1. Thrombotic MicroAngiopathy (TMA) &
Atypical Hemolytic Uremic Syndrome (aHUS)
In a Nutshell
Ahmad Kaddourah, MD, MS
Pediatric Nephrology Consultant
Lead Physician of the Center for Acute Nephrologic Extracorporeal Therapies (CANET).
Sidra Medical and Research Medical Center
Assistant Professor of Clinical Pediatrics
Weill Cornell Medical College in Qatar

2. TMA / aHUS………..in 20 minutes
Define TMA
Go through the historical stages of the spectrum of TMA
Describe the pathophysiology
DDx
Reminder of the complement pathway
Provide work up plan
Review the therapeutic approach and compare the therapeutic options
Discuss the long terms plans
The role of genetic testing
Most recent updates and innovations in this field
And many………..

3. Objectives Define TMA and aHUS Quick historical overview
How to approach
Discuss the current therapies
Updates on the most recent advances in the management of aHUS

4. What is TMA?
Syndrome = Microangiopathic hemolytic anemia + Thrombocytopenia + Organ injury
Wide spectrum of diversity: age, acuity, and pathophysiology.
Pathological features:
The pathological features are vascular damage that is manifested
by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium
and vessel wall.

5. History of TMAs TTP (1924) Dr Eli Moschcowitz Switzerland
Mount Sinai Hospital
HUS (1955) Dr Conrad von Gasser
Switzerland
aHUS (1965)
Barnard PJ & Kibel M 1965
A report of 11 cases
Kaplan, et al (1975)
- Hemolytic uremic syndrome in families. N Engl J Med
16-year-old girl with pallor, purpura, and hemiparesis. Autopsy revealed hyaline thrombi in terminal arterioles and capillaries throughout most organs, including the kidneys.
In 2001: ADAMTS-13 Discovery.
5 children with diarrhea, hemolytic uremia, thrombocytopenia, and AKI
Biopsy/autopsy noted: hemorrhagic colitis, thrombosis of capillaries and precapillary arterioles in the lungs, brain, heart, and kidneys as well as renal cortical necrosis
J.George and C. Nester. N Engl J Med 2014;371:

6. TTP vs aHUS
TTP
aHUS
ADAMTS-13
ADAMTS-13
Deficiency

7. What Are the DDx Etiologies of TMAs?

8. How Do you Approach the DDx of TTP, aHUS, and STEC-HUS?

9. What is the Likelihood of aHUS Presenting With Complement – Amplifying Conditions?

10. Genetics and aHUS
Be sure you mention here the that the genetic testing is not necessary for diagnosis

11. Treatment Strategies and Updates

12. Plasma Exchange/Infusion
Kaplan-Meier Survival Analysis of Patients Without Severe ADAMTS13 Deficiencya
100
HR = 0.88 (95% CI, )
Stratified log-rank P = 0 .72 75
Survival, % 50 25
Patients who received PEb
Patients who did not receive PE
Used with permission from Li A, et al. Transfusion. 2016;56(8): © 2016 AABB.
All patients in this study had ADAMTS13 levels greater than 10% and TMA
Outcomes were compared between patients who did and did not receive plasma exchange therapy
Patients were matched based on clinical criteria including age; sex; ethnicity; Charlson Comorbidity Index score; history of prior solid organ or bone marrow transplant; presence of neurological symptoms, sepsis, shock, and/or multiorgan failure; platelet count; creatinine level; LDH level; and international normalized ratio
Patients who received plasma exchange therapy did not have improved rates of survival, suggesting that there were no additional clinical benefits with plasma exchange in patients with ADAMTS13 levels greater than 10%
Reference
Li A, et al. Transfusion. 2016;56(8): 20 40 60 80
100
Time, d
Number at risk 59 42 48 36 34 33 33 30
a Adult patients included in the Harvard TMA Research Collaborative registry (N = 186, of which 71 had received at least 1 PE session) were matched based on clinical criteria, including age; sex; ethnicity; Charlson Comorbidity Index score; history of prior solid organ or bone marrow transplant; presence of neurological symptoms, sepsis, shock, and/or multiorgan failure; platelet count; creatinine level; LDH level; and international normalized ratio. b Mean number of PE session: 5 (range: 3-7); mean units of plasma transfused: 58 (range: 38-83).
Li A, et al. Transfusion. 2016;56(8):

13. Complement Activation
C3a
C5a
C3b
C5 Convertase C3
C3b Bb
C3b
C3 Convertase B Bb C5
MAC
C5b-9

14. Eculizumab (introduced in 2007)
C3a
C5a
C3b
C5 Convertase C3
C3b Bb
C3b
C3 Convertase B Bb C5
MAC
C5b-9

15. Pediatric Trial: Platelet Count
Mean (SD) change from baseline at week 27:
164 (76) x 109/L
(P≤0.0001)
*P≤0.0001
Greenbaum LA et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016

16. Mean change from baseline at week 27:
Pediatric Trial: eGFR
Mean change from baseline at week 27:
64 mL/min/1.73 m2
(P<0.0001)
*P≤0.01
†P≤0.001
‡P≤0.0001
Greenbaum LA et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016

17. Discontinued Dialysis During the Study Median (range): 7 (4-15) days
Free of Dialysis…..
Patients on Dialysis at Baselinea (n=11)
9 of 11 patients on dialysis at baseline were able to discontinue dialysis during the study
Of the 11 patients not on dialysis at baseline, all patients (100%) remained dialysis-free through the end of the study evaluation period
Discontinued Dialysis During the Study
Median (range): 7 (4-15) days
82%
(9/11)
9 of 11 patients on dialysis at baseline were able to discontinue dialysis during the study
Of the 11 patients not on dialysis at baseline, all patients (100%) remained dialysis-free through the end of the study evaluation period
Reference
Greenbaum LA, et al. Kidney Int. 2016;89(3):
a One patient discontinued dialysis during baseline window and before first dose of eculizumab.
Greenbaum LA, et al. Kidney Int. 2016;89(3):

18. New Approaches ALXN1210: Purified factor H:
longer-acting anti-C5 antibody
Dosing every 8 weeks vs. every 2 weeks with Eculizumab
Alexion is currently enrolling patients in Phase 3 trials
Recruitment for children has not started yet.
Purified factor H:
Production of biologically active complement factor H in therapeutically useful quantities from Pichia pastoris cells (2014)

19. Compstatin: Cyclic Tridecapeptide
C3b
C5 Convertase C3
C3b Bb
C3b
C3 Convertase B
Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models
Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage
No clinincal trials on it
Discuus the idea of blckinhg higher ut causing more infection Bb C5
MAC
C5b-9

20. Factor D blockade with Small Molecule Inhibitor (Achillion Pharmaceuticals)
C3b
Factor D
C3b
C3 Convertase B
Factor D, a serine protease that has the lowest plasma concentration (1-2 mcg/ml) of all complement components, occupies an upstream position in the complement alternative cascade. It plays a central role in AP and, subsequently, overall complement activation through what is called the amplification loop. Representing an attractive “control point” for complement activation, factor D is not only amenable to potent inhibition by small-molecule drugs dosed orally once- or twice-daily but also provides a promising therapeutic target in a variety of rare diseases and more common serious conditions.

21. CCX168 (Avacopan): C5a Receptor Blockade with Small Molecule Inhibitor (ChemoCentryx) AND Small Interfering RNA (Alynlam): Prevents C5 Production
aHUS trial: oral C3
C3a
C5a
C3b
C5 Convertase C3
C3b Bb
C3b
C3 Convertase B
Orally administered
ASN 2016
Mainly to treat the thrombus effect” •After 14 days of dosing in aHUS patients, the mean decrease in thrombus size was 83%” Bb C5
MAC
C5b-9

22. Reminder TMA is a deleterious syndrome and should be recognized early.
TTP and aHUS are TMAs but managed differently and efforts should be employed to differentiate the 2 conditions ASAP.
aHUS is a clinical diagnosis. Genetics can rule in but not out the disease
Anti-complement therapy is first line therapy for aHUS.