Renal failure and thrombocytopaenia? Don t forget TTP/HUS Jonathan Wala Nephrologist
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
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
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
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
Diagnosis AKI with MAHA and thrombocytopaenia: DDx: Septic AKI with DIC HUS/TTP SLE with autoimmune anaemia and thrombocytopaenia (Evans syndrome) and lupus nephritis
Management Haemodialysis Blood component transfusion: RBC transfusion Platelet transfusion Plasma transfusion (FFP) Antibiotic cover (empirical)
Hospital course of platelet count and creatinine of case 1 600 HD + 4 RBCs HD + FFP HD + FFP 500 HD + 6 platelets 400 300 200 Antibiotics Platelet count Serum creatinine (umol/l) 100 0-2 0 1 2 3 4 5 6 7 Days after admission
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
CASE 2
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
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
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
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 100-150ml/min Plasma volume exchanged: 50mL/kg = ~ 3500ml plasma = 25 units FFP Alternate days for 1 week
Hospital course of platelet count and creatinine of case 2 350 300 250 HD Plasma transfusion 15 units HD TPE 25 units HD + TPE 20 units TPE 25 units 200 150 100 Antibiotics 50 0 Serum creatinine (umol/l) Platelet count 1 2 3 4 5 6 7 8 9 10 11 12 13 Days after admission
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 120-130umol/L: egfr 50-55mL/min
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
Case 3 Laboratory: Hb 12.4 9.0, WBC 7.3, platelet 116 64 PBF: fragmented RBCs, burr cells Coagulation profile: normal LDH 691 U/mL Creat 273 290 322umol/L Urinalysis: protein 3+, blood +, granular casts CRP 8mg/L LFTs normal MRI brain: motion artifacts, cerebral atrophy
Case 3 Diagnosis: Thrombotic microangiopathy complicated by: DDx: Renal failure Neurological manifestations Vasculitis Sepsis with DIC SLE with lupus nephritis and neurolupus
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
600 500 Course of creatinine and platelet for case 3 Daily TPE 25-30 units FFP Bleeding diasthesis Alternate-day HD Candidaemia Diffuse alveolar haemorrhage 400 300 Platelet count Serum creatinine umol/l 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Days after admission
Discussion 3 cases presenting with AKI, thrombocytopaenia and MAHA Consistent with thrombotic microangiopathy Major differential diagnosis: Sepsis with septic AKI and thrombocytopaenia
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
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
Pathogenesis of typical HUS
Pathogenesis of atypical HUS
Pathogenesis of TTP
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
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
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
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