Haemolytic Uraemic Syndrome

David V Milford

Paediatric Nephrology for the General Paediatrician 2012Manchester

Overview

• Presentation• Diagnosis• Management• Prognosis and follow-up• Atypical HUS

Haemolytic uraemic syndromes in childhood

Syndrome comprising

acute renal failure of varying severity microangiopathic anaemia thrombocytopenia of varying severity

Multiple aetiologies

BPSU National HUS study 1985-1988

D+ D-reported 282 (94.6%) 16 (5.4%)dialysed 165 (59%) 9 (56%)

followed for > 4 months 259 15

lone hypertension 3 2CRF 17 2ESRF 0 5

died 15 3

13.6% 78%

Arch. Dis. Child 1990; 65:716‑721

Arch. Dis. Child 1990; 65:716‑721

Evolution of lab resultsin HUS – outbreak in aninstitution

Diagnosis• Diarrhoea (often bloody)• Haematological – microangiopathic haemolytic

anaemia- thrombocytopenia

Fragmented red cells

Absence of platelets

Acute Kidney Injury

Shiga toxin producing E.coli (STEC) isolates BAPN/CDC study 1985-88

isolates VTEC O157

HUS 185 60 39 Bloody diarrhoea 48 4 3

Diarrhoea 54 3 1

Controls 46 2 0

Arch. Dis. Child. 1990; 65:722‑727

D+ HUS and EHEC

• EHEC colonise cattle• Transmission – contaminated meat, milk,

water, fruit, vegetables• Exposure to EHEC → diarrhoea in ≈ 10%

children• HUS develops in ≈ 15% of children with EHEC

diarrhoea• O157:H7 predominant serotype in the UK

– O26:H11, O103:H2, O111:NM, O121:H19, O145:NM

Annual STEC cases in the UK

Emerging Infectious Diseases 2005; 11: 590-6

Non-renal complications

• Seizures– hyponatraemia– neurotoxicity (STx receptors – neurones,

endothelium)

• Hypertension• Gut

– rectal prolapse– toxic megacolon, perforation, intussception

• Cardiomyopathy• Diabetes mellitus

Acute CNS changes

6 months

Clin J Am Soc Nephrol 2010; 5:1218–1228,

Even in patients with severe CNS involvement onacute imaging studies, prognosis can be favourable for clinical outcome and resolution of pathological imagingfindings

Pediatr Radiol (2004) 34: 805–810

Air in bowel

Late change - stricture

Rectal prolapse

Emerging Infectious Diseases 2005; 11: 590-6

395 D+ HUS

329 (83%) O157 +ve culture/serology

1 O26 65

18 D- HUS

No infection identified 59

Campylobacter 2

Shigella Sonnei 1

S pneumonae 1

Staph aureus 1

S pneumonae 7

CKD 1Died 2

(out of 8 cases)

Infections in HUS 1997-2001

Emerging Infectious Diseases 2005; 11: 590-6

Northern German outbreak May-July 2011

• Source: bean sprout farm in Lower Saxony• Sprouted from batch of seeds from Egypt• 3793 cases of diarrhoea – O104:H4• Delay in symptoms, ingestion → diarrhoea 8

days• 827 (22%) developed HUS, 88% in adults• 53 deaths• 2010 European data

– 4000 STEC cases reported, 5.5% developed HUS– O157 (41%), 026 (7%), O103 (2.5%)

Management• Conservative

– Monitor fluid balance, sodium, potassium, H+,BP– Furosemide may be useful early– Sodium, protein restriction; high calorie intake– Transfuse with caution– Avoid antibiotics/anti-motility agents/NSAID

• Transfer to regional centre– Oliguria +

• Fluid overload, need for transfusion, high K

– Anuria– Complications of D+ HUS

Prognosis and follow-up• BCH (n=250) 56% required acute dialysis• Prognostic markers

– Neutrophils >20 at presentation– Dialysis > 2weeks

• Mortality– 5% (BPSU 1985-88)– 1.8% (BPSU 1997-2001)

• Long term: HBP, reduced GFR, proteinuria– Variable in studies, probably 20-30% – BCH n=201 19% poor outcome at 5,10,0r 15 yrs

J Pediatr 1991; 118:191‑4

Poor outcome

Good outcome

Proteinuria at 1 year and outcome

• Follow-up– Frequently until Hb and creatinine normal– BP, PCr and EMU protein at 1 year after illness– BP, EMU protein, formal GFR, renal USS at 5 years

and every 5 years until post pubertal– BP, EMU protein by GP at intervals once

discharged

• Lifestyle advice– Avoid overweight, high sodium intake– Avoid smoking– Girls need renal function/proteinuria monitoring

during pregnancy

Level 1: aetiology advanced1.i Infection induced(a) Shiga and shiga-like toxin-producing bacteria;enterohaemorrhagic Escherichia coli, Shigelladysenteriae type 1, Citrobacter freundii(b) Streptococcus pneumoniae, neuraminidase andT-antigen exposure1.ii Disorders of complement regulation(a) Genetic disorders of complement regulation(b) Acquired disorders of complement regulation, e.g.anti-factor H antibody1.iii von Willebrand proteinase, ADAMTS13, deficiency(a) Genetic disorders of ADAMTS13(b) Acquired ADAMTS13 deficiency; autoimmune,drug induced1.iv Defective cobalamin metabolism1.v Quinine inducedLevel 2: aetiology unknown2.i Human immunodeficiency virus (HIV)2.ii Malignancy, cancer chemotherapy and ionising radiation2.iii Calcineurin inhibitors and transplantation2.iv Pregnancy, HELLP syndrome and oral contraceptive pill2.v Systemic lupus erythematosus and antiphospholipidantibody syndrome2 vi Glomerulopathy2.vii Familial, not included in part 12.viii Unclassified

Atypical/non-diarrhoeal/D- HUS

Typical/diarrhoeal/D+ HUS

Alternative complement pathway

Johnson, Eur J Pediatr 2008:167;965–971

Non-diarrhoeal HUS

• Requires urgent referral to a nephrology centre

• Associated with– High risk of death, CKD, hypertension, CNS events,

recurrent episodes, familial

• Therapies used– Plasmapheresis– Plasma infusion (especially ADAMTS13)– Eculizumab (binds to C5 and blocks C5 convertase)– Liver, liver/kidney transplantation

QUESTIONS?

n=7

Glomerular size in HUS patients with proteinuria3.3-7 years after illness

J Pediatr 1998; 133:220-3