Posttransplant Medical Adherence: What Have We Learned and Can We Do Better?
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Purpose of review
Non-adherence to the medical regimen after kidney transplantation can contribute to poor clinical outcomes, and strategies to maximize adherence are sought by care providers and patients alike. We assessed recent evidence on prevalence, risk factors, and clinical outcomes associated with non-adherence to the medical regimen after kidney transplantation. We summarized recent clinical trials testing interventions to improve adherence and generated recommendations for future research and clinical practice.
A large evidence base documents rates of non-adherence to each of the multiple components of the regimen, including medication-taking, lifestyle activities, clinical care requirements, and substance use restrictions. Some risk factors for non-adherence are well known but the full range of risk factors remains unclear. Non-adherence to immunosuppressants and to other components of the regimen increases morbidity and mortality risks. Recent interventions, including education and counseling; electronic health strategies; and medication dose modifications, show promise for reducing immunosuppressant non-adherence. However, most of these interventions would be difficult to deploy in everyday clinical practice. Systematic dissemination of efficacious interventions into clinical practice has not been undertaken.
Rates and risk factors for non-adherence to the medical regimen have been examined and there is evidence that non-adherence may be ameliorated by a range of interventions. Although gaps in the evidence base remain, it would be timely to devote greater efforts to dissemination of findings. Thus, efforts are needed to assist transplant programs in using existing evidence to better identify patients who are non-adherent and to design and implement strategies to reduce or prevent non-adherence.
KeywordsKidney transplantation Medical non-adherence Immunosuppressant non-adherence Substance use Risk factors Non-adherence interventions
Preparation of this report was supported in part by Grants R01 DK101715 and R01 DK110737 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance ••Of major importance
- 3.Tong A, Morton R, Howard K, Craig JC. Adolescent experiences following organ transplantation: a systematic review of qualitative studies. J Pediatr. 2008;155:542–9.Google Scholar
- 4.Yazigi NA. Adherence and the pediatric transplant patient. Sem Pediatr Surg. 2017;26:267–71.Google Scholar
- 5.• Belaiche S, Décaudin B, Dharancy S, Noel C, Odou P, Hazzan M. Factors relevant to medication non-adherence in kidney transplant: a systematic review. Int J Clin Pharm. 2017;39:582–93. Because this report described a systematic review, the paper provides a thorough description of the range of rates of nonadherence reported in the literature, and the risk factors that have been examined to date. However, it is difficult to interpret the information on adherence rates because the duration of observation time differed in each study (i.e., patients observed for longer would have more opportunity to demonstrate nonadherence than those with short observation time). PubMedGoogle Scholar
- 9.•• Kuypers DRJ, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013;95:333–40. The authors report the results of a trial comparing once-daily dosing to conventional twice-daily dosing. Strengths of the study include the assessment of multiple aspects of medication-taking (e.g., doses taken, timing, drug holidays) and careful consideration of strengths and limitations of the trial. PubMedGoogle Scholar
- 10.• Lehner LJ, Reinke P, Horstrup JH, Rath T, Suwelack B, Kramer BK, et al. Evaluation of adherence and tolerability of prolonged-release tacrolimus (AdvagrafTM) in kidney transplant patients in Germany: a multicenter, noninterventional study. Clin Transplant. 2018;32:e13142. The authors build directly on the findings of the randomized clinical trial conducted by Kuypers et al.  in order to conduct an observational study of immunosuppressant medication adherence at multiple centers that have adopted once-daily dosing of tacrolimus. The report illustrates the direct application of clinical trial results to clinical practice, with evaluation of outcomes over 18 months of follow-up. Google Scholar
- 11.•• Duerinckx N, Burkhalter H, Engberg SJ, Kirsch M, Klem ML, Sereika SM, et al. Correlates and outcomes of posttransplant smoking in solid organ transplant recipients: a systematic literature review and meta-analysis. Transplantation. 2016;100:2252–63. This is a very thorough review and analysis of the evidence on posttransplant smoking, including consideration of numerous potential risk factors. Outcomes of smoking are also examined. It is difficult to interpret findings on rates of smoking because the duration of observation time differed in each study (i.e., patients observed for longer would have more opportunity to smoke than those with short observation time). PubMedGoogle Scholar
- 13.• Greenan G, Ahmad SB, Anders MG, Leeser A, Bromberg JS, Niederhaus SV. Recreational marijuana use is not associated with worse outcomes after renal transplantation. Clin Transplant. 2016;30:1340–6. Despite some methodologic limitations (reliance on unstructured clinical collection of data from self-report of marijuana use for some patients, single-center design, assumption that post-transplant marijuana use was identical to pre-transplant use), this is one of the few empirical examinations of marijuana use in transplant recipients. Google Scholar
- 15.De Geest S, Burkhalter H, Bogert L, Berben L, Glass TR, Denhaerynck K, et al. Describing the evolution of medication nonadherence from pretransplant until 3 years post-transplant and determining pretransplant medication nonadherence as risk factor for post-transplant nonadherence to immunosuppressives: the Swiss transplant cohort study. Transpl Int. 2014;27:657–66.PubMedGoogle Scholar
- 21.Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2014;11:CD000011.Google Scholar
- 23.Sabaté, E. Adherence to long-term therapies: evidence for action. Geneva: World Health Organization. 2003. http://apps.who.int/medicinedocs/pdf/s4883e/s4883e.pdf.
- 25.•• Neuberger JM, Bechstein WO, Kuypers DR, Burra P, Citterio F, De Geest S, et al. Practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients: a guidance report and clinical checklist by the consensus on managing modifiable risk in transplantation (COMMIT) group. Transplantation. 2017;101(4S Suppl 2):S1–56. This document, written by experts in the field, summarizes evidence and recommendations for the management of kidney (as well as liver) recipients beyond the first year posttransplant. It is an essential document for both researchers and clinicians in the field. Google Scholar
- 30.Israni AJ, Weng FL, Cen YY, Joffe M, Kamoun M, Feldman HI. Electronically-measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation. Clin Transpl. 2011;25:E124–31.Google Scholar
- 32.Patzer RE, Serper M, Reese PP, Przytula K, Koval R, Ladner DP, et al. Medication understanding, non-adherence, and clinical outcomes among adult kidney transplant recipients. Clin Transpl. 2016;30:1294–305.Google Scholar
- 35.Fierz K, Steiger J, Denhaerynck K, Dobbels F, Bock A, De Geest S. Prevalence, severity and correlates of alcohol use in adult renal transplant recipients. Clin Transpl. 2006;20:171–8.Google Scholar
- 36.• Ettenger R, Albrecht R, Alloway R, Belen O, Cavaillé-Coll MW, Chisholm-Burns MA, et al. FDA Public meeting on patient-focused drug development and medication adherence in solid organ transplant patients. Am J Transplant. 2018;18:564–73. This report summarizes a public meeting and scientific workshop held by the United States Food and Drug Administration, in which feedback from transplant recipients and family caregivers was obtained regarding costs and benefits associated with posttransplant medications. Experts summarized empirical evidence in the field. Comments from patient and family stakeholders are important for identifying issues to be addressed as new medications are developed for transplant recipients. Google Scholar
- 37.•• Jamieson NJ, Hanson CS, Josephson MA, Gordon EJ, Craig JC, Halleck F, et al. Motivations, challenges, and attitudes to self-management in kidney transplant recipients: a systematic review of qualitative studies. Am J Kidney Dis. 2016;67:461–78. A valuable systematic review of the qualitative literature examining patients’ perceptions of self-management issues related to the medical regimen after kidney transplantation. See also commentary by Dew and DeVito Dabbs . PubMedGoogle Scholar
- 39.Marsicano EO, Fernandes Silva N, Marsicano EO, Fernandes NS, Colugnati FA, Fernandes NM, et al. Multilevel correlates of non-adherence in kidney transplant patients benefitting from full cost coverage for immunosuppressives: a cross-sectional study. PLoS One. 2015;10(11):e0138869.PubMedPubMedCentralGoogle Scholar
- 45.O'Regan JA, Canney M, Connaughton DM, O'Kelly P, Williams Y, Collier G, et al. Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation. J Nephrol. 2016;29:269–76.Google Scholar
- 49.Spivey CA, Chisholm-Burns MA, Damadzadeh B, Billheimer D, et al. Determining the effect of immunosuppressant adherence on graft failure risk among renal transplant recipients. Clin Transpl. 2014;28:96–104.Google Scholar
- 56.•• Wiebe C, Rush DN, Nevins TE, Birk PE, Blydt-Hansen T, Gibson IW, et al. Class II eplet mismatch modulates tacrolimus trough levels required to present donor-specific antibody develop. J Am Soc Nephrol. 2017;28:3353–62. This paper, part of a series of important publications by Wiebe and colleagues [53–55], suggests the important role that adherence to immunosuppression plays in potentiating other biological factors that can lead to poor clinical outcomes in kidney recipients. PubMedGoogle Scholar
- 59.•• Rai HS, Winder GS. Marijuana use and organ transplantation: a review and implications for clinical practice. Curr Psychiatry Rep. 2017;19:91. This review provides a thorough and useful summary of both clinical observations and research evidence on the impact of marijuana use in transplant recipients. A valuable discussion is also provided on the issue of patient selection for transplantation and how marijuana use should be evaluated and considered in the selection process.Google Scholar
- 63.Bessa AB, Felipe CR, Hannun P, Sayuri P, Felix MJ, Ruppel P, et al. Prospective randomized trial investigating the influence of pharmaceutical care on the intra-individual variability of tacrolimus concentrations early after kidney transplant. Ther Drug Monit. 2016;38:447–55.Google Scholar
- 64.• Breu-Dejean N, Driot D, Dupouy J, Lapeyre-Mestre M, Rostaing L. Efficacy of psychoeducational intervention on allograft function in kidney transplant patients: 10-year results of a prospective randomized study. Exp Clin Transplant. 2016;14:38–44. This trial is noteworthy for its relatively long clinical follow-up after conclusion of the intervention. Although the intervention resulted in better adherence than that in the comparison group, there was no demonstrable impact on clinical outcomes. This suggests that additional (or more prolonged) intervention strategies may be needed in order to sustain any adherence improvements. PubMedGoogle Scholar
- 67.• Reese PP, Bloom RD, Trofe-Clark J, Mussell A, Leidy D, Levsky S, et al. Automated reminders and physician notification to promote immunosuppression adherence among kidney transplant recipients: a randomized trial. Am J Kidney Dis. 2017;69:400–9. This trial examined an intervention with monitoring of patient medication-taking, customized reminders to patients to take medications, and provider notification if adherence worsened. The intervention is potentially useful for routine clinical practice. PubMedGoogle Scholar
- 68.• Schmid A, Hils S, Kramer-Zucker A, Bogatyreva L, Hauschke D, De Geest S, et al. Telemedically supported case management of living-donor renal transplant recipients to optimize routine evidence-based aftercare: a single-center randomized controlled trial. Am J Transplant. 2017;17:1594–605. This trial examined not only medication adherence but quality of life and return to work. The trial examined an intervention that may usable in routine clinical practice, adding to the practical and clinical significance of the work. PubMedGoogle Scholar
- 69.• Mathes T, Großpietsch K, Neugebauer EAM, Pieper D. Interventions to increase adherence in patients taking immunosuppressive drugs after kidney transplantation: a systematic review of controlled trials. Syst Rev. 2017;6(1):236. This review encompasses studies conducted over the past several decades that have focused on interventions to improve immunosuppressant adherence after kidney transplantation. It includes clinical trials as well as other cohort studies. PubMedPubMedCentralGoogle Scholar
- 70.• Dew MA, DeVito Dabbs AJ, Posluszny DM, DiMartini AF. Adherence and self-management in the context of chronic disease: transplantation. In: Howren MB, Christensen AJ, editors. Patient adherence to medical treatment regimens and health lifestyle behaviors: Promoting evidence-based research and practice. New York: Springer Publishing, in press. This chapter provides a review of clinical issues and research findings regarding adherence to all aspects of the medical regimen after either kidney, liver, heart, or lung transplantation. Google Scholar
- 72.Lorenz EC, Amer H, Dean PG, Stegall MD, Cosio FG, Cheville AL. Adherence to a pedometer-based physical activity intervention following kidney transplant and impact on metabolic parameters. Clin Transpl. 2015;29:560–8.Google Scholar
- 74.Pita-Fernández S, Seijo-Bestilleiro R, Pértega-Díaz S, Alonso-Hernández Á, Fernández-Rivera C, Cao-López M, et al. A randomized clinical trial to determine the effectiveness of CO-oximetry and anti-smoking brief advice in a cohort of kidney transplant patients who smoke: study protocol for a randomized controlled trial. Trials. 2016;17:174.PubMedPubMedCentralGoogle Scholar
- 76.•• Fleming JN, Taber DJ, McEllligott J, McGillicuddy JW, Treiber F. Mobile health in solid organ transplant: the time is now. Am J Transplant. 2017;17:2263–76. This narrative review considers recent evidence on use of mobile health interventions and activities in organ transplantation research and potential uses of such interventions in clinical practice. Gaps in both evidence and practice are noted. PubMedGoogle Scholar
- 77.• Thakkar J, Kurup R, Laba TL, Santo K, Thiagalingam A, Rodgers A. Mobile telephone text messaging for medication adherence in chronic disease: a meta-analysis. JAMA Intern Med. 2016;176:340–9. Although this work is not focused on kidney transplantation, it is a high-quality review and meta-analysis of the use of text messaging with implications for clinical care of kidney recipients. PubMedGoogle Scholar
- 78.DeVito Dabbs AD, Myers BA, McCurry KR, Dunbar-Jacob J, Hawkins RP, Begey A, et al. User-centered design and interactive health technologies for patients. Comput Inform Nurs. 2009;27:175–83.Google Scholar
- 79.Vanhoof JMM, Vandenberghe B, Geerts D, Philippaerts P, De Mazière P, DeVito Dabbs A, et al. Technology experience of solid organ transplant patients and their overall willingness to use interactive health technology. J Nurs Scholarsh.Google Scholar
- 80.•• Kidney Disease: Improving Global outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–157. A critical document produced by experts in the field addressing clinical issues in the care of kidney recipients. Google Scholar
- 82.• Oberlin SR, Parente ST, Pruett TL. Improving medication adherence among kidney transplant recipients: findings from other industries, patient engagement, and behavioral economics—a scoping review. Sage Open Med. 2016;4:2050312115625026. The authors examined medical, social sciences and business-related literatures in order to identify factors linked to improved adherence to medications. Specific recommendations are offered for transplant programs seeking to improve their care to kidney recipients, especially with regard to identifying and helping patients to adhere to their medical regimens. PubMedPubMedCentralGoogle Scholar
- 85.Chisholm MA, Lance CE, Williamson GM, Mulloy LL. Development and validation of the immunosuppressant therapy adherence instrument (ITAS). Patient Ed Couns. 2005;59:13–20.Google Scholar
- 86.Shäfer-Keller P, Steiger J, Bock A, Denhaerynck K, De Geest S. Diagnostic accuracy of measurement methods to assess non-adherence to immunosuppressive drugs in kidney transplant recipients. Am J Transplant. 2008;8:616–26.Google Scholar
- 89.Craig C, Marshall A, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exer. 2003;35:1381–95.Google Scholar
- 90.Department of Health (UK). The general practice physical activity questionnaire: a screening tool to assess adult physical activity levels, within primary care. 2009 https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/192453/GPPAQ_-_guidance.pdf.
- 102.Yudko E, Lozhkina O, Fouts A. A comprehensive review of the psychometric properties of the drug abuse screening test. J Subst Abus Treat. 2007;32:189–98.Google Scholar
- 103.WHO ASSIST Working Group. The alcohol, smoking and substance involvement screening test (ASSIST): development, reliability and feasibility. Addiction. 2002;97:1183–94.Google Scholar
- 106.Richter L, Johnson PB. Current methods of assessing substance use: a review of strengths, problems, and developments. J Drug Issues. 2001;31:809–32.Google Scholar
- 107.Grigsby TJ, Sussman S, Chou CP, Ames SL. Assessment of substance misuse. In: VanGeest JB, Johnson TP, Alemagno SA, editors. Research methods in the study of substance abuse. Cham: Springer; 2017. p. 197–234.Google Scholar
- 109.DiMartini AF, Dew MA, Crone C. Organ transplantation. In: Sadock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadock’s comprehensive textbook of psychiatry, 10th ed. Philadelphia: Wolters Kluwer; 2017. p. 2357–73.Google Scholar
- 111.•• Stirratt MJ, Dunbar-Jacob J, Crane HM, Simoni JM, Czajkowski S, Hilliard ME, et al. Self-report measures of medication adherence behavior: recommendations on optimal use. Transl Behav Med. 2015;5:470–82. This report, prepared by experts in the field, carefully evaluates the pros and cons of using self-report measures of adherence and makes recommendations on optimal use in different research and clinical scenarios. It is a must-read paper for researchers and clinicians. PubMedPubMedCentralGoogle Scholar