REVIEW ARTICLE

Is it Important to Prevent and Treat

Protein-Energy Wasting in Chronic Kidney
Disease and Chronic Dialysis Patients?
Bereket Tessema Lodebo, MD, MPH,* Anuja Shah, MD,*,† and Joel D. Kopple, MD*,†,‡

Protein-energy wasting (PEW), which essentially refers to decreased body protein mass and fuel (energy) reserves, is common in
advanced chronic kidney disease (CKD) patients and end-stage kidney disease patients undergoing chronic dialysis. The term PEW
is used rather than protein-energy malnutrition because many causes of PEW in CKD and end-stage kidney disease patients does
not involve reduced nutrient intake (e.g., catabolic illness, oxidants, biologicals lost in urine and dialysate, acidemia). The prevalence
of PEW in CKD increases as glomerular filtration rate declines and is highest in chronic dialysis patients. PEW in CKD is important
because it is associated with substantially increased morbidity and mortality and reduced quality of life. Many signs of PEW can be
improved with nutritional therapy. It is not known whether amelioration or eradication of PEW by treatment of underlying illnesses, nutri-
tional therapy, and/or other measures will reduce morbidity and mortality or improve quality of life. Clinical trials are indicated to answer
these questions.
Ó 2018 by the National Kidney Foundation, Inc. All rights reserved.

P ROTEIN-ENERGY WASTING (PEW) occurs

commonly in nondialyzed patients with advanced
chronic kidney disease (CKD). It is reported to occur in
approximately 20-30 percent of advanced CKD patients
(i.e., glomerular filtration rate [GFR] of #20 mL/min/
1.73 m2 i.e., CKD stage 4b and 5) and is more common
in chronic dialysis (CD) patients.1-5 PEW is an important
concern in these patients because it is associated with a
much higher incidence of adverse events including
mortality.
Definition and Diagnosis of PEW
PEW can be defined as a state of reduced body reserves of
protein and energy, particularly fat.6 We recognize that this
definition is not entirely satisfactory because some very
healthy people can have, for their height, very low body
fat mass and normal or possibly low body protein; for
example, marathon runners. However, the enzymatic
apparatus and metabolic activity of the skeletal muscle of
*
Division of Nephrology and Hypertension, Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical Center, Torrance, California.
†
David Geffen School of Medicine at UCLA, Los Angeles California.
‡
UCLA Fielding School of Public Health, Los Angeles, California.
Financial Disclosure: JD Kopple has received honoraria or research support
from Nephroceuticals, Dr. Schar Company, Chugai Pharmaceuticals and Shire
Pharmaceuticals. BT Lodebo and A Shah declare no conflicts of interest.
Address correspondence to Joel D. Kopple, MD, Professor of Medicine and
Public Health, David Geffen School of Medicine at UCLA and UCLA Fielding
School of Public Health, Los Angeles Biomedical Research Institute at Harbor-
UCLA Medical Center, 1124 West Carson Street, Torrance, California 90502.
E-mail: jkopple@labiomed.org
Ó 2018 by the National Kidney Foundation, Inc. All rights reserved.
1051-2276/$36.00
https://doi.org/10.1053/j.jrn.2018.04.002
these latter individuals can be superbly adapted for rapid
long distance running.
According to the International Society for Renal Nutri-
tion and Metabolism, PEW is most readily diagnosed by
the presence of at least 3 of the following four signs: (1)
low serum albumin, transthyretin (prealbumin), or choles-
terol; (2) decreased body mass (low body mass index
[BMI], unintentional weight loss, or decreased body fat);
(3) reduced muscle mass (low mid-arm muscle circumfer-
ence or area, decreased creatinine appearance or recent his-
tory of loss of muscle mass); (4) unintentional low energy
or protein intake.6 Other measures which may be used
to help detect or confirm PEW include reduced skeletal
muscle strength or function (e.g., low handgrip strength
or gait speed).7,8 Inflammatory cytokines can predispose
to PEW (see below). However, it is the authors’ view
that increased levels of inflammatory cytokines are not
part of the diagnostic criteria for PEW, which is
determined by the presence of decreased body protein
and fuel mass. Future research will probably demonstrate
more relevant and helpful ways of monitoring PEW; for
example, the propensity of PEW to arterial inflammation
or atherogenesis, antibody responses, lymphocyte or
neutrophil function, or the activities of subcellular
structures.
All the foregoing measures, although useful, have limita-
tions for diagnosing PEW.6-9 For example, many serum
proteins may decrease acutely and transiently, particularly
in response to inflammation; the normal range of
laboratory values may vary from laboratory to laboratory;
and the magnitude of the abnormalities in measurements
that should be necessary for the diagnosis of PEW is not
welldefined. Body protein and fat mass can be estimated

Journal of Renal Nutrition, Vol -, No - (-), 2018: pp 1-11 1

2 LODEBO ET AL
by anthropometry, subjective global assessment,
bioelectrical impedance, or dual x-ray absorptiometry.
More precise methods of measurements of body protein
mass, such as total body nitrogen,10 possibly total body po-
tassium,11 or protein measured in biopsied skeletal muscle
are more expensive and not routinely available. It should
be noted that PEW refers to depletion of protein and en-
ergy reserves, and there are many other types of nutrient
depletion that may occur in CKD or CD patients,
including deficiencies of macrominerals (particularly cal-
cium12), trace elements (especially iron13 and zinc14), and
vitamins (especially vitamins D, C, B1, B6 and folate).15-17
Prevalence of PEW in Advanced CKD,
Maintenance Hemodialysis, and Chronic
Peritoneal Dialysis Patients
The prevalence of PEW is rather low in patients with
stage 1 and 2 CKD, but it increases progressively as GFR de-
creases and is highest in end-stage kidney disease (ESKD)
patients.1-5,18-21 In studies of patients with more
advanced CKD, using subjective global assessment (SGA)
to estimate protein-energy status, Campbell et al. reported
mild to moderate PEW in 19.6% of 56 nondialyzed patients
with an estimated GFR of 22 6 6.8 standard deviation mL/
min3; Cupisti et al. reported mild-to-moderate PEW in
28.6% of 70 nondialyzed patients with GFR ,15 mL/
min who were treated with low-protein diets or supple-
mented very low-protein diets5; and Stenvinkel et al.
observed PEW in 44% of 109 nondialyzed patients with a
GFR of 7 6 1 standard error of the mean mL/min.4 In a
cross-sectional study of 1834 nondialyzed South Korean
CKD patients, Hyun et al. also reported that the prevalence
of PEW increased progressively as the GFR declined. PEW
was observed in 2.2%, 4.4%, 8.3%, 6.2%, 15.6%, and 24.6%
of patients with CKD stage 1, 2, 3a, 3b, 4, and 5,
respectively.1
PEWappears to occur surprisingly early in many patients
during the course of progressive CKD. Ikizler et al. re-
ported that dietary protein intake and biochemical mea-
sures of protein-energy status declined progressively as the
creatinine clearance decreased below 50 mL/minute.18
Another cross-sectional study of 1785 clinically stable non-
dialyzed CKD patients who were evaluated for participa-
tion in the Modification of Diet in Renal Disease Study
indicated that decreases in measures of protein-energy sta-
tus suggesting the beginning of PEW often begins to
become apparent when the GFR decreases to about 30 to
40 mL/min/1.73 m2. Evidence for PEW becomes progres-
sively more common below these GFR levels.19 Few, if any,
of these latter patients had insulin requiring diabetes melli-
tus. Strikingly, two other more recent longitudinal studies
from the Chronic Renal Insufficiency Cohort of nondia-
lyzed CKD adults and the African American Study of Kid-
ney Disease and Hypertension22 and the CKD in Children
Study 23 also indicate that the BMI of these individuals
began to decrease when their GFR fell below 35 mL/min-
ute/1.73 m2.
The similarity of the GFR levels in these various
studies1,18,19,22,23 when evidence for PEW begins to
become apparent, roughly around 30-40 mL/min/
1.73 m2 or slightly lower in the South Korean CKD
patients, is rather striking and has clinical implications.
For example, a 45-year-old Caucasian with an estimated
glomerular filtration rate (eGFR), calculated from the
Chronic Kidney Disease Epidemiology Collaboration
equation,24 of 30 and 40 mL/minute/1.73 m2 should
have a mean serum creatinine, respectively, of 2.36 and
1.84 mg/dL for a man and 1.82 and 1.42 mg/dL for a
woman. Of course, roughly 50% of patients with these
GFR levels would have lower serum creatinine concentra-
tions. It follows that many physicians may not evaluate or
treat CKD patients for PEW who have these serum creat-
inine levels because the health care workers are unaware
that PEW may begin to occur in such CKD patients who
may look and feel well.
The prevalence of PEW in maintenance hemodialysis
(MHD) and chronic peritoneal dialysis (CPD) patients is
more common than in nondialyzed CKD pa-
tients.2,20,25-27 This has been observed in dialysis centers
worldwide.2,20,25-27 The reported frequency of PEW in
MHD and CPD patients varies widely from 28% to
60%. PEW appears to be as common in incident MHD
and CPD patients as it is in prevalent CD patients.28,29
Abnormal measures of protein-energy status at the onset
of MHD tend to improve during first 12 months of
MHD treatment. However, the abnormal nutritional
measures, although improved, often stabilize and are usu-
ally still abnormally low after 6 or 24 months of CD treat-
ment.30-33 Many studies indicate that patients well
established on CD therapy display low serum albumin
levels, reduced BMI, weight loss or low nutrient intake,
particularly for energy.2,25 These findings suggest that
the most effective way to reduce the high prevalence of
PEW in CD patients may be to prevent PEW or to
treat it before patients develop ESKD and commence
MHD or CPD.
Causes of PEW in CKD Patients
The term PEW to describe protein-energy depletion in
sick individuals is commonly preferred to the term
protein-energy malnutrition because it is recognized that
many of the factors that reduce body protein mass and en-
ergy sources are not related to the intake or losses of nutri-
ents but are due to other factors.6 The many causes of
PEW in CKD patients have been previously described
and are illustrated schematically in Figure 1.6,34,35 In
brief, PEW is usually caused by some combination of the
following: inadequate nutrient intake, inflammatory
catabolic illnesses, inflammatory processes that are not
 IMPORTANCE OF PREVENTING AND TREATING PROTEIN-ENERGY WASTING 3

Uremic toxins Decreased levels Decreased concentraons or impaired acvies of

Inflammatory catabolic
or acvies of anabolic hormones (insulin, growth Hormone, IGF-I,
illnesses (Infecon, DM, CVD, HF)
orexigens angiotensin II, corcosteroids, testosterone)

Anorexia Impaired taste/smell Nutrient losses in urine

Inflammatory processes or dialysate (protein,
that are not associated Medicines pepdes, amino Acids)
with specific diseases Inadequate Mood disorders
Increased levels or
nutrient intake (depression, anxiety)
acvies of catabolic
Acidemia hormones (PTH,
glucagon)
Aging
PEW Carbonyl stress
Physical
decondioning Oxidave stress
Intermediate outcomes*

Altered body physiology, biochemistry, immune processes and

metabolism, atherogenesis*

Clinical outcomes

Decreased quality of life* Increased morbidity* Increased mortality*

Figure 1. A Schematic Overview of Causes and Consequences of PEW. *Although PEW is strongly associated with these
adverse events, the degree, if any, to which PEW actually causes these adverse events is not known (see text). CVD, cardiovas-
cular disease; DM, diabetes mellitus; HF, heart failure; IGF-I, insulin-like growth hormone-I; PEW, protein-energy wasting; PTH,
parathyroid hormone.

associated with specific diseases other than CKD, oxidant
stress, carbonyl stress, increased nutrient losses in urine
(e.g., proteinuria) or dialysate (e.g., protein, peptide and
free amino acid losses), decreased circulating
concentrations or activities of anabolic hormones or
increased levels or activities of catabolic hormones,
acidemia due to metabolic acidosis, aging, and physical
deconditioning.6,34,35 Both the mouth and the
gastrointestinal tract may be unrecognized sources of
inflammation.36 Increased serum levels of such inflamma-
tory cytokines as tumor necrosis alpha, C-reactive protein,
interleukin-1b, and interleukin-6 can contribute to the
pathogenesis of PEW.29,37-39 These cytokines engender
both states of increased catabolism and anorexia thereby
promoting PEW by 2 separate processes.40-42 Advanced
CKD and ESKD patients may manifest increased serum
levels of other, not inflammation-related, compounds
which may also induce anorexia, increase energy expendi-
ture and protein catabolism or reduce protein synthesis,
thereby creating a hypercatabolic state. These compounds
may include alpha melanocyte-stimulating hormone,43
5-hydroxytryptophan,44 and leptin.45
In addition to inflammatory cytokines, other anorexi-
genic factors that accumulate in uremia, and possibly the
loss of orexigenic factors, impaired taste, emotional depres-
sion, which is very common in advanced CKD and ESKD
patients,46,47 are commonly associated with reduced
nutrient intake. Many ESKD patients are impoverished or
have physical difficulty with the acquisition or preparation
of food (e.g., due to severe morbidity, profound malaise,
muscle weakness or impaired mentation) or the ingestion
of food (e.g., from loss of dentures) which may also lead
to reduced nutrient intake.
It is unclear why PEW commonly begins at rather high
levels of GFR in people who do not have obvious comor-
bid illnesses. Serum proinflammatory cytokines may well
play a role because serum concentrations increase progres-
sively as eGFR diminishes, and inflammatory cytokines
often begin to increase in people who have an eGFR as
high as 50-59 mL/min/1.73 m2.48 Another theoretical
possibility that, to our knowledge, has not been investigated
is that the kidney elaborates an orexigenic factor, the pro-
duction of which diminishes as renal failure progresses. It
is important to recognize that reduced nutrient has many
causes in CKD and ESKD patients.
Associations Between Clinical Outcomes
and PEW
PEW in CKD and CD patients is associated with impaired
quality of life, greater morbidity, and increased cardiovascular
mortality, mortality from infection and total mortality
(Fig. 1).49-54 This relationship between PEW and adverse
outcomes appears to be stronger in MHD and CPD
patients than in CKD patients.9,18,22,32,53,55-57 Even when
PEW cannot be formally diagnosed, a significant
association has been described in MHD patients between
individual measures of PEW, such as low BMI,
hypoalbuminemia, and low predialysis serum creatinine
and cardiovascular- and infection-related mortality.9,18,57
Low normalized protein nitrogen appearance (nPNA,
4 LODEBO ET AL
normalized protein catabolic rate [nPCR]) is also associated
with infection-related mortality.58 Decreased bioelectrical
impedance measured-reactance, an indicator of lean body
mass, is independently associated with increased hospitaliza-
tion rates in MHD patients.18 PEW combined with comor-
bid illnesses or inflammation is more strongly associated with
morbidity and mortality than is PEW with little or no evi-
dence of inflammation.18,57,59
In the authors’ experience, it is not uncommon for peo-
ple with PEW to also be frail, as determined for the Fried
criteria.60 These patients often are also elderly. Thus, there
can be overlaps between the clinical manifestations and
possibly prognostic implications of these 3 syndromes:
PEW, frailty, and normal aging. Often an advanced CKD
or CD patient simultaneously has components of these 3
conditions.34 This overlap may make it more difficult to
examine the causal effects of PEW on clinical outcomes
or to make prognostications regarding the clinical course
of CKD or CD patients with PEW who are also frail or
elderly. More research would seem helpful to examine
the influence of different combinations of these 3 condi-
tions on the patient’s outcome.
Causal Relationship Between PEW and
Adverse Outcomes
Although PEW is strongly associated with adverse out-
comes in advanced CKD and ESKD patients,49-54 some
authorities suggest that the association of PEW with
adverse outcomes generally occurs only when
inflammatory processes or comorbid conditions are also
present; hence, there may be only a weak causal
association or no association of PEW with increased
morbidity and mortality in the absence of associated
inflammatory conditions.59 According to this perception,
the relation between PEW and adverse clinical events in
these individuals may be due to the presence of underlying
morbid or inflammatory processes that both cause PEW
and independently increase morbidity and mortality and
particularly cardiovascular or atherosclerotic morbidity.61
Many comorbid conditions lead to increased levels of
proinflammatory cytokines and other compounds that
can induce anorexia, increase energy expenditure and pro-
tein catabolism, or reduce protein synthesis and thereby
create a hypercatabolic state62 and also increase vascular dis-
ease and consequent mortality.
However, not all studies support this contention. In an
observational cohort study of 973 clinically stable HD pa-
tients who were followed for 8 years, measurements indi-
cating both PEW and increased serum CRP were each
found to be independently associated with a higher risk
of cardiovascular and all-cause mortality.63 Thus, it is not
clear whether the relationship between PEWand increased
morbidity and mortality in CKD and ESKD is due solely to
the association of PEW with inflammatory processes and
PEW is little more than an epiphenomenon with regard
to reduced quality of life or increased morbidity and mor-
tality. Moreover, one study in rats without CKD indicated
that ingestion of a nutritionally inadequate, very low pro-
tein (2% casein) diet was associated with increased serum
levels of several inflammatory cytokines.64 It is also likely
that PEW may alter important physiological and metabolic
processes in ways that are currently not recognized.
Other than observational data, there is little information
that directly examines whether PEW without associated
inflammation or other diseases, as it might occur in CKD
or ESKD patients, can adversely affect morbidity and mor-
tality. Studies in this regard have been conducted in physi-
cally healthy people who underwent voluntary fasting, e.g.,
political prisoners or other voluntary hunger strikers65-67 or
from the Ancel Keys et al. experimental starvation studies
that were carried out in conscientious objectors in the
1940’s.68,69 Clearly, prolonged absence of nutrient intake
eventually will cause death, and an extended period of
protein and energy intake inadequate to maintain normal
body fat and protein mass also can alter physiological and
mental function.65,69 However, these studies do not
indicate how much protein or energy deficit or wasting
must occur before the risk of morbidity and mortality
increases or whether protein-energy malnutrition per se in-
creases the likelihood of superimposed inflammatory
illness. Death from pure malnutrition appears to be not un-
commonly cardiovascular in nature.70 Left ventricular mass
decreases and arrhythmias are common.70,71 Such deaths
also may be caused by alterations in electrolyte balance.72
Infection-associated deaths are also described with volun-
tary starvation.70 In summary, it is not known whether in
advanced CKD or CD patients, body protein mass or fuel
reserves often become depleted to the point where these
conditions per se increase the risk for inflammation, super-
imposed illness or mortality.
Can PEW Be Successfully Prevented or
Treated in CKD and ESKD Patients?
Although the causes of PEWare multifactorial, it should
be recognized that many of these causes are associated with
reduced nutrient intake (see above). Therefore, it is impor-
tant to ascertain whether increasing nutritional intake may
prevent or improve this condition. As indicated in Tables 1
and 2, many clinical trials have addressed this question by
providing dietary counseling, oral supplements, or intradia-
lytic parenteral nutrition.101 Studies were only included in
these tables if there was a randomized or nonrandomized
control group or a crossover study, at least 9 patients partic-
ipated in the nutritional treatment arm, the nutritional
intervention lasted for at least many days, the key outcomes
were either serum chemistry or body composition mea-
surements, and the dropout rate in the treatment arm was
very large (e.g., 43%). Most of these trials were conducted
in MHD or CPD patients, although some were carried out
in patients with advanced CKD. The patients treated all had
Table 1. Randomized Prospective Controlled Trials Evaluating Nutritional Support for CKD Patients With PEW
Method and Duration of Significant Effects in
Reference Study Design No. of Patients Type of Patients Nutritional Support Treatment (Rx) Group

Allman et al, 199073 RPCT Rx – 9 MHD Oral energy supplement for [ Body weight, body fat,
Con – 12 6 months and lean body mass
Cano et al, 199074 RPCT Rx – 12 MHD Intradialytic parenteral [ Body weight, arm muscle
Con – 14 amino acid and lipid circumference, serum
supplement for 3 months albumin, and

IMPORTANCE OF PREVENTING AND TREATING PROTEIN-ENERGY WASTING

transthyretin
Tietze et al, 199175 Randomized Rx/Con – 19 MHD Oral fish protein [ Body weight, arm muscle
double-blind supplement and placebo circumference;
crossover for 3 months each normalization of many
plasma amino acids
Navarro et al, 200076 RPCT Rx – 10 MHD Parenteral intradialytic [ Serum albumin,
Con – 7 amino acid supplement transferrin, and nPCR
for 3 months (nPNA)
Eustace et al, 200077 RPCT Rx – 23 MHD, CPD Oral essential amino acids [ Serum albumin level only
Con – 24 for 3 months in MHD patients
Hiroshige et al, 200178 Randomized Rx/Con – 28 Elderly MHD Oral 3 branched chain [ Calorie and protein
double-blind amino acids for 6 months intake; serum albumin,
crossover and dextrose for body weight, lean body
6 months mass, body fat, [plasma
BCAA
Sharma et al, 200279 RPCT Rx – 26 MHD Oral protein and calorie [ Dry weight and BMI, [
Con – 14 supplement for 1 month serum albumin and
functional status
Aguirre Galindo et al, 200380 RPCT Rx – 50 CPD Calcium Caseinate diet [ Serum albumin, [ total
Con – 50 versus high-protein diet serum protein
for 4 months
Akpele et al, 200481 RPCT Rx – 26 MHD Oral nutritional supplement [ Rate of serum albumin in
Con – 14 (ONS) versus counseling the counseled group
for 14 months

lez-Espinoza et al, 200582
Gonza RPCT Rx – 13 CPD Oral egg-albumin based [ Serum albumin, calorie
Con – 15 supplement for 6 months and protein intake, and
nPNA
Leon et al, 200683 RPCT Rx – 86 MHD Rx group received dietary [ Serum albumin, [ calorie
Con – 94 counseling and help and protein intake
overcoming physical,
emotional or social
barriers to prescribed
diets.
Fanti et al, 200684 Double-blind Rx – 19 MHD Isoflavone containing soy- YCRP; [ serum albumin
RPCT Con – 13 based nutritional
supplement for 8 weeks
(Continued )

5
 Table 1. Randomized Prospective Controlled Trials Evaluating Nutritional Support for CKD Patients With PEW (Continued )

6
Method and Duration of Significant Effects in
Reference Study Design No. of Patients Type of Patients Nutritional Support Treatment (Rx) Group
Cano et al, 200785 RPCT Rx – 93 MHD ONS with or without 2-year mortality not
Con – 93 intradialytic parenteral different reduced with
nutrition (IDPN) IDPN plus ONS versus,
ONS alone. No benefits
of adding IDPN to ONS.
Fouque et al, 200886 RPCT Rx – 46 MHD Energy dense oral [ Calorie and protein
Con – 40 supplement for 3 months intake;
Campbell et al, 200887 RPCT Rx – 24 CKD with GFR Individualized counseling [ Quality of life
Con – 23 ,30 mL/min and follow-up on
nutrition for 12 weeks
Moretti et al, 200988 Randomized Rx/Con – 49 MHD, CPD Oral protein supplement for [ Serum albumin, [ nPCR
Crossover 3 months
Bolasco et al, 201189 RPCT Rx – 15 MHD Oral essential and semi- [ Serum albumin and total
Con – 15 essential amino acids proteins, [ hemoglobin,
supplementation for YCPR, [ body weight
3 months and PCR
Di Iorio et al, 201290 Randomized Rx/Con – 16 Advanced CKD Oral low-protein diet with Y Fibroblast growth factor-
Crossover with creatinine keto-acid analogues for 23 levels
clearance 2 weeks

LODEBO ET AL
$20-#55 mL/min
Rhee et al, 201791 RPCT Rx – 55 MHD High-protein meal and [ Serum albumin without
Con – 51 phosphate binder during increased serum
dialysis versus low- phosphorus
protein meal for 8 weeks
BCAA, Branched chain amino acids valine, leucine and isoleucine; BMI, body mass index; CKD, chronic kidney disease; Con, control group; CPD, chronic peritoneal dialysis; GFR,
glomerular filtration rate; MHD, maintenance hemodialysis; nPCR, normalized protein catabolic rate; nPNA, normalized protein nitrogen appearance; ONS, oral nutritional supplements;
PEW, protein-energy wasting; RPCT, randomized prospective controlled trial; Rx, treatment group.
 IMPORTANCE OF PREVENTING AND TREATING PROTEIN-ENERGY WASTING
Table 2. Nonrandomized Studies Evaluating Nutritional Support for CKD Patients With PEW
Method and Duration of Significant Effects in
Reference Study Design No. of Patients Type of Patients Nutritional Support Treatment (Rx) Group

Chertow et al, 199492 Retrospective, matched Rx – 1,679 MHD Intradialytic parenteral [ Survival
case-control Con –22,517 nutrition for 1 year
Capelli et al, 199493 Retrospective, matched Rx – 81 MHD Intradialytic parenteral [ Serum albumin; [
case-control Con - 31 nutrition for 9 months survival
Kopple et al, 199594 Prospective, without and Con/Rx - 24 CPD Nitrogen balance and More positive nitrogen and
then with dialysate 15
N-glycine study of CPD protein balance; [ serum
amino acids without (15 days) and total protein and
then with (20 days) amino transferrin with amino
acids in dialysate acids in peritoneal
dialysate
Leon et al, 200195 Prospective, Rx – 52 MHD Nutritional counseling for [ Serum albumin with
nonrandomized trial Con - 31 6 months treatment
Caglar et al, 200296 Crossover Con/Rx - 85 MHD Oral intradialytic [ Serum albumin and
supplement for 6 months prealbumin; [ SGA
score
Scott et al, 200997 Prospective, Rx- 57 MHD Nepro before or YSerum albumin and Yrole
nonrandomized trial Con - 49 immediately after each physical in the KDQOL-
HD session, thrice SFÒ scale98 in the
weekly control group
Lacson et al, 201299 Retrospective matched Rx – 2,527 MHD Oral intradialytic [ Survival
cohort Con - 2,527 supplement for 1 year
Weiner et al, 2014100 Retrospective matched Rx – 1,278 MHD Nutritional supplement Y Mortality
cohort Con - 1,278 protocol and ONS during
dialysis for 3 Months
CKD, chronic kidney disease; CPD, Chronic Peritoneal Dialysis; Con, Control Group; KDQOL-SF, Kidney Disease Quality of Life Short-FormÒ; MHD, maintenance hemodialysis; ONS,
Oral nutrition supplement; PEW, protein-energy wasting; Rx, Treatment Group; SGA, Subjective Global Assessment.

7
8 LODEBO ET AL
some evidence consistent with PEW, although many pa-
tients may not have satisfied all the criteria necessary for
the diagnosis of PEW.
The results of these trials indicate that increasing nutrient
intake in these patients does improve various measures of
protein, energy, vitamin, or mineral status. A number of
these trials have such limitations in design as small numbers
of subjects, short duration of study, or experimental subjects
who were not well characterized metabolically, clinically or
with regard to their inflammatory status. Nonetheless,
almost all trials indicate that increasing intake of nutrients,
and particularly protein or energy, is associated with
improvement in protein-energy nutritional status. More-
over, the finding that some subjects who received and re-
sponded to protein or energy supplements had
inflammation77,95 suggests that these supplements may
improve protein-energy status even in patients who are in-
flamed and who may have comorbid conditions.
Will Prevention or Treatment of PEW
Decrease Morbidity or Mortality or
Improve Quality of Life in CKD, MHD
and CPD Patients?
This is a key question for which there is no clear-cut
answer. The question is of substantial importance because
PEW is very common in advanced CKD and CD patients,
is associated with substantially increased mortality, and
often can be successfully treated. Because mortality rates
in the general CD population are quite high, an interven-
tion that may reduce this mortality rate is worthy of serious
attention. On the other hand, since PEW often occurs in
CKD and ESKD patients who have systemic inflammation
and superimposed illnesses,57 the increased mortality in
these patients may be related to their comorbid conditions
and their uremic condition, and the PEW itself may be sim-
ply an epiphenomenon that is caused by these comorbid-
ities. In this latter case, PEW would not be a cause of the
increased morbidity or mortality in these patients, and
treatment of the PEW per se might not result in an
improved clinical course. These considerations underscore
the critical need for randomized prospective controlled
clinical trials to test whether treatment to prevent or reduce
PEW will improve clinical outcome in CKD or CD pa-
tients. Such management could be multifactorial and
include treatment of comorbid conditions, prevention or
correction of acidemia, use of anti-inflammatory and
anti-oxidant agents to reduce inflammation and oxidant
stress, and nutritional support. We do not know how effec-
tive each of these maneuvers may be at reducing morbidity
or mortality, except perhaps for the effectiveness of alkali
treatment to slow the loss of GFR in CKD patients.102
Short-term studies in small numbers of CD patients con-
cerning the use of anti-inflammatory and antioxidant
agents have suggested some effectiveness, but the results
to date have not been highly encouraging.59,103 It is also
not known whether improvement or eradication of PEW
by nutritional therapy alone will improve clinical
outcomes. This is not an unimportant question, because
in many CKD or ESKD patients their comorbid illnesses
cannot be cured.
There are no randomized prospective clinical trials that
have examined whether nutritional supplements will
reduce morbidity or improve quality of life or survival in
nondialyzed CKD patients or CD patients. However,
several nonrandomized case-control studies indicate that
intradialytic parenteral nutrition and oral nutritional sup-
plements may improve survival in MHD pa-
tients.92,93,100,104 These findings provide further
justification for testing the thesis that nutritional support
for patients with PEW will reduce morbidity and
mortality and improve quality of life in these advanced
CKD and CD patients.
Practical Application
The syndrome of PEWoccurs commonly in people with
advanced CKD (i.e., eGFR ,20 mL/min/1.73 m2) and
in patients undergoing CD therapy. Although PEW has
many causes, signs of PEW often improve with nutritional
therapy. Data from some retrospective studies suggest that
treatment of PEW reduces mortality in CD patients. Ran-
domized prospective trials are needed to test more defini-
tively whether nutritional treatment of PEW will
improve morbidity, mortality, or quality of life in CKD
and CD patients.
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