RU2764742C1 - Method for selecting an immunosuppression regimen for young children in the long-term period after liver transplantation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to transplantation, clinical laboratory diagnostics, and can be used for immunosuppressive therapy after liver transplantation in young children. Therapy includes taking tacrolimus as part of the therapy regimen: tacrolimus, mycophenolate, corticosteroid. One year after transplantation, the content of insulin-like growth factor 1 (IGF-1) is determined in the blood serum of the liver recipient, and the daily dose of tacrolimus is determined by the formula: D = 0.091 + 0.0007 × G, where: D is the dose of tacrolimus, mg/kg/day; G is the content of IGF-1 in blood serum, ng/ml.

EFFECT: method provides the possibility of preventing complications caused by insufficient or excessive immunosuppression in young children after liver transplantation for congenital diseases of the hepatobiliary system in the long term by increasing the accuracy of individual selection of tacrolimus doses by objectively taking into account the state of metabolic and immune processes after liver transplantation in each patient while ensuring simplicity, accessibility of dose selection by determining a single indicator: IGF-1, which does not require a long time, unique reagents and devices.

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Description

The invention relates to medicine, namely to organ transplantation and clinical laboratory diagnostics, can be used to select an immunosuppression regimen in the long-term period after transplantation in young liver recipients operated on for acquired and congenital diseases of the hepatobiliary system.

The relevance of the problem of selecting an immunosuppression regimen after liver transplantation in young children is due to the fact that in such patients, on the one hand, when prescribing high doses of immunosuppressants, there is a high risk of developing infectious complications, and on the other hand, when prescribing minimal doses of immunosuppressants, rejection and dysfunction may develop. transplant.

In young children with congenital hepatobiliary diseases who undergo liver transplantation, the immune system is hyperreactive, while at the same time there is a high ability to develop immunological tolerance to the transplant. In each case, the total effect of these factors is difficult to assess.

It is believed that in young children after liver transplantation, the risk of infectious complications prevails, against which it becomes necessary to correct the standard protocol of immunosuppressive therapy (delayed administration of immunosuppressants, their temporary cancellation, reduction in doses of immunosuppressants). Therefore, there is a need for a method for more accurate selection of the immunosuppression regimen in young children after liver transplantation.

The selection of an immunosuppression regimen after liver transplantation in children with congenital diseases of the hepatobiliary system has been used since the 80s of the last century and is described in detail in foreign and Russian literature (for example, Murray, KF and RL Carithers, Jr. 2005. "AASLD practice guidelines: Evaluation of the patient for liver transplantation." Hepatology41(6): 1407-1432).

There is a known method of immunosuppressive therapy (triple immunosuppression), which includes the appointment of glucocorticosteroids (with gradual dose reduction up to complete withdrawal during the first year after transplantation or later), a calcineurin inhibitor (tacrolimus) and the third component - the drug mycophenolic acid (Tsirulnikova O.M. ., Lurie Yu.E., Tsirulnikova I.E.: Features of immunosuppressive therapy in children Immunosuppressive therapy in children with liver transplantation Immunosuppression in solid organ transplantation Gauthier SV - M. Tver: Triad; 2011; - 273 -337). The daily dose of the main component of immunosuppression - tacrolimus is selected empirically, starting with the minimum. The starting dose of tacrolimus at its first appointment is 0.1 mg / kg / day, in the early postoperative period - 0.2-0.3 mg / kg / day, then the dose is adjusted to achieve the target concentration of the drug in the blood of 4-8 ng / ml during the first month after transplantation and 3-6 ng / ml - in the subsequent period.

However, with this method, there are no objective laboratory indicators of the state of natural immunity, allowing you to choose the dose of tacrolimus individually for each patient. Achieving the required concentration of tacrolimus in the blood is achieved in different patients by prescribing different doses of the drug. At the same time, errors in dosage can be accompanied by complications: with a lack of tacrolimus - the development of graft rejection, and with an excess - the appearance of infectious complications. The known method does not take into account the objective laboratory indicators of the state of the liver transplant and the natural immunity of a particular recipient, allowing you to choose the dose of tacrolimus individually for each patient.

As a prototype, the selected method of immunosuppressive therapy, including the appointment of tacrolimus, mycophenolate, corticosteroid. At the same time, one year after transplantation, insulin-like growth factor 1 (IGF-1) and soluble CD30 are determined in the blood serum of a liver recipient, and the daily dose of tacrolimus is determined by the formula (RU 2619216, C1). The prototype method allows you to choose the dose of tacrolimus individually for each patient, however, it is quite laborious, requiring the determination of 2 biomarkers, and not accurate enough - its effectiveness is 71.4%.

The objective of the present invention is to develop a simple, accurate method for individual selection of immunosuppression regimen in the long term in young children after liver transplantation for congenital diseases of the hepatobiliary system.

The technical result achieved in the implementation of the invention consists in the prevention of complications caused by insufficient or excessive immunosuppression in young children after liver transplantation for congenital diseases of the hepatobiliary system in the long term by improving the accuracy of individual selection of tacrolimus doses by objectively taking into account the state of metabolic and immune processes after liver transplantation in each patient while ensuring simplicity, availability of dose selection by determining a single indicator - IGF-1, which does not require a long time, unique reagents and devices.

The essence of the invention is as follows.

Immunosuppressive therapy after liver transplantation in young children in the long term includes the appointment of tacrolimus, mycophenolate, corticosteroid. At the same time, one year after transplantation, IGF-1 is determined in the blood serum of a liver recipient. The daily dose of tacrolimus is determined by the formula:

D = 0.091 + 0.0007 × G

where:

D - dose of tacrolimus, mg/kg/day;

G - content of IGF-1 in blood serum, ng/ml.

Congenital liver diseases, which, as a rule, serve as indications for liver transplantation in young children, are accompanied by a deficiency of IGF-1, this imbalance increases as the disease progresses and the protein-synthetic function of the liver decreases. A year after transplantation, the protein level returns to normal, and the imbalance decreases to varying degrees in different recipients. IGF-1 is known to enhance lymphocyte proliferation, while tacrolimus has an inhibitory effect on T-cell division, so a higher level of IGF-1 in the body can lead to more active lymphocyte proliferation, the inhibition of which will require a higher dose of tacrolimus.

We have established for the first time that the concentration of IGF-1 in the blood of liver transplant recipients in the long term after transplantation correlates with the dose of the immunosuppressant tacrolimus. This circumstance allowed us to offer an individual calculation of the doses of the indicated drug, taking into account the concentration of a single marker.

The method is carried out as follows.

Measurement of IGF-1 is carried out by a quantitative ELISA method with a set of reagents (IDS, USA, and Bender MedSystems, Austria, respectively) (see, for example, Instructions for a set of reagents for the determination of IGF-1 IDS, USA; BC Kamyshnikov. Handbook of Clinical biochemical laboratory research and laboratory diagnostics / Moscow, MEDpress-inform, 2009, 371 pp. Liss V.L., Nikolaeva L.V., Nagornaya I.I. et al., Laboratory diagnostics and functional tests in pediatric endocrinology. St. Petersburg .: Special literature, 1996. - 136 p.) on a Zenyth 340 photometer (Anthos Labtec Instruments GmbH, Austria).

The level of IGF-1 in the patient's blood is measured 1 year after transplantation and the estimated daily dose of tacrolimus is calculated using the formula:

D = 0.091 + 0.0007G,

where:

D - dose of tacrolimus, mg/kg/day;

G - content of IGF-1 in blood serum, ng/ml.

The possibility of practical use of the method with the achievement of the specified purpose and technical result is substantiated by the data below.

Example 1

Patient R., aged 3 months, was admitted with a diagnosis of cirrhosis of the liver as a result of atresia of the biliary tract. Liver transplantation (LT) was performed from the mother of the same blood type. One year after LT, the concentration of IGF-1 in the blood was 46.9 ng/ml, the estimated dose of tacrolimus (according to the proposed method) was 0.124 mg/kg/day. The postoperative period was uneventful, no complications were observed. Correction of immunosuppressive therapy was not required. The follow-up period was 3.6 years.

Example 2

Patient M., 7 months old, was admitted with a diagnosis of cirrhosis of the liver as a result of atresia of the biliary tract. A related LT was performed, compatible by blood type. One year after LT, the concentration of IGF-1 in the blood was 80.1 ng/ml, the estimated dose of tacrolimus (according to the proposed method) was 0.147 mg/kg/day. No complications were observed in the postoperative period. Correction of immunosuppressive therapy was not required. The observation period is 4 years.

Example 3

Patient D., 2 years old, was admitted with a diagnosis of liver cirrhosis as a result of Budd-Chiari syndrome. A related LT was performed, incompatible by blood type. A year after LT, the concentration of IGF-1 in the blood was 85.0 ng/ml, the estimated dose of tacrolimus (according to the proposed method) was 0.150 mg/kg/day. No complications were observed in the postoperative period. Correction of immunosuppressive therapy was not required. The follow-up period is 4.5 years.

Example 4

Patient P., 12 months old, was admitted with a diagnosis of double liver cirrhosis as a result of biliary atresia. A related LT was performed, incompatible by blood type. One year after LT, the concentration of IGF-1 in the blood was 105.8 ng/ml, the estimated dose of tacrolimus (according to the proposed method) was 0.165 mg/kg/day. The postoperative period proceeded smoothly. Correction of immunosuppressive therapy was not required. The follow-up period was 4.6 years.

Example 5

Patient U., 12 months old, was admitted with a diagnosis of biliary cirrhosis of the liver in the outcome of Caroli's disease. A related LT was performed, incompatible by blood type. One year after LT, the concentration of IGF-1 in the blood was 153.2 ng/ml, the calculated dose of tacrolimus was 0.198 mg/kg/day. Correction of immunosuppressive therapy was not required. The follow-up period was 4.8 years. No complications were observed in the postoperative period.

The proposed method was tested in clinical practice on 56 patients, while the calculation of the dose of tacrolimus, made according to the claimed method, was satisfactory and did not require further correction in 44 cases, which amounted to 78.5%.

The use of the patented method in clinical practice enables an individual approach to the selection of an immunosuppression regimen, which suggests the possibility of increasing the effectiveness of treatment.

The proposed method for selecting an immunosuppression regimen is less laborious (one biomarker measurement is required instead of 2) and more accurate, 78.5% versus 71.4%.

Claims (5)

A method for conducting immunosuppressive therapy after liver transplantation in young children, including taking tacrolimus as part of the therapy regimen: tacrolimus, mycophenolate, corticosteroid, characterized in that one year after transplantation, the content of insulin-like growth factor 1 (IGF-1) is determined in the blood serum of the recipient of the liver ), and the daily dose of tacrolimus is determined by the formula: D = 0.091 + 0.0007 × G where: D - dose of tacrolimus, mg/kg/day; G - content of IGF-1 in blood serum, ng/ml.