Haemolytic uraemic syndrome the story of a whodunit

Transcription

1 Haemolytic uraemic syndrome the story of a whodunit Paul Warwicker Lancashire Teaching Hospitals NHS Trust RCP Kidney for the General Physician Conference Nov 17

2 Renal thrombotic microangiopathy (TMA) Anaemia Infarcts Thrombocytopenia

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4 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 Antiphospholipid syndrome Pregnancy - including Pre-eclampsia, and the HELLP syndrome Paraneoplastic Pancreatitis

5 HUS microangiopathic haemolytic anaemia acute renal failure thrombocytopenia TTP microangiopathic haemolytic anaemia renal involvement thrombocytopenia neurological involvement fever

6 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

7 Original from NEJM: Thrombotic microangiopathies. Joel L Moake. Review article. Vol 347; 8, Aug 2002

8 Von Willebrand factor-cleaving protease activity in TTP 120 Protease activity (% of control) Acutely Treatment Remission Control Tsai and Lan, N Engl J Med, 1998

9 Haemolytic uraemic syndrome STEC (Diarrhoeal associated) HUS (D+) 90% - preceding E coli O157 infection Atypical (Non diarrhoeal) HUS (D-) 10% - Sporadic, Familial

10 STEC HUS

11 Mohamed Karmali et al Diarrhoeal (STEC) HUS

12 STEC HUS

13 Cases of O157 VTEC in England and Wales Source: PHLS Laboratory Number of cases Year

14 Floods in Walkerton, Ontario - Mother s Day 2000

15 Natural History of E.coli 0157 infection E.Coli ingested Abdominal cramps + diarrhoea 3-4 days 1-2 days Bloody diarrhoea 5-7 days 95% resolution 5% HUS

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17 Shiga Toxin an Ribosomal Inactivating Protein (RIP)

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20 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

21 Atypical HUS D HUS High mortality and morbidity

22 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: ; 2. Noris M et al. Clin J Am Soc Nephrol 2010;10: ; 3. Noris M, Remuzzi G. N Engl J Med 2009;361: Langman C. European Hematology Association Annual Congress 2012 (poster 0490)

23 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

24 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

25 The 1990 s Hemolytic 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

26 1994 University of Newcastle Upon Tyne

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28 Newcastle family 1990 s Affected Unaffected

29 Atypical HUS what did we know? High Mortality Could be familial Can recur in transplants

30 Familial HUS South West Families

31 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).

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33 Exeter family

34 HUS & genetic linkage to complement regulators 1p HUS 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

35 Factor H mutations in 1998 del c C3716G R1215G Warwicker et al. Kidney Int. 1998

36 Genetic disorders Kidney International (1998) 53, 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

37 Factor H mutations in 2010

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39 Alternative pathway activation C3b B C3b Bb Cell membrane MAC

40 The complement balance ensures the protective effect of the natural defence system Inhibition Activation Health Zipfel PF Immunol Lettr

41 Alternative pathway regulation by RCA : CFH C3b B Factor H C3b Bb Cell membrane MAC

42 Complement Regulators and a-hus We now know atypical HUS is associated with mutations in a number of complement components and complement regulators.

43 A model for ahus Injury Complement activation Disease mutation polymorphisms Regulators of Complement Activation

44 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?) Richards, A, 2007, Mol Immunol 44:

45 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)

46 2009: First reported use of Eculizumab in ahus Nurnberger J et al. Eculizumab for Atypical HUS N Engl J Med 2009; 360: Gruppo RA & Rother RP. Eculizumab for Congenital Atypical HUS N Engl J Med 2009; 360:

47 Eculizumab binds C5 and blocks the terminal pathway of complement C3b B ECULIZUMAB C3b Bb X C5 Cell membrane MAC

48 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

49 2 steps 1. Signs and symptoms of TMA 1 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;

50 Differentiating TMAs Shiga Toxin (STEC HUS) ADAMTS 13 (TTP) While waiting for ADAMTS13 results: 1,2 Platelet count of >30,000/mm 3 OR Serum creatinine level of > 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

51 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.

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

53 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

54 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

55 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

56 Anaemia, Thrombocytopenia, AKI, RBC fragments and appropriate clinical history -> TMA Pt count <30, Creat <200, Neurological symptoms

57 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

58 Acknowledgements Newcastle national ahus service Tim & Judith Goodship Neil Sheerin Rosie Donne Anna Richards David Kavanagh Danny Gale The families in Newcastle, Devon and Belgium