Цель. Проанализировать исходы С3-гломерулопатии (С3-ГП) и определить ассоциированные факторы. Материалы и методы. В ретроспективное одноцентровое исследование включены 60 пациентов с впервые установленным диагнозом С3-ГП (с первичной С3-ГП – пС3-ГП – 82%). Из них 48 (80%) пациентов имели клинические данные для оценки следующих исходов заболевания: развития ремиссии и прогрессирования заболевания (по композитной конечной точке, включавшей начало хронического диализа или снижение расчетной скорости клубочковой фильтрации – рСКФ – менее 15 мл/мин/1,73 м2 или снижение рСКФ≥30% от исходной на момент биопсии почки). Медиана периода наблюдения составила 25 (7; 52) мес. Результаты. В ранние сроки наблюдения (медиана 4 [3; 9] мес) ремиссия зарегистрирована у 35% пациентов; в конце наблюдения – у 48% (при пС3-ГП – 32 и 41%). Заболевание прогрессировало у 17 пациентов. В общей группе С3-ГП вероятность достижения ранней ремиссии была выше в случае специфического лечения против поддерживающего лечения, Expβ=6,4 (95% доверительный интервал – ДИ 1,4–29,3; р=0,017). Ранняя ремиссия была связана с наличием ремиссии в конце наблюдения (Expβ=6,3, 95% ДИ 2,2–18,4; р=0,001). Со снижением риска прогрессирования заболевания ассоциированы специфическое лечение (Expβ=0,308, 95% ДИ 0,108–0,881; р=0,028) и поздняя ремиссия (Expβ=0,079, 95% ДИ 0,017–0,368; р=0,001) в мультивариантных моделях (скорректированных по рСКФ, среднему артериальному давлению). Аналогичные результаты получены для группы пациентов с пС3-ГП. Заключение. С3-ГП представляет вариант тяжелого комплемент-опосредованного поражения клубочков с неблагоприятным ренальным прогнозом, который требует своевременной персонифицированной диагностики экспертного уровня с уточнением этиопатогенеза заболевания и проведения терапии, направленной на достижение ремиссии для улучшения исходов.
Aim. To analyze the outcomes of C3-glomerulopathy (C3-GP) and determine the associated factors. Materials and methods. A retrospective single-center study included 60 patients with newly diagnosed C3-GP (with primary C3-GP – pC3-GP – 82%). Of these, 48 (80%) patients had clinical data to assess the following disease outcomes: development of remission and disease progression (by a composite endpoint that included initiation of chronic dialysis or a decrease in estimated glomerular filtration rate – eGFR –
<15 mL/min/1.73 m2 or a decrease in eGFR≥30% of baseline at the time of renal biopsy). The median follow-up period was 25 (7; 52) months. Results. At early follow-up (median 4 [3; 9] months) remission was registered in 35% of patients; at the end of follow-up, in 48% (for pC3-GP, 32 and 41%). Disease progression occurred in 17 patients. In the overall group the likelihood of achieving early remission was higher with treatment (Expβ=6.4, 95% confidence interval – CI 1.4–29.3; p=0.017). Early remission was associated with the presence of remission at the end of follow-up (Expβ=6.3, 95% CI 2.2–18.4; p=0.001). Specific treatment (Expβ=0.308, 95% CI 0.108–0.881; p=0.028) and late remission (Expβ=0.079, 95% CI 0.017–0.368; p=0.001) were associated with reduced risk of disease progression in multivariable models (adjusted for eGFR, mean blood pressure). The same results were obtained for the group of patients with pC3-GP. Conclusion. C3-GP is a variant of severe complement-mediated glomerular damage with unfavorable renal prognosis, which requires timely personalized expert-level diagnostics with clarification of etiopathogenesis of the disease followed by therapy aimed at achieving remission to improve outcomes.
1. Перечень редких (орфанных) заболеваний. Министерство здравоохранения Российской Федерации. Режим доступа: https://minzdrav.gov.ru/documents/8048/ Ссылка активна на 17.03.22 [List of rare (orphan) diseases. Ministry of Health of the Russian Federation. Available at: https://minzdrav.gov.ru/documents/8048/ Accessed: 17.03.2022 (in Russian)].
2. Pickering MC, D'Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. Kidney Int. 2013;84(6):1079-89. DOI:10.1038/ki.2013.377
3. Goodship TH, Cook HT, Fakhouri F, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-51. DOI:10.1016/j.kint.2016.10.005
4. Schena FP, Esposito P, Rossini M. A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease. Int J Mol Sci. 2020;21(2):525. DOI:10.3390/ijms2102052
5. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53. DOI:10.2215/CJN.04700513
6. Bomback AS, Santoriello D, Avasare RS, et al. C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int. 2018;93(4):977-85. DOI:10.1016/j.kint.2017.10.022
7. Ravindran A, Fervenza FC, Smith RJH, et al. C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic. Mayo Clin Proc. 2018;93(8):991-1008. DOI:10.1016/j.mayocp.2018.05.019
8. Iatropoulos P, Daina E, Curreri M, et al. Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol. 2018;29(1):283-94. DOI:10.1681/ASN.2017030258
9. Nakagawa N, Mizuno M, Kato S, et al. Demographic, clinical characteristics and treatment outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulonephritis in Japan: A retrospective analysis of data from the Japan Renal Biopsy Registry. PLoS One. 2021;16(9):e0257397. DOI:10.1371/journal.pone.0257397
10. Rabasco C, Cavero T, Román E, et al. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int. 2015;88(5):1153-60. DOI:10.1038/ki.2015.227
11. Caravaca-Fontán F, Díaz-Encarnación MM, Lucientes L, et al. Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease. Clin J Am Soc Nephrol. 2020;15(9):1287-98. DOI:10.2215/CJN.15241219
12. Добронравов В.А., Карунная А.В. Этиология и клинико-морфологическая презентация С3-гломерулопатии (одноцентровое исследование 60 случаев). Нефрология. 2021;25(6):93-8 [Dobronravov VA, Karunnaya AV. Clinical and morphological presentation of C3 glomerulopathy: a single-center study of 60 cases. Nephrology (Saint-Petersburg). 2021;25(6):93-8 (in Russian)]. DOI:10.36485/1561-6274-2021-25-6-93-98
13. Смирнов А.В., Афанасьев Б.В., Поддубная И.В., и др. Моноклональная гаммапатия ренального значения: консенсус гематологов и нефрологов России по введению нозологии, диагностике и обоснованности клон-ориентированной терапии. Нефрология. 2019;23(6):9-28 [Smirnov AV, Afanasyev BV, Poddubnaya IV, et al. Monoclonal gammopathy of renal signifi cance: Consensus of hematologists and nephrologists of Russia on the establishment of nosology, diagnostic approach and rationale for clone specific treatment. Nephrology (Saint-Petersburg). 2019;23(6):9-28 (in Russian)]. DOI:10.36485/1561-6274-2019-236-9-28
14. Caravaca-Fontán F, Díaz-Encarnación M, Cabello V, et al. Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy. Nephrol Dial Transplant. 2021;gfab075. DOI:10.1093/ndt/gfab075
15. Barbour TD, Pickering MC, Cook HT. Dense deposit disease and C3 glomerulopathy. Semin Nephrol. 2013;33(6):493-507. DOI:10.1016/j.semnephrol.2013.08.002
16. Barbour TD, Ruseva MM, Pickering PM. Update on C3 glomerulopathy. Nephrol Dial Transplant. 2016;31(5):717-25. DOI:10.1093/ndt/gfu317
17. De Vriese AS, Sethi S, Van Praet J, et al. Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: An Etiologic Approach. J Am Soc Nephrol. 2015;26(12):2917-29. DOI:10.1681/ASN.2015020184
18. Chauvet S, Frémeaux-Bacchi V, Petitprez F, et al. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood. 2017;129(11):1437‑47. DOI:10.1182/blood-2016-08-737163
19. Caravaca-Fontán F, Lucientes L, Serra N, et al. C3 glomerulopathy associated with monoclonal gammopathy: impact of chronic histologic lesions and beneficial effects of clone-targeted therapies. Nephrol Dial Transplant. 2021:gfab302. DOI:10.1093/ndt/gfab302
20. Rudnicki M. Rituximab for Treatment of Membranoproliferative Glomerulonephritis and C3 Glomerulopathies. Biomed Res Int. 2017;2017:2180508.
DOI:10.1155/2017/2180508
21. Avasare RS, Canetta PA, Bomback AS, et al. Mycophenolate mofetil in combination with steroids for treatment of C3 glomerulopathy: A case series. Clin J Am Soc Nephrol. 2018;13(3):406-13. DOI:10.2215/CJN.09080817
22. Zipfel PF, Wiech T, Rudnick R, et al. Complement Inhibitors in Clinical Trials for Glomerular Diseases. Front Immunol. 2019;10:2166. DOI:10.3389/fimmu.2019.02166
________________________________________________
1. List of rare (orphan) diseases. Ministry of Health of the Russian Federation. Available at: https://minzdrav.gov.ru/documents/8048/ Accessed: 17.03.2022 (in Russian).
2. Pickering MC, D'Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. Kidney Int. 2013;84(6):1079-89. DOI:10.1038/ki.2013.377
3. Goodship TH, Cook HT, Fakhouri F, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-51. DOI:10.1016/j.kint.2016.10.005
4. Schena FP, Esposito P, Rossini M. A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease. Int J Mol Sci. 2020;21(2):525. DOI:10.3390/ijms2102052
5. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53. DOI:10.2215/CJN.04700513
6. Bomback AS, Santoriello D, Avasare RS, et al. C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int. 2018;93(4):977-85. DOI:10.1016/j.kint.2017.10.022
7. Ravindran A, Fervenza FC, Smith RJH, et al. C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic. Mayo Clin Proc. 2018;93(8):991-1008. DOI:10.1016/j.mayocp.2018.05.019
8. Iatropoulos P, Daina E, Curreri M, et al. Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol. 2018;29(1):283-94. DOI:10.1681/ASN.2017030258
9. Nakagawa N, Mizuno M, Kato S, et al. Demographic, clinical characteristics and treatment outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulonephritis in Japan: A retrospective analysis of data from the Japan Renal Biopsy Registry. PLoS One. 2021;16(9):e0257397. DOI:10.1371/journal.pone.0257397
10. Rabasco C, Cavero T, Román E, et al. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int. 2015;88(5):1153-60. DOI:10.1038/ki.2015.227
11. Caravaca-Fontán F, Díaz-Encarnación MM, Lucientes L, et al. Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease. Clin J Am Soc Nephrol. 2020;15(9):1287-98. DOI:10.2215/CJN.15241219
12. Dobronravov VA, Karunnaya AV. Clinical and morphological presentation of C3 glomerulopathy: a single-center study of 60 cases. Nephrology (Saint-Petersburg). 2021;25(6):93-8 (in Russian). DOI:10.36485/1561-6274-2021-25-6-93-98
13. Smirnov AV, Afanasyev BV, Poddubnaya IV, et al. Monoclonal gammopathy of renal signifi cance: Consensus of hematologists and nephrologists of Russia on the establishment of nosology, diagnostic approach and rationale for clone specific treatment. Nephrology (Saint-Petersburg). 2019;23(6):9-28 (in Russian). DOI:10.36485/1561-6274-2019-236-9-28
14. Caravaca-Fontán F, Díaz-Encarnación M, Cabello V, et al. Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy. Nephrol Dial Transplant. 2021;gfab075. DOI:10.1093/ndt/gfab075
15. Barbour TD, Pickering MC, Cook HT. Dense deposit disease and C3 glomerulopathy. Semin Nephrol. 2013;33(6):493-507. DOI:10.1016/j.semnephrol.2013.08.002
16. Barbour TD, Ruseva MM, Pickering PM. Update on C3 glomerulopathy. Nephrol Dial Transplant. 2016;31(5):717-25. DOI:10.1093/ndt/gfu317
17. De Vriese AS, Sethi S, Van Praet J, et al. Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: An Etiologic Approach. J Am Soc Nephrol. 2015;26(12):2917-29. DOI:10.1681/ASN.2015020184
18. Chauvet S, Frémeaux-Bacchi V, Petitprez F, et al. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood. 2017;129(11):1437‑47. DOI:10.1182/blood-2016-08-737163
19. Caravaca-Fontán F, Lucientes L, Serra N, et al. C3 glomerulopathy associated with monoclonal gammopathy: impact of chronic histologic lesions and beneficial effects of clone-targeted therapies. Nephrol Dial Transplant. 2021:gfab302. DOI:10.1093/ndt/gfab302
20. Rudnicki M. Rituximab for Treatment of Membranoproliferative Glomerulonephritis and C3 Glomerulopathies. Biomed Res Int. 2017;2017:2180508.
DOI:10.1155/2017/2180508
21. Avasare RS, Canetta PA, Bomback AS, et al. Mycophenolate mofetil in combination with steroids for treatment of C3 glomerulopathy: A case series. Clin J Am Soc Nephrol. 2018;13(3):406-13. DOI:10.2215/CJN.09080817
22. Zipfel PF, Wiech T, Rudnick R, et al. Complement Inhibitors in Clinical Trials for Glomerular Diseases. Front Immunol. 2019;10:2166. DOI:10.3389/fimmu.2019.02166
Авторы
А.В. Карунная, В.А. Добронравов*
ФГБОУ ВО «Первый Санкт-Петербургский государственный университет им. акад. И.П. Павлова» Минздрава России, Санкт-Петербург, Россия
*dobronravov@nephrolog.ru
________________________________________________
Anna V. Karunnaya, Vladimir A. Dobronravov*
Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
*dobronravov@nephrolog.ru