Review doi: 10.1111/joim.12546 Haemolytic uraemic syndrome Diana Karpman, Sebastian Loos, Ramesh Tati & Ida Arvidsson From the Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden Abstract. Karpman D, Loos S, Tati R, Arvidsson I review, we will describe the causes of HUS. In (Clinical Sciences Lund, Lund University, Lund, addition, we will review the clinical, pathological, Sweden). Haemolytic uraemic syndrome (Review). J haematological and biochemical features, epi- Intern Med 2016; doi: 10.1111/joim.12546. demiology and pathogenetic mechanisms as well as the biochemical, microbiological, immunologi- Haemolytic uraemic syndrome (HUS) is defined cal and genetic investigations leading to diagno- by the simultaneous occurrence of nonimmune sis. Understanding the underlying mechanisms of haemolytic anaemia, thrombocytopenia and acute the different subtypes of HUS enables tailoring of renal failure. This leads to the pathological lesion appropriate treatment and management. To date, termed thrombotic microangiopathy, which there is no specific treatment for EHEC-asso- mainly affects the kidney, as well as other ciated HUS but patients benefit from supportive organs. HUS is associated with endothelial cell care, whereas patients with aHUS are effectively injury and platelet activation, although the treated with anti-C5 antibody to prevent recur- underlying cause may differ. Most cases of HUS rences, both before and after renal transplanta- are associated with gastrointestinal infection with tion. Shiga toxin-producing enterohaemorrhagic Escherichia coli (EHEC) strains. Atypical HUS Keywords: complement, enterohaemorrhagic Escher- (aHUS) is associated with complement dysregula- ichia coli, haemolytic uraemic syndrome, microve- tion due to mutations or autoantibodies. In this sicles, Shiga toxin. of the disease pathogenesis. We will provide a Introduction clinical investigation protocol, based on the known Haemolytic uraemic syndrome (HUS) is character- aetiologies of HUS, designed to achieve an appro- ized by the simultaneous development of non- priate diagnosis and thus suitable treatment. The immune haemolytic anaemia, thrombocytopenia prognosis of HUS, in terms of patient morbidity and acute renal failure. The main causes of HUS and mortality, is largely based on the underlying are Shiga toxin-producing Escherichia coli (STEC) cause and the provision of appropriate treatment. also known as enterohaemorrhagic E. coli (EHEC), Studies in recent years have generated new in which patients usually present with a gastroin- insights into the pathogenesis of the various forms testinal prodrome, and complement-mediated dis- of HUS, which will be highlighted here, as these ease [atypical HUS (aHUS)] associated with scientific advances provide the background for mutations in genes encoding complement factors novel therapies. or autoantibodies. Less common causes are other infections, other genetic causes (i.e. not affecting Classification and clinical features of HUS the complement system), malignancies, drugs, transplantation, pregnancy or malignant hyperten- Haemolytic uraemic syndrome is classified as post- sion. The clinical presentation and renal pathology infectious, complement-mediated, which may be may be similar, regardless of the primary cause. hereditary and/or autoimmune, or associated with Patient investigation should therefore be geared other co-existing conditions such as pregnancy, towards defining the aetiology, as treatment strate- human immunodeficiency virus (HIV) infection, gies may differ based on the underlying disease transplantation (bone marrow and solid organ), pathogenesis. malignancy, autoimmune diseases, drugs, malig- nant hypertension as well as other more unusual In this review, we will define the clinical and associations, some of which are hereditary laboratory features of HUS, as well as disease (Table 1). There is also some degree of overlap epidemiology and pathology, and describe aspects between aetiologies; for example, pregnancy- ª 2016 The Association for the Publication of the Journal of Internal Medicine 1 D. Karpman et al. Review: Haemolytic uraemic syndrome Table 1 Classification of haemolytic uraemic syndrome (HUS) based on aetiology Aetiology Cause and features Comment Reference Specific Shiga Enterohaemorrhagic Most prevalent serotypes: [230] infectious toxin-producing Escherichia coli (EHEC) O157, O26, O104, O111, agent bacteria O103, O145, O121, O45 Shigella dysenteriae type 1 [231] Citrobacter freundii [232] Streptococcus Neuraminidase producing [193] pneumoniae Influenza A H1N1 Neuraminidase producing [192] (possible explanation) Enteroviruses Coxsackie A and B, Echo Unclear association [233] HIV [234] Pseudomonas Neuraminidase producing [235] aeruginosa (possible explanation) Complement Genetic Mutations in genes encoding Resulting in dysregulated [55, 154] dysregulation for factor H, factor I, MCP, C3, complement activation via the factor B, clusterin, alternative pathway thrombomodulin Rearrangements or deletions Associated with antibodies to [156] in genes encoding factor H complement factor H-related proteins Factor H CFH-H3 and MCP [156, 161] ggaac risk haplotypes Acquired Anti-factor H antibodies Associated with genetic [169] rearrangements or deletions in factor H-related proteins Monoclonal gammopathy [236] Mutations in Loss-of-function recessive [32] diacylglycerol mutations kinase-e (DGKE) Autoimmune Systemic lupus [237] erythematosus Anti-phospholipid [238] syndrome Scleroderma [239] Pregnancy related HELLP syndrome May be associated with [240] complement dysregulation Postpartum [240] Transplantation Solid organ [241] Bone marrow [242] CMV viraemia [243] 2 ª 2016 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine D. Karpman et al. Review: Haemolytic uraemic syndrome Table 1 (Continued ) Aetiology Cause and features Comment Reference Malignancy Cancer Mitomycin, cisplatin, [244] chemotherapy bleomycin Ionizing radiation [245] Drugs Quinine [244] Calcineurin Also in combination with [244] inhibitors everolimus Oral contraceptives [244] Antiplatelet Clopidogrel, ticlopidine [244] agents VEGF inhibitors [246] Malignant [247] hypertension Cobalamin Cobalamin type C MMACHC [248] metabolism mutations, methylmalonic aciduria and homocystinuria Denys–Drash WT1 mutations [249] syndrome Unknown May be familial [36] MCP, membrane cofactor protein; HELLP, haemolysis, elevated liver enzymes, low platelets; VEGF, vascular endothelial growth factor; CMV, cytomegalovirus; MMACHC, methylmalonic aciduria and homocystinuria, cblC type; WT, Wilm’s tumour. associated HUS and post-transplant HUS may be during the gastrointestinal phase of infection may associated with complement mutations [1, 2]. increase the risk of developing HUS [13, 14]. Patients with HUS, regardless of aetiology, present Furthermore, young children (<5 years) and the with pallor, signs and symptoms of kidney failure, elderly are more prone to develop HUS [11, 15] possible jaundice and/or bleeding and purpura. although HUS developed mostly in middle-aged women during the more recent large German outbreak of EHEC in 2011 [16]. EHEC-associated HUS The most common cause of HUS is gastrointestinal Patients typically present with acute pallor and infection with EHEC. EHEC infection was first symptoms of renal failure (oedema, nausea and associated with haemorrhagic colitis during an emesis, oliguria and/or high blood pressure). In outbreak in the USA in 1982 [3] and at approxi- addition to renal failure, extra-renal manifesta- mately the same time was associated with HUS in tions may occur including cardiac, neurological, sporadic cases [4]. EHEC-associated HUS may respiratory and pancreatic involvement [17–21] as occur in larger or smaller outbreaks [5–10] or in well as elevated liver function tests. Neurological sporadic cases, and typically presents as haemo- symptoms may vary from mild jerks to severe coma lytic anaemia, thrombocytopenia and acute renal or stroke in approximately 30% of cases and are failure developing after gastroenteritis, within 2– associated with a worse outcome. Other factors 12 days after the debut of diarrhoea, which may related to a worse outcome are leukocytosis [22, manifest as haemorrhagic colitis with bloody diar- 23] and low platelet counts [22, 24]. EHEC- rhoea. Approximately 15% of cases of EHEC- associated HUS usually does not recur. associated gastroenteritis will develop HUS [11], although the gastroenteritis itself may be very aHUS severe and cause morbidity (rectal prolapse, colo- nic gangrene or perforation) and even mortality aHUS may be sporadic or familial and is associated [12]. The use of antibiotics and antimotility agents with an underlying dysregulation of the alternative ª 2016 The Association for the Publication of the Journal of Internal Medicine 3 Journal of Internal Medicine D. Karpman et al. Review: Haemolytic uraemic syndrome pathway of complement. The complement abnor- elderly [34, 35]. After an incubation period of mality may be a mutation, genetic rearrangement or 4–7 days, EHEC-infected patients develop diar- deletion in a gene encoding a complement factor, or rhoea [36] and approximately 15% of cases the presence of a homozygous complement gene develop HUS [11] within an additional 2–10 days. haplotype or of an autoantibody to complement Patients may be infected by intake of contami- regulator factor H. The complement abnormality nated food including raw, processed or under- itself is not sufficient for