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ATYPICAL HEMOLYTIC-UREMIC SYNDROME AND COMPLEMENT DEFICIENCIES. Gary C. Pien, MD/PhD Division of Allergy/Immunology Children’s Hospital of Philadelphia 34 th St and Civic Center Blvd Philadelphia, PA 19104. HEMOLYTIC-UREMIC SYNDROME. HEMOLYTIC-UREMIC SYNDROME

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slide1

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

AND COMPLEMENT DEFICIENCIES

Gary C. Pien, MD/PhD

Division of Allergy/Immunology

Children’s Hospital of Philadelphia

34th St and Civic Center Blvd

Philadelphia, PA 19104

slide2

HEMOLYTIC-UREMIC SYNDROME

  • HEMOLYTIC-UREMIC SYNDROME
  • triad of clinical manifestations
    • microangiopathic hemolytic anemia
    • thrombocytopenia
    • acute nephropathy
  • 90% of pediatric cases due to Shiga toxin-producing E. coli (O157:H7)
  • 10% are atypical cases with other causes
    • of these, 40% associated with pneumococcus
    • 50% associated with disorders of complement
  • thrombotic thrombocytopenic purpura (TTP)
    • TTP-HUS spectrum of related disorders
    • TTP has same manifestations, PLUS …
      • neurologic involvement
      • fever

Cochran, JB, 2004, Pediatr Nephrol 19:317-321.

slide3

HEMOLYTIC-UREMIC SYNDROME

CLINICAL SPECTRUM OF TTP-HUS

Veyradier, A, 2001, Blood 98:1765-1772.

slide4

ATYPICAL HUS

Other causes of atypical hemolytic-uremic syndrome

Other pathogens

S. pneumoniae HIV

Q fever CMV

Staphylococcus Hantavirus

Drugs

cyclosporine bleomycin

tacrolimus cisplatin

mitomycin

Underlying medical conditions

Upshaw-Shulman syndrome MCP deficiency

factor H deficiency factor I deficiency

cobalamin-C disease

Cochran, JB, 2004, Pediatr Nephrol 19:317-321.

slide5

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • PNEUMOCOCCAL-ASSOCIATED
  • pathogenesis
    • microbial neuraminidase exposes Thomsen-Friedenreich (T) antigen
    • cryptic T-antigen found on erythrocytes, platelets, and glomeruli
    • overexpressed by carcinoma
    • neuraminidase cleaves sialic acid, exposing T-antigen
    • bound by “natural” anti-T IgM antibodies
    • results in thrombotic microangiopathy

Cochran, JB, 2004, Pediatr Nephrol 19:317-321.

slide6

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

DRUG-ASSOCIATED

Cyclosporine/Tacrolimus

Sirolimus

Stepkowski, SM, 2000, Exp Rev Mol Med fig002ssh, fig003ssh.

slide7

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • DRUG-ASSOCIATED
  • cyclosporine/tacrolimus-associated
    • mechanism unclear
    • seen in solid-organ or stem-cell transplantation, and non-transplant
    • estimated incidence of 1-5% following stem-cell transplantation
    • no clear dose-response association to risk
    • usually observed in first 6 months after transplantation
    • disease can be localized or systemic
    • events associated with higher rate of graft loss or mortality
    • therapeutic interventions
      • treat co-inciting factors (CMV infection)
      • dose reduction
      • withhold drug, switch to alternate drug
      • plasma exchange transfusion
      • corticosteroids
      • IVIG
  • also reported with Campath (alemtuzumab, anti-CD52)

Zakarija A, et al, 2005, Semin Thromb Hemost 31:681-690.

slide8

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • UPSHAW-SHULMAN SYNDROME
  • congenital deficiency of ADAMTS-13
    • protease cleaves vWF multimers
  • presents at birth with hemolytic anemia and thrombocytopenia
  • renal involvement develops later in life
  • inhibitor auto-antibodies to ADAMTS-13 can also cause similar syndrome

Brass, L, 2001, Nature Med 7:1177-1178.

slide9

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COBALAMIN-C DEFICIENCY
  • disorder of vitamin B12 (cobalamin) metabolism
    • hyperhomocysteiemia
    • methylmalonic aciduria
  • presents with atypical HUS and neurological symptoms
    • early onset seizures
    • hypotonia
    • developmental delay
    • retinopathy
    • macrocytic anemia
    • neutropenia

Tefferi, A, et al, 1994, Mayo Clin Proc 69:181-186.

slide10

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • complement components and pathways

Janeway, C, et al, Immunobiology, New York: Garland Science, 2005.

slide11

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • complement regulation

http://www.biochem.ucl.ac.uk/~becky/FH/proteinInfo.php?protein=FH

slide12

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • factor H, factor I, or MCP deficiency accounts for 50% of atypical HUS
  • FACTOR H
  • 150kD plasma glycoprotein synthesized in liver
  • 20 homologous units of 61 residues (short consensus repeats – SCRs)
  • N-terminal domains SCR1 – SCR4 bind C3b
    • complement decay accelerating activity located here
  • H = three heparin binding sites
    • tertiary structure through to be bent backwards
    • exposes C-terminal SCR20
  • functions as co-factor for factor I-mediated degradation of C3b,Bb

http://www.biochem.ucl.ac.uk/~becky/FH/proteinInfo.php?protein=FH

slide13

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • FACTOR H DEFICIENCY
  • thought to account for 10-22% of atypical HUS cases
  • reported in both familial and sporadic forms
  • usually presents in infancy or early childhood, but may present in adulthood
  • one study of 16 FH-deficient patients
    • 6 with homozygous deficiency
      • 4 had membranoproliferative glomerulonephritis
      • 2 had atypical HUS
    • 10 had heterozygous deficiency
      • all developed atypical HUS
  • homozygotes had low levels of FH, C3, FB and CH50
  • heterozygotes had low to normal values
  • some patients present with meningococcal infections
    • acquired C3 or terminal C’ deficiencies
  • some present with SLE, having combined FH and C2 deficiency

Dragon-Durey, M-A, et al, 2004, J Am Soc Nephrol 15:787-795.

slide14

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • FACTOR H DEFICIENCY
  • 69 different FH mutations identified to date
  • 3 patients have been described with atypical HUS and acquired anti-FH
  • autoantibodies

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide15

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

FACTOR H DEFICIENCY

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide16

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

FACTOR H DEFICIENCY

  • FACTOR H DEFICIENCY
  • type I = absent or reduced protein level
  • type II = normal protein level, abnormal function

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide17

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • FACTOR I
  • 88kD plasma serine protease synthesized in liver
  • N-terminal heavy chain
    • LDL-receptor domains x2
    • CD5 domain
    • FIMAC domain (factor I membrane attack complex)
  • C-terminal catalytic domain
  • functions to directly cleave C4b or C3b to inactivate complement
  • efficient cleavage requires co-factors (C4bp, FH, MCP)

http://www.biochem.ucl.ac.uk/~becky/FH//proteinInfo.php?protein=FI

slide18

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • FACTOR I DEFICIENCY
  • reported only in sporadic forms of atypical HUS
  • in one study, 2 out of 76 patients with atypical HUS had FI deficiency
  • most reported cases involve hyterozygous mutations
    • no increased susceptibility to infection
  • homozygous FI deficiency associated with increased infection susceptibility
    • encapsulated organisms (meningococcus, pneumococcus, hemophilus)
    • acquired C3 deficiency due to uncontrolled consumption
  • variable penetrance and expressivity
  • C3 can be low to normal

Dragon-Durey, M-A, et al, 2005, Springer Semin Immun 27:359-374.

Kavanagh, D, et al, 2005, J Am Soc Nephrol 16:2150-2155.

slide19

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • FACTOR I DEFICIENCY
  • 11 different FI mutations identified to date

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide20

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • FACTOR I DEFICIENCY
  • type I = absent or reduced protein level
  • type II = normal protein level, abnormal function

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide21

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • MEMBRANE COFACTOR PROTEIN (MCP = CD46)
  • ~65 kD transmembrane glycoprotein
  • on leukocytes, platelets, endothelial & epithelial cells, fibroblasts, kidney
  • extracellular domain
    • four SCR domains
    • alternative splice sites for O-glycosylation
    • multiple isoforms exist
  • transmembrane domain
  • cytoplasmic C-terminal anchor
  • functions as cofactor for FI
  • pathogen receptor for measles, adenovirus, HHV-6, Neisseria, and GAS

http://www.biochem.ucl.ac.uk/~becky/FH//proteinInfo.php?protein=MCP

slide22

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • MCP DEFICIENCY
  • reported only in familial forms of atypical HUS
  • both homozygous and heterozygous types seen
  • 80% of patients are heterozygotes

Fremeaux-Bacchi, V, et al, 2006, J Am Soc Nephrol 17:2017-2025.

slide23

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • MCP DEFICIENCY
  • 25 different MCP mutations identified to date

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide24

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • MCP DEFICIENCY
  • type I = absent or reduced protein level
  • type II = normal protein level, abnormal function

http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

slide25

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • pathogenesis of atypical HUS
  • infection/inflammation increases rate of C3b formation
  • activates complement cascade and C3a/C5a
  • C3a/C5a attract leukocytes, producing TNF and IL-8
  • cytokines cause endothelial damage and exposure of extracellular matrix
  • ECM exposure amplifies deposition of C3b and complement activation
  • lack of normal factor H, factor I, or MCP results in unchecked activation
  • progressive tissue damage occurs

http://www.biochem.ucl.ac.uk/~becky/FH/hus.php

slide26

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • FH, FI, and MCP deficiency have incomplete penetrance
    • disease modifiers or other factors may have role
  • environmental triggers
    • infections
      • preceded 70% of those with FH mutation
      • 60% of those with FI mutation
      • 100% of cases of HUS in MCP-mutants
    • pregnancy
      • trigger in 4% of FH-HUS
      • 40% of FI-HUS
  • multiple-hits
    • one pedigree in which atypical HUS occurred only with inheritance of ALL:
      • MCP P131S mutation
      • MCP promoter polymorphism
      • dinucleotide insertion into FI gene
      • resulted in 50% expression level of each protein

Richards, A, 2007, Mol Immunol 44:111-122.

slide27

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • outcomes of atypical HUS
    • overall 50% of patients develop ESRD
    • 25% mortality during acute illness
  • end-stage renal disease
    • 70% with FH-deficiency HUS develop ESRD or die
    • >60% with FI-deficiency HUS develop ESRD
    • 86% with MCP-deficiency HUS remain dialysis-free
      • 70% had recurrence of HUS

Richards, A, 2007, Mol Immunol 44:111-122.

slide28

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

  • COMPLEMENT DYSREGULATION
  • treatment
    • plasma exchange and plasma infusions of FFP
    • 32 FH-deficient patients treated with FFP
      • 67% in remission
    • similar results in FI-deficient patients
    • MCP-deficiency not amenable to FFP infusions or plasma exchange
      • renal transplantation protective
  • renal transplantation
    • 30 FH-deficient patients underwent renal transplantation
      • 80% had disease recurrence
    • 6 FI-deficient patients underwent renal transplantation
      • 100% had disease recurrence
    • transplanted MCP-deficient patients
      • 10 MCP-deficient patients transplanted
      • 1 had recurrence of HUS
      • low C3 and factor B levels – disease modifiers?

Richards, A, 2007, Mol Immunol 44:111-122.

slide29

SUMMARY

Zipfel, PF, et al, 2006, Semin Thromb Hemost 32:146-154.

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