Review Articles

Uremic Malnutrition: New Insights Into an Old Problem

Lara B. Pupim and T. Alp Ikizler
Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center,
Nashville, Tennessee

ABSTRACT
Uremic malnutrition is highly prevalent and is associated with
poor clinical outcomes in end-stage renal disease (ESRD)
patients. Inadequate diet and a state of persistent catabolism
play major roles in predisposing these patients to uremic
malnutrition and appear to have an additive eect on overall
outcome. Recent studies highlight the existence of a complex syndrome involving chronic inammation, metabolic

abnormalities, and hormonal derangements contributing to

the increased morbidity and mortality observed in ESRD
patients. Novel strategies such as appetite stimulants, antiinammatory drugs, and anabolic hormones along with
conventional nutritional supplementation may provide potential interventions to improve clinical outcome in ESRD
patients.

The incidence and prevalence of chronic renal failure

(CRF) leading to end-stage renal disease (ESRD) is
increasing at an alarming rate, especially in industrialized
countries. The number of incident patients on renal
replacement therapy (RRT) has doubled over the last
decade; there are currently approximately 300,000
patients on RRT in the United States (1). More alarming
is the excessively high mortality rate of this patient
population (21% in 1998), despite signicant advances in
the management strategies in RRT (1). It is therefore
vital to identify and treat conditions associated with these
poor clinical outcomes.
The importance of nutritional status as a predictor of
morbidity and mortality has been established by the
studies of Lowrie et al. (2). These studies were followed
by multiple additional reports, all pointing out the value
of certain nutritional parameters in predicting clinical
outcomes in ESRD patients. Based on the abundance of
such studies and the concordance of results and conclusions, that is, that nutrition is an important determinant
of clinical outcome, one would expect to see changes in
practice patterns and improvements in outcomes that are
nutritionally related in ESRD patients (3). Nonetheless,
there have been limited changes in the nutritional
management of ESRD patients over the last decade. In
fact, the nutritional support available to ESRD patients
has regressed rather than advanced, mainly due to
heavily imposed Medicare restrictions.
In the following article we will provide an overview of
recent advances in nutritionally related research in ESRD
patients, with specic emphasis on newly identied risk

factors for poor nutritional status. We will also provide

insights into the assessment of nutritional status and
discuss recent studies on nutritional interventions in this
patient population.

Protein and Energy Malnutrition versus

Uremic Malnutrition
Protein energy malnutrition (PEM) is classically
dened as poor nutritional status due to inadequate
nutrient intake (4). Indeed, the contribution of low
protein and energy intake due to restrictive dietary
prescriptions, taste abnormalities, and uremia-related
anorexia is well recognized in the pathogenesis of PEM in
all stages of CRF (Table 1) (3). Since nutrients are the
substrate necessary for cell and tissue development and
maintenance, it seems obvious that over time, insucient
amounts of protein and energy intake may result in
PEM. Nevertheless, advanced PEM solely related to
inadequate nutrient intake is relatively uncommon, even
in chronic disease states.
Studies have shown that healthy subjects as well as
chronic kidney disease (CKD) patients who have not
reached ESRD are usually able to maintain neutral
nitrogen balance with lower levels of protein intake (0.6
g/kg/day) if energy intake is adequate (5). In stable CKD
patients, this compensatory response is mediated
through a combination of metabolic adjustments, such
as a reduction in amino acid oxidation and protein
breakdown and an increase in protein synthesis, all in an
attempt to maintain neutral nitrogen balance (6).
Further, once CKD patients initiate maintenance hemodialysis (HD), their dietary protein intake increases, at
least during the rst year of therapy (79).
The high prevalence of poor nutritional status in spite
of relatively adequate dietary protein and energy intake
suggests that PEM is not the only cause of poor

Address correspondence to: T. Alp Ikizler, MD, Vanderbilt

University Medical Center, 1161 21st Ave. South & Garland,
Division of Nephrology, S-3223 MCN, Nashville, TN 372322372, or e-mail: alp.ikizler@vanderbilt.edu.
Seminars in DialysisVol 16, No 3 (MayJune) 2003
pp. 224232
224

UREMIC MALNUTRITION

TABLE 1. Important etiologic factors for uremic malnutrition

Inadequate protein and energy intake
Anorexia (due to uremic toxicity, taste abnormalities,
and glucose caloric load and abdominal discomfort in PD)
Frequent hospitalizations
Multiple medications
Abnormal gastric emptying
Comorbidities
Diabetes mellitus
Gastrointestinal diseases
Cardiovascular diseases
Inammation (systemic inammatory response syndrome)
Metabolic and hormonal derangements
Metabolic acidosis
Resistance to anabolic hormones (insulin, IGF-1, GH)
Increased resting energy expenditure
Inadequate dialysis dose
HD-associated catabolism
Amino acid losses
Bioincompatibility
Inammation
GH, growth hormone; HD, hemodialysis; IGF-1, insulin-like
growth factor-1; PD, peritoneal dialysis.

nutritional status in ESRD patients. Further, the

denition of PEM does not explain the observed
combination of metabolic and hormonal abnormalities
leading to a state of protein catabolism and loss of lean
body mass associated with uremia. We believe that the
poor nutritional status observed in ESRD patients can be
better termed uremic malnutrition, since it represents a
unique form of malnutrition related to uremia-induced
complications.
Nutritional Parameters and Relevance to
Clinical Outcome
The critical importance of nutritional status in ESRD
patients is suggested by the observation that certain
measures of nutritional status are closely associated with
clinical outcome. For example, hypoalbuminemia is the
most powerful predictor of death in ESRD patients (2).
Therefore the validity of these measures, as they reect
the nutritional status, is of extreme importance. An ideal
and reliable nutritional marker should either predict
clinically important outcomes, such as hospitalization
and death, or identify patients who should receive
nutritional intervention.
Over the last several years, concerns have been raised
regarding the validity of the biologic markers used to
evaluate nutritional status in ESRD patients. The most
clinically relevant of these concerns is related to serum
albumin. A large number of studies have shown that
serum albumin is a reliable indicator of nutritional status
(2,1016), which also displays a notable response to
nutritional intervention. On the other hand, ESRD
represents a unique condition that inuences serum
albumin homeostasis in multiple ways. ESRD patients
have substantially altered total body water distribution
and frequently experience changes in plasma volume,
both of which are known to aect albumin turnover and
consequently serum albumin concentrations (12,17).
Further, chronic inammation is highly prevalent in

225

ESRD patients, another metabolic state known to

inuence albumin turnover (12,17,18). To date, there
have been very limited studies evaluating the validity of
serum albumin as a nutritional marker in the presence of
inammation and/or other metabolic conditions.
Based on the available data and the strong predictive
value of serum albumin regarding clinical outcomes, it is
very unlikely that a patient with hypoalbuminemia will
be considered well-nourished by a clinician (10). Therefore serum albumin should be routinely assessed to
identify potentially low protein stores and uremic
malnutrition in ESRD patients. In the meantime, there
is a need for prospective studies evaluating the validity of
serum albumin as a nutritional marker and its ability to
predict clinical outcome under dierent metabolic conditions.
In addition to serum albumin, serum prealbumin and
serum transferrin have been proposed as biochemical
nutritional markers in ESRD patients. While these
markers have certain advantages, such as earlier response
to nutritional changes and more precise assays, both are
also aected by inammatory response and have other
limitations inherent to ESRD. Prealbumin is excreted
through the kidney and transferrin is closely related to
iron metabolism. Further, neither of these parameters
has been studied as thoroughly as albumin in ESRD
(1921). Perhaps the spread of the use of immunoassays
for the measurement of serum albumin and other
markers will bring us more denitive conclusions about
the contributions of dierent outcome predictors in the
ESRD population (22).
Measurement of somatic protein stores is commonly
used for assessment of nutritional status in ESRD
patients. Anthropometrics, lean body mass measurements by dual-energy X-ray absorptiometry (DEXA),
and bioelectrical impedance analysis (BIA), as well as
certain more sophisticated techniques such as total
body nitrogen (TBN), have been studied in this patient
population. DEXA seems to be the most reliable body
composition method for ESRD population (2325),
with fewer assumptions regarding the inuence of uid
status on fat mass measurements compared to BIA
(24). A recent report found BIA to be an accurate
method to measure lean body mass against TBN, a
gold standard technique (2628). Further, several BIAderived parameters (i.e., phase angle and reactance)
have been associated with other nutritional parameters
and clinical outcomes in ESRD patients (28,29). It
should be noted that, as with biochemical markers,
these techniques are also inuenced by ESRD-related
limitations (30).
Subjective global assessment (SGA) has recently
gained signicant attention in the nephrology community (31). It refers to an overall clinical evaluation,
including assessment of weight and weight change,
dietary intake, gastrointestinal symptoms, and functional status. For subjective measurements such as SGA,
standardization, guidelines, and experience are important. Clinicians should note dierences between certain
changes in function that are related to nutritional status
and those that are not (31). Similarly extracellular
volume status needs to be accounted for in order to

226

Pupim and Ikizler

avoid masking muscle wasting by the presence of edema

(32). SGA has been generally well correlated with
commonly used and objective measures of nutritional
status in dierent populations, including CKD and
ESRD, and is associated with clinical outcomes in
peritoneal dialysis (PD) patients (26,3134). There have
been suggestions that 1) SGA is a measure of health
status rather than nutritional status and that 2) nutritional status alters muscle performance (detected by
SGA) earlier than body composition (not accurately
detected by SGA) (35,36). Indeed, a recent study by
Cooper et al. (26) suggested that SGA may not reliably
predict degrees of uremic malnutrition. Further, there are
no studies to date, at least to our knowledge, showing
longitudinal changes in SGA rating with nutritional
intervention. These studies are still needed to validate
SGA as a nutritional marker in ESRD patients.
It is surprising that randomized controlled studies are
still lacking on the impact of improvements in any of
these parameters of nutritional intervention on important clinical outcomes. Nevertheless, the use of combinations of these (and other) measurements currently is the
only practical means of diagnosing uremic malnutrition.
They should be rigorously employed to assess patients
for uremic malnutrition and guide us for appropriate
nutritional intervention.
Factors Associated with Uremic Malnutrition
Metabolic and Hormonal Derangements
Multiple metabolic and hormonal derangements are
associated with uremic malnutrition. Extensive studies
by Mitch and Goldberg (37,38) have conclusively shown
that metabolic acidosis, through activation of the
ubiquitin-proteasome pathway by a glucocorticoiddependent mechanism, induces protein breakdown and
amino acid oxidation and decreases muscle protein
synthesis, which will ultimately result in loss of lean body
mass. Further, the correction of acidosis has been shown
to improve nutritional status and to prevent acidosisrelated muscle wasting (39).
More recently it has been suggested that abnormalities
in growth hormone (GH) and the insulin-like growth
factor (IGF)-1 axis constitute an important factor in the
development of malnutrition in uremic patients (40). GH
is the major promoter of growth in children and exerts
several anabolic actions in adults, such as enhanced
protein synthesis, increased fat mobilization and
increased gluconeogenesis. IGF-1 is the major mediator
of these actions. Evidence suggests that uremia is
associated with the development of resistance to GH
action at the cellular level. In animal experiments, uremia
is characterized by reduced hepatic GH receptor messenger RNA (mRNA), as well as reduced hepatic IGF-1
mRNA expression (41) and a defect in GH signal
transduction (42). This blunted response would be
expected to attenuate the anabolic actions of these
hormones.
Insulin is a major anabolic hormone, stimulating
muscle protein synthesis and suppressing protein degradation (43,44). Uremia is also characterized by resistance

to insulin. While the insulin binding to its receptor in

CKD and ESRD patients is normal, there is a postreceptor defect in tissue insulin responsiveness, causing
insulin resistance and glucose intolerance. These abnormalities can also be observed with decreased food intake,
as well as in experimental metabolic acidosis. Metabolic
acidosis further causes impaired function and/or resistance to several anabolic hormones, including insulin,
GH, and thyroid hormone (45,46). In the aggregate,
current evidence suggests an interesting, as yet ill-dened
interrelationship between these hormonal, metabolic,
and nutritional factors, that is, that they are all involved
in the evolution of malnutrition in CKD and ESRD
patients.
HD-Associated Catabolism
That HD is a catabolic procedure was suggested by the
studies of Borah et al. (5). They showed that on dialysis
days, patients were in negative nitrogen balance, even
with high levels of protein intake. These studies were
based on indirect measures of protein and energy
metabolism, that is, nitrogen balance. Using more precise
methodology, namely stable isotope tracer technique,
Lim et al. (47) studied the eects of HD on whole-body
protein metabolism and reported that the catabolic
eects of HD were limited to amino acid losses.
In a more recent study, our laboratory has conrmed
that the HD procedure is indeed a catabolic process via
dierent mechanisms than those previously suggested.
These include decreased levels of circulating amino
acids, accelerated rates of whole-body and muscle
proteolysis, and stimulation of muscle release of amino
acids, resulting in increased net whole-body and muscle
protein loss. Further, these abnormalities persisted for at
least 2 hours after completion of an HD treatment, an
observation that has not been reported previously (48).
Notably these derangements were observed with the use
of biocompatible HD membranes and relatively pure
dialysate. The implications of these ndings are that the
HD procedure initiates certain metabolic pathways,
resulting in both decreased protein synthesis and
increased protein breakdown. In addition to eects on
protein homeostasis, substrate oxidation was also
signicantly altered following HD, with diminished
carbohydrate and accelerated lipid and amino acid
oxidation.
Inflammation as a Catabolic Factor in ESRD
Recent studies have pointed out that ESRD patients
have a high prevalence of elevated levels of inammatory
markers (29,4952). Kimmel et al. (49) have reported
that mean concentrations of most proinammatory
cytokines in chronic dialysis patients are several-fold
higher than in normal healthy controls. In addition,
several cross-sectional studies have shown that levels of
C-reactive protein (CRP), a well-established marker of
acute-phase response, are very commonly elevated in
both HD and PD patients (29,51,53).
The etiology of chronic inammation in dialysis
patients is multifactorial, as discussed in a recent, detailed

227

UREMIC MALNUTRITION

review by Kaysen (54). In brief, these factors include

decreased clearance of cytokines and accumulation of
uremic toxins (middle molecules, parathyroid hormone,
leptin) due to decreased renal function, certain dialytic
factors such as HD membrane-associated complement
activation, endotoxin transfer, protein catabolism, peritoneal dialysate bioincompatibility, and vascular access
(polytetrauoroethylene (PTFE) grafts, catheters), as
well as certain comorbidities including chronic infections
(periodontal disease, peritonitis), diabetes mellitus,
atherosclerosis, and congestive heart failure (Fig. 1)
(5557).
An additional interesting observation is that markers of inammation and uremic malnutrition tend to
coexist in ESRD patients. A study by Stevinkel et al.
(51) demonstrates this relationship in advanced CKD
patients not yet on maintenance dialysis. In this study
of 109 patients with advanced CKD, 44% had
moderate to severe uremic malnutrition by SGA and
32% had signs of inammation by elevated CRP
concentrations (51). Most importantly, 53% of the
patients with uremic malnutrition had signs of inammation and 72% of the patients with inammation
had signs of uremic malnutrition. A similar observation was made by Qureshi et al. (52) in dialysis
patients. Those with severe uremic malnutrition had
about a fourfold higher prevalence of chronic inam-

mation (CRP > 20 mg/L) than did well-nourished

dialysis patients (52).
Chronic Inflammation Contributes to the
Development of Uremic Malnutrition
Inammation, more correctly termed systemic inammatory response syndrome, is a complex combination of
physiologic, immunologic, and metabolic eects occurring in response to a variety of stimulators resulting from
tissue injury or disease processes. Certain cytokines, such
as interleukin (IL)-1, IL-6, and tumor necrosis factor
(TNF)-a, are the primary mediators of these eects. Since
the predominant metabolic eects of these cytokines are
catabolic, it is important for the host to limit their
biologic activities by eliciting a strong anti-inammatory
response. However, in conditions where the inammatory response is ongoing and cannot be controlled
eectively, such as in chronic diseases, adverse eects on
the host may result. In these circumstances there are
repetitive stimuli for cytokine release with subsequent
adverse eects to the host.
The metabolic and nutritional eects of chronic
inammation are many and include anorexia, increased
skeletal muscle protein breakdown, increased wholebody protein catabolism, cytokine-mediated hypermetabolism, and disruption of the GH and IGF-1 axis

Decreased Renal Function

Dialytic Factors

Co-morbidities

Decreased clearance of cytokines

Accumulation of uremic toxins

Bioincompatibility
Backfiltration/Endotoxins
Protein Catabolism
Vascular Access

Chronic infections
Diabetes mellitus
Atherosclerosis
Congestive heart failure

Inflammation

Anorexia

Hormonal Derangements

Protein and Energy Intake

Energy Expenditure

Complement Activation

Leptin

GH and IGF-1 Resistance

Net Protein Catabolism

Loss of Lean Body Mass

Fig. 1. Proposed interrelationship between inammation and uremic malnutrition.

228

Pupim and Ikizler

leading to decreased anabolism (Fig. 1) (55,58). These

eects closely mimic the metabolic abnormalities leading
to uremic malnutrition observed in dialysis patients.
These ndings, along with the fact that chronic inammation and uremic malnutrition are highly prevalent in
dialysis patients and tend to coexist, lead us to believe
that the chronic inammation observed in dialysis
patients is a causative factor for their poor nutritional
status.
Anorexia or suppression of nutrient intake is a wellestablished metabolic eect of inammation. Clearly,
proinammatory cytokines such as IL-1 and TNF-a
are capable of this eect. Animal studies suggest that
the direct eects of these cytokines on the satiety
center probably explain this nding. Prostaglandins
may be involved in this chronic process since prophylactic use of anti-inammatory agents blunts the
anorectic eects of cytokines (59). Further, animal
studies have also shown an increased skeletal muscle
protein breakdown with TNF-a (with or without IL-1)
administration (60). Elevated levels of IL-6 are also
associated with increased muscle proteolysis, and the
administration of IL-6 receptor antibody can block
this eect (61). In surgical patients, sepsis is associated
with increased whole-body protein catabolism (62).
Thus the combined presence of decreased nutrient
intake and a state of increased protein breakdown
worsens the overall nitrogen balance, predisposing the
patients to accelerated PEM.
Another well-known eect of inammation is the
activation of the complement system. The activation of
the complement cascade secondary to the use of
bioincompatible HD membranes may in turn add to
the burden of uremic malnutrition in these patients.
Experimental studies by Gutierrez et al. (63) have shown
the protein catabolic eects of bioincompatible membranes. In addition, our laboratory has conrmed the
benecial nutritional eects of biocompatible membranes in dialysis patients in a prospective randomized
trial (64). Specically the use biocompatible membrane
was associated with signicantly higher concentrations
of serum albumin and serum IGF-1 as well as signicantly higher weight gain compared to the use of
bioincompatible membranes (cuprophane, cellulose
acetate, and cellulose diacetate). While recent epidemiologic studies suggest that bioincompatible HD membrane use in the United States is sharply declining (22%
in 1996), this is one of the potential causes of the adverse
metabolic eects of inammation that can be easily
prevented.
Chronic inammation is also associated with cytokine-mediated hypermetabolism. Indeed, increased resting
energy expenditure (REE) is observed in most chronic
inammatory states, such as congestive heart failure,
rheumatoid arthritis, and most forms of cancer (65).
While the exact mechanism of the increased REE in these
patients is not well delineated, a commonly high REE has
been observed in association with increased concentrations of proinammatory cytokines. ESRD patients also
have increased REE (66), which is further increased by
HD, even using biocompatible membranes (48,67).
Under such conditions, chronic dialysis patients are at

risk for a large negative energy balance predisposing

them to uremic malnutrition, especially since their
dietary energy intake is frequently inadequate to compensate for their increased REE (66).
Several other indirect eects of chronic inammation
can also predispose CRF patients to hypercatabolism
(55). Chronic inammation induces a decrease in
voluntary activity and the disease initiating the inammation may require bed rest. A prolonged decrease in
muscle activity is associated with muscle weakness,
muscle atrophy, and negative nitrogen balance, all
leading to loss of lean body mass. Finally, there are
certain hormonal derangements observed during chronic
inammation. These include disruption of the GH and
IGF-1 axis, leading to decreased anabolism and
increased leptin concentrations, which may induce
anorexia due to central eects (68).
Coexistence of Uremic Malnutrition and
Inflammation Increases Morbidity and
Mortality Risk
As noted previously, uremic malnutrition constitutes
the most important risk factor for poor clinical outcomes
in ESRD patients (2,29,40,69). Recent studies have
pointed out that markers of chronic inammation are
also independently associated with adverse clinical
outcomes in ESRD patients (29,53,7074). While these
two unfavorable conditions independently predispose
ESRD patients to an increased risk of morbidity and
mortality (55), their coexistence has an exponential
relationship to morbidity and mortality, that is, a small
increase in the severity of either condition leads to
signicant worsening of morbidity and mortality. This
observation emphasizes the critical importance of these
two unfavorable conditions in chronic dialysis patients
and calls for novel treatment strategies.
Treatment Options for Uremic Malnutrition
Given the signicance of the problem, as well as the
complexity of the pathophysiologic basis of uremic
malnutrition, it is evident that the prevention and
treatment options of uremic malnutrition are both
critical and complex. To date, there is not a single
treatment approach that will alleviate the multiple
adverse consequences of uremic malnutrition. In the
subsequent section we will provide an overview of
established prevention and treatment options for uremic
malnutrition as well as certain promising novel strategies.
General Measures
Certain general measures for prevention and treatment of uremic malnutrition should be considered in all
ESRD patients. Considering the catabolic nature of
uremia and chronic dialysis, it is clear that ESRD
patients should be continuously encouraged to maintain an adequate protein and energy intake. Most of
these patients tend to continue their predialysis diets

229

UREMIC MALNUTRITION

Nutritional Supplementation
Due to the magnitude of the catabolic processes
leading to uremic malnutrition, dietary counseling
alone fails to optimize dietary intake in certain
subgroups of malnourished dialysis patients. For these
patients, other forms of supplementation such as
enteral (including oral protein, amino acid tablets and
energy supplementation, nasogastric tubes, and percutaneous endoscopic gastroscopy or jejunostomy tubes)
as well as intradialytic parenteral nutrition (IDPN) can
be considered.
Oral Supplementation. There are only a limited
number of studies evaluating the efcacy of oral
nutritional supplementation in dialysis patients and they
have shown conicting results (7678). Nevertheless,
recent preliminary reports provide intriguing data
regarding benecial effects of oral nutritional supplementation in chronic dialysis patients. Eustace et al. (79)
reported that oral amino acid supplements signicantly
improved serum albumin concentration in HD subjects
in a prospective, randomized, placebo-controlled pilot
study. In a more recent study, Caglar et al. (80) found
that oral nutritional supplementation improved several
nutritional parameters (including serum albumin and
serum prealbumin concentrations, as well as SGA) in a
large group of malnourished chronic HD patients. A
novel aspect of this study is that nutritional supplementation was given during HD, which not only improved
compliance, but also provided supplements at a time
when catabolism is at its highest level in these patients
(80). While provocative, these studies can be considered
as preliminary, with ndings that warrant larger, randomized clinical trials. In the meantime, as a practical
measure, oral nutritional supplementation should be
attempted in malnourished dialysis patients if the
problems that could be responsible for reducing nutrition
intake cannot be resolved.

of precise tools for the assessment of response to

treatment. The most commonly utilized biochemical
markersserum albumin, serum prealbumin, and
serum transferrinare aected by multiple covariates,
as previously noted. Due to the lack of precision, large
sample sizes are required to obtain statistically meaningful results evaluating IDPN in dialysis patients. On
the other hand, there are markers that provide reliable
quantitative data in a relatively short period of time and
are directly aected by the nutritional intervention,
namely assessment of metabolic response with the use of
tracer methods that utilize stable isotopes. Using
metabolic assessment techniques, we have recently
shown that IDPN promoted a robust increase in wholebody protein synthesis and a concomitant decrease in
whole-body proteolysis along with a signicant increase
in forearm muscle protein synthesis in chronic HD
patients (83). The net result was a change from an
essentially catabolic state to a highly positive protein
balance both in whole-body and forearm muscle
compartments (Fig. 2) (83).
These preliminary observations provide evidence to
support the limited number of long-term clinical studies
reporting benecial eects of IDPN administration in
ESRD patients. Cano et al. (82), in a randomized
controlled study, reported improvements in multiple
nutritional parameters with IDPN in a group of 26
malnourished chronic HD patients. In a retrospective
analysis of more than 1500 chronic HD patients treated
with IDPN, Chertow et al. (84) reported a decreased risk
of death with the use of IDPN, particularly in patients
with serum albumin concentrations less than 3.5 g/dl and
serum creatinine concentrations less than 8 mg/dl; these
patients showed substantial improvements in nutritional
parameters following the use of IDPN. Over a 9-month

whole-body protein metabolism (mg/kg FFM/min)

while on RRT. It is therefore especially important to

ensure that the protein and energy intake of these
patients meets their increased requirements after initiation of RRT (3). Frequent comprehensive dietary
counseling by an experienced dietitian is important, as
is detection of early signs of uremic malnutrition. Such
eorts should be made not only in outpatient settings,
but also when the patients are hospitalized, a setting in
which protein and energy intake is frequently even
more decient (75).

7.0
P<0.05

6.0
5.0

P<0.05

P<0.05

4.0
3.0
2.0
1.0
0.0

IDPN. Several recent reports have recommended that

-1.0
IDPN be used in malnourished chronic dialysis patients
if enteral nutritional supplementation is not effective.
-2.0
Early studies, as well as several subsequent studies,
-3.0
reported positive effects of intradialytic infusions of
Protein Synthesis
Proteolysis
Net Balance
nutrients on several nutritional parameters (81,82). In
contrast, other studies were not able to show any benet
Control IDPN
of IDPN. Of note, these studies had drawbacks in design
and the choice of patient populations.
Fig. 2. Whole-body protein components during hemodialysis
An important downside for the studies evaluating
with and without IDPN. Units are mg/kg FFM/min. Republished
parenteral and/or enteral supplementation is the lack 60 with permission from Journal of Clinical Investigation.

230

Pupim and Ikizler

period, Mortelmans et al. (85) prospectively evaluated 26

malnourished chronic HD patients who failed to
improve with diet counseling. They reported signicant
increases in body weight, fat mass, and triceps skin fold.
This treatment mode is therefore most eective in
patients with moderate to severe malnutrition.
Similar studies using amino acid dialysate (AAD) as a
nutritional intervention in malnourished PD patients
have provided conicting results. Jones et al. (86)
reported a benet from AAD, with increases in serum
transferrin and total protein concentrations as well as a
tendency of plasma amino acid proles toward normal
levels with one or two exchanges of AAD. Of interest is
that there were signicant improvements in serum
albumin and prealbumin concentrations in malnourished PD patients, particularly in those who had serum
albumin concentrations in the lowest tertile (86). It
should also be noted that an increase in blood urea
nitrogen (BUN) concentration associated with exacerbation of uremic symptoms, as well as metabolic acidosis,
remains a complication of AAD (87). These results are
consistent with reports suggesting that these interventions are most useful in dialysis patients with severe
malnutrition.
Overall the available evidence suggests that IDPN and
AAD may be useful in the treatment of malnourished
chronic dialysis patients and oers an alternative method
of nutritional intervention in dialysis patients in whom
oral or enteral intake cannot be maintained. However,
available data support the limited number of long-term
prospective studies reporting benecial eects of IDPN
and AAD in ESRD patients. Furthermore, there are no
data to show that aggressive nutritional supplementation
through the gastrointestinal tract is inferior to parenteral
supplementation in dialysis patients. Until a controlled
study comparing various forms of nutritional supplementation in similar patient groups is completed, one
should be cautious in choosing very costly nutritional
interventions. In the meantime, large scale, well-designed
nutritional intervention studies in chronic dialysis
patients with overt uremic malnutrition are desperately
needed.
Experimental Nutritional Therapies
Anabolic Agents. The availability of recombinant
forms of certain anabolic agents has made it possible to
utilize pharmacologic doses of these agents to promote
net anabolism in multiple patient populations. Several
preliminary studies have suggested that recombinant
human growth hormone (rhGH) administration, especially when given along with nutritional supplementation, results in signicant improvements in nitrogen
balance, serum albumin, serum transferrin, and IGF-1
concentrations (88,89). Recombinant human IGF-1
(rhIGF-1) has also been proposed as an anabolic agent,
but the side effect prole of this agent, at least as
observed in CRF patients, may impede its widespread
use at this time (90). Of interest is that the combined use
of rhGH and rhIGF-1 in healthy subjects has yielded
the most efcient anabolic action, with the fewest side
effects (91). Whether long-term use of these agents in

malnourished HD and PD patients will result in

improved nutritional parameters and better outcomes
is not yet known.
Appetite Stimulants. Appetite stimulants such as
megestrol acetate are new treatment options for which
only very limited studies exist in the ESRD population
(92). Although a variety of benets have been
suggested, compliance, appropriate dosing, and side
effect proles are important issues that remain to be
evaluated in these drugs. Large-scale prospective
studies are needed to assess whether they are of value
as an adjunctive nutritional therapy in dialysis patients
(9395).
Anti-Inflammatory Interventions. With the
understanding that chronic inammation is an important catabolic factor, new strategies aimed at blocking the
adverse effects of inammation have been proposed in
multiple patient populations. At present there are few
studies in ESRD patients evaluating the use of antiinammatory interventions to ameliorate the adverse
effects of chronic inammation on nutritional status. The
goal of such anti-inammatory therapy is to selectively
block, inhibit, decrease production, or increase degradation of proinammatory substances, while avoiding
compromise of host defenses. For example, 3 months
of therapy with thalidomide, a drug with inhibitory
effects on TNF-a production (9698), COX-2 expression
(99,100), and TNF-a mRNA levels (101,102), signicantly improved muscle mass in AIDS patients in a
double-blind, placebo-controlled clinical trial (103).
Whether this or another anti-inammatory drug would
be helpful in terms of improving uremic malnutrition
needs to be determined by future studies.

Acknowledgments
This work is supported in part by NIH grant no. R01 45604, FDA
grant no. 000943, Satellite Health Extramural Grant Program, Clinical
Nutrition Research Unit grant no. DK-26657, and General Clinical
Research Center grant no. RR 00095. Lara B. Pupim is partly
supported by the Master of Science in Clinical Investigation Program at
Vanderbilt University Medical Center.

References
1. Cooper L: USRDS: 2001 Annual Data Report. Nephrol News Issues 15:31,
3435, 38 passim, 2001
2. Lowrie EG, Huang WH, Lew NL, Liu Y: The relative contribution of
measured variables to death risk among hemodialysis patients. In: Friedman
EA (ed). Death on Hemodialysis. Amsterdam: Kluwer Academic, 1994:121
141
3. Kopple JD: National Kidney Foundation K/DOQI clinical practice
guidelines for nutrition in chronic renal failure. Am J Kidney Dis 37:S66
S70, 2001
4. Sardesai VM: Fundamentals of nutrition. In: Dekker M (ed). Introduction to
Clinical Nutrition. New York: Sardesai, 1998:113
5 Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, Wolfson M, Humphreys MH: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 14:491500, 1978
6. Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: protein and
amino acid metabolism. Semin Nephrol 14:232237, 1994

UREMIC MALNUTRITION
7. Pollock CA, Ibels LS, Zhu FY, Warnant M, Caterson RJ, Waugh DA,
Mahony JF: Protein intake in renal disease. J Am Soc Nephrol 8:777783,
1997
8. Pupim LB, Kent P, Caglar K, Shyr Y, Hakim RM, Ikizler TA: Improvement in nutritional parameters after initiation of chronic hemodialysis. Am J
Kidney Dis 40:143151, 2002
9. Mehrotra R, Berman N, Alistwani A, Kopple JD: Improvement of nutritional status after initiation of maintenance hemodialysis. Am J Kidney Dis
40:133142, 2002
10. Kaysen GA, Levin NW: Why measure serum albumin levels? J Ren Nutr
12:148150, 2002
11. Kaysen GA, Dubin JA, Muller HG, Mitch WE, Rosales LM, Levin NW:
Relationships among inammation nutrition and physiologic mechanisms
establishing albumin levels in hemodialysis patients. Kidney Int 61:2240
2249, 2002
12. Kaysen GA, Stevenson FT, Depner TA: Determinants of albumin
concentration in hemodialysis patients. Am J Kidney Dis 29:658668,
1997
13. Anderson CF, Wochos DN: The utility of serum albumin values in the
nutritional assessment of hospitalized patients. Mayo Clin Proc 57:181184,
1982
14. Reinhardt GF, Myscofski JW, Wilkens DB, Dobrin PB, Mangan JE, Jr.,
Stannard RT: Incidence and mortality of hypoalbuminemic patients in
hospitalized veterans. J Parenter Enteral Nutr 4:357359, 1980
15. Apelgren KN, Rombeau JL, Twomey PL, Miller RA: Comparison of nutritional indices and outcome in critically ill patients. Crit Care Med 10:305
307, 1982
16. Kaw M, Sekas G: Long-term follow-up of consequences of percutaneous
endoscopic gastrostomy (PEG) tubes in nursing home patients. Dig Dis Sci
39:738743, 1994
17. Kaysen GA, Rathore V, Shearer GC, Depner TA: Mechanisms of
hypoalbuminemia in hemodialysis patients. Kidney Int 48:510516,
1995
18. Cueto Manzano AM: [Hypoalbuminemia in dialysis. Is it a marker for
malnutrition or inammation?] Rev Invest Clin 53:152158, 2001
19. Neyra NR, Hakim RM, Shyr Y, Ikizler TA: Serum transferrin and serum
prealbumin are early predictors of serum albumin in chronic hemodialysis
patients. J Ren Nutr 10:184190, 2000
20. Chertow GM, Ackert K, Lew NL, Lazarus JM, Lowrie EG: Prealbumin is
as important as albumin in the nutritional assessment of hemodialysis
patients. Kidney Int 58:25122517, 2000
21. Holland DC, Meers C, Lawlor ME, Lam M: Serial prealbumin levels as
predictors of outcomes in a retrospective cohort of peritoneal and hemodialysis patients. J Ren Nutr 11:129138, 2001
22. Goldwasser P: Prealbumin and mortality. Kidney Int 59:2375, 2001
23. Abrahamsen B, Hansen TB, Hogsberg IM, Pedersen FB, Beck-Nielsen H:
Impact of hemodialysis on dual X-ray absorptiometry, bioelectrical impedance measurements, and anthropometry. Am J Clin Nutr 63:8086, 1996
24. Kerr PG, Strauss BJ, Atkins RC: Assessment of the nutritional state of
dialysis patients. Blood Purif 14:382387, 1996
25. Borovnicar DJ, Wong KC, Kerr PG, Stroud DB, Xiong DW, Strauss BJ,
Atkins RC: Total body protein status assessed by dierent estimates of
fat-free mass in adult peritoneal dialysis patients. Eur J Clin Nutr 50:607
616, 1996
26. Cooper BA, Bartlett LH, Aslani A, Allen BJ, Ibels LS, Pollock CA: Validity
of subjective global assessment as a nutritional marker in end-stage renal
disease. Am J Kidney Dis 40:126132, 2002
27. Chertow GM, Lazarus JM, Lew NL, Ma L, Lowrie EG: Development of a
population-specic regression equation to estimate total body water in
hemodialysis patients. Kidney Int 51:15781582, 1997
28. Chertow GM, Jacobs DO, Lazarus JM, Lew NL, Lowrie EG: Phase angle
predicts survival in hemodialysis patients. J Ren Nutr 7:204207, 1997
29. Ikizler TA, Wingard RL, Harvell J, Shyr Y, Hakim RM: Association of
morbidity with markers of nutrition and inammation in chronic hemodialysis patients: a prospective study. Kidney Int 55:19451951, 1999
30. Chertow GM, Lazarus JM, Lew NL, Ma L, Lowrie EG: Bioimpedance
norms for the hemodialysis population. Kidney Int 52:16171621, 1997
31. Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S,
Mendelson RA, Jeejeebhoy KN: What is subjective global assessment of
nutritional status? J Parenter Enteral Nutr 11:813, 1987
32. Enia G, Sicuso C, Alati G, Zoccali C: Subjective global assessment of
nutrition in dialysis patients. Nephrol Dial Transplant 8:10941098, 1993
33. Hirsch S, de Obaldia N, Petermann M, Covacevic S, Burmeister R, Llorens
P, Iturriaga H, Bunout D: Nutritional status of surgical patients and the
relationship of nutrition to postoperative outcome. J Am Coll Nutr 11:21
24, 1992
34. Cianciaruso B, Brunori G, Kopple JD, Traverso G, Panarello G, Enia G,
Strippoli P, De Vecchi A, Querques M, Viglino G, et al.: Cross-sectional
comparison of malnutrition in continuous ambulatory peritoneal dialysis
and hemodialysis patients. Am J Kidney Dis 26:475486, 1995
35. Jeejeebhoy KN: How should we monitor nutritional support: structure or
function? New Horiz 2:131138, 1994
36. Jeejeebhoy KN, Detsky AS, Baker JP: Assessment of nutritional status.
J Parenter Enteral Nutr 14:S193S196, 1990

231

37. Mitch WE, Goldberg AL: Mechanisms of muscle wasting. The role of the
ubiquitin-proteasome pathway. N Engl J Med 335:18971905, 1996
38. Mitch WE: Metabolic acidosis stimulates protein metabolism in uremia.
Miner Electrolyte Metab 22:6265, 1996
39. Stein A, Moorhouse J, Iles-Smith H, Baker F, Johnstone J, James G,
Troughton J, Bircher G, Walls J: Role of an improvement in acid-base status
and nutrition in CAPD patients. Kidney Int 52:10891095, 1997
40. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int
50:343357, 1996
41. Chan W, Valerie KC, Chan JCM: Expression of insulin-like growth factor-1
in uremic rats: growth hormone resistance and nutritional intake. Kidney Int
43:790795, 1993
42. Schaefer F, Chen Y, Tsao T, Nouri P, Rabkin R: Impaired JAK-STAT
signal transduction contributes to growth hormone resistance in chronic
uremia. J Clin Invest 108:467475, 2001
43. Louard RJ, Fryburg DA, Gelfand RA, Barrett EJ: Insulin sensitivity of
protein and glucose metabolism in human forearm skeletal muscle. J Clin
Invest 90:23482354, 1992
44. Nair KS, Ford GC, Ekberg K, Fernqvist-Forbes E, Wahren J: Protein
dynamics in whole body and in splanchnic and leg tissues in type I diabetic
patients. J Clin Invest 95:29262937, 1995
45. DeFronzo RA, Beckles AD: Glucose intolerance following chronic metabolic acidosis in man. Am J Physiol 236:E328E334, 1979
46. Brunger M, Hulter HN, Krapf R: Eect of chronic metabolic acidosis on the
growth hormone/IGF-1 endocrine axis: new cause of growth hormone
insensitivity in humans. Kidney Int 51:205215, 1997
47. Lim VS, Bier DM, Flanigan MJ, Sum-Ping ST: The eect of hemodialysis
on protein metabolism: a leucine kinetic study. J Clin Invest 91:24292436,
1993
48. Ikizler TA, Pupim LB, Brouillette JR, Levenhagen DK, Farmer K, Hakim
RM, Flakoll PJ: Hemodialysis stimulates muscle and whole body protein
loss and alters substrate oxidation. Am J Physiol Endocrinol Metab
282:E107E116, 2002
49. Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Weihs KL, Alleyne S,
Cruz I, Yanovski JA, Veis JH: Immunologic function and survival in
hemodialysis patients. Kidney Int 54:236244, 1998
50. Owen WF, Lowrie EG: C-reactive protein as an outcome predictor for
maintenance hemodialysis patients. Kidney Int 54:627636, 1998
51. Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L,
Jogestrand T: Strong association between malnutrition, inammation, and
atherosclerosis in chronic renal failure. Kidney Int 55:18991911, 1999
52. Qureshi AR, Alvestrand A, Danielsson A, Divino-Filho JC, Gutierrez A,
Lindholm B, Bergstrom J: Factors predicting malnutrition in hemodialysis
patients: a cross-sectional study. Kidney Int 53:773782, 1998
53. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inammation
enhances cardiovascular risk and mortality in hemodialysis patients. Kidney
Int 55:648658, 1999
54. Kaysen GA: The microinammatory state in uremia: causes and potential
consequences. J Am Soc Nephrol 12:15491557, 2001
55. Bergstrom J, Lindholm B, Lacson E, Owen W, Lowrie EG, Glassock RJ,
Ikizler TA, Wessels FJ, Moldawer LL, Wanner C, Zimmermann J: What
are the causes and consequences of the chronic inammatory state in chronic
dialysis patients? Semin Dial 13:163175, 2000
56. Panichi V, Tetta C, Rindi P, Palla R, Lonnemann G: Plasma C-reactive
protein is linked to backltration associated interleukin-6 production.
ASAIO J 44:M415M417, 1998
57. Ross R: Atherosclerosisan inammatory disease. N Engl J Med 340:115
126, 1999
58. Bistrian BR: Role of the systemic inammatory response syndrome in the
development of protein-calorie malnutrition in ESRD. Am J Kidney Dis
32:S113S117, 1998
59. Dinarello CA, Roubeno RA: Mechanisms of loss of lean body mass in
patients on chronic dialysis. Blood Purif 14:388394, 1996
60. Flores EA, Bistrian BR, Pomposelli JJ, Dinarello CA, Blackburn GL, Istfan
NW: Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic eect with interleukin 1. J Clin Invest
83:16141622, 1989
61. Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami E, Suzuki K, Tanaka
K, Katsume A, Ohsugi Y, Shiozaki H, Monden M: Interleukin 6 receptor
antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J Clin Invest 97:244249, 1996
62. Shaw JH, Wildbore M, Wolfe RR: Whole body protein kinetics in severely
septic patients. The response to glucose infusion and total parenteral
nutrition. Ann Surg 205:288294, 1987
63. Gutierrez A, Alvestrand A, Wahren J, Bergstrom J: Eect of in vivo contact
between blood and dialysis membranes on protein catabolism in humans.
Kidney Int 38:487494, 1990
64. Parker III TF, Wingard RL, Husni L, Ikizler TA, Parker RA, Hakim RM:
Eect of the membrane biocompatibility on nutritional parameters in
chronic hemodialysis patients. Kidney Int 49:551556, 1996
65. Roubeno R, Roubeno RA, Cannon JG, Kehayias JJ, Zhuang H,
Dawson-Hughes B, Dinarello CA, Rosenberg IH: Rheumatoid cachexia:
cytokine-driven hypermetabolism accompanying reduced body cell mass in
chronic inammation. J Clin Invest 93:23792386, 1994

232

Pupim and Ikizler

86.
66. Neyra RN, Chen KY, Sun M, Shyr Y, Hakim RM, Ikizler TA: Increased
resting energy expenditure in patients with end-stage renal disease. J Par33,34
enter Enteral Nutr : (In press), 2002
67. Ikizler TA, Wingard RL, Sun M, Harvell J, Parker RA, Hakim RM:
Increased energy expenditure in hemodialysis patients. J Am Soc Nephrol
7:26462653, 1996
87.
68. Don BR, Rosales LM, Levine NW, Mitch W, Kaysen GA: Leptin is a
negative acute phase protein in chronic hemodialysis patients. Kidney Int
59:11141120, 2001
69. Lowrie EG, Lew NL: Death risk in hemodialysis patients: the predictive 51
value of commonly measured variables and an evaluation of death rate
88.
dierences between facilities. Am J Kidney Dis 15:458482, 1990
70. Verdery RB: Malnutrition and chronic inammation: causes or eects of
37
frailty? Aging 4:262263, 1992
71. Yeun JY, Levine RA, Mantadilok V, Kaysen GA: C-Reactive protein
89.
predicts all-cause and cardiovascular mortality in hemodialysis patients. Am
J Kidney Dis 35:469476, 2000
72. Stenvinkel P, Barany P, Heimburger O, Pecoits-Filho R, Lindholm B:
Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of
90.
interleukin-6? Kidney Int 61(suppl 80):103108, 2002
73. Stenvinkel P, Heimburger O, Jogestrand T: Elevated interleukin-6 predicts
progressive carotid artery atherosclerosis in dialysis patients: association
91.
with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 39:274282,
2002
74. Bologa RM, Levine DM, Parker TS, Cheigh JS, Serur D, Stenzel KH,
92.
Rubin AL: Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia,
and mortality in hemodialysis patients. Am J Kidney Dis 32:107114, 1998
75. Ikizler TA, Greene JH, Wingard RL, Hakim RM: Nitrogen balance in
93.
hospitalized chronic hemodialysis patients. Kidney Int Suppl 57:S53S56,
40
1996
76. Hecking E, Kohler H, Zobel R, Lemmel EM, Mader H, Opferkuch W,
94.
Prellwitz W, Keim HJ, Muller D: Treatment with essential amino acids in
patients on chronic hemodialysis: a double blind cross-over study. Am J Clin
Nutr 31:18211826, 1978
77. Cockram DB, Hensley MK, Rodriguez M, Agarwal G, Wennberg A, Ruey
95.
P, Ashbach D, Hebert L, Kunau R: Safety and tolerance of medical nutritional products as sole sources of nutrition in people on hemodialysis. J Ren
Nutr 8:2533, 1998
96.
78. Phillips ME, Havard J, Howard JP: Oral essential amino acid supplementation in patients on maintenance hemodialysis. Clin Nephrol 9:241248,
97.
1978
79. Eustace JA, Coresh J, Kutchey C, Te PL, Gimenez LF, Scheel PJ, Walser M:
98.
Randomized double-blind trial of oral essential amino acids for dialysisassociated hypoalbuminemia. Kidney Int 57:25272538, 2000
80. Caglar K, Fedje L, Dimmitt R, Hakim RM, Shyr Y, Ikizler TA: Therapeutic
99.
eects of oral nutritional supplementation during hemodialysis. Kidney Int
62:10541059, 2002
100.
81. Heidland A, Kult J: Long-term eects of essential amino acids supplementation in patients on regular dialysis treatment. Clin Nephrol 3:234239,
1975
101.
82. Cano N, Labastie-Coeyrehourq J, Lacombe P, Stroumza P, CostanzoDufetel Jd, Durbec J-P, Coudray-Lucas C, Cynober L: Perdialytic parenteral nutrition with lipids and amino acids in malnourished hemodialysis
patients. Am J Clin Nutr 52:726730, 1990
102.
83. Pupim LB, Flakoll PJ, Brouillette JR, Levenhagen DK, Hakim RM, Ikizler
TA: Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients. J Clin Invest 110:483492, 2002
84. Chertow GM, Ling J, Lew NL, Lazarus JM, Lowrie EG: The association of
103.
intradialytic parenteral nutrition with survival in hemodialysis patients. Am
J Kidney Dis 24:912920, 1994
85. Mortelmans AK, Duym P, Vandenbroucke J, De Smet R, Dhondt A,
Lesaer G, Verwimp H, Vanholder R: Intradialytic parenteral nutrition
in malnourished hemodialysis patients: a prospective long-term study.
48,49
J Parenter Enteral Nutr 1999

Jones M, Hagen T, Boyle CA, Vonesh E, Hamburger R, Charytan C,

Sandroni S, Bernard D, Piraino B, Schreiber M, Gehr T, Fein P, Friedlander
M, Burkart J, Ross D, Zimmerman S, Swartz R, Knight T, Kraus A, Jr.,
McDonald L, Hartnett M, Weaver M, Martis L, Moran J: Treatment of
malnutrition with 1.1% amino acid peritoneal dialysis solution: results of a
multicenter outpatient study. Am J Kidney Dis 32:761769, 1998
Kopple JD, Bernard D, Messana J, Swartz R, Bergstrom J, Lindholm B,
Lim V, Brunori G, Leiserowitz M, Bier DM, Stegink LD, Martis L,
Boyle CA, Serkes KD, Vonesh E, Jones MR: Treatment of malnourished
CAPD patients with an amino acid based dialysate. Kidney Int 47:1148
1157, 1995
Kotzmann H, Yilmaz N, Lercher P, Riedl M, Schmidt A, Schuster E,
Kreuzer S, Geyer G, Frisch H, Horl WH, Mayer G, Luger A: Dierential
eects of growth hormone therapy in malnourished hemodialysis patients.
Kidney Int 60:15781585, 2001
Schulman G, Wingard RL, Hutchinson RL, Lawrence P, Hakim RM: The
eects of recombinant human growth hormone and intradialytic parenteral
nutrition in malnourished hemodialysis patients. Am J Kidney Dis 21:527
534, 1993
Hammerman MR: Insulin-like growth factor I treatment for end-stage renal
disease at the end of the millennium. Curr Opin Nephrol Hypertens 9:13,
2000
Kupfer SR, Underwood LE, Baxter RC, Clemmons DR: Enhancement of
the anabolic eects of growth hormone and insulin-like growth factor I by
use of both agents simultaneously. J Clin Invest 91:391396, 1993
Burrowes JD, Bluestone PA, Wang J, Pierson RN Jr: The eects of moderate doses of megestrol acetate on nutritional status and body composition
in a hemodialysis patient. J Ren Nutr 9:8994, 1999
Boccanfuso JA, Hutton M, McAllister B: The eects of megestrol acetate
on nutritional parameters in a dialysis population. J Ren Nutr 10:3643,
2000
Loprinzi CL, Ellison NM, Schaid DJ, Krook JE, Athmann LM, Dose AM,
Mailliard JA, Johnson PS, Ebbert LP, Geeraerts LH: Controlled trial of
megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl
Cancer Inst 82:11271132, 1990
Von Roenn JH, Armstrong D, Kotler DP, Cohn DL, Klimas NG,
Tchekmedyian NS, Cone L, Brennan PJ, Weitzman SA: Megestrol acetate
in patients with AIDS-related cachexia. Ann Intern Med 121:393399, 1994
Hashimoto Y: Novel biological response modiers derived from thalidomide. Curr Med Chem 5:163178, 1998
Hashimoto Y: Structural development of biological response modiers
based on thalidomide. Bioorg Med Chem 10:461479, 2002
Noguchi T, Shimazawa R, Nagasawa K, Hashimoto Y: Thalidomide and
its analogues as cyclooxygenase inhibitors. Bioorg Med Chem Lett 12:1043
1046, 2002
Onn A, Tseng JE, Herbst RS: Thalidomide, cyclooxygenase-2, and angiogenesis: potential for therapy. Clin Cancer Res 7:33113313, 2001
Fujita J, Mestre JR, Zeldis JB, Subbaramaiah K, Dannenberg AJ: Thalidomide and its analogues inhibit lipopolysaccharide-mediated induction of
cyclooxygenase-2. Clin Cancer Res 7:33493355, 2001
Moraes MO, Sarno EN, Teles RM, Almeida AS, Saraiva BC, Nery JA,
Sampaio EP: Anti-inammatory drugs block cytokine mRNA accumulation in the skin and improve the clinical condition of reactional leprosy
patients. J Invest Dermatol 115:935941, 2000
Moreira AL, Tsenova-Berkova L, Wang J, Laochumroonvorapong P,
Freeman S, Freedman VH, Kaplan G: Eect of cytokine modulation by
thalidomide on the granulomatous response in murine tuberculosis. Tuber
Lung Dis 78:4755, 1997
Reyes-Teran G, Sierra-Madero JG, Martinez del Cerro V, Arroyo-Figueroa
H, Pasquetti A, Calva JJ, Ruiz-Palacios GM: Eects of thalidomide on
HIV-associated wasting syndrome: a randomized, double-blind, placebocontrolled clinical trial. AIDS 10:15011507, 1996