Pediatr Nephrol
DOI 10.1007/s00467-017-3637-0
REVIEW
Adherence in pediatric kidney transplant recipients:
solutions for the system
Elizabeth A. Steinberg 1 & Mary Moss 2 & Cindy L. Buchanan 1,3 & Jens Goebel 4
Received: 5 December 2016 / Revised: 24 February 2017 / Accepted: 27 February 2017
# IPNA 2017
Abstract Non-adherence remains a significant problem
among pediatric (and adult) renal transplant recipients. Non-
adherence among solid organ transplant recipients results in
US$15–100 million annual costs. Estimates of non-adherence
range from 30 to 70% among pediatric patients. Research
demonstrates that a 10% decrement in adherence is associated
with 8% higher hazard of graft failure and mortality. Focus has
begun to shift from patient factors that impact adherence to the
contributing healthcare and systems factors. The purpose of
this review is to describe problems within the systems impli-
cated in non-adherence and potential solutions that may be
related to positive adherence outcomes. Systems issues in-
clude insurance and legal regulations, provider and care team
barriers to optimal care, and difficulties with transitioning to
adult care. Potential solutions include recognition of how sys-
tems can work together to improve patient outcomes through
improvements in insurance programs, a multi-disciplinary
care team approach, evidence-based medical management,
Dedication The authors wish to dedicate this article to the memory of
Dennis Drotar, PhD, who recently passed away and without whose
mentorship and leadership in the field the work summarized and
referenced here would not have been possible.
* Elizabeth A. Steinberg
Elizabeth.Steinberg@ucdenver.edu
1
Department of Psychiatry, University of Colorado School of
Medicine, Aurora, CO, USA
2
Department of Pharmacy, Children’s Hospital Colorado, Aurora, CO,
USA
3
Department of Surgery, University of Colorado School of Medicine,
Aurora, CO, USA
4
Department of Pediatrics, University of Colorado School of
Medicine, Aurora, CO, USA
pharmacy-based applications and interventions to simplify
medication regimens, improved transition protocols, and
telehealth/technology-based multi-component interventions.
However, there remains a significant lack of reliability in the
application of these potential solutions to systems issues that
impact patient adherence. Future efforts should accordingly
focus on these efforts, likely by leveraging quality improve-
ment and related principles, and on the investigation of the
efficacy of these interventions to improve adherence and graft
outcomes.
Keywords Adherence . Kidney transplant . Healthcare
system . Pediatric . Quality improvement .
Immunosuppression
Introduction
Non-adherence has significant implications for kidney trans-
plant patients, including increased healthcare utilization, med-
ical complications, allograft rejection and loss, and patient
death [1–3]. Estimates of non-adherence among pediatric re-
nal transplant recipients range from 30 to 70% [4–6]. Non-
adherence leads to unnecessary tests, additional treatments,
procedures, surgeries, clinic visits, and hospitalizations [7].
Further, research has demonstrated that each 10% decrement
in adherence is associated with an 8% higher hazard of graft
failure and mortality [8, 9] and that non-adherence is the lead-
ing cause of antibody-mediated rejection [6] due to the devel-
opment of new donor-specific antibodies in the setting of in-
sufficient immunosuppression. Importantly, research suggests
that the creation of donor-specific antibodies may lead to
antibody-mediated rejection and eventual risk of graft failure
and loss [10]. Studies have shown that non-adherence has
been a factor in almost half of graft losses in adult renal

transplant recipients [10–12], and research in adolescent and
young adult transplant recipients has demonstrated that death-
censored graft failure rates are highest in 17- to 24-year-olds
[2] (Fig. 1). Mortality may also result from antibody sensiti-
zation, organ shortages and non-adherence preventing re-
transplantation. Further, non-adherence may compromise im-
portant clinical trial outcomes [13].
In addition to serious health implications, non-adherence
has significant economic consequences. Estimates of annual
healthcare systems costs for adherent kidney transplant recip-
ients are $16,844 (USD) versus $82,765 for a patient in graft
failure versus $70,581 for a dialysis patient [14]. Non-
adherence among patients with chronic illness leads to be-
tween $100 and $300 billion in estimated avoidable costs
annually, and to $15–100 million costs annually for solid or-
gan transplant recipients [15–17].
Definition of adherence
Adherence is defined as Bthe extent to which a person’s be-
havior (e.g., taking medication, following a diet or fluid tar-
gets, catheterizing on a timed schedule, and/or executing life-
style changes), corresponds with agreed recommendations
from a health care provider^ [18]. Commonly, for kidney
transplant recipients, the term adherence simply refers to their
successful management of immunosuppressive medication.
However, there are various components of adherence,
Fig. 1 Crude age-specific death-
censored graft failure rates
(failures per 100 person-years) in
each 1-year age interval are
shown with 95% confidence
intervals (CI) for all recipients (a)
and recipients with at least 1 year
of graft function (b). These rates
are not adjusted for time since
transplant. Reproduced with
permission from Foster et al. [2]
Pediatr Nephrol
including dosing adherence (taking the appropriate dose of a
medication), timing adherence (taking the medication at the
appropriate times), taking adherence (taking the medication at
all), and persistence (continuing the medication for as long as
the regimen prescribes) [19]. An important, although difficult
to verify, component of this definition is that adherence refers
to an agreed upon medical plan between a provider and patient
[19], with adherence implying a non-judgmental stance from
the provider. In contrast, compliance typically refers to
conforming to a treatment plan decided upon by the provider
and implies a more passive role on the part of the patient [20].
Adherence also refers to additional important healthcare tasks,
including scheduling and attending clinic appointments, get-
ting the necessary bloodwork, returning provider phone calls,
maintaining proper diet and exercise, avoiding alcohol and
drug use, or globally following the treatment regimen [21, 22].
In Dobbels et al.’s meta-analysis, rates of immunosuppres-
sive medication non-adherence were estimated at 43.2%
among adolescent kidney transplant recipients (compared to
a rate of 22.4% non-adherence in kidney transplant recipients
younger than 10 years of age) [23]. Non-adherence rates may
be threefold higher in adolescents than in younger children
[21]. A >5 years post-transplant follow-up study deemed out-
comes significantly worse in adolescent age groups than in
younger transplant recipients [24–26], with one likely contrib-
uting cause being non-adherence [4]. A meta-analysis inves-
tigating non-adherence in pediatric kidney transplant recipi-
ents found that missing clinic appointments and tests is the
most prevalent form of non-adherence (rate = 12.7, standard
Pediatr Nephrol
error = 4.4, N = 4 studies), with the authors highlighting
follow-up adherence difficulties for certain patients and ad-
dressing potential systemic issues in post-transplant care.
The rate of immunosuppression non-adherence across heart,
liver, and kidney transplant patients was six cases per 100
patients per year [21]. This meta-analysis also found that
non-adherence to substance use restrictions, exercise, diet,
and additional healthcare tasks ranged from 0.6 to eight cases
per 100 patients per year [21]. Thus, non-adherence presents a
significant challenge and concern among adolescents with
kidney transplants.
The World Health Organization has identified five interre-
lated risk and protective categories that impact adherence,
namely, patient-related factors, socio-economic factors,
condition-related factors, therapy-related factors, and
healthcare factors [4, 18] (Fig. 2). Patient-related variables
include individual factors such as knowledge and understand-
ing of disease and medications, mental health concerns, cog-
nitive functioning, coping mechanisms, and social support
[18]. Examples of socio-economic factors include socio-
economic status, family support and functioning, and race/
cultural background [18]. Condition-related factors include
duration of illness, health beliefs, time since transplant, and
living donor renal transplantation [27, 28]. Treatment-related
factors include side effects, number of medications and doses
per day, complexity of medication regimen, and cost of med-
ication [18]. Finally, healthcare system- and healthcare team-
related factors include insurance and overall organization of
healthcare and culture of care [18, 19]. Although there is a
fairly significant literature base describing individual and fam-
ily factors and barriers that impact adherence, the body of
literature on systems-level factors that also likely impact ad-
herence in this population is smaller [4, 29].
Fig. 2 Five interacting dimensions of adherence according to the World
Health Organization. HCT Healthcare factors. Reproduced with
permission from E. Sabaté for the World Health Organization [18]
Defining the system
Prior research among pediatric populations has often focused
on individual, condition, treatment, and socio-economic fac-
tors as the primary contributors to non-adherence, focusing
less on healthcare system and patient-related factors [4, 23].
Healthcare system-level processes as factors in adherence
have recently begun to be explored [19]. Systems factors in-
clude quality of interactions with the healthcare team, trust in
care providers, accessibility to care providers, expertise of
individuals on the multi-disciplinary team, communication
with the team, and clinic structure, along with more global
factors such as insurance (medication and care coverage),
the culture of care, and organization of healthcare [19]. Thus
far, research in adult populations has explored how insurance
status, a poor patient–provider relationship, and the inability
of the provider to deliver optimal care influences outcomes
[30–33]. However, research on these topics in pediatric pop-
ulations is more limited, and studies of more nuanced aspects
of healthcare systems among pediatric populations are
lacking.
Problems in the system
Before examining systemic issues that lead to difficulties
treating non-adherence, it is important to note that difficulties
assessing adherence are also a concern, as there is no gold
standard for assessing adherence [34]. Some studies have
demonstrated that a combined strategy of patient self-report,
medical team collateral report, and drug assay levels has the
highest sensitivity in detecting non-adherence rates, although
it is difficult to implement such a complex analysis of non-
adherence in clinical practice [35–38]. Some researchers argue
that due to limitations associated with self-report measures,
assessment of non-adherence should be an objective measure,
such as electronic pillboxes or drug assays [39]. Further, ad-
herence research is hampered by the fact that those who are
most likely to participate in the research are also those who are
most likely to be adherent, whereas drop-out is highest among
non-adherent patients.
The complexity of the healthcare system in the USA, in-
cluding regulatory, compliance, and legal frameworks, as well
as the variations in the healthcare systems and outcomes
across the lifespan, present challenges for a pediatric patient
with a chronic illness [40]. Over one-third of child and ado-
lescent healthcare financing in the USA is provided by
Medicaid and Children’s Health Insurance Programs [41],
and the difficulty in navigating these systems is often over-
whelming for families. Although special insurance policies
and coverage exist for children and adolescents, coverage be-
comes more complicated once these benefits are discontinued
for young adults. Indeed, adults with Medicare in the USA

face a loss of immunosuppression drug coverage 3 years after
transplantation [11]. A direct association between loss of in-
surance coverage and allograft failure has been demonstrated;
a lower income zip code is also related to a significantly great-
er risk of graft loss, and patients without private health insur-
ance (who are often minorities) are at increased risk of graft
failure [42, 43]. Comparisons of the USA to other countries
demonstrate higher non-adherence with immunosuppressive
agents in North America compared to Europe where immu-
nosuppression coverage extends longer or is even universal
and where comprehensive health insurance is generally more
available [32]. Another study demonstrated decreased 5- and
10-year survival rates in the USA versus Canada, the UK, and
Australia, even controlling for differences in patient case mix
and socio-demographic characteristics [44]. Qualitative pa-
tient surveys have shown the financial hardship that immuno-
suppressive regimens place on families, and 56% of pediatric
kidney transplantation programs have indicated that >20% of
their patients had difficulty paying for their immunosuppres-
sants [45, 46]. It is likely that adults have more difficulty
paying for immunosuppressants due to fewer supplemental
insurance options for adults; therefore, young adults may be
especially at risk for non-adherence when their coverage de-
creases [47]. In addition to cost of immunosuppressive med-
ications, patients and families are burdened by additional as-
pects of the healthcare system. Remembering to order refills,
the process of ordering them, and timing of delivery for mail-
order medications is often a barrier to adherence for families
[48]. Patients can also experience limited access to specialty
medications (i.e., immunosuppression) and compounded
medications when living in rural areas and using small local
pharmacies with limited access to specialty care services [49].
Medical providers and other members as well as features of
the care team may also present barriers to successful adher-
ence. Monitoring of immunosuppression levels, blood draws
in general, and clinic appointment attendance require a signif-
icant time investment from providers, teams, and systems, not
to mention patients and families. Further, the availability and
applicability of evidence-based guidelines [50] regarding im-
munosuppression and beyond are not universal and have thus
been the subject of some debate [51–53], creating additional
uncertainty and time burdens for providers who may end up
consulting colleagues across the country for specialized or
complex cases. Lastly, despite research demonstrating that
individualizing a dosing regimen of mycophenolate mofetil
(MMF) may reduce the incidence of acute rejection and fur-
ther improve clinical outcomes after solid organ transplanta-
tion, in one study physicians were reluctant to increase doses
during a concentration-controlled trial, leading to underexpo-
sure to MMF in over 35% of patients early after transplanta-
tion and thus to an increased risk of acute rejection [13]. Lack
of gold standards for additional aspects of the medical man-
agement of adolescent kidney transplant recipients adds
Pediatr Nephrol
further complexity to care provision. One study demonstrated
inconsistent cardiovascular care among adolescents with
chronic kidney disease or a kidney transplant, showing that
only 58% of five recommended cardiovascular risk assess-
ments were documented, despite cardiovascular disease mor-
tality rates of up to 1000-fold higher in this patient population
than in age-matched peers [54]. Additional research highlights
that, despite the substantial mortality due to cardiovascular
disease in pediatric kidney transplant recipients, a concerning
lack of attention to the prevalence of metabolic syndrome, a
risk factor for cardiovascular-associated morbidity and mor-
tality in this population, exists across centers [55].
Treatment-related factors may highlight issues that pro-
viders do not always take into account when prescribing care
regimens. Research demonstrates that considerations for pa-
tients’ schedules and convenience of medication administra-
tion for an individual patient and/or family may impact adher-
ence, with increased dosing frequency and number of pills
associated with non-adherence [23, 56–58]. Medication palat-
ability and size, difficulty of administration, and timing for
morning doses are linked with non-adherence [59, 60]. The
need for frequent outpatient visits may interfere with norma-
tive adolescent activities, such as school, social events, and
extracurricular activities, and place a burden on parents who
may have to miss work, thereby further exacerbating adoles-
cent transplant recipients’ feelings of being different from
peers and potentially resulting in non-adherence with follow-
up appointments and medications [61]. Additionally,
treatment-related factors, such as body image concerns asso-
ciated with immunosuppressive medication side effects (e.g.,
growth retardation, acne, moon face, and weight gain) and
surgery scars, also may cause feelings of alienation and dif-
ference from peers [59, 62, 63]. Providers may not always be
sensitive to these various treatment-related consequences, and
adolescents may not always feel comfortable voicing their
concerns.
Follow-up appointment and medication non-adherence may
be further thwarted by a lack of trust in the medical team or lack
of consistent providers. Patients may even be given the impres-
sion that adherence is not important from the providers them-
selves, who may schedule follow-up clinic visits at the exact
time of medication administration [31]. Poor communication
between parents and the medical team is linked to non-
adherence in pediatric patients [30]. A review of the literature
on adult transplant recipients shows that aspects of a transplant
center, a poor patient–provider relationship, and an inability of
providers to deliver optimal care are systems factors related to
non-adherence (for review, see Dobbels et al. [23]). Optimal
care may not be possible when teams do not include members
of a variety of disciplines who are trained in techniques to
improve adherence, if clinic structure and follow-up frequency
are not convenient for patients, and if language barriers prevent
clear communication between provider and patient [19].
Pediatr Nephrol
Additionally, research demonstrates that transition to adult
healthcare corresponds to even poorer adherence in the ado-
lescent and young adult population, who are already at risk for
non-adherence [19]. One study of 440 kidney transplant re-
cipients demonstrated that transferring to adult healthcare be-
fore the age of 21 years was associated with a 57% higher risk
of graft failure than transition after the age of 21 years [64]; the
study also reported 29% mortality after transition [65].
However, another study of kidney transplant patients found
that adherence prior to transitioning was not significantly dif-
ferent from adherence after transitioning, although this study
was a small sample size of 25 transitioned patients [66].
Another study of 115 kidney transplant patients demonstrated
similar rates of allograft loss after transition, although the au-
thors noted that their study may not be generalizable to pa-
tients who do not have access to universal healthcare, as this
study took place in Canada [67]. Transitioning to adult
healthcare results in a change in care provider, which may
create feelings of discomfort as pediatric patients may be
followed closely by the same trusted providers for many
years, and patients may fear that adult providers will not tend
to their needs in the same manner [68–70]. In addition, tran-
sition involves an expectation of increased autonomy and self-
management of health, such as medication adherence, blood
tests, attending appointments, understanding insurance issues,
and discussing and managing one’s disease [19, 71]. Poor
preparation for transition may result in missed appointments
and non-adherence [65, 72]. Of note, being ill-prepared for
transition or having an unsuccessful transition may be a sys-
temic issue rather than a patient issue. However, the lack of
research advising transition protocols often precludes an em-
pirically based framework and standard of care [71, 73, 74].
Difficulties with communication and coordination among pe-
diatric and adult teams, lack of planning, resistance of patients
and families to transition, insufficient skills and knowledge of
health management tasks, and unclear transition timelines of-
ten set the stage for non-adherence post transition or unsuc-
cessful outcomes [75].
Solutions for the system
With recognition of the relevance of flaws in the system that
contribute to pediatric transplant patient non-adherence comes
the need for potential solutions for the system, with the search
for solutions gaining importance over interventions targeted at
the individual patient level in recent years. Research illustrat-
ing the need for overhaul of the system factors that contribute
to non-adherence has elucidated potential solutions. The
Chronic Illness Management (CIM) and Innovative Care for
Chronic Conditions (ICCC) models emphasize the impor-
tance of the healthcare organization, community, and policy
environment to improve patient outcomes, although little is
still known of practice patterns in transplant programs
[76–78]. The Building Research Initiative Group: Chronic
Illness Management and Adherence in Transplantation
(BRIGHT) study addresses the gap in investigations of sys-
tems and practice pattern factors as contributors to patient
outcomes [76]. The BRIGHT study uses a survey design in
40 adult heart transplant centers across 11 countries on four
continents to assess healthcare interventions utilized by trans-
plant centers to enhance adherence. The theoretical frame-
work of BRIGHT, which is based on Bronfenbrenner’s eco-
logical model, integrates healthcare systems factors into ex-
planations of patient behavior (i.e., how healthcare provider,
organization, and policy correlate with patient non-adherence)
[79, 80]. For example, data are collected on patient satisfac-
tion and trust in the transplant team (healthcare provider lev-
el), on whether the transplant centers meet core competencies
through the role of advanced practice nurses (healthcare orga-
nization level), and on insurance status, type of healthcare
system in each respective country, and perceived treatment-
related financial burden (healthcare system and policy level).
These data are then correlated to medication non-adherence.
However, similar extensive research on these systems-level
barriers to adherence in pediatric centers is lacking, congruent
with the fact that pediatric-focused research typically lags be-
hind adult research [81]. While extensive studies of the effi-
cacy of various solutions and interventions for each systems-
level factor have not been conducted in pediatric centers, data
from similar research on solutions in adult populations and
various interventions that have been studied among pediatric
patients provide a growing evidence base indicating the im-
portance of these investigations.
At the macro-level, improved and comprehensive user-
friendly insurance systems are necessary to address financial
barriers to adherence. Lifetime immunosuppression drug cov-
erage would address financial barriers to adherence and de-
crease the risk of graft loss and subsequent costs associated
with the return to dialysis or re-transplantation. Data show that
Medicare-insured patients have a greater risk of kidney graft
failure than those insured through private insurance that pro-
vides lifelong immunosuppressant coverage [44]. When
Medicare extended its coverage of immunosuppressive agents
from 1 year post-transplant to 3 years post-transplant, cost and
income-related disparities in outcomes among kidney graft
recipients were reduced, although Medicare patients still dem-
onstrate increased risk for kidney transplant failure after the
3 years compared to privately insured patients [44]. Further,
seamless communication between payers, providers, pharma-
cies, and patients would decrease frustrations due to delays in
care and prescription coverage. Programs such as
RationalMed® attempt to address these communication gaps
by providing comprehensive, user-friendly insurance as well
as utilizing a team of social workers, financial counselors,
drug assistance programs, and patient/family support groups

to promote access to medications [45]. In addition, many
health plans are attempting to facilitate chronic disease man-
agement through programs with healthcare providers. These
programs utilize algorithms that analyze claims data and lab-
oratory results to identify opportunities for aligning with
evidence-based practice and to identify patient adherence pat-
terns. Such reports are made available to providers within a
network. A study of adult kidney transplant patients utilized
an advanced practice nurse-led interprofessional collaborative
chronic care model and demonstrated improved clinical out-
comes compared with a traditional physician-led model [82].
A limited number of studies have demonstrated success in
adolescents with asthma [83] and Type I diabetes [84].
Extending a similar service to the transplant population
through Medicare and private insurance has the potential to
identify patients at risk for non-adherence.
Increasing education for providers, staff, and patients is a
necessary step that should be implemented systematically.
However, transplant centers tend to rely on methods aimed
to address adherence that are quick and convenient—and have
been shown to be the least effective at improving adherence—
while ignoring methods that are more effective [85]. The use
of multi-disciplinary care teams that include transplant exper-
tise in various fields, i.e., physicians, surgeons, trained nurses
(e.g., nurse practitioners and nurse coordinators), pharmacists,
social workers, and psychologists, has demonstrated im-
proved health outcomes for patients [86]. Although there is
limited data available on the evidence base of adherence in-
terventions in transplant patients, multi-component behavioral
and educational interventions have demonstrated the most ef-
ficacy to date. Dobbels et al. [87] conducted a randomized
controlled trial (RCT) investigating the efficacy of a multi-
component behavioral intervention for adult transplant pa-
tients, including electronic monitoring and feedback, goal set-
ting, action planning, and motivational interviewing, and
found improved adherence. However, there is a need for
healthcare providers, including nurses, transplant coordina-
tors, and additional team members, to be trained on
implementing these interventions more systematically and
for additional investigations on the young transplant popula-
tion. The TRANSIT study (Pediatric Heart Transplantation:
Transitioning to Adult Care [88]) is a RCT with the aim to
develop and test a standardized, tailored transition program
focused on enhancing adherence to improve outcomes for
young adults transitioning to adult care. This study is utilizing
heart transplant coordinators to support transition, with sup-
port from pediatric and adult cardiologists and mental health
professionals. The study closed recruitment and data collec-
tion in November 2016.
Centers now have detailed clinical practice guidelines for
the care of their transplant recipients prior to transition [50].
These guidelines enable consistent and comparable manage-
ment of the patients across centers rather than center-specific
Pediatr Nephrol
strategies that are perhaps based on historical and anecdotal
experience but not evidence. A recent, excellent review spe-
cifically of pediatric kidney transplantation is also available
[89]. Nonetheless, reliable implementation of current knowl-
edge and evidence-based clinical practice guidelines can re-
main a challenge for the care delivery system and therefore
requires innovative strategies for success. Such strategies are
largely based on quality improvement (QI) and have been
developed, refined, and applied in learning and care networks
for patients with conditions other than kidney disease (e.g.,
ImproveCareNow, http://www.improvecarenow.org).
Following such examples, a number of pediatric kidney
transplant programs in the USA are currently launching the
Improving Renal Outcomes Collaborative (IROC, https://
www.cincinnatichildrens.org/service/j/anderson-center/
learning-networks/active-emerging), which is intended as a
chronic care model-based learning and QI network to opti-
mize the care and outcomes for pediatric and young adult
kidney transplant recipients. One key pillar of this
Collaborative is the systematic application of pre-visit plan-
ning, a strategy that has been shown to improve a number of
aspects of outpatient care. With regards to kidney transplant
recipients, pre-visit planning has even been identified as an
important element in efforts to monitor and manage cholester-
ol [90], and it can be a forum for systematic screening of these
patients for adherence Bred flags^ (e.g., significant fluctua-
tions in medication blood levels, see below) and barriers, an
important assessment that can also be achieved during the
actual clinic visit [91].
The above-referenced clinical practice guidelines for the
care of transplant recipients [50] actually include recommen-
dations for the prevention, detection, and treatment of non-
adherence (as do several more recent publications [92–95])
and strategies to reduce drug costs (which can be prohibitive
and thus be related to non-adherence). Reducing the number
and frequency of medications is one of several suggestions for
improving medication adherence, but this strategy is of limit-
ed utility in pediatric kidney transplantation as several drugs
(such as extended-release tacrolimus or belatacept [96, 97])
that can simplify recipients’ regimens may not have regulatory
approval for use in children in a number of countries, nor may
they be supported by insurance plans or relevant practice
guidelines. That being said, conversion studies to once-daily
tacrolimus in pediatric kidney and liver transplant recipients
have demonstrated similar pharmacokinetic profiles as twice-
daily tacrolimus formulations, supporting the potential use of
these agents in the pediatric population [98, 99]. Just once-
daily dosing of immunosuppressants (and ideally other med-
ications) could otherwise also be accomplished by applying
outcomes data that question long-term superiority of twice-
daily mycophenolic acid over its once-daily predecessor aza-
thioprine [100]. A comprehensive comparison of these two
agents has recently been published [101].
Pediatr Nephrol
There continues to be a need for additional effective multi-
pronged interventions addressing systems-level barriers to ad-
herence. Research to date has focused more on patient-level
factors, and there is a lack of RCTs determining the effective-
ness of these programs; however, in general, adherence inter-
ventions for pediatric patients of other chronic illnesses that
utilize behavioral or multi-component interventions have
proven to be the most effective per a meta-analysis by
Kahana et al. [102]. A recent RCT including adult heart, liver,
and kidney transplant patients demonstrating a theory-based
multi-component medication adherence intervention (utilizing
motivational interviewing and behavioral change techniques)
resulted in increased post-intervention adherence as well as 6-
month follow-up adherence and 5-year clinical event-free sur-
vival [87]. Studies have also shown that the use of a Bpersonal
trainer,^ who is outside of the healthcare team, and text mes-
sage reminders also improve adherence [103, 104]. The Teen
Adherence in Kidney Transplant, Effectiveness of
Intervention Trial (TAKE-IT) study addresses the lack of ran-
domized controlled prospective trials by implementing and
evaluating a clinic-based intervention that includes education-
al, organizational, and behavioral components [105].
Participants meet with a study Bcoach^ who addresses the
participants’ personalized barriers to adherence and helps
them set goals. Participants also use an electronic pillbox, with
data sent to the study team so the coach can provide person-
alized adherence feedback via text messages, emails, or visual
cue dose reminders [105].
The recent focus on investigating systems-level issues has
led to attention being paid to targeted interventions. For ex-
ample, business models for pharmacies have begun to address
systems-level issues, such as difficulties accessing and
refilling transplant medications, affordability of high-cost
medications, gaps in prescription insurance coverage, and
continuity of care.
In fact, many healthcare plans and health systems have iden-
tified the need for targeted pharmacy services for high-risk and
chronic disease states and have employed specialty pharmacy
services for these populations. Beyond traditional medication
dispensing, specialty pharmacies can provide patient education,
financial coordination, refill reminders, and proactive adher-
ence monitoring and screening. When appropriate, specialty
pharmacies will contact the healthcare providers to communi-
cate clinical concerns and facilitate interventions to address
non-adherence [106]. Success with these programs with
regards to adherence, positive outcomes, and revenue genera-
tion are well documented for several disease states, particularly
with oncology practices [107]. An analysis of transplantation
specialty pharmacy services for adult transplant recipients with-
in a single healthcare center demonstrated significant reduc-
tions in non-adherence rates from 33.3% to as low as 4.2%
for transplant immunosuppression medications following the
implementation of a specialty pharmacy program [108].
Additional resources and tools are available to patients for
improving access to medication and adherence that can be
tailored to fit their needs. Capsule Pharmacy© (New York,
NY) is a digital pharmacy startup that manages prescriptions,
delivers to patients’ homes, and provides access to pharma-
cists via in-app chat, although it is currently only available in
New York City [109]. Round Refill© is a smart bottle that
lights up at medication administration time and records when
it is opened, syncing wirelessly with a smartphone [110]. The
service includes home delivery. However, it is also not widely
available and requires signing up and paying an extra fee on
top of co-pays. PillPack© (Manchester, NH) increases conve-
nience when there are multiple medications per day by sepa-
rating and organizing medications by date and time and deliv-
ering them to patient homes; however, it does not account for
frequent changes in dose or medications that transplant pa-
tients often endure [111].
In this electronic era, technological interventions prove to
be particularly relevant and interesting to pediatric and ado-
lescent patients. SMS text message reminders regarding med-
ication administration have been shown to improve adherence
outcomes [112], and Smartphone adherence applications have
grown in popularity, with over 400 options on the market as of
June 2014. Transplant-specific mobile health applications de-
signed to support medication adherence in adolescent trans-
plant recipients are currently under evaluation as well [113]
(e.g., Transplant Hero™ [114]). To address varying quality
and the health literacy level of these applications, a website
was created to aid in evaluating and rating these resources
(www.medappfinder.com) [115]. Systems and tools that
leverage technology are easily disseminated to the public
and have the potential to increase adolescent renal transplant
patient adherence.
In addition to promoting patient adherence, resources that
can also accurately report adherence rates directly to providers
are desirable. In 2012, the Ingestion Event Marker, a novel
technology created by Proteus Biomedical, received approval
by the Food and Drug Administration. This system is com-
prised of an ingestible sensor embedded within a medication
that is activated following medication administration and then
communicates with an adhesive sensor worn on the skin.
Information sent to the sensor is then available to providers
on a cloud-based system. Successful application of this system
has been documented in adult kidney transplant recipients
with overall adherence rates exceeding 99% during a 12-
week pilot study [116]. However, the system requires adher-
ence to wearing the sensor, and this study documented a 40%
rate of discontinuation due to issues with using and tolerating
the system. Some pediatric transplant centers have begun to
test this system in trials in their patient population, but pub-
lished results are not available at this time [117].
Targeted transition programs and interventions have also
begun that show promising preliminary results. Annunziato

et al. [71] conducted a survey of healthcare management be-
haviors in pediatric patients and then implemented a compre-
hensive clinical protocol, including a transition checklist and
close follow-up and coordination with a transition coordinator
at both the pediatric and adult centers. Another study has
begun implementing pre-transplant, post-transplant, and late
transplant education sessions aimed at improving adherence
and optimizing transition for 13- to 25-year-olds and has de-
termined excellent feasibility and acceptability [118]. The use
of peer networks and mentoring also has important implica-
tions [119]. One study used community-based clinics and peer
support and demonstrated improved outcomes over a 4-year
period, including no graft loss for 12 patients versus 67% graft
loss for nine patients who did not undergo the protocol [120].
It has also been shown that there are benefits not only to
recipients, but also to peer mentors themselves—peer mentors
who assumed leadership roles in supporting younger trans-
plant patients demonstrated clinically significant decreases in
the standard deviation of their trough tacrolimus blood levels,
and the program was generally feasible and acceptable for the
mentors [121].
Telehealth is another promising modality that may help to
improve adherence in transplant patients. Advancements in
technology have resulted in more sophisticated, cheaper, more
user-friendly, and far more broadly-applied applications of
telehealth [122, 123]. Telehealth reduces costs for patients
and holds the promise of cost-reduction for providers and
healthcare systems alike [124–126]. Patients are usually very
comfortable in communicating with providers through
telehealth, and most have the required technology [127].
Telehealth and videoconferencing technology have been dem-
onstrated to be acceptable, feasible, and effective for patients
with chronic illnesses [128], and telehealth has been utilized
with individual adult transplant recipients [129–131].
Blumenthal and colleagues [129] found that a telephone-
based coping intervention can be effectively delivered to pa-
tients awaiting lung transplantation to improve their quality of
life. Leimig and colleagues [130] have utilized telehealth to
conduct live interactive appointments with digitized equip-
ment to perform physical examination of post-transplant pa-
tients who have received kidney, liver, or kidney/pancreas
transplants. They have found no difference in infection rates,
rejection episodes, and hospitalizations when conducting
follow-up visits via telehealth as compared to standard post-
transplant care. Notably, the telehealth visits allowed for min-
imally disruptive healthcare. When Thompson and colleagues
[131] reviewed the ability to screen for depressive symptoms
and to determine if patients that are participating in telehealth
visits might be more likely to experience depressive symp-
toms, they found that they were able to screen and evaluate
via telehealth and that there was no difference in depressive
symptoms between telehealth and standard care on these do-
mains. Another interesting telehealth study, conducted with
Pediatr Nephrol
adults who had received stem cell transplants, implemented
a clinic-based videoconferencing psychoeducational support
group with good patient satisfaction, attendance, and feasibil-
ity [132]. This study also showed reduced cost to patients,
patient comfort with technology, and group cohesion through
the videoconferencing medium.
Telehealth has also been used to improve adherence for
patients with chronic medical conditions. Hommel and his
colleagues have described multi-component behavioral inter-
ventions with adolescents and their caregivers targeted at im-
proving adherence through behavior modification, problem-
solving, and monitoring through both individual family inter-
ventions [133] and multi-family group interventions [134] in
patients with inflammatory bowel disease. They expanded this
service to include individual family interventions delivered
via videoconferencing and found the medium to be feasible
and acceptable to patients and caregivers [135]. Our research
team has developed a home-based group telehealth interven-
tion to address medication adherence for adolescent heart,
kidney, and liver transplant recipients. We implemented a
five-session telehealth group intervention targeting medica-
tion adherence in adolescent transplant recipients via a secure,
videoconferencing platform. Early analyses suggest that this
group is acceptable and feasible. Implementation of telehealth
group interventions has the potential to expand services and
improve outcomes for transplant recipients, providing an in-
novative solution to barriers to quality care.
Future directions
Non-adherence remains a tremendous challenge in pediatric
and young adult kidney transplantation and beyond. While
non-adherence has typically been viewed as predominantly
patient- and family-related, it is now abundantly clear that
the various components of the healthcare system required for
these patients and families can also be non-adherent.
Moreover, such Bsystem non-adherence^ negatively affects
outcomes and is difficult to overcome within traditional care
delivery models. Accordingly, sustained and innovative ef-
forts are needed to improve the care system’s ability to assure
optimal outcomes in kidney transplantation: First, refinement
and use of reliable and valid measures of adherence (objective
and subjective) and post-transplant outcomes, a variety of
medical and psychosocial outcomes assessments, and collab-
oration across multiple transplant centers will hopefully help
overcome past and present limitations. Second, continued de-
velopment of interventions, such as adherence education pro-
grams for healthcare teams, peer mentoring, technological in-
terventions, transition protocols, and evidence-based medical
management of kidney transplant, are necessary on a larger
scale and as critical parts of outcomes-driven research. Third,
there is a need for longitudinal tracking of changes in
Pediatr Nephrol
adherence, adherence trajectories, and the efficacy of systems-
level interventions, as much of the little research data currently
available are of cross-sectional nature. Lastly, further devel-
opment and reliable implementation of systems-level proto-
cols for pediatric kidney transplant centers leveraging addi-
tional and novel strategies, such as QI principles and modern
communication technologies, should lead to improved clinical
outcomes in this population.
Authors’ contributions All authors listed have made substantial, direct,
and intellectual contributions to the work, and approved it for publication.
Compliance with ethical standards
Conflict of interest All authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
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