Title: Atypical HUS and Complement Deficiencies
1ATYPICAL 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
2HEMOLYTIC-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.
3HEMOLYTIC-UREMIC SYNDROME
CLINICAL SPECTRUM OF TTP-HUS
Veyradier, A, 2001, Blood 981765-1772.
4ATYPICAL 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.
5ATYPICAL 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.
6ATYPICAL HEMOLYTIC-UREMIC SYNDROME
DRUG-ASSOCIATED
Cyclosporine/Tacrolimus
Sirolimus
Stepkowski, SM, 2000, Exp Rev Mol Med fig002ssh,
fig003ssh.
7ATYPICAL 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.
8ATYPICAL 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.
9ATYPICAL 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.
10ATYPICAL HEMOLYTIC-UREMIC SYNDROME
- COMPLEMENT DYSREGULATION
- complement components and pathways
Janeway, C, et al, Immunobiology, New York
Garland Science, 2005.
11ATYPICAL HEMOLYTIC-UREMIC SYNDROME
- COMPLEMENT DYSREGULATION
- complement regulation
http//www.biochem.ucl.ac.uk/becky/FH/proteinInfo
.php?proteinFH
12ATYPICAL 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
13ATYPICAL 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.
14ATYPICAL 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
15ATYPICAL HEMOLYTIC-UREMIC SYNDROME
FACTOR H DEFICIENCY
http//www.biochem.ucl.ac.uk/becky/FH//stats.php
16ATYPICAL 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
17ATYPICAL 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
18ATYPICAL 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.
19ATYPICAL HEMOLYTIC-UREMIC SYNDROME
- FACTOR I DEFICIENCY
- 11 different FI mutations identified to date
http//www.biochem.ucl.ac.uk/becky/FH//stats.php
20ATYPICAL 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
21ATYPICAL 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
22ATYPICAL 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.
23ATYPICAL HEMOLYTIC-UREMIC SYNDROME
- MCP DEFICIENCY
- 25 different MCP mutations identified to date
http//www.biochem.ucl.ac.uk/becky/FH//stats.php
24ATYPICAL 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
25ATYPICAL 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
26ATYPICAL 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.
27ATYPICAL 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.
28ATYPICAL 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.
29SUMMARY
Zipfel, PF, et al, 2006, Semin Thromb Hemost
32146-154.