the story of a whodunit
Transcript of 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
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(% o
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0
20
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80
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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
Cases of O157 VTEC in England and WalesSource: PHLS Laboratory
Year
1980 1985 1990 1995 2000
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mb
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of ca
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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