bruises (some small), and later bleeding
  • Symptoms from other non-renal, non-gastrointestinal complications (e.g. cardiac, strokes).

Haemolytic Uraemic Syndrome – Zero To Finals

Notes

  1. Fever does not always occur
  2. Very occasionally perforation of the bowel due to microvascular ischaemic infarction
  3. Patients with pneumococcal-related HUS may have pneumonia, meningitis, or sepsis.
6. Diagnosis

HUS is diagnosed based on clinical symptoms, blood tests showing haemolytic anemia and thrombocytopenia, and signs of AKI.

A blood film is important. It will usually show fragmented red blood cells indicative of microangiopathic haemolysis (schistocytes: helmet cells, triangular RBCs).

Hemolytic-Uremic Syndrome

Blood film shows schistocytes (red blood cell fragments) and reduced number of platelets.

There is usually other evidence of haemolysis (falling hemoglobin level, polychromasia, elevated reticulocyte count, elevated serum LDH and bilirubin, reduced haptoglobin).

Complemen levels and an ADAMTS13 blood test should be sent off. Low complement levels are suggestive of, but not specific to aHUS. But ADAMST13 is usually low in aHUS. Stool samples should be tested for STEC.

Renal biopsy

(b) Light microscopy of kidney biopsy specimen demonstrating acute thrombotic microangiopathy without chronic findings of glomerulosclerosis or interstitial fibrosis. There is glomerular capillary dilatation, increased mesangial matrix, as well as platelet and fibrin thrombi in glomerular loops with focal and segmental necrosis. There is extension to afferent arterioles with fibrinoid change. RBC fragments are present in the glomerulus. Tubules have large resorption droplets, are often dilated with RBC casts. The interstitium has focal RBC (Hematoxylin and eosin; original magnification x 400) 

Renal biopsy showing acute thrombotic microangiopathy (TMA). There are platelet/fibrin thrombi (clots) in glomerular capillaries. Red cell fragments are also present in the glomerulus.

Notes

  1. Renal biopsy is not often done due to the risk of bleeding (low platelets)
  2. Normal platelets do not exclude HUS. In its early stages (especially if its caused by a drug), platelets can be normal
  3. Disseminated intravascular coagulation (DIC) is part of the differential diagnosis for HUS. DIC is characterised by a prolonged prothrombin time and activated partial thromboplastin time, elevated D dimer, and elevated fibrin degradation products (FDPs); however these tests are usually normal in HUS.
Differential diagnosis

Initially HUS may present similarly to other TMAs such as DIC/sepsis, HELLP, and systemic vasculitis. Often clinical presentations and laboratory testing will rule out other causes.

7. Treatment
  • Stopping drugs that may have caused HUS, and/or treating the underlying cause (see above)
  • Treatment of typical HUS caused by STECs is supportive
  • IV fluids to maintain hydration
  • Blood transfusion may be necessary
  • Platelet transfusions should be used sparingly to avoid thrombotic complications
  • IV blood plasma
  • Plasma exchange (for aHUS only)
  • aHUS (due to complement factor mutations/deficiency) may respond to complement C5 inhibitors, such as eculizumab or ravulizumab. They are monoclonal antiboidies. Eculizumab has been used for both treatment and prevention of primary aHUS, and aHUS after transplantation. These are very expensive drugs
  • Dialysis if required.

Note. Antibiotics are usually avoided as they can worsen the condition.

8. Outlook (prognosis)

When HUS was first described by Gasser, 1955 severe cases were usually fatal.

Fortunately now, with prompt treatment, most children make a full recovery from typical HUS without long-term effects. If they have AKI, they normally return to normal kidney function (even if they have dialysis).

However, in severe cases, chronic kidney disease/ESRF and other long-term complications occur.

The risk of progression to stage 3 or 4 chronic kidney disease (CKD) and end-stage renal failure (ESRF) in aHUS is high. In contrast to typical HUS, patients with aHUS often fail to regain kidney function without treatment. Untreated, approximately 50% of aHUS cases progress to dialysis dependency, with a mortality rate of 25%,

9. HUS and kidney transplantation

HUS has a high recurrence rate after kidney transplantation. Treatment or prophylaxis with eculizumab is effective in reversing or preventing aHUS, interestingly whether or not genetic complement mutations are identified (Dany, 2014).

10. Prevention

Preventing STEC infection is key to reducing HUS risk, for infective causes.

E coli infections can occur after eating contaminated food, such as undercooked meat, drinking unpasteurised juices or dairy products, or being in contact with cattle and other farm animals or with a person who has the infection. This is why outbreaks occur in children visiting petting farms.

This includes practicing good hand hygiene, cooking meat thoroughly, avoiding unpasteurised dairy products, and preventing cross-contamination in the kitchen.

Summary

We have described what is haemolytic uraemic syndrome or HUS. We hope it has been helpful.

Other resources

E Coli O145 outbreak in UK – HUS and AKI
Haemolytic uraemic syndrome review articles: Corrigan, 2001; Sheerin, 2019; Kuter, 2024
Argentina has the highest rate of HUS worldwide, with 70% of the cases associated with STEC infections: Carbonari, 2022

 

 

 

 

 

Last Reviewed on 9 June 2024

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