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INTRODUCTION

In 2018, there were 20,904 renal transplants performed in the United States.¹ Transplantation is the preferred treatment option for end-stage renal disease (ESRD) due to decreased mortality and increased cost effectiveness.² Although graft survival is used as a primary measurement of transplant efficacy, there are many more significant outcomes. Physical, social, and psychological well-being are all effected by transplantation. Ultimately, the goal of renal transplant is to increase the quality and quantity of life beyond what patients can get with dialysis in addition to the increased cost-effectiveness of transplantation versus dialysis.

The World Health Organization defines Quality of Life (QOL) as an “individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns. It is a broad ranging concept affected in a complex way by the person's physical health, psychological state, personal beliefs, social relationships, and their relationship to salient features of their environment.”³ More specifically, health-related QOL (HRQOL) helps clarify how much disease symptoms affect overall QOL both physically and emotionally.⁴ With regard to ESRD, HRQOL has been found to be an independent risk factor for mortality in dialysis patients.⁴

Hemodialysis (HD) is the most common mode of dialysis. It results in large shifts of fluid, is usually performed 3 times weekly, and leads to complications including hypotonia, muscle cramps, itching, headaches, nausea, and low blood pressure. HD also typically requires patients to travel to receive dialysis at a facility, although some patients perform hemodialysis at home more frequently and for shorter durations. It can also be a time burden on patients, making it challenging to work. Peritoneal dialysis (PD) is less effective than HD at removing toxins and requires a much more rigorous, regimented routine to avoid infections, but PD can be performed at home while sleeping or in shifts.⁴

In a study comparing HRQOL in HD, PD, and renal transplant, patients who had undergone transplant had higher physical HRQOL scores, but no difference in mental HRQOL scores. Posttransplant patients also had better scores related to work and kidney disease burden.⁴ Even though patients are documented to have improved HRQOL, there are trade-offs regarding transplantation. The organ may not work immediately or at all. Patients may experience repeat hospitalizations due to complications such as infections or surgical-related issues, and there is an increased risk of comorbidities such as diabetes and hypertension as well as cancer. There are a number of excellent resources including the United Network of Organ Sharing (UNOS) and the National Kidney Foundation (NKF) that outline these complications for patients.^5,6 In addition, the total daily pill burden often increases posttransplant due to the number of immunosuppressive and prophylactic medications as compared to pretransplant.⁷

A patient survey was completed to assess the most common concerns of patients with regard to renal transplant.⁸ These concerns were related to how long the graft will last and when they will lose graft function, in addition to comorbidities including diabetes, high blood pressure, pain, cancer, recurrent urinary tract infections, and heart disease. In addition, 22% of patients reflected on cost and health insurance. Cost and health insurance is a significant concern in the US, especially in kidney transplant patients. Medicare is the primary payer for renal transplant, and patients lose Medicare 3 years after transplant if they do not otherwise qualify, making this a potential stressor for patients.⁸

This article will discuss HRQOL after renal transplant as it relates to potential complications and immunosuppressive medications. It will also review opportunities for increasing HRQOL, medication adherence, long-term monitoring, and the crucial role of the pharmacist as part of the multidisciplinary team required to care for this patient population.

POTENTIAL COMPLICATIONS

Balancing rejection of the new kidney and risk of infection is the cornerstone of posttransplant management. This is highlighted by the fact that some patients have rejection and infection episodes. Patients may have infections first, leading to reduction of immunosuppression and resulting in rejection, or patients may have rejection first, leading to an increase in immunosuppression and then a subsequent infection.⁹ This balance is also particularly difficult as there are many factors that determine a patient’s risk for rejection versus infection. Induction agents may be selected based on a patient’s risk of rejection, high versus low risk, but maintenance immunosuppression is typically not tailored, with perhaps the exception of long-term use of steroids versus steroid withdrawal. This makes understanding the risk of rejection and infection very important.

In a study published by Cippà and colleagues, the researchers examined the parameters that were associated with increased infection risk or increased rejection risk.⁹ Factors that influenced infection included older age, deceased donor, higher number of human leukocyte antigen (HLA) mismatches, and high risk for cytomegalovirus (CMV) disease. Patients were at higher risk of rejection if they had a deceased donor, a higher number of HLA mismatches, or immunosuppression with cyclosporine versus tacrolimus.⁹

Another adverse outcome after transplant that is related to over-immunosuppression is the risk of developing certain cancers. In fact, cancer is one of the leading causes of death after renal transplant, secondary to cardiovascular disease and infections.¹⁰ Patients are at an increased risk for lung, colon, liver, lymphoma, and melanoma/nonmelanoma skin cancers; however, there is no increased risk for breast, prostate, ovarian, brain, or cervical cancer.¹¹ Risk for cancer can be broken into patient, transplant, and medication-related factors displayed in Table 1.¹¹

Cardiovascular disease after renal transplantation is a challenge. Many patients present with cardiovascular disease and advanced atherosclerotic risk factors related to dialysis even before transplantation.¹² The top two reasons patients need a renal transplant are related to microvascular complications of diabetes and hypertension, which further complicates cardiovascular disease. After transplant, drugs like tacrolimus further enhance diabetes through toxicity of beta islet cells, and steroids are well known to lead to increased blood glucose levels. Diabetes can develop in patients who did not otherwise have the disease due to the adverse effects of posttransplant medications. In addition, hypertension is not alleviated by transplant and generally requires lifelong drug therapy. Additional risk factors for cardiovascular disease include poor graft function, proteinuria, anemia, moderate hyperhomocysteinemia, and elevated serum C-reactive protein concentrations. Ultimately, these factors lead to a 50-fold higher risk of death from cardiovascular disease in renal transplant patients as compared to the general population.¹²

In addition to cardiovascular disease, there are possible surgical complications related to renal transplant, although these are less common.¹² These include vascular complications, which may require stents or lead to thrombosis and ureteral complications requiring stents or nephrostomy tubes. Patients may also experience poor wound healing, especially in the setting of obesity or diabetes. These potential complications contribute to a difficult postoperative course. Due to a high likelihood of complications, it is important for patients to be informed and part of the decision-making process. Any concerns should be addressed early and even prior to transplantation.¹²

CASE STUDY 1

A 32-year-old white female is visiting the pretransplant clinic to determine if she is a candidate for a renal transplant. Her kidney disease was caused by type 1 diabetes mellitus, and she has been on dialysis for 2 years. Her mother is interested in being a living donor. She has been exposed to CMV and makes sure to use sunscreen when she is outside.

Given this scenario, consider the risk factors for this patient. Review decisions that will be made after transplant that might affect her risk for complications. Propose ways to discuss those risks with her so that she is aware of all potential complications.

IMMUNOSUPPRESSION

New transplant patients leave the hospital on approximately 10 medications including immunosuppressants, antimicrobial prophylaxis, and maintenance drugs for hyperglycemia, hypertension, dyslipidemia, and calcium-phosphate balance.¹³ Many of these agents are new to the patient and require detailed education to understand the indication, appropriate schedule, monitoring, adverse effects, and other drugs and foods to avoid. The patient can be overwhelmed in the first few days posttransplant with all of the information being provided; therefore, it is important that education is continually provided in the outpatient setting.

Each transplant center uses the available immunosuppressive medications differently, but there are some generalities. Patients are typically on two to three maintenance immunosuppressives. The backbone of the immunosuppressive regimen is typically a calcineurin inhibitor (CNI), more commonly tacrolimus versus cyclosporine.¹⁴ The dosing of a CNI is dependent on therapeutic drug monitoring, requiring patients to obtain regular laboratory draws and dose adjustments throughout their life. The second drug is usually an antiproliferative agent such as mycophenolic acid or azathioprine to block T-cell proliferation through multiple mechanisms, which works in collaboration with a CNI. Steroids are the typical third medication in a regimen, usually prednisone. Some transplant centers withdraw steroids completely after just a few days, while others leave patients on a low dose such as prednisone 5 mg daily. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus can be used in place of a CNI or the antiproliferative agent, but they require continual therapeutic drug monitoring and dose adjustments. Belatacept, a costimulation blocker, can be used as the backbone agent in combination with mycophenolic acid and a steroid. The advantage to this medication is that it is a once-monthly infusion that does not require therapeutic drug monitoring.¹⁴ All of these agents must be considered in the larger picture of maintenance medications with regard to drug-drug interactions and adherence.

It is important for patients to be aware of potential adverse effects they may experience. CNIs can cause nephrotoxicity, hypertension, and electrolyte disturbances, specifically hyperkalemia and hypomagnesemia.¹⁴ Cyclosporine can lead to hirsutism, gingival hyperplasia, and hypercholesterolemia, while tacrolimus can cause alopecia, neurotoxicity (eg, tremors, headaches, short term memory loss, seizures), and hyperglycemia. The preferred agent tends to be tacrolimus with its more favorable cosmetic adverse-effect profile (alopecia versus hirsutism and gingival hyperplasia), as evidenced by more favorable HRQOL scores.¹⁵ Alternatively, mTOR inhibitors cause delays in wound healing, hypertriglyceridemia, mouth ulcers, and lymphocele formation. The most frequently seen adverse effects of belatacept include infusion-related irritation, headaches, and edema. Mycophenolic acid is known for its gastrointestinal (GI) effects, including nausea and diarrhea, as well as bone marrow suppression. Adverse effects related to azathioprine include bone marrow suppression, rash, flulike symptoms, and pancreatitis.¹⁴ Table 2 provides a summary of these adverse effects.^14,15

The adverse-effect profile of immunosuppressant agents is so significant that one study found 28% of patients had adverse effects with a mean of 6.4 adverse effects per patient.¹⁶ Some of these adverse effects have long-term complications, especially related to cardiovascular complications, and will require very close monitoring and follow-up on a routine basis. This vast adverse-effect profile has potential negative ramifications on adherence and QOL after renal transplant and requires proper management and patient education.¹⁶

RISKS AND IMPACT OF NONADHERENCE

There are a number of factors that can impact adherence, ranging from condition- and treatment-related factors to provider, sociodemographic, and psychosocial factors.¹⁷ Nonadherence has been associated with increased risk of both cellular and antibody medication rejection. A meta-analysis reviewed outcomes associated with nonadherence and found that 36% of graft losses were associated with prior nonadherence and that the risk of graft failure is increased seven times in nonadherent patients compared to patients adherent to their immunosuppression.¹⁸ Recent data suggest that adherence of less than 95% can increase the risk of rejection and graft loss.¹⁷

A study using Mayo Clinic Specialty Pharmacy refill data as a marker for adherence 5 years posttransplant determined that patients at risk for nonadherence were younger age recipients and on sirolimus-based immunosuppression regimens.¹⁹ Interestingly, adherence increased between years 3 and 5 as compared to years 1 and 3. This suggests some benefit of the interventions that a specialty pharmacy can provide, especially education with regard to medication coverage after termination of Medicare. The increased adherence over time in this study contrasts with other studies without targeted interventions that found decreased adherence over time.¹⁸ In addition, the most impactful results of this study showed just how significant adherence was related to outcomes. Fibrosis and inflammation on biopsy 5 years posttransplant, which is known to shorten graft survival, was associated with nonadherence and independent of other variables including induction, maintenance, and rejection history. Nonadherence specifically to the antimetabolite was most closely associated with poor biopsy outcomes. Additionally, mean estimated glomerular filtration rates (eGFR) for patients with fibrosis and inflammation were significantly lower than those without fibrosis and inflammation. This study provides an excellent example of how the significant impact of nonadherence can have negative long-term consequences on renal transplant outcomes.¹⁹

QUALITY OF LIFE AFTER RENAL TRANSPLANT

There are a number of surveys available that can be separated into general, disease specific, and symptom specific as related to QOL posttransplant. The general surveys are used to measure global HRQOL and disease-specific surveys could be either ESRD or transplant specific. Symptom-specific surveys could be related to immunosuppression or other specific symptoms a patient may be experiencing such as GI symptoms.²⁰ A summary of the most common tools that have been used in assessing QOL and HRQOL after transplant are available in Table 3. ^15,20

In addition to advantages already discussed, it important to highlight the QOL benefit of transplant versus dialysis. The SF-36 was used to compare QOL outcomes in hemodialysis patients versus renal transplant.²¹ SF-36 is a generic, global tool that is short, reliable, and comprehensive. It can be used to detect positive and negative states of health. In this study, QOL scores were dependent on outcomes after transplant, specifically serum creatinine levels. Patients with higher serum creatinine had lower QOL scores. Past rejection did not affect SF-36 scores, as long as the graft was currently functioning. Scores also varied widely, which indicates the large variation that patients experience.²¹

In a patient survey at the University of Michigan, 48% of posttransplant patients responded that they had an improvement in QOL and a return to normalcy, especially related to the impact dialysis had on their schedule.⁸ Patients also reported being able to participate in activities that they did not have the energy to participate in before transplant, and 17% reported better health and more energy.⁸ However, this was not true for everyone, and 9% of patients reported burdens of posttransplant regimens commenting on the number and schedule of medications. Additionally, 7% of patients reported no change in QOL and 6% reported worsened or less energy related to poor transplant outcomes or comorbidities.⁸

Studies have reported differences in QOL based on gender and race, with being male and Caucasian having the perceived greatest impact.¹⁵ In another study, where patients were their own controls, males and younger/fitter patients experienced higher impacts on QOL after transplantation.¹⁵ Further research has found that receiving disability and low monthly income contributed to low QOL, along with advanced age, being female, having children, unemployment, living alone, chronic graft dysfunction, presence of adverse effects, and use of cardiovascular medications.¹⁶ There are a number of different factors that affect QOL after renal transplant, and although QOL generally improves, it is important to recognize that for some patients it may actually worsen.

QUALITY OF LIFE AND IMMUNOSUPPRESSANTS

All of the studies previously discussed have looked at the general impact of transplant on QOL; nevertheless, only 1.8% of randomized controlled trials evaluating maintenance immunosuppression in renal transplant included QOL outcomes.²⁰ In addition, immunosuppressive studies run the gamut of which QOL metrics were used and cannot be compared to each other. However, some things are important to note. In a small study comparing patients who were not on immunosuppression after kidney transplant because they underwent tolerance protocols, patients were on significantly less hypertension medications, had higher overall health on QOL surveys, and were less likely to experience depression and excessive appetite.²² These patients were still posttransplant, allowing the authors to compare immunosuppressive therapy versus no immunosuppressive therapy and demonstrate the impact these therapies have on QOL.

With regard to comparison of specific medications, there is additional data. In a study comparing cyclosporine plus sirolimus versus sirolimus alone using the Kidney Transplant Questionnaire (KTQ) to review HRQOL outcomes, scores favored the regimen with sirolimus alone with regard to fatigue, emotions, and appearance.²³ SF-36 scores also favored sirolimus alone for improved general health, social function, and role-physical scores. The study noted that vitality scores increased in the sirolimus alone group but decreased in the cyclosporine plus sirolimus group. These HRQOL results indicate that the elimination of cyclosporine from a combined regimen at 3 months after kidney transplantation results in decreased fatigue, increased vitality, general health perceptions, and social functioning compared with continuous treatment with cyclosporine over 3 years. Other studies have shown similar results in confirming that if one can eliminate cyclosporine then HRQOL seems to improve.²³

In the original trials that gained FDA approval of belatacept, researchers assessed SF-36 and Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSDS) in belatacept versus cyclosporine patients through the first 3 years following transplant.²⁴ Both the physical and mental composite scores increased for patients on belatacept (who received standard criteria kidney grafts at 12 and 36 months as compared to baseline), but not for cyclosporine. Patients also experienced decreased adverse effects with belatacept. Of note, and similar to results previously discussed, patients had improved HRQOL with better kidney function.²⁴

With regard to mycophenolic acid products (enteric-coated (EC) mycophenolic acid or mycophenolate mofetil), studies have investigated if the EC product would decrease GI adverse effects.²⁵ Using the Gastrointestinal Symptom Rating Scale (GSRS), more patients on the EC formulation had improvement in the scale, but the GSRS was not significantly different in the two groups. Results suggest that EC mycophenolic acid may be better for some patients, but it may largely depend on which symptoms they are experiencing, specifically indigestion if they have diabetes or are on steroids.²⁵

Walker and colleagues studied the impact of conversion to tacrolimus from cyclosporine versus remaining on cyclosporine on adverse effects and QOL.²⁶ They found no difference in SF-36 scores between groups, but they did find that patients on tacrolimus had improvements in their disfigurement scores, while patients still on cyclosporine had decreases in their disfigurement scores, demonstrating the impact of adverse effects on physical perception.²⁶

Evidence has demonstrated improved QOL with sirolimus, tacrolimus, or belatacept as compared to cyclosporine and using the EC formulation of mycophenolic acid for indigestion.^23-26 Ultimately, this information gives us a better understanding of the impact that adverse effects and efficacy of immunosuppressants have on the perceived HRQOL that patients experience.

QUALITY OF LIFE AND MEDICATION ADHERENCE

There have been some published studies looking specifically at HRQOL as it relates to immunosuppression adherence. In a study of 136 posttransplant patients in Poland, patients were on more medications if they had higher body mass index, lower glomerular filtration rate, and higher rates of comorbidities.⁷ This study showed that the more drugs patients were on after kidney transplant, the lower their HRQOL for physical functioning, pain, and social function.^7,21 Additionally, increased patient costs associated with medications and total weekly pill burden also led to decreased QOL scores.⁷

In a study by Scheel et al, assessment of HRQOL factors associated with nonadherence led to the identification that transplant recipients with lower perceived social support, lower mental HRQOL and high physical HRQOL scores were associated with patient-reported nonadherence.²⁷ This correlation of nonadherence with higher physical HRQOL is an interesting concept. The authors suggest that this might be related to people being more mobile and thus having more perceived barriers to adherence and potentially sensing a lower threat of disease burden. Another opportunity for improving adherence suggested by this data is helping to increase the social support of the patient to act as a buffer against fear and stress.²⁷ This is an important group of patients to identify and support with psychosocial intervention.

Qualitative studies that focus on patient perceptions of adherence after transplant are critically important to assessment of adherence and development of the most appropriate tools for enhancing adherence. Nevins and colleagues summarized the themes found in these qualitative studies when looking at the patient perspective of adherence: 1) empowerment, 2) fear of consequences, 3) managing regimen demands, 4) concerns about overmedicalizing life, and 5) social accountability and motivation.¹⁸ Multicomponent interventions seem more likely to be efficacious than single-component interventions; this is similar to other literature on medication adherence interventions.¹⁸ Patients experience these in different degrees, which further highlights the need to adapt strategies to the patient as their needs may change over time. Although there is not extensive data on the impact of QOL on medication adherence after renal transplant, there are some key takeaways that can help us better understand what our patients are going through and provide the best tools to increase their adherence and QOL.

PHARMACIST IMPACT ON MEDICATION ADHERENCE AND QUALITY OF LIFE

In order to address adherence, it is critical to first determine when and how to assess medication adherence in our renal transplant recipients. New evidence suggests that nonadherence is a significant issue even in the early posttransplant period, which makes early intervention so important.¹⁸ Asking just two questions may help give the pharmacist a sense of patient adherence: 1) How often did you miss a dose of your immunosuppressive medication in the past 4 weeks?; and 2) Did you miss more than one consecutive dose of your immunosuppressive medication in the past 4 weeks?¹⁸ Although a patient can always deny missing doses, any answer that is “yes” is important to investigate.

QOL studies in transplant have highlighted the need to minimize treatment burden to avoid over- or underutilizing health care, poor QOL, or nonadherence. ²⁸ Ways that a pharmacist can help to minimize treatment burden can include noting adverse effects, reporting those side effects to providers, and even helping to manage them. For example, biotin supplements might be appropriate for patients experiencing hair loss from tacrolimus.²⁶

Cost of medications may be a huge barrier to adherence, especially in patients who lose their insurance due to job changes or those who lose Medicare after 3 years posttransplant.¹⁹ Ensuring that cost is not a barrier for patients to get their medications and stay adherent is critical and there are numerous patient assistance programs available to help with cost reduction of prescription drugs. The National Kidney Foundation has an excellent and up-to-date online resource with links and phone numbers to programs relevant to patients in regards to particular medication assistance programs.²⁹ This link should be shared with patients who are experiencing high copays or adherence issues related to costly medications.

Other interventions made by the pharmacist include reducing pill burden to increase HRQOL. Research has demonstrated this to be a crucial intervention in the HIV patient population, who are also on rigorous medication regimens. Many of the additional medications patients are on are related to comorbidities such as hypertension or diabetes.⁷ Combination products or using the most effective medications to treat these comorbidities can make a significant impact on pill burden and help increase adherence and QOL. In cases where pill burden cannot be significantly reduced, the pharmacist can ensure patients have appropriate pill boxes to help organize medication schedules and confirm that they have a refill reminder set either directly from the pharmacy or through other means. Meta-analyses have shown that feedback on past nonadherence is one of the most motivating factors to increasing adherence by patients.¹⁸ Using this feedback in combination with new tools to increase adherence as part of a multicomponent intervention may be the most beneficial to patients.

Other pharmacist interventions have included ongoing, continuous education, behavioral contracts, and the use of tools such as smartphones and calendars.^30,31 Experts agree that multicomponent interventions are the most effective but that benefits of interventions on adherence do not often persist once the intervention stops.¹⁸ This highlights the necessity of continuous education after renal transplant, which puts the pharmacist in an excellent position to provide that education and reminders to increase adherence. One way to provide continuous and long-lasting impact services are through specialty pharmacies, which can be tailored based on the patient’s needs, including pill box fills, refill reminders, and scheduled deliveries. In a study published by Tschida et al, specialty pharmacy services were provided to renal transplant patients including medication delivery, refill reminders, and adherence screening and intervention.³² Patients who used the service had 13% lower total health care costs than patients who did not use the service. Patients were also found to have increased adherence rates based on refill data. Unfortunately, there were no differences in transplant complications between groups during the study period.³² Adherence is based on patient-specific factors, and tailoring an approach to increase adherence can significantly impact QOL.

CASE STUDY 2

A 72-year-old African American male comes into the pharmacy a few months after his renal transplant. He reports being tired and frustrated that his blood pressure has not improved after transplant. He is now on 10 medications: two immunosuppressants (tacrolimus and mycophenolic acid), three for antimicrobial prophylaxis, two for diabetes, and three for blood pressure. With so many prescription drugs, he is forgetting to take his blood pressure medication in the middle of the day. His creatinine is also getting worse and he is upset that the kidney is not working how it was supposed to.

As presented above, think about what might be impacting the patient’s current HRQOL. Consider available tools or education that could be provided to improve adherence and his QOL. Develop a monitoring plan with regard to his current medications and comorbidities.

SUMMARY

After renal transplant, the ultimate goal is to preserve graft function. To do that, immunosuppressive medications are required. This means weighing the benefits of good graft function with complications such as infections, cancer, cardiovascular effects, and other adverse effects. This management is a matter of life or death for renal transplant recipients and can weigh heavily on their QOL.

There is an integral relationship between adherence and QOL. Decreased adherence reduces QOL due to declining kidney function, and perceived QOL can either positively or negatively influence adherence. Thus, there is a need to be selective when it comes to choosing immunosuppression for transplant patients¾weighing the risk of benefit with harm regarding health outcomes, including complications and QOL. It is essential to provide patients with the right tools and ongoing education to increase adherence and improve QOL, as the skills of the pharmacist can prove to be invaluable to improve patient care in the renal transplant patient.

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REFERENCES

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