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ATYPICAL HEMOLYTIC-UREMIC SYNDROME AND COMPLEMENT DEFICIENCIES

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

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  1. 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

  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 (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.

  3. HEMOLYTIC-UREMIC SYNDROME CLINICAL SPECTRUM OF TTP-HUS Veyradier, A, 2001, Blood 98:1765-1772.

  4. 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.

  5. 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.

  6. 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 31:681-690.

  8. 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.

  9. 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.

  10. ATYPICAL HEMOLYTIC-UREMIC SYNDROME • COMPLEMENT DYSREGULATION • complement components and pathways Janeway, C, et al, Immunobiology, New York: Garland Science, 2005.

  11. ATYPICAL HEMOLYTIC-UREMIC SYNDROME • COMPLEMENT DYSREGULATION • complement regulation http://www.biochem.ucl.ac.uk/~becky/FH/proteinInfo.php?protein=FH

  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?protein=FH

  13. 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.

  14. 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

  15. ATYPICAL HEMOLYTIC-UREMIC SYNDROME FACTOR H DEFICIENCY http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

  16. 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

  17. 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

  18. 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.

  19. 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

  21. 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

  22. 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.

  23. ATYPICAL HEMOLYTIC-UREMIC SYNDROME • MCP DEFICIENCY • 25 different MCP mutations identified to date http://www.biochem.ucl.ac.uk/~becky/FH//stats.php

  24. 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

  25. 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 44:111-122.

  27. 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.

  28. 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.

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

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