When the story begin, it was last year

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2 When the story begin, it was last year Mr. Ho, YC 58/ M Ex smoker PMH : HT, hyperlipidaemia Med: adalat retard, lopid and losartan Presented to POH on 17 th Feb., 2016 High fever and URTI symptom

3 On admission Hb: 11.1 WCC : 17.4 increased in neutrophils Plt: 267 Cr: 193 Urea : 27 Total Bil.: 29 Normal LFT INR: 1.3

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5 He was started on augmentin and tamiflu

6 He has persistent swinging fever Stepped antibiotic to Rocephin MSU : negative Blood culture : negative Sputum: commensal only Urine legionella : negative No diarrhoea, stool no pathogen identified

7 AKI 17/2/ /2/ /2/ /2/2016 Urea Creatinine WCC Hb Plt

8 Work up for AKI Hx of taken NSAID before admission USG : normal sized kidneys, no hydronephrosis RF, ANA, anti ds DNA: negative Low C3, C4 (0.79, 0.13) HBV, HCV, HIV: negative ASOT : negative Ig pattern : normal, SPE: no abnormal band ANCA, anti GBM: negative G6PD: normal

9 MSU : negative Granular cast : positive Urine: no dysmorphic red cell No eosinophils Spot urine TP/ Cr: 0.63 mg/mg

10 Fluid over load on Admitted to ICU in POH for haemodialysis 17/2/ /2/ /2/ /2/ /2/2016 Urea Creatinine LDH WCC Hb Plt

11 Blood film Occ. Schistocytes Occ. Atypical lymphocytes Haptoglobin: 2.50 (not low) Normal LDH, Bil Renal biopsy performed in ICU with plt cover on 22 nd Feb.

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15 Renal Biopsy Result 1. Thrombotic microangiopathy, with focal glomerular infarction 2. Acute interstitial nephritis with eosinophils

16 No feature suggestive of intravascular haemolysis, after reviewing the film by haematologist Plasma exchange was started( for renal biopsy show TMA) And steroid for the? NSAID induced interstitial nephritis

17 27 th Feb., 2016 Started on prednisolone 15mg BD Plasma exchange on alternate day 27/2/ /2/2016 2/3/2016 Urea Creatinine LDH WCC Hb Plt

18 3 rd March, 2016 The day after 3 rd PE Acute Lt loin pain Hb drop from 8 to 6 Urgent CT abd

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21 4 th March, 2016 New Rt loin pain and abd distesnsion Hypotension Hb down to 5 4 unit of pack cell transfused Another CT abd

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28 Seen by Rheumatologist Suggest pulse steroid then cyclophosphamide Started on pulse steroid on 4 th March (same day) 5 th March: 2 nd dose of pulse steroid 6 th March: high fever and decreased SaO2

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30 Changed to iv hydrocortisone Cyclophosphamide did not start Back to general ward on 8 th March for con t Mx of the RLL pneumonia Next day. Persistance fever, desaturation and resp failure Intubated and back to ICU

31 After multiple work up Melioidosis pneumonia

32 Started on meropenem But cyclophosphamide was not started Condition improved Extubated, back to general ward Temp HD and active rehab Given 4 weeks of meropenem then changed to septrin for 6 more weeks

33 Noted to have renal recovery and last HD on Just came back Fu last month Urea : 12.7 Cr: 231 Spot urine TP/ Cr: 0.44mg/mg Med : Adalat GITS, pantoloc, NaHCO3, labetalol and prednisolone 5 mg daily

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36 Polyarteritis nodosa (PAN)

37 Polyarteritis nodosa (PAN) Systemic necrotizing vasculitis targeting medium-sized arteries and not associated with glomerulonephritis or small vessel involvement. Anti-neutrophil cytoplasmic antibodies are typically negative. Clinical manifestations of PAN can be systemic or confined to a single organ or systems.

38 Laboratory abnormalities reveal a prominent acute phase response but are non-specific. Histologic confirmation of vasculitis in medium sized arteries is desirable. While renal biopsy are usu normal. If biopsies are negative or cannot be obtained, visceral angiography, may reveal multiple micro-aneurysms supporting the diagnosis of PAN.

39 PAN may be triggered by viral infections: HBV HCV HIV Parvovirus B19 remains idiopathic in most cases. Hernández-Rodríguez J, et al., Diagnosis and classification of polyarteritis nodosa, Journal of Autoimmunity(2014),

40 The American College of Rheumatology (ACR) 1990 criteria for the classification of polyarteritis nodosa Used for patients with known primary systemic vasculitis. These criteria do not differentiate between PAN and microscopic polyangiitis (MPA); both are included under the umbrella of PAN.

41 Three of the following 10 criteria are required: Weight loss 4 kg Livedo reticularis Testicular pain or tenderness Myalgias, weakness, or leg tenderness Mononeuropathy or polyneuropathy Diastolic blood pressure >90 mmhg Elevated urea or creatinine Positivity for hepatitis B virus (HBV) infection Arteriographic abnormality Biopsy of small- or medium-sized artery containing polymorphonuclear leukocytes.

42 French Vasculitis Study Group (FVSG) proposal for diagnostic criteria for polyarteritis nodosa. The FVSG has proposed a set of predictive items to be used as a paradigm for diagnostic criteria. These items were derived from patients with known vasculitis but not from undifferentiated patients. They are used in classification rather than diagnostic criteria. Arthritis Rheum May;58(5): doi: /art

43 The positive predictive items were: Positivity for hepatitis B virus infection Arteriographic abnormalities Mononeuropathy or polyneuropathy. The negative predictive items were: Presence of anti-neutrophil cytoplasmic antibodies (ANCA) Asthma Ear, nose, or throat signs Glomerulopathy Cryoglobulinaemia.

44 Final publication of the guideline anticipated in See more at: Quality/Clinical-Support/Clinical-Practice- Guidelines/Vasculitis#sthash.NWAPpQAB.dpuf

45 Management Based on clinical trials. Current treatment policy includes high-dose corticosteroids, which are combined with immunosuppressive agents (cyclosphosphamide).

46 Recommendations for the Management of Primary Small and Medium Vessel Vasculitis We recommend a combination of cyclophosphamide (intravenous or oral) and glucocorticoids for remissioninduction of generalised primary small and medium vessel vasculitis. [Level of evidence 1A for WG and MPA, Grade of recommendation A] [Level of evidence 1B for PAN and CSS, Grade of recommendation A] Ann Rheum Dis 2009;68(3):

47 In patients with PAN, the combination of cyclophosphamide and glucocorticoid achieves better control of disease as compared to glucocorticoid alone but the long term survival remains unchanged

48 Thrombotic Microangiopathy (TMA)

49 Thrombotic microangiopathy (TMA) is a pathologic condition with abnormalities in the blood vessel walls of arterioles and capillaries resulting in microvascular thrombosis. Clinically TMA is always accompanied by microangiopathic hemolytic anemia (MAHA), a non-immune hemolytic anemia resulting from intravascular red cell fragmentation with schistocytosis and thrombocytopenia due to consumption. But it was not a must.

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51 Diagnosis?

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53 And Swine flu

54 Could this 3 things come together?

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59 Our case : Renal biopsy : TMA Blood smear : not suggestive of haemolysis Haptoglobin not low LDH, Bil : normal TMA without MAHA? TMA = Thrombotic microangiopathy MAHA = Microangiopathic hemolytic anemia Any other cases?

60 Yes! Two patients had a kidney biopsy that showed features of TMA in one patient and TMA and podocyte effacement in another. MAHA was not present in either case (53,55) Chapter 11. Chemotherapy and Kidney Injury, American Society of Nephrology, Onco- Nephrology Curriculum

61 1 st patient A 50-year-old man, diagnosed with advanced renal cell carcinoma (RCC), who was treated with sorafenib as second line treatment. Develop impaired renal function and renal biopsy show TMA feature, without MAHA in blood smear.

62 2 nd patient A 44-year-old woman with a history of malignant skin hidradenoma was started on sunitinib for refractory disease. One month later, proteinuria was discovered at 1.1 g/day whereas serumcreatinine level remained stable at 64μmol/land microhaematuria was undetectable. Biological signs oftma were absent (haemoglobin level 13.3 g/dl, plateletcount /mm3, schistocytes undetectable, LDH: 581IU/l). Guillaume Bollee et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant (2009) 24:

63 Six months after sunitinib was started, persistance proteinurea. Still, no haematological features of MAHA had been detected. Antigenic dosages in serum of C3, C4, CH50, Factor H, Factor I and CD46/MCP were in the normal range. ADAMTS13 activity was also normal. Renal ultrasound showed normal kidneys.

64 The renal biopsy contained 13 glomeruli, none of which were globally sclerotic. Almost all showed typical features of TMA: with widespread duplication of the glomerular basement membranes, endothelial swelling, focal glomerular capillary thrombosis, mesangiolysis and fibrin deposits

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68 In a nutshell, Viral infection can associated with TMA and medium vessels vasculitis TMA can occur without MAHA HUS can happened without thrombocytopenia H1N1 induced TMA without MAHA, in a patient with PAN

69 Clear? Not clear?

70 One thing for sure is clear Mr. Ho, did not die of respiratory failure, and now dialysis free.

71 Thank you.