Hemolytic uremic syndrome D59.3

First described in 1955 by the pediatrician Conrad Gasser

Haemolytic uraemic syndrome (abbreviation: HUS), also known as Gasser syndrome, is an acute disease of the small blood vessels and one of two forms of thrombotic microangiopathy, along with thrombotic thrombocytopenic purpura (syn. Moschcowitz syndrome). HUS remains one of the most common causes of acute kidney injury (AKI) in pediatrics (Walsh PR et al. 2019).

The main clinical manifestation is acute renal failure. HUS is characterized by the following triad (Cody EM et al. 2019):

• Microangiopathic hemolytic anemia (loss of red blood cells due to mechanical damage to the erythrocytes in the thrombotic small blood vessels)
• Thrombocytopenia (reduced platelet count)
• Acute kidney failure

If all three signs of the disease are present, it is referred to as complete enteropathic HUS; if only two of these signs are present, it is referred to as incomplete enteropathic HUS.

HUS is further classified according to etiological aspects. HUS can be divided into:

• typical HUS (shigatoxin-associated HUS with accompanying diarrhea; also diarrhea-associated HUS) and an

• atypical HUS (aHUS) without accompanying diarrhea.

The aetiology of typical HUS includes diarrhoeal infections caused by shigatoxin-producing bacteria, complement deficiency, pneumococcal infection and cobalamin deficiency (Webster K et al. 2014). See also Fig.

In 90 % of cases, HUS is the result of an intestinal infection with Shiga toxin-producing Escherichia coli. This form is also known as EHEC-HUS (enterohaemorrhagic Escherichia coli, EHEC) or STEC-HUS (Cody EM et al. 2019). In children, this syndrome occurs in up to 10% of cases after EHEC infection with E. coli O157.H7 and E. coli O104:H4 (Ko H et al. 2016). This symptomatology rarely occurs after a respiratory infection with Streptococcus pneumoniae (SP-HUS).

In addition to infections, other HUS-triggering factors are:

• Pregnancy
• Medication (sulphonamides, oestrogens, tacrolimus, gemcitabine, clopidogrel)
• collagenoses

aHUS: The cause of aHUS (no diarrhea symptoms) is considered to be a mutation-related increased activation of the complement system. The following genes are involved: CFI gene, CFH gene, CFHRP1-5 (Complement Factor H Related 1-5), thrombomodulin(THBD) gene, CD46 gene.

The syndrome mainly affects infants and young children (median age 36.4 months), in whom it is the most common cause of acute renal failure. However, it can also occur in adults. HUS is one of the acquired hemolytic anemias.

While typical HUS is more common in children, the atypical form of HUS (aHUS) is more common in adults.

Thrombocytopenia, schistocytes (erythrocytes with altered shape), erythroblasts, Coombs test negative.

ADAMST13 levels are normal (Ko H et al. 2016)

Important (also for therapeutic reasons) in EHEC-HUS are the detection of the pathogen and the detection of shigatoxin or the shigatoxin gene.

Therapies include supportive care, cobalamin supplementation and plasma infusion and exchange (Webster K et al. 2014).

The administration of antibiotics is absolutely contraindicated in EHEC infection, as these do not act against the bacterial toxin, but there are indications that treatment with antibiotics promotes the development of HUS, probably due to increased toxin release (see EHEC below).

ACE inhibitors may be indicated to control the frequently high blood pressure caused by the systemic effects of the toxins. If necessary, dialysis or hemofiltration is performed to remove the toxins from the bloodstream.

End-stage renal disease can be the result and transplantation is curative in some forms of the disease.

Immunotherapy to prevent autoantibodies (eculizumab): Since 2009, there have been case reports on the use of the monoclonal anti-C5 antibody eculizumab in children with HUS who did not respond to plasmapheresis (Walsh PR et al. 2019; Monet-Didailler C et al. 2020). However, in a study of 54 children (median age 40.6 months) with STEC-HUS, 18 of whom were treated with eculizumab, the benefit of eculizumab on the renal and extrarenal sequelae of STEC-HUS could not be demonstrated, so further results are awaited (Monet-Didailler C et al. 2020). All patients in both groups survived.

However, good treatment results were achieved with eculizumab in aHUS. However, the role of complement and anti-complement therapy in STEC-HUS remains unclear (Walsh PR et al. 2019).

Note: A differentiation between TTP, shigatoxin-associated HUS and atypical HUS (aHUS) should be made at an early stage. Eculizumab binds to the complement protein C5 and thereby blocks its cleavage into the fragments C5a/b and thus the formation of the terminal complement complex C5b-9.

The acute mortality rate in STEC-HUS is now less than 5%; however, significant long-term renal morbidity exists in approximately 30% of survivors.

1. Cody EM et al (2019) Hemolytic uremic syndrome. Pediatr Clin North Am 66:235-246.
2. Dixon BP et al (2018) Atypical hemolytic uremic syndrome. Pediatr Clin North
3. Am 65:509-525.
4. Joseph A et al (2020) Shiga toxin-associated hemolytic uremic syndrome: A Narrative Review. Toxins (Basel) 12:67.
5. Ko H et al. (2016) Hemolytic uremic syndrome associated with Escherichia coli O157:H7 infection in older adults: a case report and review of the literature. J Med Case Rep 10:175.
6. Kremer Hovinga JA et al (2017) Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers 6:437-454.
7. Monet-Didailler C et al (2020) Outcome of children with Shiga toxin-associated haemolytic uraemic syndrome treated with eculizumab: a matched cohort study. Nephrol Dial Transplant 35:2147-2153.
8. Moschcowitz E (1925) An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. Arch Intern Med 36: 89-93
9. Page EE et al. (2017) Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv 1:590-600.
10. Viteri B et al (2020) Hemolytic uremic syndrome. Pediatr Rev 41:213-215.
11. Walsh PR et al (2019) Eculizumab in the treatment of Shiga toxin haemolytic uremic syndrome. Pediatr Nephrol 34:1485-1492.
12. Webster K et al (2014) Hemolytic uremic syndrome. Handb Clin Neurol 120:1113-1123.
13. Zheng X et al (2003) Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Ann Intern Med 138: 105-108