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INTRODUCTION

In the United States, more than 90,000 patients are on the waiting list for a renal transplant.¹ These patients have to wait a median of 4 years before receiving their transplant due to the scarcity of organs.² Because of this long wait, around 9,000 patients are removed from the waitlist annually due to death or deteriorating medical condition.^1,2 It is the goal of transplant providers to prevent complications including acute and long-term rejection to maximize the life of the graft.

In 2016, the most recent data available, 13,501 deceased-donor and 5,335 living-donor renal transplants were performed in the United States.¹ The chief reason why patients lose their grafts is acute and/or long-term graft rejection. Rejection can be mediated by T-cells, acute cellular rejection (ACR), B-cells and antibodies, or antibody-mediated rejection (AMR). Risk factors for acute and long-term rejection include sensitization (exposure and antibody formation against non-self human antigen through blood transfusions), pregnancy, previous transplant, black race, younger age, and most significantly nonadherence to medications.³

During the early years of transplantation, rates of acute rejection within the first year after transplant were high, around 50%–60%. Rates of acute rejection within 1 year after transplant have significantly decreased with the use of maintenance immunosuppression medications. Unfortunately, long-term graft survival has not significantly increased in the last 10 years. Patient survival at 5 years after renal transplant is about 87%.¹ This may seem relatively high, but it is important to note that with each episode of rejection, graft survival decreases, going from 97% at 5 years in patients with no episodes of rejection to 78% in patients with one episode of rejection to below 50% in patients with 3 or more episodes or rejection.⁴ With each rejection episode, renal function also decreases; even if a graft is still functioning after 3 episodes of rejection, the patient is likely to have a glomerular filtration rate of only 15–20 mL/min.⁵

As nonadherence to medications is the most important risk factor for both acute and long-term rejection, it is important to ensure that providers have the tools that they need to increase medication adherence.

ACUTE AND LONG-TERM REJECTION

Injury to the graft, presenting as acute or late rejection, does not have to be related to medication nonadherence. If patients already have antibodies to their donor, called donor-specific antibodies or DSA, rejection is more likely regardless of medication adherence because of the recipient’s ability to quickly form antibodies against the graft.

Additionally, rejection is also more common in black patients. This is thought to be in part related to genetic differences in enzymes that metabolize immunosuppressants, primarily tacrolimus. Black patients are generally rapid metabolizers, as they are more likely to have more enzymes that metabolize tacrolimus to its inactive form. These patients have higher tacrolimus dose requirements; studies consistently demonstrate that these patients often are outside the therapeutic range, increasing the likelihood of rejection.⁶

Younger recipients also have increased risk for rejection. This is related to changes in the T-cell immune response in older patients, but also partially related to lower adherence in adolescence, which will be discussed below.⁷ An analysis of the Scientific Registry of Transplant Recipients from 1995 to 2002 found that patients aged 18–44 years were 23% more likely to experience acute rejection by 1 year than those aged 45–59.⁸

Renal transplant recipients are more likely to die from cardiovascular disease than from any other cause, even with a functioning graft. The rate of cardiovascular death is 50 times higher among renal transplant recipients than among nontransplant recipients. Risk factors for cardiovascular disease in renal transplant patients are common and include comorbidities such as hypertension, dyslipidemia, hyperglycemia, and calcium–phosphate imbalance. If these comorbidities are not appropriately managed, the risk for graft loss after transplant increases.⁹

There are other reasons that patients may lose their grafts not related to rejection. These can include graft thrombosis leading to early ischemic injury and chronic disease such as diabetes or autoimmune diseases.

It is important to recognize that renal transplant recipients have multiple risks for post-transplant complications. If these risks can be minimized through appropriate HLA matching, immunosuppression selection, and management of comorbidities, adherence becomes an important determinant of graft survival over the long term.

RISK FACTORS FOR NONADHERENCE AND IMPACT ON PATIENT AND GRAFT SURVIVAL

Nonadherence is defined as “deviation from the prescribed medication regimen sufficient to influence adversely the regimen’s intended effect.”¹⁰ Based on this, it is important to recognize that adherence is not just related to taking the right dose, but also at the right time. The repercussions of nonadherence vary based on the disease being treated. Adherence rates of less than 95% are associated with increased risk of acute rejection and poor long-term outcomes.¹¹ To determine the average rate of immunosuppressant nonadherence across types of solid organ transplant, a meta-analysis included 147 studies. Based on the studies included, the average rate of immunosuppressant nonadherence in all transplant patients was 22.6 cases per 100 persons per year (PPY). However, renal transplant recipients had an even higher rate of 35.6 cases per 100 PPY.¹² To identify appropriate interventions for minimizing nonadherence in these patients, risk factors must be identified and managed.

Risk Factors Associated With Nonadherence

The risk of medication nonadherence increases with each additional medication that a patient is prescribed,¹³ and nonadherence increases the risks of graft failure, cardiovascular disease, and death. Patients are also at risk for drug–drug interactions with each additional medication, which can lead to adverse effects or even ineffectiveness of a medication. The typical recipient of a renal graft leaves the hospital after the transplant with an average of 10 medications, most of them new; because of this, patients generally need to demonstrate ability to adhere to medications before being added to a transplant list.¹⁴ However, adherence may change after transplant without appropriate education and follow-up. Some adherence studies have demonstrated that pretransplant nonadherence correlates with posttransplant nonadherence.¹⁵ Many transplant centers take pretransplant adherence into consideration when deciding whether to list the patient for transplant.

The number of daily drug doses affects adherence rates. One study reported that nonadherence rates of once-daily regimens were significantly lower than rates with 4-times-daily regimens (43% versus 73%, respectively). There was no difference in nonadherence rates between once-daily and twice-daily regimens.¹⁶

In an effort to evaluate psychosocial and neurocognitive effects on adherence, a model was created to assess the impact of problem-solving abilities, depression, and self-efficacy (an individual’s belief that he or she has the ability to implement a behavior that will produce a desired outcome).¹⁷ Prior studies have demonstrated that each of these factors separately has been associated with self-reported nonadherence.¹⁸ Researchers included multiple self-report measures for assessing self-efficacy and accepted tasks for depression, neurocognition, and everyday problem solving. Drug level monitoring, pharmacy refill data, and patient surveys were used to assess adherence. Based on this information the researchers found that everyday problem solving and self-efficacy positively predicted medication adherence. However, depression and neurocognition did not directly affect adherence.¹⁸

In the meta-analysis discussed above, the two psychosocial variables with robust associations with immunosuppressant nonadherence were poor social support and poor perceived health. Nonwhite ethnicity was also associated with nonadherence but to a much lesser extent.¹² Social support is another area that many transplant centers assess when listing patients for transplant as these patients are also likely to have poorer outcomes and inadequate follow-up.

Younger age has been reported as a risk factor for nonadherence.¹⁹ Medication nonadherence among pediatric patients often emerges in the period when patients are transitioning from administration being controlled by a parent or caregiver to self-administered medications. This was demonstrated in a study reviewing medication nonadherence in pediatric renal transplant recipients; overall, 20% of patients had at least 1 episode of medication nonadherence reported in their medical records. Patients who were at least 10 years old had a significantly shorter time to nonadherence (2.7 years) than patients who were younger than 10 years old (4.1 years). Nonadherent patients were more likely to be African American, male, or the recipient of a deceased-donor kidney, or to have recurrence of native disease or legal issues. With the exception of legal issues, these are similar to the risk factors reported in many adult studies of nonadherence.²⁰

Gender-associated nonadherence was also found in another study of adolescent and young adult renal transplant patients. In patients aged 11–16 years, gender was not associated with nonadherence. However, in patients aged 17–24, females were 3 times more likely to have higher adherence scores. Interestingly, there was no difference in adherence based on self-report or standard deviation of tacrolimus trough levels.²¹

Nonadherence Related to Intention and Side Effects

Unintentional versus intentional nonadherence is also important to distinguish, as the interventions used to mitigate them differ. Tong and colleagues found that patients who were most adherent to their medications used reminders, were able to tolerate side effects, and wanted to protect their organ and avoid disappointing their providers. Alternatively, patients with low adherence reported both unintentional reasons such as forgetting and life events and intentional reasons such as side effects and cost.²²

Further evaluating predictors of unintentional versus intentional nonadherence, Griva and colleagues surveyed 152 adult RT recipients transplanted in Singapore. Patients who self-reported unintentional nonadherence were more likely to have received a living-donor renal transplant, have been engaged in formal work, or had a history of autoimmune nephritis. Patients who self-reported intentional nonadherence were more likely to have more comorbidities and misconception of side effects of their medications.²³

This leads to another discussion on the risks of nonadherence when patients are experiencing side effects or perceiving the presence of side effects. In 2016, the Food and Drug Administration (FDA) held a public forum to obtain the perspective of transplant recipients and their caregivers on the impact of transplant on their daily lives; this included perspectives on their medications. Patients reported challenges including intolerability to immunosuppressants and inability to find a better alternative, having to take medications to counter side effects of immunosuppressants, and overall burden of having to take and monitor immunosuppressants.²⁴

More specifically, one study found that patients who reported low adherence to their medications on the Modified Medication Adherence Scale reported more side effects, including tiredness, muscle weakness, thinning of hair or hair loss, and concentration and/or memory problems, compared with patients who reported high adherence. These are all well-known adverse effects of immunosuppressant regimens.²⁵ Gastrointestinal complications, diabetes, and infections have also been associated with increased nonadherence to immunosuppressant medications.²⁶

Nonadherence due to adverse effects is concerning, especially since patients may be able to be switched to alternative immunosuppressant medications to decrease the occurrence of the offending adverse effect. Some regimens had weaker associations with medication nonadherence than others; cyclosporine with mycophenolate mofetil was associated with the highest rate of adherence in a study by Pinsky and colleagues.²⁶ Patients are typically counseled on the importance of reporting adverse effects to their providers, but data suggest that renal transplant recipients do not always follow the recommendations of their providers when it comes to adverse effects.²⁴

Another study prospectively assessed patient beliefs regarding transplant, medications, and goals of life and the impacts these beliefs had on adherence to transplant medications. The study also assessed if these perceptions could predict nonadherence. A total of 113 patients participated in the interviews, which used surveys to evaluate medication adherence, goal cognition, illness perception, and beliefs about medications. Most patients (87%) had comorbidities such as hypertension and diabetes. Nonadherence increased over time, similar to previous studies. However, this study showed continued decline in adherence, which is different than other findings showing a decrease at 6 months in patients’ perception of the need for medications followed by greater awareness at 18 months after transplant. Patients who reported adherence to be a life goal were more likely to be adherent to their medications than those without this goal.²⁷

These results support previously published data that indicate that patients who know the importance of their medications are not necessarily more likely to take their medications than patients who do not recognize the importance of medications.²⁸ However, these findings give providers potential areas on which to focus, as discussed below.

Clinical Outcomes Related to Nonadherence

Several risk factors are associated with nonadherence in patients with renal transplant. Additionally, numerous published studies have identified clinical outcomes associated with nonadherence. A meta-analysis found that nonadherence significantly contributes to graft loss, with 36% of all graft loss associated with prior nonadherence. This rate of graft loss in nonadherent patients was 7 times the rate in those who were adherent.²⁹

Loss of a graft is a serious life event for the transplant recipient, and it also has a significant impact on the health care system as a whole. Medicare covered about 70% of patients who received deceased-donor renal transplants in 2016.¹ An analysis of Medicare claims data demonstrated that transplant patients who had consistently low adherence had overall health care costs that were on average $12,840 higher than costs for patients with consistently high adherence. In addition, persistent nonadherence increased adjusted medical costs by $7,253 over a 3-year time period.²⁶

It is important to recognize that early nonadherence is especially problematic in transplant patients. A prospective study of 195 renal transplant recipients used electronic monitoring of medication bottles to identify nonadherence in patients on mycophenolate mofetil, azathioprine, or sirolimus for approximately 1 year after transplant. In all, 22.6% of patients had a 7% or more decrease in adherence from month 1 to month 2 after transplant. Significant clinical findings included increased early acute rejection less than 3 months posttransplant, increased overall rate of acute rejection, and increased rate of death-censored graft loss. However, there were no significant differences in death rate or time to death. This study demonstrated that early nonadherence patterns can predict continued nonadherence and its impact on a graft survival.¹⁶ Similar results were found in nonadherent pediatric patients; nonadherent patients had more biopsy-proven acute rejection and lower rates of graft survival.²⁰

Ultimately, nonadherence is associated with nonmodifiable and modifiable risk factors (Table 1). Regardless of the reason for nonadherence, the outcomes can be worsened, including higher rates of rejection, graft loss, and death. Ultimately, providers need to give patients all the tools that they need to be successful. Fortunately, this is an area of huge growth over the last 5 years; tools for helping patients are improving and becoming more numerous.

INTERVENTIONS FOR IMPROVING ADHERENCE

Recent focus groups with experts in solid organ transplantation have made literature-based recommendations on the best methods of improving adherence in patients with renal transplants. In addition to the patient perspectives discussed earlier, the FDA held a scientific session specifically related to medication adherence and experience with intervention. The limitations of current methods for adherence monitoring were highlighted. Direct measurements and electronic monitoring are a challenge due to cost. Indirect measures such as pharmacy refill records can be incorrect due to frequent dose changes. Drug level monitoring has been found to be one of the more realistic measures, especially with tacrolimus and cyclosporine. However, these do not represent adherence to all transplant medications. Lastly, subjective reporting from patients have been consistently found to overestimate adherence while physician reporting underestimate adherence.²⁴

The American Society of Transplantation (AST) Psychosocial Community of Practice Adherence Task Force published a white paper on real-world options for promoting adherence. They highlighted multiple strategies discussed above including pharmacist counseling and MI, education, and use of technology. The Task Force ultimately recommended using validated adherence screening tools pre and post-transplant and using a multi-modal approach to assessing adherence.¹⁷

Pharmacist Counseling, Education, and Motivational Interviewing

One option to increase adherence is to decrease the number of times per day patients have to take medications. A study of 219 RT patients who were either converted to once-daily, extended-release tacrolimus or remained on twice-daily, immediate-release tacrolimus were found to have better adherence at 6 months with scores of 88.2% and 78.8%, respectively.³⁰ When this was repeated in a Norwegian cohort of 91 RT patients, adherence with respect to both taking medications and timing of administration increased from 45.6% at baseline to 58.1% at month 1; this returned to baseline at subsequent follow-up.³¹ This is possibly related to the fact that patients are likely taking other medications twice daily for their transplant and overall switching one medication to daily may not improve taking and timing of medications. Ultimately, once-daily medications are a good option for patients, particularly when they report that the number of daily doses or the timing of medication administration as reasons for nonadherence.

The TAKE-IT randomized controlled trial was used to assess adherence in adolescents and young adults using a multicomponent intervention in 169 patients who were more than 3 months post-transplantation. Patients were randomized to either the intervention or control arm. Patients in both arms completed the Medication Barriers Survey and a self-report adherence questionnaire at enrollment with pillbox teaching and pillbox monitoring throughout the study. The control group had visits every 3 months with generalized social support and pillbox support and self-report adherence questionnaire. The intervention group also had visits every 3 months along with support team formation and education at 3 months, action-focused problem solving, feedback on adherence data for the prior 3 months, pillbox support, and self-report adherence questionnaire.³²

Patients in the intervention arm had improved taking-and-timing adherence as compared with participants in control groups who showed no changes in their adherence behaviors. Of note, there was no difference between groups with regard to the standard deviation of tacrolimus troughs. Acute rejection was numerically but not statistically lower in the intervention group. However, the study was not powered to see a difference in rejection; perhaps if more patients were enrolled, the numeric difference would have achieved significance.³² Although this study was conducted in adolescents and young adults, its results are likely relevant to adult patients in older age ranges.

Motivational interviewing (MI) is an approach used in other chronic disease states that is being applied to transplantation. MI can be learned by anyone, and pharmacists are in a great position to be the health care provider participating in this patient-centered approach to increase medication adherence. The principles of MI include expressing empathy, developing discrepancy, rolling with resistance, and supporting self-efficacy, which was demonstrated above as a marker for nonadherence. The thought is that it might be most efficient in patients with intentional nonadherence due to negative beliefs about medications.³³

Cukor and colleagues randomized 33 patients to standard care or cognitive-behavioral adherence promotion program that consisted of a two-session group program using MI. Patients in the intervention group were found to have higher levels of adherence than those in the control arm. Although tacrolimus trough levels were not significantly difference, there was less variation in levels in the intervention arm over time. The authors suggest that this may indicate more consistent medication taking.³⁴

Other studies are needed to expand the use of MI in transplantation.

Telemedicine and Specialty Pharmacy

Another growing area of adherence improvement is the use of telemedicine to promote good medication-taking practices. One example of this opportunity comes from New York Presbyterian Hospital, where the transplant pharmacy team implemented a pharmacy telemedicine practice. The telemedicine visits included multiple components including medication teaching, pharmacotherapy review, and assessment of medication adherence. In a retrospective report, patients responded favorably (100%) to adherence questions.³⁵ Although nothing specific can be drawn from this, telemedicine technology could be used in a multicomponent approach to replace an in-person visit, especially for patients living great distances from the transplant center. This would provide a “face-to-face” encounter for the patient while reinforcing accountability with the provider.

Reese and colleagues performed a multicomponent adherence intervention using technology that took advantage of patients’ desire not to disappoint providers. Patients with kidney transplants were randomized to wireless pill bottle plus customized reminders such as text messaging; wireless pill bottle plus customized reminders and provider notification if adherence was less than 90%; or a wireless pill bottle use alone. Mean adherence was highest in the multicomponent intervention at 88%, but adherence was also high in the alert-alone arm at 78% compared with the bottle intervention at 58%. Tacrolimus levels were not significantly different between groups and there was no clinical end point assessment, but this report is a great example of how technology and reliability can be used to promote adherence.³⁶

Specialty pharmacies play a unique and critical role in the care of transplant patients and can tailor services to the needs of patients. Tschida and colleagues reported on a specialty pharmacy service for renal transplant recipients that provided medication delivery in addition to refill reminders and adherence screening and intervention. Educational information was also provided regarding adverse effect management and financial assistance. The primary outcome during 1 year of follow-up was total health care costs, compared between those who received the specialty pharmacy service and those who did not. Patients who used the service had 15% lower total health care costs than patients who did not use the service. Patients in the service were also found to have increased adherence rates based on refill data. There were no differences in transplant complications between groups during the study period.³⁷ This information is useful for developing and implementing a specialty pharmacy service to help increase adherence in the renal transplant patient population. Further studies are needed to clarify the impact of pharmacy services on transplant-related outcomes such as rejection rates and graft survival.

Ultimately, it is clear that these innovative approaches using multicomponent approaches can improve adherence in patients with transplants. The AST Transplant Pharmacy Community of Practice also published consensus recommendations regarding future research on immunosuppressant nonadherence after transplant after a consensus conference was held in 2017. Future research goals include assessing how patients prefer to be educated and what tools they would prefer to use to increase adherence, evaluating mentorship with regard to adherence, and evaluating paper education versus more interactive forms of education.¹⁰ One such research effort currently under way is the TRANSAFE Rx study, which uses a pharmacist-led intervention and mobile health technology to assess increase in adherence in 136 patients with renal transplants. The primary outcome to be assessed is the incidence and severity of medication errors and side effects; clinical end points will be secondary measures.³⁸ The results of this study will help to further demonstrate the use of technology in promoting adherence and the pharmacist’s role.

CONCLUSION

Acute and long-term rejection after renal transplant can occur because of any number of issues, one of which is adherence to medications. Nonadherence is in fact the leading cause of rejection. Pharmacists should identify risks for rejection in patients with renal transplants and be able to address these risks through a multicomponent approach. There is no “one size fits all” model for nonadherence in transplant; pharmacists are in an excellent position to increase the odds of patients with renal transplants having successful outcomes.

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