Atypical HUS and Complement Deficiencies

1
ATYPICAL HEMOLYTIC-UREMIC SYNDROME AND COMPLEMENT
DEFICIENCIES
Gary C. Pien, MD/PhD Division of
Allergy/Immunology Childrens Hospital of
Philadelphia 34th St and Civic Center
Blvd Philadelphia, PA 19104
2
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 (O157H7)
• 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 19317-321.
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HEMOLYTIC-UREMIC SYNDROME
CLINICAL SPECTRUM OF TTP-HUS
Veyradier, A, 2001, Blood 981765-1772.
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ATYPICAL HUS
Other causes of atypical hemolytic-uremic
syndrome Other pathogens S. pneumoniae HIV Q
fever CMV Staphylococcus Hantavirus Drugs cyc
losporine bleomycin tacrolimus cisplatin mitom
ycin Underlying medical conditions Upshaw-S
hulman syndrome MCP deficiency factor H
deficiency factor I deficiency cobalamin-C
disease
Cochran, JB, 2004, Pediatr Nephrol 19317-321.
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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 19317-321.
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ATYPICAL HEMOLYTIC-UREMIC SYNDROME
DRUG-ASSOCIATED
Cyclosporine/Tacrolimus
Sirolimus
Stepkowski, SM, 2000, Exp Rev Mol Med fig002ssh,
fig003ssh.
7
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
31681-690.
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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 71177-1178.
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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
69181-186.
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ATYPICAL HEMOLYTIC-UREMIC SYNDROME

• COMPLEMENT DYSREGULATION
• complement components and pathways

Janeway, C, et al, Immunobiology, New York
Garland Science, 2005.
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ATYPICAL HEMOLYTIC-UREMIC SYNDROME

• COMPLEMENT DYSREGULATION
• complement regulation

http//www.biochem.ucl.ac.uk/becky/FH/proteinInfo
.php?proteinFH
12
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?proteinFH
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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
15787-795.
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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
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ATYPICAL HEMOLYTIC-UREMIC SYNDROME
FACTOR H DEFICIENCY
http//www.biochem.ucl.ac.uk/becky/FH//stats.php
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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
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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//proteinInf
o.php?proteinFI
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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 27359-374. Kavanagh, D, et al, 2005, J Am
Soc Nephrol 162150-2155.
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ATYPICAL HEMOLYTIC-UREMIC SYNDROME

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

http//www.biochem.ucl.ac.uk/becky/FH//stats.php
20
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
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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//proteinInf
o.php?proteinMCP
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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
172017-2025.
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ATYPICAL HEMOLYTIC-UREMIC SYNDROME

• MCP DEFICIENCY
• 25 different MCP mutations identified to date

http//www.biochem.ucl.ac.uk/becky/FH//stats.php
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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
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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
26
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 44111-122.
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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
• gt60 with FI-deficiency HUS develop ESRD
• 86 with MCP-deficiency HUS remain dialysis-free
• 70 had recurrence of HUS

Richards, A, 2007, Mol Immunol 44111-122.
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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 44111-122.
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SUMMARY
Zipfel, PF, et al, 2006, Semin Thromb Hemost
32146-154.