TMA CASE STUDY Pamela Harmon, RN & Keturah Tomlin, RN Toronto General Hospital Apheresis Unit
Cumulative fraction of patients free of events ahus is a catastrophic disease that can result in sudden & progressive vital organ failure and premature death 33 40% of patients die or progress to end-stage renal disease (ESRD) at 30 days, despite PE or PI 2,3 1.00 0.75 0.50 65% of all patients die, require dialysis, or have permanent renal damage within 1 year after diagnosis despite plasma exchange or plasma infusion 2 0.25 0.00 0 3 6 12.5 25 Follow-up (months) Modified from Caprioli J et al. 2006. CFH mutation depicted. 1. Sallee M et al. Nephrol Dial Transplant 2010;25:2028 2032; 2. Caprioli J et al. Blood 2006;108:1267 1272; 3. Noris M et al. CJASN 2010;10:1844 1859; 4. Noris M et al. N Engl J Med 2009;361:1676 1687.
Recap of Patient s Organs affected by ahus Renal More than 50% of patients progress to ESRD 7 Elevated creatinine Proteinuria 2 Edema, 3 malignant hypertension 4 Decreased egfr 5 CNS Up to 48% of patients experience neurological symptoms 2 Confusion 6 Stroke 6 Encephalopathy 4 Seizure 2 Blood Thrombocytopenia 7 Decreased haptoglobin 7 Elevated LDH 7 Decreased hemoglobin 7 Schistocytes 7 Organs Effected in Patient Case Visual Ocular occlusion 14 Cardiovascular Up to 43% of patients experience cardiovascular symptoms 2 Myocardial infarction 8 Hypertension 9 Diffuse vasculopathy 5 Peripheral gangrene 10 Gastrointestinal Up to 30% of patients present with diarrhea 11 Colitis 6 Nausea/Vomiting 12 Pancreatitis 12 Abdominal pain 6 Gastroenteritis 2 Liver necrosis 2 Pulmonary Dyspnea 8 Pulmonary hemorrhage 13 Pulmonary edema 8 egfr = estimated glomerular filtration rate; LDH = Lactate dehydrogenase. 1. Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687 696; 2. Neuhaus TJ et al. Arch Dis Child 1997;76:518 521. 3. Ståhl A-L et al. Blood 2008;111:5307 5315. 4. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844 1859; 5. Loirat C et al. Pediatr Nephrol 2008;23:1957 1972; 6. Ohanian M et al. Clin Pharmacol 2011;3:5 12 ; 7. Caprioli J et al. Blood 2006;108:1267 1279; 8. Sallée M et al. Nephrol Dial Transplant 2010;25:2028 2032; 9.Kavanagh D et al. Med Bull 2006;77 78:5 22; 10. Malina M et al. Pediatr Nephrol 2011;26:1678; 11. Zuber J et al. Nat Rev Nephrol 2011;7:23 35; 12. Dragon-Durey M-A et al. J Am Soc Nephrol 2010;21:2180 2187; 13.Sellier-Leclerc A-L al; French Society of Pediatric Nephrology. J Am Soc Nephrol 2007;18:2392-2400; 14. Larakeb A et al. Pediatr Nephrol 2007;22:1967 1970.
ahus Genetic mutations cannot be identified in 30%-50% of patients with ahus.2 No requirement for identification of a complement mutation in the diagnosis of ahus. Patients with more than one mutation has been detected in 4% of families.1 1. Fremeaux-Bacchi et al, CJASN, 2013. 2. Noris M et al. Clin J Am Soc Nephrol, 2010;5:1844-1859.
Proximal Terminal In ahus, Chronic Dysregulation of the Alternative Pathway of the Complement System Leads Systemic End Organ Damage Lectin pathway Classical pathway Alternative pathway C3 Ba + Gain of Function Mutations: C3, CFB C3b C3-Convertase - Loss of function Mutations: CFH, CFI, MCP, THBD, anti-fh antibodies C5-Convertase C5 Platelets PMP Coagulation Platelet activation C5b-9 deposition on endothelial cell Adapted from Noris et al. NEJM, 2009 C5b Subendothelial matrix Endothelial cell C5b-9 Proteinases Oxygen radicals Endothelial-cell damage and retraction Thrombus formation Endothelial injury = TMA 1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67-I74. 2.Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4:359-395. 3. Walport MJ. N Engl J Med. 2001;344:1058-1066. 4. Rother RP et al. Nat Biotechnol. 2007;25:1256-1264. 5. Meyers G et al. Blood. 2007;110:abs 3683. 6. Hill A et al. Br J Haematol. 2010;149:414-425. 7. Hillmen P et al. Am J Hematol. 2010;85:553-559. 8. Parker C et al. Blood. 2005;106:3699-3709. 9. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 10. Nishimura J et al. Medicine. (Baltimore) 2004;83:193-207. 11. Caprioli J et al. Blood. 2006;108:1267-1279. 12. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859. 13. George JN. Blood. 2010;116:4060-4069. 14. Loirat C et al. Pediatr Nephrol. 2008;23:1957-1972. 15. Ståhl AL et al. Blood. 008;111:5307-5315. 16. Hosler GA et al. Arch Pathol Lab Med. 2003;127;834-839. 17. Ariceta G et al. Pediatr Nephrol. 2009;24:687-696.
TMA Case PMHx 57 yrs. female Mother to three sons active community volunteer and passionate skier Gall bladder removed 2008/2009 Routine knee surgery in 2014 Patient had pancreatitis post ERCP at the age of 19 Sister has a history of pancreatitis Middle son has shown symptoms of ahus (pancreatitis) and received a kidney transplant several years ago.
Clinical History July 23 20014 Patient was transferred from Centenary Hospital to UHN, post total right knee replacement. Dx: anemia/thrombocytopenia & jaundice Platelet Count of 82 Hgb 82 ( 8% fragmentation) LDH 2149 Haptoglobin 0.50 Renal Function Cr 402 Ferritin 2829 TBili 50, C3-1.14, C4-0.25 Hypertensive 148/93
TREATMENT PLAN July 24, 2014 Prior to PLEX blood work done to confirm: - ADAMTS-13 Activity >50% - Complement System Activity - CH50 - Genetics sent to Sick Kids Lab - Antibody testing: Anti-GBM (Anti-Glomerular Basement Membrane ), APLA (Antiphospholipid Antibodies), ANA (anti-nuclear antibodies) - Cryoglobulin: rule out infectious/autoimmune causes of TMA (HIV, Lupus, etc) Patient initiated on daily PLEX - FFP as replacement fluid 1.5 PV Daily hemodialysis started, for clearance and fluid overload. Antihypertensive medications initiated August 2 nd, 2014 Prednisone added to treatment Ongoing hemolysis despite daily apheresis
Clinical History Cont d Course in Hospital No significant response to daily PLEX Status of kidney function unchanged, now dialysis 3xper week. Feeding Tube inserted in response to ongoing bouts of pancreatitis Platelets increased from 85 to 175 LDH improved from 2149 U/L to 205 U/L Creatinine continued to increase despite PLEX 402 to 613
Clinical History Cont d Dx: Atypical Hemolytic Uremic Syndrome (ahus) Submitted request to the Exceptional Access Program (EAP) for coverage of Soliris EAP declined coverage of Soliris- 25/8/14 Genetic testing received after one month - Heterozygeous Pathogenic mutations in MCP gene - Uncertain variant in CFI gene
Markham woman, family struggle for lifesaving drug http://www.yorkregion.com/news-story/4964866-markham-woman-family-struggle-for-lifesaving-drug/
Emotional Journey Patient: They had me hooked up to dialysis and plasma exchange, and my life was turned upside down 1 1. Toronto Star, Nov 15 2014
Clinical History Continued October 2014 Discharged Home Patient spends 15 hours a week in hospital undergoing dialysis Frequency of PLEX continued 3 x per week Further weaned to PLEX - 2 x per week. Several recurrent hospitalizations for bouts of pancreatitis.
Patients Journey Ontario Agrees to Fund Life-Saving Drug for 6 months http://www.thestar.com/news/gta/2014/11/15/ontario_agrees_to_fund_lifesaving_drug_for_6_months.html
Starting Soliris Received immunization (Menactra & Bexsero) prior to start of Solaris. PLEX discontinued and Soliris initiated on October 23 rd, 2014 Dose 900 mg weekly for 4 weeks, then 1200mg on 5 th week, and every other week, thereafter.
SOLIRIS ECULIZUMAB
Soliris works on the bottom half of the Complement Pathway, preventing Endothelial Injury and Organ Damage Defective regulation of the alternative pathway of complement Continuous complement activation Lectin Classical Alternative C3 C5 TMA C5b-9 Formation on endothelium Platelet activation Adapted from Noris et al Nat Rev Neph 2014 1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67 74; 2. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359 395; 3. Walport MJ. N Engl J Med 2001;344:1058 1066; 4. Rother RP et al. Nat Biotechnol 2007;25:1256 1264; 5. Meyers G et al. Blood 2007;110:abs 3683; 6. Hill A et al. Br J Haematol 2010;149:414 425; 7. Hillmen P et al. Am J Hematol. 2010;85:553 559; 8. Parker C et al. Blood 2005;106:3699 3709; 9. Hillmen P et al. N Engl J Med 1995;333:1253 1258; 10. Nishimura J et al. Medicine (Baltimore) 2004;83:193 207; 11. Caprioli J et al. Blood 2006;108: 1267 1279; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844 1859; 13. George JN. Blood 2010;116:4060 4069; 14. Loirat C et al. Pediatr Nephrol 2008;23:1957 1972; 15. Ståhl AL et al. Blood 2008;111:5307 5315; 16. Hosler GA et al. Arch Pathol Lab Med 2003;127;834 839; 17. Ariceta G et al. Pediatr Nephrol. 2009;24:687 696. 17
Some benefits of SOLIRIS occur rapidly and are sustained, while others continue to improve over time egfr estimated glomerular filtration ratio Hematologic Normalization = Platelet count >150,000, normal LDH Hematological Parameters (Platelet Count and LDH) improve quickly with Soliris, while kidney function continues to improve over time. Legendre CM et al. N Engl J Med. 2013;368:2169-2181; Greenbaum L et al. ASH 2012.
Renal Response is dependent on Time from Initial TMA to Soliris In the clinical studies, dialysis was discontinued in 4/5 (80%) patients in who required dialysis at the time of initiation of Soliris1 The duration of dialysis before the initiation of Soliris treatment, ranged from 6 to 26 days.1 Shorter interval between the ahus TMA and initiation of Soliris is associated with significantly greater improvement in renal function.1 Our patient was on dialysis for 3 months prior to initiation of Soliris 1. Legendre et al, NEJM 2013;368:2169-2181
Hematological response to plasma therapy is a poor indicator of long-term outcomes Affected Protein Short-term Hematological Response to Plasma Therapy* Long-Term Outcome at 3 years Factor H 50% Death or ESRD: 77% MCP 94% Death or ESRD: 6% Factor I (CFI) 40% Death or ESRD: 60% Factor B 30% Death or ESRD: 70% C3 42% Death or ESRD: 67% THBD 54% Death or ESRD: 54% CFH autoantibodies 63% No mutation identified 63% *Includes partial and complete responses Death or ESRD: 63% Death or ESRD: 50% Noris M et al. CJASN 2010 5:1844-1859
Patient Case October 23 rd, 2014 - Patient receives her first infusion of Soliris Clinical Parameters Initial TMA (July 2014) Prior to Tx with Soliris (October 2014) Post Tx with Soliris (July 2015) Hgb (g/l) 82 96 125 Platelets 82 175 227 SrCr 402 613 209 LDH 2149 205 205 BP 148/93 109/71* Haptoglobin 0.50 - - Urine Output Anuric Anuric Now producing Urine * Hypertensive medications decreasing doses
Patient Case As of July 2015 Nocturnal Dialysis 5 nights per week Patient is feeling more energized Patient has started producing urine BP low, medication decreased. Soliris treatment at home Q 2WEEKS Feeling well, good appetite and good energy levels No further TMA or Pancreatitis episodes I m staying positive, and hoping that this will eventually be just a distant nightmare