transplantologiyaТрансплантологияTransplantologiya. The Russian Journal of Transplantation2074-05062542-0909IPO Association of Transplantologists10.23873/2074-0506-2026-18-2-164-184transplantologiya-1096Research ArticleАКТУАЛЬНЫЕ ВОПРОСЫ ТРАНСПЛАНТОЛОГИИACTUAL ISSUES OF TRANSPLANTATIONРазработка клинического протокола персонализированной минимизации иммуносупрессии у реципиентов печени в отдаленные сроки после трансплантацииDevelopment of a clinical protocol for personalized minimization of immunosuppression in liver recipients in the long-term period after transplantationhttps://orcid.org/0000-0002-0002-9183МойсюкЯ. Г.MoysyukYa. G.

Ян Геннадиевич Мойсюк, проф., д-р мед. наук, руководитель отделения хирургии и трансплантации печени

129110, Москва, ул. Щепкина, д. 61/2

Yan G. Moysyuk, Prof., Dr. Sci. (Med.), Head of the Department of Surgery and Liver Transplantation

61/2 Shchepkin St., Moscow 129110

moysyuktrans@list.ruhttps://orcid.org/0000-0003-3440-6685СумцоваО. В.SumtsovaO. V.

Ольга Васильевна Сумцова, научный сотрудник отделения хирургии и трансплантации печени

129110, Москва, ул. Щепкина, д. 61/2

Olga V. Sumtsova, Researcher, Department of Surgery and Liver Transplantation

61/2 Shchepkin St., Moscow 129110

ovmoniki@gmail.comhttps://orcid.org/0000-0003-4864-1483КокинаК. Ю.KokinaK. Yu.

Ксения Юрьевна Кокина, канд. мед. наук, старший научный сотрудник отделения хирургии и трансплантации печени

129110, Москва, ул. Щепкина, д. 61/2

Ksenia Yu. Kokina, Cand. Sci. (Med.), Senior Researcher, Department of Surgery and Liver Transplantation

61/2 Shchepkin St., Moscow 129110

kseniaur@yandex.ruhttps://orcid.org/0000-0003-2019-7878СидоренкоА. Б.SidorenkoA. B.

Алексей Борисович Сидоренко, заведующий хирургическим отделением № 3 (хирургии и трансплантации печени)

129110, Москва, ул. Щепкина, д. 61/2

Аlexey B. Sidorenko, Head of Surgical Department № 3 (the Department of Surgery and Liver Transplantation)

61/2 Shchepkin St., Moscow 129110

https://orcid.org/0000-0003-4580-278XМалиновскаяЮ. О.MalinovskayaYu. O.

Юлия Олеговна Малиновская, канд. мед. наук, старший научный сотрудник отделения хирургии и трансплантации печени

129110, Москва, ул. Щепкина, д. 61/2

Yulia O. Malinovskaya, Cand. Sci. (Med.), Senior Researcher, Department of Surgery and Liver Transplantation

61/2 Shchepkin St., Moscow 129110

yumalinovskaya@gmail.comhttps://orcid.org/0000-0002-6225-5856ГригоревскаяА. О.GrigorevskayaA. O.

Анна Олеговна Григоревская, младший научный сотрудник отделения хирургии и трансплантации печени

129110, Москва, ул. Щепкина, д. 61/2

Anna O. Grigorevskaya, Junior Researcher, Department of Surgery and Liver Transplantation

61/2 Shchepkin St., Moscow 129110

anna_gy@bk.ruПавловаТ. В.PavlovaT. V.

Татьяна Владимировна Павлова, врач патологоанатом патологоанатомического отделения

129110, Москва, ул. Щепкина, д. 61/2

Tatyana V. Pavlova, Pathologist, Pathology Department

61/2 Shchepkin St., Moscow 129110

pavtv@rambler.ruКачмазоваМ. А.KachmazovaM. A.

Марета Александровна Качмазова, младший научный сотрудник отделения хирургии и трансплантации печени

129110, Москва, ул. Щепкина, д. 61/2

Mareta A. Kachmazova, Junior Researcher, Department of Surgery and Liver Transplantation

61/2 Shchepkin St., Moscow 129110

kamareta@yandex.ruГБУЗ МО МОНИКИ им. М.Ф. ВладимирскогоРоссияMoscow Regional Research and Clinical Institute n.a. M.F. VladimirskiyRussian Federation202606062026182164184Copyright © Мойсюк Я.Г., Сумцова О.В., Кокина К.Ю., Сидоренко А.Б., Малиновская Ю.О., Григоревская А.О., Павлова Т.В., Качмазова М.А., 20262026Мойсюк Я.Г., Сумцова О.В., Кокина К.Ю., Сидоренко А.Б., Малиновская Ю.О., Григоревская А.О., Павлова Т.В., Качмазова М.А.Moysyuk Y.G., Sumtsova O.V., Kokina K.Y., Sidorenko A.B., Malinovskaya Y.O., Grigorevskaya A.O., Pavlova T.V., Kachmazova M.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jtransplantologiya.ru/jour/article/view/1096Актуальность

Актуальность. Длительная иммуносупрессия в стандартных режимах, предотвращая отторжение, увеличивает в то же время заболеваемость и смертность реципиентов после трансплантации печени. Минимизация или отмена иммуносупрессии может уменьшить это бремя. Допустимые границы, безопасность, переносимость, клинические исходы и отдаленные результаты этой стратегии не определены и требуют тщательного изучения и уточнения.

Цель

Цель. Разработать клинический протокол и изучить возможность и клиническую безопасность персонализированной минимизации иммуносупрессии в отдаленном периоде после трансплантации печени.

Материал и методы

Материал и методы. Сорок стабильных реципиентов печени через 74±7,21 месяца (от 6 до 182 месяцев) после трансплантации включены в ретропроспективное одноцентровое исследование. Средний возраст на момент включения составил 56,3±1,4 года. Двадцать два (55%) пациента получали иммуносупрессивную монотерапию такролимусом, 18 (45%) – комбинацию такролимуса с эверолимусом. Дозу такролимуса снижали постепенно в течение 8 (4;11) месяцев.

Результаты

Результаты. Развитие дисфункции трансплантата зарегистрировано в 32,5% случаев (n=13) при снижении дозы на 25–95%. Из них у 7 (17,5%) пациентов диагностировано отторжение легкой или умеренной степени. Все эпизоды дисфункции были полностью обратимыми и успешно купированы. Медиана длительности последующего безрецидивного в отношении дисфункции трансплантата периода у всех нетолерантных пациентов составила 28 (26;33) месяцев. Двадцать семь (67,5%) пациентов оказались толерантными к режиму минимизации. Среди них 15 (37,5%) полностью прекратили прием такролимуса, 12 (30%) достигли снижения дозы на 40–87,5%, в среднем на 62,7%. Медиана длительности наблюдения за толерантными пациентами после завершения минимизации составила 26 (20;30) месяцев. При контрольных биопсиях, проведенных через 1–33 месяца (медиана 15 месяцев) после завершения минимизации, ни у одного из 15 толерантных и 10 нетолерантных реципиентов не было выявлено отрицательной динамики. При сравнении группы, получавшей эверолимус, и группы монотерапии установлены значимые различия: доля толерантных пациентов 83% vs 55% (p=0,053); отмена такролимуса – 72,2% vs 9,1% (p<0,001); степень снижения дозы – 100 (90,3;100) % vs 56 (42,5;78,8) % (p<0,001). СКФ к концу периода наблюдения возросла по сравнению с исходом: 62 (50;70) мл/мин/1,73 м2 vs 66,5 (54;80) мл/мин/1,73 м2 (p=0,011).

Заключение

Заключение. Контролируемая минимизация иммуносупрессии в поздние сроки после трансплантации оказывается успешной и безопасной у значительной части тщательно отобранных реципиентов при строгом соблюдении протокола. Максимальное снижение дозы такролимуса значительно чаще и с меньшим риском отторжения достигается у пациентов, получающих эверолимус. Установлено положительное влияние минимизации на функцию почек.

Актуальность

Актуальность. Длительная иммуносупрессия в стандартных режимах, предотвращая отторжение, увеличивает в то же время заболеваемость и смертность реципиентов после трансплантации печени. Минимизация или отмена иммуносупрессии может уменьшить это бремя. Допустимые границы, безопасность, переносимость, клинические исходы и отдаленные результаты этой стратегии не определены и требуют тщательного изучения и уточнения.

Цель

Цель. Разработать клинический протокол и изучить возможность и клиническую безопасность персонализированной минимизации иммуносупрессии в отдаленном периоде после трансплантации печени.

Материал и методы

Материал и методы. Сорок стабильных реципиентов печени через 74±7,21 месяца (от 6 до 182 месяцев) после трансплантации включены в ретропроспективное одноцентровое исследование. Средний возраст на момент включения составил 56,3±1,4 года. Двадцать два (55%) пациента получали иммуносупрессивную монотерапию такролимусом, 18 (45%) – комбинацию такролимуса с эверолимусом. Дозу такролимуса снижали постепенно в течение 8 (4;11) месяцев.

Результаты

Результаты. Развитие дисфункции трансплантата зарегистрировано в 32,5% случаев (n=13) при снижении дозы на 25–95%. Из них у 7 (17,5%) пациентов диагностировано отторжение легкой или умеренной степени. Все эпизоды дисфункции были полностью обратимыми и успешно купированы. Медиана длительности последующего безрецидивного в отношении дисфункции трансплантата периода у всех нетолерантных пациентов составила 28 (26;33) месяцев. Двадцать семь (67,5%) пациентов оказались толерантными к режиму минимизации. Среди них 15 (37,5%) полностью прекратили прием такролимуса, 12 (30%) достигли снижения дозы на 40–87,5%, в среднем на 62,7%. Медиана длительности наблюдения за толерантными пациентами после завершения минимизации составила 26 (20;30) месяцев. При контрольных биопсиях, проведенных через 1–33 месяца (медиана 15 месяцев) после завершения минимизации, ни у одного из 15 толерантных и 10 нетолерантных реципиентов не было выявлено отрицательной динамики. При сравнении группы, получавшей эверолимус, и группы монотерапии установлены значимые различия: доля толерантных пациентов 83% vs 55% (p=0,053); отмена такролимуса – 72,2% vs 9,1% (p<0,001); степень снижения дозы – 100 (90,3;100) % vs 56 (42,5;78,8) % (p<0,001). СКФ к концу периода наблюдения возросла по сравнению с исходом: 62 (50;70) мл/мин/1,73 м2 vs 66,5 (54;80) мл/мин/1,73 м2 (p=0,011).

Заключение

Заключение. Контролируемая минимизация иммуносупрессии в поздние сроки после трансплантации оказывается успешной и безопасной у значительной части тщательно отобранных реципиентов при строгом соблюдении протокола. Максимальное снижение дозы такролимуса значительно чаще и с меньшим риском отторжения достигается у пациентов, получающих эверолимус. Установлено положительное влияние минимизации на функцию почек.

Background

Background. Long-term immunosuppression in standard regimens, though preventing a rejection, simultaneously increases morbidity and mortality in liver transplant recipients. Minimization or discontinuation of immunosuppressive drugs may reduce this burden; however, the permissible limits, safety, tolerability, clinical outcomes, and long-term results of this strategy remain undefined and require thorough study and clarification.

Objective

Objective. To develop a clinical protocol and investigate the feasibility and clinical safety of personalized immunosuppression minimization in the long-term period after liver transplantation.

Material and methods

Material and methods. Forty stable liver recipients, at 74±7.21 months (range: 6–182 months) post-transplantation, were included in a retrospective single-center study on tacrolimus minimization/discontinuation. Mean age at enrollment was 56.3±1.4 years. Twenty-two (55%) patients were on tacrolimus monotherapy, and 18 (45%) on a combination tacrolimuseverolimus therapy. Tacrolimus dose was gradually reduced over 8 (4;11) months.

Results

Results. Graft dysfunction developed in 32.5% of cases (n=13) with dose reductions of 25–95%. Rejection was diagnosed in 7 (17.5%) patients based on laboratory and morphological data, 3–9 months after starting minimization. All dysfunction episodes were reversible. The median duration of subsequent dysfunction-free graft period in all intolerant patients was 28 (26;33) months. Twenty-seven (67.5%) patients tolerated minimization: 15 (37.5%) completely discontinued tacrolimus, and 12 (30%) achieved a 40–87.5% dose reduction (mean 62.7%). Median follow-up for tolerant patients after completing the minimization was 26 (20;30) months. Control biopsies performed 1–33 months (median 15 months) after completing the minimization showed no negative dynamics in histological patterns. Comparison between the everolimus group and the monotherapy group revealed significant differences: tolerant patients to immunosuppression minimization accounted for 83% vs. 55% (p=0.053); tacrolimus discontinuation was achieved in 72.2% vs. 9.1% (p<0.001); the dose reduction extent was 100 (90.3;100) % vs. 56 (42.5;78.8) % (p<0.001). In the whole cohort, the estimated GFR increased from the baseline of 62 (50;70) mL/min/1.73 m2 to 66.5 (54;80) mL/min/1.73 m2 by the end of the follow-up (p=0.011).

Conclusion

Conclusion. Controlled immunosuppression minimization in the long-term post-transplant period is successful in a significant proportion of carefully selected recipients. The procedure being safe with strict protocol adherence. A maximal tacrolimus dose reduction is achieved more frequently and with lower rejection risk in patients on everolimus. A positive effect of minimization on kidney function has been confirmed.

трансплантация печениминимизация иммуносупрессиитакролимусэверолимусотторжение трансплантата печенинефротоксичность такролимусаliver transplantationminimization of immunosuppressiontacrolimuseverolimusliver transplant rejectiontacrolimus nephrotoxicityReferencesHalloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715–2729. PMID: 15616206 https://doi.org/10.1056/NEJMra033540Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715–2729. PMID: 15616206 https://doi.org/10.1056/NEJMra033540Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348(17):1681–1691. PMID: 12711744 https://doi.org/10.1056/NEJMra022137Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348(17):1681–1691. PMID: 12711744 https://doi.org/10.1056/NEJMra022137Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. 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The authors declare that there are no conflicts of interest present.