Новый подход к быстрой индукции ремиссии у больных при мембранозной нефропатии
DOI: 10.26442/00403660.2021.06.200865
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Dobronravov VA, Bystrova OB, Kochoyan ZSh, Fomicheva EN. A novel approach to rapid induction of remission in primary membranous nephropathy. Terapevticheskii Arkhiv (Ter. Arkh.). 2021; 93 (6): 706–712.
DOI: 10.26442/00403660.2021.06.200865
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Материалы и методы. В открытое проспективное сравнительное исследование включены 56 пациентов с диагнозом ПМН в возрасте 18–70 лет с нефротическим синдромом и повышением уровня антител к рецептору фосфолипазы А2 (анти-PLA2R) в циркуляции (средний возраст 51±12 лет, мужчин – 70%). Регистрировали демографические и клинические показатели на момент биопсии почки, данные светооптического и иммуноморфологического исследований. Все пациенты получали стабильные дозы блокаторов ренин-ангиотензиновой системы. Сравнивали эффективность лечения в отношении развития клинических и иммунологических ремиссий в группе пациентов, получивших экспериментальное лечение RTX, ЦФ и стероидами (группа RTX+ЦФ+С, n=14), и двух контрольных группах: высокодозной терапии RTX (группа RTX, n=12), циклоспорина и стероидов (группа циклоспорина А+С, n=30).
Результаты. В группе RTX+ЦФ+С ремиссия достигнута в 100% случаев (из них полная ремиссия – 21,4%). Медиана периода времени до развития ремиссии составила 2,5 [1,0; 3,5] мес и достоверно меньше в сравнении с контрольными группами: RTX (8,7 [6,6; 14,0] мес, р=0,005) и циклоспорина А+С (12,4 [6,5; 19,9] мес, р<0,001). Кумулятивная частота развития клинических и иммунологических ремиссий также достоверно выше в группе RTX+ЦФ+С (р<0,001) и не отличается в контрольных группах. Аналогичные результаты получены при сравнительных анализах в тех же группах терапии ПМН, подобранных по индексу соответствия. Кумулятивная частота достижения клинических и иммунологических ремиссий в группе RTX+ЦФ+С выше, чем в объединенной группе пациентов, получивших другую терапию (р<0,001). Частота серьезных нежелательных явлений оказалась низкой и не отличалась в сравниваемых группах.
Заключение. Применение многоцелевой комбинированной терапии RTX, ЦФ и стероидами является эффективным подходом для быстрой индукции ремиссии ПМН и предупреждения осложнений нефротического синдрома.
Ключевые слова: первичная мембранозная нефропатия, антитела к рецептору фосфолипазы A2 M-типа, лечение, ритуксимаб, стероиды, циклофосфамид, циклоспорин, ремиссия, иммунологическая ремиссии
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Aim. То evaluate the effectiveness of a novel multi-targeted treatment approach including rituximab (RTX), cyclophosphamide (CPH) and steroids (S) to the induction of remission in patients with primary membranous nephropathy (PMN) compared to standard immunosuppression (IST).
Materials and methods. An open-label prospective comparative study included 56 PMN patients (pts) with nephrotic syndrome (NS) and high serum level of antibodies to the phospholipase A2 receptor – anti-PLA2R (mean age 51±12 years, men – 70%). We recorded demographic and clinical parameters at the time of kidney biopsy, data from light-optical and immunomorphological studies. All pts were on stable doses of the renin-angiotensin systems blockers. We compared the effectiveness of different treatments in the inductions of clinical and immunological remissions in pts who received experimental treatment with RTX, CPH and S (RTX+CPH+S group, n=14) and two control groups: high-dose RTX therapy (group RTX, n=12), cyclosporine and steroids (group CsA+S, n=30).
Results. In the RTX+CPH+S group, remission was achieved in 100% of cases (of which complete remissions – CR in 21.4%). The median time-to-remission (2.5 [1.0; 3.5] months) was significantly lower compared to both control groups: RTX (8.7 [6.6; 14.0] months, p=0.005) and CsA+S (12.4 [6.5; 19.9] months, p<0.001). The cumulative incidence of clinical and immunological remissions was also significantly higher in the RTX+CPH+S group than in the control groups. These results were confirmed in comparative analyzes in the same treatment groups after propensity score matching. The cumulative incidence of clinical and immunological remissions in the RTX+CPH+S group was higher than in the combined group of patients who received other therapies (p<0.001). The incidence of serious adverse events was low and did not differ between groups.
Conclusion. The use of multi-targeted therapy with rituximab, cyclophosphamide, and steroids seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications.
Keywords: primary membranous nephropathy, anti-PLA2R antibodies, treatment, rituximab, steroids, cyclophosphamide, cyclosporine, clinical remission, immunological remission
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3. Schlumberger W, Hornig N, Lange S, et al. Differential diagnosis of membranous nephropathy with autoantibodies to phospholipase A2 receptor 1. Autoimmun Rev. 2014;13:108-13. DOI:10.1038/srep08803
4. Ma H, Sandor DG, Beck LH Jr. The role of complement in membranous nephropathy. Semin Nephrol. 2013; 33:6:531-42. DOI:10.1016/j.semnephrol.2013.08.004
5. Passerini P, Ponticelli C. Membranous nephropathy. In: Treatment of Primary Glomerulonephritis. Eds. C Ponticelli, R Glassock. 2nd edn. Oxford University Press: Oxford, UK, 2009; p. 261-312. DOI:10.1093/med/9780199552887.001.0001
6. Chen Y, Schieppati A, Chen X, et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2014;10:CD004293. DOI:10.1002/14651858.CD004293.pub3
7. Zou PM, Li H, Cai JF, et al. Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis. Chin Med Sci J. 2018;33(1):9-19. DOI:10.24920/21803
8. Lu W, Gong S, Li J, et al. Efficacy and safety of rituximab in the treatment of membranous nephropathy: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(16):e19804. DOI:10.1097/MD.0000000000019804
9. Ren S, Wang Y, Xian L, et al. Comparative effectiveness and tolerance of immunosuppressive treatments for idiopathic membranous nephropathy: A network meta-analysis. PLoS One. 2017;12(9):e0184398. DOI:10.1371/journal.pone.0184398
10. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med. 2019;381(1):36-46. DOI:10.1056/NEJMoa1814427
11. Добронравов В.А., Майер Д.А., Бережная О.В., и др. Мембранозная нефропатия в российской популяции. Терапевтический архив. 2017;89(6):21-9 [Dobronravov VA, Majer DA, Berezhnaja OV, et al. Membranous nephropathy in a Russian population. Terapevticheskii Arkhiv (Ter. Arkh.). 2017;89(6):21-9 (in Russian)].
DOI:10.17116/terarkh201789621-29
12. Churg J, Ehrenreich T. Membranous nephropathy. Perspect Nephrol Hypertens. 1973;1:443-8
13. Levey AS, Stevens LA, Schmid CH, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12. DOI: 10.7326/0003-4819-150-9-200905050-00006
14. U.S. Food and Drug Administration What is a Serious Adverse Event? Available at: https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event. Accessed: 04.03.2021.
15. Rosenbaum PR, Rubin DB. The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika. 1983;70(1):41-55. DOI:10.1093/biomet/70.1.41
16. Cattran DC, Feehally J, Cook HT, et al. Kidney disease: Improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2(2):186-97. DOI:10.1038/kisup.2012.20
17. KDIGO Clinical Practice Guideline On Glomerular Diseases. Public Review Draft. June 2020. Available at: https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdf. Accessed: 04.07.2020.
18. Huang L, Dong QR, Zhao YJ, et al. Rituximab for the management of idiopathic membranous nephropathy: a meta-analysis. Int Urol Nephrol. 2021;53(1):111-9. DOI:10.1007/s11255-020-02633-5
19. Wu W, Shang J, Tao C, et al. The prognostic value of phospholipase A2 receptor autoantibodies on spontaneous remission for patients with idiopathic membranous nephropathy: A meta-analysis. Medicine (Baltimore). 2018;97(23):e11018. DOI:10.1097/MD.0000000000011018
20. Dong D, Fan TT, Wang YY, et al. Relationship between renal tissues phospholipase A2 receptor and its serum antibody and clinical condition and prognosis of idiopathic membranous nephropathy: a meta-analysis. BMC Nephrol. 2019;20(1):444. DOI:10.1186/s12882-019-1638-x
21. Waldman M, Beck LH Jr, Braun M, et al. Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab. Kidney Int Rep. 2016;1(2):73-84. DOI:10.1016/j.ekir.2016.05.002
22. Liu D, Yang Y, Kuang F, et al. Risk of infection with different immunosuppressive drugs combined with glucocorticoids for the treatment of idiopathic membranous nephropathy: A pairwise and network meta-analysis. Int Immunopharmacol. 2019;70:354-61. DOI:10.1016/j.intimp.2019.03.002
23. Zheng Q, Yang H, Liu W, et al. Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis. BMJ Open. 2019;9(9):e030919.
DOI:10.1136/bmjopen-2019-030919
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1. Glassock RJ. The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey. Am J Kidney Dis. 2010;56:157-67. DOI:10.1053/j.ajkd.2010.01.0082
2. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11-21. DOI:10.1056/NEJMoa0810457
3. Schlumberger W, Hornig N, Lange S, et al. Differential diagnosis of membranous nephropathy with autoantibodies to phospholipase A2 receptor 1. Autoimmun Rev. 2014;13:108-13. DOI:10.1038/srep08803
4. Ma H, Sandor DG, Beck LH Jr. The role of complement in membranous nephropathy. Semin Nephrol. 2013; 33:6:531-42. DOI:10.1016/j.semnephrol.2013.08.004
5. Passerini P, Ponticelli C. Membranous nephropathy. In: Treatment of Primary Glomerulonephritis. Eds. C Ponticelli, R Glassock. 2nd edn. Oxford University Press: Oxford, UK, 2009; p. 261-312. DOI:10.1093/med/9780199552887.001.0001
6. Chen Y, Schieppati A, Chen X, et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2014;10:CD004293. DOI:10.1002/14651858.CD004293.pub3
7. Zou PM, Li H, Cai JF, et al. Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis. Chin Med Sci J. 2018;33(1):9-19. DOI:10.24920/21803
8. Lu W, Gong S, Li J, et al. Efficacy and safety of rituximab in the treatment of membranous nephropathy: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(16):e19804. DOI:10.1097/MD.0000000000019804
9. Ren S, Wang Y, Xian L, et al. Comparative effectiveness and tolerance of immunosuppressive treatments for idiopathic membranous nephropathy: A network meta-analysis. PLoS One. 2017;12(9):e0184398. DOI:10.1371/journal.pone.0184398
10. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med. 2019;381(1):36-46. DOI:10.1056/NEJMoa1814427
11. Dobronravov VA, Majer DA, Berezhnaja OV, et al. Membranous nephropathy in a Russian population. Terapevticheskii Arkhiv (Ter. Arkh.). 2017;89(6):21-9 (in Russian)
DOI:10.17116/terarkh201789621-29
12. Churg J, Ehrenreich T. Membranous nephropathy. Perspect Nephrol Hypertens. 1973;1:443-8
13. Levey AS, Stevens LA, Schmid CH, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12. DOI: 10.7326/0003-4819-150-9-200905050-00006
14. U.S. Food and Drug Administration What is a Serious Adverse Event? Available at: https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event. Accessed: 04.03.2021.
15. Rosenbaum PR, Rubin DB. The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika. 1983;70(1):41-55. DOI:10.1093/biomet/70.1.41
16. Cattran DC, Feehally J, Cook HT, et al. Kidney disease: Improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2(2):186-97. DOI:10.1038/kisup.2012.20
17. KDIGO Clinical Practice Guideline On Glomerular Diseases. Public Review Draft. June 2020. Available at: https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdf. Accessed: 04.07.2020.
18. Huang L, Dong QR, Zhao YJ, et al. Rituximab for the management of idiopathic membranous nephropathy: a meta-analysis. Int Urol Nephrol. 2021;53(1):111-9. DOI:10.1007/s11255-020-02633-5
19. Wu W, Shang J, Tao C, et al. The prognostic value of phospholipase A2 receptor autoantibodies on spontaneous remission for patients with idiopathic membranous nephropathy: A meta-analysis. Medicine (Baltimore). 2018;97(23):e11018. DOI:10.1097/MD.0000000000011018
20. Dong D, Fan TT, Wang YY, et al. Relationship between renal tissues phospholipase A2 receptor and its serum antibody and clinical condition and prognosis of idiopathic membranous nephropathy: a meta-analysis. BMC Nephrol. 2019;20(1):444. DOI:10.1186/s12882-019-1638-x
21. Waldman M, Beck LH Jr, Braun M, et al. Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab. Kidney Int Rep. 2016;1(2):73-84. DOI:10.1016/j.ekir.2016.05.002
22. Liu D, Yang Y, Kuang F, et al. Risk of infection with different immunosuppressive drugs combined with glucocorticoids for the treatment of idiopathic membranous nephropathy: A pairwise and network meta-analysis. Int Immunopharmacol. 2019;70:354-61. DOI:10.1016/j.intimp.2019.03.002
23. Zheng Q, Yang H, Liu W, et al. Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis. BMJ Open. 2019;9(9):e030919.
DOI:10.1136/bmjopen-2019-030919
ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России
*dobronravov@nephrolog.ru
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Vladimir A. Dobronravov*, Olga B. Bystrova, Zinaida Sh. Kochoyan, Evgeniya N. Fomicheva
Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
*dobronravov@nephrolog.ru