DYNAMICS OF BLOOD TACROLYMUS CONCENTRATION IN PREGNANT WOMEN AFTER RENAL TRANSPLANTATION

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 126 DYNAMICS OF BLOOD TACROLYMUS CONCENTRATION IN PREGNANT WOMEN AFTER RENAL TRANSPLANTATION Z.T. Matkarimov1, N.B. Elmuradova2, M.T. Azimova3, D.N. Komilova4, M.O. Rustamov5, J.B. Urinov6, I.Z. Rustamov7, I.M. Turdiyev8 Republican Specialized Scientific and Practical Medical Center of Surgery named after Academician V. Vakhidov1,2,3,4,5,6,7,8 https://doi.org/10.5281/zenodo.17744279 Abstract. The article describes the importance of monitoring the concentration of tacrolimus during pregnancy in women with kidney transplantation. Its importance lies not only in preserving the function of the transplant, but also in increasing pregnancy safety, minimizing complications, and improving perinatal outcomes. Keywords: kidney transplantation, tacrolimus pharmacokinetics, pregnancy, rejection, azathioprine. Introduction. Due to the increasing prevalence of chronic kidney diseases and the increasing effectiveness of renal replacement therapy methods aimed at improving the quality of life and increasing life expectancy, there is an increase in the frequency of kidney transplantation. A significant portion of recipients are women of reproductive age, which actualizes issues related to the restoration of reproductive function and ensuring the possibility of giving birth to healthy offspring [1,2,3]. Pregnancy after kidney transplantation is possible, but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is usually dosed based on the drug's concentration in whole blood before administration. However, maintaining these concentrations is difficult, as physiological changes during pregnancy affect the pharmacokinetics of tacrolimus. Tacrolimus is the primary drug for sustained immunosuppressive therapy in kidney transplant recipients. Its effectiveness in preventing transplant rejection has been proven by numerous studies, however, the drug has a narrow therapeutic window, making its concentration in the blood a necessary condition for successful patient management. During pregnancy, the pharmacokinetics of the tacrolimus changes significantly. Physiological processes such as increased circulating blood volume, decreased albumin and hematocrit levels, increased glomerular filtration rate, and liver enzyme activity affect drug distribution and clearance. As a result, pregnant recipients of the transplant often experience a decrease in trough concentrations at standard doses, which increases the risk of rejection episodes. On the other hand, attempting to mechanically increase the dose without considering hematocrit and protein profile can lead to toxic effects - nephrotoxicity, hypertension, liver dysfunction, and pregnancy complications. Regular monitoring of the level of tacrolimus allows minimizing the risk of both transplant rejection and pregnancy complications (preeclampsia, intrauterine growth retardation, premature birth). Furthermore, the accumulated data indicate the safety of breastfeeding against the background of therapy: the amount of the drug entering the baby's body with milk does not exceed 0.3-1% of the mother's dose and is considered clinically insignificant. SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 127 Materials and methods of research. We conducted a clinical analysis of the course and outcome of pregnancy (retrospectively and prospectively) in 23 recipients of kidney transplantation observed at the " RSNPMC of surgery named after academician V. Vakhidov " State Institution from 2021 to 2025. Results. All our patients underwent immunosuppressive therapy before pregnancy, the drug combination was the same in all 23 cases. Three-component therapy included tacrolimus, azathioprine, and glucocorticosteroids (GCS). 100% of patients received this therapy. Mycophenolate mofetil was canceled immediately during the pregnancy planning phase due to its teratogenicity. GCS doses in all cases were minimal: prednisolone - 5 mg/day, methylprednisolone - 4 mg/day and remained stable throughout pregnancy. Tacrolimus (TAC) and the changes in its metabolism and pharmacokinetics observed during pregnancy and after childbirth are of particular interest. Analysis of tacrolimus dosages by month (2-9 months) is shown in Table 1. This table reflects the average, minimum, and maximum doses of tacrolimus for each month. Table 1 Analysis of tacrolimus dosage by months Month Average dose (mg) Min (mg) Max (mg) 2nd month 3.39 2.0 6.0 3rd month 3.60 2.0 7.0 4th month 3.86 2.0 7.0 5th month 4.04 2.0 9.0 6th month 4.33 2.0 9.0 7th month 4.47 2.0 9.0 8th month 4.67 2.0 9.0 9th month 4.66 2.0 9.0 The table shows a persistent increase in the average dose from the 2nd to the 8th month, with subsequent stabilization. For clarity, we have constructed the trend of the average dose over time, whereas the graph shows that from the 2nd to the 6th month, there is a steady increase in the dose from 3.4 to 4.3 mg, from the 6th to the 8th month, the increase continues but slows down, and by the 9th month, a plateau appears: the dose remains at ~4.66 mg. The diagram shows boxplot graphs of tacrolimus dosage by month (2 to 9 months). Each boxplot reflects the median, interquartile range (IQR), minimum and maximum values, and emissions. The diagram shows that the median dose values are increasing: from ~3.5 mg (2-3 months) to ~5.0 mg (7-9 months), reflecting the gradual titration of doses in the posttransplantation period. An increase in dose dispersion has been observed since the 6th month, indicating personalized therapy. Dosage varies widely, reaching up to 9 mg/day in individual patients. The presence of discharge (9 mg) starting from 6 months requires assessing the condition of the transplant and possible clinical complications. Based on the range diagram (Fig. 1), we can say that there is a statistically expressed tendency towards an increase in the dose of tacrolimus in recipients of kidney transplantation during pregnancy. From 2 to 6 months, both median and average dosage values increase, after which the therapeutic plateau is reached by 7-9 months. Along with this, variability increases, SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 128 which is confirmed by the expansion of IQR and the appearance of doses above 8 mg, requiring an individual approach and intensification of therapeutic monitoring. Figure 1. Diagram of tacrolimus dosage range from 1 to 9 months of pregnancy The frequency of blood TAC concentration determination depended on the gestational age. In the first trimester, the concentration was determined monthly, in the second trimester once every 2 weeks, and in the third trimester, the concentration was determined weekly. Dynamic observation revealed a tendency towards a decrease in blood TAC levels during pregnancy, despite increased doses, these changes were observed in all patients receiving TAC without exception. Clinical examples can be the next patient. Patient D., 32 years old, was admitted to the RSNPCH named after Academician V. Vakhidov at the State Institution with the diagnosis: Chronic glomerulonephritis, CPN terminal stage. She had been ill for 2 years, received programmed hemodialysis for about 15 months through a double-channel hemodialysis catheter inserted into the right IVV, then through an AV fistula inserted into the right forearm. In 2019, a 29-year-old patient underwent right-sided heterotropic kidney transplantation from a living relative donor. The postoperative period proceeded smoothly, the kidney transplant function was immediate. The patient was systematically monitored by transplantologists and nephrologists at our center. A few years after the accident, she expressed a desire to become pregnant. The period from transplantation to pregnancy was 3 years. The transplant function is stable, creatinine is within 45-50 μmol/l, proteinuria is absent, and blood pressure is within normal limits. The pregnancy was planned after consulting with a transplantologist and gynecologist. Careful preparation and correction of immunosuppressive therapy were carried out before conception: mycophenolate mofetil was discontinued 2 weeks before pregnancy planning and SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 129 replaced with azathioprine, tacrolimus therapy and low doses of methylprednisolone continued. The pregnancy proceeded without complications. The patient was under observation throughout the gestation period. Regular consultations with a transplantologist, nephrologist, and obstetriciangynecologist were conducted. The functional indicators of the transplant remained stable throughout the gestation period. Observation dynamics: urine analysis - without pathological changes. Tacrolimus levels were monitored monthly in the first trimester, every two weeks in the second trimester, and every week in the third trimester. The dose was adjusted taking into account the concentration change. A gradual decrease in the level of tacrolimus was observed against the background of physiological changes during pregnancy (metabolic changes) (Figure 2). Fig. 2. Dynamics of tacrolimus concentration in patient D. during pregnancy. Despite the decrease, the level remained close to the lower limit of the therapeutic range until the 8th month. After 32 weeks, there was a risk of falling below the therapeutic threshold, resulting in a decision to increase the dose. Swelling was not observed throughout the pregnancy. Proteinuria was observed closer to childbirth (0.066). The fetus developed according to the term, no defects were observed on ultrasound. Low doses of anticoagulants were used during pregnancy. The patient received multivitamin complexes and folic acid. Blood pressure monitoring was conducted. At 40 weeks, the patient's contractions began. The childbirth proceeded naturally, without complications. The child was born with a mass of 2750 g. In the postpartum period, the patient's condition remained stable, and the kidney transplant function indicators were within normal limits. The level of tacrolimus in the blood was monitored and restored to its previous dosage. Thus, analyzing the data, we want to note that the trend towards increasing the dose of tacrolimus in the first 6 months of pregnancy occurs with the goal of achieving stable immunosuppression. The presented data confirms the need to adjust the dosage of tacrolimus, taking into account individual pharmacokinetic and clinical factors, especially starting from 6 months of pregnancy. 0 2 4 6 8 1st month 3rd month 5th month 8th month 9th month 7.59 5.67 5.13 4.5 3.25 Dynamics of tacrolimus concentration in patient D. during pregnancy SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 130 Conclusions. Based on the above, it can be concluded that pregnancy during kidney transplantation can proceed successfully with careful planning, stable transplant function, and adherence to an individual observation approach. Important conditions are stable transplant function for ≥1 year, absence of arterial hypertension and pronounced proteinuria; discontinuation of teratogenic drugs (for example, mycophenolate mofetil); adequate control of immunosuppressor levels; multidisciplinary approach involving transplantologists and obstetrician-gynecologists. REFERENCES 1. Kravchenko N.F., Kandidova I.E., Khodzhaeva Z.S. Management of pregnancy and childbirth after solid organ transplantation // Obstetrics and Gynecology: news, opinions, training. 2017. Vol. 2, No. 16. P. 15-20. 2. European best practice guidelines for kidney transplantation. Section IV: Long-term management of the transplant recipient. IV.10. Pregnancy in recipients of kidney transplantation // Nephrol. Dial. Transplant. 2002. Vol. 17, Suppl. 4. P. 50-55. 3. Rupley D.M., Janda A.M., Kapeles S.R., Wilson N.M., Berman D., Mathur A.K. Preconception counseling, fertility, and pregnancy complications after abdominal organ transplantation: a survey and cohort study of 532 recipients // Clin. Transplant. 2014. Vol. 28, No. 9. P. 937-945. DOI: 10.1111/ctr.12393.