Diagnostic effectiveness of transforming growth factor beta 1 (TGF-β1) at adjustment of tacrolimus individual dose in pediatric liver recipients

Blood level of transforming growth factor beta 1 (TGF-β1) is associated with liver function and immune homeostasis, which suggests it as a potential biomarker for immunosuppressant tacrolimus dose requirement at liver transplantation (LT).

Aim. To evaluate diagnostic efficacy of TGF-β1 blood level at determination of individual tacrolimus dose requirement in children at LT.

Materials and methods. 89 children with end stage liver disease aged from 3 to 73 months were examined. Children underwent living related LT, then the recipients received 2–3 component immunosuppressive therapy, including tacrolimus. Blood concentration of tacrolimus and TGF-β1 was measured by ELISA.

Results. TGF-β1 blood level in children before LT was significantly lower than in healthy children: 3.7 (1.3–8.4) and 19.3 (12.6–25.5) ng/ml, p = 0.001. A month after LT, its concentration increased to 8.1 (1.8–15.3) ng/ml (p = 0.02). A year after LT, the cytokine level remained higher than before transplantation: 6.6 (1.9–12.6) ng/ml, p = 0.01. TGF-β1 level did not correlate with tacrolimus blood concentration, determined 12 hours after the last administration of the drug, neither a month, nor a year after transplantation. At the same time, the cytokine level one month after LT was associated with a tacrolimus daily dose one year after the operation (r = –0.23, p = 0.04). In the recipients, who received smaller daily doses (0.4–2.5 mg) of tacrolimus, TGF-β1 level was higher than in those receiving large doses (3.0–6.0 mg) of the drug: 9.1 (2.6–16.2) ng/ml vs. 4.2 (1.3–9.2) ng/ ml, p = 0.04. Evaluation of diagnostic efficacy of the TGF-β1 level as a test for the detection of tacrolimus dose requirement showed that the area under the ROC curve (AUC) was 0.66 ± 0.07; 95% CI [0.53–0.79], the sensitivity and specificity of the test were 60 and 74% at threshold value 6.7 ng/ml. Relative risk of higher tacrolimus dose requirement was 3.14 ± 0.48; 95% CI [1.24–7.96].

Conclusion. TGF-β1 blood level in one month after LT less than 6.7 ng/ml is 3 times higher risk factor of tacrolimus dose requirement more than 3.0 mg per day. The likehood of the test is 66%, the sensitivity and specificity – 60 and 74%.

1. Готье СВ. Трансплантология: итоги и перспективы. Том VI. 2014 год. М. –Тверь: Триада, 2015: 448. Gautier SV. Transplantologiya: itogi i perspectivy. Tom VI. 2014 god. M. –Tver: Triada, 2015: 448. [In Russian]

2. Meirelles Junior RF, Salvalaggio P, Rezende MB, Evangelista AS, Guardia BD, Matielo CE et al. Liver transplantation: history, outcomes and perspectives. Einstein. 2015; 13 (1): 149–152.

3. 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.

4. Brooks E, Tett SE, Isbel NM, Staatz CE. Population Pharmacokinetic Modelling and Bayesian Estimation of Tacrolimus Exposure: Is this Clinically Useful for Dosage Prediction Yet? Clin Pharmacokinet. 2016; 55 (11): 1295–1335.

5. 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.

6. Bohler T, Nolting J, Kamar N, Gurragchaa P, Reisener K, Glander P et al. Validation of immunological biomarkers for the pharmacodynamic monitoring of immunosuppressive drugs in humans. Ther Drug Monit. 2007; 29 (1): 77–86.

7. Курабекова РМ, Шевченко ОП, Цирульникова ОМ, Можейко НП, Цирульникова ИЕ, Олефиренко ГА. Связь уровня трансформирующего фактора роста бета 1 с фиброзом печени у детей с врожденными заболеваниями гепатобилиарной системы. Клиническая лабораторная диагностика. 2017; 62 (4): 221–225. Kurabekova RM, Shevchenko OP, Tsirulnikova OM, Mozheyko NP, Tsirulnikova IE, Olefirenko GA. The relationship of level of transforming growth factor beta 1 with liver fibrosis in children with congenital diseases of hepatobilliary system. Klin Lab Diagn. 2017; 4 (62): 221–225. [In Russian]

8. Курабекова РМ, Цирульникова ОМ, Шевченко ОП, Цирульникова ИЕ, Макарова ЛВ, Олефиренко ГА и др. Способ подбора режима иммуносупрессии после трансплантации печени детям раннего возраста. Пат. 2602302. Российская Федерация: Федеральный научный центр трансплантологии и искусственных органов имени академика В. И. Шумакова; Опубл. 20. 11. 2016, Бюл № 32. Kurabekova RM, Tsirulnikova OM, Shevchenko OP, Tsirulnikova IE, Makarova LV, Olefirenko GA et al. Method of immunosuppression dosage adjustment after liver transplantation in children of early age. Pat. 2602302. Russian Federation: Federal Shumakov Research Center. Publ. 20. 11. 2016, Bull. № 32. [In Russian]

9. Цирульникова ОМ, Лурье ЮЭ, Цирульникова ИЕ. Особенности иммуносупрессивной терапии у детей. Иммуносупрессивная терапия у детей при трансплантации печени. Иммуносупрессия при трансплантации солидных органов. М. – Тверь: Триада, 2011: 273–337. Tsirulnikova OM, Lurie YE, Tsirulnikova IE. Features of immunosupressive therapy in children. Immunosupressive therapy in children at liver transplantation. Immunosupression at solid organ transplantation. M. – Tver: Triada, 2011: 273–337. [In Russian]

10. Pencina MJ, D’Agostino RB, Sr., D’Agostino RB, Jr., Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008; 27 (2): 157–172.

11. Briem­Richter A, Leuschner A, Krieger T, Grabhorn E, Fischer L, Nashan B et al. Peripheral blood biomarkers for the characterization of alloimmune reactivity after pediatric liver transplantation. Pediatr Transplant. 2013; 17 (8): 757–764.

12. Шевченко ОП, Цирульникова ОМ, Курабекова РМ, Цирульникова ИЕ, Олефиренко ГА, Готье СВ. Уровень трансформирующего фактора роста β1 в плазме крови детей – реципиентов печени и его связь с функцией трансплантата. Иммунология. 2015; 36 (6): 343–347. Shevchenko OP, Tsirulnikova OM, Kurabekova RM, Tsirulnikova IE, Olefirenko GA, Gautier SV. Blood plasma level of transforming growth factor β1 in pediatric liver transplant recipients and its relationship with graft function. Immunologiya. 2015; 36 (6): 343–347. [In Russian (abstract in English)]

13. Li W, Kuhr CS, Zheng XX, Carper K, Thomson AW, Reyes JD et al. New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am J Transplant. 2008; 8 (8): 1639–1651.

14. Shalev I, Selzner N, Shyu W, Grant D, Levy G. Role of regulatory T cells in the promotion of transplant tolerance. Liver Transpl. 2012; 18 (7): 761–770.