the story of a whodunit

Haemolytic uraemic syndrome … the story of a whodunit

Paul Warwicker

Lancashire Teaching Hospitals NHS Trust

RCP Kidney for the General Physician Conference Nov ‘17

Anaemia

Thrombocytopenia

Infarcts

Renal thrombotic microangiopathy(TMA)

Renal thrombotic microangiopathies

• Infection associated HUS

– Shiga toxin associated (E coli, S dysenteriae) – STEC HUS

– Streptococcus pneumoniae sepsis – pHUS

– HIV

• aHUS

• TTP

• Drug related

• Accelerated hypertension

• Disseminated intravascular coagulation

• Connective tissue disorders – including SLE and Anti-phospholipid syndrome

• Pregnancy - including Pre-eclampsia, and the HELLP syndrome

• Paraneoplastic

• Pancreatitis

HUS

microangiopathic haemolytic anaemia

acute renal failure

thrombocytopenia

TTP

microangiopathic haemolytic anaemia

renal involvement

thrombocytopenia

neurological involvement

fever

1925 - Eli Moschcowitz M.D.

An acute febrile pleiochromic anemia with hyaline thrombosis of

terminal arterioles and capillaries: An undescribed disease.

Archives of Internal Medicine, Chicago, 1925, 36: 89

Original from NEJM: Thrombotic microangiopathies. Joel L Moake.

Review article. Vol 347; 8, Aug 2002

Von Willebrand factor-cleaving protease activity in TTPP

rote

ase a

cti

vit

y

(% o

f co

ntr

ol)

0

20

40

60

80

100

120

Acutely Treatment Remission Control

Tsai and Lan, N Engl J Med, 1998

Haemolytic uraemic syndrome

• STEC (Diarrhoeal associated) HUS (D+)

90%

- preceding E coli O157 infection

• Atypical (Non diarrhoeal) HUS (D-) 10%

- Sporadic, Familial

STEC HUS

Diarrhoeal (STEC) HUS

Mohamed Karmali et al

STEC HUS

Cases of O157 VTEC in England and WalesSource: PHLS Laboratory

Year

1980 1985 1990 1995 2000

Nu

mb

er

of ca

se

s

0

200

400

600

800

1000

1200

Floods in Walkerton, Ontario - Mother’s Day 2000

Natural History of E.coli 0157 infection

E.Coli ingested

Abdominal cramps + diarrhoea

Bloody diarrhoea

95% resolution

5% HUS

3-4 days

1-2 days

5-7 days

Shiga Toxin – an Ribosomal

Inactivating Protein (RIP)

1955 - Conrad von Gasser

Hämolytisch-urämische Syndrome: Bilaterale Nierenrindennekrosen bei

akuten erworbenen hämolytischen Anämien.

C. Gasser, E. Gautier, A. Steck, R. E. Siebmann, R. Oechslin. Schweiz.

Med. Wochenschr. Band 85, 1955, S. 905–909

Atypical HUS

• ‘D – HUS’

• High mortality

and morbidity

aHUS• Affects all ages

• 30-40% die or progress to established renal failure at presentation, 65% by a year (despite plasma exchange) 1-3

• Affects organs other than the kidneys in 63% (cardiovascular 37%, gastrointenstinal 37%, neurology 17%) 4

1. Caprioli J et al. Blood 2006;108:1267-79;

2. Noris M et al. Clin J Am Soc Nephrol 2010;10:1844-59;

3. Noris M, Remuzzi G. N Engl J Med 2009;361:1676-87

4. Langman C. European Hematology Association Annual Congress 2012 (poster 0490)

Case History 1 • A 28 year old male business consultant

• 1 month history of nausea, vomiting and blurred vision

• On admission he had malignant hypertension with grade 4 hypertensive retinopathy and AKI (creatinine 540umol/l), with low platelet count (114) red cell fragments and a raised LDH

• Initially it was uncertain whether this was all due to malignant hypertension or some other underlying pathology

• The following day his renal function deteriorated further , and he was referred to the renal service - an IJ vascath was inserted and HD commenced

• Renal biopsy showed thrombotic microangiopathy with segmental cortical infarction

• Plasma exchange was performed

• But this was in the pre-Eculizumab era, and unfortunately, his renal function did not improve and he remained dialysis dependent

• A dialysis catheter was inserted and regular HD was arranged at our satellite unit.

• He suffered a sudden cardiac death 4 months later – PM showed cardiac microangiopathy

The 1990’sHemolytic Uremic syndrome and

Thrombotic Thrombocytopenic Purpura Ed. Kaplan, Trompeter and Moake (1992)

“The pathogenesis of inherited (and non diarrhoeal) HUS is unknown”

• Speculation that these patients may have defect in the metabolism of prostacyclin

• Abnormal von Willebrand factor multimers

• A few patients with low C3 levels

1994 University of

Newcastle Upon Tyne

Newcastle family 1990’s

Affected

Unaffected

Atypical HUS – what did we know?

• High Mortality

• Could be familial

• Can recur in transplants

FamilialHUS

South West Families

2,3 2,2 4,4 2,2 1,2 3,4 1,4 3,4 2,3 3,4 2,2

Example of microsatellite polymorphism profile derived from genomic DNA

obtained from whole blood (surviving family members) and archival tissue

(including deceased family members).

Exeter family

HUS & genetic linkage to

complement regulators

HUS

1p

1q

1q 32

RCA GENE CLUSTER

Factor XIIIb

Complement Factor H

Factor H related proteins

C4bp

DAF

CR2

CR1

MCP

Warwicker et al, KI 1998

Warwicker et al. Kidney Int. 1998

Factor H mutations in 1998

del c.155-157

C3716GR1215G

Genetic disorders Kidney International (1998) 53, 836–844

Genetic studies into inherited and sporadic hemolytic uremic syndrome

Paul Warwicker, Timothy H J Goodship, Rosemary L Donne, Yves Pirson, Anthony Nicholls, Roy M Ward, Peter Turnpenny and Judith A Goodship

Department of Medicine, and Department of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, England, United Kingdom, Renal Unit, Cliniques Universitaires St. Luc, Universite' Catholique de Louvain, Brussels, Belgium, Renal Unit, and Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter, and Department of Immunology, Royal Victoria Infirmary Trust, Newcastle upon Tyne, England, United Kingdom

Factor H mutations in 2010

C3b B

C3b Bb

Cell membrane

Alternative pathway activation

MAC

The complement balance ensures the protective effect of the natural defence system

Inhibition Activation

Zipfel PF Immunol Lettr. 2009 1267

Health

C3b B

C3b Bb

Cell membrane

Alternative pathway –

regulation by RCA :

CFH

MAC

Factor H

Complement Regulators and a-HUS

We now know atypical HUS is associated with

mutations in a number of complement

components and complement regulators.

Injury

Complement

activationDisease

Regulators of Complement Activation

• mutation

• polymorphisms

A model for aHUS

Richards, A, 2007, Mol Immunol 44:111-122.

Treatment aHUS

• Pl Ex reduces mortality from 50 to about 25%

• Success depends on amount, frequency, and

method admin (Pl ex better than Pl infusion?)

Treatment aHUS

• Pl Ex reduces mortality from 50 to about 25%

• Success depends on amount, frequency, and

method admin (Pl ex better than Pl infusion?)

• Exquisite control of BP (ACE I, ARB)

Gruppo RA & Rother RP. Eculizumab for Congenital Atypical HUSN Engl J Med 2009; 360:544-546

Nurnberger J et al. Eculizumab for Atypical HUSN Engl J Med 2009; 360:542-544

2009: First reported use of Eculizumab in aHUS

C3b B

C3b Bb

Cell membrane

MAC

C5

ECULIZUMAB

X

Eculizumab binds C5 and blocks the terminal pathway of complement

aHUS and TTP: early diagnosis is important

• Advancements in treatment options

warrant early diagnosis and intervention

• These are clinical diagnoses supported by appropriate laboratory tests

• Challenges – similar presentations

2 steps 1. Signs and symptoms of TMA1

– Clinical suspicion (eg renal, neurological, severe hypertension)

– Decreased platelet count

– Evidence of microangiopathic haemolysis –schistocytes, raised LDH

– Evidence of organ impairment / damage

2. Differentiate TMA diseases

1. Loirat C, Frémeaux-Bacchi V. Orphanet J Rare Dis 2011;6:60-90;

Differentiating TMAs

Shiga Toxin (STEC HUS)

ADAMTS 13 (TTP)

While waiting for ADAMTS13 results:1,2

– Platelet count of >30,000/mm3 OR

– Serum creatinine level of >150–200 μmol/L

• ….. almost eliminates a diagnosis of severe

ADAMTS13 deficiency / TTP

1. Zuber J et al. Nat Rev Nephrol 2012;8:643-57;

2. Campistol JM et al. Nefrologia 2013;33:27-45

Other tests

• Genetic analysis – not required for diagnosis, takes some time, normal in 30-50% of cases

• Complement levels – normaL, or very slightly reduced, in a majority of cases of aHUS.

Case History 2

• 29 yo woman was admitted with AKI, severe hypertension with features of a microangiopathy(Creat 800, Hb 80, Pt count 65)

• She presented to the A/E extremely unwell (‘peri-arrest’)

• During resuscitation in A/E she had a PEA arrest probably secondary to hyperkalaemia, requiring intubation , ventilation and ITU care.

• Anaemia, thrombocytopenia, AKI

-> Clinical evidence of TMA – suspicion ****

• Platelet count 65 (>30) , Creatinine 800 (>200) – unlikely to be TTP. History and findings suggestive of aHUS.

• Plan:

1. Check ADAMT13 activity & Shiga toxin if available

2. Control of BP (ACE I / ARB)

3. Plasma exchange

4. Eculizumab

• A diagnosis of aHUS was made

• She was plasma exchanged and treated and daily HDx

• Despite this died soon after admission from a large intra-cerebral haemorrhage probably secondary to hypertension

• Subsequently found to have a familial Factor H mutation

• **** Cousin died of sudden ‘hypertensive heart failure’ in her youth

Case History 3

• 41 yo man admitted with AKI, hypertension and fluctuating level of consciousness. No fever.

• Hb 71 g/l

• Pt 6

• Creatinine 130

• INR 1.1, APTR 1.0

• CRP 66

• Bil 114, ALT 166, ALP 69

• RBC Fragments on blood film, Reticulocytosis

• Anaemia, Thrombocytopenia, AKI, RBC

fragments and appropriate clinical

history -> TMA

• Pt count <30, Creat <200, Neurological

symptoms

• Anaemia, Thrombocytopenia, AKI, RBC

fragments and appropriate clinical

history -> TMA

• Pt count <30, Creat <200, Neurological

symptoms – likely TTP

• Check ADAMT13 activity (UCH)

confirmed < 5% …TTP

Acknowledgements

• Newcastle national aHUSservice

– Tim & Judith Goodship

– Neil Sheerin

– Rosie Donne

– Anna Richards

– David Kavanagh

– Danny Gale

• The families in Newcastle, Devon and Belgium