Atypical hus
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Transcript of Atypical hus
Atypical HUS:Save Your Complements for Later
Tyler Stewart
Resident Update Talk, April 20th 2015
Department of Internal Medicine, UT Southwestern
Overview
• Clinical presentation of atypical hemolytic uremic syndrome (aHUS)
• Differentiate aHUS and other thrombotic microangiopathies
• Pathophysiology of aHUS and differentiate from typical HUS
• Layout therapies tried and current management with specific focus on eculizumab
Take Home Points
• Atypical HUS is a thrombotic microangiopathy caused by dysregulation of the complement pathway
• Usually there is an underlying genetic predisposition that is unmasked with stress-responses leading to clinical symptoms
• Atypical HUS must be considered in the differential for thrombotic microangiopathy because appropriate treatment is most effective when started early
• Eculizumab, a C5 inhibitor, is extremely effective in the treatment and prevention of recurrence of atypical HUS; however the cost of the medication creates barriers to treatment
The Case of M.V.
• 20 year old Hispanic female, 35 weeks pregnant
• History of FSGS (biopsied diagnosed after proteinuria found after her previous pregnancy, recent baseline Cr 0.9), HTN
• Admitted to the MFM service for elevated proteinuria (1.5g 10g) and worsening HTN (160s/90s)
• C-section performed 11/21 for concern for pre-eclampsia, but had subsequent worsening AKI, anemia and thrombocytopenia; heme consult 3 days post-op
• Vitals notable for BP 145/97
Labs
23-Nov 25-Nov 26-Nov
Creatinine 1.89 5.18 7.16
Hgb (BL 12) 9.5 8.1 6.4 (tx)
Platelets 123 41 37
Haptoglobin < 5 < 5 < 5
INR 1 1 1
LD 578 981 1290
Baseline 0.9
C-section Nov 21st
Oh Schistocytes!
Differential Diagnosis
• Pre-eclampsia• Should resolve with delivery, maybe 1-2 days after
• Disseminated Intravascular Coagulation (DIC)• PT/INR, PTT normal; not septic
• Thrombotic Thrombocytopenic Purpura (TTP)• Renal Failure usually not featured, ADAMSTS-13 activity normal
• Vasculitis• Difficult, but no other systemic disease; renal biopsy
• Typical HUS• No hx diarrhea
• Atypical HUS• Pregnancy induced, recurrent disease, picture of HUS, sounds like a winner
Hemolytic Uremic Syndrome (HUS)
• A thrombotic mircoangiopathy (TMA) characterized by:
• Non-immune Microangiopathic Hemolytic Anemia (MAHA)• Elevated LD, low haptoglobin, schistocytes
• Thrombocytopenia
• Acute Kidney Injury
• Can involve multiple organ systems (CNS, cardiac, pulmonary, liver, etc)
Typical vs Atypical?
• Historically - Hemolytic Uremic Syndrome is classified into 2 major groups: with diarrhea or without diarrhea
• With diarrhea (Typical HUS); infectious• ~90% of HUS (mostly in children)• Most (~90%) caused by shiga-toxin producing E. coli (O157:H7),
pneumococcus ~10%, influenza, HIV• Toxin produces endothelial damage thrombus formation HUS
• Without diarrhea (Atypical HUS)• Everything else is atypical; HUS without bloody diarrhea
So what causes Atypical HUS?
• HUS, but not predominantly related to bloody diarrhea
• Ran in families• Twins
• Families
• C3 levels reduced in some patients suggesting a role for complement
So what is atypical HUS?
• Complement-mediated hemolytic uremic syndrome• CM-HUS better name than aHUS
• An increase in action of the alternative pathway of the complement system due to dysregulation which leads to endothelial damage and thrombin formation
Overview of Complement
Part of Immune System
Three Pathways
1. Classical
2. Lectin
3. Alternative
C3
C3b
C3a
Factor B
C3bBb(C3 Convertase)
Factor D
C3bBb3b(C5 Convertase)
C5 C5b C5aC3bB
Membrane Attack Complex(MAC)
Endothelial Cell
Alternative Pathway
C3 C3b C3bBb3b(C5 Convertase)
C5
C5b C5a
Membrane Attack Complex(MAC)
Endothelial Cell
Factor HFactor I
Alternative Pathway
MCP
So what goes wrong?
C3 C3b C3bBb3b(C5 Convertase)
C5
C5b C5a
Membrane Attack Complex(MAC)
Endothelial Cell
Factor HFactor I
Alternative Pathway
MCP
Genetic and Immunologic Predisposition
• Complement Regulator Protein Deficiencies
• Point Mutations of Regulator Proteins
• Autoantibodies to Regulator Proteins• Factor H antibody
• Gain-of-function of genes in alternative pathway
20% Familial 80% Sporadic
If I’ve had this my whole life… why now?
• Atypical HUS - there is an underlying genetic predisposition that is unmasked with stress-responses
• Triggers• Infection• HIV• Cancer• Organ Transplant• Pregnancy• Chemotherapy• Immunosuppresion (cyclosporine, tacrolimus)
HEMOLYTIC UREMIC SYNDROME
Hemolytic Anemia
Thrombocytopenia
Kidney injury
Our Case: M.V.
• ADAMSTS13 activity normal; renal biopsy c/w TMA
• Pregnancy had likely unmasked a complement deficiency/abnormality leading to atypical HUS
• 6 days after her c-section, with a new baby girl, she was on dialysis… compassionate dialysis
Therapies
• Plasma Therapy• Infusion/Exchange
• Transplant• Kidney
• Kidney-Liver
• Eculizumab
Rationale for Plasma Therapy
• Replace deficient factors
• Eliminate antibodies
• It worked for TTP
Plasma therapy
• Plasma Infusion and Plasma exchange was standard of care• Hinged on expert opinion with retrospective studies
• Suggest decrease in mortality by 25-50%
• Studies riddled with flaws; aHUS often included with typical HUS or TTP
• Noris et al., 2011; retrospective study from an international registry• Plasma treatment induced complete or partial remission of 63, 25, 57, 88, and
75% of episodes in patients with CFH, CFI, C3, THBD mutations or anti-CFH autoantibodies, respectively
• 40-70% of these patients developed ESRD or died within the first 3 years
Clin J Am Soc Nephrol 5: 1844–1859, 2010
Plasma Therapy
• Many die or progress to ESRD despite plasma therapy
Transplants
• Kidney Transplant• 50% recurrence rate after renal transplant
• 80-90% of those with recurrence have renal failure
• Exception for those with MCP deficiency• MCP is made in the kidney
• Combined Kidney-Liver Transplant• Complement proteins made in liver
• Case reports with mixed outcomes
Transplant
• Underlying disorder not treated Repeat failure
Case Report, NEJM, 2009
• A patient with atypical HUS had renal failure at 25
• Transplant #1 – at age 30• Recurrent disease in 5 weeks with loss of graft despite 18 plasma exchanges
• Transplant #2 – at age 37• Recurrent disease in 6 weeks with progression despite 4 plasma exchanges
• And then…
Pathological Findings and Laboratory Values.
Nürnberger J et al. N Engl J Med 2009;360:542-544.
Eculizumab
• C5 Inhibitor
• Used for PNH
Eculizumab in aHUS
• Legendre et al, 2013, NEJM
• Two prospective phase 2 trials with patients with aHUS• Trial 1 – Patients with progressive TMA had renal disease and thrombocytopenia
• Trial 2 – Patient without progressive TMA in 8 week pre-treatment observation period, had renal disease but no evidence of thrombocytopenia
• Received eculizumab for 26 weeks and during long-term extension
• Received Meningococcus vaccine +/- prophylactic antibiotics
Legendre et al. NEJM;368 2013
Eculizumab for aHUS
Legendre et al. NEJM;368 2013
• Trial 1
• 53% normal platelet count by day 7; 86% by week 26
• All people who finished 26 weeks had normalization of platelets
Eculizumab for aHUS
• Trial 1
• Dialysis was discontinued in 4 of 5 patients
• Earlier intervention of eculizumab was associated with greater improvement in eGFR.
Legendre et al. NEJM;368 2013
Eculizumab for aHUS
• Trial 2
• 80% of the patients had TMA event-free status by week 26.
Legendre et al. NEJM;368 2013
Eculizumab and aHUS
• PLEX/infusions discontinued in 88% in trial 1 and 100% in trial 2.
• No infection-related serious adverse events were observed
Legendre et al. NEJM;368 2013
Eculizumab Post-Transplant
• Eculizumab highly effective in treating and preventing aHUS-related relapsing kidney failure
American Journal of Transplantation 2012; 12: 3337–3354
Eculizumab – Points to Consider
• Costs > $400,000 per year
• Frequency of dosing (currently every other week)• Can be given by home infusions
• When to stop therapy (if ever)
Our Case: M.V.
• Started on eculizumab in hospital• Now receiving as outpatient every 2 weeks
• Received dialysis until 12/19; then dialysis was discontinued
• Cr ~2.0 in February
• But how long will she be able to receive eculizumab?
Take Home Points
• Atypical HUS is a thrombotic microangiopathy caused by dysregulation of the complement pathway
• Usually there is an underlying genetic predisposition that is unmasked with stress-responses leading to clinical symptoms
• Atypical HUS must be considered in the differential for thrombotic microangiopathy because appropriate treatment is most effective when started early
• Eculizumab, a C5 inhibitor, is extremely effective in the treatment and prevention of recurrence of atypical HUS; however the cost of the medication creates barriers to treatment
Thanks
• Dr. Phat Huy Le
• Dr. Yu-Min Shen
Questions
References
• Noris et al. NEJM 2009;361:1676-1687
• George et al. NEJM 2014;371:654-666
• Noris et al. Clin J Am Soc Nephrol 2010;5:1844–1859
• Cataland et al. Blood 2014;123:2478-2484
• Nurnberger et al. NEJM 2009;360:542-544
• Noris et al. Blood 2014;124:1715-1726
• Legendre et al. NEJM 2013;368:2169-2181
Is it aHUS or TTP?
• TTP• ADAMSTS13 activity < 10% caused by congenital deficiency or autoantibody• Usually does not have such overt renal failure; SCr usually <2• Never involves lungs; rarely involves liver• Plt count usually <30k
• Biomarkers?• C3a, C5a, Bb, C5b-9 – elevated in aHUS• Sensitivity and specificity have not been clarified• 21 day turn-around• In future could be used for diagnosis to justify long term therapy?