C4d和供者特异性抗体检测在肾移植抗体介导排斥反应中的应用研究进展
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摘要
抗体介导排斥反应(AMR)已经成为导致移植物丢失的主要原因。C4d在管周毛细血管(PTC)部位沉积是肾移植体液免疫活跃的标志,单纯C4d阳性不能确诊为AMR,当临床上出现循环供者特异性抗体(DSA)、病理特征和/或移植肾功能不全时必须考虑AMR。C4d和DSA检测阳性与移植物存活率下降密切相关,特别是在检测时就出现移植物功能不全者。本文主要围绕C4d和DSA检测在肾移植AMR中的应用研究作一综述。
Antibody-mediated rejection( AMR) has become a main reason in graft loss. The detection of C4 d deposition in peritubular capillarie( PTC) is a valuable marker of humoral activity in the renal allograft. C4 d positivity alone is nondiagnostic for antibody-mediated rejection. Presence of circulating HLA donor-specific antibody( DSA),histologic features,and/or graft dysfunction must be considered in the context of the clinical scenario. C4 d positivity and DSA,particularly complement fixing,are associated with decreased allograft survival,particularly when detected in the setting of graft dysfunction.
Antibody-mediated rejection( AMR) has become a main reason in graft loss. The detection of C4 d deposition in peritubular capillarie( PTC) is a valuable marker of humoral activity in the renal allograft. C4 d positivity alone is nondiagnostic for antibody-mediated rejection. Presence of circulating HLA donor-specific antibody( DSA),histologic features,and/or graft dysfunction must be considered in the context of the clinical scenario. C4 d positivity and DSA,particularly complement fixing,are associated with decreased allograft survival,particularly when detected in the setting of graft dysfunction.
引文
1 Sethi S,Hernandez LH,Alexander MP,et al.C4d as a marker for masked immune deposits[J].Kidney International,2016,90(1):223-224.
2 Sellarés J,de Freitas DG,Mengel M,et al.Understanding the causes of kidney transplant failure:the dominant role antibody mediated rejection and nonadhererence[J].Am J Transplant,2012,12(2):388-399.
3 González-Molina M,Ruiz-Esteban P,Caballero A,et al.Immune response and histology of humoral rejection in kidney transplantation[J].Nefrologia,2016,36(4):354-367.
4 Kikic'Z,Kozakowski N,Regele H,et al.Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts[J].Transpl Int,2014,27(3):312-321.
5 Hattori Y,Bucy RP,Kubota Y,et al.Antibody-mediated rejection of single classⅠMHC-disparate cardiac allografts[J].Am J Transplant,2012,12(8):2017-2028.
6 Mengel M,Sis B,Haas M,et al.Banff 2011 meeting report:new concepts in antibody-mediated rejection[J].Am J Transplant,2012,12(3):563-570.
7 Haas M,Sis B,Racusen LC,et al.Banff 2013 meeting report:inclusion of c4d-negative antibody-mediated rejection and antibodyassociated arterial lesions[J].Am J Transplant,2014,14(2):272-283.
8 Loupy A,Lefaucheur C,Vernerey D,et al.Complement-binding anti-HLA antibodies and kidney-allograft survival[J].N Engl J Med,2013,369(13):1215-1226.
9 Haas M.The significance of C4d staining with minimal histologic abnormalities[J].Curr Opin Organ Transplant,2010,15(1):21-27
10 Magil AB.Infiltrating cell types in transplant glomerulitis:relationship to peritubular capillary C4d deposition[J].Am J Kidney Dis,2005,45(6):1084.
11 Sund S,Reisaeter AV,Scott H,et al.Glomerular monocyte/macrophage influx correlates strongly with complement activation in 1-week protocol kidney allograft biopsies[J].Clin Nephrol,2004,62(2):121-130.
12 Desvaux D,Le Gouvello S,Pastural M,et al.Acute renal allograft rejections with major interstitial oedema and plasma cell-rich infiltrates:high gamma-interferon expression and poor clinical outcome[J].Nephrol Dial Transplant,2004,19(4):933-939.
13 Jordan SC,Vo AA.Donor-specific antibodies in allograft recipients:etiology,impact and therapeutic approaches[J].Curr Opin Organ Transplant,2014,19(6):591-597.
14 Sapir-Pichhadze R,Pcurran S,John R,et al.A systematic review of the role of C4d in the diagnosis of acuteantibody-mediated rejection[J].Kidney international,2015,67(1):182-194.
15 Regele H,Exner M,Watschinger B,et al.Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection[J].Nephrol Dial Transplant,2001,16(10):2058-2066.
16 Pedraza N,Girón F,Baez Y,et al.Positive C4d in kidney transplantation biopsy:clinical impact[J].Transplant Proc,2014,46(9):2966-2971.
17 Feucht HE,Felber E,Gokel MJ,et al.Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection[J].Clin Exp Immunol,1991,86(3):464-470.
18 Feucht HE,Schneeberger H,Hillebrand G,et al.Capillary deposition of C4d complement fragment and early renal graft loss[J].Kidney Int,1993,43(6):1333-1338.
19 Crespo M,Pascual M,Tolkoff-Rubin N,et al.Acute humoral rejection in renal allograft recipients:Ⅰ.Incidence,serology and clinical characteristics[J].Transplantation,2001,71(5):652-658.
20 Haas M,Rahman MH,Racusen LC,et al.C4d and C3d staining in biopsies of ABO-and HLA-incompatible renal allografts:correlation with histologic findings[J].Am J Transplant,2006,7(3):724.
21 Zhang Q,Liang LW,Gjertson DW,et al.Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction[J].Transplantation,2005,79(5):591-598.
22 Mohan S,Palanisamy A,Tsapepas D,et al.Donor-specific antibodies adversely affect kidney allograft outcomes[J].J Am Soc Nephrol,2012,23(12):2061-2071.
23 Wiebe C,Gibson IW,Blydt-Hansen TD,et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant[J].Am J Transplant,2012,12(5):1157-1167.
24 Loupy A,Lefaucheur C,Vernerey D,et al.Complement-binding anti-HLA antibodies and kidney-allograft survival[J].N Engl J Med,2013,369(13):1215-1226.
25 Feucht HE.Complement C4d in graft capillaries-the missing link in the recognition of humoral alloreactivity[J].Am J Transplant,2003,3(6):646-652.
26 Dragun D,Müller DN,Brsen JH,et al.AngiotensinⅡtype 1-receptor activating antibodies in renal-allograft rejection[J].N Engl J Med,2005,352(352):2027-2028.
27 Fuss A,Hope CM,Deayton S,et al.C4d-negative antibodymediated rejection with high anti-angiotensinⅡtypeⅠreceptor antibodies in absence of donor-specific antibodies[J].Nephrology,2015,20(7):467-473.
28 廖涛,启全.移植肾抗体介导的排斥反应的发病机制研究进展[J].器官移植,2015,6(4):276-282.
29 Martin L,Guignier F,Bocrie O,et al.Detection of anti-HLA antibodies with flow cytometry in needle core biopsies of renal transplants recipients with chronic allograft nephropathy[J].Transplantation,2005,79(10):1459-1461.
30 Verghese P,Dunn T,Najafian B,et al.The impact of C4d and microvascular inflammation before we knew them[J].Clinical Transplantation,2013,27(3):388-396.
31 Loupy A,Hill GS,Suberbielle C,et al.Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies(DSA)[J].Am J Transplant,2011,11(1):56-65.
32 de Kort H,Willicombe M,Brookes P,et al.Microcirculation inflammation associates with outcome in renal transplant patients with de novo donor-specific antibodies[J].Am J Transplant,2013,3(2):485-492.
33 Sis B,Jhangri GS,Bunnag S,et al.Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining[J].Am J Transplant,2009,9(10):2312-2323.
34 Mauiyyedi S,Crespo M,Collins AB,et al.Acute humoral rejection in kidney transplantation:Ⅱ.Morphology,immunopathology,and pathologic classification[J].J Am Soc Nephrol,2002,13(3):779-787.
35 Sampaio WLV,Mazzali M.C4d Deposits in borderline rejection:an early marker for chronic renal dysfunction?[J].Transplant Proc,2014,46(6):1710-1712.
36 B9hmig GA,Exner M,Habicht A,et al.Capillary C4d deposition in kidney allografts:a specific marker of alloantibody-dependent graft injury[J].J Am Soc Nephrol,2002,13(4):1091-1099.
37 Kedainis RL,Koch MJ,Brennan DC,et al.Focal C4d+in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival[J].Am J Transplant,2009,9(4):812-819.
38 Legendre C.Antibody-mediated vascular rejection of kidney allograft:characterization of different kidney allograft rejection phenotypes via histology,C4d deposition and donor-specific antibodies[J].Clin Exp Immunol,2014,178(S1):59-60.
2 Sellarés J,de Freitas DG,Mengel M,et al.Understanding the causes of kidney transplant failure:the dominant role antibody mediated rejection and nonadhererence[J].Am J Transplant,2012,12(2):388-399.
3 González-Molina M,Ruiz-Esteban P,Caballero A,et al.Immune response and histology of humoral rejection in kidney transplantation[J].Nefrologia,2016,36(4):354-367.
4 Kikic'Z,Kozakowski N,Regele H,et al.Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts[J].Transpl Int,2014,27(3):312-321.
5 Hattori Y,Bucy RP,Kubota Y,et al.Antibody-mediated rejection of single classⅠMHC-disparate cardiac allografts[J].Am J Transplant,2012,12(8):2017-2028.
6 Mengel M,Sis B,Haas M,et al.Banff 2011 meeting report:new concepts in antibody-mediated rejection[J].Am J Transplant,2012,12(3):563-570.
7 Haas M,Sis B,Racusen LC,et al.Banff 2013 meeting report:inclusion of c4d-negative antibody-mediated rejection and antibodyassociated arterial lesions[J].Am J Transplant,2014,14(2):272-283.
8 Loupy A,Lefaucheur C,Vernerey D,et al.Complement-binding anti-HLA antibodies and kidney-allograft survival[J].N Engl J Med,2013,369(13):1215-1226.
9 Haas M.The significance of C4d staining with minimal histologic abnormalities[J].Curr Opin Organ Transplant,2010,15(1):21-27
10 Magil AB.Infiltrating cell types in transplant glomerulitis:relationship to peritubular capillary C4d deposition[J].Am J Kidney Dis,2005,45(6):1084.
11 Sund S,Reisaeter AV,Scott H,et al.Glomerular monocyte/macrophage influx correlates strongly with complement activation in 1-week protocol kidney allograft biopsies[J].Clin Nephrol,2004,62(2):121-130.
12 Desvaux D,Le Gouvello S,Pastural M,et al.Acute renal allograft rejections with major interstitial oedema and plasma cell-rich infiltrates:high gamma-interferon expression and poor clinical outcome[J].Nephrol Dial Transplant,2004,19(4):933-939.
13 Jordan SC,Vo AA.Donor-specific antibodies in allograft recipients:etiology,impact and therapeutic approaches[J].Curr Opin Organ Transplant,2014,19(6):591-597.
14 Sapir-Pichhadze R,Pcurran S,John R,et al.A systematic review of the role of C4d in the diagnosis of acuteantibody-mediated rejection[J].Kidney international,2015,67(1):182-194.
15 Regele H,Exner M,Watschinger B,et al.Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection[J].Nephrol Dial Transplant,2001,16(10):2058-2066.
16 Pedraza N,Girón F,Baez Y,et al.Positive C4d in kidney transplantation biopsy:clinical impact[J].Transplant Proc,2014,46(9):2966-2971.
17 Feucht HE,Felber E,Gokel MJ,et al.Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection[J].Clin Exp Immunol,1991,86(3):464-470.
18 Feucht HE,Schneeberger H,Hillebrand G,et al.Capillary deposition of C4d complement fragment and early renal graft loss[J].Kidney Int,1993,43(6):1333-1338.
19 Crespo M,Pascual M,Tolkoff-Rubin N,et al.Acute humoral rejection in renal allograft recipients:Ⅰ.Incidence,serology and clinical characteristics[J].Transplantation,2001,71(5):652-658.
20 Haas M,Rahman MH,Racusen LC,et al.C4d and C3d staining in biopsies of ABO-and HLA-incompatible renal allografts:correlation with histologic findings[J].Am J Transplant,2006,7(3):724.
21 Zhang Q,Liang LW,Gjertson DW,et al.Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction[J].Transplantation,2005,79(5):591-598.
22 Mohan S,Palanisamy A,Tsapepas D,et al.Donor-specific antibodies adversely affect kidney allograft outcomes[J].J Am Soc Nephrol,2012,23(12):2061-2071.
23 Wiebe C,Gibson IW,Blydt-Hansen TD,et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant[J].Am J Transplant,2012,12(5):1157-1167.
24 Loupy A,Lefaucheur C,Vernerey D,et al.Complement-binding anti-HLA antibodies and kidney-allograft survival[J].N Engl J Med,2013,369(13):1215-1226.
25 Feucht HE.Complement C4d in graft capillaries-the missing link in the recognition of humoral alloreactivity[J].Am J Transplant,2003,3(6):646-652.
26 Dragun D,Müller DN,Brsen JH,et al.AngiotensinⅡtype 1-receptor activating antibodies in renal-allograft rejection[J].N Engl J Med,2005,352(352):2027-2028.
27 Fuss A,Hope CM,Deayton S,et al.C4d-negative antibodymediated rejection with high anti-angiotensinⅡtypeⅠreceptor antibodies in absence of donor-specific antibodies[J].Nephrology,2015,20(7):467-473.
28 廖涛,启全.移植肾抗体介导的排斥反应的发病机制研究进展[J].器官移植,2015,6(4):276-282.
29 Martin L,Guignier F,Bocrie O,et al.Detection of anti-HLA antibodies with flow cytometry in needle core biopsies of renal transplants recipients with chronic allograft nephropathy[J].Transplantation,2005,79(10):1459-1461.
30 Verghese P,Dunn T,Najafian B,et al.The impact of C4d and microvascular inflammation before we knew them[J].Clinical Transplantation,2013,27(3):388-396.
31 Loupy A,Hill GS,Suberbielle C,et al.Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies(DSA)[J].Am J Transplant,2011,11(1):56-65.
32 de Kort H,Willicombe M,Brookes P,et al.Microcirculation inflammation associates with outcome in renal transplant patients with de novo donor-specific antibodies[J].Am J Transplant,2013,3(2):485-492.
33 Sis B,Jhangri GS,Bunnag S,et al.Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining[J].Am J Transplant,2009,9(10):2312-2323.
34 Mauiyyedi S,Crespo M,Collins AB,et al.Acute humoral rejection in kidney transplantation:Ⅱ.Morphology,immunopathology,and pathologic classification[J].J Am Soc Nephrol,2002,13(3):779-787.
35 Sampaio WLV,Mazzali M.C4d Deposits in borderline rejection:an early marker for chronic renal dysfunction?[J].Transplant Proc,2014,46(6):1710-1712.
36 B9hmig GA,Exner M,Habicht A,et al.Capillary C4d deposition in kidney allografts:a specific marker of alloantibody-dependent graft injury[J].J Am Soc Nephrol,2002,13(4):1091-1099.
37 Kedainis RL,Koch MJ,Brennan DC,et al.Focal C4d+in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival[J].Am J Transplant,2009,9(4):812-819.
38 Legendre C.Antibody-mediated vascular rejection of kidney allograft:characterization of different kidney allograft rejection phenotypes via histology,C4d deposition and donor-specific antibodies[J].Clin Exp Immunol,2014,178(S1):59-60.