Atypical HUS

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

2. 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

3. 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

4. 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

5. 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

6. Oh Schistocytes!

7. 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

8. 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)

9. 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

10. 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

11. 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

12. Overview of
Complement
Part of Immune System
Three Pathways
1. Classical
2. Lectin
3. Alternative

13. C3
C3b
C3a
Factor B
C3bBb
(C3 Convertase)
Factor D
C3bBb3b
(C5 Convertase)
C5 C5b C5a
C3bB
Membrane
Attack
Complex
(MAC)
Endothelial Cell
Alternative Pathway

14. C3 C3b C3bBb3b
(C5 Convertase)
C5
C5b C5a
Membrane
Attack
Complex
(MAC)
Endothelial Cell
Factor H
Factor I
Alternative Pathway
MCP

15. So what goes wrong?

16. C3 C3b C3bBb3b
(C5 Convertase)
C5
C5b C5a
Membrane
Attack
Complex
(MAC)
Endothelial Cell
Factor H
Factor I
Alternative Pathway
MCP

17. 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

18. 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

19. 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

20. Therapies
• Plasma Therapy
• Infusion/Exchange
• Transplant
• Kidney
• Kidney-Liver
• Eculizumab

21. Rationale for Plasma Therapy
• Replace deficient factors
• Eliminate antibodies
• It worked for TTP

22. 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

23. Plasma Therapy
• Many die or progress to ESRD despite plasma therapy

24. 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

25. Transplant
• Underlying disorder not treated  Repeat failure

26. 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…

27. Pathological Findings and Laboratory Values.
Nürnberger J et al. N Engl J Med 2009;360:542-544.

28. Eculizumab
• C5 Inhibitor
• Used for PNH

29. 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

30. 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

31. 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

32. Eculizumab for aHUS
• Trial 2
• 80% of the patients had TMA
event-free status by week 26.
Legendre et al. NEJM;368 2013

33. 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

34. Eculizumab Post-Transplant
• Eculizumab highly effective in treating and preventing aHUS-related
relapsing kidney failure
American Journal of Transplantation 2012; 12: 3337–3354

35. 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)

36. 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?

37. 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

38. Thanks
• Dr. Phat Huy Le
• Dr. Yu-Min Shen

39. Questions

40. 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

41. 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?