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Современные тенденции в диагностике и лечении иммуновоспалительных заболеваний почек: трансляция фундаментальных открытий в клиническую практику
Современные тенденции в диагностике и лечении иммуновоспалительных заболеваний почек: трансляция фундаментальных открытий в клиническую практику
Буланов Н.М., Моисеев С.В. Современные тенденции в диагностике и лечении иммуновоспалительных заболеваний почек: трансляция фундаментальных открытий в клиническую практику. Терапевтический архив. 2023;95(12):1075–1082. DOI: 10.26442/00403660.2023.12.202502
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
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Аннотация
Гломеруло- и тубулоинтерстициальные нефриты – не ведущая причина развития хронической болезни почек в популяции, но сложности их диагностики и лечения, а также более быстрые по сравнению с сахарным диабетом и артериальной гипертензией темпы прогрессирования почечной дисфункции обосновывают актуальность решения этой проблемы для внутренней медицины. Благодаря фундаментальным открытиям в области морфологии и патофизиологии, а также внедрению различных методов лабораторного и инструментального обследования во второй половине XX в. стал возможным существенный прогресс в диагностике и лечении этой группы заболеваний. Современные стандарты диагностики подразумевают комплексную оценку клинико-лабораторных и гистологических данных с целью верификации нозологической формы заболевания. Накопление знаний о патогенезе этой группы нозологий привело к очередному пересмотру подхода к классификации гломерулонефритов, в основе которого должен лежать патогенетический принцип с выделением фенотипов, ассоциированных с инфекциями, аутоиммунными, аутовоспалительными и аллоиммунными реакциями, а также моноклональной гаммапатией, с обязательной оценкой активности иммунного воспаления и склеротических изменений (хронизация) в ткани почки. Стал возможным персонализированный выбор оптимальной тактики лечения на основании не только нозологической формы, но и тяжести течения заболевания, а также индивидуальных особенностей пациента. При этом ведущими тенденциями становятся рациональное применение глюкокортикостероидов (стероид-сберегающие схемы) и неселективных цитостатиков, в первую очередь циклофосфамида, а также внедрение мультитаргетных схем лечения, в том числе с использованием биологических препаратов и малых молекул, избирательно подавляющих B-лимфоциты или различные пути активации системы комплемента. Помимо иммуносупрессивной терапии обязательным компонентом лечения стала нефропротективная терапия, основанная на применении не только традиционных антагонистов ренин-ангиотензин-альдостероновой системы, но и антагонистов эндотелиновых рецепторов, а также ингибиторов натрийглюкозного котранспортера 2-го типа. Не меньшее значение придается немедикаментозным компонентам нефропротективной стратегии. Рациональная комбинация этих подходов позволяет оптимизировать подходы к ведению пациентов с иммуновоспалительными заболеваниями почек, однако требует от врача глубокой подготовки и приверженности зафиксированным в рекомендациях принципам.
Ключевые слова: гломерулонефрит, тубулоинтерстициальный нефрит, иммуносупрессивная терапия, нефропротективная терапия, хроническая болезнь почек
Keywords: glomerulonephritis, tubulointerstitial nephritis, immune suppressive therapy, nephroprotection, chronic kidney disease
Ключевые слова: гломерулонефрит, тубулоинтерстициальный нефрит, иммуносупрессивная терапия, нефропротективная терапия, хроническая болезнь почек
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Keywords: glomerulonephritis, tubulointerstitial nephritis, immune suppressive therapy, nephroprotection, chronic kidney disease
Полный текст
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73. Taguma Y, Kitamoto Y, Futaki G, et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl J Med. 1985;313(26):1617-20. DOI:10.1056/NEJM198512263132601
74. Pitcher D, Braddon F, Hendry B, et al. Long-term outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727-38. DOI:10.2215/CJN.0000000000000135
75. Caravaca-Fontán F, Stevens K, Padrón M, et al. Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis. Nephrol Dial Transplant. 2023:gfad175. DOI:10.1093/ndt/gfad175
76. Heerspink HJL, Radhakrishnan J, Alpers CE, et al. Sparsentan in patients with IgA nephropathy: A prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023;401(10388):1584-94. DOI:10.1016/S0140-6736(23)00569-X
77. Stern EP, Host LV, Wanjiku I, et al. Zibotentan in systemic sclerosis-associated chronic kidney disease: A phase II randomised placebo-controlled trial. Arthritis Res Ther. 2022;24(1):130. DOI:10.1186/S13075-022-02818-6
2. Rhee CM, Kovesdy CP. Spotlight on CKD deaths – increasing mortality worldwide. Nat Rev Nephrol. 2015;11(4):199. DOI:10.1038/NRNEPH.2015.25
3. Jager KJ, Kovesdy C, Langham R, et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019;96(5):1048-50. DOI:10.1016/J.KINT.2019.07.012
4. Esayan AM, Arutyunov GP, Melikhov OG. Prevalence of chronic kidney disease among primary care patients in 12 regions of Russia. Clinical Nephrology. 2021;13(3):6-16 (in Russian). DOI:10.18565/nephrology.2021.3.6-16
5. Heron M. Deaths: Leading causes for 2019. Natl Vital Stat Rep. 2021;70(9):1-114. DOI:10.15620/cdc:107021
6. Ahmad FB, Cisewski JA, Xu J, Anderson RN. COVID-19 Mortality Update – United States, 2022. MMWR Morb Mortal Wkly Rep. 2023;72(18):493-6. DOI:10.15585/MMWR.MM7218A4
7. Rumyantseva EI. Chronic kidney disease as a global public health problem: Trends in morbidity and mortality. Health Care Standardization Problems. 2021;1-2:41-9 (in Russian). DOI:10.26347/1607-2502202101-02041-049
8. Hesaraki M, Behzadmehr R, Goli H, et al. Causes of chronic kidney disease in the general population of Iran: A systematic review and meta-analysis. Nephrol Ther. 2022;18(7):584-90. DOI:10.1016/J.NEPHRO.2022.09.001
9. Bowman W. On the structure and use of the Malpighian bodies of the kidney, with observations on the circulation through that gland. Philos Trans R Soc Lond. 1842;132:57-80. DOI:10.1098/RSTL.1842.0005
10. Morel F. The loop of Henle, a turning-point in the history of kidney physiology. Nephrol Dial Transplant. 1999;14(10):2510-5. DOI:10.1093/NDT/14.10.2510
11. Fogazzi GB, Cameron JS. Urinary microscopy from the seventeenth century to the present day. Kidney Int. 1996;50(3):1058-68. DOI:10.1038/KI.1996.409
12. Richet G. From Bright’s disease to modern nephrology: Pierre Rayer’s innovative method of clinical investigation. Kidney Int. 1991;39(4):787-92. DOI:10.1038/KI.1991.96
13. Jaffe M. Ueber den Niederschlag, welchen Pikrinsäure in normalem Harn erzeugt und Über eine neue Reaction des Kreatinins. Z Physiol Chem. 1886;10:391-400. DOI:10.1515/bchm1.1886.10.5.391
14. Cameron S, Hicks J. The introduction of renal biopsy into nephrology from 1901 to 1961: A paradigm of the forming of nephrology by technology. Am J Nephrol. 1997;17(3-4):347-58. DOI:10.1159/000169122
15. Mellors RC, Arias-Stella J, Siegel M, Pressman D. Analytical pathology. II. Histopathologic demonstration of glomerular-localizing antibodies in experimental glomerulonephritis. Am J Pathol. 1955;31(4):687-715. PMID:14388127
16. Farquhar MG, Vernier RL, Good RA. An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus. J Exp Med. 1957;106(5):649-60. DOI:10.1084/JEM.106.5.649
17. Germuth FG Jr, McKinnon GE. Studies on the biological properties of antigen-antibody complexes. I. Anaphylatic shock induced by soluble antigen-antibody complexes in unsensitized normal guinea pigs. Bull Johns Hopkins Hosp. 1957;101(1):13-44. PMID:13436933
18. Dixon FJ. The pathogenesis of glomerulonephritis. Am J Med. 1968;44(4):493-8. DOI:10.1016/0002-9343(68)90050-8
19. Lerner RA, Glassock RJ, Dixon FJ. The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med. 1967;126(6):989-1004. DOI:10.1084/JEM.126.6.989
20. Beck LH, Bonegio RGB, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21. DOI:10.1056/NEJMOA0810457
21. van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet. 1985;325(8426):425-9. DOI:10.1016/S0140-6736(85)91147-X
22. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63(3):1164-77. DOI:10.1046/j.1523-1755.2003.00843.x
23. Willows J, Brown M, Sheerin NS. The role of complement in kidney disease. Clin Med (Lond). 2020;20(2):156-60. DOI:10.7861/CLINMED.2019-0452
24. Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):S1-S276. DOI:10.1016/j.kint.2021.05.021
25. Tomana M, Novak J, Julian BA, et al. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest. 1999;104(1):73-81. DOI:10.1172/JCI5535
26. Sethi S, Madden B. Mapping antigens of membranous nephropathy: Almost there. Kidney Int. 2023;103(3):469-72. DOI:10.1016/j.kint.2023.01.003
27. Watts AJB, Keller KH, Lerner G, et al. Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol. 2021;33(1):238-52. DOI:10.1681/ASN.2021060794
28. Nasr SH, Vrana JA, Dasari S, et al. DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep. 2018;3(1):56-64. DOI:10.1016/J.EKIR.2017.07.017
29. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539-51. DOI:10.1056/NEJMRA1104650
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50. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with de novo minimal change disease: A multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-18. DOI:10.2215/CJN.06180519
51. Li X, Liu Z, Wang L, et al. Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome. J Am Soc Nephrol. 2017;28(4):1286-95. DOI:10.1681/ASN.2016030342
52. Duncan N, Dhaygude A, Owen J, et al. Treatment of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. Nephrol Dial Transplant. 2004;19(12):3062-7. DOI:10.1093/NDT/GFH536
53. Mahevas M, Audard V, Rousseau A, et al. Efficacy and safety of methylprednisolone pulse followed by oral prednisone vs. oral prednisone alone in sarcoidosis tubulointerstitial nephritis: A randomized, open-label, controlled clinical trial. Nephrol Dial Transplant. 2023;38(4):961-8. DOI:10.1093/NDT/GFAC227
54. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79(6):S713-23. DOI:10.1136/annrheumdis-2020-216924
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57. Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. J Am Soc Nephrol. 2017;28(1):348-58. DOI:10.1681/ASN.2016040449
58. 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
59. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-32. DOI:10.1056/NEJMoa0909905
60. Jones RB, Tervaert JWC, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-20. DOI:10.1056/NEJMoa0909169
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64. Fakhouri F, Schwotzer N, Golshayan D, Frémeaux-Bacchi V.The rational use of complement inhibitors in kidney diseases. Kidney Int Rep. 2022;7(6):1165-78. DOI:10.1016/J.EKIR.2022.02.021
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68. Cortazar FB, Cerda J, Dhanani R, et al. Avacopan in patients with rapidly progressive glomerulonephritis requiring dialysis. Kidney Int Rep. 2023;8(8):1687-91. DOI:10.1016/J.EKIR.2023.05.017
69. Uhlin F, Szpirt W, Kronbichler A, et al. Endopeptidase cleavage of anti-glomerular basement membrane antibodies in vivo in severe kidney disease: An open-label phase 2a study. J Am Soc Nephrol. 2022;33(4):829-38. DOI:10.1681/ASN.2021111460
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71. Melica ME, Antonelli G, Semeraro R, et al. Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice. Sci Transl Med. 2022;14(657). DOI:10.1126/SCITRANSLMED.ABG3277
72. Ruggenenti P, Perna A, Mosconi L, et al. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-63. DOI:10.1016/S0140-6736(96)11445-8
73. Taguma Y, Kitamoto Y, Futaki G, et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl J Med. 1985;313(26):1617-20. DOI:10.1056/NEJM198512263132601
74. Pitcher D, Braddon F, Hendry B, et al. Long-term outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727-38. DOI:10.2215/CJN.0000000000000135
75. Caravaca-Fontán F, Stevens K, Padrón M, et al. Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis. Nephrol Dial Transplant. 2023:gfad175. DOI:10.1093/ndt/gfad175
76. Heerspink HJL, Radhakrishnan J, Alpers CE, et al. Sparsentan in patients with IgA nephropathy: A prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023;401(10388):1584-94. DOI:10.1016/S0140-6736(23)00569-X
77. Stern EP, Host LV, Wanjiku I, et al. Zibotentan in systemic sclerosis-associated chronic kidney disease: A phase II randomised placebo-controlled trial. Arthritis Res Ther. 2022;24(1):130. DOI:10.1186/S13075-022-02818-6
2. Rhee CM, Kovesdy CP. Spotlight on CKD deaths – increasing mortality worldwide. Nat Rev Nephrol. 2015;11(4):199. DOI:10.1038/NRNEPH.2015.25
3. Jager KJ, Kovesdy C, Langham R, et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019;96(5):1048-50. DOI:10.1016/J.KINT.2019.07.012
4. Есаян А.М., Арутюнов Г.П., Мелихов О.Г. Распространенность хронической болезни почек среди пациентов, обратившихся в учреждения первичной медико-санитарной помощи. Результаты проспективного наблюдательного исследования в 12 регионах России. Клиническая нефрология. 2021;13(3):6-16 [Esayan AM, Arutyunov GP, Melikhov OG. Prevalence of chronic kidney disease among primary care patients in 12 regions of Russia. Clinical Nephrology. 2021;13(3):6-16 (in Russian)]. DOI:10.18565/nephrology.2021.3.6-16
5. Heron M. Deaths: Leading causes for 2019. Natl Vital Stat Rep. 2021;70(9):1-114. DOI:10.15620/cdc:107021
6. Ahmad FB, Cisewski JA, Xu J, Anderson RN. COVID-19 Mortality Update – United States, 2022. MMWR Morb Mortal Wkly Rep. 2023;72(18):493-6. DOI:10.15585/MMWR.MM7218A4
7. Румянцева Е.И. Хроническая болезнь почек как глобальная проблема для общественного здоровья: динамика заболеваемости и смертности. Проблемы стандартизации в здравоохранении. 2021;1-2:41-9 [Rumyantseva EI. Chronic kidney disease as a global public health problem: Trends in morbidity and mortality. Health Care Standardization Problems. 2021;1-2:41-9 (in Russian)]. DOI:10.26347/1607-2502202101-02041-049
8. Hesaraki M, Behzadmehr R, Goli H, et al. Causes of chronic kidney disease in the general population of Iran: A systematic review and meta-analysis. Nephrol Ther. 2022;18(7):584-90. DOI:10.1016/J.NEPHRO.2022.09.001
9. Bowman W. On the structure and use of the Malpighian bodies of the kidney, with observations on the circulation through that gland. Philos Trans R Soc Lond. 1842;132:57-80. DOI:10.1098/RSTL.1842.0005
10. Morel F. The loop of Henle, a turning-point in the history of kidney physiology. Nephrol Dial Transplant. 1999;14(10):2510-5. DOI:10.1093/NDT/14.10.2510
11. Fogazzi GB, Cameron JS. Urinary microscopy from the seventeenth century to the present day. Kidney Int. 1996;50(3):1058-68. DOI:10.1038/KI.1996.409
12. Richet G. From Bright’s disease to modern nephrology: Pierre Rayer’s innovative method of clinical investigation. Kidney Int. 1991;39(4):787-92. DOI:10.1038/KI.1991.96
13. Jaffe M. Ueber den Niederschlag, welchen Pikrinsäure in normalem Harn erzeugt und Über eine neue Reaction des Kreatinins. Z Physiol Chem. 1886;10:391-400. DOI:10.1515/bchm1.1886.10.5.391
14. Cameron S, Hicks J. The introduction of renal biopsy into nephrology from 1901 to 1961: A paradigm of the forming of nephrology by technology. Am J Nephrol. 1997;17(3-4):347-58. DOI:10.1159/000169122
15. Mellors RC, Arias-Stella J, Siegel M, Pressman D. Analytical pathology. II. Histopathologic demonstration of glomerular-localizing antibodies in experimental glomerulonephritis. Am J Pathol. 1955;31(4):687-715. PMID:14388127
16. Farquhar MG, Vernier RL, Good RA. An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus. J Exp Med. 1957;106(5):649-60. DOI:10.1084/JEM.106.5.649
17. Germuth FG Jr, McKinnon GE. Studies on the biological properties of antigen-antibody complexes. I. Anaphylatic shock induced by soluble antigen-antibody complexes in unsensitized normal guinea pigs. Bull Johns Hopkins Hosp. 1957;101(1):13-44. PMID:13436933
18. Dixon FJ. The pathogenesis of glomerulonephritis. Am J Med. 1968;44(4):493-8. DOI:10.1016/0002-9343(68)90050-8
19. Lerner RA, Glassock RJ, Dixon FJ. The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med. 1967;126(6):989-1004. DOI:10.1084/JEM.126.6.989
20. Beck LH, Bonegio RGB, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21. DOI:10.1056/NEJMOA0810457
21. van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet. 1985;325(8426):425-9. DOI:10.1016/S0140-6736(85)91147-X
22. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63(3):1164-77. DOI:10.1046/j.1523-1755.2003.00843.x
23. Willows J, Brown M, Sheerin NS. The role of complement in kidney disease. Clin Med (Lond). 2020;20(2):156-60. DOI:10.7861/CLINMED.2019-0452
24. Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):S1-S276. DOI:10.1016/j.kint.2021.05.021
25. Tomana M, Novak J, Julian BA, et al. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest. 1999;104(1):73-81. DOI:10.1172/JCI5535
26. Sethi S, Madden B. Mapping antigens of membranous nephropathy: Almost there. Kidney Int. 2023;103(3):469-72. DOI:10.1016/j.kint.2023.01.003
27. Watts AJB, Keller KH, Lerner G, et al. Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol. 2021;33(1):238-52. DOI:10.1681/ASN.2021060794
28. Nasr SH, Vrana JA, Dasari S, et al. DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep. 2018;3(1):56-64. DOI:10.1016/J.EKIR.2017.07.017
29. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539-51. DOI:10.1056/NEJMRA1104650
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50. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with de novo minimal change disease: A multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-18. DOI:10.2215/CJN.06180519
51. Li X, Liu Z, Wang L, et al. Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome. J Am Soc Nephrol. 2017;28(4):1286-95. DOI:10.1681/ASN.2016030342
52. Duncan N, Dhaygude A, Owen J, et al. Treatment of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. Nephrol Dial Transplant. 2004;19(12):3062-7. DOI:10.1093/NDT/GFH536
53. Mahevas M, Audard V, Rousseau A, et al. Efficacy and safety of methylprednisolone pulse followed by oral prednisone vs. oral prednisone alone in sarcoidosis tubulointerstitial nephritis: A randomized, open-label, controlled clinical trial. Nephrol Dial Transplant. 2023;38(4):961-8. DOI:10.1093/NDT/GFAC227
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Авторы
Н.М. Буланов*, С.В. Моисеев
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*bulanov_n_m@staff.sechenov.ru
Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
*bulanov_n_m@staff.sechenov.ru
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*bulanov_n_m@staff.sechenov.ru
________________________________________________
Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
*bulanov_n_m@staff.sechenov.ru
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