Gfaa 016

Nephrol Dial Transplant (2020) 1–14
doi: 10.1093/ndt/gfaa016
An overview of frailty in kidney transplantation: measurement,

management and future considerations
Downloaded from https://academic.oup.com/ndt/advance-article-abstract/doi/10.1093/ndt/gfaa016/5810137 by guest on 23 March 2020

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 metric that can be used to monitor KT candidates and recipi-
help identify older adults with increased vulnerability when ents. Although frailty is an independent risk factor for post-
confronted with a health stressor. This article is a review of transplant adverse outcomes, it is not factored into the current
studies in which frailty has been applied to pre- and posttransplant program risk-adjustment equations. Future studies
kidney transplantation (KT) populations. Although KT is the are needed to explore pre- and post-KT interventions to im-
optimal treatment for end-stage kidney disease (ESKD), KT prove or prevent frailty.
candidates often must overcome numerous health challenges Keywords: aging, frailty, kidney transplantation, physical
associated with ESKD before receiving KT. After KT, the function, survival
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-
INTRODUCTION
tify KT candidates and recipients at risk for adverse health
outcomes and those who could potentially benefit from inter- Frailty is a syndrome characterized by diminished strength, en-
ventions to improve their frail status. The Physical Frailty durance and reduced physiologic function, increasing an indi-
Phenotype (PFP) is the most commonly used frailty metric in vidual’s vulnerability for developing increased dependency and/
ESKD research, and KT recipients who are frail at KT (~20% of or dying when confronted with a stressor [1]. The construct of
recipients) are twice as likely to die as nonfrail recipients. In ad- frailty was first established by geriatricians and gerontologists
dition to the PFP, many other metrics are currently used to as- who identified the need to distinguish the physiological age
sess pre- and post-KT vulnerability in research and clinical 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 continuous access to the working documents to provide in-
most vulnerable individuals in older populations by going be- put, critical review and revisions.
yond traditional risk factors such as age and comorbidity. In re-
cent years there has also been a proliferation of research on IDENTIFYING FRAILTY IN KT CANDIDATES
frailty in nonelderly populations and in numerous medical AND RECIPIENTS
subpopulations, including those with kidney disease and solid
organ transplants [3, 4]. Instruments to measure frailty
In kidney transplantation (KT), clinical care paradigms are Although there is an agreement regarding the underlying
adapting to an aging transplant candidate pool [5–7] and in- conceptual framework of frailty, there is a low level of consen-
creasing waiting times [8, 9]. These trends underscore the need sus regarding the constituent elements to be included in

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

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

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 prevalence of frailty is high among all KT candidates, including
are likely needed [4]. 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
PRETRANSPLANT FRAILTY: PREVALENCE, ESKD, and those who are selected for KT waitlists may be
RISK FACTORS AND OUTCOMES healthier still. A large multicenter study identified 18% of indi-
Prevalence of frailty in populations with CKD and viduals as frail at the time of initial evaluation, while only 12%
of individuals were identified as being frail among those who
ESKD
were ultimately listed for KT [57]. Furthermore, frailty status
People with CKD and ESKD have a high prevalence of may change considerably from the time of listing to the time of
frailty: there is 15–21% frailty prevalence in the CKD popula- KT. For example, in a single-center study of 569 adult KT can-
tion versus 3–6% in the general population [54, 55]. Among didates, 22% of the cohort was more frail at the time of KT than
dialysis-dependent individuals, the prevalence of frailty is likely at the time of KT evaluation, whereas 24% were less frail at KT
higher, ranging from 14 to 73%, and is common among those [58]. Approximately 20% of KT recipients are frail at the time
<40 years of age (63%) [16, 56]. These data suggest that the 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 defined by cystatin-based glomerular filtration rate (GFR) cal-
low physical activity (49%) [59]. Given the dynamic nature of culations [66]. However, the association between CKD stage
frailty, periodic reassessments of frailty may be warranted prior and frailty is attenuated when GFR is estimated using creatinine
to the surgical stressor of KT. as opposed to cystatin C, a finding that is potentially explained
by the relation of creatinine to muscle mass (i.e. lower serum
Risk factors and correlates for frailty creatinine may reflect sarcopenia). Therefore creatinine-based
Many of the risk factors for frailty in potential KT candidates estimated GFR (eGFR) may overestimate actual GFR in frail
are not modifiable (Figure 2). For example, studies have consis- people with sarcopenia, an important consideration given that
tently shown that KT candidates of advanced age and female waiting time for deceased donor KT (DDKT) cannot be accrued
sex are more likely to be frail than younger candidates and in the USA until individuals have eGFRs 20 mL/min/1.73 m2.

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

physical performance tests had an AUC that was superior to functional status and listing outcomes [83–85]. However, con-
commonly measured biomarkers of CKD, including eGFR, se- cerns arise about the potential of unintended consequences
rum bicarbonate, hemoglobin, C-reactive protein and albumin when integrating frailty assessments into the KT evaluation
[74]. Therefore, knowledge of frailty could inform shared process. Earlier in this article, we described evidence that frail
decision-making about the risks and benefits of KT between po- individuals with ESKD may still receive a substantial survival
tential KT candidates and their providers beyond the standard benefit from KT compared with remaining on dialysis [51], and
biomarkers that are commonly assessed and reviewed. that frailty is potentially reversible with successful KT [20].
Indeed, data suggest that selected older patients and those with
Frailty and access to KT long dialysis exposures who receive KT are likely to have better
Among individuals who are being evaluated for KT, frailty is survival and quality of life than similar patients who do not re-

associated with reduced access to the waiting list and higher ceive KT [86, 87]. However, among US KT programs that use a
waiting list mortality. In a study of 7078 individuals who were frailty metric during KT candidate assessments, 53% reported
evaluated at three transplant centers between 2009 and 2018, that they were less likely to list a frail KT candidate for trans-
frail individuals were almost half as likely as nonfrail individuals plant [53]. These findings have led to concerns that until
to be placed on a KT waiting list [hazard ratio (HR) 0.62 (95% transplant programs are no longer disincentivized from
CI 0.56–0.69)] [57]. In another study of 128 individuals who accepting high-risk KT candidates, individuals with ESKD
were evaluated for KT, 30.4% of frail individuals were subse- who are assessed (accurately or inaccurately) to be frail will
quently listed for KT, compared with 57.6% of nonfrail individ- have reduced access to KT [11].
uals [77]. Among those who are successfully wait-listed, frail
KT candidates may be more likely to be inactive, less likely to Longevity matching
receive KT [51] and more likely to die while wait-listed than Given the independent association between frailty and sur-
nonfrail KT candidates [61]. Healthcare utilization might be an- vival, another potential role of frailty metrics is to improve
other useful proxy for frailty in predicting waiting list outcomes: efforts to maximize utility in organ allocation. The revised US
compared with listed KT candidates with no hospitalization Kidney Allocation System (KAS) incorporated a continuous
days in the first year after listing, a study of 51,111 wait-listed scale called the Estimated Post-Transplant Survival (EPTS) to
individuals in the USA found that candidates with 15 hospi- facilitate allocation of the highest quality deceased donor organs
talized days had a >2-fold risk of subsequent waiting list mor- to recipients who are expected to live the longest (i.e. ‘longevity
tality [HR 2.07 (95% CI 1.99–2.15)] [78]. matching’) [88]. Under the revised KAS, candidates with the
longest predicted post-transplant survival (EPTS 20%) are
POTENTIAL ROLES FOR FRAILTY METRICS prioritized for kidneys from donors ranked as ‘top 20%’ highest
IN PRE-TRANSPLANTATION SETTINGS quality based on the Kidney Donor Profile Index. The EPTS is
based on candidate age, duration of dialysis, diabetes and prior
KT candidate assessment solid organ transplant status, and has a C-statistic of 0.69 (i.e.
Given the extent to which KT candidate selection relies on considered ‘good’ discriminatory ability) [89]. An important
provider perceptions of patients, clinicians who rely solely on area for future research is to examine whether the inclusion of
clinical acumen for health surveillance of their KT candidates frailty may improve the current longevity matching paradigm.
may be likely to misclassify some patient subgroups as frail. In a
study of 146 hemodialysis patients from a single dialysis facility, POSTTRANSPLANT FRAILTY: EARLY AND
investigators assessed agreement between measured frailty using LATE OUTCOMES
the Fried et al. criteria to nephrologists’ subjective ratings of pa-
Early outcomes among frail KT recipients
tient frailty. Nephrologists were inaccurate in their ratings of
frailty in 37% of cases, and older adults were the patient sub- Increasing evidence suggests that frail KT recipients are
group that was most likely to be misclassified as frail [79]. more vulnerable to the immediate surgical and immunologic
Misclassification of frailty could have large implications for ac- stressors of KT than nonfrail recipients (Table 2). In a prospec-
cess to KT, as individuals who are inaccurately deemed ‘too old, tive cohort study of 183 KT recipients transplanted between
ill or frail’ to undergo KT may be less likely to receive transplant 2008 and 2010, frailty was independently associated with a
education or referral as a result [79–82]. To minimize frailty mis- nearly 2-fold higher risk of delayed graft function (DGF) [ad-
classification that may improperly restrict access to KT, nephrol- justed relative risk (aRR) 1.94 (95% CI 1.13–3.36)] [21]. Frailty
ogists may consider augmenting their clinical assessments of is also associated with a 2-fold higher risk of post-KT delirium
potential KT candidates with direct and objective measures of [aOR 2.05 (95% CI 1.02–4.13)] [90]. These findings suggest that
frailty, particularly among older individuals with ESKD. frail KT candidates are likely to require more support during
their initial KT hospitalization.
Unintended consequences: frailty assessments and Frail KT recipients and those with physical impairments
transplant center practices are also likely to have higher healthcare utilization post-KT.
Knowledge of frailty in the KT evaluation and selection pro- For example, lower extremity impairment at the time of KT,
cesses may help to promote individualized care of the most vul- objectively measured by the Short Physical Performance
nerable patients, permitting timely interventions to improve Battery (SPPB), is associated with a longer hospital length of

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

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

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

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
McAdams- Prospective cohort Physical frailty pheno- Frailty at KT: 20% Age was the only KT recipients with exhaustion
DeMarco 663 KT recipients at type defined as conventional factor and slowed walking speed
et al. [59] a one center (December score 2 associated with frailty [HR 2.43 (95% CI 1.17–
2008–August 2015) However, factors rarely 5.03)] and poor grip
39% LDKT measured as part of strength, exhaustion and
clinical practice (e.g. slowed walking speed [HR
HRQOL, IADL dis- 2.61 (95% CI 1.14–5.97)]
ability and depressive had increased mortality
symptoms) were risk over an average of
significant correlates 3.1 years of follow-up
of frailty
Lynch et al. [93] Retrospective cohort Hospitalization days Hospitalization days Patients with highest After adjusting for other
37 623 Medicare-in- within 1 year before in pre-KT year: level of pre-KT hos- baseline factors, pre-KT
sured KT recipients in KT as proxy for 0: 51%; pitalization days hospitalization days (1–7,
the USRDS (January frailty 1–7: 25%; were more com- 8–14, 15þ) bore graded
2000–December 2010) 8–14: 11%; monly: women, pre- associations with readmis-
%LDKT not reported 15þ: 13% vious sion in the first year after
transplant recipients, KT [aHR 1.28 (95% CI
diabetic and those 1.17–1.70)] and with mor-
with CHF, athero- tality [aHR 1.42 (95% CI
sclerotic vascular dis- 1.20–1.70)] and all-cause
ease and COPD graft loss [aHR 1.30 (95%
CI 1.15–1.44)] >3 years
post-KT
Lynch et al. [78] Retrospective cohort Hospitalization days in Hospitalization days More hospitalization After adjusting for other baseline
51 111 Medicare-in- first year after wai- in first year after days associated with factors, hospitalization days
sured KT recipients in tlisting as a proxy for listing: female sex, white after listing (1–7, 8–14, 15þ)
the USRDS (January frailty 0: 46.9%; race, previous bore graded associations with
2000–December 2010) 1–7: 22.6%; transplant, death after listing [aHR 1.49
0% LDKT 8–14: 11.7%; diabetes, CHF, ath- (95% CI 1.24–2.07)] and with
15þ: 18.7% erosclerotic vascular decreased likelihood of KT
disease and COPD 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 Longer-term patient and graft survival outcomes in frail
experience early hospital readmission within 30 days of KT recipients
discharge from KT than nonfrail recipients [45.8% versus The long-term benefits of KT are not uniform or guaranteed,
28.0%; aRR for readmission among frail recipients 1.61 (95% but rather vary based on factors including recipient age, comor-
CI 1.18–2.19)] [22]. Thus, interventions that can improve PF bidities, the timing of transplantation and organ quality [7, 94,
and frailty status prior to KT could have the potential to de- 95]. Independent of traditional risk factors, the PFP is associ-
crease the number of hospital days and readmissions post- ated with a 2.2-fold higher risk of mortality after KT, whereas
KT and reduce costs. intermediate frailty is associated with a 1.5-fold higher risk of

mortality [23]. Similarly, lower extremity impairment, objec- POTENTIAL ROLES FOR FRAILTY METRICS
tively measured by the SPPB, is associated with a 2.3-fold higher IN POSTTRANSPLANTATION SETTINGS:
post-KT mortality risk and a 16% absolute increase in 5-year GRADING TRANSPLANT PROGRAM
mortality post-KT [46]. With respect to self-reported PF, a ret- PERFORMANCE
rospective cohort study of 19 242 US KT recipients with linked Given the strong associations between frailty and adverse post-
dialysis center records including SF-12 PCS scores found that KT outcomes, frailty assessments may augment posttransplant
lower SF-12 PCS scores were associated with reduced 3-year clinical care and help providers to identify KT recipients who
survival (84% versus 92% for the lowest versus highest quar- require additional support. Furthermore, the independent
tiles) [41]. Nonetheless, KT was associated with a statistically association between frailty and adverse post-KT outcomes has
significant survival benefit over dialysis by 9 months for patients important implications in the regulation of US transplant pro-

in every PF quartile in this study. These results suggest that the gram performance. Currently, program performance is graded
survival advantage of KT persists across KT recipients of vary- based on risk-adjusted computations of expected 1-year patient
ing PF. 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-
Post-KT changes in frailty status come expectations and this may serve as a disincentive for
KT itself is associated with dynamic changes in frailty status: transplant programs to accept frail candidates for KT. Given
patients are confronted with surgical and immunologic the data that suggest frail candidates can receive survival and
stressors, but also experience restored kidney function. In a HRQOL benefits from KT, an important question is whether
prospective cohort of 349 KT recipients, investigators found incorporation of frailty-based risk scores into program-specific
reports could reduce disincentives for transplant programs to
that among recipients of all ages, frailty initially worsened in the
select frail individuals who may benefit from KT [11].
first-month post-KT but then improved by 3 months post-KT
The Organ Procurement and Transplantation Network
[20]. Furthermore, KT recipients who were frail at KT were
(OPTN) already collects information on the Karnofsky
more likely than nonfrail recipients to show improvements in
Performance Score, a measure of self-reported or observed
physiological reserve over time, suggesting that frailty is poten-
functional status that has been shown to enhance prediction of
tially reversible with KT [20]. Some evidence suggests that frail posttransplant survival [103]. However, the subjective nature of
KT recipients receive outsized benefits from KT with respect to the Karnofsky Performance Score has rendered its inclusion in
improvements in health-related quality-of-life (HRQOL). In a national risk adjustment (constructed by the Scientific Registry
retrospective cohort study of 443 KT recipients at two US cen- of Transplant Recipients with OPTN data) problematic, and it
ters, frail recipients experienced significantly higher rates of im- is no longer included in post-KT risk adjustment equations.
provement in physical HRQOL and kidney disease–specific Therefore, developing a consensus on objective instruments to
HRQOL with KT than nonfrail recipients [92]. These studies measure frailty that can be widely implemented across trans-
suggest that carefully selected frail KT candidates can receive plant programs is an important goal for the future [104].
substantial benefits from KT.
FRAILTY, AGING AND IMMUNE SYSTEM
The immunosenescence phenotype of aging and chronic
IMAGING STUDIES, MORPHOMETRIC AGE disease
AND KT OUTCOMES
Akin to physiologic aging and chronic disease, frailty has
Whereas dedicated frailty instruments are not a uniform feature
been associated with alterations in the immune system [61,
of KT candidate assessments, KT candidates often undergo
105–107] and these changes may have important implications
cross-sectional imaging as part of their preoperative workup. In
for graft survival and immunosuppressive management for frail
the general surgical literature, preoperative imaging has allowed
KT recipients. Immunosenescence, a state of deteriorating and
for the quantification of interrelated concepts including sarco- compromised immune response, has been studied in the con-
penia, morphometric age and fat composition as potentially text of aging and among older KT recipients [108]. Notably,
modifiable predictors of postoperative outcomes [96–98]. physiologic aging appears to be linked to an imbalance of innate
Sarcopenia, as measured by low psoas muscle cross-sectional and adaptive immunity, with innate immune responses gaining
area and density on computed tomography (CT), is associated prominence (Figure 3, Panel A). Chronic disease processes such
with higher waiting list mortality in KT candidates [99], but as CKD may also enhance the state of immunosenescence.
studies on postoperative outcomes are lacking. As opposed to Studies of immune function in pediatric patients with CKD
chronologic age, older morphometric age, as quantified using have shown premature T-cell aging, including a reversal of the
CT-measured aortic calcifications, psoas muscle cross-sectional CD4:CD8 ratio, reduced portions of native T-cells with an evi-
area and psoas muscle density, is associated with higher mortal- dence of T-cell exhaustion and loss of CD28 expression [111].
ity among both kidney and liver transplant recipients [100, Immunosenescence, as defined by immunophenotyping or
101]. Taken together, these results suggest that morphometric measurement of telomere length, has been linked to broad
measurements may have a role in frailty assessment. 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

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

Table 3. Take-home points and recommended future research in frailty and KT
Take-home points Related areas of recommended research
1 The ideal frailty metric for KT candidate • Compare the reliability, construct validity, and predictive ability of existing and
evaluation is unknown novel frailty metrics in diverse ESKD and KT populations
• Develop a standard, feasible, multidimensional, and ESKD-specific frailty metric
2 Frailty is common among patients with CKD and • Identify modifiable determinants of frailty in CKD and ESKD
ESKD with numerous negative implications for • Test interventions to improve frailty and frailty-related outcomes in pre- and
health status post-KT settings

3 Periodic reassessments and interventions such • Determine whether prehabilitation can improve frailty before KT
as prehabilitation may mitigate the impacts of • Define intermediate and long-term outcome measures to assess whether
long waiting time for DDKT on the risks of frailty prehabilitation programs for KT candidates are successful
and other adverse outcomes • Examine whether certain subgroups with frailty (e.g., older KT candidates) are
more likely to benefit from prehabilitation
4 Although frail individuals with ESKD may benefit • Determine whether frailty metrics improve upon clinical prognostication in KT
from KT over dialysis, frailty may reduce the candidate and recipient evaluations
likelihood of receiving KT • 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
5 Optimal immunosuppressive management for • Identify the optimal maintenance immunosuppression to manage KT recipients
frail KT recipients is unknown 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
6 Interventions are needed to reduce the high • Define the role of post-KT exercise as an intervention for frailty in clinical
burden of frailty among KT recipients and to trial settings
prevent frailty-related adverse post-KT outcomes • 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
frailty components (weakness, slowness and low energy expen- have demonstrated the potential for physical therapy programs
diture) to delay functional decline and disability rather than to to benefit frail patients with CKD and ESKD [83].
prime patients before a major stressor [123, 124]. Interventions
that significantly reduce frailty among community-dwelling Prehabilitation before KT
older adults include physical activity interventions and pre- Prehabilitation, or intensive exercise therapy prior to an
emptive rehabilitation (i.e. prehabilitation) [125]. elective surgical intervention, shifts the focus to optimization
prior to surgery rather than rehabilitation after surgery [84]. In
Exercise trials: data from populations with CKD and a recent survey, both clinicians (97%) and patients (94%) agreed
ESKD that pre-KT prehabilitation could help patients undergoing KT
It remains an open question as to whether exercise can im- and that prehabilitation could make ESKD patients less frail
prove overall vulnerability among CKD and ESKD patients. (clinicians 100%, patients 84%). Additionally, 97% of clinicians
However, several randomized trials of patients with CKD and and 80% of patients agreed that patients would be interested in
ESKD have demonstrated the potential benefits of physical ex- pre-KT prehabilitation [13]. In a pilot study [85], 18 KT candi-
ercise programs to prevent or reverse sarcopenia and improve dates participated in weekly physical therapy sessions with at-
PF [126–130]. A Cochrane review evaluating the effect of home exercise. After 2 months, participants improved their
exercise on CKD and KT patients that included 45 randomized physical activity by 64% (P ¼ 0.004). These data suggest that
controlled trials showed that regular exercise improved physical prehabilitation is a promising intervention for KT candidates
fitness, cardiovascular dimensions, serum albumin and health- with frailty. However, larger studies with longer durations of
related quality of life [128]. A meta-analysis evaluating 41 trials follow-up are likely needed to determine whether exercise pro-
that compared any regular exercise training for at least 8 weeks grams can improve pre- and peritransplant vulnerability
with sham or no exercise in CKD and ESKD showed any type to health stressors.
of exercise significantly increased aerobic capacity and mid-
thigh muscle area (four trials) but found no change in walking Posttransplant rehabilitation
capacity [131]. Neither the Cochrane review nor the meta- Several studies have investigated the role of exercise therapy
analysis focused specifically on frail individuals. Small trials in ambulatory KT recipients. Two European centers report

efficacy from a structured rehabilitation program post-KT [132, Diabetes and Digestive and Kidney Diseases (NIDDK)
133]. In a US trial (N ¼ 97), an individualized home exercise grant K23DK105207. M.K.R. was supported by NIH
regimen starting at 1-month posttransplant and monitored National Institute on Aging (NIA) grant R03AG053294.
with regular phone follow-up improved peak oxygen uptake K.J.W. was supported by NIH/NIDDK contract
(a surrogate of cardiopulmonary fitness), muscle strength and HHSN276201400001C. M.A.M.D. is supported by NIH NIA
self-reported physical functioning compared with usual care at and NIDDK grants R01AG055781, R01DK120518 and
1 year [134]. The average age in the trial was low (40 6 13 years R01DK114074R01AG055781 as well as the Johns Hopkins
in the exercise arm) and 43% of the cohort did not complete the University Claude D. Pepper Older Americans
exercise protocol. A subsequent UK trial recruited 60 older Independence Center (P30AG021334). K.L.L. is supported
patients (age 55 6 11 years in the exercise arm) within 1 year of by NIH grants R01DK120518, U01DK116042 and

KT and tested the effect of 12 weeks of supervised structured ex- R01DK120551. D.L.S. is supported by NIH NIDDK grant
ercise classes twice per week for 12 weeks (aerobic versus resis- K24DK101828. J.C.T. was supported by the John M.
tance training versus usual care) and reported improvement in Sobrato Fund. K.L.J. is supported by NIH NIDDK grant
peak oxygen uptake attributable to both aerobic and resistance K24DK085153.
training compared with usual care [135]. Together, these stud-
ies suggest that KT itself improves cardiorespiratory fitness AUTHORS’ CONTRIBUTIONS
within the first-year posttransplant and that these improve-
ments can be further augmented by aerobic and resistance M.N.H., M.K.R., K.J.W., K.L.J., K.L.L., S.G.T., R.F.P., T.A.,
exercise. 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.,
CONCLUSION
J.L., R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D. and M.A.M.-
In this review we discussed the evidence that frailty is highly D. participated in writing of the article. M.N.H., M.K.R.,
prevalent among individuals before and after KT, with implica- K.J.W., K.L.J., K.L.L., S.G.T., R.F.P., T.A., J.B., X.S.C., J.L.,
tions for post-KT outcomes and the need for future research on R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D. and M.A.M.-D.
interventions and access to KT (Table 3). Many tools exist that participated in the performance of the research. M.N.H.,
may assist clinicians in identifying KT candidates and recipients 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.,
who are uniquely vulnerable to health stressors. However, re- J.L., R.L., S.P., J.C.T., D.L.S., B.K., J.K., D.M.D. and M.A.M.-
search is needed to compare the discriminatory ability of exist- D. reviewed and approved the final manuscript.
ing frailty metrics for monitoring patient-oriented KT
outcomes. A harmonized dynamic measure that captures de-
CONFLICT OF INTEREST STATEMENT
creased physiologic reserve in ESKD patients may be needed.
Furthermore, the preponderance of evidence suggests that D.L.S. reports personal fees from Sanofi-Aventis and Novartis
frailty is an independent and commonly unmeasured risk factor outside the submitted work. D.M.D. reports personal fees
for numerous adverse outcomes among KT candidates and from Veloxis Pharmaceutical, Inc. and AlloVir Inc. outside
recipients, underscoring the urgent need to prospectively evalu- the submitted work. There are no other disclosures or finan-
ate the impact of targeted frailty interventions (e.g. structured cial conflicts of interest reported. Results presented in this ar-
exercise, physical therapy and dietician support) on access to ticle have not been published previously in whole or part.
KT and post-KT outcomes. Finally, although pre- and post-KT
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Nephrol Dial Transplant (2020) 1–14

An overview of frailty in kidney transplantation: measurement,

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*These authors contributed equally to this work.

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

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2 M.N. Harhay et al.

Frailty indicator Components Limitations Scoring Populations studied

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Review of frailty and KT 3

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Outcomes of frailty in populations with nondialysis-

instrumental activity of daily living and mobility were 15, 60

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

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

4 M.N. Harhay et al.

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Review of frailty and KT 5

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6 M.N. Harhay et al.

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Review of frailty and KT 7

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Review of frailty and KT 9

Take-home points Related areas of recommended research

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10 M.N. Harhay et al.

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Review of frailty and KT 11

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Review of frailty and KT 13

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14 M.N. Harhay et al.

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