vtioВестник трансплантологии и искусственных органовRussian Journal of Transplantology and Artificial Organs1995-1191Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation10.15825/1995-1191-2021-2-13-20vtio-1367Research ArticleТРАНСПЛАНТАЦИЯ ОРГАНОВORGAN TRANSPLANTATIONВзаимосвязь уровня инсулиноподобного фактора роста 1 с дозой такролимуса у детей – реципиентов печениCorrelation between insulin-like growth factor 1 levels and tacrolimus dose in pediatric liver recipientsКурабековаР. М.KurabekovaR. M.

Москва

Moscow

ЦирульниковаО. М.TsirulnikovaO. M.

Москва

Moscow

ГичкунО. Е.GichkunO. E.

Москва

Moscow

ОлефиренкоГ. А.OlefirenkoG. A.

Москва

Moscow

ПашковаИ. Е.PashkovaI. E.

Москва

Moscow

БельченковА. А.BelchenkovA. A.

Москва

Moscow

ШевченкоО. П.ShevchenkoO. P.

Шевченко Ольга Павловна

123182, Москва, ул. Щукинская, д. 1

Olga Shevchenko

1, Shchukinskaya str., Moscow, 123182

transplant2009@mail.ruФГБУ «Национальный медицинский исследовательский центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава РоссииРоссияShumakov National Medical Research Center of Transplantology and Artificial OrgansRussian FederationФГБУ «Национальный медицинский исследовательский центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава России; ФГАОУ ВО Первый Московский государственный медицинский университет имени И.М. Сеченова Минздрава России (Сеченовский университет)РоссияShumakov National Medical Research Center of Transplantology and Artificial Organs; Sechenov UniversityRussian Federation2021110720212321320Copyright © Курабекова Р.М., Цирульникова О.М., Гичкун О.Е., Олефиренко Г.А., Пашкова И.Е., Бельченков А.А., Шевченко О.П., 20212021Курабекова Р.М., Цирульникова О.М., Гичкун О.Е., Олефиренко Г.А., Пашкова И.Е., Бельченков А.А., Шевченко О.П.Kurabekova R.M., Tsirulnikova O.M., Gichkun O.E., Olefirenko G.A., Pashkova I.E., Belchenkov A.A., Shevchenko O.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.transpl.ru/vtio/article/view/1367Введение

Введение. Для предупреждения посттрансплантационных осложнений, связанных с несбалансированной иммуносупрессией, необходимы объективные показатели, отражающие состояние иммунной системы и ассоциированные с дозой иммуносупрессанта. При трансплантации печени детям важным показателем гепатоцеллюлярной функции и восстановления антропометрических характеристик является инсулиноподобный фактор роста-1 (ИФР‑1), который проявляет свойства как неспецифического, так и селективного иммуномодулятора.

Цель работы – оценить связь уровня гормона роста и ИФР‑1 с дозой и концентрацией такролимуса в крови детей – реципиентов печени и определить возможности использования уровня ИФР‑1 для подбора дозы препарата, необходимой для достижения его целевой концентрации в крови.

Материалы и методы

Материалы и методы. Обследовано 156 детей в возрасте от 2 до 105 (медиана – 8) месяцев с циррозом печени различной этиологии, которым выполнялась трансплантация печени от живого родственного донора. Концентрацию гормона роста и ИФР‑1 определяли в плазме крови до, через месяц и год после трансплантации с помощью иммуноферментного метода. Остаточную концентрацию такролимуса измеряли в цельной крови пациента иммунохимическим методом.

Результаты

Результаты. Уровень гормона роста в крови детей – реципиентов печени не коррелировал с дозой или концентрацией иммуносупрессанта такролимуса через месяц или год после трансплантации, тогда как содержание ИФР‑1 было прямо связано с дозой такролимуса через год (r = 0,41, р = 0,001), но не через месяц после операции. У реципиентов с неосложненным течением посттрансплантационного периода коэффициент корреляции (r = 0,51, p = 0,002) был выше, чем у реципиентов с осложнениями (r = 0,26, p = 0,17). Диагностическая эффективность уровня ИФР‑1 как объективного критерия для подбора дозы такролимуса, необходимой для достижения его целевой концентрации в крови, составила 0,80 ± 0,11; 95% ДИ [0,58–1,00] (p = 0,007). У реципиентов с уровнем ИФР‑1 в крови ≥115,7 нг/мл вероятность назначения дозы такролимуса ≥0,25 мг/кг/сут была в 14 раз выше, чем у детей с меньшим содержанием ИФР‑1 в крови. Расчетная точность теста составила 83%, положительная прогностичность – 71%, а отрицательная прогностичность – 85%.

Заключение

Заключение. Выявлена корреляция уровня ИФР‑1 с величиной дозы такролимуса у детей – реципиентов печени через год после трансплантации. Диагностическая эффективность ИФР‑1 как потенциального показателя для подбора дозы такролимуса, необходимой для достижения его целевой концентрации в крови, составляет 80%, что позволяет рекомендовать дальнейшее изучение теста для оценки эффективности иммуносупрессии и подбора индивидуальной дозы имунносупрессанта.

 Introduction

 Introduction. To prevent post-transplant complications associated with unbalanced immunosuppression, objective indicators reflecting the state of the immune system and associated with the immunosuppressant dose are required. In pediatric liver transplantation, an important indicator of hepatocellular function and restoration of anthropometric characteristics is insulin-like growth factor 1 (IGF-1), which exhibits both nonspecific and selective immunomodulator properties.

Objective

Objective: to assess the correlation between growth hormone and IGF-1 levels and tacrolimus dose and blood concentrations in pediatric liver recipients and to determine the possibility of using the IGF-1 level in selecting the drug dose required to achieve its target concentration in the blood. Materials and methods. We examined 156 children aged from 2 to 105 (median – 8) months with liver cirrhosis of various etiology, who received liver from a living related donor. The concentration of growth hormone and IGF-1 was determined in blood plasma before, one month, and one year after transplantation using the enzyme-linked immunosorbent assay. Tacrolimus residual concentration was measured in the patient’s whole blood by immunochemical method.

Results

Results. Growth hormone levels in the blood of pediatric liver recipients did not correlate with the dose or concentration of immunosuppressant tacrolimus one month or one year after transplantation, whereas the IGF-1 content was directly related to tacrolimus dose one year later (r = 0.41, p = 0.001), but not a month after surgery. The correlation coefficient was higher in uncomplicated post-transplant recipients (r = 0.51, p = 0.002) than in those with complications (r = 0.26, p = 0.17). The diagnostic efficiency of the IGF-1 level as an objective criterion for selecting the tacrolimus dose required to achieve its target blood concentration was 0.80 ± 0.11; 95% CI [0.58–1.00] (p = 0.007). In recipients with blood IGF-1 levels ≥115.7 ng/mL, the probability of prescribing a tacrolimus dose ≥0.25 mg/kg/day was 14 times higher than in children with lower blood IGF-1 levels. The estimated accuracy of the test was 83%, positive predictive value was 71%, and negative predictive value was 85%.

Conclusion

Conclusion. The IGF-1 level was found to correlate with tacrolimus dose in liver transplant recipients one year after transplantation. The diagnostic efficiency of IGF-1 as a potential indicator for choosing the tacrolimus dose required to achieve its target blood concentration is 80%, which suggests further study of the test to assess the effectiveness of immunosuppression and selection of an individual immunosuppressant dose.

трансплантация печени от живого родственного донораврожденные заболевания желчевыводящих путейбиомаркерэффективность иммуносупрессииliving-donor liver transplantationcongenital biliary tract diseasesbiomarkereffectiveness of immunosuppressionReferencesMiloh T, Barton A, Wheeler J, Pham Y, Hewitt W, Keegan T et al. Immunosuppression in pediatric liver transplant recipients: Unique aspects. Liver Transpl. 2017; 23 (2): 244–256.Miloh T, Barton A, Wheeler J, Pham Y, Hewitt W, Keegan T et al. Immunosuppression in pediatric liver transplant recipients: Unique aspects. Liver Transpl. 2017; 23 (2): 244–256.Catic-Dordevic A, Cvetkovic T, Stefanovic N, VelickovicRadovanovic R. Current Biochemical Monitoring and Risk Management of Immunosuppressive Therapy after Transplantation. J Med Biochem. 2017; 36 (1): 1–7.Catic-Dordevic A, Cvetkovic T, Stefanovic N, VelickovicRadovanovic R. Current Biochemical Monitoring and Risk Management of Immunosuppressive Therapy after Transplantation. J Med Biochem. 2017; 36 (1): 1–7.Venkataramanan R, Shaw LM, Sarkozi L, Mullins R, Pirsch J, MacFarlane G et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol. 2001; 41 (5): 542–551.Venkataramanan R, Shaw LM, Sarkozi L, Mullins R, Pirsch J, MacFarlane G et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol. 2001; 41 (5): 542–551.Sood S, Haifer C, Yu L, Pavlovic J, Churilov L, Gow PJ et al. A novel immune function biomarker identifies patients at risk of clinical events early following liver transplantation. Liver Transpl. 2017; 23 (4): 487–497.Sood S, Haifer C, Yu L, Pavlovic J, Churilov L, Gow PJ et al. A novel immune function biomarker identifies patients at risk of clinical events early following liver transplantation. Liver Transpl. 2017; 23 (4): 487–497.Sharon E, Shi H, Kharbanda S, Koh W, Martin LR, Khush KK et al. Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype. PLoS Comput Biol. 2017; 13 (8).Sharon E, Shi H, Kharbanda S, Koh W, Martin LR, Khush KK et al. Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype. PLoS Comput Biol. 2017; 13 (8).Shipkova M, Wieland E. Editorial: Immune monitoring in solid organ transplantation. Clin Biochem. 2016; 49 (4–5): 317–319.Shipkova M, Wieland E. Editorial: Immune monitoring in solid organ transplantation. Clin Biochem. 2016; 49 (4–5): 317–319.Crespo E, Bestard O. Biomarkers to assess donor-reactive T-cell responses in kidney transplant patients. Clin Biochem. 2016; 49 (4–5): 329–337.Crespo E, Bestard O. Biomarkers to assess donor-reactive T-cell responses in kidney transplant patients. Clin Biochem. 2016; 49 (4–5): 329–337.Schlickeiser S, Boes D, Streitz M, Sawitzki B. The use of novel diagnostics to individualize immunosuppression following transplantation. Transpl Int. 2015; 28 (8): 911–920.Schlickeiser S, Boes D, Streitz M, Sawitzki B. The use of novel diagnostics to individualize immunosuppression following transplantation. Transpl Int. 2015; 28 (8): 911–920.Mannon RB, Morris RE, Abecassis M, Axelrod D, Bala S, Friedman GS et al. Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report. Am J Transplant. 2020; 20 (6): 1495–1502.Mannon RB, Morris RE, Abecassis M, Axelrod D, Bala S, Friedman GS et al. Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report. Am J Transplant. 2020; 20 (6): 1495–1502.Шевченко ОП, Цирульникова ОМ, Цирульникова ИЕ, Курабекова РМ, Олефиренко ГА, Степанова ОИ и др. Динамика инсулиноподобного фактора роста 1 (ИФР 1) при трансплантации печени детям от донора, не совместимого по группе крови. Вестник трансплантологии и искусственных органов. 2014; XVI (2): 46–51.Shevchenko OP, Tsirulnikova OM, Tsirulnikova IE, Kurabekova RM, Olefirenko GA, Stepanova OI et al. Dynamics of insulin-like growth factor-1 (IGF-1) in children after AB0-incompatible liver transplantation. Vestnik transplantologii i iskusstvennykh organov. 2014; XVI (2): 46–51.Курабекова РМ, Цирульникова ОМ, Пашкова ИЕ, Макарова ЛВ, Можейко НП, Монахов АР, Шевченко ОП и др. Связь уровней гормона роста и инсулиноподобного фактора роста 1 (ИФР 1) с функцией печени и краткосрочной выживаемостью детей – реципиентов печени. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2020; 30 (4): 44–51.Kurabekova RM, Tsiroulnikova OM, Pashkova IE, Makarova LV, Mozheyko NP, Monakhov AR, Shevchenko OP. Association between Growth Hormone and Insulin-like Growth Factor-1 (IGF-1) Levels, Liver Function and Short-Term Survival of Paediatric Liver Recipients. Gastroenterology, Hepatology, Coloproctology. 2020; 30 (4): 44–51.Weigent DA. Lymphocyte GH-axis hormones in immunity. Cell Immunol. 2013; 285 (1–2): 118–132.Weigent DA. Lymphocyte GH-axis hormones in immunity. Cell Immunol. 2013; 285 (1–2): 118–132.Van Buul-Offers SC, Kooijman R. The role of growth hormone and insulin-like growth factors in the immune system. Cell Mol Life Sci. 1998; 54 (10): 1083–1094.Van Buul-Offers SC, Kooijman R. The role of growth hormone and insulin-like growth factors in the immune system. Cell Mol Life Sci. 1998; 54 (10): 1083–1094.Robbins K, McCabe S, Scheiner T, Strasser J, Clark R, Jardieu P. Immunological effects of insulin-like growth factor-I – enhancement of immunoglobulin synthesis. Clin Exp Immunol. 1994; 95 (2): 337–342.Robbins K, McCabe S, Scheiner T, Strasser J, Clark R, Jardieu P. Immunological effects of insulin-like growth factor-I – enhancement of immunoglobulin synthesis. Clin Exp Immunol. 1994; 95 (2): 337–342.Walsh PT, Smith LM, O’Connor R. Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytes. Immunology. 2002; 107 (4): 461–471.Walsh PT, Smith LM, O’Connor R. Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytes. Immunology. 2002; 107 (4): 461–471.Li SY, Fang CX, Aberle NS, 2nd, Ren BH, Ceylan-Isik AF, Ren J. Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function. J Endocrinol. 2005; 186 (3): 491–503.Li SY, Fang CX, Aberle NS, 2nd, Ren BH, Ceylan-Isik AF, Ren J. Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function. J Endocrinol. 2005; 186 (3): 491–503.González-Juanatey JR, Piñeiro R, Iglesias MJ, Gualillo O, Kelly PA, Diéguez C et al. GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism. J Endocrinol. 2004; 180 (2): 325–335.González-Juanatey JR, Piñeiro R, Iglesias MJ, Gualillo O, Kelly PA, Diéguez C et al. GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism. J Endocrinol. 2004; 180 (2): 325–335.Maestri M, Dionigi P, Pettenazza P, Visconti F, Rademacher J, Gaspari A et al. Treatment of the nephrotoxicity of immunosuppressive drugs with insulin-like growth factor-I. Minerva Chir. 1998; 53 (5): 391–396.Maestri M, Dionigi P, Pettenazza P, Visconti F, Rademacher J, Gaspari A et al. Treatment of the nephrotoxicity of immunosuppressive drugs with insulin-like growth factor-I. Minerva Chir. 1998; 53 (5): 391–396.Mabuchi M, Kawamura I, Takeshita S, Fushimi M, Takakura S, Hirosumi J et al. Insulin-like growth factor-I enhances choleretic action of FK506 in rats. Transplant Proc. 2003; 35 (4): 1596–1598.Mabuchi M, Kawamura I, Takeshita S, Fushimi M, Takakura S, Hirosumi J et al. Insulin-like growth factor-I enhances choleretic action of FK506 in rats. Transplant Proc. 2003; 35 (4): 1596–1598.Kawamura I, Takeshita S, Fushimi M, Mabuchi M, Seki J, Goto T. Induction of choleresis by immunosuppressant FK506 through stimulation of insulin-like growth factorI production in the liver of rats. Eur J Pharmacol. 2001; 419 (1): 99–105.Kawamura I, Takeshita S, Fushimi M, Mabuchi M, Seki J, Goto T. Induction of choleresis by immunosuppressant FK506 through stimulation of insulin-like growth factorI production in the liver of rats. Eur J Pharmacol. 2001; 419 (1): 99–105.Maes M, Sokal E, Otte JB. Growth factors in children with end-stage liver disease before and after liver transplantation: a review. Pediatr Transplant. 1997; 1 (2): 171–175.Maes M, Sokal E, Otte JB. Growth factors in children with end-stage liver disease before and after liver transplantation: a review. Pediatr Transplant. 1997; 1 (2): 171–175.Clark R, Strasser J, McCabe S, Robbins K, Jardieu P. Insulin-like growth factor-1 stimulation of lymphopoiesis. J Clin Invest. 1993; 92 (2): 540–548.Clark R, Strasser J, McCabe S, Robbins K, Jardieu P. Insulin-like growth factor-1 stimulation of lymphopoiesis. J Clin Invest. 1993; 92 (2): 540–548.Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009; 4 (2): 481–508.Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009; 4 (2): 481–508.Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation. 1996; 62 (7): 920–926.Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation. 1996; 62 (7): 920–926.De Palo EF, Bassanello M, Lancerin F, Spinella P, Gatti R, D’Amico D et al. GH/IGF system, cirrhosis and liver transplantation. Clin Chim Acta. 2001; 310 (1): 31–37.De Palo EF, Bassanello M, Lancerin F, Spinella P, Gatti R, D’Amico D et al. GH/IGF system, cirrhosis and liver transplantation. Clin Chim Acta. 2001; 310 (1): 31–37.Leung KC, Ho KK. Measurement of growth hormone, insulin-like growth factor I and their binding proteins: the clinical aspects. Clin Chim Acta. 2001; 313 (1–2): 119–123.Leung KC, Ho KK. Measurement of growth hormone, insulin-like growth factor I and their binding proteins: the clinical aspects. Clin Chim Acta. 2001; 313 (1–2): 119–123.

The authors declare that there are no conflicts of interest present.