特发性膜性肾病血清抗磷脂酶A_2受体抗体与免疫治疗关系的研究
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摘要
目的:观察特发性膜性肾病(idiopathic membranous nephropathy,IMN)血清抗磷脂酶A_2受体(phospholipase A_2 receptor,PLA_2R)抗体表达情况,探讨血清抗PLA_2R抗体和免疫治疗疗效的关系。方法:选取经肾活检确诊为IMN的患者60例,用间接免疫荧光法检测血清抗PLA_2R抗体,免疫组织化学染色后观察肾组织PLA_2R的表达。根据血清抗PLA_2R抗体检测结果,将患者分为血清抗PLA_2R抗体阳性组44例,血清抗PLA_2R抗体阴性组16例,均给予激素联合环磷酰胺方案治疗,疗程12个月。观察治疗前后24 h尿蛋白、血清白蛋白、血肌酐、估计肾小球滤过率(glomerular filtration rate,eGFR)变化以及血清抗PLA_2R抗体转阴情况。结果:(1)60例IMN患者在基线时检测血清抗PLA_2R抗体阳性为44例,阳性率73.3%。基线时血清抗PLA_2R抗体阳性患者肾组织PLA_2R表达也呈阳性。(2)抗PLA_2R抗体阴性组患者24 h尿蛋白、血白蛋白恢复情况优于抗PLA_2R抗体阳性组(P<0.05)。(3)治疗6个月后抗PLA_2R抗体阳性和阴性组总缓解率分别为47.7%和93.9%,治疗12个月总缓解率分别为56.8%和100%。结论:血清抗PLA_2R抗体是IMN的特异性生物标志物。血清抗PLA_2R抗体阳性的患者免疫治疗效果差。IMN患者检测血清抗PLA_2R抗体有助于判断病情,对于治疗策略的选择和病情的监测具有重要意义。
Objective:To observe the expression of serum anti-phospholipase A_2 receptor(PLA_2R) antibodies in idiopathic membranous nephropathy(IMN),and also to explore the relationship between serum anti-PLA_2R antibodies and immunotherapy.Methods:Serum anti-PLA_2R antibodies and immunohistochemical staining were used to detect the expression levels of anti-PLA_2R antibodies in the renal tissue of 60 IMN patients. According to the detection results of serum anti-PLA_2R antibodies,they were divided into the positive group(44 cases) and the negative group(16 cases). The two groups were all treated with hormone combined with cyclophosphamide for a treatment course of 12 months.The changes in 24-h urinary protein,serum albumin,serum creatinine and glomerular filtration rate(eGFR) were observed before and after the treatment. And negative turning of serum anti-PLA_2R antibodies before and after the treatment was also observed.Results:(1) Of the 60 patients with IMN,there were 44 patients with positive serum anti-PLA_2R antibodies at baseline,with a positive rate of 73.3%. The expression of anti-PLA_2R antibodies in the renal tissue of the patients with positive serum anti-PLA_2R antibodies was also positive at baseline.(2) 24-h urinary protein and serum albumin recovery of the patients in the negative group were better than those in the positive group(P<0.05).(3)The total remission rates of the anti-PLA_2R antibodies in the positive group and the negative group were 47.7% and 93.9% respectively after 6 months of the treatment,and total remission rates of the 2 groups were 56.8% and 100% respectively after 12 months of the treatment.Conclusion:Serum anti-PLA_2R antibodies is a specific biomarker of IMN. Patients with positive serum anti-PLA_2R antibodies show poor immunotherapy effect. Detection of serum anti-PLA_2R antibodies in the IMN patients is helpful to judge the illness condition of the patient,and is of great importance for the choice of treatment strategy and monitoring of the disease.
Objective:To observe the expression of serum anti-phospholipase A_2 receptor(PLA_2R) antibodies in idiopathic membranous nephropathy(IMN),and also to explore the relationship between serum anti-PLA_2R antibodies and immunotherapy.Methods:Serum anti-PLA_2R antibodies and immunohistochemical staining were used to detect the expression levels of anti-PLA_2R antibodies in the renal tissue of 60 IMN patients. According to the detection results of serum anti-PLA_2R antibodies,they were divided into the positive group(44 cases) and the negative group(16 cases). The two groups were all treated with hormone combined with cyclophosphamide for a treatment course of 12 months.The changes in 24-h urinary protein,serum albumin,serum creatinine and glomerular filtration rate(eGFR) were observed before and after the treatment. And negative turning of serum anti-PLA_2R antibodies before and after the treatment was also observed.Results:(1) Of the 60 patients with IMN,there were 44 patients with positive serum anti-PLA_2R antibodies at baseline,with a positive rate of 73.3%. The expression of anti-PLA_2R antibodies in the renal tissue of the patients with positive serum anti-PLA_2R antibodies was also positive at baseline.(2) 24-h urinary protein and serum albumin recovery of the patients in the negative group were better than those in the positive group(P<0.05).(3)The total remission rates of the anti-PLA_2R antibodies in the positive group and the negative group were 47.7% and 93.9% respectively after 6 months of the treatment,and total remission rates of the 2 groups were 56.8% and 100% respectively after 12 months of the treatment.Conclusion:Serum anti-PLA_2R antibodies is a specific biomarker of IMN. Patients with positive serum anti-PLA_2R antibodies show poor immunotherapy effect. Detection of serum anti-PLA_2R antibodies in the IMN patients is helpful to judge the illness condition of the patient,and is of great importance for the choice of treatment strategy and monitoring of the disease.
引文
[1] Glassock R J.The pathogenesis of membranous nephropathy:evolution and revolution[J].Curr Opin Nephrol Hypertens,2012,21(3):235-242.
[2] Hoxha E,Knei ler U,Stege G,et al.Enhanced expression of the M-type phospholipase A2 receptor in glomernli correlates with serum receptor antibodies in primary membranous nephropathy[J].Kidney Int,2012,82(7):797-804.
[3] Beck L H Jr,Fervenza F C,Beck D M,et al.Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy[J].J Am Soc Nephrol,2011,22(8):1543-1550.
[4] Svobodova B,Honsova E,Ronco P,et al.Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy[J].Nephrol Dial Transplant,2013,28(7):1839-1844.
[5] Anony.Chapter 7:Idiopathic membranous nephropathy[J].Kidney Int Suppl(2011),2012,2(2):186-197.
[6] Beck L H Jr,Bonegio R G,Lambeau G,et al.M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy[J].N Engl J Med,2009,361(1):11-21.
[7] QIN Weisong,Beck L H Jr,ZENG Caihong,et al.Anti-phospholipase A2 receptor antibody in membranous nephropathy[J].J Am Soc Nephrol,2011,22(6):1137-1143.
[8] Bech A P,Hofstra J M,Brenchley P E,et al.Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy[J].Clin J Am Soc Nephrol,2014,9(8):1386-1392.
[9] 韩丹诺,谌贻璞,王艳艳,等.特发性膜性肾病中血清磷脂酶A2受体抗体的临床意义[J].中国实用内科杂志,2015,35 (4):351-354.HAN Dannuo,CHEN Yipu,WANG Yanyan,et al.Detection of serum phospholipase A2 receptor antibodies and its clinical significance in patients with idiopathic membranous nephropathy[J].Chin J Pract Int Med,2015,35 (4):351-354.In Chinese with English abstract.
[10] 周俊,罗素珊,潘海燕.血清抗磷脂酶A2受体抗体表达与特发膜性肾病相关性[J].青岛大学学报(医学版),2018,54(4):439-442.ZHOU Jun,LUO Sushan,PAN Haiyan.Association of the expression of anti-phospholipase A2 receptor antibody in serum with idiopathic membranous nephropathy[J].J Qingdao Univ(Med Sci),2018,54(4):439-442.In Chinese with English abstract.
[11] 宋东旭,王武涛,林鹭,等.成人特发性膜性肾病血清抗M型磷脂酶A2受体抗体临床意义研究[J].中国实用内科杂志,2015,35(5):414-418.SONG Dongxu,WANG Wutao,LIN Lu,et al.Clinical significance of autoantibodies against phospholipase A2 receptor in adult patients with idiopathic membranous nephropathy[J].Chin J Pract Int Med,2015,35(5):414-418.In Chinese with English abstract.
[12] Skoberne A,Behnert A,Teng B,et al.Serum with phospholipase A2 receptor autoantibodies interferes with podocyte adhesion to collagen[J].Eur J Clin Invest,2014,44(8):753-765.
[13] 黄俊,李剑文,梁鸣,等.他克莫司联合激素治疗血清抗PLA2R抗体持续高滴度的难治性特发性膜性肾病[J].实用医学杂志,2018,34(8):1355-1359.HUANG Jun,LI Jianwen,LIANG Ming,et al.Tacrolimus combined with prednisone for treatment of refractory idiopathic membranous nephropathy with persistent high serum anti phospholipase A2 receptor antibody titers[J].J Pract Med,2018,34(8):1355-1359.In Chinese with English abstract.
[14] Segarra-Medrano A,Jatem-Escalante E,Carnicer-C ceres C,et al.Evolution of antibody titre against the M-type phospholipase A2 receptor and clinical response in idiopathic membranous nephropathy patients treated with tacrolimus[J].Nefrologia,2014,34(4):491-497.
[15] 张丽丽,王祥,范小丽,等.成人特发性膜性肾病血清抗M型磷脂酶A2受体抗体与病情的相关性研究[J].中国现代医学杂志,2016,26(9):44-48.ZHANG Lili,WANG Xiang,FAN Xiaoli,et al.Correlation between serum anti-PLA2R antibody and adult idiopathic membranous nephropathy[J].China J Mod Med,2016,26(9):44-48.In Chinese with English abstract.
[16] Kanigicherla D,Gummadova J,McKenzie E A,et al.Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy[J].Kidney Int,2013,83(5):940-948.
[2] Hoxha E,Knei ler U,Stege G,et al.Enhanced expression of the M-type phospholipase A2 receptor in glomernli correlates with serum receptor antibodies in primary membranous nephropathy[J].Kidney Int,2012,82(7):797-804.
[3] Beck L H Jr,Fervenza F C,Beck D M,et al.Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy[J].J Am Soc Nephrol,2011,22(8):1543-1550.
[4] Svobodova B,Honsova E,Ronco P,et al.Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy[J].Nephrol Dial Transplant,2013,28(7):1839-1844.
[5] Anony.Chapter 7:Idiopathic membranous nephropathy[J].Kidney Int Suppl(2011),2012,2(2):186-197.
[6] Beck L H Jr,Bonegio R G,Lambeau G,et al.M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy[J].N Engl J Med,2009,361(1):11-21.
[7] QIN Weisong,Beck L H Jr,ZENG Caihong,et al.Anti-phospholipase A2 receptor antibody in membranous nephropathy[J].J Am Soc Nephrol,2011,22(6):1137-1143.
[8] Bech A P,Hofstra J M,Brenchley P E,et al.Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy[J].Clin J Am Soc Nephrol,2014,9(8):1386-1392.
[9] 韩丹诺,谌贻璞,王艳艳,等.特发性膜性肾病中血清磷脂酶A2受体抗体的临床意义[J].中国实用内科杂志,2015,35 (4):351-354.HAN Dannuo,CHEN Yipu,WANG Yanyan,et al.Detection of serum phospholipase A2 receptor antibodies and its clinical significance in patients with idiopathic membranous nephropathy[J].Chin J Pract Int Med,2015,35 (4):351-354.In Chinese with English abstract.
[10] 周俊,罗素珊,潘海燕.血清抗磷脂酶A2受体抗体表达与特发膜性肾病相关性[J].青岛大学学报(医学版),2018,54(4):439-442.ZHOU Jun,LUO Sushan,PAN Haiyan.Association of the expression of anti-phospholipase A2 receptor antibody in serum with idiopathic membranous nephropathy[J].J Qingdao Univ(Med Sci),2018,54(4):439-442.In Chinese with English abstract.
[11] 宋东旭,王武涛,林鹭,等.成人特发性膜性肾病血清抗M型磷脂酶A2受体抗体临床意义研究[J].中国实用内科杂志,2015,35(5):414-418.SONG Dongxu,WANG Wutao,LIN Lu,et al.Clinical significance of autoantibodies against phospholipase A2 receptor in adult patients with idiopathic membranous nephropathy[J].Chin J Pract Int Med,2015,35(5):414-418.In Chinese with English abstract.
[12] Skoberne A,Behnert A,Teng B,et al.Serum with phospholipase A2 receptor autoantibodies interferes with podocyte adhesion to collagen[J].Eur J Clin Invest,2014,44(8):753-765.
[13] 黄俊,李剑文,梁鸣,等.他克莫司联合激素治疗血清抗PLA2R抗体持续高滴度的难治性特发性膜性肾病[J].实用医学杂志,2018,34(8):1355-1359.HUANG Jun,LI Jianwen,LIANG Ming,et al.Tacrolimus combined with prednisone for treatment of refractory idiopathic membranous nephropathy with persistent high serum anti phospholipase A2 receptor antibody titers[J].J Pract Med,2018,34(8):1355-1359.In Chinese with English abstract.
[14] Segarra-Medrano A,Jatem-Escalante E,Carnicer-C ceres C,et al.Evolution of antibody titre against the M-type phospholipase A2 receptor and clinical response in idiopathic membranous nephropathy patients treated with tacrolimus[J].Nefrologia,2014,34(4):491-497.
[15] 张丽丽,王祥,范小丽,等.成人特发性膜性肾病血清抗M型磷脂酶A2受体抗体与病情的相关性研究[J].中国现代医学杂志,2016,26(9):44-48.ZHANG Lili,WANG Xiang,FAN Xiaoli,et al.Correlation between serum anti-PLA2R antibody and adult idiopathic membranous nephropathy[J].China J Mod Med,2016,26(9):44-48.In Chinese with English abstract.
[16] Kanigicherla D,Gummadova J,McKenzie E A,et al.Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy[J].Kidney Int,2013,83(5):940-948.