EDITORIAL

Journal of Cachexia, Sarcopenia and Muscle (2019)

Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.12421

Kidney cachexia or protein-energy wasting in chronic

kidney disease: facts and numbers

Laetitia Koppe1* , Denis Fouque1 & Kam Kalantar-Zadeh2

1
Centre Hospitalier Lyon-Sud, Univ Lyon, CarMeN, Dept Nephrology, Pierre-Bénite, France, 2Harold Simmons Center for Kidney Disease Research and Epidemiology, Division
of Nephrology and Hypertension, University of California, Irvine, School of Medicine, Orange, Irvine, CA, USA

Abstract
Weight loss and homeostatic disturbances of both energy and protein balances are characteristics of several illnesses including
cancer, heart failure, and chronic kidney disease (CKD). Different definitions have been used to describe this deleterious pro-
cess. The term protein-energy wasting (PEW) has been proposed for CKD patients by the International Society of Renal Nutri-
tion and Metabolism. Since its inception, the term PEW has been exceptionally successful, highlighted by 327 original
publications referenced in PubMed over 10 years. Using this classification, several studies have confirmed that PEW is among
the strongest predictors of mortality in CKD patients [hazard ratio of 3.03; confidence interval of 1.69–5.26 in 1068
haemodialysis patients and 1.40 (1.04–1.89) in 1487 non-dialysed patients across PEW stages 0 to 4]. Based on this classifica-
tion, prevalence of PEW is 28% to 54% among 16 434 adults undergoing maintenance dialysis. PEW prevalence increases when
renal function declines, that is, from <2% in CKD stages 1–2 to 11–54% in CKD stages 3–5. A more general definition of ca-
chexia for all chronic diseases proposed by the Society on Sarcopenia, Cachexia and Wasting Disorders was also published con-
currently. In the CKD area, we found 180 publications using ‘cachexia’ underlining that some confusion or overlap may exist.
The definitions of PEW and cachexia are somewhat similar, and the main difference is that a loss of body weight >5% is a man-
datory criterion for cachexia but only supportive for PEW. The recent understanding of cachexia physiopathology during CKD
progression suggests that PEW and cachexia are closely related and that PEW corresponds to the initial state of a continuous
process that leads to cachexia, implicating the same metabolic pathways as in other chronic diseases. Despite the success of
the definition of PEW, using a more uniform term such as ‘kidney disease cachexia’ could be more helpful to design future
research through collaborative groups of researchers with focus on cachexia.
Keywords Cachexia; Protein-energy wasting; Chronic kidney disease; Energy intake; Malnutrition

*Correspondence to: Dr Laetitia Koppe, Dept Nephrology Nutrition and dialysis, Centre Hospitalier Lyon Sud, Pierre Bénite F-69495, France: Tel: +33 4 72 67 87 15; Fax: +33 4
72 67 87 10, Email: [email protected]

Protein-energy wasting/cachexia atherosclerosis (or cachexia) syndrome were used inter-

prevalence changeably, which might have caused confusion. Hence, the
exact criteria used to define the prevalence of cachexia and
Nutritional deficiencies have long been recognized as an ad- protein-energy wasting (PEW) in CKD were not consistent
verse effect of chronic kidney disease (CKD) and are associ- across studies, making it difficult to aggregate data. Using a
ated with reduced physical activity and poor survival.1–5 nutritional scoring system such as the subjective global as-
However, cachexia is poorly defined and managed in these sessment or by subjective global assessment or
patients, and a clearer definition of this condition is needed. malnutrition–inflammation score, the prevalence of
Indeed, the terms wasting, cachexia, malnutrition, protein- cachexia/PEW was found to be 28–80% of adults undergoing
energy malnutrition, and malnutrition–inflammation maintenance dialysis6–9 and as an increasing prevalence

© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcsopenia, Cachexia and Wasting Disorders
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
2 Editorial

when renal function declines. Indeed, during stages 1–2 CKD, period, still in CKD, 180 publications used ‘cachexia’
this prevalence is less than 2%9,10 and in stages 3–5 is esti- underlining that some confusion was still present.
mated to be 11–46%.10–13 In the last meta-analysis, including
16 434 patients on maintenance dialysis, 25th–75th percen-
tiles range in PEW prevalence was 28–54%.14 During stages
3–5 in 1778 patients, PEW prevalence was ranging from
What is the difference between
11% to 54%.14 cachexia and protein-energy wasting in
chronic kidney disease?
As shown in Table 1, the diagnostic criteria for cachexia (pro-
Definition of protein-energy wasting posed by the Society on Sarcopenia, Cachexia and Wasting
and kidney cachexia Disorders)15 and for PEW (proposed by the ISRNM)16 are sim-
ilar, but not identical. However, there is no obvious distinc-
The term ‘wasting’ was proposed by the World Health Orga- tion between PEW and cachexia from a pathophysiologic
nization in 1983 and was defined as an involuntary loss of standpoint, and limiting the term cachexia to extreme forms
weight of more than 10% of patient’s previous value in ab- of PEW is perhaps too restrictive. With our understanding
sence of an opportunistic infection, cancer, or chronic diar- of the mechanisms involved in the PEW/cachexia, should
rhea. Wasting or malnutrition were once believed to be these definitions evolve and reconcile?
invariably caused by inadequate nutritional intake and should
be reserved for this situation only. If wasting is often present
in CKD in response to anorexia-induced insufficient energy in- Body weight and body composition
take, it is not the only component of nutritional alterations. In
order to unify the description of the global systemic disorder The main criterion for cachexia (Table 1) is either a weight
including the loss of homeostatic control of both energy and loss >5% in the previous 12 months or a body mass index
protein balances, panels of experts participated in formal (BMI) <20 kg/m2 and does not seem satisfactory in the
consensus processes. A subsequent generic definition of ca- CKD context because low BMI is not always present at the
chexia (for all types of cachexia) was published in 2008 by early stages of nutritional disorders. Indeed, due to a ten-
the Society on Sarcopenia, Cachexia and Wasting Disorders.15 dency for elevated body weight in CKD, given that the aver-
Cachexia was defined as a complex metabolic syndrome asso- age BMI of US dialysis patients is >25 kg/m2,17 waiting for
ciated with underlying illness and characterized by a loss of a low BMI to consider cachexia would certainly induce a late
muscle, with or without loss of fat. At the same time, the In- diagnosis. In this regard, the use of BMI in the PEW definition
ternational Society of Renal Nutrition and Metabolism pro- and cachexia has been challenged.18 It is the authors’ opinion
posed a specific classification of uraemia-induced wasting that a specific BMI cut-off level should not be considered any-
disorders in which cachexia was the most severe stage of more in these classifications given racial and ethnic diversities
PEW.16 This classification became successful and the message and because the information provided by BMI does not over-
fairly well reached the nephrology community. Ten years come that brought by body weight. By contrast, weight loss is
later, a PubMed literature search (from inception to 12 Sep- an easy and more sensitive tool to monitor as the primary
tember 2018) identified 327 CKD publications that used clinical manifestation of cachexia. Indeed, body composition
PEW in their title (Figure 1). However, during the same is difficult to measure with precision in a clinical setting. Body

Figure 1 PubMed search using ‘Protein energy wasting (PEW)’ or ‘cachexia’ in chronic kidney disease (CKD) keywords.

Journal of Cachexia, Sarcopenia and Muscle 2019

DOI: 10.1002/jcsm.12421
 Editorial

Table 1 Criteria for the clinical diagnosis of protein-energy wasting (PEW) and cachexia in adults with chronic kidney disease

Criteria PEW (ISRNM) Cachexia (SCWD)

Serum chemistry Serum albumin <38 g/L Serum albumin <32 g/L
Serum prealbumin (transthyretin) <300 mg per 100 mL
(for maintenance dialysis patients only)
a
Serum cholesterol <100 mg per 100 mL
Anaemia <12 g/dL
Increased inflammatory markers CRP (>5.0 mg/L), IL-6 (>4.0 pg/mL)
2 2
Body mass BMI <23 kg/m BMI <20 kg/m
Unintentional weight loss over time at least 5% over 3 months or 10% Unintentional weight loss of at least 5% in 12 months
over 6 months
Total body fat percentage <10%
2
Muscle mass Muscle wasting: reduced muscle mass 5% over 3 months or 10% over Reduction of appendicle skeletal muscle index by DEXA (kg/m )
6 months <5.45 in women and <7.25 in men.
Reduced mid-arm muscle circumference area (reduction >10% in Reduced mid-arm muscle circumference area (<10th percentile for
relation to 50th percentile of reference population) age and gender)
Low creatinine appearance Fatigue = defined as physical and/or mental weariness resulting
from exertion; an inability to continue exercise at the same
intensity with a resultant deterioration in performance.
1 1 e 1 1
Dietary intake Unintentional low DPI <0.80 g kg day for at least 2 months for Unintentional low DEI <20 kcal kg day
dialysis patients
1 1
or <0.6 g kg day for patients with CKD stages 2–5
1 1 e
Unintentional low DEI <25 kcal kg day for at least 2 months Unintentional DEI <70% of usual food intake
Poor appetite
2
Definition of PEW/ At least three out of the four listed categories (and at least one Weight loss of at least 5% in 12 months or BMI <20 kg/m , plus
cachexia test in each of the selected category) three of the other criteria

BMI, body mass index; CKD, chronic kidney disease; DEI, dietary energy intake; DPI, dietary protein intake; IL-6, interleukin 6; ISRNM, International Society of Renal Nutrition and Me-
tabolism; SCWD, Society on Sarcopenia, Cachexia and Wasting Disorders.

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DOI: 10.1002/jcsm.12421
3
4 Editorial

weight loss remains a valid criterion; in a recent study includ- Biological criteria
ing almost 5000 patients, a significant weight loss began rel-
atively early during the course of CKD and was associated To assess nutritional disorders, biological criteria should be
with a substantially higher risk for death after dialysis therapy able to identify and risk stratify patients with PEW/cachexia,
initiation.19 Overall, both classifications have identified a non- distinguishing the causes and consequences of PEW/cachexia
voluntary weight loss as a phenotypical criterion based on a and the underlying diseases that lead to PEW/cachexia. How-
robust literature: greater than 5% within the past 6 months ever, some nutritional markers used in cachexia, such as
or >10% beyond 6 months as recently proposed by the anaemia, are influenced by CKD and cannot be used. There
Global Leadership Initiative on Malnutrition.20 The presence is also no consensus on the role and pertinence of inflamma-
of a critical weight loss (>5% in 6 months) should probably tion in the criteria of PEW and cachexia. In the initial defini-
be considered as a major criterion to define cachexia/PEW. tion of PEW, it was proposed that inflammation could be a
By contrast, a more moderate weight loss (<5%) should be source of confusion by supposing that PEW was exclusively
considered as one criterion among others. because of inflammation.16 The central role of cytokines or
Muscle wasting (or sarcopenia) is obviously acknowl- inflammation into the pathophysiology of cachexia is still an
edged as an important feature in the pathophysiology of outstanding question. Numerous experimental and clinical
the cachexia phenotype and predisposes to increased risk data have highlighted that inflammation acts directly on tar-
of co-morbid complications.15,21,22 In both definitions, mea- get tissues as well as through alteration of central nervous
sures of muscle mass by mid-arm muscle circumference system (dysregulation of appetite), neuroendocrine targets
area are present. In contrast to PEW, the diagnostic criteria (such as the release of adrenal steroids), sickness behaviour
for cachexia emphasize muscle functional measures (such (such as anorexia and fatigue), and muscle catabolism.34
as muscle strength or fatigue). Indeed, muscle strength is In cancer cachexia, the important role of inflammation is
an independent predictor of renal outcomes in CKD now indisputably admitted. Numerous pro-inflammatory
patients and can be helpful in diagnosing cachexia/PEW in cytokines are generated through tumour crosstalk with
this population.23,24 In the PEW definition, creatinine ap- associated stromal cells, and the immune system and inflam-
pearance is proposed to estimate muscle mass but its accu- mation is the cornerstone of cancer cachexia.35 In CKD, in-
racy and reproducibility are weak, and in our opinion, this creased serum inflammatory cytokines predispose to the
criterion is probably not used much nowadays.25 Mechani- pathogenesis of PEW.36–38 Accumulating data also suggest
cally, an increase in muscle proteolysis by a common tran- that during CKD, specific accretion of uremic toxins may have
scriptional programme is always present despite the diverse a direct effect on inflammation stimulation and cytokines
nature of cachexia, primarily through the ubiquitin- production.39 Therefore, inflammation contributes to PEW/
proteasome system and the coordinated induction of cachexia in several ways, both by direct and indirect mecha-
atrophy-related genes (atrogenes) by FOXO transcription nisms of muscle proteolysis and by impinging upon and
factors.21,26,27 magnifying other causes of PEW in a vicious circle. Therefore,
There is questioning about the role of fat in cachexia and the rationale not to include inflammatory criteria in the
until now, fat loss is not considered as an important feature PEW criteria might be reconsidered.
of cachexia except in the PEW classification. In epidemiologi-
cal studies, adipose tissue wasting has been associated with
an increased risk of death in different cachexia diseases.28– Protein and energy intake
30
The discovery about the ability of white adipose tissue to
be turned towards the brown adipose phenotype with ther- An unintentional reduction in dietary energy intake is a crite-
mogenesis capacity, leading to increased energy expenditure rion of both cachexia and PEW definitions. In the PEW–CKD
and lipid mobilization, underlines the importance of this field, an intake less than 25 kcal per kg body weight is
tissue in cachexia. Experimental data also suggest that this proposed, and for cachexia, it is 20 kcal per kg body weight.
phenomenon appears before skeletal muscle atrophy.31–33 It is recognized that there are pitfalls in identifying a decrease
The browning inductors could be similar in different cachexia in energy intake. In order to help energy intake management,
such as those induced by parathyroid hormone (PTH) in the gap between energy expenditure and energy intake can
CKD and PTH-related peptide (PTHrP) in cancer.33 In this be estimated from direct measures of resting energy expendi-
situation, PTH/PTHrP-induced fat-derived molecules, that is, ture (indirect calorimetry) and indirect measures by records
adipokines, free fatty acids, or other metabolites, mediate of dietary intake.40 However, this is not routinely performed
the crosstalk between muscle and fat that contributes in a and until now, there is no consensual value of a ‘low’ energy
major way to tissue catabolism. Despite this, there is cur- intake. The other main difference is protein intake, which has
rently no consensus about the optimal fat mass or fat loss only been considered in the PEW definition. Although it is
value suggesting the presence of PEW, and fat was not generally accepted that the protein needs of cachectic pa-
retained in the last nutrition recommendation.20 tients are increased, the existing international guidelines on

Journal of Cachexia, Sarcopenia and Muscle 2019

DOI: 10.1002/jcsm.12421
Editorial 5

the optimal amounts of protein and amino acid intakes are very similar and induce a comparable phenotype. We would
vague.41 This suggests that protein intake could be integrated like to suggest that PEW is cachexia and should be termed
in the cachexia criteria and is not specific of the uremic con- ‘kidney disease cachexia’ as a continuum with PEW first
dition. For instance, a low protein diet is suggested for the followed by cachexia. Substituting PEW by kidney disease ca-
management of CKD with normal nutrition status.42 chexia might be less confusing to describe a similar phenom-
enon observed in other cachectic diseases as seen in
cancer.22 Finally, cachexia definition should evolve to better
Conclusion describe the reality and take into account fat loss and insuffi-
cient protein intake. Future research will undoubtedly dem-
Assessment of protein and energy status is a broad and com- onstrate and confirm that criteria of cachexia are similar
plex topic, in particular in CKD. No consensus is available on and helpful in monitoring nutritional disorders in CKD.
the definition of and methods for measuring skeletal muscle
depletion, reduced food intake, and the biological indicators
of altered metabolism. The aim of PEW nomenclature was Acknowledgement
to unify terminology to describe a cachectic disorder that oc-
curs in many patients with CKD. The implementation of this This study was supported by Université de Lyon and Hospices
classification was a great success, and contrary to the generic Civils de Lyon, France.
cachexia definition proposed by Evans and co-workers,15 PEW L.K. and D.F. have no conflict of interest to disclose. K.K.Z.
has been validated to predict mortality in several cohorts of has received honoraria from Abbott Nutrition and Fresenius
CKD patients.5,43 In addition, using a generic vs. a specific def- Kabi.
inition in the kidney disease population has not been per- All authors declare that the submitted work has not
formed so far. We do not know whether this may improve been published before (neither in English nor in any other
diagnosis and management of adverse outcomes in these pa- language) and that the work is not under consideration for
tients. However, differences between PEW16 and cachexia15 publication elsewhere.
are very limited (Table 1) and without strong justification. Ini- The authors certify that they comply with the ethical
tial triggers of cachexia may be different between chronic dis- guidelines for publishing in the Journal of Cachexia,
eases but the catabolic pathway and physiopathology are Sarcopenia and Muscle: update 2017.44

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Journal of Cachexia, Sarcopenia and Muscle 2019

DOI: 10.1002/jcsm.12421