Hemolytic uremic syndrome D59.3

First described in 1955 by the pediatrician Conrad Gasser.

Hemolytic uremic syndrome (abbreviation HUS), also known as Gasser syndrome, along with thrombotic thrombocytopenic purpura Moschcowitz syndrome, is an acute disease of small blood vessels and one of two forms of thrombotic microangiopathy in a disease group. HUS remains one of the most common causes of acute renal insufficiency (AKI) in pediatrics (Walsh PR et al. 2019).

Clinically, HUS is characterized by acute renal failure. The following triad characterizes HUS (Cody EM et al 2019):

• Microangiopathic hemolytic anemia (loss of red blood cells due to mechanical damage to erythrocytes in thrombosed small blood vessels).
• Thrombocytopenia (decreased platelet count).
• Acute renal failure.

If all three signs of disease are present, it is called complete enteropathic HUS; if only two are present, it is called incomplete enteropathic HUS.

A further classification of HUS is based on etiological aspects. HUS can be differentiated into:

• typical HUS (shigatoxin-associated HUS with accompanying diarrhoea; also diarrhoea-associated HUS)
• and an
• atypical HUS (aHUS) without accompanying diarrhea.

The etiology of typical HUS includes diarrheal infections caused by Shiga toxin-producing bacteria, complement deficiency, pneumococcal infection, and cobalamin deficiency (Webster K et al. 2014). S.a. Fig.

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

Further HUS-causing factors besides infections are:

• Pregnancy
• Medications (sulfonamides, estrogens, tacrolimus, gemcitabine, clopedigrel),
• collagenoses

aHUS: The cause of aHUS (no diarrhea symptoms) is 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 (shape altered erythrocytes), erythroblasts, Coombs test negative.

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

In EHEC-HUS, it is important (also for therapeutic reasons) to detect the pathogen and the shiga toxin or the shiga toxin gene.

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

In the case of EHEC infection, the administration of antibiotics is absolutely contraindicated, as these are not effective against the bacterial toxin, but on the other hand there is evidence that treatment with antibiotics promotes the development of HUS, probably due to increased toxin release (see below EHEC).

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

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

Immunotherapy to prevent autoantibodies (eculizumab): Since 2009, there have been case reports of the use of the anti-C5 monoclonal 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 renal and extrarenal sequelae in STEC-HUS was not demonstrated, so further results are awaited here (Monet-Didailler C et al 2020). All patients in the two groups survived.

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

Note: Early differentiation should be made between TTP, Shiga toxin-associated HUS, and atypical HUS (aHUS). Eculizumab binds to complement protein C5, thereby blocking its cleavage into 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.

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