Key words : Child, Kidney transplantation, Medication compliance

Introduction
Pediatric renal transplant patients have unique challenges in maintaining medication adherence. Maintaining medication adherence is crucial for graft survival and long-term outcomes. Despite developments in transplant medicine, nonadherence to immunosuppressive therapy remains a significant concern, and nonadherence can lead to increased risk of rejection and complications.^1-3 However, adherence is the most important modifiable factor that affects treatment outcomes.⁴

Numerous factors contribute to medication nonadherence in pediatric patients, including age-related issues, low education and socioeconomic levels, forgetting, poor organization, complexity of the treatment, lack of belief in the effectiveness of the treatment, anxiety, cost, insufficient education, drug toxicity, and adverse effects.^5-7 Risk factors related to parental and child psychological and behavioral functioning, parental stress, and burden are also important.⁸

Addressing challenges of nonadherence requires tailored interventions that consider the specific needs of pediatric groups. Recent studies have focused on various strategies to enhance medication adherence as educational, psychological, or behavioral interventions using different technological devices, techniques, or tools, with interventions conducted by individual or multidisciplinary teams in different settings, including health care facilities, home, or remotely.^9-13 Transplant teams such as physicians, nurses, pharmacists, psychologists, and social workers have also demonstrated effectiveness in promoting adherence and addressing underlying psychosocial factors.^10,14

Education programs have focused on transplant medication knowledge, dose and side effect management, and adherence skills.^15-18 Behavioral and psychological interventions, including motivational interviewing and cognitive-behavioral techniques, have been designed to address psychological barriers and enhance patient motivation.^15-17 Technology has also been integrated in interventions, such as medication reminder or monitoring devices, mobile applications, web-based programs, text messages, and telehealth services, which have facilitated remote monitoring and support for patients and their families.^19-21

Despite advancements in nonadherence interventions, challenges remain in implementing and sustaining adherence-promoting interventions, especially in diverse patient populations with varying socioeconomic backgrounds and cultural beliefs. Although investigations to increase medication adherence have been conducted in pediatric populations, results on which interventions are effective have been unclear.^4,22

Materials and Methods
This systematic review aimed to determine the effectiveness of interventions designed to improve medication adherence among pediatric renal transplant recipients.

In this study, we searched the PubMed (MEDLINE), the Cochrane, EBSCO, SCOPUS, Web of Science and National Thesis Center and TÜBİTAK (TR Index) databases for randomized, quasi-experimental, and interventional studies that were performed between 1980 and 2024. We searched for the following key words using medical subjects headings and Turkish Science Terms and Boolean connectors: renal transplantation AND (medication OR immunosuppressive) AND (compliance OR adherence) AND (child OR pediatrics).

Inclusion criteria included studies that had patient samples of <18 years old and only renal transplant or renal transplant with other solid-organ transplants. Studies written in languages other than Turkish and English were excluded.

We reviewed the studies and identified articles that met the criteria. The quality of data extraction can affect the accuracy and reliability of the data collected. Risk of bias assessment is the process of evaluating the quality and reliability of individual studies included in the systematic review.²³ We used PICO to guide data extraction and the Critical Appraisal Skills Programme (CASP) checklist for quality assessment.²⁴

We followed a systematic approach to identify and select studies for inclusion using the PRISMA guidelines.²⁵ In the identification step, we conducted a comprehensive search that followed 2-way database searching and citation searching. Our initial search yielded 970 studies. We removed 44 duplicate studies using an automation system. We independently screened, based on inclusion and exclusion criteria, titles and abstracts of the remaining studies to identify relevant articles. We identified 34 potentially relevant studies for further evaluation. We examined the full text of these studies to determine their eligibility for inclusion in the review. After this assessment, 9 studies were deemed eligible. The 9 eligible studies underwent a quality assessment to evaluate the robustness of their methodology and the reliability of their findings. Only 1 study met our criteria (Figure 1).

Results
Studies in our search included different types of organ transplant participants. Some studies were pilot or protocol design, and 1 study had initial results. The patient sample of the studies included a wide age range and adult populations; time since transplantation also varied in these studies.^27-34 Only 1 study in our search included children under the age of 12 years²⁷ (Table 1).

Studies were conducted in different settings and platforms, including hospitals, homes, telehealth, and web-based platforms or mobile applications. Health care centers had varied timing and content of posttransplant programs. Approaches that use a self-care model and motivational interviewing emphasized patient education, self-management skills, and behavior change techniques to improve medication adherence and overall health outcomes (Table 2). Although not investigated here, another limitation is that some studies do not use objective monitoring methods to monitor participant medication adherence.

The study from Foster and colleagues met the criteria after quality assessment.²⁷ Although this study had some limitations, the strengths were that the sample met the systematic review criteria, the intervention started 3 months after transplant, the factors that affected participant adherence were determined, and a self-management model was used. In addition, different methods and tools, including a device, were used to objectively monitor the participants²⁷ (Table 3).

Discussion
We performed a systematic review to determine the effectiveness of pediatric interventions aimed at improving medication adherence among renal transplant recipients. The characteristics of the studies can greatly affect the quality of the results. Four studies included in the systematic review were nonrandomized or included 1 group.^26,28,30,32 These factors could lead to increased risk of bias and confounding of variables. However, nonrandomized designs are often used in transplant research because of ethical considerations and practical constraints. Some studies were pilot studies or released first experiences.^31,33,34 These early studies provided valuable insights into the design, feasibility, and preliminary outcomes of interventions. However, they may not capture the full effect or long-term effectiveness of interventions. Some studies included a wide age range or adult population.^3,29,33,34 Three studies included different types of solid-organ transplants.^28,30,31 These factors can make it difficult to draw clear conclusions because different age groups and transplant types may respond differently to treatments or interventions. Combining adult and pediatric groups in studies can also introduce challenges. The needs, responses, and outcomes for adult transplant recipients may greatly vary from pediatric transplant recipients.

High dropout rate or small sample size was another limitation of the studies.^{26,28,29,33,34} High rates of participant dropout or small sample size can introduce selection bias and compromise the validity of study findings. Another limitation was the varying duration since organ transplant. Lapse of time since organ transplant can affect a patient’s adherence to medication, health status, and adjustment to posttransplant life (Table 1).

In the studies included in the systematic review, interventions to increase medication compliance in pediatric transplant patients were carried out in different settings. These studies were performed in health care settings,²⁶ home, or both environments.^27,29,33,34 Each environment has its advantages and disadvantages. In interventions conducted by health care teams in the hospital environment, participants reported that they were pleased with having the opportunity to ask questions of the health care team and communicate directly.²⁶ With regard to study results, direct communication with health care teams and opportunities to ask questions provide valuable support and reassurance for patients. Patient-centered communication enhanced patient satisfaction and improved adherence to medications. Difficulties in ensuring continuity of services provided at home or technical problems and unfamiliarity with technology in services provided remotely via telehealth have negatively affected compliance with such programs.^30,34

Today, technology is extensively used to increase medication adherence in patients undergoing pediatric renal transplant. In studies examined within the scope of the systematic review, applications such as mobile applications, web-based programs, telehealth, telephonic coaching, and electronic multidose pillboxes were used to increase adherence to medication. In addition to these initiatives, methods such as dose reminders by text messages, E-mails, and visual cues have also been used to remind patients of time or dose when taking medication.^27,29-31,33 Despite the potential benefits of technology-supported interventions, challenges such as slow internet connectivity and technical difficulties can hinder access and usability for some patients. Although adolescents generally had positive feedback about web pages and mobile technologies, they reported that the contents that took a long time to read, slow internet connections, and internet interruptions were negative aspects, and they expressed their concerns about privacy and sharing data electronically.^28,29,31 Technical issues may disrupt the delivery of intervention components, limit patient engagement, and compromise the effectiveness of the intervention. In addition, in a study of a digital medicine program, encapsulated medications with ingestible sensors were used, and these capsules were monitored via mobile application. However, some participants in this study reported problems, such as skin reactions to the patches attached to the skin and difficulty in swallowing the capsules.²⁸

Different models and approaches were used among studies to increase medication adherence among pediatric renal transplant recipients. Although studies were predominantly based on the self-management and self-efficacy model,^27,33,34 different approaches such as self-determination theory, action-focused problem-solving, improving coping skills, goal-setting, and motivational interviewing have also been used.^27,30 Each of these approaches must be individually oriented, so that the program is designed according to the needs of the patient and with an aim to increase the individual’s coping and problem-solving skills (Table 2).

Other limitations among the studies were problems with reliable tools, devices, or methods for monitoring adherence. Ensuring that patients adhere to their medication regimen is crucial for successful transplant outcomes. Adherence can be challenging for health care providers to identify and address effectively. Patient perspectives and preferences were not sufficiently taken into account during design of posttransplant programs. However, incorporating patient feedback and participation can lead to more patient-centered care and better outcomes.

Conclusions
In this systematic review, which examined studies about the effectiveness of interventions to improve medication adherence in pediatric renal transplants, we determined that different models and approaches were used. The studies had some limitations and strengths. Heterogeneous samples, variability in timing of programs posttransplant, limited methods for monitoring medication adherence, and lack of patient involvement in program organization were limitations of the studies. Another limitation was the small number of studies involving children under 12 years of age. The strengths of the studies were use of models to strengthen self-management, development of problem-solving skills, and support with technology.

Enhancing medication adherence is essential for optimizing outcomes in pediatric renal transplant recipients. The use of a multidimensional approach encompassing education, behavior modification, technology, and interdisciplinary collaboration can allow health care providers to effectively support patients in adhering to their medication regimens, ultimately improving transplant success rates and quality of life. Health care providers can improve medication adherence by integrating multiple components, including a team approach, user-friendly technology, patient involvement, self-management promotion, identification of barriers, and motivational initiatives. Future research should also focus on long-term outcomes, cost-effectiveness, and personalized approaches to optimize medication adherence in pediatric renal transplant patients.

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