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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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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


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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.


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HEMOLYTIC-UREMIC SYNDROME

CLINICAL SPECTRUM OF TTP-HUS

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


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ATYPICAL HUS

Other causes of atypical hemolytic-uremic syndrome

Other pathogens

S. pneumoniae HIV

Q fever CMV

Staphylococcus Hantavirus

Drugs

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.


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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 19:317-321.


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ATYPICAL HEMOLYTIC-UREMIC SYNDROME

DRUG-ASSOCIATED

Cyclosporine/Tacrolimus

Sirolimus

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


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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.


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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 7:1177-1178.


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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 69:181-186.


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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?protein=FH


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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


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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 15:787-795.


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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//proteinInfo.php?protein=FI


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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 27:359-374.

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


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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


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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//proteinInfo.php?protein=MCP


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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 17:2017-2025.


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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


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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.


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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

    • >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.


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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 44:111-122.


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SUMMARY

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


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