Medication non-adherence after kidney transplantation: A critical appraisal and systematic review

Medication non-adherence is one of the most important causes for shortened graft survival subsequently leading to a reduction in kidney graft survival results. Our aim was to provide an overview of its prevalence, risk factors, diagnostic methods and interventions to improve adherence in kidney transplant recipients. Therefore, we systematically searched the databases PubMed, COCHRANE Library, Web of Science and EMBASE for studies addressing “medication adherence”, “compliance”, “adherence”, “kidney transplantation” and “life style factors”. We identified 96 studies that satisfied our inclusion criteria. A problematic lack of a uniformly accepted definition for non-adherence was found, consequently leading to a wide range in non-adherence prevalence (36–55%). Using one uniformly accepted non-adherence definition should therefore be encouraged. A wide range in diagnostic methods makes it difficult to accurately detect non-adherence. Heterogeneous results of intervention studies make it difficult to select the best adherence enhancing method, challenging the battle against medication non-adherence. Literature suggests a combination of personalized interventions, based on patient-specific non-adherent behavior, to be most successful in improvement of adherence. High quality diagnostic methods and multidisciplinary, personalized interventions with focus on relevant clinical outcome are essential in overcoming medication non-adherence in kidney transplant recipients.     

肾移植受者应对方式对服药依从性及自我管理的影响

目的探讨肾移植受者疾病应对方式、服药依从性及其自我管理的特点,并分析应对方式对服药依从性和自我管理依从性的影响。 方法采用便利抽样选取2019年3月至5月广州医科大学附属第三医院器官移植随访门诊就诊的肾移植受者作为研究对象。采用一般情况调查表、医学应对问卷、免疫抑制剂依从性Basel评估量表(BAASIS)及肾移植受者自我管理调查量表作为调查工具。所有问卷调查均在肾移植受者门诊随访时进行。采用成组t检验比较肾移植组和慢病常模组面对、回避和屈服因子得分。应用分层回归方程分析肾移植受者应对方式对服药依从性和自我管理的影响。P<0.05为差异有统计学意义。 结果肾移植受者面对因子得分[(19.8±2.9)分]最高。肾移植组和慢病常模组回避因子得分分别为(15.1±2.7)和(14.4±3.0)分,差异有统计学意义(t＝-2.320,P<0.05)。肾移植受者BAASIS得分平均为(22.2±2.6)分,125例受者中53例(42.4%)受者服药依从性好。36例(28.8%)曾在过去1个月中至少漏服1次免疫抑制剂;19例(15.2%)在过去1个月中曾出现至少1次连续漏服状况;63例(50.4%)曾在过去1个月中提前或推迟2 h服药;9例(7.2%)曾不按医嘱剂量服药。肾移植受者自我管理总得分为(91±8)分,其中68例(54.4%)自我管理水平良好,57例(45.6%)自我管理处于中等水平。受者饮食、治疗、躯体活动和社会心理管理得分分别为(29.5±3.0)、(33.4±3.4)、(15.7±2.1)和(12.4±1.6)分。面对、回避和屈服3个变量分别解释服药依从性总变异的8.6%,治疗管理总变异的13.7%,躯体活动管理总变异的7.0%,社会心理管理总变异的25.0%,整体自我管理总变异的15.0%。服药依从性的预测因子为屈服(β＝-0.252,P<0.01),饮食管理的预测因子为面对(β＝0.212,P<0.05),治疗管理的预测因子为面对(β＝0.348,P<0.01),躯体活动管理的预测因子为面对(β＝0.255,P<0.01),社会心理管理的预测因子为面对和屈服(β＝0.394和-0.271,P均<0.01),整体自我管理的预测因子为面对(β＝0.365,P<0.01)。 结论肾移植受者应对方式是服药依从性和自我管理的重要影响因素,应重视其对待疾病的态度和方式,及时转换其消极的应对策略,以提高其服药依从性和自我管理水平。     

Immunosuppressant treatment adherence, barriers to adherence and quality of life in renal and liver transplant recipients in Spain

To assess the adherence to immunosuppressant therapy (IST) and perceived barriers affecting IST adherence and quality of life (QOL) in patients who had received a renal (RT) or liver transplant (LT), a questionnaire was sent to over 9000 RT and LT recipients in Spain. Questionnaire comprised questions about patient's socio-demographic, organ transplant and medication characteristics; IST adherence and patient's perceived barriers to adherence; and patient's QOL using the EuroQol. Data from 1983 RT patients and 1479 LT patients were analyzed. Self-reported adherence to IST in RT (92.6%) and LT (88.5%) recipients was high. Daily medication intake (mean of 2-3 doses/d per patient) was considered a lifestyle restriction in about 25% of transplant recipients and was the most common barrier to adherence perceived by over 30% of RT and LT patients. Overall, high-intensity treatment regimens were associated with poorer QOL (EuroQol <70) compared with low-intensity treatment regimens. Most RT (71.0%) and LT (61.4%) patients would prefer to suppress the evening dose if they were able to. Although high adherence rates to IST were reported in this first large Spanish survey in RT and LT patients, adjustment of daily treatment intensity by less frequent dosing may be an adequate strategy to minimize barriers to adherence and improve QOL.     

Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients

Russell C, Conn V, Ashbaugh C, Madsen R, Wakefield M, Webb A, Coffey D, Peace L. Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
Clin Transplant 2011: 25: 864–870. © 2010 John Wiley & Sons A/S. Abstract: Background: Immunosuppressive medication non‐adherence is one of the most prevalent but preventable causes of poor outcomes in adult renal transplant recipients, yet there is a paucity of studies testing interventions in this area. Methods: Using a randomized controlled trial design, 30 adult renal transplant recipients were screened for medication non‐adherence using electronic monitoring. Fifteen non‐adherent participants were randomized to receive either a continuous self‐improvement intervention or attention control management. The six‐month continuous self‐improvement intervention involved the participant and clinical nurse specialist collaboratively identifying the person’s life routines, important people, and possible solutions to enhance medication taking. The participant then received individual monthly medication taking feedback delivered via a graphic printout of daily medication taking generated from electronic monitoring. Results: The mean medication adherence score for the continuous self‐improvement intervention group (n = 8) was statistically significantly higher than the attention control group’s (n = 5) mean medication adherence score (p = 0.03). The continuous self‐improvement intervention effect size (Cohen’s d) was large at 1.4. Participants’ perceptions of the intervention were highly favorable. Conclusions: The continuous self‐improvement intervention shows promise as an effective and feasible approach to improve medication adherence in adult renal transplant recipients. A fully‐powered study with a diverse sample is needed to confirm these preliminary findings.     

Measuring compliance with drug regimens after renal transplantation: comparison of self-report and clinician rating with electronic monitoring

Nonadherence to immunosuppressants in renal transplant recipients is a major factor affecting graft survival, but it is difficult to detect accurately in clinical practice. Adherence was measured in 153 adult renal transplant recipients using self-report questionnaires and interview, clinician rating, and cyclosporine levels. The sensitivity and specificity of these measures were determined by comparison with electronic monitoring in a randomly selected subsample of 58 subjects. Measures of adherence in current clinical use do not perform well when tested against electronic monitoring. Self-report at a confidential interview was the best measure of adherence for the detection of both missed doses and erratic timing of medication. However, the use of a confidential interview is not directly applicable to a clinical setting. Further research on how best to facilitate disclosure in clinical settings may be the best way to develop adherence measures for use in routine practice.     

Culturally responsive interventions to enhance immunosuppressive medication adherence in older African American kidney transplant recipients

CONTEXT: Immunosuppressive medication nonadherence is variable among older kidney transplant recipients and is a problem in African American recipients despite the severe consequences of this behavior. Many factors place older African American recipients at risk for medication nonadherence. OBJECTIVE: To provide an overview of interventions to enhance immunosuppressive medication adherence in older African American kidney transplant recipients using a culturally responsive model. Culturally sensitive, innovative, and transformation interventions are discussed. Situations when each intervention would be most and least appropriate are described. CONCLUSION: Moving culturally appropriate interventions forward into practice and testing their effectiveness in improving adherence outcomes in vulnerable, older African American kidney transplant recipients is a worthy practice and research goal for transplant nursing.     

Non‐adherence to immunosuppressive medication in renal transplant recipients within the scope of the integrative model of behavioral prediction: a cross‐sectional study

Schmid‐Mohler G, Pechula Thut M, Wüthrich RP, Denhaerynck K, De Geest S. Non‐adherence to immunosuppressive medication in renal transplant recipients within the scope of the integrative model of behavioral prediction: a cross‐sectional study.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01056.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Non‐adherence to immunosuppressive medication is strongly associated with poor outcomes. Identifying the factors influencing it is a first step in developing adherence interventions. This study’s objective was to investigate the prevalence of self‐reported and collaterally‐reported non‐adherence to immunosuppressives, and, based on the Integrative Model of Behavioral Prediction, to explore the association between non‐adherence, intention to adhere, attitudes, norms and self‐efficacy. Methods: This cross‐sectional study included a convenience sample of 114 renal transplant recipients in follow‐up care, one to five yr post‐transplant. Non‐adherence was measured by self‐reports and collateral reports. Factors of the Integrative Model of Behavioral Prediction were assessed using a self‐report questionnaire. Results: Self‐reports showed non‐adherence of 23.7%; collateral reports showed 3.8%; and a combination of the two showed 26.4%. Logistic regression analysis showed that the attitude “Not all immunosuppressive drugs are necessary to prevent rejection” was less frequent in patients with higher intentions to adhere, with an odds ratio (OR) of 0.05 (95% CI 0.01–0.50). The barrier of “Forgetfulness/Interruption of daily routine” was associated with non‐adherence, with an OR of 3.74 (95% CI 1.55–9.03). Conclusions: Forgetfulness is the most powerful barrier against adherence. Intention to adhere plays a minor role in non‐adherence in renal transplant recipients.     

Is social support associated with post-transplant medication adherence and outcomes? A systematic review and meta-analysis

Although social support is used to determine transplant eligibility, the relationship between social support, medication adherence, and survival among transplant recipients remains unclear. We estimated the relationship between social support and post-transplant medication adherence and outcomes using 10 electronic databases from inception to January 2016. Study quality was assessed and all review stages were conducted independently by 2 reviewers. Systematic review and meta-analysis were conducted. Thirty-two studies (9102 participants) met inclusion criteria: 21 assessed medication adherence (5197 participants), and 13 assessed clinical outcomes (3905 participants). Among high quality studies, neither social support nor marital status was predictive of medication adherence or post-transplant outcomes. Social support was not associated with medication adherence. It was associated with superior post-transplant outcomes, but the relationship was not significant among high quality studies. Compared to unmarried recipients, married recipients were more likely to adhere to medication post-transplant, but this relationship was not significant among high quality studies. Marital status was not significantly associated with transplant success. Social support is weakly and inconsistently associated with post-transplant adherence and outcomes. Larger prospective studies using consistent and validated measures are needed to justify the use of inadequate social support as a contraindication to transplantation.     

Psychological Distress and Adherence to the Medical Regimen Among Adolescent Renal Transplant Recipients

This longitudinal pilot study of adolescent renal transplant recipients (a) describes the prevalence of psychological distress, (b) describes the prevalence of nonadherence, and (c) explores the association between the recipient's psychological distress and his/her subsequent medical adherence. Twenty-two adolescents, aged 13-18 years, completed two interviews that were separated by approximately 12 months. Psychological distress was assessed in three domains: symptoms of depression, anxiety, and anger. Adherence was assessed in three domains: medication taking, blood work, and clinic attendance. At the initial interview, 36.4% had symptoms of depression, 36.4% endorsed anxiety, and 18.2% endorsed excessive state anger. Non-adherence rates were 13.6% for medication, 22.7% for blood work, and 50% for missed clinic. At the second interview, nonadherence with medication remained the same and the other domains decreased. Our small pilot sample, however, limited our ability to detect statistically significant changes over time. Predictive analyses demonstrated that adolescents with excessive anger were at greater risk for subsequently missing medications than adolescents without excessive anger. These findings suggest that while symptoms of depression and anxiety are observed among some adolescents with renal transplants, only anger is associated with elevated risk for nonadherence with medication.     

Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation

Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26 to 0.72; P = 0.001). Cause of renal disease, Powerful Others health locus of control, transplant center, and dosing frequency were also associated with adherence. After adjustment for transplant center and dosing frequency, the association between black race and decreased adherence was substantially attenuated (OR, 0.65; 95% CI, 0.38 to 1.14, P = 0.13). Transplant center (P = 0.003) and increased dosing frequency (OR, 0.43; 95% CI, 0.22 to 0.86, for three or four times per day dosing; OR, 2.35; 95% CI, 1.01 to 5.45, for daily dosing; versus two times per day dosing; P = 0.003) remained independently associated with adherence. Other baseline demographic, socioeconomic, medical, surgical, and psychosocial characteristics were not associated with adherence. The transplant center and dosing frequencies of immunosuppressive medications are associated with adherence and explain a substantial proportion of the race-adherence relationship.     

The Synergistic Effect of Class II HLA Epitope‐Mismatch and Nonadherence on Acute Rejection and Graft Survival

Predicting long‐term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of posttransplant histologic and serologic monitoring. Nonadherence and human leukocyte antigen (HLA) mismatch are risk factors that have been associated with poor long‐term outcomes and may help individualize care. In the present study, class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA‐DR, ≥17 HLA‐DQ) or low epitope‐mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. Nonadherent recipients with HLA‐DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p < 0.01) compared to adherent recipients with low epitope mismatch. At the HLA‐DQ locus nonadherent recipients with HLA‐DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p < 0.01) compared to adherent recipients with low epitope mismatch. Subclinical nonadherence early posttransplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, histologic, and serologic monitoring.     

Prevalence, severity and correlates of alcohol use in adult renal transplant recipients

BACKGROUND: Severe alcohol use is recognized as a major public health concern, even though light to moderate alcohol use might have beneficial effects on health. Alcohol use has been studied to some extent in solid organ transplant populations, yet evidence is lacking on alcohol use and its correlates in the renal transplant population. The aim of this study was therefore to determine the prevalence, severity and correlates of alcohol use in renal transplant recipients. METHODS: This cross-sectional study is a secondary analysis of the Supporting Medication Adherence in Renal Transplantation (SMART) study. Alcohol use was assessed by patient's self-report. At risk and binge drinkers were classified using World Health Organization criteria. The following correlates of alcohol use were explored: adherence with immunosuppression (Siegal questionnaire; electronic monitoring), smoking, coping style (UCL), depressive symptomatology (BDI) and busyness/routine in life style (ACQ Busyness Scale). RESULTS: Two hundred and eighty-four patients were included in this analysis, 58.1% male, with a mean age of 54 yr (range 20-84) and a median of seven (interquartile ranges [IQR] 8) yr post-transplantation. A total of 52.8% of study participants reported to drink alcohol at least once a week. Two hundred and eighty of 284 subjects (98.5%) were drinking at low risk, four at moderate risk (1.5%). None of the participants were drinking severely. Correlates of alcohol use were male gender and being professionally active. CONCLUSION: Alcohol use is less prevalent in renal transplant recipients than in the general population. Severe alcohol use does not seem to represent a serious problem in renal transplant patients.     

Couples After Renal Transplantation: Impact of Sex and Relationship Quality on Adherence in a Prospective Study

BackgroundIn patients after kidney transplantation, nonadherence to immunosuppressant medication is a common problem. Identifying factors that influence adherence could optimize medical care and prevent nonadherence. Kidney transplantation is a stressful situation for the patient and also for the relatives. The recipients of renal transplants as well as the family system have to be taken into account as potential impact factors.MethodsFifty-six couples with a renal transplant recipient were investigated regarding adherence, relationship satisfaction, social support, and quality of life. Moreover, sex and role differences (patient vs partner) as well as differences within the couple were analyzed. Impact factors on adherence were identified.ResultsFemale recipients of renal transplant reported higher relationship satisfaction than male recipients, female spouses, and male spouses. Physical quality of life was lower in renal transplant recipients compared with caregivers. For male renal transplant recipients, significant predictors of adherence, such as social support, relationship quality, and quality of life emerged, whereas for female renal transplant recipients mental quality of life and education level were found to influence adherence.ConclusionsThe study reveals the importance of relationship functioning of couples after kidney transplantation, as well as considering sex and role differences. There is a need to examine the posttransplantation nonadherence risk profile of women and men separately.     

Determining the effect of immunosuppressant adherence on graft failure risk among renal transplant recipients

The objective was to use the United States Renal Data System (USRDS) to quantify the relationship between immunosuppressant therapy (IST) adherence and risk of graft failure among adult renal transplant recipients (RTRs). A secondary objective was to examine the relationship among select patient characteristics and IST adherence. The study sample included adult RTRs who: received primary transplant between January 1, 1999 and December 31, 2005; experienced graft survival for at least 12 months post‐transplant and had at least 12 months of data in the USRDS; utilized Medicare coverage for IST; and were prescribed cyclosporine or tacrolimus. IST adherence was measured by medication possession ratio (MPR). Pearson chi‐square tests were used to examine associations between patient characteristics and MPR quartiles. Cox proportional hazards regression was used to assess relationships among time to graft failure, MPR, and patient characteristics. Thirty‐one thousand nine hundred and thirteen RTRs met inclusion criteria. Older age, female gender, white race, deceased donors, and tacrolimus were associated with greater adherence (p < 0.001). Cox proportional hazard modeling indicated greater adherence, white race, and having a living donor were significantly associated with longer graft survival (p < 0.05). Future prospective studies should further examine the clinical significance of IST nonadherence as it relates to graft failure.     

Evaluation of adherence and tolerability of prolonged‐release tacrolimus (Advagraf™) in kidney transplant patients in Germany: A multicenter,noninterventional study

This study assessed adherence to prolonged‐release tacrolimus (PR‐T)‐based immunosuppression during routine maintenance of renal transplant recipients in Germany. Patients had received PR‐T for ≥1 month at inclusion. Data were collected during four visits (V): baseline (V1), 6 (V2), 12 (V3), and 18 (V4) months. Composite primary endpoint: nonadherence at V4, defined as self‐reported nonadherence on the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS^©), investigator‐rated nonadherence, and/or V4 tacrolimus trough level outside a predefined range. Secondary endpoints: individual BAASIS items, incidence of rejection, kidney function, and safety. Overall, 153 adult kidney recipients (mean [standard deviation] time post‐transplant 5.8 [4.6] years) were included. Nonadherence was high at V4 (67.7% [95% confidence interval 58.9%, 75.6%]). Medication‐taking adherence was 86.9% and 91.3% at V1 and V4, respectively; adherence to timing of medication intake was 58.2% and 58.3%, with little evidence of missed doses/drug holidays. Investigators rated adherence “good” in 85.6% of patients (V4). Two (1.3%) patients had acute rejection episodes. Kidney function remained stable (mean creatinine clearance, V1: 62.1 mL/min; V4: 65.3 mL/min). Investigators rated effectiveness of PR‐T as “very good”/“good” in 91.5% of patients. Most patients (94.7%) found PR‐T dosing more convenient than immediate‐release tacrolimus. PR‐T was well tolerated with high medication persistence.     

Factors related to immunosuppressant medication adherence in renal transplant recipients

Chisholm‐Burns M, Pinsky B, Parker G, Johnson P, Arcona S, Buzinec P, Chakravarti P, Good M, Cooper M. Factors related to immunosuppressant medication adherence in renal transplant recipients. Abstract: Non‐adherence to immunosuppressant medications (ISM) is a significant issue for transplant recipients. This study examines factors influencing ISM adherence in renal transplant recipients (RTRs). Patient‐reported data were collected through a cross‐sectional survey including use of ISMs, adherence behaviors, perceived adherence barriers, beliefs and attitudes toward ISMs, and patient life satisfaction. Logistic regression was conducted to examine how RTRs’ beliefs about use of ISMs, life satisfaction, and ISM adherence barriers were related to adherence. A total of 512 adult commercial insurance enrollees following renal transplantation were included in the analysis. One hundred and seventy‐seven RTRs were non‐adherent (34.5%); the most frequently cited reason was forgetfulness. RTRs aged 18–29 yr were more likely to be non‐adherent than recipients 46–64 yr old (p ≤ 0.001). Non‐adherent RTRs had greater adherence barriers than adherent RTRs (p < 0.001). Adherent RTRs believed their ISMs were more necessary than non‐adherent RTRs (p < 0.001), while non‐adherent RTRs had greater concerns about taking ISMs (p = 0.009) and believed they had less control over their lives than adherent RTRs (p < 0.001). Non‐adherent RTRs had lower life satisfaction (p < 0.001). Non‐adherence is significantly associated with patients’ beliefs about ISMs, perceived barriers, and lower life satisfaction. Strategies to increase ISM adherence are discussed.