生物制剂在原发性肾病综合征中的应用

doi:10.12372/jcp.2022.21e1440

Abstract

Abstract:

Idiopathic nephrotic syndrome (INS) is the commonest glomerular disease in children. Refractory nephrotic syndromes such as frequent relapses, steroid dependence and steroid resistance are still the current difficulties in clinical INS treatment. In recent years, it has been reported that rituximab (RTX) and other biological agents have been used in the treatment of refractory nephrotic syndrome and have achieved good results. This article reviews the application progress of RTX and other biological agents in INS.

Key words: nephrotic syndrome, biological agent, rituximab, child

WANG Qianhui, LIU Fei, FU Haidong, MAO Jianhua. Application of biological agents in idiopathic nephrotic syndrome[J].Journal of Clinical Pediatrics, 2022, 40(10): 787-794.

Figures/Tables 2

References 59

[1]	Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children[J]. Lancet, 2018, 392(10141): 61-74. doi: S0140-6736(18)30536-1 pmid: 29910038
[2]	Chen J, Qiao XH, Mao JH. Immunopathogenesis of idiopathic nephrotic syndrome in children: two sides of the coin[J]. World J Pediatr, 2021, 17(2): 115-122. doi: 10.1007/s12519-020-00400-1 pmid: 33660135
[3]	Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases[J]. Kidney Int, 2021, 100(4): 753-779. doi: 10.1016/j.kint.2021.05.015 pmid: 34556300
[4]	Trautmann A, Vivarelli M, Samuel S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2020, 35(8): 1529-1561. doi: 10.1007/s00467-020-04519-1 pmid: 32382828
[5]	Wei C, Trachtman H, Li J, et al. Circulating suPAR in two cohorts of primary FSGS[J]. J Am Soc Nephrol, 2012, 23(12): 2051-2059. doi: 10.1681/ASN.2012030302 pmid: 23138488
[6]	Fornoni A, Sageshima J, Wei C, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis[J]. Sci Transl Med, 2011, 3(85): 85ra46.
[7]	Benz K, Dötsch J, Rascher W, et al. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy[J]. Pediatr Nephrol, 2004, 19(7): 794-797. pmid: 15071769
[8]	Boumediene A, Vachin P, Sendeyo K, et al. NEPHRUTIX: a randomized, double-blind, placebo vs Rituximab-controlled trial assessing T-cell subset changes in minimal change nephrotic syndrome[J]. J Autoimmun, 2018, 88: 91-102. doi: S0896-8411(17)30583-8 pmid: 29056249
[9]	Iwabuchi Y, Miyabe Y, Makabe S, et al. Comparison of the response of frequently relapsing steroid-dependent minimal change nephrotic syndrome to rituximab therapy between childhood-onset and adult-onset disease[J]. Medicine (Baltimore), 2018, 97(42): e12704.
[10]	Hogan J, Deschenes G. How to improve response to rituximab treatment in children with steroid-dependent nephrotic syndrome: answer to Drs. Fujinaga and Nishino[J]. Pediatr Nephrol, 2019, 34(2): 361-362. doi: 10.1007/s00467-018-4133-x pmid: 30406369
[11]	Maxted AP, Dalrymple RA, Chisholm D, et al. Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome[J]. Pediatr Nephrol, 2019, 34(5): 855-863. doi: 10.1007/s00467-018-4172-3 pmid: 30564878
[12]	Ravani P, Magnasco A, Edefonti A, et al. Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial[J]. Clin J Am Soc Nephrol, 2011, 6(6): 1308-1315. doi: 10.2215/CJN.09421010
[13]	Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial[J]. Lancet, 2014, 384(9950): 1273-1281. doi: 10.1016/S0140-6736(14)60541-9 pmid: 24965823
[14]	Ahn YH, Kim SH, Han KH, et al. Efficacy and safety of rituximab in childhood-onset, difficult-to-treat nephrotic syndrome: a multicenter open-label trial in Korea[J]. Medicine (Baltimore), 2018, 97(46): e13157.
[15]	Basu B, Sander A, Roy B, et al. Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: a randomized clinical trial[J]. JAMA Pediatr, 2018, 172(8): 757-764. doi: 10.1001/jamapediatrics.2018.1323 pmid: 29913001
[16]	Ravani P, Lugani F, Drovandi S, et al. Rituximab vs low-dose mycophenolate mofetil in recurrence of steroid-dependent nephrotic syndrome in children and young adults: a randomized clinical trial[J]. JAMA Pediatr, 2021, 175(6): 631-632. doi: 10.1001/jamapediatrics.2020.6150 pmid: 33616641
[17]	Kim JH, Park E, Hyun HS, et al. Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome[J]. Kidney Res Clin Pract, 2017, 36(3): 257-263. doi: 10.23876/j.krcp.2017.36.3.257 pmid: 28904877
[18]	Gulati A, Sinha A, Jordan SC, et al. Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report[J]. Clin J Am Soc Nephrol, 2010, 5(12): 2207-2212. doi: 10.2215/CJN.03470410
[19]	Magnasco A, Ravani P, Edefonti A, et al. Rituximab in children with resistant idiopathic nephrotic syndrome[J]. J Am Soc Nephrol, 2012, 23(6): 1117-1124. doi: 10.1681/ASN.2011080775 pmid: 22581994
[20]	Hoseini R, Sabzian K, Otukesh H, et al. Efficacy and safety of rituximab in children with steroid- and cyclosporine-resistant and steroid- and cyclosporine-dependent nephrotic syndrome[J]. Iran J Kidney Dis, 2018, 12(1): 27-32. pmid: 29421774
[21]	Nakagawa T, Shiratori A, Kawaba Y, et al. Efficacy of rituximab therapy against intractable steroid-resistant nephrotic syndrome[J]. Pediatr Int, 2016, 58(10): 1003-1008. doi: 10.1111/ped.12948 pmid: 26865241
[22]	Zachwieja J, Silska-Dittmar M, Żurowska A, et al. Multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab in children with steroid-resistant nephrotic syndrome[J]. Clin Exp Pharmacol Physiol, 2019, 46(4): 313-321. doi: 10.1111/1440-1681.13046
[23]	Kamei K, Okada M, Sato M, et al. Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2014, 29(7): 1181-1187. doi: 10.1007/s00467-014-2765-z pmid: 24500706
[24]	Fujinaga S, Nishino T, Umeda C, et al. Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome[J]. Pediatr Nephrol, 2019, 34(2): 353-357. doi: 10.1007/s00467-018-4145-6 pmid: 30426219
[25]	Ruggenenti P, Ruggiero B, Cravedi P, et al. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome[J]. J Am Soc Nephrol, 2014, 25(4): 850-863. doi: 10.1681/ASN.2013030251 pmid: 24480824
[26]	Delbet JD, Leclerc G, Ulinski T. Idiopathic nephrotic syndrome and rituximab: may we predict circulating B lymphocytes recovery?[J]. Pediatr Nephrol, 2019, 34(3): 529-532. doi: 10.1007/s00467-018-4139-4 pmid: 30542932
[27]	Kamei K, Ogura M, Sato M, et al. Infusion reactions associated with rituximab treatment for childhood-onset complicated nephrotic syndrome[J]. Pediatr Nephrol, 2018, 33(6): 1013-1018. doi: 10.1007/s00467-018-3900-z pmid: 29426974
[28]	Kamei K, Takahashi M, Fuyama M, et al. Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature[J]. Nephrol Dial Transplant, 2015, 30(1): 91-96. doi: 10.1093/ndt/gfu258
[29]	Ardelean DS, Gonska T, Wires S, et al. Severe ulcerative colitis after rituximab therapy[J]. Pediatrics, 2010, 126(1): e243-e246.
[30]	Sellier-Leclerc AL, Belli E, Guérin V, et al. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome[J]. Pediatr Nephrol, 2013, 28(9): 1875-1879. doi: 10.1007/s00467-013-2485-9 pmid: 23700173
[31]	Boren EJ, Cheema GS, Naguwa SM, et al. The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases[J]. J Autoimmun, 2008, 30(1-2): 90-98. doi: 10.1016/j.jaut.2007.11.013 pmid: 18191544
[32]	Tsutsumi Y, Kanamori H, Mori A, et al. Reactivation of hepatitis B virus with rituximab[J]. Expert Opin Drug Saf, 2005, 4(3): 599-608. pmid: 15934864
[33]	Basu B. Ofatumumab for rituximab-resistant nephrotic syndrome[J]. N Engl J Med, 2014, 370(13): 1268-1270. doi: 10.1056/NEJMc1308488
[34]	Bonanni A, Rossi R, Murtas C, et al. Low-dose ofatu-mumab for rituximab-resistant nephrotic syndrome[J]. BMJ Case Rep, 2015, 2015: bcr2015210208.
[35]	Vivarelli M, Colucci M, Bonanni A, et al. Ofatumumab in two pediatric nephrotic syndrome patients allergic to rituximab[J]. Pediatr Nephrol, 2017, 32(1): 181-184. pmid: 27687621
[36]	Wang CS, Liverman RS, Garro R, et al. Ofatumumab for the treatment of childhood nephrotic syndrome[J]. Pediatr Nephrol, 2017, 32(5): 835-841. doi: 10.1007/s00467-017-3621-8
[37]	Ravani P, Pisani I, Bodria M, et al. Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial[J]. Pediatr Nephrol, 2020, 35(6): 997-1003. doi: 10.1007/s00467-020-04481-y pmid: 31993781
[38]	Ravani P, Colucci M, Bruschi M, et al. Human or chimeric monoclonal anti-CD20 antibodies for children with nephrotic syndrome: a superiority randomized trial[J]. J Am Soc Nephrol, 2021, 32(10): 2652-2663. doi: 10.1681/ASN.2021040561 pmid: 34544820
[39]	Bonanni A, Calatroni M, D'Alessandro M, et al. Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome[J]. Br J Clin Pharmacol, 2018, 84(6): 1238-1249. doi: 10.1111/bcp.13548 pmid: 29436729
[40]	Alachkar N, Carter-Monroe N, Reiser J. Abatacept in B7-1-positive -positive proteinuric kidney disease[J]. N Engl J Med, 2014, 370(13): 1263-1264.
[41]	Garin EH, Diaz LN, Mu W, et al. Urinary CD80 excretion increases in idiopathic minimal-change disease[J]. J Am Soc Nephrol, 2009, 20(2): 260-266. doi: 10.1681/ASN.2007080836 pmid: 19056875
[42]	Salant DJ. Podocyte expression of B7-1/CD80: is it a reliable biomarker for the treatment of proteinuric kidney diseases with abatacept?[J]. J Am Soc Nephrol, 2016, 27(4): 963-965. doi: 10.1681/ASN.2015080947 pmid: 26400567
[43]	Kaneko K, Tsuji S, Kimata T, et al. Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes[J]. World J Pediatr, 2015, 11(1): 21-28. doi: 10.1007/s12519-015-0003-9 pmid: 25822700
[44]	Chen P, Chen Y, Jiang M, et al. Usefulness of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset minimal change disease[J]. Peer J, 2020, 8: e9854. doi: 10.7717/peerj.9854
[45]	Szeto CC, Lai FM, Chow KM, et al. Long-term outcome of biopsy-proven minimal change nephropathy in Chinese adults[J]. Am J Kidney Dis, 2015, 65(5): 710-718. doi: 10.1053/j.ajkd.2014.09.022
[46]	Grellier J, Del Bello A, Milongo D, et al. Belatacept in recurrent focal segmental glomerulosclerosis after kidney transplantation[J]. Transpl Int, 2015, 28(9): 1109-1110. doi: 10.1111/tri.12574 pmid: 25847461
[47]	Novelli R, Gagliardini E, Ruggiero B, et al. Any value of podocyte B7-1 as a biomarker in human MCD and FSGS?[J]. Am J Physiol Renal Physiol, 2016, 310(5): F335-341. doi: 10.1152/ajprenal.00510.2015
[48]	Hansrivijit P, Puthenpura MM, Ghahramani N. Efficacy of abatacept treatment for focal segmental glomerulosclerosis and minimal change disease: a systematic review of case reports, case series, and observational studies[J]. Clin Nephrol, 2020, 94(3): 117-126. doi: 10.5414/CN110134 pmid: 32589135
[49]	Trachtman H, Gipson DS, Somers M, et al. Randomized clinical trial design to assess abatacept in resistant nephrotic syndrome[J]. Kidney Int Rep, 2018, 3(1): 115-121. doi: 10.1016/j.ekir.2017.08.013 pmid: 29340321
[50]	Mishra OP, Kumar R, Narayan G, et al. Toll-like receptor 3 (TLR-3), TLR-4 and CD80 expression in peripheral blood mononuclear cells and urinary CD80 levels in children with idiopathic nephrotic syndrome[J]. Pediatr Nephrol, 2017, 32(8): 1355-1361. doi: 10.1007/s00467-017-3613-8 pmid: 28210837
[51]	Trachtman H, Fervenza FC, Gipson DS, et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis[J]. Kidney Int, 2011, 79(11): 1236-1243. doi: 10.1038/ki.2011.33 pmid: 21368745
[52]	Vincenti F, Fervenza FC, Campbell KN, et al. A phase 2, double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis[J]. Kidney Int Rep, 2017, 2(5): 800-810. doi: 10.1016/j.ekir.2017.03.011 pmid: 29270487
[53]	Joy MS, Gipson DS, Powell L, et al. Phase 1 trial of adalimumab in focal segmental glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group[J]. Am J Kidney Dis, 2010, 55(1): 50-60. doi: 10.1053/j.ajkd.2009.08.019 pmid: 19932542
[54]	Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group[J]. BMC Nephrol, 2015, 16: 111. doi: 10.1186/s12882-015-0094-5 pmid: 26198842
[55]	Schmidt T, Schulze M, Harendza S, et al. Successful treatment of PLA2R1-antibody positive membranous nephropathy with ocrelizumab[J]. J Nephrol, 2021, 34(2): 603-606. doi: 10.1007/s40620-020-00874-2 pmid: 33026632
[56]	Wolinsky JS, Arnold DL, Brochet B, et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial[J]. Lancet Neurol, 2020, 19(12): 998-1009. doi: 10.1016/S1474-4422(20)30342-2 pmid: 33129442
[57]	Ayrignac X, Bilodeau PA, Prat A, et al. Assessing the risk of multiple sclerosis disease-modifying therapies[J]. Expert Rev Neurother, 2019, 19(7): 695-706. doi: 10.1080/14737175.2019.1627201 pmid: 31195842
[58]	Le Quintrec M, Lapeyraque AL, Lionet A, et al. Patterns of clinical response to eculizumab in patients with C3 glomerulopathy[J]. Am J Kidney Dis, 2018, 72(1): 84-92. doi: S0272-6386(17)31139-3 pmid: 29429752
[59]	Ruggenenti P, Daina E, Gennarini A, et al. C5 convertase blockade in membranoproliferative glomerulonephritis: a single-arm clinical trial[J]. Am J Kidney Dis, 2019, 74(2): 224-238. doi: S0272-6386(19)30100-3 pmid: 30929851

生物制剂	主要作用机制	RCT文献（作者/年份）	例数	治疗效果
rituximab	靶向B细胞CD20,介导B细胞凋亡;通过CD80和CTLA4调节适应性免疫力并调节T细胞	Ravani / 2011 ^[12]	54	与标准治疗组相比,RTX治疗组蛋白尿、复发率及3个月无药概率更低
		Iijima / 2014 ^[13]	48	与安慰剂组相比,RTX组50％无复发期更长
		Basu / 2018 ^[15]	120	利妥昔单抗在维持疾病缓解和减少皮质类固醇暴露方面似乎比他克莫司更有效
		Ahn / 2018 ^[14]	61	治疗后6个月,RTX组缓解率较对照组更高,平均维持时间更长
		Ravani / 2021 ^[16]	30	RTX组复发风险更低,中位复发时间更长,对维持SDNS长期缓解有效
		Magnasco / 2012 ^[19]	31	利妥昔单抗组和安慰剂组之间蛋白尿程度无显著差异
ofatumumab	同rituximab	Ravani / 2020 ^[37]	13	1年后所有参与者均未出现蛋白尿完全或部分缓解,研究因无效而终止
ofatumumab	同rituximab	Ravani / 2021^[38]	140	在类固醇依赖性和钙调磷酸酶抑制剂依赖性肾病综合征患儿中,应用单剂量ofatumumab疗效并不优于单剂量RTX
abatacept	结合APC表面CD80,调节T细胞免疫	Trachtman / 2018^[49]	约90	结果未出
fresolimumab	结合TGF-β,抑制淋巴细胞分化及细胞因子产生	Vincenti / 2017 ^[52]	36	未达到减少蛋白尿的疗效终点,但与安慰剂相比,试验期间Fresolimumab组出现多次“部分缓解”的患者更多,肾功能相对更稳定
adalimumab	结合TNF-α,阻止炎症反应	Phase 1 trial / 2010^[53]	10	每10例蛋白尿患者中有4例降低50％以上
adalimumab	结合TNF-α,阻止炎症反应	Phase 2 trial / 2015^[54]	21	阿达木单抗治疗的7例受试者蛋白尿均未降低50％

Application of biological agents in idiopathic nephrotic syndrome

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 2

References 59

Related Articles 15

Metrics

Comments

Recommended 0

[1]	LUO Mingjing, YU Jiaming, WANG Xiaodong, ZHANG Xiaoling, YU Yue, ZHANG Yu, WEN Feiqiu, LIU Sixi. Clinical analysis of invasive fungal disease secondary to allogeneic hematopoietic stem cell transplantation in 424 children with thalassemia [J]. Journal of Clinical Pediatrics, 2025, 43(1): 21-28.
[2]	LIU Dongxia, JIN Rong, LIN Rongjun. Risk factors analysis of severe refractory Mycoplasma pneumoniae pneumonia complicated with bronchitis obliterans in children [J]. Journal of Clinical Pediatrics, 2025, 43(1): 29-34.
[3]	ZHONG Jinhong, WANG Can, CHEN Fang. Progress in the research of infantile fiberoptic bronchoscopy sedation [J]. Journal of Clinical Pediatrics, 2025, 43(1): 50-55.
[4]	JIANG Weiqin, WANG Jing, CHENG Anna, CHEN Tingting, HUANG Yujuan. Predictors of recurrent febrile seizures during the same febrile illness in children with febrile seizures [J]. Journal of Clinical Pediatrics, 2025, 43(1): 8-13.
[5]	QIU Xiu, WEI Dongmei, LIN Shanshan, XIA Huimin, ZHOU Wenhao. Principles and practice of the Born in Guangzhou Cohort Study [J]. Journal of Clinical Pediatrics, 2024, 42(9): 747-752.
[6]	FAN Jianxia. The origins and development of the healthy life trajectory program: a cohort of community-family-mother-child multidimensional interventions for overweight and obesity in children [J]. Journal of Clinical Pediatrics, 2024, 42(9): 768-773.
[7]	JIANG Tao, LI Shuangjie, TANG Lian, OUYANG Wenxian. Immunobiological properties of peripheral blood MAIT cells in children with chronic hepatitis B [J]. Journal of Clinical Pediatrics, 2024, 42(9): 787-790.
[8]	ZHOU Jie, LIU Keqiang, WANG Jinling, WANG Ying. Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by MYH11 elongating mutation : a case report and literatures review [J]. Journal of Clinical Pediatrics, 2024, 42(9): 798-804.
[9]	CHU Sijia, TANG Jihong. Research progress of central nervous system injury associated with pediatric acute lymphoblastic leukemia and its treatment [J]. Journal of Clinical Pediatrics, 2024, 42(9): 811-816.
[10]	DING Yaping, XIA Shanshan, ZHANG Chenmei. Interpretation of “2023 Children’s Renal Nutrition Working Group Clinical Practice Recommendations: Nutritional Management of Children with Acute Kidney Injury” [J]. Journal of Clinical Pediatrics, 2024, 42(8): 667-672.
[11]	LI Yirong, LI Huiping, GAO Jingyu, XIAO Yuhua, CHEN Xiaomin, LU Yanling, ZHAO Nana, FENG Xiaoqin. Comparison of different doses of cytarabine for induction chemotherapy in children with acute myeloid leukemia in FLAG-IDA regimen [J]. Journal of Clinical Pediatrics, 2024, 42(8): 673-677.
[12]	HUANG Bo, DONG Yanying, SONG Linlan. Clinical characteristics of 348 children with infectious mononucleosis [J]. Journal of Clinical Pediatrics, 2024, 42(8): 678-683.
[13]	WANG Dan, SHAO Jingbo, LI Hong, ZHANG Na, ZHU Jiashi, FU Pan, WANG Zhen. Clinical analysis of 38 cases of hematological malignancies complicated with tumor lysis syndrome in children [J]. Journal of Clinical Pediatrics, 2024, 42(8): 684-690.
[14]	MA Yan, WEI Xingjiao, BAI Hua, ZHANG Yan, TIAN Xinmin, Aqsa Ahmad, LIANG Lijun. Analysis of etiological composition and clinical features of stage 5 chronic kidney disease in children in a tertiary hospital in western China [J]. Journal of Clinical Pediatrics, 2024, 42(8): 697-703.
[15]	WANG Ye, ZHANG Linlin, CHI Zuofei, SUN Ruowen, JIANG Zehui, XU Gang. A case of clinical report of T-lymphoblastic lymphoma secondary to acute promyelocytic leukemia in children [J]. Journal of Clinical Pediatrics, 2024, 42(8): 722-727.