Objectives: This study evaluated the long-term clinical outcomes and dynamics of immunosuppressive therapy in kidney transplant recipients in Uzbekistan, which was compared with international data.
Materials and Methods: This retrospective multicenter cohort study included 3437 kidney transplant recipients. Data were obtained from the national transplant registry. Follow-up ranged from 1 to 30 years. Clinical outcomes, graft survival, recipient survival, and immunosuppressive therapy parameters were analyzed. Repeated-measures analysis of variance and life-table analysis were used for statistical evaluation.
Results: A gradual reduction in tacrolimus dose was observed from 6.68 mg/day at year 1 to 5.58 mg/day at year 10, accompanied by a decrease in mean blood concentration from 8.28 to 6.55 ng/mL. Mycophenolate mofetil dosing decreased significantly over time (P < .⁰⁰¹), whereas mycophenolic acid dosing remained stable (P > .⁰⁵). The incidence of graft loss requiring return to hemodialysis was 2.88%. A biphasic pattern of graft loss was identified, with peaks within the first 3 years and after 10 years posttransplant. Recipient survival rates were 98.8% at 1 year and 96.9% at 10 years.
Conclusions: Kidney transplantation in Uzbekistan demonstrates favorable long-term outcomes comparable to international benchmarks. Immuno-suppressive therapy shows a trend toward controlled minimization. The identified biphasic risk of graft loss highlights the importance of long-term monitoring and individualized management strategies.

Key words : Graft survival, Immunosuppressive therapy, Kidney transplantation, Tacrolimus

Introduction
Organ and tissue transplant is one of the leading and dynamically developing fields of modern surgery, aimed at the complete restoration of the function of a diseased organ through its replacement with a donor graft. The establishment of this discipline became possible because of advances in vascular anastomosis techniques, whereas its widespread clinical implementation followed the emergence and evolution of immunosuppressive therapy.¹ International studies consistently demonstrate that kidney transplant not only improves clinical outcomes but is also a more cost-effective strategy compared with long-term renal replacement therapy (hemodialysis). Analyses incorporating quality-adjusted life years (QALYs) show that transplantation provides a greater QALY gain at comparable or lower costs than dialysis and is considered the most economically advantageous strategy across different health care systems. For example, in a comparative analysis, kidney transplant yielded 2.98 QALYs versus 2.10 QALYs for dialysis over a 5-year period at similar overall expenditures, indicating superior cost-effectiveness and improved quality of life for patients.² The development of transplant medicine in the Republic of Uzbekistan has progressed through 5 key stages, closely associated with changes in the regulatory and legal framework. The first stage (1972-1991) was marked by the first kidney transplant performed in the republic on September 14, 1972, following the adoption of foundational legal acts in 1970 regulating organ and tissue transplantation. The second stage (1991-1998) was characterized by the disintegration of the transplant care system due to a legislative prohibition of transplant activities, leading to a complete suspension of clinical practice. The third stage (1998-2017) was associated with the resumption of clinical activity. Based on a special order issued by the Ministry of Health of the Republic of Uzbekistan, a series of 48 kidney transplant procedures from living related donors was performed. The fourth stage (2017-2022) represented a period of significant quantitative growth. In accordance with Resolution No. 859 of the Cabinet of Ministers of the Republic of Uzbekistan dated October 17, 2017, 849 kidney transplant and 22 liver transplant procedures were performed, all from living related donors. The fifth and current stage began on May 11, 2022, with the enactment of the new Law of the Republic of Uzbekistan “On Transplantation of Human Organs and (or) Tissues,” which established the legal basis for organ procurement from both living and deceased donors. This legislation created the foundation for expanding the donor pool and improving access to transplant services.³ In this study, our aim was to conduct a retrospective analysis of 3437 kidney transplant recipients and to compare the obtained results with national and international kidney transplant data over the past 30 years.

Materials and Methods
We conducted a retrospective multicenter cohort study that included 3437 patients who underwent kidney transplant from living related donors (Table 1). Of these, 2532 recipients (73.6%) received their transplant in medical institutions in Uzbekistan, and 905 patients (26.3%) underwent transplant in clinics abroad (both neighboring and distant countries). The follow-up period ranged from 1 to 30 years posttransplant. The primary inclusion criterion was history of kidney transplant with available follow-up data of at least 1 year. We obtained data from the Unified Registry of Organ and Tissue Transplant Recipients of the Republic of Uzbekistan (https://trans.nefro.uz). Clinical data collected included the site of transplant, graft survival, pharmacokinetic and pharmacodynamic parameters of immunosuppressive therapy, and recipient survival. Table 1 presents cumulative patient data according to posttransplant follow-up duration, including mean tacrolimus trough concentration in 1511 patients, mean daily tacrolimus dose in 2640 patients, number of patients receiving cyclosporine (n = 32), mean daily dose of mycophenolate mofetil in 2841 patients, mean daily dose of mycophenolic acid in 399 patients, number of patients who returned to hemodialysis (n = 99), and number of deaths (n = 152). For analysis of continuous variables, such as immunosuppressant concentrations and doses, we used repeated measures analysis of variance, followed by post hoc testing. We evaluated graft survival dynamics and the cumulative incidence of adverse events (return to dialysis, need for therapy modification) by using life-table analysis with calculation of proportions. We presented categorical variables as absolute numbers and percentages. We used SPSS software, version 23.0 (IBM Corp), for all statistical analyses

Ethical considerations
This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the local ethics committee. Given the retrospective design of the analysis, the requirement for individual informed consent was waived by decision of the ethics committee, provided that full anonymization of personal and medical data was ensured.

Results
Analyses of changes in mean daily dose of tacrolimus evaluated over a period from 1 to 10 years following kidney transplant included 2640 patients. At each time point, the proportion of patients receiving tacrolimus ranged from 90.8% to 96%. A significant trend in gradual tacrolimus dose reduction was observed: from 6.68 mg/day during year 1 to 5.58 mg/day by year 10 of follow-up. The most pronounced dose reduction occurred within the first 3 posttransplant years, whereas, during subsequent years (years 4-10), the dose curve reached a relative plateau with minimal fluctuations (Figure 1). Analysis showed an association between mean blood concentration of tacrolimus and the duration of the posttransplant period. A consistent downward trend was observed in tacrolimus blood concentration, with levels decreasing from 8.28 ng/mL at 1 year posttransplant to 6.55 ng/mL at 10 years posttransplant. The total cohort size in this analysis was cumulative in nature, increasing from 292 patients at year 1 to 1511 patients at year 10. At the same time, the proportion of patients receiving tacrolimus for whom concentration data were available remained relatively stable across all time points, ranging from 57.2% to 58.2% (Figure 2). During the first 10 years after transplant, the annual incidence of tacrolimus replacement with cyclosporine due to posttransplant diabetes mellitus progressively increased from 0.1% (2 of 3437 patients) in year 1 to 0.5% (16 of 3437 patients) by year 10. Over the entire subsequent follow-up period (>10 years), the cumulative incidence of this event reached 0.9% (32 cases). Thus, the overall prevalence of posttransplant diabetes mellitus requiring conversion from tacrolimus to cyclosporine was 0.9% (32 of 3437 patients) (Figure 3). To assess the dynamics of mycophenolate mofetil dosing in kidney transplant recipients, a long-term analysis of the mean daily dose was performed at follow-up points of 1, 3, 5, 7, and 10 years after transplant. A significant progressive reduction in the mean daily dose of the mycophenolate mofetil was observed over the 10-year period (P < .⁰⁰¹, repeated measures analysis). By year 3 posttransplant, the dose had decreased by 7.4% (133.6 mg) compared with the year 1 baseline level. Doses decreased by 10.1% (182.5 mg) at year 5, decreased by 10.7% (194.2 mg) at year 7, and decreased by 11.6% (209.2 mg) at year 10. This trend reflected clinical practice involving gradual reduction of immunosuppressive therapy in the setting of stable graft function and absence of signs of acute rejection (Table 2). Patients receiving mycophenolic acid (the active metabolite of mycophenolate mofetil) accounted for 11.9% to 14.0% of the cohort at different follow-up time points. The mean daily dose of mycophenolic acid remained relatively stable over the 10-year period, ranging from 1142.7 to 1198.3 mg/day. The highest mean dose was observed during year 1 posttransplant (1198.3 mg/day), followed by a moderate decrease by year 5 (1142.7 mg/day) and a slight increase by year 10 (1157.9 mg/day). No significant progressive dose reduction was identified (P > 0.05), in contrast to the dynamics observed for mycophenolate mofetil over the same period (Table 3). During the study, among 3437 total patients, 99 (2.9%) had kidney graft failure, resulting in the need to resume hemodialysis. The temporal distribution of these events was nonlinear, demonstrating 2 pronounced risk peaks. The first peak occurred within the first 3 years after transplant, during which 39 cases were registered (1.1% of the cohort). The second peak was observed in the late posttransplant period, more than 10 years after transplant, also comprising 39 cases (1.1% of the cohort). Between 3- and 10-years post-transplantation, the risk was substantially lower (21 cases among 3437 patients, 0.6%), reaching its minimum between 5 and 7 years (4 cases, 0.1%). The cumulative risk of graft loss by year 10 was 1.7%, increasing to 2.9% when all subsequent events were considered (Table 4). Recipient survival analysis demonstrated a 1-year survival rate of 98.8%, a 3-year survival rate of 97.4%, and a 5-year survival rate of 97.1%. Seven- and 10-year recipient survival rates were both 96.9%, and 10-year graft survival was 95.5%.

Discussion
In this retrospective cohort study of 3437 kidney transplant recipients, both long-term clinical outcomes and changes in immunosuppressive therapy strategies over an extended follow-up period were characterized. In the Republic of Uzbekistan, immunosuppressive medications for transplant recipients are provided at state expense, which led to the establishment of a national transplant recipient registry. Because the registry is primarily designed to determine demand and ensure appropriate distribution of immunosuppressive drugs, data regarding prescribed agents and their dosages are comprehensively represented in this dataset. In contrast, tacrolimus blood concentration data were available for 57.2% of patients receiving tacrolimus. The achieved recipient survival rates of 98.8% at 1 year and 96.9% at 10 years posttransplant indicated stable and reproducible clinical outcomes and are comparable to data reported by international registries such as the Collaborative Transplant Study registry and the Scientific Registry of Transplant Recipients under real-world clinical conditions.^4-6 The early peak of graft loss within the first 3 years after transplant is primarily driven by immunological and surgical factors. During this period, acute rejection episodes, variability in calcineurin inhibitor exposure, suboptimal adherence, and early vascular and urological complications play critical roles.^7-9 In analyses of the dynamics of immunosuppressive therapy, a consistent reduction is shown in daily tacrolimus dose and blood concentration, as well as in mycophenolate mofetil dosing over time. This pattern corresponds to contemporary strategies of controlled immunosuppression minimization in patients with stable graft function, aimed at reducing the risks of chronic nephrotoxicity, cardiovascular complications, and metabolic disorders.^10,11 At the same time, the relative stability of mycophenolic acid dosing despite the reduction in mycophenolate mofetil dose may reflect a targeted pharmacokinetic approach to maintaining adequate exposure to the active metabolite. Therapeutic drug monitoring of mycophenolic acid, including area under the curve-guided strategies, has previously been shown to significantly optimize the efficacy and safety of immunosuppressive therapy.^12,13 The safety profile of calcineurin inhibitors warrants particular attention. Although the rate of conversion from tacrolimus to cyclosporine due to posttransplant diabetes mellitus was low (0.9%), the difference was significant, underscoring the necessity of long-term metabolic monitoring in kidney transplant recipients, including during late posttransplant periods. Studies involving Uzbekistan or similar regions have emphasized the central role of calcineurin inhibitors in maintaining graft function while highlighting the importance of individualized dosing strategies in long-term follow-up.^14-17 The most clinically significant finding of this study was the confirmation of a biphasic distribution of graft loss risk. The early peak (during years 0-3) is traditionally associated with surgical complications and acute rejection, whereas the second peak, identified more than 10 years posttransplant and accounting for 39.4% of all cases requiring return to hemodialysis, reflects the increasing effects of chronic allograft nephropathy.^18,19 The higher cumulative incidence of graft loss after 10 years compared with periods from year 3 to year 10 (1.1% vs 0.6%) suggests the need to reconsider long-term follow-up paradigms with greater emphasis on prevention of late risk factors. Study limitations included our retrospective design, incomplete availability of certain parameters, particularly mycophenolic acid dosing data, and heterogeneity of the patient cohort. The absence of histological verification of graft loss etiology limited deeper pathophysiological interpretation. According to work from Uzbekistan and similar regions, late chronic graft dysfunction is largely associated with prolonged exposure to nephrotoxic effects of immunosuppressive therapy.²⁰

Conclusions
The retrospective analysis of 3437 kidney transplant recipients in Uzbekistan demonstrated high-quality long-term clinical outcomes: 1-year recipient survival was 98.8%, and 10-year survival reached 96.9%, confirming the effectiveness and sustainability of the implemented transplant protocols. The dynamics of immunosuppressive therapy showed a gradual reduction in tacrolimus and mycophenolate mofetil dosing in the setting of stable graft function, consistent with contemporary strategies of controlled immunosuppression minimization and reduction of nephrotoxic, cardiovascular, metabolic, and infectious complications. A biphasic risk pattern of graft loss was identified, with an early peak during the first 3 years and a second peak occurring more than 10 years after transplant, underscoring the importance of prolonged follow-up and prevention of late risk factors. Our findings provide a basis for optimization of recipient management, individualization of immunosuppressive therapy, and refinement of long-term monitoring strategies in kidney transplant clinical practice.