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?