Renal failure and thrombocytopaenia? Don t forget TTP/HUS. Jonathan Wala Nephrologist

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1 Renal failure and thrombocytopaenia? Don t forget TTP/HUS Jonathan Wala Nephrologist

2 Thrombotic microangiopathies Disorders characterized by: thrombocytopaenia microangiopathic haemolytic anaemia (MAHA) microvascular occlusion, often resulting in brain and kidney ischaemia Result from microvascular occlusion by hyaline thrombi Spectrum ranges from TTP to HUS

3 Thrombotic microangiopathies Although rare, should always be considered in any pt presenting with AKI assoc with thrombocytopaenia Therapeutic plasma infusion or exchange are effective treatment modalities 3 case reports are presented to heighten the index of suspicion regarding this catastrophic disorder and to illustrate challenges faced in its diagnosis and management

4 Case 1 44y-old lady, S.P. DOA: 13/1/2012 Presentation: Diarrhoea X 2/52 Jaundice and vomiting X 2/52 Managed for viral hepatitis Progressive dyspnoea hospitalization PMHx: unremarkable Examination: Respiratory distress Bilateral leg petechiae Jaundice Pallor PR 106/min, BP 139/79 Clear chest auscultation Alert but agitated No hepatosplenomegaly Urine output: nil

5 Case 1 Laboratory: Hb 6.7g/dL, WBC 38 X 109/L, platelet 37 X 109/L PBF: anisilopoikilocytosis with microspherocytes and few schistocytes Marked neutrophilia with left shift and toxic granulations Thrombocytopaenia INR 2.3 Urea 26.8mmol/L, creat 567umol/L, K+ 3.7mmol/L Bilirubin 184umol/L (direct 102umol/L), AST 184, ALT 36 LDH 825 U/mL CRP 266 mg/l Blood and urine culture: sterile Requested but no result: Stool culture ± E. coli typing Stool Shiga toxin assay ADAMTS13 serum levels Complement protein assays

6 Diagnosis AKI with MAHA and thrombocytopaenia: DDx: Septic AKI with DIC HUS/TTP SLE with autoimmune anaemia and thrombocytopaenia (Evans syndrome) and lupus nephritis

7 Management Haemodialysis Blood component transfusion: RBC transfusion Platelet transfusion Plasma transfusion (FFP) Antibiotic cover (empirical)

8 Hospital course of platelet count and creatinine of case HD + 4 RBCs HD + FFP HD + FFP 500 HD + 6 platelets Antibiotics Platelet count Serum creatinine (umol/l) Days after admission

9 Outcome Anuric at discharge and maintained intermittent HD Progressive recovery of renal function thereafter Stopped haemodialysis 3 weeks later Last follow-up 10 months later: creatinine 70umoL/L

10 CASE 2

11 Case 2: AK 60y-old lady, AM DOA: 16/10/2012 Type 2 diabetes on metformin Presentation: Cough X 1/52 Diarrhoea X 3/7 Dyspnoea and fever X 2/7 Examination: Sick, respiratory distress PR 128/min, BP 91/54mmHg RR 34/min, SO2 84% on room air Bilateral crepitations No hepatosplenomegaly Urine output 15mL/h after fluid resuscitation and IV Furosemide, anuric by 2 nd day

12 Case 2 Laboratory: Hb 12.5g/dL, WBC 5.7 X 109/L, platelets 34 X 109/L PBF: anisilopoikilocytosis with few schistocytes Urea 14.9mmol/L, creat 272umol/L, Na+ 123mmol/L, K+ 3.6mmol/L Bil 28umol/L, AST 56 LDH 748 U/mL Urinalysis: blood 2+, protein +, granular casts CRP 339mg/L Blood culture: Escherichia coli (MDR) Urine culture: Escherichia coli (MDR) Stool culture: no growth (sample obtained 2 days after antibiotics commenced) Requested but not available: E. coli typing Stool Shiga toxin assay Serum ADAMTS13 level Complement assays

13 Case 2 Diagnosis Septic shock from lobar pneumonia AKI with thrombocytopaenia Differential diagnosis: TTP/HUS: Shiga-toxin associated E. coli Neuraminidaseproducing Streptococcus pneumoniae Septic AKI with DIC

14 Management Septic shock: Fluid resuscitation Norepinephrine Antibiotic: Imipenem Respiratory failure: endotracheal intubation and mechanical ventilation AKI: alternate-day intermittent haemodialysis TTP/HUS: Plasma infusion with ultrafiltration across haemodialysis Therapeutic plasma exchange: Plasmapharesis with a plasma filter Duration 3h Blood flow ml/min Plasma volume exchanged: 50mL/kg = ~ 3500ml plasma = 25 units FFP Alternate days for 1 week

15 Hospital course of platelet count and creatinine of case HD Plasma transfusion 15 units HD TPE 25 units HD + TPE 20 units TPE 25 units Antibiotics 50 0 Serum creatinine (umol/l) Platelet count Days after admission

16 Outcome At discharge: Ambulant Haemodynamically stable Hb 7.0g/dL, WBC 5.8 X 109/L, platelet 196 X 109/L Creat 131umol/L, urea 7.4mmol/L, K+ 4.0mmol/L, Na+ 136mmol/L Follow up at 4 months: Creatinine umol/L: egfr 50-55mL/min

17 Case 3 68y-old lady, S.S. DOA: 25/5/2012 Comorbidity: HTN, GERD, previous PTB Presentation: Abdominal pain + 1 episode of non-bloody diarrhoea Chills Examination: Afebrile (fever later) Tender epigastrium No petechiae After admission: 3 generalized tonicclonic seizures ICU, ventilation, anticonvulsants

18 Case 3 Laboratory: Hb , WBC 7.3, platelet PBF: fragmented RBCs, burr cells Coagulation profile: normal LDH 691 U/mL Creat umol/L Urinalysis: protein 3+, blood +, granular casts CRP 8mg/L LFTs normal MRI brain: motion artifacts, cerebral atrophy

19 Case 3 Diagnosis: Thrombotic microangiopathy complicated by: DDx: Renal failure Neurological manifestations Vasculitis Sepsis with DIC SLE with lupus nephritis and neurolupus

20 Case 3 Management: Initially for sepsis: Antibiotics Acyclovir for presumed encephalitis Haemodialysis initiated Plasma transfusion: 8 units FFP Steroids: methylprednisolone Transferred for plasmapharesis on day 4

21 Course of creatinine and platelet for case 3 Daily TPE units FFP Bleeding diasthesis Alternate-day HD Candidaemia Diffuse alveolar haemorrhage Platelet count Serum creatinine umol/l Days after admission

22 Discussion 3 cases presenting with AKI, thrombocytopaenia and MAHA Consistent with thrombotic microangiopathy Major differential diagnosis: Sepsis with septic AKI and thrombocytopaenia

23 Thrombotic microangiopathy Clinico-pathological syndrome resulting from hyaline thrombi in microvasculature of various organs Presents acutely with: MAHA thrombocytopaenia variable degrees of organ dysfunction Depending on predominant distribution of lesions (CNS or kidney) 2 pathologically identical but clinically distinct syndromes: Haemolytic uraemic syndrome Thrombotic thrombocytopaenic purpura

24 Syndromes of thrombotic microangiopathy Thrombotic thrombocytopenic purpura (TTP): Abruptly devt of VWF- and platelet-rich thrombi in arterioles and capillaries of brain, heart, other organs Neurological abnormalities are common Mild renal abnormalities e.g. haematuria, proteinuria Rare: hypertension, AKI requiring dialysis Prognosis: without treatment: very high mortality rate (> 90%) plasma infusion or plasma exchange: 70 90% survival HUS: Usually in young children AKI and absent or minimal neurological involvement May be: diarrhoea associated: typical HUS no diarrhoea: atypical HUS Prognosis of typical HUS: Dialysis in 50% Benign: 90% recover fully

25 Pathogenesis of typical HUS

26 Pathogenesis of atypical HUS

27 Pathogenesis of TTP

28 Kidney biopsies Hemolytic uremic syndrome, D+ Glomerular capillary lumina closed by thickening of capillary walls RBCs and fragmented RBCs in mesangial areas Thrombotic thrombocytopenic purpura Glomerular capillary lumina occluded by homogenous eosinophilic thrombi

29 New classification Known aetiopathogenesis: Infection-induced: Shiga and verocytotoxin (shiga-like toxin)-producing bacteria: Enterohemorrhagic Escherichia coli Shigella dysenteriae type 1 Citrobacter freundii Streptococcus pneumoniae: neuraminidase T-antigen exposure Disorders of complement regulation: Genetic Acquired ADAMTS13 deficiency Genetic disorders of ADAMTS13 Acquired ADAMTS13 deficiency: autoimmune drug induced Defective cobalamine metabolism Quinine-induced Clinical associations: etiology unknown HIV Malignancy-related: Disseminated carcinoma Chemotherapy: mitomycin, gemcitabine Ionizing radiation Transplant-related: Calcineurin inhibitors Bone marrow transplantation Pregnancy-related: Pregnancy HELLP syndrome Oral contraceptive pill SLE-related: SLE antiphospholipid antibody syndrome Others: Glomerulopathy Familial Unclassified

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31 Challenges for us Diagnostic challenges: High-index of suspicion Laboratory deficiencies: Peripheral blood film for schistocytes Stool culture with appropriate culture media Unavailable assays: Shiga toxin ADAMTS13 activity Complement factors Treatment challenges: Confirmed typical HUS: Supportive No role for plasma therapy Atypical HUS and TTP: Benefit from plasma therapy Expensive treatment Unavailable Plenty of FFPs required = many donors required Nursing expertise (and patience) required

32 Final word Thrombotic microangiopathies are a catastrophic cause of AKI High index of suspicion needed whenever AKI is accompanied by thrombocytopaenia Appropriate lab back-up needed Plasma therapy, when required, provides good outcomes but is fraught with cost and logistical challenges