Atypical hus

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Atypical HUS: Save Your Complements for Later Tyler Stewart Resident Update Talk, April 20 th 2015 Department of Internal Medicine, UT Southwestern

Transcript of Atypical hus

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Atypical HUS:Save Your Complements for Later

Tyler Stewart

Resident Update Talk, April 20th 2015

Department of Internal Medicine, UT Southwestern

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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

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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

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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

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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

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Oh Schistocytes!

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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

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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)

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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

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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

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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

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Overview of Complement

Part of Immune System

Three Pathways

1. Classical

2. Lectin

3. Alternative

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C3

C3b

C3a

Factor B

C3bBb(C3 Convertase)

Factor D

C3bBb3b(C5 Convertase)

C5 C5b C5aC3bB

Membrane Attack Complex(MAC)

Endothelial Cell

Alternative Pathway

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C3 C3b C3bBb3b(C5 Convertase)

C5

C5b C5a

Membrane Attack Complex(MAC)

Endothelial Cell

Factor HFactor I

Alternative Pathway

MCP

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So what goes wrong?

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C3 C3b C3bBb3b(C5 Convertase)

C5

C5b C5a

Membrane Attack Complex(MAC)

Endothelial Cell

Factor HFactor I

Alternative Pathway

MCP

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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

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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

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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

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Therapies

• Plasma Therapy• Infusion/Exchange

• Transplant• Kidney

• Kidney-Liver

• Eculizumab

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Rationale for Plasma Therapy

• Replace deficient factors

• Eliminate antibodies

• It worked for TTP

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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

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Plasma Therapy

• Many die or progress to ESRD despite plasma therapy

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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

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Transplant

• Underlying disorder not treated Repeat failure

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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…

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Pathological Findings and Laboratory Values.

Nürnberger J et al. N Engl J Med 2009;360:542-544.

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Eculizumab

• C5 Inhibitor

• Used for PNH

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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

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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

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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

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Eculizumab for aHUS

• Trial 2

• 80% of the patients had TMA event-free status by week 26.

Legendre et al. NEJM;368 2013

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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

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Eculizumab Post-Transplant

• Eculizumab highly effective in treating and preventing aHUS-related relapsing kidney failure

American Journal of Transplantation 2012; 12: 3337–3354

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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)

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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?

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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

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Thanks

• Dr. Phat Huy Le

• Dr. Yu-Min Shen

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Questions

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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

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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?