Современные фармакологические подходы к лечению первичного нефротического синдрома

Обзор посвящен рассмотрению наиболее распространенных лекарственных средств, применяемых в настоящее время в процессе лечения первичного нефротического синдрома. Проанализированы механизмы фармакологической активности глюкокортикостероидов, АКТГ, ингибиторов кальциневрина циклоспорина А и такролимуса, алкилирующих соединений циклофосфамида и хлорамбуцила, микофенолата мофетила, левамизола, абатацепта, ритуксимаба и ряда других, недавно созданных моноклональных АТ. Предпринята попытка выделить иммунные и неиммунные механизмы действия наиболее распространенных препаратов, касающиеся как воздействия на звенья иммуногенеза отмеченных заболеваний, так и прямого влияния на подоциты, обеспечивающие проницаемость клубочкового фильтрационного барьера и развитие протеинурии. Иммунные механизмы действия кортикостероидов обусловлены взаимодействием с глюкокортикоидными рецепторами лимфоцитов, а неиммунные – со стимулированием этих же рецепторов в подоцитах. Выяснено, что активация АКТГ меланокортиновых рецепторов вносит вклад в благоприятный эффект препарата при нефротическом синдроме. Обсуждается, что иммунный механизм ингибиторов кальциневрина обеспечивается подавлением тканевого и гуморального иммунитета, а неиммунный в значительной степени обусловлен сохранением активности таких белков подоцитов, как синаптоподин и кофилин. Приведены доказательства, убеждающие, что благоприятный эффект ритуксимаба при гломерулопатиях связан с взаимодействием препарата с белком SMPDL-3b в лимфоцитах и подоцитах. Рассматриваются механизмы действия микофенолата мофетила, ингибирующего активность фермента инозин 5-монофосфатдегидрогеназы, что обусловливает подавление синтеза гуанозиновых нуклеотидов как в лимфоцитах, так и в клетках клубочкового мезангиума. Подчеркнуто, что действие левамизола при нефротическом синдроме, вероятно, связано с нормализацией соотношения цитокинов, вырабатываемых различными Т-хелперами, а также c увеличением экспрессии и активности глюкокортикоидных рецепторов. Рассмотрены механизмы фармакологической активности ряда моноклональных АТ, а также галактозы, благоприятный эффект которой, возможно, обеспечивается связыванием с предполагаемым фактором проницаемости, вырабатываемым лимфоцитами.

1. Зверев ЯФ, Рыкунова АЯ. Нарушения клубочкового фильтрационного барьера как причина протеинурии при нефротическом синдроме. Нефрология 2019;23(4):96-111. https://doi.org/10.24884/1561-6274-2019-23-4-96 Zverev YaF, Rykunova AYa. Disorders of glomerular filtration barrier as the cause of proteinuria in the nephrotic syndrome. Nephrology (Saint-Petersburg) 2019;23(4):96-111. (In Russ.)

2. Козловская ЛВ, Фомин ВВ. Нефротический синдром: подходы к диагностике и лечению. Consilium Med 2005;7(7):520-523 Kozlovskaya LV, Fomin VV. Nephrotic syndrome: approaches to diagnosis and treatment. Consilium Med 2005;7(7):520-523. (In Russ.)

3. Немцова ВД. Нефротический синдром. Часть II. Мистецтво лiкування 2008;51(5):25-30 Nemtsova VD. Nephrotic syndrome: Part II. Mystetstvo likuvannya 2008;51(5):25-30. (In Russ.)

4. Грене ГЙ, Кисс Е. Нефротический синдром: гистопатологическая дифференциальная диагностика. Часть 1: определение, классификация, патофизиология, генетические формы. Нефрология 2007;11(2):88-93 Grene GJ, Kiss E. Nephrotic syndrome: histopathologic differential diagnostics. Part 1: Definition, classification, pathophysiology, genetic forms. Nephrology (Saint-Petersburg) 2007;11(2):88-93. (In Russ.)

5. Бобкова ИН, Кахсуруева ПА, Ставровская ЕВ, Филатова ЕЕ. Эволюция в понимании патогенеза идиопатической мембранозной нефропатии: от экспериментальных моделей к клинике. Альманах клин мед 2017;45(7):553-564. https://doi.org/10.18786/2072-0505-2017-45-7-553-564 Bobkova IN, Kakhsurueva PA, Stavrovskaya EV, Filatova EE. Evolution in the understanding of idiopathic membranous nephropathy pathogenesis: from experimental models to the clinic. Almanakh klin med 2017;45(7):553-564. (In Russ)

6. Арьев АЛ, Изотова АБ. Современные представления о патогенезе идиопатического мембранозного гломерулонефрита. Нефрология 2004;8(4):92-95 Ariev AL, Izotova AB. A modern image of pathogenesis of idiopathic membranous glomerulonephritis. Nephrology (SaintPetersburg) 2004;8(4):92-95. (In Russ.)

7. Петросян ЭК. Фокально-сегментарный гломерулосклероз - этиопатогенетические, клинические и морфологические особенности. Педиатрия 2007;86(3):129-132 Petrosjan JeK. Focal segmental glomerulosclerosis - etiopathogenetic, clinical and morphological features. Pediatrics 2007;86(3):129-132. (In Russ.)

8. Смирнов АВ, Трофименко ИИ, Сиповский ВГ. Болезнь минимальных изменений у взрослых. Нефрология 2013;17(6):9-36 Smirnov AV, Trofimenko II, Sipovskiy VG. Minimal change disease in adults. Nephrology (Saint-Petersburg) 2013;16(6):9-36. In Russ.)

9. Цыгин А. Нефротический синдром при болезни минимальных изменений. Врач 2013;6:2-6 Tsygin A. Nephrotic syndrome in minimal change disease. Vrach 2013;6:2-6. (In Russ.)

10. Петросян ЭК, Длин ВВ. Клинические рекомендации по диагностике и лечению болезни минимальных изменений у детей. Нефрология 2015;19(3):90-96 Petrosjan JeK, Dlin VV. Clinical practice guidelines for the diagnostics and treatment of minimal change disease in children. Nephrology (Saint-Petersburg) 2015;19(3):90-96. (In Russ)

11. Yoo T-H, Fornoni A. Nonimmunologic targets of immunosuppressive agents in podocytes. Kidney Res Clin Pract 2015;34:69-75. https://doi.org/10.1016/j.krcp.2015.03.003

12. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000Res 2016;5.pii:F1000 Faculty Rev-412. https://doi.org/10.12688/f1000research.7300.1

13. Bierzynska A, Saleem M. Recent advances in understanding and treating nephrotic syndrome. F1000Res 2017;6:121. https://doi.org/10.12688/f1000research.10165.1

14. Wen Y, Shah S, Campbell KN. Molecular mechanisms of proteinuria in focal segmental glomerulosclerosis. Front Med (Lausanne) 2018;5:98. https://doi.org/10.3389/fmed.2018.00098

15. Мельник АА. Фокально-сегментарный гломерулосклероз: генетический анализ и целевая терапия. Почки 2018 7(1):35-49 Melnyk AA. Focal segmental glomerulosclerosis: genetic analysis and target therapy. Pochki 2018;7(1):35-49. (In Russ.)

16. Suzuki T, Matsusaka T, Nakayama M et al. Genetic podocyte lineage reveals progressive podocytopenia with parietal cell hyperplasia in a murine model of cellular/collapsing focal segmental glomerulosclreosis. Am J Pathol 2009;174(5):1675-1682. https://doi.org/10.2353/ajpath.2009.080789

17. Akchurin O, Reidy KJ. Genetic causes of proteinuria and nephrotic syndrome: Impact on podocyte pathobiology. Pediatr Nephrol 2014;30(2):221-233. https://doi.org/10.1007/s00467-014-2753-3

18. Nguyen TQ, Goldschmeding R, van den Heuvel LP. Genetic testing for podocyte genes in sporadic focal segmental glomerulosclerosis. Nephrol Dial Transplant 2014;29:1985-1986. https://doi.org/10.1093/ndt/glu247

19. Pollak MR. Familial FSGS. Adv Chronic Kidney Dis 2014;21(5):422-425. https://doi.org/10.1053/j.ackd.2014.06.001

20. Chen YM, Liapis H. Focal segmental glomerulosclerosis: molecular genetics and targeted therapies. BMC Nephrology 2015;16(101):1-10. https://doi.org/10.1186/s12882-015-0090-9

21. Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol 2015;11(2):76-87. https://doi.org/10.1038/nrneph.2014.2016

22. Trautmann A, Lipska-Ziętkiewicz BS, Schaefer F. Exploring the clinical and genetic spectrum of steroid resistant nephrotic syndrome: The PodoNet registry. Front Pediatr 2018;6:200. https://doi.org/10.3389/fped.2018.00200

23. Bensimhon AR, Williams AE, Gbadegesin RA. Treatment of steroid-resistant nephrotic syndrome in the genomic era. Pediatr Nephrol 2019;34(11):2279-2293. https://doi.org/10.1007/s00467-018-4093-1

24. Arneil GC, Wilson HEC. Cortisone treatment of nephrosis.Arch Dis Child 1952;27(134):322-328. https://doi.org/10.1136/adc.27.134.322

25. Barbieri DD. Early results of prednisone therapy of nephrotic syndromes. Minerva Med 1955;46(99):1728

26. Chaudhuri JN, Ghosal SP. Observations on prednisolone treated cases of nephrotic syndrome. Indian J Pediatr 1958;25(5):201-209. https://doi.org/10.1007/BF02903017

27. Pal A, Kaskel F. History of nephrotic syndrome and evolution of its treatment. Front Pediatr 2016;4:56. https://doi.org/10.3389/fped.2016.00056

28. Downie ML, Lallibois C, Parekh RS, Noone DG. Nephrotic syndrome in infants and children: pathophysiology and management. Pediatrics Health 2017;37(4):248-258. https://doi.org/10.1080/20469047.2017.1374003

29. Schijvens AM, ter Heine R, de Wildt SN, Schreuder MF. Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome. Pediatr Nephrol 2019;34:389-403. https://doi.org/10.1007/s00467-018-3929-z

30. Zhao J, Liu Z. Treatment of nephrotic syndrome: going beyond immunosuppressive therapy. Pediatr Nephrol 2019;March 23, Publ online. https://doi.org/10.1007/s00467-019-04225-7

31. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:139-274

32. Руденко ЕВ, Томилина НА, Захарова ЕВ. Применение Циклоспорина А для лечения нефротических типов хронических гломерулонефритов - болезни минимальных изменений и фокально-сегментарного гломерулосклероза. Нефрол диал 2015;17(2):156-172 Rudenko EV, Tomilina NA, Zakharova EV. Cyclosporin A usage for the treatment of nephrotic syndrome in glomerulonephrytes - minimal changes disease and focal segmental glomeruosclerosis. Nephrol Dial 2015;17(2):156-172. (In Russ.)

33. Yan K, Kudo A, Hirano H et al. Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus. Kidney Int 1999;56:65-73

34. Gamal Y, Badawy A, Swelam S et al. Glomerular glucocorticoid receptors expression and clinicopathological types of childhood nephrotic syndrome. Fetal Pediatr Pathol 2017;36(1):16-26. https://doi.org/10.1080/15513815.2016.1225872

35. Zhao X, Khurana S, Charkraborty S et al.αactinin 4 (ACTN4) regulates glucocorticoid receptor-mediated transactivation and transrepression in podocytes. J Biol Chem 2017;292(5):1637-1647. https://doi.org/10.1074/jbc.M116.755546

36. Wada T, Pippin JW, Marshall CB et al. Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2 related family proteins. J Am Soc Nephrol 2005;16(9):2615-2625. https://doi.org/10.1681/ASN.2005020142

37. Ransom RF, Lam NG, Hallett MA et al. Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int 2005;68(6):2473-2483. https://doi.org/10.1111/j.1523-1755.2005.00723.x

38. Xing CY, Saleem MA, Coward RJ et al. Direct effects of dexamethasone on human podocytes. Kidney Int 2006;70(6):1038- 1045. https://doi.org/10.1038/sj.ki.5001655

39. International Study of Kidney Disease in Children. The primary nephrotic syndrome in children. Identification of patients with minimal change nephritic syndrome from initial response to prednisone. J Pediatr 1981;98(4):561-564

40. Nourbakhsh N, Mak RH. Steroid-resistant nephrotic syndrome: past and current perspectives. Pediatric Health Med Ther 2017;8:29-37. https://doi.org/10.2147/PHMT.S100803

41. Iijima K, Sako M, Kamei K, Nozu K. Rituximab in steroid-sensitive nephrotic syndrome: lessons from clinical trials. Pediatr Nephrol 2018;33(9):1449-1455. https://doi.org/10.1007/s00467-017-3746-9

42. Kemper MJ, Valentin L, van Husen M. Difficult-to-treat idiopathic nephrotic syndrome: established drugs, open questions and future options. Pediatr Nephrol 2018;33(10):1641-1649. https://doi.org/10.1007/s00467-017-3780-7

43. Tullus K, Webb H, Bagga A. Management of steroidresistant nephrotic syndrome in children and adolescents. Lancet Child Adolesc Health 2018;2(12):880-890. https://doi.org/10.1016/s2352-4642(18)30283-9

44. Lieberman KV, Pavlova-Wolf A. Adrenocorticotropic hormone therapy for the treatment of idiopathic nephrotic syndrome in children and young adults: a systematic review of early clinical studies with contemporary relevance. J Nephrol 2017;30:35-44. https://doi.org/10.1007/s40620-016-0308-3

45. Bomback AS, Tumlin JA, Baranski J et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther 2011;5:147-153. https://doi.org/10.2147/DDDT.S17521

46. Bomback AS, Canetta PA, Beck LH Jr. et al. Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: a prospective trial. Am J Nephrol 2012;36(1):58-67. https://doi.org/10.1159/000339287

47. Hogan J, Bomback AS, Mehta K et al. Treatment of idiopathic FSGS with adrenocorticotropic hormone gel. Clin J Am Soc Nephrol 2013;8(12):2072-2081. https://doi.org/10.2215/CJN.02840313

48. Tumlin JA, Galphin CM, Rovin BH. Advanced diabetic nephropathy with nephrotic range proteinuria: a pilot study of the long-term efficacy of subcutaneous ACTH gel on proteinuria, progression of CKD, and urinary levels of VEGF and MCP-1. J Diabetes Res 2013;2013:489869. https://doi.org/10.1155/2013/489869

49. Watson MJ. Membranous glomerulopathy and treatment with Achtar®: a case study. Int J Nephrol Renovasc Dis 2013;6:229- 232. https://doi.org/10.2147/IJNRD.S50660

50. Hladunewich MA, Cattran D, Beck LH et al. A pilot study to determine the dose and effectiveness of adrenocorticotropic hormone (H.P.Acthar® Gel) in nephrotic syndrome due to idiopathic membranous nephropathy. Nephrol Dial Transplant 2014;29(8):1570-1577. https://doi.org/10.1093/ndt/gfu069

51. Mittal T, Dedhia P, Roy-Chaudhury P et al. Complete remission of post-transplantation recurrence of focal segmental glomerulosclerosis with the use of adrenocorticotropic hormone gel: case report. Transplant Proc 2015;47(7):2219-2222. https://doi.org/10.1016/j.transproceed.2015.07.013

52. Madan A, Mijovic-Das S, Stankovic A et al. Acthar gel in the treatment of nephrotic syndrome: a multicenter retrospective case series. BMC Nephrology 2016;17:37. https://doi.org/10.1186/s12882-016-0241-7

53. Siligato R, Cernaro V, Nardi C et al. Emerging therapeutic strategies for minimal change disease and focal and segmental glomerulosclerosis. Expert Opin Investig Drugs 2018;27(11):839- 879. https://doi.org/10.1080/13543784.2018.1540587

54. Olsen NJ, Decker DA, Higgins P et al. Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro. Arthritis Res Ther 2015;17:300-308. https://doi.org/10.1186/s13075-015-0823-y

55. Lindskog A, Ebefors K, Johansson ME et al. Melanocortin 1 receptor agonists reduce proteinuria. J Am Soc Nephrol 2010;21(8):1290-1298. https://doi.org/10.1681/ASN.2009101025

56. Elvin J, Buvall L, Lindskog Jonsson A et al. Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation. Am J Physiol Renal Physiol 2016;310(9):F846-F856. https://doi.org/10.1152/ajprenal.00231.2015

57. Gong R. Leveraging melanocortin pathways to treat glomerular diseases. Adv Chronic Kidney Dis 2014;21(2):134-151. https://doi.org/10.1053/j.ackd.2013.09.004

58. Lieberman KV, Ettinger L, Picarelli C. Adrenocorticotropic hormone for steroid-intolerant children with minimal change nephrotic syndrome. J Clin Pediatr Nephrol 2014;2:2

59. Обухова ВА, Игнатова МС, Длин ВВ. Эффективность циклоспорина при лечении стероидрезистентного нефротического синдрома у детей. Нефрология 2009;13(3):113 Obuchova VA, Ignatova MS, Dlin VV. Effectiveness ofcyclosporine in the treatment of steroid resistant nephrotic syndrome in children. Nephrology (Saint-Petersburg) 2009;13(3):113. (In Russ.)

60. Матвеева МВ, Зробок ОИ, Вашурина ТВ и др. Оценка эффективности такролимуса у детей с нефротическим синдромом, рефрактерным к терапии циклоспорином А. Педиатрия 2014;93(2):81-85 Matveeva MV, Zrobok OI, Vashurina TV et al. Evaluating the effectiveness of tacrolimus in children with nephrotic syndrome refractory to cyclosporin A therapy. Pediatrics 2014;93(2):81-85. (In Russ.)

61. Кальянова ЕВ, Бирюкова ЛС, Томилина НА и др. Течение болезни минимальных изменений у взрослых в условиях применения циклоспорина А. Нефрол диал 2013;15(4):315-316 Kalyanova EV, Biryukova LS, Tomilina ON et al. The course of the disease of minimal changes in adults under the conditions of cyclosporine A. Nephrol Dial 2013;15(4):315-316. (In Russ.)

62. Нефротический синдром у детей. Клинические рекомендации. Союз педиатров России 2016. МКБ 10:N04 Nephrotic syndrome in children. Clinical recommendations. Union of pediatricians of Russia. 2016. ICD 10: N04. (In Russ.)

63. Shah SR, Altaf A, Arshad MH et al. Use of cyclosporine therapy in steroid resistant nephrotic syndrome (SRNS): A review. Glob J Health Sci 2015;8(4):136-141. https://doi.org/10.5539/gihs.v8n4p136

64. Нестеренко ОВ, Елизарова СЮ, Горемыкин ВИ и др. Опыт использования иммуносупрессивной терапии в лечении детей с рецидивирующим нефротоксическим синдромом. Рос вестн перинатол и педиатр 2015;60(4):212 Nesterenko OV, Elizarova SYu, Goremykin VI et al. Experience in using immunosuppressive therapy in the treatment of children with recurrent nephrotic syndrome. Ros Vestn Perinatol i Pediatr 2015;60(4):212. (In Russ.)

65. Laurin L-P, Nachman PH, Foster BJ. Calcineurin inhibitors in the treatment of primary focal segmental glomerulosclerosis: a systematic review and meta-analysis of the literature. Can J Kidney Health Dis 2017;4:1-14. https://doi.org/10.1177/2054358117692559

66. Бобкова ВВ, Носов ВП, Филина ЛВ. Возможности улучшения результатов терапии стероид-резистентного нефротического синдрома. Нефрол диал 2013;15(4):307-308 Bobkova VV, Nosov VP, Filina LV. Possibilities for improving the results of treatment of steroid-resistant nephrotic syndrome. Nephrol dial 2013;15(4):307-308. (In Russ.)

67. Чеботарева НВ, Приходина ЛС, Шилов ЕМ. Стероид- и циклофосфамид-резистентный нефротический синдром. Леч врач 2013;2:65 Chebotareva NV, Prikhodina LS, Shilov EM. [Steroid - and cyclophosphamide-resistant nephrotic syndrome. Lech vrach 2013;2:65. (In Russ.)

68. Beaudreuil S, Lorenzo HK, Elias M et al. Optimal management of primary focal segmental glomerulosclerosis in adults. Int J Nephrol Renovasc Dis 2017;10:97-107. https://doi.org/10.2147/IJNRD.S126844

69. Buscher AK, Kranz B, Buscher R et al. Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2010;5(11):2075-2084. https://doi.org/10.2215/CJN.01190210

70. Buscher AK, Beck BB, Melk A et al. Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid resistant nephrotic syndrome. Clin J Am Soc Nephrol 2016;11(2):245-253. https://doi.org/10.2215/CJN.07370715

71. Клим Ф. Такролимус при трансплантации почки. Сообщение I. Нефрология 2007;11(2):7-25 Klim F. Tacrolimus in transplantation of the kidney. Communication 1. Nephrology (Saint-Petersburg) 2007;11(2):7-25. (In Russ.)

72. Arslansoyu Çamlar S, Soylu A, Kavukçu S. Cyclosporine in pediatric nephrology. Iranian J Kidney Dis 2018;12(6):319-330

73. Liu F, Mao J-H. Calcineurin inhibitors and nephrotoxicity in children. World J Pediatr 2018;14(2):121-126. https://doi.org/10.1007/s12519-018-0125-y

74. Приходина ЛС, Тупитко ОЮ, Длин ВВ, Игнатова МС. Такролимус в лечении стероид-резистентного нефротического синдрома у детей (Предварительные результаты одноцентрового исследования). Нефрол диал 2010;12(4):266-272 Prikhodina LS, Turpitko OYu, Dlin VV, Ignatova MS.Tacrolimus in treatment of steroid-resistant nephrotic syndrome in children (Preliminary results of a single-center study). Nefrol dial 2010;12(4):266-272. (In Russ.)

75. Faul C, Donnelly M, Merscher-Gomez S et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. A Nat Med 2008;14(9):931-938. https://doi.org/10.1038/nm.1857

76. Tian X, Ishibe S. Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease. Nephrol Dial Transplant 2016;31:1577-1583. https://doi.org/10.1093/ndt/gfwo21

77. Bertelli R, Bonanni A, Caridi G et al. Molecular and cellular mechanisms for proteinuria in minimal change disease. Front Med (Lausanne) 2018;5:170. https://doi.org/10.3389/fmed.2018.00170

78. Li X, Liu H. Role of cofilin in kidney disease. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018;43(10):1159-1163. https://doi.org/10.11817/j.issn.1672-7347.2018.10.018

79. Li X, Zhang X, Li X et al. Cyclosporine A protects podocytes via stabilization of cofilin-1 expression in the unphosphorylated state. Exp Biol Med (Maywood) 2014;239(8):922-936. https://doi.org/10.1177/1535370214530365

80. Shen X, Jiang H, Ying M et al. Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models. Sci Rep 2016;6:32087. https://doi.org/10.1038/srep32087

81. Nankivell BJ, P'Ng CH, O'Connell PJ, Chapman JR. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras. Transplantation 2016;100(8):1723-1731. https://doi.org/10.1097/TP.0000000000001243

82. Ponticelli C, Escoli R, Moroni G. Does cyclophosphamide still play a role in glomerular diseases? Autoimmun Rev 2018;17(10):1022-1027. https://doi.org/10.1016/j.autrev.2018.04.007

83. Madanchi N, Bitzan M, Takano T. Rituximab in minimal change disease: mechanisms of action and hypothesis for future studies. Can J Kidney Health Dis 2017;4:1-15. https://doi.org/10.1177/2054358117698667

84. Maloney DG, Grillo-López AJ, White JA et al. IDEC-C2B8 (Rituximab) anti- CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodkin’s lymphoma. Blood 1997;90(6):2188-2195

85. Benz K, Dötsch J, Rascher W, Stachel D. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 2004;19(7):794-797. https://doi.org/10.1007/s00467-004-1434-z

86. Пулин АА, Горностаева ЕЮ, Рощупкина СВ и др. Эффективность лечения ритуксимабом больного идиопатической мембранозной нефропатией, резистентной к стандартной иммуносупрессивной терапии. Клин нефрол 2011;5:72-77 Pulin AA, Gornostaeva EYu, Roschupkina SV et al. Effectiveness of treatment with rituximab in patients with idiopathic membranous nephropathy resistant to standard immunosuppressive therapy. Clin nephrol 2011;5:72-77. (In Russ.)

87. Вашурина ТВ, Зробок ОИ, Комарова ОВ и др. Применение ритуксимаба при стероид-зависимом нефротическом синдроме у детей. Нефрол диал 2016;18(1):50-61 Vashurina TV, Zrobok OI, Komarova OV et al. Rituximab treatment for idiopathic steroid-dependent nephrotic syndrome in children. Nephrol dial 2016;18(1):50-61. (In Russ.)

88. Ravani P, Bonanni A, Rossi R et al. Anti-CD20 antibodies for idiopathic nephrotic syndrome in children. Clin J Am Soc Nephrol 2016;11(4):710-720. https://doi.org/10.2215/CJN.08500815

89. Kallash M, Smoyer WE, Mahan JD. Rituximab use in the management of childhood nephrotic syndrome. Front Pediatr 2019;7:178. https://doi.org/10.3389/fped.2019.00178

90. Kamei K, Ishikura K, Sako M et al. Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol 2020;35(1):17-24. https://doi.org/10.1007/s00467-018-4166-1

91. Colucci M, Carsetti R, Cascioli S et al. B cell reconstitution after rituximab treatment in idiopathic nephrotic syndrome. J Am Soc Nephrol 2016;27:1811-1822. https://doi.org/10.1681/ASN.2015050523

92. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013;13(4):227-242. https://doi.org/10.1038/nri3405

93. Hoffman W, Lakkis FG, Chalasani G. B cells, antibodies, and more. Clin J Am Soc Nephrol 2016;11(1):137-154. https://doi.org/10.2215/CJN.09430915

94. Biancone L, Andres G, Ahn H et al. Inhibition of the CD40-CD40 ligand pathway prevents murine membranous glomerulonephritis. Kidney Int 1995;48(2):458-468. https://doi.org/10.1038/ki.1995.314

95. Kairaitis L, Wang Y, Zheng L et al. Blockade of CD40-CD40 ligand protects against renal injury in chronic proteinuric renal disease. Kidney Int 2003;64(4):1265-1272. https://doi.org/10.1046/j.1523-1755.2003.00223.x

96. Lee VW, Qin X, Wang Y et al. The CD4-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis. Nephrol Dial Transplant 2010;25(3):717-730. https://doi.org/10.1093/ndt/gfp569

97. Prasad N, Jaiswal AK, Agarwal V et al. Differential alteration in peripheral T-regulatory and T-effector cells with change in P-glycoprotein expression in Childhood Nephrotic Syndrome: a longitudinal study. Cytokine 2015;72(2):190-196. https://doi.org/10.1016/j.cyto.2014.12.028

98. Araya C, Diaz L, Wasserfall C et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 2009;24(9):1691-1698. https://doi.org/10.1007/s00467-009-1214-x

99. Le Berre L, Bruneau S, Naulet J et al. Induction of T regulatory cells attenuates idiopathic nephrotic syndrome. J Am Soc Nephrol 2009;20(1):57-67. https://doi.org/10.1681/ASN.2007111244

100. Sfikakis PP, Souliotis VL, Fragiadaki KG et al. Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin Immunol 2007;123(1):66-73. https://doi.org/j.clim.2006.12.006

101. Stasi R, Cooper N, Del Poeta G et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008;112(4):1147-1150. https://doi.org/10.1182/blood-2007-12-129262

102. van de Veerdonk FL, Lauwerys B, Marijnissen RJ et al. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum 2011;63(6):1507-1516. https://doi.org/10.1002/art.30314

103. Melet J, Mulleman D, Goupille P et al. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum 2013;65(11):2783-2790. https://doi.org/10.1002/art.38107

104. Eggleton P, Bremer E. Direct and indirect rituximabinduced T cell depletion: comment on the article by Melet et al. Arthritis Rheum 2014;66(4):1053. https://doi.org/10.1002/art.38347

105. Piantoni S, Scarsi M, Tincani A, Airò P. Circulating CD40Tcell number decreases in rheumatoid patients with clinical response to rituximab. Rheumatol Int 2015;35(9):1571-1573. https://doi.org/10.1007/s00296-015-3295-0

106. Alunno A, Carubbi F, Bistoni O et al. Interleukin (IL)-17- producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjorgen's syndrome: a pilot study. Clin Exp Immunol 2016;184(3):284-292. https://doi.org/10.1111/cei.12771

107. Roccatello D, Sciascia S, Di Simone D et al. New insights into immune mechanisms underlying response to Rituximab in patients with membranous nephropathy: a prospective study and a review of the literature. Autoimmun Rev 2016;15(6):529-538. https://doi.org/10.1016/j.autrev.2016.02.014

108. Fornoni A, Sageshima J, Wei C et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 2011;3(85):85ra46. https://doi.org/10.1126/scitranslmed.3002231

109. Yoo TH, Pedigo CE, Guzman J et al. Sphingomyelinaselike phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. J Am Soc Nephrol 2015;26(1):133-147. https://doi.org/10.1681/ASN.2013111213

110. Мершер С, Форнони А. Патология подоцитов и нефропатия - роль сфинголипидов в гломерулярных болезнях. Нефрология 2016; 20(1):10-23 Merscher S, Fornoni A. Podocyte pathology and nephropathy - sphingolipids in glomerular diseases. Nephrology (SaintPetersburg) 2016;20(1):10-23. (In Russ.)

111. Takahashi Y, Ikezumi Y, Saitoh A. Rituximab protects podocytes and exerts anti-proteinuric effects in rat adriamycininduced nephropathy independent of B-lymphocytes. Nephrology 2017;22(1):49-57. https://doi.org/10.1111/nep.12737

112. Allison AC, Kowalski WJ, Muller CD, Eugui EM. Mechanisms of action of mycophenolic acid. Ann N Y Acad Sci 1993;696:63-87. https://doi.org/10.1111/j.1749-6632.1993.tb17143.x

113. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47(2-3): 85-118. https://doi.org/10.1016/s0162-3109(00)00188-0

114. Hackl A, Ehren R, Weber LT. Effect of mycophenolic acid in experimental, nontransplant glomerular diseases: new mechanisms beyond immune cells. Pediatr Nephrol. 2017; 32(8): 1315-1322. https://doi.org/10.1007/s00467-016-3437-y

115. Приходина ЛС, Турпитко ОЮ, Длин ВВ, Игнатова МС. Микофенолата мофетил в лечении стероид-резистентного нефротического синдрома у детей. Клин нефрол 2011;2:56-60 Prikhodina LS, Turpitko OYu, Dlin VV, Ignatova MS. Mycophenolate mofetil in the treatment of steroid-resistant nephrotic syndrome in children. Clin nephrol 2011;2:56-60. (In Russ.)

116. Вознесенская ТС, Сергеева ТВ. Мофетила микофенолат в терапии нефротического синдрома у детей. Нефрол диал 2003;5(1):45-47 Voznesenskaya TS, Sergeeva TV. Mofetil mycophenolate in the treatment of nephrotic syndrome in children. Nephrol dial 2003;5(1):45-47. (In Russ.)

117. Канатбаева АБ, Диканбаева СА, Абеулова БА и др. Микофенолата мофетил в терапии гломерулопатий у детей. Нефрол диал 2006; 8(4): 355-358 Kanatbaeva AB, Dikanbaeva SA, Abeulova BA et al. Mycophenolate mofetil in the treatment of glomerulopathy in children. Nephrol dial 2006;8(4):355-358. (In Russ.)

118. Briggs WA, Choi MJ, Scheel PJ. Successful mycophenolate mofetil treatment of glomerular disease. Am J Kidney Dis 1998;31(2):213-217. https://doi.org/10.1053/ajkd.1998.v.31.pm9469489

119. Senthi Nayagam L, Ganguli A, Rathi M et al. Mycophenolate mofetil or standart therapy for membranous nephropathy and focal segmental glomerulosclerosis: a pilot study. Nephrol Dial Transplant 2008;23(6):1926-1930. https://doi.org/10.1093/ndt/gfm538

120. Kim J, Patnaik N, Chorny N et al. Second-line immunosuppressive treatment of childhood nephrotic syndrome: a single-center experience. Nephron Extra 2014;4(1):8-17. https://doi.org/10.1159/000357355

121. Dehoux L, Hoqan J, Dossier C et al. Mycophenolate mofetil in steroid-dependent idiopathic nephrotic syndrome. Pediatr Nephrol 2016;31(11):2095-2101. https://doi.org/10.1007/s00467-016-3400-y

122. Han KH, Kim SH. Recent advances and treatments of primary focal segmental glomerulosclerosis in children. BioMed Res Intern 2016;2016:30537706. https://doi.org/10.1155/2016/3053706

123. Afzal K, Bagga A, Menon S et al. Treatment with mycophenolate mofetil and prednisolone for sterjid-dependent nephrotic syndrome. Pediatr Nephrol 2007;22(12):2059-2065. https://doi.org/10.1007/s00467-007-0617-9

124. Dorresteijn EM, Kist-van Holthe JE, Levtchenko EN et al. Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome. Pediatr Nephrol 2008;23(11):2013- 2020. https://doi.org/10.1007/s00467-008-0899-6

125. Sinha A, Gupta A, Kalaivani M et al. Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome. Kidney Int 2017;92(1):248-257. https://doi.org/10.1016/j.kint.2017.01.019

126. Halloran PF. Molecular mechanisms of new immunosuppressants. Clin Transplant 1996;10(1 Pt 2):118-123

127. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005;14(Suppl 1):s2-s8

128. Blaheta RA, Leckel K, Witting B et al. Mycophenolate mofetil impairs transendothelial migration of allogeneic CD4 and CD8 T-cells. Transplant Proc 1999;31(1-2):1250-1252. https://doi.org/10.1016/s0041-1345(98)01984-8

129. Cohn RG, Mirkovich A, Dunlap B et al. Mecophenolic acid increases apoptosis, lysosomes and lipid droplets in human lymphoid and monocytic cell lines. Transplantation 1996;68(3): 411-418. https://doi.org/10.1097/00007890-199908150-00014

130. Cohn RG, Mirkovich A, Caulfield J, Eugui EM. Apoptosis of human activated peripheral T-cells and T lymphocitic and promonocytic cell lines induced by mycophenolic acid, the active metabolite of CellCept. In: The Sixth Basic Sciences Symposium of the Transplantation Society. Monterey, CA, 1999; 173

131. Andrikos E, Yavuz A, Bordoni V et al. Effect of cyclosporine mycophenolate mofetil, and their combination with steroids on apoptosis in a human cultured monocytic U937 cell line. Transplant Proc 2005;37(7):3226-3229. https://doi.org/10.1016/j.transproceed.2005.07.001

132. Nakamura M, Ogawa N, Shalabi A et al. Positive effect on T-cell regulatory apoptosis by mycophenolate mofetil. Clin Transplant 2001;15(Suppl 6):36-40

133. Takahashi K, Reynolds M, Ogawa N et al. Augmentation of T-cell apoptosis by immunosuppressive agents. Clin Transplant 2004;18(Suppl 12):72-75. https://doi.org/10.1111/j.1399-0012.2004.00222.x

134. Ziswiler R, Steinmann-Niggli K, Kappeler A et al. Mycophenolic acid: a new approach to the therapy of experimental mesangial proliferative glomerulonephritis. J Am Soc Nephrol 1998;9(11):2055-2066

135. Hauser IA, Renders L, Radeke HH et al. Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion. Nephrol Dial Transplant 1999;14(1):58-63. https://doi.org/10.1093/ndt/14.1.58

136. Chiara M, Menegatti E, Di Simone D et al. Mycophenolate mofetil and roscovitine decrease cyclin expression and increase p27 (kip1) expression in anti Thy1 mesangial proliferative nephritis. Clin Exp Immunol 2005;139(2):225-235. https://doi.org/10.1111/j.1365-2249.2004.02684.x

137. Nakhoul F, Ramadan R, Khankin E et al. Glomerular abundance of nephrin and podocin in experimental nephrotic syndrome: different effects of antiproteinuric therapies. Am J Physiol Renal Pgysiol 2005;289(4):880-890. https://doi.org/10.1152/ajprenal.00451.2004

138. Lv W, Lou J, Zhang Y et al. Mycophenolate mofetil inhibits hypertrophy and apoptosis of podocyte in vivo and in vitro. Int J Clin Exp Med 2015;8(10):19781-19790

139. Lv W, Zhang Y, Guan G et al. Mycophenolate mofetil and valsartan inhibit podocyte apoptosis in streptozotocin-induced diabetic rats. Pharmacology 2013;92(3-4):227-234. https://doi.org/10.1159/000354600

140. Imaizumi T, Kawasaki Y, Matsuura H et al. Efficacy of steroid pulse, plasmapheresis, and mizoribine in a patient with focal segmental glomerulosclerosis. Pediatr Nephrol 2007;22(8):1215- 1218. https://doi.org/10.1007/s00467-007-0461-y

141. Aizawa-Yashiro T, Tsuruda K, Watanabe S et al. Novel multidrug therapy for children with cyclosporine-resistant or -intolerant nephrotic syndrome. Pediat Nephrol 2011;26(8):1255-1261. https://doi.org/10.1007/s00467-011-1876-z

142. Tanphaichitr P, Tanphaichitr D, Sureeratanan J, Chatasingh S. Treatment of nephrotic syndrome with levamisole. J Pediatr 1980;96(3 Pt 1):490-493. https://doi.org/10.1016/S0022-3476(80)80707-4

143. British Association for Paediatric Nephrology. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. Lancet 1991;337(8757):1555-1557

144. Bagga A, Ali U, Banerjee S et al. Management of steroid sensitive nephrotic syndrome: revised guidelines. Indian Pediatr 2008;45(3):203-214

145. Gruppen MB, Bouts AH, Jansen-van der Weide MC et al. A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome. Kidney Int 2018;93(2):510-518. https://doi.org/10.1016/j.kint.2017.08.011

146. Kemper MJ, Neuhaus TJ. Levamisole in relapsing steroidsensitive nephrotic syndrome: Where do we stand? Kidney Int 2018;93(2):310-313. https://doi.org/10.1016/j.kint.2017.09.024

147. Sinha A, Puraswani M, Kalaivani M et al. Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an open-label randomized controlled trial. Kidney Int 2019;95(1):210-218. https://doi.org/10.1016/j.kint.2018.08.039

148. Yap HK, Cheung W, Murugasu B et al. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol 1999;10(3):529-537

149. Shalaby SA, Al-Edressi HM, El-Tarhouny SA et al. Type1/ type2 cytokine serum levels and role of interleukin-18 in children with steroid-sensitive nephrotic syndrome. Arab J Nephrol Transpl 2013;6(2):83-88

150. Kim AH, Chung JJ, Akilesh S et al. B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2017;2(21): e81836. https://doi.org/10.1172/jci.insight.81836

151. Mühlig AK, Lee JY, Kemper MJ. et al. Levamisole in children with idiopathic nephrotic syndrome: clinical efficacy and pathophysiological aspects. J Clin Med 2019; 8(6):E860. https://doi.org/10.3390/jcm8060860

152. Szeto C, Gillespie KM, Mathieson PW. Levamisole induces interleukin-18 and shifts type1/type2 cytokine balance. Immunology 2000;100(2):217-224. https://doi.org/10.1046/j.1365-2567.2000.00042.x

153. Jiang L, Dasgupta I, Hurcombe JA et al. Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte. Clin Sci (Lond) 2015;128(12):883-893. https://doi.org/10.1042/CS20140749

154. Basu B. Ofatumumab for rituximab-resistant nephrotic syndrome. N Engl J Med 2014;370(13):1268-1270. https://doi.org/10.1056/NEJMc1308488

155. Bonanni A, Rossi R, Murtas C, Ghiggeri GM. Low-dose ofatumumab for rituximab-resistant nephrotic syndrome. BMJ Case Rep 2015; 2015:bcr2015210208. https://doi.org/10.1136/bcr-2015-210208

156. Ravani P, Bonanni A, Ghiggeri GM. Randomised controlled trial comparing ofatumumab to rituximab in children with steroiddependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: study protocol. BMJ Open 2017;7(3):e013319. https://doi.org/10.1136/bmjopen-2016-013319

157. Wang C, Liverman RS, Garro R et al. Ofatumumab for treatment of childhood nephrotic syndrome. Pediatr Nephrol 2017;32(5):835-841. https://doi.org/10.1007/s00467-017-3621-8

158. Joy MS, Gipson DS, Powell L et al. Phase 1 trial of adalimumab in Focal Segmental Glomeruloslerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group. Am J Kidney Dis 2010;55(1):50-60. https://doi.org/10.1053/j.ajkd.2009.08.019

159. Peyser A, Machardy N, Tarapore F et al. Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study. BMC Nephrol 2010;11:2. https://doi.org/10.1186/1471-2369-11-2

160. Trachtman H, Vento S, Herreshoff E et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of font clinical trial group. BMC Nephrol 2015;16:111. https://doi.org/10.1186/s12882-015-0094-5

161. Trachtman H, Fervenza FC, Gipson DS et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 2011;79(11):1236-1243. https://doi.org/10.1038/ki.2011.33

162. Ling H, Li X, Jha S et al. Therapeutic role ofTGF-beta-neutralizing antibody in mouse cyclosporin A nephropathy: morphologic improvement associated with functional preservation. J Am Soc Nephrol 2003;14(2):377-388. https://doi.org/10.1097/01.asn.0000042168.43665.9b

163. 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. Kidney Int Rep 2017;2(5):800-810. https://doi.org/10.1016/jekir.2017.03.011

164. Delville M, Sigdel TK, Wei C et al. A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 2014;6(256):256ra136. https://doi.org/10.1126/scitranslmed.3008538

165. Sansom DM. CD28, CTLA-4, and their ligands: who does what and to whom? Immunology 2000;101(2):169-177. https://doi.org/10.1046/j.1365-2567.2000.00121.x

166. Novelli R, Benigni A, Remuzzi G. The role of B7-1 in proteinuria of glomerular origin. Nat Rev Nephrol 2018;14(9):589-596. https://doi.org/10.1038/s41581-018-0037-z

167. Gardner D, Jeffery LE, Sansom DM. Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. Am J Transplant 2014;14(9):1985-1991. https://doi.org/10.1111/ajt.12834

168. Reiser J, von Gersdorff G, Loos M et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 2004;113:1390-1397. https://doi.org/10.1172/JCI20402

169. Yu CC, Fornoni A, Weins A et al. Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 2013;369(25):2416-2423. https://doi.org/10.1056/MEJMoa1304572

170. Savin VJ, McCarthy ET, Sharma R et al. Galactose binds to focal segmental glomerulosclerosis permeability factor and inhibits its activity. Transl Res 2008;151(6):288-292. https://doi.org/10.1016/j.trsl.2008.04.001

171. De Smet E, Rioux JP, Ammann H et al. FSGS permeability factor-associated nephrotic syndrome: remission after oral galactose therapy. Nephrol Dial Transplant 2009;24(9):2938-2940. https://doi.org/10.1093/ndt/gfp278

172. Kopac M, Meglic A, Rus RR. Partial remission of resistant nephrotic syndrome after oral galactose therapy. Ther Apher Dial 2011;15(3):269-272. https://doi.org/10.1111/j.1744-9987.2011.00949.x

173. Sgambat K, Banks M, Moudgil A. Effect of galactose on glomerular permeability and proteinuria in steroid-resistant nephrotic syndrome. Pediatr Nephrol 2013;28(11):2131-2135. https://doi.org/10.1007/s00467-013-2539-z