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Hämolytisch-urämisches Syndrom und membranoproliferative Glomerulonephritis

Ein Spektrum?

Hemolytic-uremic syndrome and membranoproliferative glomerulonephritis

A spectrum?

  • Pädiatrische Nephrologie
  • Published:
Der Nephrologe Aims and scope

Zusammenfassung

Die membranoproliferative Glomerulonephritis (MPGN), insbesondere Typ II oder DDD („dense deposit disease“), und das atypische hämolytisch-urämische Syndrom (aHUS) sind Erkrankungen, die durch Defekte in der Regulation des alternativen Komplementwegs verursacht werden. Während bei der MPGN Störungen der Komplementregulation im Plasma überwiegen, ist beim aHUS die Komplementregulation vor allem auf der Oberfläche von Endothelzellen defekt. Therapeutische Strategien für beide Erkrankungen zielen auf die Wiederherstellung der Aktivitätskontrolle des alternativen Komplementwegs oder dessen gezielte Inhibierung. Moderne pathophysiologische Konzepte gehen von einem Spektrum von Komplementerkrankungen aus, bei dem interagierende Systeme wie das Gerinnungs- oder Inflammationssystem bzw. zusätzliche genetische oder Umwelteinflüsse entscheidenden Einfluss auf den endgültigen Phänotyp haben. Fortschritte im Verständnis der Krankheitsentstehung werden zweifellos zur Entwicklung verbesserter Strategien zur Diagnosestellung und Behandlung dieser Erkrankungen führen.

Abstract

Membranoproliferative glomerulonephritis (MPGN), especially type II or dense deposit disease (DDD) and atypical hemolytic uremic syndrome (aHUS) are caused by an underlying defect in the regulation of the alternative complement pathway. While in MPGN complement dysregulation mainly occurs in plasma, in aHUS loss of complement control is mainly situated on the surface of endothelial cells. Therapeutic approaches aim at recovering control over the activation of the alternative pathway or its targeted blockade. Recent pathophysiological concepts postulate a spectrum of complement disorders and appreciate a crucial role for the interaction of the complement with the coagulation and/or the inflammatory systems as well as other epigenetic factors in determining the individual phenotype. A better understanding of the underlying pathogenetic mechanisms will inevitably result in improved strategies for diagnosis and treatment of these diseases.

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Literatur

  1. Delvaeye M, Conway EM (2009) Coagulation and innate immune responses: can we view them separately? Blood 114(12):2367–2374

    Article  PubMed  CAS  Google Scholar 

  2. Abdul AA, Gunasekaran K, Volanakis JE et al (2006) The structure of complement C3b provides insights into complement activation and regulation. Nature 444(7116):221–225

    Article  Google Scholar 

  3. Botto M, Kirschfink M, Macor P et al (2009) Complement in human diseases: lessons from complement deficiencies. Mol Immunol 46(14):2774–2783

    Article  PubMed  CAS  Google Scholar 

  4. Gasser C, Gautier E, Steck A et al (1955) Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 85(38–39):905–909

    Google Scholar 

  5. Pickering MC, Cook HT (2008) Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin Exp Immunol 151(2):210–230

    Article  PubMed  CAS  Google Scholar 

  6. Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361(17):1676–1687

    Article  PubMed  CAS  Google Scholar 

  7. Skerka C, Zipfel PF, Muller D et al (2010) The autoimmune disease DEAP-hemolytic uremic syndrome. Semin Thromb Hemost 36(6):625–632

    Article  PubMed  CAS  Google Scholar 

  8. Licht C, Fremeaux-Bacchi V (2009) Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis. Thromb Haemost 101(2):271–278

    PubMed  CAS  Google Scholar 

  9. Walport MJ (2001) Complement. First of two parts. N Engl J Med 344(14):1058–1066

    Article  PubMed  CAS  Google Scholar 

  10. Thurman JM, Holers VM (2006) The central role of the alternative complement pathway in human disease. J Immunol 176(3):1305–1310

    PubMed  CAS  Google Scholar 

  11. Abrera-Abeleda MA, Xu Y, Pickering MC et al (2007) Mesangial immune complex glomerulonephritis due to complement factor D deficiency. Kidney Int 71(11):1142–1147

    Article  PubMed  CAS  Google Scholar 

  12. Appel GB, Cook HT, Hageman G et al (2005) Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 16(5):1392–1403

    Article  PubMed  Google Scholar 

  13. Rodriguez de CS, Esparza-Gordillo J, Goicoechea de JE et al (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41(4):355–367

    Article  Google Scholar 

  14. Ault BH, Schmidt BZ, Fowler NL et al (1997) Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem 272(40):25168–25175

    Article  PubMed  CAS  Google Scholar 

  15. Rose KL, Paixao-Cavalcante D, Fish J et al (2008) Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice. J Clin Invest 118(2):608–618

    PubMed  CAS  Google Scholar 

  16. Richards A, Kathryn LM, Kavanagh D et al (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 44(1–3):111–122

    Google Scholar 

  17. Delvaeye M, Noris M, De VA et al (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361(4):345–357

    Article  PubMed  CAS  Google Scholar 

  18. Leung VW, Yun S, Botto M et al (2009) Decay-accelerating factor suppresses complement C3 activation and retards atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol 175(4):1757–1767

    Article  PubMed  CAS  Google Scholar 

  19. Khera R, Das N (2009) Complement receptor 1: disease associations and therapeutic implications. Mol Immunol 46(5):761–772

    Article  PubMed  CAS  Google Scholar 

  20. Brodsky RA (2008) Advances in the diagnosis and therapy of paroxysmal nocturnal hemoglobinuria. Blood Rev 22(2):65–74

    Article  PubMed  CAS  Google Scholar 

  21. Benz K, Amann K (2009) Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS)/thrombocytic thrombopenic purpura (TTP). Thromb Haemost 101(2):265–270

    PubMed  CAS  Google Scholar 

  22. Servais A, Fremeaux-Bacchi V, Lequintrec M et al (2007) Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 44(3):193–199

    Article  PubMed  CAS  Google Scholar 

  23. Habbig S, Mihatsch MJ, Heinen S et al (2009) C3 deposition glomerulopathy due to a functional factor H defect. Kidney Int 75(11):1230–1234

    Article  PubMed  Google Scholar 

  24. Fakhouri F, Fremeaux-Bacchi V, Noel LH et al (2010) C3 glomerulopathy: a new classification. Nat Rev Nephrol 6(8):494–499

    Article  PubMed  CAS  Google Scholar 

  25. Schwertz R, Rother U, Anders D et al (2001) Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up. Pediatr Allergy Immunol 12(3):166–172

    Article  PubMed  CAS  Google Scholar 

  26. Jokiranta TS, Solomon A, Pangburn MK et al (1999) Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol 163(8):4590–4596

    PubMed  CAS  Google Scholar 

  27. Strobel S, Zimmering M, Papp K et al (2010) Anti-factor B autoantibody in dense deposit disease. Mol Immunol 47(7–8):1476–1483

    Google Scholar 

  28. Hegasy GA, Manuelian T, Hogasen K et al (2002) The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. Am J Pathol 161(6):2027–2034

    Article  PubMed  CAS  Google Scholar 

  29. Hogasen K, Jansen JH, Mollnes TE et al (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J Clin Invest 95(3):1054–1061

    Article  PubMed  CAS  Google Scholar 

  30. Jansen JH (1993) Porcine membranoproliferative glomerulonephritis with intramembranous dense deposits (porcine dense deposit disease). APMIS 101(4):281–289

    Article  PubMed  CAS  Google Scholar 

  31. Pickering MC, Cook HT, Warren J et al (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31(4):424–428

    PubMed  CAS  Google Scholar 

  32. Pickering MC, Warren J, Rose KL et al (2006) Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc Natl Acad Sci USA 103(25):9649–9654

    Article  PubMed  CAS  Google Scholar 

  33. Gale DP, Jorge EG de, Cook HT et al (2010) Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376(9743):794–801

    Article  PubMed  CAS  Google Scholar 

  34. Martinez-Barricarte R, Heurich M, Valdes-Canedo F et al (2010) Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest 120(10):3702–3712

    Article  PubMed  CAS  Google Scholar 

  35. Murphy B, Georgiou T, Machet D et al (2002) Factor H-related protein-5: a novel component of human glomerular immune deposits. Am J Kidney Dis 39(1):24–27

    Article  PubMed  CAS  Google Scholar 

  36. Levin A (1999) Management of membranoproliferative glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 70:S41–S46

    Article  PubMed  CAS  Google Scholar 

  37. Licht C, Heinen S, Jozsi M et al (2006) Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int 70(1):42–50

    Article  PubMed  CAS  Google Scholar 

  38. Fakhouri F, Jorge EG de, Brune F et al (2010) Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice. Kidney Int 78(3):279–286

    Article  PubMed  CAS  Google Scholar 

  39. Hillmen P, Young NS, Schubert J et al (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 355(12):1233–1243

    Article  PubMed  CAS  Google Scholar 

  40. Smith RJ, Alexander J, Barlow PN et al (2007) New approaches to the treatment of dense deposit disease. J Am Soc Nephrol 18(9):2447–2456

    Article  PubMed  CAS  Google Scholar 

  41. Weiss R, Niecestro R, Raz I (2007) The role of sulodexide in the treatment of diabetic nephropathy. Drugs 67(18):2681–2696

    Article  PubMed  CAS  Google Scholar 

  42. Scheiring J, Rosales A, Zimmerhackl LB (2010) Clinical practice. Today’s understanding of the haemolytic uraemic syndrome. Eur J Pediatr 169(1):7–13

    Article  PubMed  Google Scholar 

  43. Garg AX, Suri RS, Barrowman N et al (2003) Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 290(10):1360–1370

    Article  PubMed  CAS  Google Scholar 

  44. Garg AX, Clark WF, Salvadori M et al (2006) Absence of renal sequelae after childhood Escherichia coli O157:H7 gastroenteritis. Kidney Int 70(4):807–812

    Article  PubMed  CAS  Google Scholar 

  45. Gerber A, Karch H, Allerberger F et al (2002) Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997–2000, in Germany and Austria: a prospective study. J Infect Dis 186(4):493–500

    Article  PubMed  Google Scholar 

  46. Ariceta G, Besbas N, Johnson S et al (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24(4):687–696

    Article  PubMed  Google Scholar 

  47. Manuelian T, Hellwage J, Meri S et al (2003) Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 111(8):1181–1190

    PubMed  CAS  Google Scholar 

  48. Bienaime F, Dragon-Durey MA, Regnier CH et al (2010) Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77(4):339–349

    Article  PubMed  CAS  Google Scholar 

  49. Goicoechea de JE, Harris CL, Esparza-Gordillo J et al (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 104(1):240–245

    Article  Google Scholar 

  50. Fremeaux-Bacchi V, Miller EC, Liszewski MK et al (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112(13):4948–4952

    Article  PubMed  CAS  Google Scholar 

  51. Fremeaux-Bacchi V, Moulton EA, Kavanagh D et al (2006) Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 17(7):2017–2025

    Article  PubMed  CAS  Google Scholar 

  52. Dragon-Durey MA, Loirat C, Cloarec S et al (2005) Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16(2):555–563

    Article  PubMed  CAS  Google Scholar 

  53. Jozsi M, Licht C, Strobel S et al (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111(3):1512–1514

    Article  PubMed  CAS  Google Scholar 

  54. Moore I, Strain L, Pappworth I et al (2010) Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 115(2):379–387

    Article  PubMed  CAS  Google Scholar 

  55. Lapeyraque AL, Wagner E, Phan V et al (2008) Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations. Pediatr Nephrol 23(8):1363–1366

    Article  PubMed  Google Scholar 

  56. Kose O, Zimmerhackl LB, Jungraithmayr T et al (2010) New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost 36(6):669–672

    Article  PubMed  Google Scholar 

  57. Zimmerhackl LB, Hofer J, Cortina G (2010) Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med 362(18):1746–1748

    Article  PubMed  Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: vergütete wissenschaftliche Beratung der Firmen Alexion Pharmaceuticals Inc., CSL Behring (CL).

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Authors and Affiliations

  1. Department für Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck, Innsbruck, Österreich

    M. Riedl

  2. Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, MSG IX8, Canada

    C. Licht MD, FASN

  3. University of Toronto, Toronto, ON, Canada

    C. Licht MD, FASN

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Correspondence to C. Licht MD, FASN.

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Riedl, M., Licht, C. Hämolytisch-urämisches Syndrom und membranoproliferative Glomerulonephritis. Nephrologe 6, 355–364 (2011). https://doi.org/10.1007/s11560-011-0531-9

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