Renal Vasculitis in Children

Chapter
First Online:

Abstract

In this chapter, we focus on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and glomerulonephritis (GN) as a prototype of “renal vasculitis” in children. Vasculitis is a clinical and pathological “merged” entity that has undergone substantial changes during the past decades; this has created some confusion in understanding it. In particular, several changes in the concept and terminology of vasculitis and the classical clinical entity of rapidly progressive glomerulonephritis (RPGN) have caused confusion in the diagnosis of vasculitis and ANCA-associated GN. The differences in perspectives among nephrologists, rheumatologists, and pathologists have exacerbated the confusion as well. Therefore, we have tried to arrange these perspectives so as to be simple. We will review the recent genome-wide association analysis, which has revealed the genetic difference between granulomatosis with polyangiitis and microscopic polyangiitis, as well as discuss the roles of ANCA itself, human lysosomal membrane protein-2 (hLAMP-2) and neutrophil extracellular traps (NETs) in the pathogenesis of ANCA-associated glomerulonephritis. Recent therapies and the prognosis of ANCA-associated glomerulonephritis are also illustrated.

Keywords

Antineutrophil cytoplasmic antibody (ANCA) Small vessel vasculitis Microscopic polyangiitis (MPA) Pauci-immune glomerulonephritis Crescentic glomerulonephritis PR3-ANCA MPO-ANCA Rituximab Rapidly progressive glomerulonephritis Necrotizing glomerulonephritis 

Abbreviations

AAGN

ANCA-associated glomerulonephritis

AAV

ANCA-associated vasculitis

ANCA

Antineutrophil cytoplasmic antibody

CPA

Oral cyclophosphamide

EGP

Eosinophilic granuloma with polyangiitis (Churg-Strauss syndrome)

ENT

Ear nose, and throat

GBM

Glomerular basement membrane

GN

Glomerulonephritis

GPA

Granulomatous polyangiitis (WG)

HSPN

Henoch-Schönlein purpura nephritis

LAMP-2

Lysosome-associated membrane protein-2

MHC

Major histocompatibility complex

MMI

Methimazole

MPA

Microscopic polyangiitis

MPO

Myeloperoxidase

NCGN

Necrotizing crescentic glomerulonephritis

NETs

Neutrophil extracellular traps

PAN

Polyarteritis nodosa

PE

Plasma exchange

PR3

Proteinase-3

PTU

Propylthiouracil

RLV

Renal-limited vasculitis

RPGN

Rapidly progressive glomerulonephritis

SNP

Single nucleotide polymorphism

SOV

Single-organ vasculitis

VVV

Variable vessel vasculitis

WG

Wegener’s granulomatosis (GPA)

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

References

  1. 1.
    Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63(3):1164–77.CrossRefPubMedGoogle Scholar
  2. 2.
    Bell ET. A clinical and pathological study of subacute and chronic glomerulonephritis, including lipoid nephrosis. Am J Pathol. 1938;14(6):691–736.5.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Ellis A. Natural history of Bright’s disease. Clinical, histological and experimental observations. Lancet. 1942;239(6176):34–6.CrossRefGoogle Scholar
  4. 4.
    Duncan DA, Drummond KN, Michael AF, Vernier RL. Pulmonary hemorrhage and glomerulonephritis. Report of six cases and study of the renal lesion by the fluorescent antibody technique and electron microscopy. Ann Intern Med. 1965;62:920–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Sturgill BC, Westervelt FB. Immunofluorescence studies in a case of Goodpasture’s syndrome. JAMA. 1965;194(8):914–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Bacani RA, Velasquez F, Kanter A, Pirani CL, Pollak VE. Rapidly progressive (nonstreptococcal) glomerulonephritis. Ann Intern Med. 1968;69(3):463–85.CrossRefPubMedGoogle Scholar
  7. 7.
    Martinez JS, Kohler PF. Variant “Goodpasture’s syndrome”? The need for immunologic criteria in rapidly progressive glomerulonephritis and hemorrhagic pneumonitis. Ann Intern Med. 1971;75(1):67–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Whitworth JA, Morel-Maroger L, Mignon F, Richet G. The significance of extracapillary proliferation. Clinicopathological review of 60 patients. Nephron. 1976;16(1):1–19.CrossRefPubMedGoogle Scholar
  9. 9.
    Stilmant MM, Bolton WK, Sturgill BC, Schmitt GW, Couser WG. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. 1979;15(2):184–95.CrossRefPubMedGoogle Scholar
  10. 10.
    Cunningham 3rd RJ, Gilfoil M, Cavallo T, Brouhard BH, Travis LB, Berger M, et al. Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature. Pediatr Res. 1980;14(2):128–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Davies DJ, Moran JE, Niall JF, Ryan GB. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed). 1982;285(6342):606.CrossRefGoogle Scholar
  12. 12.
    Croker BP, Lee T, Gunnells JC. Clinical and pathologic features of polyarteritis nodosa and its renal-limited variant: primary crescentic and necrotizing glomerulonephritis. Hum Pathol. 1987;18(1):38–44.CrossRefPubMedGoogle Scholar
  13. 13.
    Chen KT. Renal-limited polyarteritis nodosa. Hum Pathol. 1987;18(10):1074–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Jennette JC, Falk RJ. The pathology of vasculitis involving the kidney. Am J Kidney Dis. 1994;24(1):130–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Feehally J, Wheeler DC, Wallis J, Jones S, Lockwood CM, Savage CO. A case of microscopic polyarteritis associated with antineutrophil cytoplasmic antibodies. Clin Nephrol. 1987;27(4):214–5.PubMedGoogle Scholar
  16. 16.
    Walters MD, Savage CO, Dillon MJ, Lockwood CM, Barratt TM. Antineutrophil cytoplasm antibody in crescentic glomerulonephritis. Arch Dis Child. 1988;63(7):814–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988;318(25):1651–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, Hack CE, van den Ende ME, Kallenberg CG, et al. Wegener’s granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest. 1989;84(5):1577–87.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Charles LA, Falk RJ, Jennette JC. Reactivity of anti-neutrophil cytoplasmic autoantibodies with HL-60 cells. Clin Immunol Immunopathol. 1989;53(2 Pt 1):243–53.CrossRefPubMedGoogle Scholar
  20. 20.
    Hogan SL, Nachman PH, Wilkman AS, Jennette JC, Falk RJ. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. 1996;7(1):23–32.PubMedGoogle Scholar
  21. 21.
    Hauer HA, Bajema IM, van Houwelingen HC, Ferrario F, Noël LH, Waldherr R, et al. Renal histology in ANCA-associated vasculitis: differences between diagnostic and serologic subgroups. Kidney Int. 2002;61(1):80–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Vizjak A, Rott T, Koselj-Kajtna M, Rozman B, Kaplan-Pavlovcic S, Ferluga D. Histologic and immunohistologic study and clinical presentation of ANCA-associated glomerulonephritis with correlation to ANCA antigen specificity. Am J Kidney Dis. 2003;41(3):539–49.CrossRefPubMedGoogle Scholar
  23. 23.
    Haas M, Eustace JA. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004;65(6):2145–52.CrossRefPubMedGoogle Scholar
  24. 24.
    Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11.CrossRefPubMedGoogle Scholar
  25. 25.
    Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628–36.CrossRefPubMedGoogle Scholar
  26. 26.
    Eleftheriou D, Dillon MJ, Tullus K, Marks SD, Pilkington CA, Roebuck DJ, et al. Systemic polyarteritis nodosa in the young: a single-center experience over thirty-two years. Arthritis Rheum. 2013;65(9):2476–85.CrossRefPubMedGoogle Scholar
  27. 27.
    Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol. 1997;8(2):314–22.PubMedGoogle Scholar
  28. 28.
    Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65(7):936–41.CrossRefPubMedGoogle Scholar
  29. 29.
    Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990;87(11):4115–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Charles LA, Caldas ML, Falk RJ, Terrell RS, Jennette JC. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol. 1991;50(6):539–46.PubMedGoogle Scholar
  31. 31.
    Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int. 1992;41(2):375–83.CrossRefPubMedGoogle Scholar
  32. 32.
    Johnson PA, Alexander HD, McMillan SA, Maxwell AP. Up-regulation of the endothelial cell adhesion molecule intercellular adhesion molecule-1 (ICAM-1) by autoantibodies in autoimmune vasculitis. Clin Exp Immunol. 1997;108(2):234–42.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rarok AA, Limburg PC, Kallenberg CG. Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies. J Leukoc Biol. 2003;74(1):3–15.CrossRefPubMedGoogle Scholar
  34. 34.
    Schreiber A, Pham CT, Hu Y, Schneider W, Luft FC, Kettritz R. Neutrophil serine proteases promote IL-1β generation and injury in necrotizing crescentic glomerulonephritis. J Am Soc Nephrol. 2012;23(3):470–82.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Schlieben DJ, Korbet SM, Kimura RE, Schwartz MM, Lewis EJ. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis. 2005;45(4):758–61.CrossRefPubMedGoogle Scholar
  36. 36.
    van Paassen P, Tervaert JW, Heeringa P. Mechanisms of vasculitis: how pauci-immune is ANCA-associated renal vasculitis? Nephron Exp Nephrol. 2007;105(1):e10–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Kain R, Matsui K, Exner M, Binder S, Schaffner G, Sommer EM, et al. A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells. J Exp Med. 1995;181(2):585–97.CrossRefPubMedGoogle Scholar
  38. 38.
    Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008;14(10):1088–96.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kain R, Tadema H, McKinney EF, Benharkou A, Brandes R, Peschel A, et al. High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibody-associated vasculitis. J Am Soc Nephrol. 2012;23(3):556–66.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Kessenbrock K, Krumbholz M, Schönermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623–5.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Knight A, Sandin S, Askling J. Risks and relative risks of Wegener’s granulomatosis among close relatives of patients with the disease. Arthritis Rheum. 2008;58(1):302–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Willcocks LC, Lyons PA, Rees AJ, Smith KG. The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis. Arthritis Res Ther. 2010;12(1):202.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Heckmann M, Holle JU, Arning L, Knaup S, Hellmich B, Nothnagel M, et al. The Wegener’s granulomatosis quantitative trait locus on chromosome 6p21.3 as characterised by tagSNP genotyping. Ann Rheum Dis. 2008;67(7):972–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Audrain MA, Sesboüé R, Baranger TA, Elliott J, Testa A, Martin JP, et al. Analysis of anti-neutrophil cytoplasmic antibodies (ANCA): frequency and specificity in a sample of 191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects. Nephrol Dial Transplant. 2001;16(1):39–44.CrossRefPubMedGoogle Scholar
  46. 46.
    Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214–23.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    McCormic RV. Periarteritis occurring during propylthyourasil treatment. JAMA. 1950;144(17):1453–4.CrossRefGoogle Scholar
  48. 48.
    Dolman KM, Gans RO, Vervaat TJ, Zevenbergen G, Maingay D, Nikkels RE, et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet. 1993;342(8872):651–2.CrossRefPubMedGoogle Scholar
  49. 49.
    Vogt BA, Kim Y, Jennette JC, Falk RJ, Burke BA, Sinaiko A. Antineutrophil cytoplasmic autoantibody-positive crescentic glomerulonephritis as a complication of treatment with propylthiouracil in children. J Pediatr. 1994;124(6):986–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Fujieda M, Hattori M, Kurayama H, Koitabashi Y, Members and Coworkers of the Japanese Society for Pediatric Nephrology. Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody-positive glomerulonephritis associated with propylthiouracil treatment. J Am Soc Nephrol. 2002;13(2):437–45.PubMedGoogle Scholar
  51. 51.
    Wang C, Gou SJ, Xu PC, Zhao MH, Chen M. Epitope analysis of anti-myeloperoxidase antibodies in propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res Ther. 2013;15(6):R196.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yu F, Chen M, Gao Y, Wang SX, Zou WZ, Zhao MH, et al. Clinical and pathological features of renal involvement in propylthiouracil-associated ANCA-positive vasculitis. Am J Kidney Dis. 2007;49(5):607–14.CrossRefPubMedGoogle Scholar
  53. 53.
    Hogan SL, Cooper GS, Savitz DA, Nylander-French LA, Parks CG, Chin H, et al. Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. Clin J Am Soc Nephrol. 2007;2(2):290–9.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. 1994;120(1):12–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Gendelman S, Zeft A, Spalding SJ. Childhood-onset eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): a contemporary single-center cohort. J Rheumatol. 2013;40(6):929–35.CrossRefPubMedGoogle Scholar
  56. 56.
    Vanoni F, Bettinelli A, Keller F, Bianchetti MG, Simonetti GD. Vasculitides associated with IgG antineutrophil cytoplasmic autoantibodies in childhood. Pediatr Nephrol. 2010;25(2):205–12.CrossRefPubMedGoogle Scholar
  57. 57.
    Hattori M, Kurayama H, Koitabashi Y, Japanese Society for Pediatric Nephrology. Antineutrophil cytoplasmic autoantibody-associated glomerulonephritis in children. J Am Soc Nephrol. 2001;12(7):1493–500.PubMedGoogle Scholar
  58. 58.
    Eleftheriou D, Dillon MJ, Brogan PA. Advances in childhood vasculitis. Curr Opin Rheumatol. 2009;21(4):411–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Tullus K, Marks SD. Vasculitis in children and adolescents: clinical presentation, etiopathogenesis, and treatment. Paediatr Drugs. 2009;11(6):375–80.CrossRefPubMedGoogle Scholar
  60. 60.
    Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines – application to the individual patient. Kidney Int. 2012;82(8):840–56.CrossRefPubMedGoogle Scholar
  61. 61.
    Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniex, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36–44.CrossRefPubMedGoogle Scholar
  62. 62.
    Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. 1996;7(1):33–9.PubMedGoogle Scholar
  63. 63.
    Yu F, Huang JP, Zou WZ, Zhao MH. The clinical features of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese children. Pediatr Nephrol. 2006;21(4):497–502.CrossRefPubMedGoogle Scholar
  64. 64.
    Siomou E, Tramma D, Bowen C, Milford DV. ANCA-associated glomerulonephritis/systemic vasculitis in childhood: clinical features-outcome. Pediatr Nephrol. 2012;27(10):1911–20.CrossRefPubMedGoogle Scholar
  65. 65.
    Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007;18(7):2180–8.CrossRefPubMedGoogle Scholar
  66. 66.
    de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670–80.CrossRefPubMedGoogle Scholar
  67. 67.
    Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol. 2010;11:12.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Jones RB, Tervaert JW, Hauser T, Lugmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211–20.CrossRefPubMedGoogle Scholar
  69. 69.
    Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417–27.CrossRefPubMedGoogle Scholar
  71. 71.
    Glöckner WM, Sieberth HG, Wichmann HE, Backes E, Bambauer R, Boesken WH, et al. Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: a controlled, multi-center study. Clin Nephrol. 1988;29(1):1–8.PubMedGoogle Scholar
  72. 72.
    Cole E, Cattran D, Magil A, Greenwood C, Churchill D, Sutton D, et al. A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis. 1992;20(3):261–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Walsh M, Catapano F, Szpirt W, Thorlund K, Bruchfeld A, Guillevin L, et al. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis. 2011;57(4):566–74.CrossRefPubMedGoogle Scholar
  74. 74.
    Westman KW, Bygren PG, Olsson H, Ranstam J, Wieslander J. Relapse rate, renal survival, and cancer morbidity in patients with Wegener’s granulomatosis or microscopic polyangiitis with renal involvement. J Am Soc Nephrol. 1998;9(5):842–52.PubMedGoogle Scholar
  75. 75.
    Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304(21):2381–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of PediatricsNihon University Itabashi HospitalTokyoJapan
  2. 2.Department of Kidney and Vascular PathologyUniversity of TsukubaTsukuba-CityJapan
  3. 3.Department of PediatricsNihon University School of MedicineTokyoJapan

Personalised recommendations