Adherence to Immunosuppressive Therapy in Kidney Transplant Recipients : Integrative Literature

Background: Kidney transplantation requires strict adherence to the immunosuppressive therapy. Non-adherence is a common multifactorial problem among kidney transplant recipients. Objectives: To identify the factors influencing the adherence to the immunosuppressive therapy among kidney transplant recipients. Methodology: This is an integrative literature review. After establishing the inclusion and exclusion criteria and analyzing the studies, we selected 10 primary studies that answered the research question. These articles were published between 2009 and 2014 and were obtained through the online platforms EBSCOhost and Online Knowledge Library (B-on). Results: Adherence to immunosuppressive therapy is mainly influenced by socio-economic and cultural factors (age, gender, education, occupational situation), patient-related factors (forgetfulness, daily routines), condition-related factors (time since transplant, depression), and therapy-related factors (complexity of the therapeutic regimen). Conclusion: Knowing the factors that influence adherence allow planning (both educational and behavioral) nursing interventions aimed at promoting the adherence to immunosuppressive therapy, thus improving the patients’ health.


Introduction
Kidney transplantation is considered to be the treatment of choice for patients with End-Stage Renal Disease and, in comparison to the general healthy population of the same age group, allows obtaining the best outcomes in terms of survival, as well as the best indicators of health-related quality of life (Ministério da Saúde.Direção-Geral da Saúde, 2012).Transplant recipients undergo a health/ illness transition process in which the adherence to the therapeutic regimen, and in particular to the immunosuppressive therapy, play a significant role in their health and well-being.The immunosuppressive therapy aims to prevent acute and chronic rejection.According to the International Council of Nurses (ICN; 2011), adherence is a self-initiated action to promote wellness, recovery and rehabilitation, following directions without deviation, devoted to a set of actions or behaviours.Compliant with treatment regimen, taking medicine as instructed, behaviour change for the better, signs of healing, collection of medicine on due date, internalisation of the value of health care behaviour and obeying instructions regarding treatment.(p.38) Adherence requires the patient's agreement to the health professionals' recommendations, and patients should be active partners in their own care.According to the World Health Organization (WHO; 2003), good communication between patients and health professionals is a must for an effective clinical practice with health gains.In 2008, the Consensus Conference, which brought together several North-American organizations to discuss immunosuppressant non-adherence in transplant recipients, defined immunosuppressant non-adherence as the "deviation from the prescribed medication regimen sufficient to influence adversely the regimen's intended effect" (Fine et al., 2009, p. 36).The poor adherence or non-adherence to treatment causes physical and psychological complications in the patients, reduces their quality of life, increases the likelihood of development of drug resistance, and wastes resources, compromising the efforts of the health system to improve the health of the population (ICN, 2009).Thus, measuring adherence is imperative in order to determine the magnitude of the problem and to identify the contributing factors.
Evidence shows that non-adherence is a common multifactorial problem among kidney transplant recipients, who have substantially higher rates than other recipients of solid organs (Chisholm-Burns et al., 2012;Griva, Davenport, Harrison, & Newman, 2012;Weng et al., 2013).Approximately 35% of kidney graft losses are related to non-adherence to immunosuppressive therapy, being that the probability of graft failure is seven times higher in non-adherent patients than in adherent patients.In addition, life expectancy is four times lower in non-adherent patients than in adherent patients (Chisholm-Burns, Spivey, & Wilks, 2010).In light of the above, the ICN proposes a combination of educational and behavioral strategies to promote adherence.A multidisciplinary approach is mandatory, in which the family, community, and patients' organizations are key partners in promoting adherence (ICN, 2009).This integrative literature review aims at identifying the factors influencing adherence to immunosuppressive therapy.After the identification of these factors, we also intend to identify nursing interventions capable of improving adherence among kidney transplant recipients.Our objective is to answer the following research question: Which factors influence the adherence to immunosuppressive therapy among kidney transplant recipients?

Methodological Procedures of the Integrative Review
The integrative literature review was performed in six steps, as recommended by Botelho, Cunha, and Macedo (2011): identification of the theme and selection of the research question; establishment of the inclusion and exclusion criteria; identification of the pre-selected and selected studies; classification of the selected studies; analysis and interpretation of results; and, finally, presentation of the review/ synthesis of knowledge.The review question was defined on the basis of the PI(C)O method.The participants (P) are the kidney transplant recipients.The independent variables (I) are the influencing factors.The outcome (O) is the adherence to the immunosuppressive therapy.The literature search was performed in the last week of March, 2014 on the online platforms EBSCOhost, Online Knowledge Library (B-on), and in the Open The descriptors used in the search were "adherence" and "kidney transplantation", linked with the Boolean operator AND.In RCAAP, we used the same descriptors, but in Portuguese (adesão e transplante renal).In order to systemize the information on the articles, we designed an observation grid with the following topics of analysis.

Results and Interpretation
In a first phase, two researchers reviewed the titles of all articles.In a second phase, three researchers read the abstracts.In a third phase, two or more researchers analyzed the full text of all potentially relevant articles to be included in this integrative literature review.Figure 1 shows the data reduction process of the integrative literature review.The 10 selected articles were independently analyzed in full by two or more researchers until a consensus was reached (in terms of methodology, content, and relevance of results) for the integration of the studies in this integrative literature review.Table 2 shows the selected studies.The articles included in the integrative literature review result from quantitative studies, with most of them being descriptive-exploratory studies.We assessed the methodological quality of the 10 selected articles by means of a modified version of a quality appraisal tool adapted by Crombie in 1996 (Steele, Bialocerkowski, & Grimmer, 2003).This instrument is composed of 16 items, where one point is allocated if the item is reflected in the study, and zero points if the item is missing or unclear (Steele et al., 2003).Taking into account the total score, most of the articles (80%) showed a high quality, whereas two articles (S1 and S4) showed a moderate quality.We elaborated Table 3 in order to synthesize and easily consult the obtained data (sample/data collection tool, and main results).and health care team and system-related factors.The same organization also classifies therapeutic non--adherence as intentional (when the patient does not comply with the treatment, despite knowing it) or unintentional (when the patient does not understand the information provided by the health professional, when the patient forgets to take the medication, or has difficulty in managing the treatment; WHO, 2003).

Socio-Economic and Cultural Factors
Studies S1 and S8 show that there is no statistically significant association between age and adherence to immunosuppressive therapy.On the contrary, studies S2, S3, S6, S7 and S10 report that, as age increases, patients tend to adhere more to the immunosuppressive therapy.In S2, patients in the 46-64 age group show a higher level of adherence, in comparison to younger patients (aged 18-29 years).S3 and S6 reveal that the level of non-adherence is lower in younger transplant recipients, since they are more likely to be occupationally and socially active, having to face bigger challenges.
Studies S1, S2, S7 and S10 indicate that gender and adherence to immunosuppressive therapy are not related.On the other hand, S3 and S6 report a statistically significant correlation between gender and adherence, in which male patients tend to be more non-adherent than female patients.S6 shows a positive association between the female gender and the occupational situation, with homemakers reporting a higher level of adherence due to their greater availability.Studies S2, S7 and S10 show that there is no association between education and adherence to immunosuppressive therapy.In contrast, studies S1, S3 and S8 report a statistically significant association between education and adherence, being that patients with a lower level education are less adherent to treatment.However, according to S1, patients with a lower level of education are more interested in acquiring knowledge about the treatment.Study S8 reports an association between monthly income and adherence to immunosuppressive therapy, being that the lower the income, the lower the level of adherence.Depending on each country's health system and medication costs, patients sometimes choose to skip some daily doses.However, S2 refers that monthly income and adherence are not associated.
Studies S2, S7 and S10 show no association between marital status and adherence to immunosuppressive therapy.However, S3 indicates that marital status and adherence are related, being that married/co-habiting that the shorter the time elapsed since the kidney transplant, the higher the level of adherence.In the comparative S7 study, the authors concluded that patients show a high level of adherence (around 83%) six weeks after the transplant, falling to 73% six months after the transplant.As regards depression, S3 considers it to be a factor of non-adherence to immunosuppressive therapy.Therefore, Bugalho and Carneiro (2004) refer that patients with psychiatric disorders have indeed a lower level of adherence, which is related to their social isolation and altered cognitive function.
However, studies S8 and S10 found no association between adherence and depression.

Patient-Related Factors
Studies S2, S3, S5 and S8 report an association between forgetfulness and non-adherence to immunosuppressive therapy.Forgetfulness is often related to changes in the daily routine.In this sense, studies S2, S5 and S8 confirm an association between adherence and daily routines.These studies report that both forgetfulness and the interruption/change of daily routines are the major barriers to therapeutic adherence.Cabral and Silva (2010) refer that forgetfulness is one of the most common behaviors, both in terms of forgetting to take the medication, and not remembering the relevant information about how the treatment should be done.Study S1 confirms an association between motivation and adherence to immunosuppressive therapy, being that the more motivated the patients are, the higher is the level of adherence.Non-adherent patients have lower levels of satisfaction and less control over their lives, as shown in S2, which reports an association between satisfaction with life and non-adherence to treatment.Studies S2, S3 and S5 refer that there is an association between beliefs and adherence to immunosuppressive therapy, being that non-adherent patients are more likely to question the need for treatment.In contrast, S7 concludes that there is a statistically significant association between adherence and the beliefs about the treatment.Study S10 considered self-efficacy to be a factor of adherence.Self-efficacy is a concept associated with self-care.According to the Quality Standards for Nursing Care (Padrões de Qualidade dos Cuidados de Enfermagem), in the "constant demand for patients have a lower level of adherence.According to the same study, adherence may be undermined by a poor marital satisfaction, or by the relationship itself, since patients, by being involved in household responsibilities, may push aside adherence to treatment.Studies S2, S7, and S10 report that profession/ occupational situation and adherence to immunosuppressive therapy are not related.However, S3 states that patients in an active occupational situation show a lower level of adherence.S6 reports adherence in some occupational situations, as are the cases of full-time homemakers and unemployed individuals, since these patients are more available (are at home and have no other type of occupation).Studies S8 and S10 refer that social support and adherence to immunosuppressive therapy are not related.On the other hand, S4 states that there is a positive association between adherence and social support, being that transplant recipients with better social support are most likely to adhere to immunosuppressive therapy.This is corroborated by Cabral and Silva (2010) and Dias et al. (2011), who state that the support received by transplant recipients from their social networks to comply with the treatment can influence their behavior.In turn, transplant recipients who live alone or have a limited social network are more likely to experience difficulties in following the recommended indications.
In view of the above, we found that there is some controversy regarding the association between adherence and socio-economic and cultural factors.This is emphasized by the WHO (2003) which argues that age, sex, education, occupation, income, marital status, race, religion, ethnic background and urban versus rural living are factors that have not been clearly associated with therapeutic adherence.

Condition/Comorbidities-Related Factors
Studies S1 and S7 report that type of donor and adherence to immunosuppressive therapy are not related.On the contrary, S6 refers that there is an association in the case of living donors, in which the level of adherence is higher.Study S10 refers that time since the transplant and adherence to immunosuppressive therapy are not related.However, S2 and S9 report an association between the time since the transplant and adherence.S6 also confirms this association, while showing relationship established between health professionals and patients has a positive effect in the level of adherence, with communication being an essential part of the whole process.In this relationship of trust, two levels of knowledge coexist: lay beliefs and professional beliefs, interacting in a dyad in which communication influences the patient's adherence, expectations, and decisions (Dias et al., 2011).The above-mentioned analysis shows that the phenomenon of adherence is multifactorial.This aspect should be assessed before and after the transplant, particularly regarding the involvement and the emotional and educational support of patients, relatives and friends.The provision of social support, by preparing meals, gardening and/or doing domestic chores, among other activities, although not directly related to adherence, contributes to reducing stress and helps the transplant recipients to relax and focus on their health; Developing a reminder/alarm system, by asking a friend to call regularly (daily, at the same time) or the spouse to organize a daily dose pill box to overcome situations of forgetfulness; Simplifying, whenever possible, the drug regimens of the immunosuppressive therapy; Providing organized daily dose pill boxes and written information about the need and importance of immunosuppressants (guides or leaflets); Electronic monitoring, which is a valid and reliable instrument for managing medications, but it is not easily available and requires additional financial resources; Elaborating behavioral contracts, which are cost-effective and can be done excellence in professional practice, the nurse maximizes the patients' well-being and complements/ adds to the activities of daily living in which the patient is dependent" (Ordem dos Enfermeiros.Conselho de Enfermagem, 2012, p. 16).Individuals perform self-care activities as an integral part of their lives whenever they act for their own benefit to maintain their health and well-being, and whenever they provide care to their families or community in general.
Study S8 reports that perceived stress, anxiety and literacy have no statistically significant association with non-adherence to immunosuppressive therapy.
In what concerns patient-related factors, Cabral and Silva (2010) mention that patients' knowledge about the disease, as well as their personal attitudes and beliefs about treatment effectiveness have been widely recognized as consistent predictors of the level of adherence.

Therapy-Related Factors
Studies S1, S3, S5 and S6 report an association between the complexity of the treatment regimen and non-adherence to immunosuppressive therapy, i.e., the higher the complexity (frequency of intake and number of medications), the lower the level of adherence.Bugalho andCarneiro (2004), andDias et al. (2011) confirm this result, mentioning that treatment complexity and duration, frequent changes in medication, the lack of immediate clinical improvement, and the presence of secondary effects can compromise adherence.Additionally, Cabral and Silva (2010) state that the simultaneous prescription of multiple medications, as well as a high frequency of daily doses, or high dosages, can also contribute to a lower level of therapeutic adherence.

Health Care Team and System-Related Factors
No factors directly related to the health services and professionals emerged from the analysis of the selected studies.However, Bugalho and Carneiro (2004) refer that weak health care systems, the shortage of training on chronic diseases for health professionals, the lack of time for a more effective monitoring (consultations), and the lack of instruments to assess adherence interfere with therapeutic adherence.Cabral and Silva (2010), and Dias et al. (2011) added that the quality of the in person or by telephone; Providing the contacts of specialized support groups.
Nurses must be permanently vigilant in order to ensure the early identification of any risk factor and situation of non-adherence (Fine et al., 2009).According to the ICN, better adherence is linked to patient safety, leads to better health outcomes, and reduces healthcare costs (ICN, 2009).
According to Bugalho and Carneiro (2004) (Bugalho & Carneiro, 2004).Therefore, nursing consultations can contribute to maximize these interventions.Another alternative is to establish contacts by telephone, regular mail or email.It is essential to explain and understand the indications and side effects of the medication, as well as the ways to overcome them.These are some strategies to promote adherence.It is also important for patients to be informed of their progress and laboratory results (Bugalho & Carneiro, 2004).
Patients should be actively involved in their treatment, namely by trying to find strategies to prevent them for forgetting to take the medication (using memos, marking the dates of consultations and renewal of medical prescriptions on the calendar; Bugalho & Carneiro, 2004).
Although there are some recommendations, the current literature still does not allow designing an effective intervention program to promote therapeutic adherence.However, studies show that interventions should address several risk factors, combining educational, behavioral and emotional interventions that must be sustained over time (Bleser Matteson, Dobbels, Russell, & Geest, 2009;Fine et al., 2009).An ideal intervention program should be able to identify the patient's factors that require intervention, determine the relevance of the strategies based on the patient's cultural sensitivity, and decide when and where the intervention should start (Fine et al., 2009).

Conclusion
Understanding the behavior of kidney transplant recipients and the factors influencing therapeutic adherence is beneficial to all concerned.Based on the integrative literature review, we found that the main factors contributing to the adherence to immunosuppressive therapy are: socio-economic and cultural factors (age, gender, education, monthly income, marital status, profession/occupational situation, and social support), therapy-related factors (type of donor, time since transplant, and depression), patient-related factors (forgetfulness, daily routines, motivation, satisfaction with life, beliefs, and selfefficacy), and therapy-related factors (complexity of the therapeutic regimen).Although there is no guaranteed method leading to therapeutic adherence, the identification of the factors influencing it allows designing nursing interventions aimed ultimately at promoting the adherence to immunosuppressive therapy.Thus, through the combination of educational and behavioral interventions, nurses should promote adherence and self-care, which will translate into health gains.The need and importance of pre-and post-transplant nursing consultations the teaching-learning process of the kidney transplant recipient was also emphasized.
Although the WHO (2003) reports an association between adherence and health care team/health system-related factors, the studies analyzed in this integrative literature review did not address these factors.For this reason, studies involving these factors should be conducted, in particular regarding the communication between the nurse and the transplant recipient.
The major limitation of this study was the difficulty to equitably compare the 10 studies included, given that the factors influencing the adherence to the immunosuppressive therapy were analyzed from

Figure 1 .
Figure 1.Data reduction process of the Integrative Literature Review.
Table 1 describes the inclusion and exclusion criteria for article selection.

Table 3
Summary of the selected studies The rate of non-adherence ranged from 26.4% to 76% in the analyzed studies.Based on the analysis of the results, we decided to classify the factors that influence therapeutic adherence based on the categories proposed by the WHO (2003): social-economic and cultural factors; patient-related factors; condition-related factors; social-economic and cultural factors; patient-related factors; condition-related factors; therapy-related factors;