Association between anti-β2 glycoprotein I antibodies and renal glomerular C4d deposition in lupus nephritis patients with glomerular microthrombosis: a prospective study of 155 cases

Abstract

Glomerular microthrombosis (GMT) is a common vascular change in patients with lupus nephritis (LN). The mechanism underlying GMT is still unknown. In our previous study, we found that the level of IgG anti-β2 glycoprotein I (β2GPI) antibodies was higher in the LN-GMT group than in the LN-non-GMT group, which indicated that anti-β2GPI antibodies may play a role in GMT formation. Many studies have demonstrated that the activation of the classical complement pathway may play a critical role in fetal loss and aPL-induced thrombosis formation. To investigate whether complement activation plays a role in GMT formation and to evaluate its relationship with aPL, we prospectively investigated deposition of C4d in 155 renal biopsy specimens of LN patients. The results revealed a strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi (p < 0.001). The detection rate of IgG anti-β2GPI antibodies was higher in the LN-GMT group than in the LN-non-GMT group (p < 0.05). Further, the intensity of glomerular C4d staining was significantly related with IgG anti-β2GPI antibodies (p < 0.05). The results of our study suggest that anti-β2GPI antibodies may play a role in GMT formation, and this process might involve complement activation. Lupus (2010) 19, 1195—1203.

Keywords

anti-β2 glycoprotein I antibodies C4d glomerular microthrombosis lupus nephritis

Get full access to this article

View all access options for this article.

References

Mok CC Prognostic factors in lupus nephritis. Lupus 2005; 14: 39-44.

Cameron JS Lupus nephritis. J Am Soc Nephrol 1999; 10: 413-424.

Jain R. , Chartash E. , Susin M. , Furie R. Systemic lupus erythematosus complicated by thrombotic microangiopathy. Semin Arthritis Rheum 1994; 24: 173-182.

Hughson MD , Nadasdy T. , McCarty GA , Sholer C. , Min KW , Silva F. Renal thrombotic microangiopathy in patients with systemic lupus erythematosus and the antiphospholipid syndrome. Am J Kidney Dis 1992; 20: 150-158.

Loizou S. , Samarkos M. , Norsworthy PJ , Cazabon JK , Walport MJ , Davies KA Significance of anticardiolipin and anti-beta2-glycoprotein I antibodies in lupus nephritis. Rheumatology (Oxford ) 2000; 39: 962-968.

Nochy D. , Daugas E. , Huong DL , Piette JC , Hill G. Kidney involvement in the antiphospholipid syndrome. J Autoimmun 2000; 15: 127-132.

Tektonidou MG , Sotsiou F. , Nakopoulou L. , Vlachoyiannopoulos PG , Moutsopoulos HM Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum 2004; 50: 2569-2579.

Bhandari S. , Harnden P. , Brownjohn AM , Turney JH Association of anticardiolipin antibodies with intraglomerular thrombi and renal dysfunction in lupus nephritis. QJM 1998; 91: 401-409.

Cohen D. , Koopmans M. , Kremer Hovinga IC , et al. Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis. Arthritis Rheum 2008; 58: 2460-2469.

10.

Gong R. , Liu Z. , Li L. Epistatic effect of plasminogen activator inhibitor 1 and beta-fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: interaction with environmental/ clinical factors. Arthritis Rheum 2007; 56: 1608-1617.

11.

Miranda JM , Garcia-Torres R. , Jara LJ , Medina F. , Cervera H. , Fraga A. Renal biopsy in systemic lupus erythematosus: significance of glomerular thrombosis. Analysis of 108 cases. Lupus 1994; 3: 25-29.

12.

Zheng H. , Chen Y. , Ao W. , et al. Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study of 124 cases. Arthritis Res Ther 2009; 11: R93.

13.

Pierangeli SS , Girardi G. , Vega-Ostertag M. , Liu X. , Espinola RG , Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum 2005; 52: 2120-2124.

14.

Pierangeli SS , Chen PP , Gonzalez EB Antiphospholipid antibodies and the antiphospholipid syndrome: an update on treatment and pathogenic mechanisms. Curr Opin Hematol 2006; 13: 366-375.

15.

Navratil JS , Manzi S. , Kao AH , et al. Platelet C4d is highly specific for systemic lupus erythematosus. Arthritis Rheum 2006; 54: 670-674.

16.

Peerschke EI , Yin W. , Alpert DR , Roubey RA , Salmon JE , Ghebrehiwet B. Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 2009; 18: 530-538.

17.

Feucht HE , Opelz G. The humoral immune response towards HLA class II determinants in renal transplantation . Kidney Int 1996; 50: 1464-1475.

18.

Racusen LC , Colvin RB , Solez K. , et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3: 708-714.

19.

Hochberg MC Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

20.

Salmon JE , Girardi G. Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation . J Reprod Immunol 2008; 77: 51-56.

21.

Weening JJ , D’Agati VD , Schwartz MM , et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241-250.

22.

Austin HA , Muenz LR , Joyce KM , Antonovych TT , Balow JE Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int 1984; 25: 689-695.

23.

Wakai S. , Matsumura O. , Koike T. , Maruyama N. , Yumura W. Anti-cardiolipin antibody and renal microthrombi in lupus nephritis. Ryumachi 1991; 31: 481-487.

24.

Kant KS , Pollak VE , Weiss MA , Glueck HI , Miller AN , Hess EV Glomerular thrombosis in systemic lupus erythematosus: prevalence and significance . Medicine (Baltimore) 1981; 60: 71-86.

25.

Levine JS , Branch DW , Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752-763.

26.

Giannakopoulos B. , Passam F. , Rahgozar S. , Krilis SA Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood 2007; 109: 422-430.

27.

Truedsson L. , Bengtsson AA , Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 2007; 40: 560-566.

28.

Yang DH , Chang DM , Lai JH , Lin FH , Chen CH Usefulness of erythrocyte-bound C4d as a biomarker to predict disease activity in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2009; 48: 1083-1087.

29.

Pierangeli SS , Colden-Stanfield M. , Liu X. , Barker JH , Anderson GL , Harris EN Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 1999; 99: 1997-2002.

30.

Nangaku M. , Quigg RJ , Shankland SJ , Okada N. , Johnson RJ , Couser WG Overexpression of Crry protects mesangial cells from complement-mediated injury . J Am Soc Nephrol 1997; 8: 223-233.

31.

Fischetti F. , Durigutto P. , Pellis V. , et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor . Blood 2005; 106: 2340-2346.

32.

Seshan SV , Franzke CW , Redecha P. , Monestier M. , Mackman N. , Girardi G. Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies. Blood 2009 ; 114: 1675-1683.

33.

Suzuki T. , Horita S. , Kadoya K. , et al. C4d Immunohistochemistry in glomerulonephritis with different antibodies. Clin Exp Nephrol 2007; 11: 287-291.

34.

Zwirner J. , Felber E. , Herzog V. , Riethmuller G. , Feucht HE Classical pathway of complement activation in normal and diseased human glomeruli . Kidney Int 1989; 36: 1069-1077.

35.

Kusunoki Y. , Itami N. , Tochimaru H. , Takekoshi Y. , Nagasawa S. , Yoshiki T. Glomerular deposition of C4 cleavage fragment (C4d) and C4-binding protein in idiopathic membranous glomerulonephritis. Nephron 1989; 51: 17-19.