Nephrol Dial Transplant (2020) 1–14

doi: 10.1093/ndt/gfaa016

An overview of frailty in kidney transplantation: measurement,

management and future considerations

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REVIEW
Meera N. Harhay 1,2,3,*, Maya K. Rao4,*, Kenneth J. Woodside5,*, Kirsten L. Johansen6, Krista L. Lentine7,
Stefan G. Tullius8, Ronald F. Parsons9, Tarek Alhamad10, Joseph Berger11, XingXing S. Cheng12,
Jaqueline Lappin13, Raymond Lynch9, Sandesh Parajuli14, Jane C. Tan12, Dorry L. Segev15,16, Bruce Kaplan17,
Jon Kobashigawa18, Darshana M. Dadhania 19,* and Mara A. McAdams-DeMarco 15,16,*
1
Department of Medicine, Division of Nephrology, Drexel University College of Medicine, Philadelphia, PA, USA, 2Department of Epidemiology
and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA, USA, 3Tower Health Transplant Institute, Tower Health
System, West Reading, PA, USA, 4Division of Nephrology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA,
5
Department of Surgery, University of Michigan, Ann Arbor, MI, USA, 6Hennepin Healthcare, University of Minnesota, Minneapolis, MN,
USA, 7Center for Abdominal Transplantation, St Louis University School of Medicine, St Louis, MO, USA, 8Department of Surgery, Division of
Transplant Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, 9Department of Surgery, Emory University
School of Medicine, Atlanta, GA, USA, 10Division of Nephrology, Washington University School of Medicine, St Louis, MO, USA, 11Department
of Internal Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, TX, USA, 12Department of Medicine, Division of
Nephrology, Stanford University School of Medicine, Palo Alto, CA, USA, 13St. David’s North Austin Medical Center, North Austin, TX, USA,
14
Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA,
15
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 16Department of Epidemiology, Johns Hopkins
Bloomberg School of Public Health, Baltimore, MD, USA, 17Vice President System Office, Baylor Scott and White Health, Temple, TX, USA,
18
Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA and 19Department of Transplantation Medicine, New
York Presbyterian Hospital - Weill Cornell Medical Center, New York, NY, USA

*These authors contributed equally to this work.

Correspondence to: Meera N. Harhay; E-mail: mnh52@drexel.edu; Twitter handles: @MeeraHarhay;
@McAdamsDeMarco; @KristaLentine; @ronaldfparsons; @Dorry_Segev

ABSTRACT practice, underscoring the need for a disease-specific frailty

The construct of frailty was first developed in gerontology to
help identify older adults with increased vulnerability when
confronted with a health stressor. This article is a review of
studies in which frailty has been applied to pre- and post-
kidney transplantation (KT) populations. Although KT is the
optimal treatment for end-stage kidney disease (ESKD), KT
candidates often must overcome numerous health challenges
associated with ESKD before receiving KT. After KT, the
impacts of surgery and immunosuppression represent addi-
tional health stressors that disproportionately impact individu-
als with frailty. Frailty metrics could improve the ability to iden-
tify KT candidates and recipients at risk for adverse health
outcomes and those who could potentially benefit from inter-
ventions to improve their frail status. The Physical Frailty
Phenotype (PFP) is the most commonly used frailty metric in
ESKD research, and KT recipients who are frail at KT (~20% of
recipients) are twice as likely to die as nonfrail recipients. In ad-
dition to the PFP, many other metrics are currently used to as-
sess pre- and post-KT vulnerability in research and clinical
metric that can be used to monitor KT candidates and recipi-
ents. Although frailty is an independent risk factor for post-
transplant adverse outcomes, it is not factored into the current
transplant program risk-adjustment equations. Future studies
are needed to explore pre- and post-KT interventions to im-
prove or prevent frailty.
Keywords: aging, frailty, kidney transplantation, physical
function, survival
INTRODUCTION
Frailty is a syndrome characterized by diminished strength, en-
durance and reduced physiologic function, increasing an indi-
vidual’s vulnerability for developing increased dependency and/
or dying when confronted with a stressor [1]. The construct of
frailty was first established by geriatricians and gerontologists
who identified the need to distinguish the physiological age
from the chronological age of older adults [2]. Metrics of frailty

C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
V 1
were developed to improve the ability to accurately identify the
most vulnerable individuals in older populations by going be-
yond traditional risk factors such as age and comorbidity. In re-
cent years there has also been a proliferation of research on
frailty in nonelderly populations and in numerous medical
subpopulations, including those with kidney disease and solid
organ transplants [3, 4].
In kidney transplantation (KT), clinical care paradigms are
adapting to an aging transplant candidate pool [5–7] and in-
creasing waiting times [8, 9]. These trends underscore the need
to accurately identify KT candidates and recipients who are at
higher risk of adverse outcomes when facing health stressors,
including the surgical and immunologic stressors of KT. Some
experts suggest that a patient’s frailty status could inform
decisions about the referral, evaluation and management of
KT candidates as well as optimal rehabilitation plans after
transplant surgery [10, 11].
In this review we summarize available tools to measure
frailty. We then discuss the impact of frailty on access to KT
and on morbidity and mortality before and after KT. Next, we
consider topics relating to the immunosuppressive manage-
ment of frail KT recipients and examine the most recent
data on interventions to improve frailty. Finally, we emphasize
key areas in which research is needed to improve the identifica-
tion and clinical management of frailty in the KT patient
population.
METHODOLOGY
In 2017, members from the American Society of
Transplantation (AST) Kidney Pancreas Community of
Practice (KPCOP) formed a Frailty Work Group with the goal
of summarizing the current literature on frailty metrics, the im-
pact of frailty on end-stage kidney disease (ESKD) and KT pop-
ulations and potential interventions and areas for additional
research. This project was part of a larger AST initiative to build
consensus related to frailty measurement and care in solid or-
gan transplantation [4]. We first conducted a PubMed search
for literature on relevant topics in frailty, including search
terms such as ‘frail elderly’, ‘frail instrument’ and ‘kidney trans-
plant’. Our search strategy yielded 641 unique articles. We sup-
plemented this search with searches in the EMBASE,
Community Index to Nursing and Allied Health Literature and
Cochrane databases. An updated search of the PubMed
database was also performed in April 2019. Members of the
KPCOP Frailty Work Group were divided into six subgroups
of three to four individuals who reviewed the literature on a
specific subtopic and created a summary. The information
was shared with the KPCOP Frailty Work Group via a series
of teleconferences and web-based communications from
August 2017 to February 2018. The products of the sub-
groups were collated into a single harmonized manuscript by
three primary authors (M.N.H., M.K.R. and K.J.W.) and two
senior authors (M.M.D. and D.M.D.). A complete draft
was circulated to the work group for feedback and revision,
resulting in the final review manuscript. All authors had
2 M.N. Harhay et al.
continuous access to the working documents to provide in-
put, critical review and revisions.
IDENTIFYING FRAILTY IN KT CANDIDATES
AND RECIPIENTS
Instruments to measure frailty
Although there is an agreement regarding the underlying
conceptual framework of frailty, there is a low level of consen-
sus regarding the constituent elements to be included in
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operational definitions of frailty [12, 13]. At least 67 different
frailty scales have been used in population-based studies [14,
15], and there is similar heterogeneity in studies of patients with
ESKD [16]. In Table 1, we summarize a nonexhaustive list of
the available frailty instruments that have been applied to popu-
lations with chronic kidney disease (CKD), dialysis dependence
and KT. Instruments were included if they have been applied to
patients with ESKD in at least one study of prevalence and/or
outcome prediction. As in the geriatric arena, the PFP, origi-
nally described by Fried et al. in 2001 [17], has emerged as the
most commonly applied frailty assessment in studies of patients
with ESKD [16]. The PFP includes five domains: weakness,
slowness, unintentional weight loss, exhaustion and low
physical activity. Individuals who meet three or more of these
criteria are at high risk of adverse outcomes when faced with
health stressors. A number of factors such as advancing age,
comorbidities, polypharmacy and malnutrition contribute to
this phenotype among individuals with ESKD, exacerbating
vulnerability to illness and to treatment interventions such as
dialysis, transplant surgery and immune therapy (Figure 1).
Although there are several validated, self-reported instru-
ments that are simpler to apply in clinical settings than the PFP
[e.g. the Kidney Disease Quality of Life Short Form Physical
Component Subscale (SF-12 PCS)] [51], there are potential
trade-offs in utilizing assessments that may not directly assess
physiologic reserve. Conversely, as the KT evaluation setting
might make some patients reluctant to reveal the extent of their
functional limitations to KT providers, a purely objective frailty
instrument, such as the Short Physical Performance Battery
[52], may be desirable. The vast number of available frailty met-
rics and the differences between them underscore the impor-
tance of developing more unified measures to assess
vulnerability across the broad population of KT candidates and
recipients.
In a national survey of 133 KT centers representing 79% of
all adult KT candidates in the USA [53], there was substantial
heterogeneity in the metrics used in clinical settings to assess
pre-KT frailty (n ¼ 18 distinct metrics). The majority of centers
(67%) reported utilizing more than one frailty metric in their
transplant evaluation process and the most common metric uti-
lized by KT centers was a timed walk test (19%) (Table 1). The
variability in KT center practices with respect to measurement
and utilization of frailty instruments is likely a result of the lack
of consensus in the transplant community about how frailty
should be assessed. Accordingly, a recent AST consensus
Table 1. Summary of commonly utilized frailty and functional metrics in studies of dialysis and KT populations

Frailty indicator Components Limitations Scoring Populations studied

Clinical frailty scale 8-point scale with brief descriptions based Subjective From 1 (very fit) to 8 Incident dialysis [19]
[18] on clinical interview that takes into Does not include multimor- (very severely frail)
account: bidity but does include
Mobility; energy; physical activity; disability
function
Physical frailty pheno- Five components: Subjective and objective Score 0–5; KT [2026]
type [17] Shrinking (i.e. unintentional weight loss); components 0 ¼ Robust Prevalent hemodialysis [27, 28]
exhaustion; physical inactivity; weakness; 1–2 ¼ Intermediate Incident dialysis [29]
slowness 3 ¼ Frail

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Groningen frailty 15 items: mobility [4]; self-rated physical Subjective and objective Scores 0–15 Predialysis clinic [31]
indicator [30] fitness [1]; vision [1]; hearing; nourish- components Predialysis and prevalent dialysis
ment [1]; morbidity [1]; cognition [1]; Includes morbidity and [32]
psychosocial [5] disability Incident dialysis [29]
Prevalent dialysis [33]
Tilburg frailty 15 components: physical [8]; psychologic Subjective Scores 0–15 Prevalent dialysis [33]
indicator [34, 35] [4]; social [3] Does not include morbidity
or disability
Frailty index [36, 37] Deficit accumulation, including comorbid Components vary 0–1, scored as the num- Predialysis and prevalent
illness, poor health attitudes, signs Includes multimorbidity and ber of deficits present dialysis [32]
of disease and self-reported disabilities; disability divided by the total
40–70 deficits typically included number assessed
Edmonton frail Eight items: cognition; general health Subjective and objective Scores 0–17; >7 ¼ frail Prevalent dialysis [33]
scale [38] status; functional independence; social Includes morbidity and
support; medication use; nutrition; disability
mood; continence; functional
performance
FRAIL scale [39] Five domains: Fatigue; resistance (ability to Subjective Scores 0–5; Prevalent dialysis [33]
climb one flight of stairs); ambulation Includes morbidity and 0 ¼ not frail
(ability to walk 1 block); illnesses (>5); disability 1–2 ¼ pre-frail
loss of weight (>5%) 3 ¼ frail
1994 frailty measure 16 items, including 4 domains: physical Subjective Score of 3 on any item- Prevalent dialysis [33]
or Strawbridge functioning [4]; nutritive functioning [2]; Does not include morbidity ¼ problem or difficulty
questionnaire [40] cognitive functioning [4]; sensory prob- or disability with that domain;
lems [6] frail ¼ difficulty in 2
domains
SF-12 PCS 12-item assessment of physical functioning. Subjective 0–100 (lower Prevalent dialysis [41, 42]
Subscale of the Kidney Disease Quality score ¼ worse PF) KT [43]
of Life-36 instrument
SPPB [44] Three items: balance; chair standing; Does not include Scores 0–12 KT [45, 46]
gait speed multimorbidity or
disability
Timed up and go [47] Standing from chair, walking a short Does not include Score in seconds KT [48]
distance, returning and sitting multimorbidity or
disability
Gait speed [49] Timed walking over a short distance Does not include Score in seconds or ESKD [50]
multimorbidity or meters per second
disability

statement opined that organ system–specific frailty assessments
are likely needed [4].
PRETRANSPLANT FRAILTY: PREVALENCE,
RISK FACTORS AND OUTCOMES
Prevalence of frailty in populations with CKD and
ESKD
People with CKD and ESKD have a high prevalence of
frailty: there is 15–21% frailty prevalence in the CKD popula-
tion versus 3–6% in the general population [54, 55]. Among
dialysis-dependent individuals, the prevalence of frailty is likely
higher, ranging from 14 to 73%, and is common among those
<40 years of age (63%) [16, 56]. These data suggest that the
prevalence of frailty is high among all KT candidates, including
pre-emptive candidates and younger candidates.
Individuals who are referred for KT evaluation are likely to
be healthier than the overall population of individuals with
ESKD, and those who are selected for KT waitlists may be
healthier still. A large multicenter study identified 18% of indi-
viduals as frail at the time of initial evaluation, while only 12%
of individuals were identified as being frail among those who
were ultimately listed for KT [57]. Furthermore, frailty status
may change considerably from the time of listing to the time of
KT. For example, in a single-center study of 569 adult KT can-
didates, 22% of the cohort was more frail at the time of KT than
at the time of KT evaluation, whereas 24% were less frail at KT
[58]. Approximately 20% of KT recipients are frail at the time
of KT [59], and the frailty components most commonly

Review of frailty and KT 3

observed in this population are weak grip strength (50%) and
low physical activity (49%) [59]. Given the dynamic nature of
frailty, periodic reassessments of frailty may be warranted prior
to the surgical stressor of KT.
Risk factors and correlates for frailty
Many of the risk factors for frailty in potential KT candidates
are not modifiable (Figure 2). For example, studies have consis-
tently shown that KT candidates of advanced age and female
sex are more likely to be frail than younger candidates and
defined by cystatin-based glomerular filtration rate (GFR) cal-
culations [66]. However, the association between CKD stage
and frailty is attenuated when GFR is estimated using creatinine
as opposed to cystatin C, a finding that is potentially explained
by the relation of creatinine to muscle mass (i.e. lower serum
creatinine may reflect sarcopenia). Therefore creatinine-based
estimated GFR (eGFR) may overestimate actual GFR in frail
people with sarcopenia, an important consideration given that
waiting time for deceased donor KT (DDKT) cannot be accrued
in the USA until individuals have eGFRs 20 mL/min/1.73 m2.

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males, respectively [57, 60, 61]. However, other risk factors,
such as obesity and low physical activity, might be modifiable.
With respect to correlates of frailty, although higher comorbid-
ity burden is also a risk factor for frailty among KT candidates,
frailty can also occur in the setting of lower comorbidity bur-
dens [62]. Diabetes and serum albumin concentration are also
associated with frailty among prevalent dialysis patients [63]
and individuals with CKD and ESKD who are frail are also
more likely to have cognitive impairment and sarcopenia, or
low muscle mass, than their nonfrail counterparts [64, 65].
Among individuals with nondialysis-dependent CKD, the
risk of frailty has an inverse relationship with CKD stage, as
Among those who are dialysis-dependent, it is unclear
whether dialysis itself improves or worsens frailty. Multiple
studies have shown a decline in functional status in older adults
who initiate dialysis [67, 68]. In a longitudinal study that mea-
sured frailty in a dialysis cohort of 762 subjects, most subjects’
scores changed from year to year [63]. However, improvement
in frailty was as common as the worsening of frailty. With re-
spect to modality of renal replacement therapy, several recent
studies have suggested that frailty and functional impairments
are similarly prevalent among patients with ESKD who receive
hemodialysis, peritoneal dialysis and conservative care [69–71].
Studies are needed to determine whether dialysis treatment–
related interventions (e.g. parenteral nutrition and duration of
treatment) could improve frailty.

Outcomes of frailty in populations with nondialysis-

Acute Aging dependent CKD and dialysis dependence
Surgical
illnesses stressors
Potential KT candidates with frailty are at high risk of multi-
ple adverse health outcomes. In a cohort of 336 subjects with
Anemia nondialysis-dependent CKD, the proportions of frail individu-
Slowness S
s als who had impairment in at least one activity of daily living,
hr
es

instrumental activity of daily living and mobility were 15, 60

ink
Weakn

Malnutrition
ing

and 40%, respectively, compared with 5% (P ¼ 0.009), 28%

Polypharmacy Frailty
Comorbid (P < 0.001) and 18% (P ¼ 0.001), respectively, among those
ti o n

without frailty [72]. Frailty is also an independent risk factor for

Lo

conditions
us
w

p hospitalization [27, 56, 73] and doubles the risk of death among
ct h y si ha
Ex
a

iv i c
Cognitive ty a l Immune therapy
individuals with ESKD and KT [19, 27, 54, 56, 72–74]. Slow gait
impairment speed [50, 74], immobility [75] and poor physical function (PF)
[76] have also been associated with a higher risk of death in
Dialysis
both CKD and ESKD. In a study of 311 subjects with nondialy-
sis-dependent CKD, the 6-min walk distance had the highest
discriminative accuracy for 3-year mortality farea under the
curve [AUC] 0.80 [95% confidence interval (CI) 0.70–0.90]g,
FIGURE 1: Frail individuals are most vulnerable to the numerous followed by gait speed [AUC 0.78 (95% CI 0.70–0.86)] and
health stressors of kidney disease. timed up and go [AUC 0.74 (95% CI 0.64–0.84)]. Each of these

CKD progression
Age Cognitive impairment Death
Diabetes/other co-morbidities Disability Falls
Risk Female sex Frailty Low albumin Outcomes Fractures
factors Lower eGFR/proteinuria correlates Multiple comorbidities Hospitalizations
Obesity Polypharmacy Poor HRQOL
Sarcopenia Reduced access to KT

FIGURE 2: The continuum of frailty in kidney disease. The figure displays current knowledge on the risk factors, correlates and outcomes of
frailty among individuals with kidney disease.

4 M.N. Harhay et al.

physical performance tests had an AUC that was superior to
commonly measured biomarkers of CKD, including eGFR, se-
rum bicarbonate, hemoglobin, C-reactive protein and albumin
[74]. Therefore, knowledge of frailty could inform shared
decision-making about the risks and benefits of KT between po-
tential KT candidates and their providers beyond the standard
biomarkers that are commonly assessed and reviewed.
Frailty and access to KT
Among individuals who are being evaluated for KT, frailty is
associated with reduced access to the waiting list and higher
waiting list mortality. In a study of 7078 individuals who were
evaluated at three transplant centers between 2009 and 2018,
frail individuals were almost half as likely as nonfrail individuals
to be placed on a KT waiting list [hazard ratio (HR) 0.62 (95%
CI 0.56–0.69)] [57]. In another study of 128 individuals who
were evaluated for KT, 30.4% of frail individuals were subse-
quently listed for KT, compared with 57.6% of nonfrail individ-
uals [77]. Among those who are successfully wait-listed, frail
KT candidates may be more likely to be inactive, less likely to
receive KT [51] and more likely to die while wait-listed than
nonfrail KT candidates [61]. Healthcare utilization might be an-
other useful proxy for frailty in predicting waiting list outcomes:
compared with listed KT candidates with no hospitalization
days in the first year after listing, a study of 51,111 wait-listed
individuals in the USA found that candidates with 15 hospi-
talized days had a >2-fold risk of subsequent waiting list mor-
tality [HR 2.07 (95% CI 1.99–2.15)] [78].
POTENTIAL ROLES FOR FRAILTY METRICS
IN PRE-TRANSPLANTATION SETTINGS
KT candidate assessment
Given the extent to which KT candidate selection relies on
provider perceptions of patients, clinicians who rely solely on
clinical acumen for health surveillance of their KT candidates
may be likely to misclassify some patient subgroups as frail. In a
study of 146 hemodialysis patients from a single dialysis facility,
investigators assessed agreement between measured frailty using
the Fried et al. criteria to nephrologists’ subjective ratings of pa-
tient frailty. Nephrologists were inaccurate in their ratings of
frailty in 37% of cases, and older adults were the patient sub-
group that was most likely to be misclassified as frail [79].
Misclassification of frailty could have large implications for ac-
cess to KT, as individuals who are inaccurately deemed ‘too old,
ill or frail’ to undergo KT may be less likely to receive transplant
education or referral as a result [79–82]. To minimize frailty mis-
classification that may improperly restrict access to KT, nephrol-
ogists may consider augmenting their clinical assessments of
potential KT candidates with direct and objective measures of
frailty, particularly among older individuals with ESKD.
Unintended consequences: frailty assessments and
transplant center practices
Knowledge of frailty in the KT evaluation and selection pro-
cesses may help to promote individualized care of the most vul-
nerable patients, permitting timely interventions to improve
Review of frailty and KT
functional status and listing outcomes [83–85]. However, con-
cerns arise about the potential of unintended consequences
when integrating frailty assessments into the KT evaluation
process. Earlier in this article, we described evidence that frail
individuals with ESKD may still receive a substantial survival
benefit from KT compared with remaining on dialysis [51], and
that frailty is potentially reversible with successful KT [20].
Indeed, data suggest that selected older patients and those with
long dialysis exposures who receive KT are likely to have better
survival and quality of life than similar patients who do not re-
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ceive KT [86, 87]. However, among US KT programs that use a
frailty metric during KT candidate assessments, 53% reported
that they were less likely to list a frail KT candidate for trans-
plant [53]. These findings have led to concerns that until
transplant programs are no longer disincentivized from
accepting high-risk KT candidates, individuals with ESKD
who are assessed (accurately or inaccurately) to be frail will
have reduced access to KT [11].
Longevity matching
Given the independent association between frailty and sur-
vival, another potential role of frailty metrics is to improve
efforts to maximize utility in organ allocation. The revised US
Kidney Allocation System (KAS) incorporated a continuous
scale called the Estimated Post-Transplant Survival (EPTS) to
facilitate allocation of the highest quality deceased donor organs
to recipients who are expected to live the longest (i.e. ‘longevity
matching’) [88]. Under the revised KAS, candidates with the
longest predicted post-transplant survival (EPTS 20%) are
prioritized for kidneys from donors ranked as ‘top 20%’ highest
quality based on the Kidney Donor Profile Index. The EPTS is
based on candidate age, duration of dialysis, diabetes and prior
solid organ transplant status, and has a C-statistic of 0.69 (i.e.
considered ‘good’ discriminatory ability) [89]. An important
area for future research is to examine whether the inclusion of
frailty may improve the current longevity matching paradigm.
POSTTRANSPLANT FRAILTY: EARLY AND
LATE OUTCOMES
Early outcomes among frail KT recipients
Increasing evidence suggests that frail KT recipients are
more vulnerable to the immediate surgical and immunologic
stressors of KT than nonfrail recipients (Table 2). In a prospec-
tive cohort study of 183 KT recipients transplanted between
2008 and 2010, frailty was independently associated with a
nearly 2-fold higher risk of delayed graft function (DGF) [ad-
justed relative risk (aRR) 1.94 (95% CI 1.13–3.36)] [21]. Frailty
is also associated with a 2-fold higher risk of post-KT delirium
[aOR 2.05 (95% CI 1.02–4.13)] [90]. These findings suggest that
frail KT candidates are likely to require more support during
their initial KT hospitalization.
Frail KT recipients and those with physical impairments
are also likely to have higher healthcare utilization post-KT.
For example, lower extremity impairment at the time of KT,
objectively measured by the Short Physical Performance
Battery (SPPB), is associated with a longer hospital length of
5
Table 2. Studies that have evaluated the association between frailty (and related constructs) and post-transplant outcomes

References Design and participants Frailty measure Frailty distribution Correlates of frailty Outcomes
Garonzik-Wang Prospective cohort Physical frailty pheno- Frailty at KT: 25% Baseline demographics, DGF: 30% versus 15% in frail
et al. [21]a 183 KT recipients at 1 type defined as score (46/183) diabetes prevalence versus nonfrail KT recipients
US center (December 3 and donor traits were Frailty was independently associ-
2008–April 2010) similar in frail and ated with twice the risk of
35% LDKT nonfrail recipients DGF [aRR 1.94 (95% CI 1.13–
3.36)]
McAdams- Retrospective cohort Physical frailty pheno- Frailty at KT: 19% Frail sample includes Frail KT recipients were more
DeMarco 383 KT recipients at 1 type defined as (72/383) more males likely to experience EHR

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et al. [22]a US center (December score 3 (71% versus 58%, within 30 day (46% versus
2008–December 2012) P ¼ 0.046) 28%, P ¼ 0.005), regardless
39% LDKT of age
After adjusting for previously
described registry-based risk
factors, frailty predicted 61%
higher risk of EHR [aRR 1.61
(95% CI 1.18–2.19)]
McAdams- Prospective cohort Physical frailty pheno- Frailty over time: Frailty scores typically worsen
DeMarco 349 KT recipients at 1 type defined as score At KT: 20%; at 1-month post-KT (mean
et al. [20]a US center (December 3 1 month: 33%; change þ0.4, P < 0.001), and
2008–March 2014) 2 months: 28%; improved by 3 months
37% LDKT 3 months: 17% post-KT (mean change 0.3,
P ¼ 0.04)
Recipients frail at time of KT
were more than twice as likely
to improve in post-KT frailty
than nonfrail recipients [aHR
2.55 (95% CI 1.17–3.82)]
Reese et al. [41] Retrospective cohort SF-36 PF subscale quar- Median (IQR) After KT, lower PF score was as-
19 242 KT recipients in tile (SF-12 PCS), ad- subscale score: 55 sociated with shorter 3-year
US with linked ministered on dialysis (35–80) survival (84% versus 92% for
Fresenius dialysis (before listing and the lowest versus highest
records time-updated) function quartiles)
10% LDKT Compared with dialysis, KT was
associated with a statistically
significant survival benefit by
9 months for patients in every
SF-12 PCS quartile
Harhay Retrospective cohort SF-36 Physical Function 28% with 1 pre-KT Lower PF score was associated
et al. [43] 8870 hemodialysis subscale quartile (SF- hospitalization with 1.24-fold EHR risk
patients who received 12 PCS), administered compared with higher quartiles
KT in US—dialysis on dialysis (before (aOR 1.08–1.43)
records linked to listing) More than one pre-KT hospitali-
UNOS and Medicare Hospitalizations in year zation associated with 1.32-
claims data before KT as proxy fold higher EHR risk [aOR
18% LDKT for frailty 1.32 (95% CI 1.17–1.49)]
Alhamad Retrospective cohort 6-min walk test at the 25% short walk Recipients with short 6- Short walk distance was not as-
et al. [91] 489 KT recipients at time of transplant <1101 feet min walk were more sociated with short-term risk
one center (2000–14) evaluation 50% medium walk likely female and had of graft failure, but was associ-
29% LDKT 1101–1414 feet a history of diabetes ated with longer-term risk
Long walk >1414 and stroke Selection bias, as recipients with
feet short walk distance would be
denied for transplant unless
they have other favorable char-
acteristics predicting excellent
short-term outcomes
McAdams- Prospective cohort Physical Frailty Frail recipients had worse physi-
DeMarco 443 KT recipients at 2 Phenotype defined cal (P < 0.001) and kidney
et al. [92]a centers (May as score 2 disease–specific HRQOL
2014–17) (P ¼ 0.001), but similar mental
35% LDKT HRQOL (P ¼ 0.43)
Continued

6 M.N. Harhay et al.

Table 2 Continued
References Design and participants Frailty measure Frailty distribution Correlates of frailty Outcomes
Frail recipients experienced
significantly greater rates of
improvement in physical
HRQOL [frail: 1.35 points/
month (95% CI 0.65–2.05);
nonfrail: 0.34 points/month
(95% CI 0.17 to 0.85);
P ¼ 0.02] and kidney disease–
specific HRQOL [frail: 3.75

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McAdams- Prospective cohort
DeMarco 663 KT recipients at
et al. [59] a one center (December
2008–August 2015)
39% LDKT
Lynch et al. [93] Retrospective cohort
37 623 Medicare-in-
sured KT recipients in
the USRDS (January
2000–December 2010)
%LDKT not reported
Lynch et al. [78] Retrospective cohort
51 111 Medicare-in-
sured KT recipients in
the USRDS (January
2000–December 2010)
0% LDKT
Physical frailty pheno- Frailty at KT: 20% Age was the only
type defined as conventional factor
score 2 associated with frailty
However, factors rarely
measured as part of
clinical practice (e.g.
HRQOL, IADL dis-
ability and depressive
symptoms) were
significant correlates
of frailty
Hospitalization days Hospitalization days Patients with highest
within 1 year before in pre-KT year: level of pre-KT hos-
KT as proxy for 0: 51%; pitalization days
frailty 1–7: 25%; were more com-
8–14: 11%; monly: women, pre-
15þ: 13% vious
transplant recipients,
diabetic and those
with CHF, athero-
sclerotic vascular dis-
ease and COPD
Hospitalization days in Hospitalization days More hospitalization
first year after wai- in first year after days associated with
tlisting as a proxy for listing: female sex, white
frailty 0: 46.9%; race, previous
1–7: 22.6%; transplant,
8–14: 11.7%; diabetes, CHF, ath-
15þ: 18.7% erosclerotic vascular
disease and COPD
points/month (95% CI 2.89–
4.60); nonfrail: 2.41 points/
month (95% CI 1.78–3.04);
P ¼ 0.01], but no difference in
mental HRQOL
KT recipients with exhaustion
and slowed walking speed
[HR 2.43 (95% CI 1.17–
5.03)] and poor grip
strength, exhaustion and
slowed walking speed [HR
2.61 (95% CI 1.14–5.97)]
had increased mortality
risk over an average of
3.1 years of follow-up
After adjusting for other
baseline factors, pre-KT
hospitalization days (1–7,
8–14, 15þ) bore graded
associations with readmis-
sion in the first year after
KT [aHR 1.28 (95% CI
1.17–1.70)] and with mor-
tality [aHR 1.42 (95% CI
1.20–1.70)] and all-cause
graft loss [aHR 1.30 (95%
CI 1.15–1.44)] >3 years
post-KT
After adjusting for other baseline
factors, hospitalization days
after listing (1–7, 8–14, 15þ)
bore graded associations with
death after listing [aHR 1.49
(95% CI 1.24–2.07)] and with
decreased likelihood of KT
Model using wait-list hospitali-
zation days alone had higher
predictive accuracy for wait-
list mortality than EPTS score

a
Distinct samples/analyses from the same cohort.
LDKT, living donor kidney transplantation; aHR, adjusted hazard ratio; USRDS, US Renal Data Service; IADL, independent activities of daily living.

stay following KT [45]. Frail KT recipients are more likely to
experience early hospital readmission within 30 days of
discharge from KT than nonfrail recipients [45.8% versus
28.0%; aRR for readmission among frail recipients 1.61 (95%
CI 1.18–2.19)] [22]. Thus, interventions that can improve PF
and frailty status prior to KT could have the potential to de-
crease the number of hospital days and readmissions post-
KT and reduce costs.
Longer-term patient and graft survival outcomes in frail
KT recipients
The long-term benefits of KT are not uniform or guaranteed,
but rather vary based on factors including recipient age, comor-
bidities, the timing of transplantation and organ quality [7, 94,
95]. Independent of traditional risk factors, the PFP is associ-
ated with a 2.2-fold higher risk of mortality after KT, whereas
intermediate frailty is associated with a 1.5-fold higher risk of

Review of frailty and KT 7

mortality [23]. Similarly, lower extremity impairment, objec-
tively measured by the SPPB, is associated with a 2.3-fold higher
post-KT mortality risk and a 16% absolute increase in 5-year
mortality post-KT [46]. With respect to self-reported PF, a ret-
rospective cohort study of 19 242 US KT recipients with linked
dialysis center records including SF-12 PCS scores found that
lower SF-12 PCS scores were associated with reduced 3-year
survival (84% versus 92% for the lowest versus highest quar-
tiles) [41]. Nonetheless, KT was associated with a statistically
significant survival benefit over dialysis by 9 months for patients
in every PF quartile in this study. These results suggest that the
survival advantage of KT persists across KT recipients of vary-
ing PF.
Post-KT changes in frailty status
KT itself is associated with dynamic changes in frailty status:
patients are confronted with surgical and immunologic
stressors, but also experience restored kidney function. In a
prospective cohort of 349 KT recipients, investigators found
that among recipients of all ages, frailty initially worsened in the
first-month post-KT but then improved by 3 months post-KT
[20]. Furthermore, KT recipients who were frail at KT were
more likely than nonfrail recipients to show improvements in
physiological reserve over time, suggesting that frailty is poten-
tially reversible with KT [20]. Some evidence suggests that frail
KT recipients receive outsized benefits from KT with respect to
improvements in health-related quality-of-life (HRQOL). In a
retrospective cohort study of 443 KT recipients at two US cen-
ters, frail recipients experienced significantly higher rates of im-
provement in physical HRQOL and kidney disease–specific
HRQOL with KT than nonfrail recipients [92]. These studies
suggest that carefully selected frail KT candidates can receive
substantial benefits from KT.
IMAGING STUDIES, MORPHOMETRIC AGE
AND KT OUTCOMES
Whereas dedicated frailty instruments are not a uniform feature
of KT candidate assessments, KT candidates often undergo
cross-sectional imaging as part of their preoperative workup. In
the general surgical literature, preoperative imaging has allowed
for the quantification of interrelated concepts including sarco-
penia, morphometric age and fat composition as potentially
modifiable predictors of postoperative outcomes [96–98].
Sarcopenia, as measured by low psoas muscle cross-sectional
area and density on computed tomography (CT), is associated
with higher waiting list mortality in KT candidates [99], but
studies on postoperative outcomes are lacking. As opposed to
chronologic age, older morphometric age, as quantified using
CT-measured aortic calcifications, psoas muscle cross-sectional
area and psoas muscle density, is associated with higher mortal-
ity among both kidney and liver transplant recipients [100,
101]. Taken together, these results suggest that morphometric
measurements may have a role in frailty assessment.
8 M.N. Harhay et al.
POTENTIAL ROLES FOR FRAILTY METRICS
IN POSTTRANSPLANTATION SETTINGS:
GRADING TRANSPLANT PROGRAM
PERFORMANCE
Given the strong associations between frailty and adverse post-
KT outcomes, frailty assessments may augment posttransplant
clinical care and help providers to identify KT recipients who
require additional support. Furthermore, the independent
association between frailty and adverse post-KT outcomes has
important implications in the regulation of US transplant pro-
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gram performance. Currently, program performance is graded
based on risk-adjusted computations of expected 1-year patient
and graft survival, and programs face serious consequences
when recipient death and/or graft loss rates ‘exceed expected’
[102]. Frailty is not one of the risk factors used to adjust out-
come expectations and this may serve as a disincentive for
transplant programs to accept frail candidates for KT. Given
the data that suggest frail candidates can receive survival and
HRQOL benefits from KT, an important question is whether
incorporation of frailty-based risk scores into program-specific
reports could reduce disincentives for transplant programs to
select frail individuals who may benefit from KT [11].
The Organ Procurement and Transplantation Network
(OPTN) already collects information on the Karnofsky
Performance Score, a measure of self-reported or observed
functional status that has been shown to enhance prediction of
posttransplant survival [103]. However, the subjective nature of
the Karnofsky Performance Score has rendered its inclusion in
national risk adjustment (constructed by the Scientific Registry
of Transplant Recipients with OPTN data) problematic, and it
is no longer included in post-KT risk adjustment equations.
Therefore, developing a consensus on objective instruments to
measure frailty that can be widely implemented across trans-
plant programs is an important goal for the future [104].
FRAILTY, AGING AND IMMUNE SYSTEM
The immunosenescence phenotype of aging and chronic
disease
Akin to physiologic aging and chronic disease, frailty has
been associated with alterations in the immune system [61,
105–107] and these changes may have important implications
for graft survival and immunosuppressive management for frail
KT recipients. Immunosenescence, a state of deteriorating and
compromised immune response, has been studied in the con-
text of aging and among older KT recipients [108]. Notably,
physiologic aging appears to be linked to an imbalance of innate
and adaptive immunity, with innate immune responses gaining
prominence (Figure 3, Panel A). Chronic disease processes such
as CKD may also enhance the state of immunosenescence.
Studies of immune function in pediatric patients with CKD
have shown premature T-cell aging, including a reversal of the
CD4:CD8 ratio, reduced portions of native T-cells with an evi-
dence of T-cell exhaustion and loss of CD28 expression [111].
Immunosenescence, as defined by immunophenotyping or
measurement of telomere length, has been linked to broad
changes of the immune response, increasing the risk of
 A B
B cells T cells
• Decrease in B cell repertoire • Decrease in naive T cell number
• Decreased expansion and • Impaired proliferation, differentiation
differentiation and migration
• Decreased antibody production • Increase in memory T cells with
• Impaired class switching compromised immune function Aging

Immunosenescence Rejection
ection
on
n Frailty Infection
Infect
Graft
ft loss
lo s Malignancy
M g
Ma
Malign
Natural killer cells Macrophages/neutrophils
• Decreased proliferative • Impaired phagocytosis
responses • Decreased cytokine production

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• Decreased cytotoxicity • Impaired chemotaxis
• Decreased cytokine production • Altered antigen presentation

FIGURE 3: Physiology of immunosenescence: the aging immune system. (Panel A) Aging is associated with immunosenescence, resulting in
alterations in the immune response. These alterations may require adjustment of immune therapy after KT [109] (Panel A redesigned with
permission from Transplantation: November 2015-Volume 99-Issue 11- p 2258-2268, Copyright V C 2015 Wolters Kluwer Health [110]).

(Panel B) In addition to aging, frailty may also influence immune therapy risks after KT. Novel immune system biomarkers may permit
individualization of immune therapy among vulnerable transplant recipients.

infection and malignancy in older adults [109, 112, 113].
However, it should be noted that the state of immunosenes-
cence does not equate to absence of inflammation. In fact, se-
nescent cells have been characterized as secreting a number of
proinflammatory cytokines, chemokines, growth factors and
proteases locally and contribute to the ‘inflammaging’ pheno-
type of the elderly [114]. Therefore, given the aging KT popula-
tions [7], research is needed to explore potential differences in
the mode of action, dosing, metabolism and pharmacokinetics
of immunosuppressants in the setting of immunosenescence.
The inflammatory phenotype of frailty
As frailty can occur across the lifespan in ESKD, it may not
always be associated with a state of immunosensecence.
However, relative to nonfrail individuals with ESKD, those with
frailty exhibit increased inflammatory markers such as C-reac-
tive protein and interleukin-6, findings that are independently
associated with higher mortality risk among ESKD patients [61].
The implications of frailty-related inflammation on the response
to immunosuppressive treatment are unclear. Importantly, there
are no definitive data that would support reduced immunosup-
pression in the context of frailty alone. In contrast, a study of 525
KT recipients showed that mycophenolate mofetil dose reduc-
tion was associated with a 5-fold higher risk of death-censored
graft loss and that this association was not modified by frailty
status [24]. Research is needed to explore whether interventions
to improve frailty can also impact systemic inflammation and
how changes in inflammation might influence KT outcomes.
New tools to tailor immunosuppressive therapy for frail
KT recipients
Given the complex interplay between frailty and physiologic
aging, developing a better understanding of the role of bio-
markers such as inflammatory markers, cytokines, T-cell pheno-
types and markers of senescent cells in targeting
immunosuppression may facilitate improved management of
frail KT recipients [105–107, 115]. A number of biomarkers have
been associated with frailty, leading to interest in developing a
biomarker-based frailty index [116]. However, studies of such an
index in ESKD and KT populations have not yet been conducted.
In addition, a number of noninvasive urine and blood
biomarkers for acute rejection of kidney allografts have been
studied and validated [116–119], but these have not been exam-
ined in the context of frailty. Validation and implementation of
noninvasive biomarkers, such as urine and blood messenger
RNA/micro-RNA profiles, T- and B-cell phenotypes, blood cyto-
kine levels and cell-free donor-derived DNA, in the frail KT pop-
ulation could lead to the development of a personalized approach
to immunosuppression for vulnerable KT recipients. Striking the
right balance between the risks of rejection and graft loss with the
risks of infection and malignancy (Figure 3, Panel B) is critical to
improving the quality of life for frail KT recipients.
The interaction between aging, frailty and the immune sys-
tem is complex. Identification of frailty status prior to KT offers
a window of opportunity to change one of the variables in the
equation. Whether improvement in frailty status alters the im-
mune phenotype of young and older frail KT candidates and
improves posttransplant outcomes needs to be studied.
Therefore it will be critical to define measures that can reduce
frailty and mitigate the deleterious immune consequences of
frailty prior to KT, which may include interventions such as
physical therapy, cognitive training and novel therapeutics, in-
cluding senolytic agents [120].
OPPORTUNITIES TO INTERVENE IN PRE-
AND POST-KT FRAILTY: STRUCTURED
EXERCISE PROGRAMS, PREHABILITATION
AND REHABILITATION
Interventions to reduce frailty in populations with CKD and
ESKD are understudied, although data from interventions
tested among frail older patients may be instructive.
Interventions to reduce frailty in community-dwelling older
adults are most often multidimensional [121] and include exer-
cise training, nutritional supplementation or pharmaceutical
agents [122]. They have focused on the reversible phenotypic

Review of frailty and KT 9

Table 3. Take-home points and recommended future research in frailty and KT
Take-home points
1 The ideal frailty metric for KT candidate
evaluation is unknown
2 Frailty is common among patients with CKD and
ESKD with numerous negative implications for
health status
3 Periodic reassessments and interventions such
as prehabilitation may mitigate the impacts of
long waiting time for DDKT on the risks of frailty
and other adverse outcomes
4 Although frail individuals with ESKD may benefit
from KT over dialysis, frailty may reduce the
likelihood of receiving KT
5 Optimal immunosuppressive management for
frail KT recipients is unknown
6 Interventions are needed to reduce the high
burden of frailty among KT recipients and to
prevent frailty-related adverse post-KT outcomes
frailty components (weakness, slowness and low energy expen-
diture) to delay functional decline and disability rather than to
prime patients before a major stressor [123, 124]. Interventions
that significantly reduce frailty among community-dwelling
older adults include physical activity interventions and pre-
emptive rehabilitation (i.e. prehabilitation) [125].
Exercise trials: data from populations with CKD and
ESKD
It remains an open question as to whether exercise can im-
prove overall vulnerability among CKD and ESKD patients.
However, several randomized trials of patients with CKD and
ESKD have demonstrated the potential benefits of physical ex-
ercise programs to prevent or reverse sarcopenia and improve
PF [126–130]. A Cochrane review evaluating the effect of
exercise on CKD and KT patients that included 45 randomized
controlled trials showed that regular exercise improved physical
fitness, cardiovascular dimensions, serum albumin and health-
related quality of life [128]. A meta-analysis evaluating 41 trials
that compared any regular exercise training for at least 8 weeks
with sham or no exercise in CKD and ESKD showed any type
of exercise significantly increased aerobic capacity and mid-
thigh muscle area (four trials) but found no change in walking
capacity [131]. Neither the Cochrane review nor the meta-
analysis focused specifically on frail individuals. Small trials
10
Related areas of recommended research
• Compare the reliability, construct validity, and predictive ability of existing and
novel frailty metrics in diverse ESKD and KT populations
• Develop a standard, feasible, multidimensional, and ESKD-specific frailty metric
• Identify modifiable determinants of frailty in CKD and ESKD
• Test interventions to improve frailty and frailty-related outcomes in pre- and
post-KT settings
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• Determine whether prehabilitation can improve frailty before KT
• Define intermediate and long-term outcome measures to assess whether
prehabilitation programs for KT candidates are successful
• Examine whether certain subgroups with frailty (e.g., older KT candidates) are
more likely to benefit from prehabilitation
• Determine whether frailty metrics improve upon clinical prognostication in KT
candidate and recipient evaluations
• Develop methods to incorporate frailty when calculating the risk/benefit ratio
of KT versus remaining on dialysis
• Examine the impacts of incorporating a clinically feasible, standardized,
objective, and kidney–disease specific frailty assessment into KT evaluations
and KT program-specific outcome reports
• Identify the optimal maintenance immunosuppression to manage KT recipients
with frailty that will avoid rejection while minimizing drug-related toxicities
• Develop and validate biomarkers to titrate doses of immunosuppressive drugs
• Design clinical trials to study the potential roles of novel therapeutics (e.g.,
senolytic agents) in optimizing immunity among frail KT candidates and recipients
• Define the role of post-KT exercise as an intervention for frailty in clinical
trial settings
• Determine whether certain subgroups (e.g., older KT recipients) receive outsized
benefits from post-KT exercise therapy
• Identify the form of exercise therapy—aerobic, resistance, or mixed—that is
most beneficial
• Examine which setting (e.g., home-based versus in-center) maximizes
adherence to and efficacy of exercise therapy
have demonstrated the potential for physical therapy programs
to benefit frail patients with CKD and ESKD [83].
Prehabilitation before KT
Prehabilitation, or intensive exercise therapy prior to an
elective surgical intervention, shifts the focus to optimization
prior to surgery rather than rehabilitation after surgery [84]. In
a recent survey, both clinicians (97%) and patients (94%) agreed
that pre-KT prehabilitation could help patients undergoing KT
and that prehabilitation could make ESKD patients less frail
(clinicians 100%, patients 84%). Additionally, 97% of clinicians
and 80% of patients agreed that patients would be interested in
pre-KT prehabilitation [13]. In a pilot study [85], 18 KT candi-
dates participated in weekly physical therapy sessions with at-
home exercise. After 2 months, participants improved their
physical activity by 64% (P ¼ 0.004). These data suggest that
prehabilitation is a promising intervention for KT candidates
with frailty. However, larger studies with longer durations of
follow-up are likely needed to determine whether exercise pro-
grams can improve pre- and peritransplant vulnerability
to health stressors.
Posttransplant rehabilitation
Several studies have investigated the role of exercise therapy
in ambulatory KT recipients. Two European centers report
M.N. Harhay et al.
efficacy from a structured rehabilitation program post-KT [132,
133]. In a US trial (N ¼ 97), an individualized home exercise
regimen starting at 1-month posttransplant and monitored
with regular phone follow-up improved peak oxygen uptake
(a surrogate of cardiopulmonary fitness), muscle strength and
self-reported physical functioning compared with usual care at
1 year [134]. The average age in the trial was low (40 6 13 years
in the exercise arm) and 43% of the cohort did not complete the
exercise protocol. A subsequent UK trial recruited 60 older
patients (age 55 6 11 years in the exercise arm) within 1 year of
KT and tested the effect of 12 weeks of supervised structured ex-
ercise classes twice per week for 12 weeks (aerobic versus resis-
tance training versus usual care) and reported improvement in
peak oxygen uptake attributable to both aerobic and resistance
training compared with usual care [135]. Together, these stud-
ies suggest that KT itself improves cardiorespiratory fitness
within the first-year posttransplant and that these improve-
ments can be further augmented by aerobic and resistance
exercise.
CONCLUSION
In this review we discussed the evidence that frailty is highly
prevalent among individuals before and after KT, with implica-
tions for post-KT outcomes and the need for future research on
interventions and access to KT (Table 3). Many tools exist that
may assist clinicians in identifying KT candidates and recipients
who are uniquely vulnerable to health stressors. However, re-
search is needed to compare the discriminatory ability of exist-
ing frailty metrics for monitoring patient-oriented KT
outcomes. A harmonized dynamic measure that captures de-
creased physiologic reserve in ESKD patients may be needed.
Furthermore, the preponderance of evidence suggests that
frailty is an independent and commonly unmeasured risk factor
for numerous adverse outcomes among KT candidates and
recipients, underscoring the urgent need to prospectively evalu-
ate the impact of targeted frailty interventions (e.g. structured
exercise, physical therapy and dietician support) on access to
KT and post-KT outcomes. Finally, although pre- and post-KT
outcomes among frail individuals are worse than outcomes
among nonfrail peers, KT may still provide survival and qual-
ity-of-life benefits for many frail individuals compared with
remaining on dialysis. Therefore we recommend that evidence
of frailty should not be used to disqualify individuals from KT
candidacy, but rather used to identify KT candidates that may
require additional surveillance and support before and after KT.
ACKNOWLEDGEMENTS
We would like to acknowledge the AST staff for their support
and the AST Education Committee for their input. KLL is the
American Society of Nephrology (ASN) Quality Committee
representative to the AST KPCOP Frailty Work Group.
FUNDING
This manuscript is a work product of the American Society
of Transplantation’s KPCOP. M.N.H. is supported by
National Institues of Health (NIH) National Institute of
Review of frailty and KT
Diabetes and Digestive and Kidney Diseases (NIDDK)
grant K23DK105207. M.K.R. was supported by NIH
National Institute on Aging (NIA) grant R03AG053294.
K.J.W. was supported by NIH/NIDDK contract
HHSN276201400001C. M.A.M.D. is supported by NIH NIA
and NIDDK grants R01AG055781, R01DK120518 and
R01DK114074R01AG055781 as well as the Johns Hopkins
University Claude D. Pepper Older Americans
Independence Center (P30AG021334). K.L.L. is supported
by NIH grants R01DK120518, U01DK116042 and
Downloaded from https://academic.oup.com/ndt/advance-article-abstract/doi/10.1093/ndt/gfaa016/5810137 by guest on 23 March 2020
R01DK120551. D.L.S. is supported by NIH NIDDK grant
K24DK101828. J.C.T. was supported by the John M.
Sobrato Fund. K.L.J. is supported by NIH NIDDK grant
K24DK085153.
AUTHORS’ CONTRIBUTIONS
M.N.H., M.K.R., K.J.W., K.L.J., K.L.L., S.G.T., R.F.P., T.A.,
J.B., X.S.C., J.L., R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D.
and M.A.M.-D. participated in research design. M.N.H.,
M.K.R., K.J.W., K.L.J., K.L.L., S.G.T, R.F.P., T.A., J.B., X.S.C.,
J.L., R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D. and M.A.M.-
D. participated in writing of the article. M.N.H., M.K.R.,
K.J.W., K.L.J., K.L.L., S.G.T., R.F.P., T.A., J.B., X.S.C., J.L.,
R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D. and M.A.M.-D.
participated in the performance of the research. M.N.H.,
M.K.R., K.J.W., K.L.J., K.L.L., S.G.T., R.F.P., T.A., J.B., X.S.C.,
J.L., R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D. and M.A.M.-
D. reviewed and approved the final manuscript.
CONFLICT OF INTEREST STATEMENT
D.L.S. reports personal fees from Sanofi-Aventis and Novartis
outside the submitted work. D.M.D. reports personal fees
from Veloxis Pharmaceutical, Inc. and AlloVir Inc. outside
the submitted work. There are no other disclosures or finan-
cial conflicts of interest reported. Results presented in this ar-
ticle have not been published previously in whole or part.
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Received: 6.9.2019; Editorial decision: 19.12.2019
M.N. Harhay et al.