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

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………..

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

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.

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;371:654-66.

TTP vs aHUS TTP aHUS ADAMTS-13 ADAMTS-13 Deficiency

What Are the DDx Etiologies of TMAs?

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

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

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

Treatment Strategies and Updates

Plasma Exchange/Infusion Kaplan-Meier Survival Analysis of Patients Without Severe ADAMTS13 Deficiencya 100 HR = 0.88 (95% CI, 0.44-1.77) 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):2069-77. © 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):2069-2077. 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):2069-2077.

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

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

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

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

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):701-711. a One patient discontinued dialysis during baseline window and before first dose of eculizumab. Greenbaum LA, et al. Kidney Int. 2016;89(3):701-711.

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)

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

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.

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

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.