ATYPICAL HEMOLYTIC UREMIC SYNDROME: WHAT’S COMPLEMENT GOT TO DO WITH IT?

RYAN CASSADAY, M.D.HEMATOLOGY FELLOWS CONFERENCESEPTEMBER 23, 2011

Outline

Case Discussion Case Discussion Review atypical hemolytic uremic syndrome (aHUS)

and complement functionand complement function Therapeutic interventions: old and new Extrapolation to other thrombotic microangiopathies Extrapolation to other thrombotic microangiopathies

(TMAs) Conclusions Conclusions

Photos from recent trip to San Juan Islands Photos from recent trip to San Juan Islands

Case Discussion: I iti l P t tiInitial Presentation 68 yof with h/o hypertension and hypothyroidism/ January 2011: progressive dyspnea Mid May 2011: admitted locally, w/u included bronch

(path = pneumonitis/fibrosis) started steroids (path = pneumonitis/fibrosis), started steroids Late May 2011:

Re-admission with new multi-organ dysfunction Acute kidney injury WBC 15, Hct 43%, plts 69; microangiopathic changes on smear Pleural and pericardial effusions No fevers or mental status changes

Dialysis, plasma exchange, high-dose steroids, IVIG ADAMTS13 level = 48% (normal > 67%)( ) Renal biopsy = TMA Failed to respond, so transferred to UWMC in mid June

Case Discussion:T f t UWMCTransfer to UWMC

Labs on arrival (on HD and TPE): Labs on arrival (on HD and TPE): WBC 8.2, Hct 31%, Plt 69, MCV 91 LDH 272, Retic Count 187/5.5%, Haptoglobin 17 LDH 272, Retic Count 187/5.5%, Haptoglobin 17 INR 1.2, PTT 34, Fibrinogen 272 Creatinine 3.12, Total Bili 0.8, Direct Coombs: negative Peripheral smear: moderate schistocytesp y

TPE stopped, HD and steroids continued Rituximab given x1 (6/25) Rituximab given x1 (6/25)

Labs During Hospital Courseg p

Labs During Hospital Courseg p

Outline

C Di i Case Discussion Review atypical hemolytic uremic

d ( HUS) d l t syndrome (aHUS) and complement functionTh ti i t ti ld d Therapeutic interventions: old and new

Extrapolation to other TMAs Conclusions

S ll b d

San Juan Islands

Stella enjoying a boat ride

September 2011

Hemolytic Uremic Syndromey y

HUS (1 to 2 cases per 100,000): HUS (1 to 2 cases per 100,000):Microangiopathic (non-immune) hemolytic anemia Thrombocytopenia Thrombocytopenia Renal failure

“Typical” HUS (90%): Typical HUS (90%): A.K.A. diarrhea-associated (D+) Shiga-like toxin producing E. coliS ga e o p oduc g . co

“Atypical” HUS (10%): No diarrhea (D-) No diarrhea (D )

Taylor CM, et al. Br J Haematol. 2010.

Classification of aHUS

Familial: Familial: Mutations in complement regulatory proteins (CRPs)

Sporadic: Sporadic: “Idiopathic” 20-40% associated with mutations in genes for CRPs20 40% associated with mutations in genes for CRPs 10% have auto-antibody to one such protein (factor H)

Definable cause Pregnancy, drugs, organ transplantation, HIV Some gene mutations seen in these cases, also

Noris & Remuzzi. New Engl J Med. 2009.

Complement Regulatory Proteinsp g y

Complement Factor B (CFB) Complement Factor B (CFB) Complement Factor H (CFH) Complement Factor H related protein 1 and 3 Complement Factor H related protein 1 and 3

(CFHR1/3) Complement Factor I (CFI) Complement Factor I (CFI) Membrane cofactor protein (MCP)

Th b d li (THBD) Thrombomodulin (THBD)

Noris & Remuzzi. New Engl J Med. 2009.

Normal Complement Regulator Function:Alt ti P thAlternative Pathway

Noris & Remuzzi. New Engl J Med. 2009.

Complement Regulator Dysfunction i HUSin aHUS

Noris & Remuzzi. New Engl J Med. 2009.

Recommended Work-Upp

Levels of C3, C4, Factor H, and Factor I Levels of C3, C4, Factor H, and Factor I Expression of CD46 (MCP) on PBMCs by flow

cytometrycytometry Mutation screening of CFH, MCP, CFI, CFB, and C3 Autoantibody against Factor H Autoantibody against Factor H Level of ADAMTS13

Taylor CM, et al. Br J Haematol. 2010.

http://www.healthcare.uiowa.edu/labs/morl/index_CDS.htm

Outline

C Di i Case Discussion Review atypical hemolytic uremic

d ( HUS) d l t syndrome (aHUS) and complement functionTh ti i t ti ld d Therapeutic interventions: old and new

Extrapolation to other TMAs Conclusions

U l R h H b

San Juan Islands

Unique service vessel in Roche Harbor

September 2011

Established Treatment:Th ti Pl E hTherapeutic Plasma Exchange

Autoantibody to Factor H Autoantibody to Factor H Category I: first-line treatment Grade 2C: weak recommendation from weak data Grade 2C: weak recommendation from weak data

Complement factor gene mutation Category II: second-line treatment Category II: second line treatment Grade 2C: see above

Initial presentation: offer to all patients Initial presentation: offer to all patients

Szczepiorkowski ZM, et al. J Clin Apher. 2010.Taylor CM, et al. Br J Haematol. 2010.

Established Treatment:Kid T l t tiKidney Transplantation

Low risk of recurrence with MCP mutation Low risk of recurrence with MCP mutation Minimize anti-Factor H antibody prior to transplant

Rituximab and plasma exchange Rituximab and plasma exchange

Significant risk of recurrence from C3 and CFBmutationsmutations

NOT recommended for CFH or CFI mutations Liver or combined liver/kidney transplant Liver or combined liver/kidney transplant

Taylor CM, et al. Br J Haematol. 2010.

Eculizumab: What It Is

Humanized monoclonal antibody against C5 Humanized monoclonal antibody against C5 Reduced C5a (anaphylotoxin) Reduced C5b (membrane attack complex) Reduced C5b (membrane attack complex)

Approved for use in paroxysmal nocturnal hemoglobinuriag Disorder of complement regulation on cell membranes

Very few toxicities Very few toxicities Headache, nausea, fatigue Risk of meningococcal disease—vaccinateg

Hillmen P, et al. New Engl J Med. 2004.Hillmen P, et al. New Engl J Med. 2006.

Eculizumab: Why It Should Worky

Eculizumab

Evidence for Eculizumab in aHUS

Authors Year Case Result

Lapeyraque, et al.

2011 Plasma-refractory, worsening renal failure

Improvement within 1 week of 1st

dose, stable for 12 months

Chatelet, et 2010 Plasma-refractory, s/p 2 Hematologic labs normalized, Cr al. failed renal txplts stabilized, treated for 17 months

Kose, et al. 2010 Recurrent TMA s/p 2 failed renal txplts

Graft function recovered and stable for 8 months after 1 dose

Plasma-refractory Renal function recovered,hematologic labs improved for 8 months after 1 dose, then relapsed

Gruppo & Rother

2009 18 month old with 4 relapses (cause unknown) despite plasma

Hematologic and renal function recovered within 48 hrs of initiation, sustained for 4 months

L lt & 2009 R l d ft l St bili ti d f l Legault & Boelkins

2009 Relapsed after renal txplt

Stabilization and recovery of renal function, resolution of TMA on bx

Response to Eculizumabp

Nuernberger J, et al. New Engl J Med. 2009.

Cost-Comparative Analysis for D iDummies

Renal transplant = $70,000 for the operation + Renal transplant $70,000 for the operation + $9000/year

Hemodialysis = $75,000/year Hemodialysis $75,000/year Eculizumab = $400,000/year

S l l b h

San Juan Islands

Seals relaxing on a beach

September 2011

Outline

C Di i Case Discussion Review atypical hemolytic uremic

d ( HUS) d l t syndrome (aHUS) and complement functionTh ti i t ti ld d Therapeutic interventions: old and new

Extrapolation to other TMAs Conclusions

Eculizumab for Other TMAs

Typical (D+) HUS Typical (D+) HUS Case series of 3 children with dramatic improvement1

Compassionate use during EHEC outbreak in Germany Compassionate use during EHEC outbreak in Germany (n > 100), data pending2

Case report in SLE and antiphospholipid syndrome3p p p p y

1Lapeyraque AL et al New Engl J Med 20111Lapeyraque AL, et al. New Engl J Med. 2011.2Kupferschmidt K. Science. 2011.

3Hadaya K, et al. Am J Transplant. 2011.

Outline

C Di i Case Discussion Review atypical hemolytic uremic

d ( HUS) d l t syndrome (aHUS) and complement functionTh ti i t ti ld d Therapeutic interventions: old and new

Extrapolation to other TMAs Conclusions

Our Case, 2 Months Later,

Remains dialysis-dependenty p Genetic work-up for aHUS (sent 7/20/11):

CFB: wild-typeC CFI: wild-type

MCP: wild-type CFHR1, -3, and -5: wild-type CFHR1, 3, and 5: wild type Anti-Factor H Ab: negative C3, CFH, and THBD sequence; Anti-C3 Ab: pending

Blood counts normal, reticulocyte count down, LDH 219

Remains on steroids for interstitial lung disease Remains on steroids for interstitial lung disease

However…

Sheep erythrocyte lysis assay: 1+ Sheep erythrocyte lysis assay: 1+ Patient serum added to sheep RBCs Normal serum will prevent alternative-pathway Normal serum will prevent alternative pathway

mediated lysis If CRPs are defective/impaired, RBC lysis occurs

“INTERPRETATION: These data indicate that surface regulation of the alternative pathway in your patient is abnormal.”

Joszi M, et al. Blood. 2007.

How To Reconcile This

Positive result from pending gene mutations Positive result from pending gene mutations Antibody/mutation affecting a different CRP False positive False positive

Unrelated hemolytic disorder Lab error Lab error

Summary/Conclusionsy/

Atypical HUS is thought to be mediated by Atypical HUS is thought to be mediated by dysregulated complement activation

Some cases are characterized by inherited or Some cases are characterized by inherited or acquired defects in complement regulatory proteins

Plasma exchange and renal transplant are first-line Plasma exchange and renal transplant are first line treatments

Emerging role for complement inhibition with Emerging role for complement inhibition with eculizumab for refractory cases

Acknowledgementsg

Dr. Jose Lopez Dr. Jose Lopez Dr. Paul Hendrie Dr Barb Konkle and Dr Raya Mawad Dr. Barb Konkle and Dr. Raya Mawad Dr. Anthony Blau

D Si b K l Dr. Sioban Keel

References (1)( )

Chatelet V, et al. Transplant Proc. 2010 Dec;42(10):4353-5. Gruppo RA & Rother RP. New Engl J Med. 2009 Jan

29;360(5):544-6. Hadaya K, et al. Am J Transplant. 2011 Aug 10. E-pub ahead y , p g p

of print. Hillmen P, et al. New Engl J Med. 2004 Feb 5;350(6):552-9. Hillmen P et al New Engl J Med 2006 Sep 21;355(12):1233- Hillmen P, et al. New Engl J Med. 2006 Sep 21;355(12):1233-

43. Joszi M, et al. Blood. 2007 Sep 1;110(5):1516-8.

K O t l S i Th b H t 2010 S 36(6) 669 72 Kose O, et al. Semin Thromb Hemost. 2010 Sep;36(6):669-72. Kupferschmidt K. Science. 2011 Jul 1;333(6038):27. Lapeyraque AL, et al. Pediatr Nephrol. 2011 Apr;26(4):621-4.

References (2)( )

Lapeyraque AL, et al. New Engl J Med. 2011 Jun p y q , g30;364(26):2561-3.

Legualt DJ & Boelkins MR. Blood (ASH Annual Meeting Ab ) 2009 114 Ab 2421Abstracts) 2009;114:Abstract 2421

Noris M, Remuzzi G. New Engl J Med. 2009 Oct 22;361(17):1676-87.22;361(17):1676 87.

Nuernberger J, et al. New Engl J Med. 2009 Jan 29;360(5):542-4.

Szczepiorkowski ZM, et al. J Clin Apher. 2010;25(3):83-177. Taylor CM, et al. Br J Haematol. 2010 Jan;148(1):37-47.

D l f f ( )

San Juan Islands

Dorsal fin of an orca (trust me)

September 2011

N l h l h C l U S

San Juan Islands

Nearly the latest sunset in the Continental U.S.

September 2011

THANK YOU!