Nutrition and Mortality in Hemodialysis1

Jonas Bergstrom2

sufficiently well proved. More and better data, gener-

J. Bergstrom, Deparlment of Renal Medicine and Bax- ated in prospective, well-controlled studies, are obvi-
ter Novum, Karolinska Institute, Huddinge University ously needed before intradialyfic parenteral nutrition
Hospital, Stockholm, Sweden can be generally recommended as therapy for mal-
(J. Am. Soc. Nephrol. 1995; 6:1329-1341) nourished HD patients.
Key Words: Albumin. anorexia. cachexia. catabolism, malnu-
fri/Ion
ABSTRACT
Protein-energy
portion of maintenance
malnutrition
hemodialysis (HD) patients,
is present in a large pro- I 960,
hemodialysis
Scribner
(HD)
et at.
treatment
(1 ), in their
of
first
patients
report
with
on

and it is associated with increased morbidity and chronic renal failure, pointed out that malnutrition
mortality. The protein requirements are increased be- may be a serious problem. Numerous studies pub-
cause of the presence of endocrine and metabolic lished thereafter have demonstrated a high prevalence
factors related to loss of renal function, the HD proce- of malnutrition in HD patients. In more recent years,
several reports have focused on the association be-
dure, and comorbidity factors, which all stimulate net
tween nutritional Intake and nutritional status, on the
protein catabolism. The intake protein and energy
one hand, and morbidity and mortality on the other,
are frequently reduced because of the underlying
lending support to the supposition that nutritional
disease, psychosocial factors, and uremic anorexia. inadequacies may be causally related to a fatal out-
However, the extent to which underdialysis contrib- come. However, the role of nutrition In this regard has
utes to anorexia and malnutrition is still not well de- not been clearly determined. Several morbidity factors
fined. Malnutrition is generally not recognized as a that per se increase the risks of a poor outcome may
common direct cause of death as reflected in health also cause malnutrition, which may not be the direct
statistics, except in the highest age groups. Anthropo- cause of death, but rather a marker of illness.
metric and biochemical signs of malnutrition are There are many causes of malnutrition in renal
associated with increased mortality. A low serum failure patients who are treated with HD, some being
related to endocrine and metabolic disturbances of
albumin level is a strong predictive risk factor that
uremia and some being related to the dialytic proce-
may reflect not only or mainly protein malnutrition but
dure. A controversial issue is the extent to which the
also the influence of several other morbidity factors adequacy of dialysis may affect the nutritional intake
(overhydration, infection, chronic disease and oth- of protein (and energy), especially If there exists a link
ers) that may entail an increased risk of death. Low between underdialysis, malnutrition, and increased
levels of serum creatinine (low muscle mass), serum morbidity/mortality.
cholesterol (energy depletion), and BUN and low
urea appearance rate (low protein intake) are also GENERAL ASPECTS OF NUTRITION AND
correlated to increased mortality. For the prevention MORTALITY
and treatment of HD-associated malnutrition, mea-
In order for an individual to survive and thrive,
sures should be taken to correct factors that may nutrients must be ingested in sufficient amounts to
suppress appetite and increase net protein catabo- serve as metabolic fuel and a substitute for tissue
lism (underdialysis, acidosis, low energy intake, co- growth and maintenance and to regulate the cellular
morbid conditions, psychosocial and economic fac- and metabolic processes. If an essential nutrient (e.g.,
tors). Dietary advice should be given with the aim of a specific amino acid or a vitamin) or a macronutrient
ensuring an adequate intake of protein- and energy- (protein, energy) is provided in insufficient amounts In
giving products. Intradialyfic parenteral nutrition may relation to the requirements, this will sooner or later
have positive effects on nutritional status when other have serious consequences for the Individual. How-
ever, a nutritional deficiency may be clinically unrec-
measures fail. However, the indications for such treat-
ognizable for some time and may be detected only by
ment have not yet been well defined, and the effects
biochemical and physiologic studies or by metabolic
on survival, morbidity, and quality of life are not experiments. As the deficiency becomes more severe,
the altered biologic and physiologic functions in the
1 Received January 19. 1995. Accepted June 21. 1995. body and clinical signs and symptoms occur, leading
2 correspondence to Dr. J. Bergstrom, Department of Renal Medicine K56, to morbidity and, finally, the death of the subject (2).
Huddinge University Hospital, 5-14186 Huddinge. Sweden.
Only then is the consequence of malnutrition reflected
104&6673/0605-1 329$03.00/0
Journal of the American Society of Nephrology
in vital statistics. It should be emphasized that even
copyright © 1995 by the American Society of Nephroiogy less severe deficiencies may (Indirectly) have a nega-

Journal of the American Society of Nephrology 1329

Nutrition and Mortality in HD

tive effect by sensitizing the individual to other morbid because it measures both the bone mineral content
factors. For instance, protein malnutrition may result and the body fat mass, measurements from which the
in an impaired immune response, carrying an in- lean body mass is calculated. The lean body mass, as
creased risk of severe or even fatal infections (3). The calculated by DEXA or by total body water determina-
regeneration of cell number and function, e.g. , after tion (by monofrequency bioimpedance or isotope dilu-
an acute illness, and wound healing may also be tion or from nomograms) is, by definition, equal to the
impaired in states of malnutrition (4). body weight minus the amount of body fat. Therefore,
it is not a reliable index of total cell mass (body
ASSESSMENT OF PROTEIN-ENERGY MALNUTRITION protein) in overhydrated dialysis patients, whose lean
body mass consists largely of excess water, mainly in
To diagnose malnutrition in maintenance dialysis
the extracellular space ( 1 2). Multifrequency bioimped-
patients, it is important to assess correctly their nu-
ance may turn out to be more useful by enabling
tritional status (see recent review articles [5,6]). The
compensation for extracellular overhydration in the
validation of nutritional status may be based on din-
calculation of body cell mass. Creatinine is generated
ical evaluation, diet history, anthropometric measure-
largely by the nonenzymatic breakdown of creatine
ments, and various biophysical and biochemical
present in the phosphocreatine-creatine pool in skel-
methods (Table 1).
etal muscle, which is the largest pool of cellular tissue
The more precise methods for calculating body com-
in the body ( 13). In addition, 10 to 30% of creatmnine
position (total water, potassium and nitrogen determi-
generation may be derived from the ingestion of crea-
nations, protein/DNA determination in muscle bi-
tine and creatinine in meat ( 1 4). Potassium, alkali-
opsy, dual x-ray photon absorptiometry [DEXA],
soluble (cell) protein, and total creatine in the skeletal
nuclear magnetic resonance, bioelectrical impedance,
muscle of normal individuals are strongly correlated
etc.) require equipment that is not available in most
( 15). The total creatinine output has been shown to
centers, some of which is complicated and expensive.
correlate well with the total body K in normal and
Among the new noninvasive methods, DEXA (7) and
continuous ambulatory peritoneal dialysis (CAPD) pa-
multifrequency bioimpedance (which can distinguish
tients, and it may be a more reliable index ofbody cell
between total body water and extracellular water) (8)
mass and nutritional status in dialysis patients than
are now under evaluation for use in patients on main-
the techniques that are based on total water determi-
tenance dialysis (9-1 1 ). DEXA may be advantageous
nations ( 16). However, the determination of the total
creatine output in HD patients requires the collection
TABLE 1 Methods . to assess nutrition used in HD of an aliquot of the total spent dialysate during the
patients dialysis session, which is not easily accomplished.
Today, most centers must rely on dietary histories,
Evaluation of Nutritional Intake evaluation of body weight indices, and other simple
Dietary history and dietary records anthropometric parameters and serum protein deter-
Urea appearance (estimation of protein intake)
minations to investigate nutritional status and detect
Simple Anthropometric Methods
signs of protein-energy malnutrition. A simple and
Body weight, body mass index, weight loss
reliable method appears to be the Subjective Global
Skinfold thickness (triceps and other sites)
Assessment, a technique by which the nutritional
Midarm muscle circumference
status is rated by the clinician in a systematic way
Muscle strength (handgrip)
Body Composition based on medical history and physical examination
DEXA ( 1 7). Although originally used to classify surgical pa-
Nuclear magnetic resonance tients, this nutritional classification system has
Computed tomography proved to be a reliable tool for assessing the nutri-
Ultrasonography tional status of dialysis patients ( 1 8, 19).
Bloelectrical impedance
Total body H20 (isotope dilution), K (40K-count), N
PREVALENCE OF MALNUTRITION IN HD PATIENTS
(neutron activation analysis)
Biochemical Methods Several reports show that malnutrition is frequently
Plasma proteins (albumin, prealbumin, transferrin, IGF-1, present in patients treated with maintenance HD
complement C3, others) therapy (20-35). The signs of malnutrition in regular
Other plasma and blood chemistries (hemoglobin, dialysis patients include the following: reduced energy
urea, creatinine, lipids, amino acids) stores (subcutaneous fat stores) and muscle mass, as
Urea appearance estimated by anthropometric methods, low total body
Creatinine output
nitrogen determined by in vivo neutron activation
Muscle alkali-soluble protein/DNA, RNA, amino acids
analysis (3 1 ,33), low concentrations of albumin,
(percutaneous biopsy)
transferrin, and other visceral proteins, low alkali-
Immunologic Methods
soluble protein in muscle in relation to dry fat-free
Total lymphocyte count
weight and DNA (22,27), as well as abnormal plasma
Delayed hypersensitivity skin tests
amino acids and intracellular amino acid profiles

1330 Volume 6 . Number 5 ‘ 1995

 BergstrOm

(24,26,34). However, other data show that adequately inducing the transcription of genes encoding for en-
treated HD patients with no complications have an zymes participating in the ATP-dependent cytosolic
essentially normal nutritional status (36,37). ubiquitin-proteasome proteolytic pathway (44). In HD
In various investigations of HD patients patients, the muscle intracellular concentration of
(27,30,32,35), a low percent ideal body weight or low free valine was found to be correlated with the predi-
body mass index was found in 1 0 to 30% of the alysis serum bicarbonate concentration, which varied
subjects, a low triceps skinfold thickness was found in between 18 and 24 mmol/L, suggesting that
20 to 60%, and a low arm muscle circumference was branched-chain amino acid catabolism Is enhanced
found in 0 to 44%. Low serum albumin was observed even by mild metabolic acidosis (45).
in 13 to 70%, and low transferrin was observed in 30 However, the clinical importance of uremic acidosis
to 60% of HD patients. The anthropometric data may
as a factor for the development of malnutrition and as
suggest that energy malnutrition is more prevalent
a death risk factor in HD is far from clear. Retrospec-
than protein malnutrition in HD patients. However,
tive analysis of laboratory data and mortality in more
results of a recent study using total body N determi-
than 12,000 HD patients showed that the risk of death
nation by neutron activation analysis indicate that
was significantly increased with metabolic acidosis,
anthropometric measurements may underestimate
but only at total CO2 levels in serum lower than 12.5
the degree ofprotein malnutrition in HD patients (33).
to 15 mmol/L (46). In a group of 133 HD patients, no
apparent association was noted between CO2 levels
PROTEIN AND ENERGY REQUIREMENTS IN
and nutritional status, as evaluated by serum albu-
HEALTHY SUBJECTS AND HEMODIALYSIS PATIENTS
mm levels (47). Nonvolatile anions (mainly sulfate
Protein requirements in normal adults are on aver- ions) together with hydrogen ions are generated by
age about 0.6 g/kg of body weight/day, which after protein breakdown and amino acid oxidation, imply-
correction for 25% variability to include 97.5% of the ing that the tendency to metabolic acidosis increases
population of young adults, raises the safe level of when the protein intake is high, whereas it decreases
intake (daily allowance) to 0.75 g/kg per day (2). This with a low protein intake. Hence, it is conceivable that
variability is the result ofgenetic differences, sex, age,
a high protein intake may stimulate protein synthesis
physical activity, environment, chemical form of nu-
to the extent that the activation of proteolysis and
trients, and the effects of other dietary constituents
amino acid oxidation induced by the ensuing meta-
(2).
bolic acidosis is counteracted. In support of this sup-
The protein requirements In HD patients are not
position is the observation by Lowrie (48) that the
well defined. It may be assumed that the variation in
anion gap, which reflects the accumulation of nonvol-
requirements is much larger than that in healthy
atile acids, is positively correlated to makers of vis-
subjects, because there are additional sources of van-
ceral protein stores (serum albumin), somatic (mus-
ability, such as physical inactivity, endocrine and
cle) protein stores (serum creatinine), and protein
biochemical abnormalities, anemia, acute and
intake (BUN); only when adjusted statistically for
chronic infections, cardiac disease, diabetes, cortico-
steroids and other drugs, as well as specific effects of various nutritional parameters was an increase in the
the HD procedure in the form ofamino acid losses and anion gaps associated with an increased death odds
the inflammatory response to dialyzer-blood interac- ratio.
tion. Each of these factors may to a varying extent In nondialyzed chronic uremic patients, the correc-
stimulate net protein catabolism and increase the tion of metabolic acidosis improves the nitrogen bal-
requirements for protein. A few nitrogen balance stud- ance and reduces urea appearance and muscle prote-
ies in small groups of HD patients and longitudinal olysis (40,49). However, in a study of HD patients, the
studies of nutritional intakes and nutritional status in correction of acidosis was reported to have had no
lager groups of patients suggest that the daily re- effect on protein degradation, but it tended to reduce
quirements for protein are considerably higher than protein synthesis and to increase leucine oxidation
those in normal individuals (38). On the basis of these (40). The correction of metabolic acidosis in HD pa-
results, an Intake of 1 .2 g of protein/kg body wt per tients over a period of 6 months by increasing the
day is generally recommended for HD patients. bicarbonate concentration In the dialysis fluid was
reported to result in a normalization of reduced mus-
Effects of Acidosis cle intracellular branched-chain amino acid concen-
It has become increasingly evident that metabolic trations (50); no other effects on nutritional status
acidosis rather than uremia per se is an important were recorded In these patients, who had no clinical
stimulus for net protein catabolism (39-42). This signs of malnutrition at the start of the study (unpub-
effect seems to be mediated by the stimulation of lished observations). Prospective, longitudinal clinical
skeletal muscle branched-chain ketoacid decarboxyl- studies of HD patients with documented malnutrition
ation, which increases the catabolism of the will obviously be needed to determine to what extent
branched-chain amino acids (valine, leucine, and iso- the correction of acidosis influences nutritional status
leucine) (43) and stimulates proteolysis In muscle by and clinical outcome.

Journal of the American Society of Nephroiogy 1331

Nutrition and Mortality in HD

HD as a Stimulus of Protein Catabolism than did the biocompatible group (63). These results
support the conclusion that the biocompatibility of
Nitrogen balance studies as well as studies of urea the membrane favorably affects nutritional status,
appearance suggest that HD stimulates net protein whatever the flux characteristics of the membrane.
catabolism (5 1 ,52). There is evidence that HD reduces Energy requirements depend on the level of physical
protein synthesis In the musculature, measured as a activity, an intake of 35 to 40 kcal/kg body wt per day
relative decrease in muscle polyribosomes, and in the being recommended for adult individuals not perform-
whole body, assessed by leucine kinetics (53,54), pre- ing heavy physical exercise. There is no evidence that
sumably elicited by the dialytic loss of amino acids the energy requirements of maintenance dialysis pa-
induced by the dialytic procedure or by other mecha- tients differ from those of normal subjects (64,65).
nisms. During HD, the average loss offree amino acids Metabolic studies in healthy individuals and In HD
is 6 to 8 g per dialysis (55-57). Protein losses by patients indicate that the utilization of protein is
hemodialysis are generally considered to be minimal. greatly dependent on the energy intake, so that a low
However, there is evidence that dialyzer permeability energy intake reduces utilization, whereas a high
is altered by dialyzer reuse. Ikitzler et at. (57) reported energy intake has a protein-saving effect (66,67). Fur-
that amino acid losses during high-flux polysulfone ther evidence that an adequate energy supply pro-
dialysis increased by 50% during the 6th reuse and motes protein anabolism is the observation that oral
that albumin losses increased substantially (to an energy supplementation increases the growth rate
average of 9 g/dialysis) after the 1 5th reuse. Kaplan et and the serum albumin level in growth-retarded chil-
at. (58) reported that the reuse of high-flux polysul- dren on HD (68). Dialysis with glucose-free dialysis
fone, using bleach in the processing fluid, resulted in fluid in fasting HD patients may be expected to en-
significantly increased protein losses in the dialysate, hance gluconeogenesis from amino acids to compen-
which increased gradually from 1 .2 g per dialysis sate for the dialytic loss of glucose (about 25 g per
during the first use to 1 7.5 g during the 23rd to 25th dialysis), thus resulting in an increase in protein
reuse, and that the removal of bleach from the reuse catabolism. However, we recently reported that there
procedure was associated with a substantial and sus- was no difference in amino acid release from the
tamed increase in the serum albumin levels. musculature, amino acid loss in the dialysate, and
The biocompatibility of the membrane may be an- urea appearance during HD after an overnight fast,
other factor of importance. Blood membrane contact whether or not glucose ( 10 mmol/L) was present In
elicits an inflammatory response, the intensity of the dialysis fluid (56).
which depends on the membrane material used and
which is more marked with cellulosic than with syn-
LOW NUTRITIONAL INTAKE AND ANOREXIA
thetic membranes (59). Sham dialysis, I.e. , the circu-
lation of blood through a dialyzer without circulating Considering all of the evidence that requirements
dialysis fluid in normal subjects, has been shown to for protein are increased in HD patients and that an
elicit an enhanced release of amino acids from leg adequate energy supply is mandatory for maintaining
tissue (mainly skeletal muscle) when a cuprophane the energy stores and optimizing the utilization of
dialyzer was used. With semisynthetic (modified cel- ingested protein, low protein and energy intakes must
lulose) and synthetic membranes, which are more be especially harmful in such patients. It may be
blocompatible than cuprophane, the release of amino difficult to fulfill the nutritional requirements, be-
acids from the musculature was insignificant (60,61). cause some dialysis patients tend to lose their appetite
After cuprophane sham dialysis, there was an in- and reduce protein and energy intakes spontane-
crease In the leg effiux and also in the plasma concen- ously.
tration of 3-methylhistidine, an amino acid that is Recent data from the MDRD study in the United
released from actinomyosin proteins and cannot be States (65) demonstrate that an adaptive reduction in
reused for protein synthesis; this indicates that an the intake of protein may start early during the pro-
increase in proteolysis plays an important part in the gression of renal failure (GFR, 25 mL/min or higher),
net catabolic process induced by blood-membrane with a further reduction in protein intake along with
interaction. It has been speculated but not estab- progression toward end-stage renal failure and an
lished that the enhanced proteolysis induced by associated reduction in energy intake and various
blood-membrane interaction is mediated by monocyte nutritional parameters (body weight, fat mass, serum
activation with the release of cytokines (interleukin- 1, albumin, and transferrin). Nutritional surveys mdi-
tumor necrosis factor), which may act in concert and cate that the mean intake ofprotein is less than 1 g/kg
induce the lysosomal catabolism of muscle protein body wt per day in a large proportion of patients on
(62). A prospective randomized study, recently pre- maintenance HD (5-8), suggesting that the require-
sented, comparing patients starting HD with either a ments for protein are not fuifilled. The energy intake,
bioincompatible or a biocompatible (low-flux) mem- like the protein intake, Is often low in groups of
brane showed that the biocompatible group had ear- dialysis patients; the mean intake in HD has been
her increases and higher levels of serum insulin-like reported to be 26 to 29 kcal/kg body wt per day
growth factor- 1 (IGF- 1), prealbumln, and albumin (23,25).

1332 Volume 6 ‘ Number 5 1995

#{149}
 BergstrOm

Anorexia, nausea, and vomiting are signs of severe more when a synthetic, biocompatible, high-flux
uremic intoxication. It is a common clinical experience membrane (AN 69) is used than when a less blocom-
that uremic patients who are anorectic regain appetite patible, low-flux, cellulose acetate membrane Is used.
after the initiation of maintenance dialysis. This sug- This observation may further support the hypothesis
gests that one (or more) uremic toxins causing an- that uremic toxins that induce anorexia are medium-
orexia has been removed by dialysis. Assuming that a sized molecules, although it does not exclude that
dialyzable uremic toxin accumulates in severe renal factors related to biocompatibility may be involved in
failure and causes anorexia, it is conceivable that the regulation of appetite. However, there are data
underdialysis affects the appetite and thus causes that show no relation between Kt/Vurea and protein
malnutrition. In the National Cooperative Dialysis intake in patients who are adequately dialyzed
Study (NCDS), a nationwide multicenter study per- (74,75). We have reported a significant correlation
formed in the United States with the aim of defining between Kt/Vurea and the estimated protein intake in
the adequacy of HD, two groups of patients with low a group of 1 5 1 HD patients studied in 1 990, many of
BUN levels and long or short dialysis times, respec- whom had Kt/Vurea levels below 1 .0 (38). When we
tively, and two groups ofpatients with high BUN levels relnvestigated our HD patients in 1992, the correla-
and long or short dialysis times, respectively, were tion was no longer present, presumably because Kt/
studied for 24 to 52 wk (69). In the high-BUN groups, Vurea had increased to levels where the protein intake
the dialysis dose of low-molecular-weight solutes became independent of the dose of dialysis (unpub-
(urea) was lower than in the low-BUN groups. In the lished observations).
short-dialysis-time groups, the removal of lager mo- In most of the aforementioned studies, the intake of
lecular weight solids, so-called middle molecules protein was assessed by urea kinetic modeling on the
(MM), was assumed to be less efficient than in the basis of the concept that the amount of urea generated
long-dialysis-time groups; plasma levels of MM were reflects the net protein catabolic rate (PCR), which in
not measured. The protein intake was correlated to patients who are in a metabolic steady state (i.e. , not
the length of dialysis, and the two groups on short markedly catabolic or anabolic), gives an estimate of
dialysis had lower mean intakes of protein at the end the protein intake (5 1 ,76). It has been argued that the
of 6 months than did the two groups on long dialysis relationship between Kt/Vurea and protein intake
(25). These results may suggest that appetite suppres- (urea appearance) reflects a mathematical coupling
sion in uremia depends to some extent on the accu- rather than a biologic relationship, because the two
mulation of toxic MM. This suggestion is supported by variables are to some extent dependent (both are
our recent finding that an MM fraction in the molec- normalized to body size, both are dependent on urea
ular weight range of 1 to 5 kilodalton isolated from determinations in plasma predialysis and postdialy-
uremic plasma ultrafiltrate and from normal urine sis) (77). Lowrie (48) reported no significant correla-
induces a dose-dependent suppression of appetite in tion between the dose of HD estimated as the urea
normal rats after Intraperitoneal injection (70). reduction rate and the serum albumin concentration,
The dose of dialysis regarding the removal of small indicating that the dose of dialysis has little effect on
molecules may be expressed as Kt/Vurea, which is the nutrition in HD patients. However, some data show
negative exponential in the equation describing the that patients with Kt/Vurea < 1 .0 have lower BUN,
disappearance by diffusion of urea from the blood serum creatinine, and serum albumin levels than do
during an HD session (K - urea clearance of the more adequately dialyzed patients, suggesting that
dialyzer [in milliliters per mmnutel, t = length of dialy- underdialysis may have resulted in a low protein
sis [In minutesi, V = distribution volume of urea [in intake and protein malnutrition (78). In another study
milliliters]). Kt/Vurea may be modified to include the (79), HD patients with low serum albumin were mon-
effects of ultrafiltration and of residual renal function. Itored longitudinally while being treated with high-
A simpler expression of the dose of dialysis for small flux dialysis (Kt/Vurea, about 1 .3), which resulted in a
molecules is the urea reduction rate, i.e. , the ratio significant increase in serum albumin, claimed by the
between predialysis minus postdialysis concentration authors to result from adequate dialysis and adequate
and the predialysis concentration of urea. protein and energy intakes. It was recently reported
Several recent studies in dialysis patients report a that an increase in the dose of dialysis from Kt/Vtirea
significant correlation between the dose of dialysis for <0.86 to Kt/Vsrea > 1 .2 1 resulted In increases in
small molecule removal (Kt/Vurea) and the protein protein intake and serum albumin along with a reduc-
intake, especially in the lowest dose intervals lion in mortality from 23 to 9% (80). In conclusion, the
(38,71 ,72). Observations in a small group of HD pa- extent to which the adequacy of dialysis affects nutri-
tients with low Kt/Vurea suggest that an Increase In tional intake and nutritional status remains unset-
the dose of dialysis results in a significant Increase in tled. It is reasonable to suppose that severe under-
the estimated protein intake (73). Lindsay et at. also dialysis results in anorexia, considering that end-
reported that the relationship between Kt/Vurea and stage renal failure patients who are not dialyzed are
protein intake seems to depend on the properties of markedly appetite suppressed. However, it remains to
the dialysis membrane used, so that for each unit define the dose of dialysis (for small molecules? lager
increase in Kt/Vurea, the protein intake increases molecules?) required before anorexia becomes impor-

Journal of the American Society of Nephrology 1333

Nutrition and Mortality in HD

tant and how much this dose may vary from one population In northern Italy reveals that malnutrition
patient to another. seems to be a common cause of death in elderly
Several additional factors may cause or contribute patients, with no less than 32.5% of the patients 65
to anorexia in HD patients-factors that in the single yr and 4 1 % of patients above 75 yr of age dying from
patient may be far more important than uremic intox- cachexia (83).
ication (Table 2). They include inadequate diets, gas-
tropathy (in diabetic patients with autonomic neurop- Nutritional Intakes and Clinical Outcome
athy), medications, and psychosocial and
socioeconomic factors, such as loneliness, depres- The NCDS showed that a PCR below 0.8 g/kg body
sion, ignorance, and poverty, especially in elderly wt per day was associated with treatment failure (84).
patients and those with alcohol and drug problems. It was therefore recommended that the protein intake
Anorexia, nausea, and vomiting during and immedi- should be sufficient to obtain a PCR of 0.8 or more
ately after HD, which are frequently associated with (84,85). However, these results hardly lend them-
cardiovascular instability and postdialysis fatigue, selves to general interpretations regarding protein
may lead to a reduction in food intake on the day of the requirements and the effect of protein intake on mor-
dialysis. bidity and mortality, because it was not demonstrated
that low protein intake (PCR) was associated with a
LOW NUTRITIONAL INTAKE, NUTRITIONAL STATUS, significant deterioration of the nutritional status, per-
AND MORTALITY haps because the study periods were too short (24 to
52 wk). Moreover, a nutritional assessment of the
Mortality Statistics NCDS patients revealed that, despite the recommen-
The large registers of patients on renal replacement dation for an adequate energy intake, the actual in-
therapy are not of very great help in determining the take was no more than an average of 23 to 26 kcal/kg
role of malnutrition as a cause of death. In the United in the four experimental groups, which is clearly
States Renal Data System (USRDS) Annual Report suboptimal and may have impaired the utilization of
(8 1 ) and in the Register of the European Dialysis and dietary protein and thus constituted an additional
Transplant Association-European Renal Association risk factor. Strict Inclusion criteria were used, exclud-
(EDTA/ERA) (82), cardiovascular and cerebrovascula ing patients over 70 yr of age and those with diabetes,
causes ofdeath predominate (about 50%), followed by heart disease, uncontrolled hypertension, excessive
death from infections ( 1 3 to 1 6%). In the USRDS weight gain, and other pathologic conditions (86). It is
report, cachexia and malnutrition are not listed questionable whether conclusions regarding nutrition
among the causes of death, and In the EDTA/ERA and clinical outcome based on the NCDS results are
register, cachexia is a relatively rare cause of applicable to such patients, who constitute a large
death-3% in patients aged 16 to 64 yr and 10% in proportion of the dialysis patients today. Most of the
patients 65 yr of age. These figures regarding the causes of death in the NCDS, which occurred after the
death rate from malnutrition are low, if mentioned, study period, did not seem to be directly related to
and may be the result of nonreporting or underreport- events that might have been caused by malnutrition
ing; it cannot be excluded that malnutrition may have (87).
contributed more than is apparent from these mortal- Other studies have confirmed that a low protein
ity statistics. However, an analysis ofa dialysis patient intake may be associated with increased mortality.
Among 120 HD patients, Acchiardo et at. (88) found
that a subgroup with a mean PCR of0.63 g/kg per day
TABLE 2. Protein catabolic factors in HD patients
had a mortality rate of 14% per year, whereas groups
General Effects of patients with higher intakes-0.93, 1 .02, and 1.29
Physical inactivity g/kg per day-had mortality rates of only 4, 3, and
Heart failure 0%, respectively. The number of hospitalizations per
Low energy intake year was also much higher in the group of patients
Endocrine abnormalities having the lowest intake of protein, with higher fre-
Corticosteroid therapy quencies of heat disease, pericarditis, infections, and
Inflammation, infection, sepsis gastrointestinal disturbances than in the other pa-
Acidosis tient groups. It was concluded that malnutrition is the
Amino acid abnormalities main factor In morbidity and mortality in HD patients,
Catabolic Effects of the HD Procedure as stated in the title of the report. However, these
Loss of amino acids 9 to 13 g/dlalysls (25 to 40 g/wk) results should be interpreted with caution regarding
Loss of glucose 25 g/dlalysis (glucose-free dialysate) the role of malnutrition, because the nutritional sta-
Blood-dialyzer contact
tus of the patients was not reported. Moreover, the
Complement activation
results do not exclude that the reduced protein intake
Endotoxins
in the risk groups was secondary to other morbidity
Cytokines
factors that may have caused or contributed to the
Inflammation- catabolism
fatal outcome.

1334 Volume 6 ‘ Number 5 ‘ 1995

 Bergstrom

In the NCDS, the two groups of patients with high tional Medical Care Inc. centers in the United States.
BUN values had a larger number of treatment failures They found that among the laboratory parameters, the
and more deaths In the poststudy phase than did the strongest predictors of death were serum albumin,
two groups with a low BUN. In this study, protein serum creatinine, and urea reduction rate (30,48).
intake was normalized to 1 . 1 ± 0.3 g/kg body wt, and Assuming that serum albumin reflects the visceral
high and low BUN levels were obtained by adjusting protein mass, these results suggest that protein mal-
the dose of dialysis, implying that the high-BUN nutrition is a major mortality risk factor in HD. This
groups were underdialyzed compared with the low- suggestion is supported by the observation that the
BUN groups. However, several other studies where the level of serum creatinine, which was correlated to that
protein Intake was not normalized have shown that a ofserum albumin, is also a strong risk factor for a fatal
low BUN level is associated with an increased risk of outcome. The generation of creatinine is mainly a
morbidity and mortality (88-90). In those studies, a function of the muscle mass, but it is also to some
low BUN may serve as an index of low protein intake extent dependent on the intake of meat containing
and the results have been interpreted to mean that precursor creatine (and animal protein); hence, low
malnutrition due to low protein intake may have been levels may be a sign of the depletion of the somatic
a causative factor in the increased mortality and that protein and a low protein intake. The urea reduction
BUN is unsuitable as a criterion for the prescription of rate appeared to be an independent risk factor not
dialysis. associated with serum albumin (48,9 1 ). A low BUN
level, presumably reflecting a low protein intake, was
also associated with an increased risk of death, but
Nutritional Status and Clinical Outcome
mortality also increased when BUN was excessively
There are now several studies suggesting that signs high, presumably as a sign of underdlalysis. BUN
of malnutrition are prognostically unfavorable for the correlated with serum albumin so that patients with a
outcome in HD patients. In most of those studies, the low BUN tended to have lower albumin concentra-
evaluation of nutritional status was mainly based on tions, but BUN was not a significant risk factor when
the measurement of serum albumin and other serum adjusted for variations in serum albumin (48). A high
proteins, but in some studies, the nutritional status anion gap, which reflects the accumulation of nonvol-
has been evaluated by the use of anthropometric atile anions (sulfate, phosphate, etc.), turned out to be
measurements. associated with a reduced risk of mortality, presum-
Bilbrey and Cohen (35) found a relationship be- ably because the accumulation of such anions may
tween a protein-calorie malnutrition index, obtained reflect a high protein intake, but it became a risk
by the addition of eight scores, including anthropo- factor for increased mortality when adjusted for van-
metric, biochemical (albumin and transferrin), total ations In serum albumin (48). Goldwasser et a!. (92)
lymphocyte counts, and clinical evaluation, and noted have confirmed that a low serum creatinine level is a
a much higher percent mortality over 14 months in predictor of mortality risk in HD patients. They also
patients with moderate (2 1 .4% mortality) and severe reported that serum prealbumin, another visceral
(23.8% mortality) malnutrition than in patients with protein with a much shorter half-life than albumin, is
little ( 10.9% mortality) or no ( 14.3% mortality) malnu- a risk factor for increased mortality.
tritIon. Oksa et at. (34) measured anthropometric Lowrie and Lew also found that low serum choles-
parameters, as well as albumin, prealbummn, trans- terol levels were associated with an increased risk of
ferrin, C3, retmnol-binding protein, and plasma amino death, suggesting that a low energy intake, reflected
acids, and found that 5 ( 1 7%) of29 patients had by a low serum cholesterol level, might also be a risk
evidence of protein malnutrition with lower serum factor for increased mortality (30). This observation
prealbumin and plasma leucine concentrations than was confirmed by Goldwasser and coworkers (93).
the others. All of the malnourished patients died The finding that serum albumin is a very strong
during a follow-up period of 3 yr. whereas only 7 of the predictor of mortality and morbidity In HD patients
other 19 patients died. Marckmann (29) assessed has been confirmed by many subsequent reports (93-
nutritional status, using a scoring system based on 96). The Canadian hemodialysis morbidity study,
relative body weight, midarm muscle circumference, published in 1992 (94), showed that patients with a
triceps skinfold thickness, and serum transferrin, and low serum albumin level (s30 g/L) at the start of HD
found In a small group of dialysis patients that 5 of 32 therapy had a higher probability of hospitalization
HD patients who died during a 24-month period had a and a lower probability of infection-free survival than
high score, demonstrating that they were malnour- did patients with higher serum albumin levels, sug-
ished. Low relative body weight has also been reported gesting that an unfavorable risk profile, including a
to be associated with Increased mortality (E.G. Lowrie, low serum albumin at the initiation of dialysis, has a
personal communication). negative effect on survival and rehabilitation. In keep-
The most extensive retrospective analysis of risk ing with this is a recent report that patients who were
factors for mortality in HD patients has been made by referred late to maintenance dialysis generally had
Lowrie and Lew (30), who analyzed laboratory data more abnormal serum biochemistries, including a
from more than 12,000 HD patients treated at Na- lower albumin, more immediate morbidity, and a

Journal of the American Society of Nephrology 1335

Nutrition and Mortality in HD

much longer hospital stay than did patients who were rather than malnutrition per Se, may be instrumental
referred early (97). Concern has been expressed that in causing the death of the patients. In other words,
prolonged treatment with a low-protein diet may hypoalbummnemia in HD patients may be more of a
cause protein malnutrition. However, the treatment of nonspecific marker of illness than a nutritional pa-
near end-stage renal failure patients with a low-pro- rameter. When hypoalbummnemia is observed, it is
teIn diet may not only reduce uremic symptoms but imperative to look not only for other signs of malnu-
may even correct low serum albumin and protein trition but also for comorbid conditions that may
levels, provided that the energy intake is high and the reduce the chances of survival.
diet is supplemented with adequate amounts of essen-
tial amino acids or ketoacids (98,99).
BY WHICH MECHANISMS IS NUTRITIONAL STATUS
ASSOCIATED WITH REDUCED SURVIVAL?
Serum Albumin as a Marker of Protein
In spite ofmultiple studies demonstrating that signs
Malnutrition
of malnutrition (mainly a low serum albumin) are
In the discussion of results showing that the serum strong predictors of morbidity and mortality In HD
albumin level is a strong predictor of mortality in HD patients, malnutrition per se is not recognized as a
patients, it is generally assumed that albumin is a key major direct cause of death, except in the elderly
index of nutritional status and reflects visceral protein dialysis population. The question has therefore been
stores. However, the serum albumin concentration is asked about a possible link between malnutrition and
affected by many non-nutritional factors, such as high cardiovascular mortality in dialysis patients
albumin synthesis inhibition, albumin degradation, ( 1 15). It was recently reported that asymmetric di-
albumin losses from the body, exchange between methyl-L-argmnine (ADMA), an endogenous inhibitor of
intravascular and extravascular compartments, and nitric oxide (NO) synthase, accumulates in renal fail-
the volume in which albumin is distributed (100). ure to such an extent that it inhibits the generation of
Serum albumin decreases with age in apparently NO in vitro, and it was proposed that high ADMA levels
healthy subjects ( 1 0 1 ). Infection, trauma, and malig- in the plasma of uremic patients could interfere with
nancy may induce an acute-phase response mediated NO synthesis in vivo, thereby interfering with the
by the release of interleukin- 1 and interleukin-6, re- regulation of vascular tone and causing hypertension
sulting in an increase in several serum proteins, such (1 16). Ritz et at. ( 1 15) have proposed that malnutri-
as haptoglobmn, complements, fibrinogen, amyloid tion, resulting in low L-aginine levels in plasma, could
protein A, and C-reactive protein, which participate in create an Imbalance between the substrate for NO
host defense ( 102-104). This is accompanied by an synthesis (L-aginine) and its inhibitor (ADMA), which
increase in catabolism and a decrease in the synthesis should further enhance the effect on cardiovascular
of albumin ( 105). The host switches from the produc- tone. However, this hypothesis, although elegant, is
tion of albumin to proteins that have host-immune offset by more recent data using a different analytical
response functions. Overhydration with pulmonary method, giving values for ADMA In plasma before HD
congestion may also reduce serum albumin by dilu- that are 5 to 10 times lower than those earlier reported
tion (106). With tissue injury, e.g., after a major ( 1 1 7) and are too low to induce an inhibiting effect on
trauma, in cancer, infection, hypertension, diabetes the NO synthase. Moreover, plasma and intracellular
mellitus, and liver cirrhosis, hypoalbuminemia may L-aginine concentrations are generally not reduced in
develop as the result of the capillary extravasation of HD patients (26,118).
albumin to the interstitial fluid because of an increase A link between malnutrition and increased mortal-
in capillary permeability ( 107-1 1 1). An association ity caused by infection and sepsis is more obvious,
between hypoalbuminemia and increased morbidity considering that malnutrition induces immunosup-
and mortality is not unique in renal failure patients presslon with a reduced cellular immune response,
but is also found in the general population of patients impaired antibody production, and Inhibition of gran-
admitted to the hospital ( 1 1 2). Findings in HD pa- ulocyte mobility and phagocytic capacity (3,119).
tients with ‘251-labeled human serum albumin sug- These abnormalities are very similar to the immuno-
gest that hypoalbuminemia and reduced albumin logic changes caused by uremia per Se, and it is
synthesis result mainly from non-nutritional factors conceivable that malnutrition and uremic toxicity may
and partly from a (negative) acute-phase response act in concert to suppress the immune response and
( 1 13). In a recent study of CAPD patients, it was increase the susceptibility to infection, resulting in
observed that low serum albumin mainly reflected the increased morbidity and mortality ( 1 19, 120). Signs of
presence of a systemic disease, which was the chief malnutrition in HD patients have been reported to
risk factor for reduced patient survival ( 1 14). correlate with reduced lymphocyte function (28). The
Hence, one should be cautious in drawing conclu- Canadian Hemodialysis Morbidity Study showed that
sions regarding the role of malnutrition in dialysis- hospitalizations for infectious diseases were more
associated mortality based only on serum albumin common in patients with serum albumin 30 g/L
data, considering that comorbid conditions, the sever- than in patients with higher serum albumin (46).
ity of which are reflected in low serum albumin levels, Hypoalbuminemia per se may also contribute to

1336 Volume 6 ‘ Number 5 1995

#{149}
 Bergstrom

morbidity and mortality. Water balance between in- TABLE 3. Causes of anorexia in maintenance
travascula and interstitial spaces may be adversely dialysis patients
affected by low intravascular oncotic pressure ( 1 2 1).
Uremic Toxicity (Underdlalysis)
Albumin also has important roles as a scavenger of
Unpalatable or Inadequate Diets
free radicals, a binding agent for toxic compounds,
Gastrointestinal Illness
and a carrier for a wide variety of drugs and hormones
Other Complicating Illnesses
( 1 22). Reduced albumin binding of drugs and endog-
Inflammation, Infection, Sepsis
enous ligands is a feature of uremia ( 1 23), and it is
Medications
conceivable that potentially adverse effects of reduced Dental Status
albumin binding are further promoted when serum Psychosocial and Socioeconomic Factors
albumin is low. However, exogenous albumin therapy Loneliness
has generally not been successful in reducing morbid- Depression
ity and mortality in intensive care patients ( 1 24) and Ignorance
there is no evidence that such therapy is of any value Poverty
in hypoalbuminemic HD patients. Alcohol and drug abuse
Withdrawal from dialysis is among the most corn- Effects of the HD Procedure
mon causes of death ( 1 3%) in maintenance dialysis Cardiovascular instability
patients, as reported in the USRDS annual report (81). Nausea, vomiting
It is conceivable that in some of these patients, who Postdialysis fatigue
are usually elderly, the presence of severe nutritional
problems may have been a reason why the decision
was made to withhold dialysis. tube, a percutaneous gastric catheter, or a gastros-
tomy button is preferable, whenever possible, to par-
EFFECT OF INTERVENTIONS ON NUTRITIONAL enteral feeding through an indwelling catheter, which
is more expensive and caries the risk of catheter-
STATUS AND SURVIVAL
related sepsis ( 1 26). The effect of such therapies on
Assuming that malnutrition is a significant risk mortality In HD has not been assessed.
factor for mortality and morbidity in HD, one might Intradialytic parenteral nutrition (IDPN), i.e. , the
expect that measures taken to improve nutritional intravenous supply of a mixture of amino acids, glu-
status should be beneficial in improving survival and cose, and lipids during the HD session, has become
rehabilitation. The elimination of catabolic factors increasingly popular in recent yeas, because it can be
such as acidosis, infectious complications, and other given without the need of a central catheter and does
comorbidity factors are obvious goals of treatment. In not confine the patient to an intravenous line (127-
underdialyzed HD patients, an increase in the dose of 133). Favorable effects on nutritional status, includ-
dialysis may have salutary effects by improving gen- ing anthropometric parameters and serum proteins,
eral well-being and survival and by promoting an have been reported in some studies. Most of the
increase in food intake (6 1 ,73,80, 1 25). However, it studies comprised small numbers of patients over
should be emphasized that it is not known to what short periods, and they lacked control groups; no
extent the beneficial effects on survival, achieved by beneficial effects on morbidity and mortality were
increasing the dose of dialysis, are mediated by the reported. Recently, Capelli et at. ( 1 34) reported the
correction of malnutrition. Moreover, anorexia in HD results of a prospective, nonrandomized study of mal-
patients may be related to various comorbidity factors nourished HD patients over an average of 9 months.
apart from underdialysis (Table 3) that must be iden- Fifty patients who received IDPN had a significantly
tified and corrected in order to ensure an adequate lower mortality rate than did 1 3 1 untreated patients
nutritional intake. Psychosocial and economic sup- ( 1 34). Chertow et at. ( 1 35) analyzed retrospective sur-
port should be provided whenever needed. Dietary vival data in a subgroup of 1 ,679 HD patients who
advice with the aim ofincreasing the quantity, quality, received IDPN (one or more infusions), comparing
and palatability ofthe food consumed may be helpful. them with data from more than 22,000 patients, and
Attention should be paid not only to the protein intake monitored the two groups for 1 yr or until death. There
but also to the energy intake, which needs to be was a significant reduction in the odds ofdeath and an
adequate for the optimal utilization of protein (67). increase in the serum albumin and creatinine levels in
Oral supplementation with special formula prepara- the IDPN-treated patients with low serum albumin
tions containing high-quality protein, essential amino compared with nontreated patients with hypoalbu-
acids, carbohydrates, and fat may be added to the diet minemia. Patients with normal serum albumin levels
(126). did not benefit from the treatment. Although the two
If severe malnutrition develops despite adequate aforementioned studies suggest that mortality is re-
dialysis and measures to eliminate various anorectic duced by IDPN in malnourished HD ratients, it
and catabolic factors, enteral or parenteral nutritional should be noted that they were both retrospective and
supplementation may be necessary to ensure an ade- potentially subject to selection bias and that the ef-
quate supply of nutrients. Feeding by a nasogastric fects noted were modest. Nor can it be excluded that

Journal of the American Society of Nephrology 1337

Nutrition and Mortality in HD

these effects might have been obtained equally well by tabolism. Only when all such measures fail to produce
intensive dietary counseling plus other measures to a positive effect, may enteral and parenteral nutrition
improve the nutritional status. Hence, the issue of be tried, although there is still Insufficient evidence
whether or not IDPN is of proven benefit is still con- that these types of therapy have a beneficial effect on
troversial ( 136, 137). Nevertheless, it is reasonable to patient survival. The same applies to treatment with
try this form of therapy in severely malnourished HD rhGH in combination with IDPN, which in short-term
patients when all other measures fail, and especially studies shows very promising results.
during episodes of concurrent illness, with deteriora-
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Journal of the American Society of Nephrology 1341