Skip to main content

Advertisement

SpringerLink
Log in

Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Glomerular thrombotic microangiopathy is a hallmark feature of haemolytic uraemic syndrome, the leading cause of acute renal failure in childhood. This paper is a review of the different mechanistic pathways that lead to this histological picture in the kidney. It will focus on atypical HUS and complement dysregulation, but will also highlight some other recent advances in our understanding of this condition, including the potential role of the molecule vascular endothelial growth factor- A (VEGF-A).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Serna A 4th, Boedeker EC (2008) Pathogenesis and treatment of Shiga toxin-producing Escherichia coli infections. Curr Opin Gastroenterol 24:38–47

    Article  CAS  PubMed  Google Scholar 

  2. Zheng XL, Sadler JE (2008) Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol 3:249–277

    Article  CAS  PubMed  Google Scholar 

  3. Ruggenenti P, Noris M, Remuzzi G (2001) Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831–846

    Article  CAS  PubMed  Google Scholar 

  4. Copelovitch L, Kaplan BS (2008) The thrombotic microangiopathies. Pediatr Nephrol 23:1761–1767

    Article  PubMed  Google Scholar 

  5. Tsai HM (2006) The molecular biology of thrombotic microangiopathy. Kidney Int 70:16–23

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Michael M, Elliott EJ, Ridley GF, Hodson EM, Craig JC (2009) Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev CD003595

  8. Franchini M (2006) Thrombotic microangiopathies: an update. Hematology 11:139–146

    Article  CAS  PubMed  Google Scholar 

  9. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24:687–696

    Article  PubMed  Google Scholar 

  10. Scheiring J, Andreoli SP, Zimmerhackl LB (2008) Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 23:1749–1760

    Article  PubMed  Google Scholar 

  11. Taylor CM, Machin S, Wigmore SJ, Goodship TH (2010) Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 148:37–47

    Article  CAS  PubMed  Google Scholar 

  12. Desch K, Motto D (2007) Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome? J Am Soc Nephrol 18:2457–2460

    Article  PubMed  Google Scholar 

  13. Pearce MC, Chase-Topping ME, McKendrick IJ, Mellor DJ, Locking ME, Allison L, Ternent HE, Matthews L, Knight HI, Smith AW, Synge BA, Reilly W, Low JC, Reid SW, Gunn GJ, Woolhouse ME (2009) Temporal and spatial patterns of bovine Escherichia coli O157 prevalence and comparison of temporal changes in the patterns of phage types associated with bovine shedding and human E. coli O157 cases in Scotland between 1998–2000 and 2002–2004. BMC Microbiol 9:276

    Article  PubMed  Google Scholar 

  14. Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, Hurault de Ligny B, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112:4948–4952

    Article  CAS  PubMed  Google Scholar 

  15. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 104:240–245

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, Taylor CM, Goodship TJ, Noris M (2007) Where next with atypical hemolytic uremic syndrome? Mol Immunol 44:3889–3900

    Article  CAS  PubMed  Google Scholar 

  18. Estaller C, Schwaeble W, Dierich M, Weiss EH (1991) Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts. Eur J Immunol 21:799–802

    Article  CAS  PubMed  Google Scholar 

  19. Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–844

    Article  CAS  PubMed  Google Scholar 

  20. Lee BH, Kwak SH, Shin JI, Lee SH, Choi HJ, Kang HG, Ha IS, Lee JS, Dragon-Durey MA, Choi Y, Cheong HI (2009) Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatr Res 66:336–340

    Article  CAS  PubMed  Google Scholar 

  21. Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971

    Article  CAS  PubMed  Google Scholar 

  22. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367

    Article  CAS  PubMed  Google Scholar 

  23. Ferreira VP, Herbert AP, Cortes C, McKee KA, Blaum BS, Esswein ST, Uhrin D, Barlow PN, Pangburn MK, Kavanagh D (2009) The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. J Immunol 182:7009–7018

    Article  CAS  PubMed  Google Scholar 

  24. Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrin D, Barlow PN (2008) A new map of glycosaminoglycan and C3b binding sites on factor H. J Immunol 181:2610–2619

    CAS  PubMed  Google Scholar 

  25. Jozsi M, Heinen S, Hartmann A, Ostrowicz CW, Halbich S, Richter H, Kunert A, Licht C, Saunders RE, Perkins SJ, Zipfel PF, Skerka C (2006) Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol 17:170–177

    Article  CAS  PubMed  Google Scholar 

  26. Licht C, Pluthero FG, Li L, Christensen H, Habbig S, Hoppe B, Geary DF, Zipfel PF, Kahr WH (2009) Platelet-associated complement factor H in healthy persons and patients with atypical HUS. Blood 114:4538–4545

    Article  CAS  PubMed  Google Scholar 

  27. Alexander JJ, Quigg RJ (2007) The simple design of complement factor H: looks can be deceiving. Mol Immunol 44:123–132

    Article  CAS  PubMed  Google Scholar 

  28. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428

    CAS  PubMed  Google Scholar 

  29. Richards A, Kavanagh D (2009) Pathogenesis of thrombotic microangiopathy: insights from animal models. Nephron Exp Nephrol 113:e97–e103

    Article  PubMed  Google Scholar 

  30. Pickering MC, de Jorge EG, Martinez-Barricarte R, Recalde S, Garcia-Layana A, Rose KL, Moss J, Walport MJ, Cook HT, de Cordoba SR, Botto M (2007) Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J Exp Med 204:1249–1256

    Article  CAS  PubMed  Google Scholar 

  31. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84

    Article  CAS  PubMed  Google Scholar 

  32. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345–357

    Article  CAS  PubMed  Google Scholar 

  33. Sadler JE (2008) Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 112:11–18

    Article  CAS  PubMed  Google Scholar 

  34. Moake J (2009) Thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies. Best Pract Res Clin Haematol 22:567–576

    Article  PubMed  Google Scholar 

  35. Banno F, Kokame K, Okuda T, Honda S, Miyata S, Kato H, Tomiyama Y, Miyata T (2006) Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 107:3161–3166

    Article  CAS  PubMed  Google Scholar 

  36. Lynn RM, O'Brien SJ, Taylor CM, Adak GK, Chart H, Cheasty T, Coia JE, Gillespie IA, Locking ME, Reilly WJ, Smith HR, Waters A, Willshaw GA (2005) Childhood hemolytic uremic syndrome, United Kingdom and Ireland. Emerg Infect Dis 11:590–596

    PubMed  Google Scholar 

  37. Psotka MA, Obata F, Kolling GL, Gross LK, Saleem MA, Satchell SC, Mathieson PW, Obrig TG (2009) Shiga toxin 2 targets the murine renal collecting duct epithelium. Infect Immun 77:959–969

    Article  CAS  PubMed  Google Scholar 

  38. Okuda T, Tokuda N, Numata S, Ito M, Ohta M, Kawamura K, Wiels J, Urano T, Tajima O, Furukawa K (2006) Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J Biol Chem 281:10230–10235

    Article  CAS  PubMed  Google Scholar 

  39. Chaisri U, Nagata M, Kurazono H, Horie H, Tongtawe P, Hayashi H, Watanabe T, Tapchaisri P, Chongsa-nguan M, Chaicumpa W (2001) Localization of Shiga toxins of enterohaemorrhagic Escherichia coli in kidneys of paediatric and geriatric patients with fatal haemolytic uraemic syndrome. Microb Pathog 31:59–67

    Article  CAS  PubMed  Google Scholar 

  40. Ergonul Z, Clayton F, Fogo AB, Kohan DE (2003) Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol 18:246–253

    PubMed  Google Scholar 

  41. Johannes L, Romer W (2010) Shiga toxins—from cell biology to biomedical applications. Nat Rev Microbiol 8:105–116

    CAS  PubMed  Google Scholar 

  42. Hertzke DM, Cowan LA, Schoning P, Fenwick BW (1995) Glomerular ultrastructural lesions of idiopathic cutaneous and renal glomerular vasculopathy of greyhounds. Vet Pathol 32:451–459

    Article  CAS  PubMed  Google Scholar 

  43. Siegler RL, Obrig TG, Pysher TJ, Tesh VL, Denkers ND, Taylor FB (2003) Response to Shiga toxin 1 and 2 in a baboon model of hemolytic uremic syndrome. Pediatr Nephrol 18:92–96

    PubMed  Google Scholar 

  44. Hoey DE, Currie C, Else RW, Nutikka A, Lingwood CA, Gally DL, Smith DG (2002) Expression of receptors for verotoxin 1 from Escherichia coli O157 on bovine intestinal epithelium. J Med Microbiol 51:143–149

    CAS  PubMed  Google Scholar 

  45. Keepers TR, Psotka MA, Gross LK, Obrig TG (2006) A murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J Am Soc Nephrol 17:3404–3414

    Article  CAS  PubMed  Google Scholar 

  46. Copelovitch L, Kaplan BS (2008) Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol 23:1951–1956

    Article  PubMed  Google Scholar 

  47. Eremina V, Baelde HJ, Quaggin SE (2007) Role of the VEGF—a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol 106:p32–p37

    Article  CAS  PubMed  Google Scholar 

  48. Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC (2010) VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer 46:439–448

    Article  CAS  PubMed  Google Scholar 

  49. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111:707–716

    CAS  PubMed  Google Scholar 

  50. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358:1129–1136

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work is supported by the British Medical Research Council (grant number G0501901).

Author information

Authors and Affiliations

  1. Department of Medical Pediatrics, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK

    Lindsay Keir

  2. Academic and Children’s Renal Unit, University of Bristol and Bristol Royal Hospital for Children, Bristol, UK

    Richard J. M. Coward

Authors
  1. Lindsay Keir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard J. M. Coward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J. M. Coward.

Additional information

Answers

1. b

2. c

3. c

4. d

5. e

Multiple choice questions

Multiple choice questions

Answers appear following the reference list.

  1. 1.

    A major cellular receptor in human Shiga toxin HUS is called

    1. a)

      crry

    2. b)

      Gb3

    3. c)

      CD42

    4. d)

      MCP

    5. e)

      Factor I

  2. 2.

    The predominant pathway that is affected by atypical HUS is the

    1. a)

      VEGF-A pathway

    2. b)

      Lectin complement pathway

    3. c)

      Alternative complement pathway

    4. d)

      Classical complement pathway

    5. e)

      Coagulation pathway

  3. 3.

    Which of the following are solid phase complement components?

    1. a)

      Factor H

    2. b)

      Factor I

    3. c)

      MCP

    4. d)

      C3

    5. e)

      C4

  4. 4.

    After renal transplantation, in which of the following is there least likely to be a recurrence of HUS in the transplanted kidney

    1. a)

      Factor H mutations

    2. b)

      Factor I mutations

    3. c)

      C3 mutations

    4. d)

      MCP mutations

    5. e)

      Thrombomodulin mutations

  5. 5.

    The cause of pneumococcal-induced HUS is thought to be

    1. a)

      Alterations in podocyte-derived VEGF-A

    2. b)

      Abnormalities in the classical complement pathway

    3. c)

      Thromboxane hyper-stimulation

    4. d)

      Exposure of neuraminidase on the cell surfaces

    5. e)

      Production of neuraminidase by the bacteria exposing the TF antigen

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keir, L., Coward, R.J.M. Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy. Pediatr Nephrol 26, 523–533 (2011). https://doi.org/10.1007/s00467-010-1637-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-010-1637-4

Keywords

Search

Navigation