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 malnutrition is present in a large pro- I 960, Scribner et at. ( 1 ), in their first report on portion of maintenance hemodialysis (HD) patients, hemodialysis (HD) treatment of patients with 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, dure, and comorbidity factors, which all stimulate net several reports have focused on the association be- 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- measures fail. However, the indications for such treat- ever, a nutritional deficiency may be clinically unrec- 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 in vital statistics. It should be emphasized that even Journal of the American Society of Nephrology 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 Delayed hypersensitivity skin tests weight and DNA (22,27), as well as abnormal plasma 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 PROTEIN AND ENERGY REQUIREMENTS IN apparent association was noted between CO2 levels HEALTHY SUBJECTS AND HEMODIALYSIS PATIENTS and nutritional status, as evaluated by serum albu- 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 #{149}1995 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 Nutritional Status and Clinical Outcome also associated with an increased risk of death, but 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%) of 29 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 Malnutrition In spite ofmultiple studies demonstrating that signs 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 #{149}1995 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- tion of nutritional status. Prospective, well-controlled REFERENCES studies are obviously needed to establish whether 1 . Scribner BH, Burl R, Caner JEZ, Hegstrom R, Burnell IDPN should be generally recommended as a therapy JM: The treatment of chronic uremia by means of for chronically malnourished HD patients, especially intermittent hemodlalysis: A preliminary report. ASAIO J 1960:4:114-122. because it is a very expensive form of therapy. 2. Young VR: Nutritional requirements of normal adults. Recombinant human growth hormone (rHGH) is In: Mitch WE, Klahr 5, Eds. Nutrition and the Kidney. now available for the treatment of growth retardation Boston: Little, Brown and Company; 1993:1-34. 3. Chandra RK: Nutrition, Immunity, and infection: and malnutrition ( 138); its anabolic effects are partly present knowledge and future direction. Lancet 1983; mediated through the induction of IGF- 1 . Treatment 1:688-691. with rHGH is now an established therapy in growth- 4. Windsor JA, Knight GS, Hill GL: Wound healing re- retarded uremic and transplanted children (139,140). sponse In surgical patients: recent food intake Is most important than nutritional status. Br J Surg 1988;75: Short-term studies in adult HD patients with malnu- 135-137. trition have demonstrated that the administration of 5. Lindholm B, Bergstrom J: Nutritional management of rHGH in combination with parenteral nutrition re- patients undergoing peritoneal dialysis. In: Nolph KD, Ed. Peritoneal Dialysis. Boston: Kluwer Academic Pub- sults in reduced urea appearance, sustained nitrogen lishers; 1989:230-260. retention, and improvement of nutritional status 6. Steinman TI, Mitch WE: Nutrition in dialysis patients. In: Maher MF, Ed. Replacement of Renal Function by ( 1 4 1 , 1 42). These very promising results suggest that Dialysis. Boston: Kluwer Academic Publishers; 1989: rHGH potentiates the anabolic effects of IDPN. How- 1088-1106. ever, the effect of this very expensive form of therapy 7. Mazess RB, Barden HS, Bisek JP, Hanson J: Dual- on morbidity and mortality has not been established. energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition. Am J Clin Recombinant human IGF- 1 (rhIGF- 1) has also been Nutr l990;51:1106-1l12. proposed as a nutritional support in malnourished 8. Segal KR, Burastero 5, Chun A, Coronel P, Pierson RN dialysis patients ( 1 43) and has been reported to cause Jr, Wang J: Estimation of extracellular and total body anabolism in a small group of CAPD patients (144). water by multiple-frequency bioelectrical-impedance measurement. Am J Clin Nutr 1991:54:26-29. However, there is evidence that HD and CAPD patients 9. Formica C, Atkinson MG, Nyulasi I, McKay J, Heale W, are resistant to the metabolic effects of rhIGF- 1 (145) Seeman E: Body composition following hemodialysis: and that treatment with rhIGF- 1 in uremic patients is Studies using dual-energy x-ray absorptlometry and bioelectrlcal Impedance analysis. Osteoporosis mt associated with a high frequency of side effects (146). l993;3: 192-197. 10. Cosentino F, Pexa D, Dennis VW, Donatucci D, Ellis P, Piedmonte M: Body composition and nutritional anal- CONCLUSIONS ysis using dual energy X-ray absorptiometry scans (DEXA) and a standard composite nutritional Index Anthropometric and biochemical signs of malnutri- (CN) In patients on hemodialysis. J Am Soc Nephrol tion in HD patients are associated with increased 1994:5:490. 1 1 . Katzarski KS, Anderstam B, Nordenstr#{246}m J, Nilsson mortality, but malnutrition per se is generally not M, Bergstrom J: Dual-energy x-ray absorptlometry recognized as a common cause of death as reflected by (DEXA) and multifrequency bloimpedance (MFB) for health statistics, except in the oldest age groups. A low assessment of nutritional status in chronic hemodialy- sis (HD) patients. Blood Purif 1994; 12:156. serum albumin level is an especially strong predictive 12. Bergstrom J, Alvestrand A, F#{252}rstP, Huitman E, Wids- risk factor; it may, however, not only or mainly reflect tam-Attorps U: Muscle intracellular electrolytes in pa- protein malnutrition, but also the influence of several tients with chronic uremia. Kidney Int 1983;(Suppl other morbidity factors (overhydration, infection, 161:Sl53-S160. 13. 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1338 Volume 6 . Number 5 ‘ 1995 BergstrOm

ysis patients: An international study. Am J Kidney Dis 4 1 . Hara Y, May RC, Kelly RC, Mitch WE: Acidosis, not 199 1; 17:462-471. azotemla, stimulates branched-chain amino acid ca- 19. Enia G, Sicuso C, Alati G, Zoccali C: Subjective global tabolism in uremic rats. Kidney Int 1987:32:808-814. assessment of nutrition in dialysis patients. J Am Soc 42. Garibotto G, Russo R, Sofia A, et at.: Skeletal muscle Nephrol 199 1;323. protein synthesis and degradation in patients with 20. Sengar DPS, Rashid A, Harris JF: In vitro cellular chronic renal failure. immunity and in vivo delayed hypersensitivity in ure- 43. May RC, Hara Y, Kelly PA, Block KP, Buse M, Mitch mic patients maintained on hemodlalysis. Archs Allergy WE: Branched-chain amino acid metabolism in rat Appl Immun 1974:47:829. muscle: Abnormal regulation In acidosis. Am J Physlol

2 1 . Schaeffer G, Heinze V. Jontofsohn R, et at.: Amino acid 1987;252:E712-E718. and protein intake in RDT patients. A nutritional and 44. Mitch WE, Medina R, Grieber S, et aL: Metabolic ad- biochemical analysis. Clin Nephrol 1975;3:228-233. dosis stimulates muscle protein degradation by activat- 22. Delaporte C, Bergstrom J, Broyer M: Variations in Ing the adenosine triphosphate-dependent pathway in- muscle cell protein of severely uremic children. Kidney volving ubiquitin and proteasomes. J Clin Invest 1994; Int 1976; 10:239-245. 93:2127-2133. 23. Bansal VK, Popli 5, Pickering J, Ing TS, Vertuno LL, 45. Bergstrom J, Alvestrand A, F#{252}rstP: Plasma and mus- Hano JE: Protein-calorie malnutrition and cutaneous dc free amino acids in maintenance hemodialysis pa- anergy in hemodialysis maintained patients. Am J Clin tients without protein malnutrition. Kidney Int 1990; Nutr 1980:33:1608-1611. 38:108-114. 24. Young GA, Swanepoel CR, Croft MR, Hobson SM, 46. Lowrie EG, Lew NL: Commonly measured laboratory Parsons FM: Anthropometry and plasma valine, amino variables in hemodialysis patients: Relationships acids, and proteins In the nutritional assessment of among them and to death risk. Semin Nephrol 1992; hemodialysis patients. Kidney Int 1982:21:492-499. 12:276-283. 25. Schoenfeld PY, Henry RR, Laird NM, Roxe DM: Assess- 47. Bergstrom J: Metabolic acidosis and nutrition in dial- ment of nutritional status of the National Cooperative ysis patients. Blood Purif 1994, in press. Study population. Kidney mt 1983;23(Suppl 131:80- 48. Lowrie EG: Chronic dialysis treatment: Clinical out- 88. come and related processes of care. Am J Kidney Dis 26. Bergstrom J, Alvestrand A, F#{252}rstP: Plasma and mus- l994;24:255-266. dc free amino acids in maintenance hemodialysis pa- 49. Papadoyannakis NJ, Stefanidis CJ, McGeown M: The tients without protein malnutrition. Kidney mt 1990; effect of the correction of metabolic acidosls on nitrogen 38:108-114. and potassium balance of patients with chronic renal 27. Guarnieri G, Toigo G, Situlin R, et at.: Muscle biopsy failure. Am J Clin Nur 1984:40:623-627. studies in chronically uremic patients: evidence for 50. Lofberg E, Wernerman J, Bergstrom J: Branched- malnutrition. Kidney mt 1983;24ESuppl 161:187-193. chain amino acids in muscle increase during correction 28. Wolfson M, Strong CJ, Minturn D, Gray DK, Kopple of metabolic acidosis In hemodialysis (HD) patients. J JD: Nutritional status and lymphocyte function in Am Soc Nephrol 1993;4:363. maintenance hemodialysis patients. Am J Cli.n Nutr 5 1 . Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, 1984;37:547-555. Wolfson M, Humphreys MH: Nitrogen balance during 29. Marckmann P: Nutritional status and mortality of pa- intermittent dialysis therapy of uremia. Kidney Int tients In regular dialysis therapy. J Intern Med 1989; 1978; 14:491-500. 226:429-432. 52. Lim VS, Flanigan MJ: The effect ofinterdialytic interval 30. Lowrie EG, Lew NL: Death risk In hemodialysis pa- on protein metabolism: Evidence suggesting dialysis- tients: the predictive value ofcommonly measured van- induced catabolism. Am J Kidney Dis 1989;14:96-lOO. ables and an evaluation of death rate differences be- 53. LOfberg E, Wernerman J, Nor#{233}eLO, Decken A, Vinnars tween facilities. Am J Kidney Dis 1990; 15:458-482. E: Ribosome and free amino acid content in muscle

3 1 . Allman MA, Allen BJ, Stewart PM, et at.: Body protein during hemodialysis. Kidney Int 199 1 ;39:984 -989. of patients undergoing hemodlalysis. Eur J Clin Nutr 54. Lim VS, Bier DM, Flanigan MJ, Sum-Ping ST: The effect 1990;44: 123-13 1. of hemodialysis on protein metabolism. A leucine ki- 32. Jacob V, Le Carpentier JE, Saizano 5, et at.: IGF-I. a netic study. J Clin Invest 1993:91:2429-2436. marker of undernutrition In hemodialysis patients. Am 55. Wolfson M, Jones MR, Kopple JD: Amino acid losses J Clin Nutr 1990:52:39-44. during hemodiaiysis with infusion of amino acids and 33. Rayner HC, Sroud DB, Salamon KM, et aL: Anthropom- glucose. Kidney Int 1982:21:500-506. etry underestimates body protein depletion in hemodi- 56. Gutierrez A, Bergstrom J, Alvestrand A: Hemodialysis- alysis patients. Nephron 1991:59:33-40. associated protein catabolism with and without glucose 34. Oksa H, Ahonen K, Pasternack A, Marnela KM: Mal- In the dialysis fluid. Kidney Int 1994:46:814-822. nutrition in hemodialysis patients. Scand J Urol Neph- 57. Ikizler TA, Flakoll PJ, Parker RA, Hakim RM: Amino rol 1991:25:157-161. acid and albumin losses during hemodialysls. Kidney 35. Bilbrey GL, Cohen TL: Identification and treatment of hit 1994:46:830-837. protein calorie malnutrition In chronic hemodialysis 58. Kaplan AA, Halley SE, Lapkin RA, Graeber CW: Dialy- patients. Dial Transplant 1989; 18:669-677. sate protein losses with bleach processed polysulphone 36. B#{225}r#{225}nyP,Pettersson E, Ahlberg M, Hultman E, Berg- dialyzers. Kidney Int 1995;47:573-578. strom J: Nutritional assessment in anemic hemodialy- 59. Cheung AK: Biocompatibility of hemodialysis mem- sis patients treated with recombinant human erythro- branes. J Am Soc Nephrol 1990; 1:150-161. poietin. Clin Nephrol 199135:270-279. 60. Gutierrez A, Alvestrand A, Wahren J, Bergstrom J: 37. Talemaitoga AS, Sanders BA, Hinton D, Lynn KL: Effect of In vivo contact between blood and dialysis Nutritional status of home hemodialysis patients. Aust membranes on protein catabolism In humans. Kidney NZ J Med 1989:19:303-309. Int 1990;38:487-494. 38. Bergstrom J, Lindholm B: Nutrition and adequacy of 6 1 . Gutlerrez A, Bergstrom J, Alvestrand A: Protein catab- dialysis. How do hemodlalysis and CAPD compare? olism In sham-hemodialysis: the effect of different Kidney Int 1 993;43[Suppl 401:S39-S50. membranes. Clin Nephrol 1992;38:20-29. 39. Reaich D, Channon SM, Scrimgeour CM, Daley SE, 62. Flores EA, Bistrian BR, Pomposelli JJ, Dinarello CA, Wilkinson R, Goodship THJ: Correction of acidosis in Blackburn GL, Istfan NW: Infusion of tumor necrosis humans with CRF decreases protein degradation and factor. Cachectin promotes muscle catabolism in the amino acid oxidation. Am J Physiol 1993;265:E230- rat. J Clin Invest 1989:83:1614-1622. 235. 63. Hakim RM, Wingard RI, Ikizler TA, et at.: Effects of 40. Lim VS, Bier DM, Flanigan MJ, Sum-Ping ST: Acidosis biocompatibiity on nutritional status In chronic hemo- increased amino acid oxidation in chronic renal failure dialysis patients (CHD). J Am Soc Nephrol l994;5:45 1. (CRY) patients. J Am Soc Nephrol 1993:4:252. 64. Monteon FJ, et at.: Energy expenditure In patients with

Journal of the American Society of Nephrology 1339 Nutrition and Mortality in HD

chronic renal failure. Kidney Int 1986:30:74 1. Study and a description of morbidity, mortality, and 65. Kopple JD, Chumlea WC, Gassman JJ, et at: Relation- patient withdrawal. Kidney Int 1983;23lSuppl 13):S42- ship between GFR and nutritional status. Results from 549. the MDRD study. J Am Soc Nephrol 1994:5:325. 88. Acchiardo SR, Moore LW, Latour PA: Malnutrition as 66. KishI K, Mlytani K, Inoue G: Requirement and utiliza- the main factor in morbidity and mortality of hemodi- tion of egg protein by Japanese young men with ma- alysis patients. Kidney Int l983;24(Suppl 16]: 199-203. glnal intakes of energy. J Nutr 1978; 198:658-669. 89. Degoulet P, Legrain M, Reach I, Ct at.: Mortality risk 67. Slomowitz LA, Monteon FJ, Grosvenor M, Laidlaw SA, factors in patients treated by chronic hemodialysis. Kopple JD: Effect of energy intake on nutritional status Nephron 1982:31:103-110. in maintenance hemodialysis patients. Kidney Int 90. Shapiro ll, Argy WP, Rakowski TA, Chester A, Siem- 1989:35:704-711. sen AS, Schreiner GE: The unsuitability of BUN as a 68. Arnold WC, Danford D, Holliday MA: Effects of caloric criterion for prescription dialysis. Trans Am Soc Artil supplementation on growth in children with uremia. Intern Organs 1983:29:129-134.

Kidney Int 1983:24:205-209. 9 1 . Owen WF, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The 69. Lowrie EG, Laird NM, Henry RR: Protocol for the Na- urea reduction ratio and serum albumin concentration tional Cooperative Dialysis Study. Kidney Int 1983; as predictors of mortality In patients undergoing hemo- 23lSuppl 131:S1 1-S 18. dialysis. N Engl J Med 1993;329:1001-1006. 70. Bergstrom J, Mamoun MI, Anderstam B, S#{246}dersten P: 92. Goldwasser P. Michel MA, Collier J, et at.: Prealbumin Middle molecules (MM) isolated from uremic ultrafil- and lipoprotein(a) in hemodialysis: relationships with trate (UF) and normal urine induce dose-dependent patient and vascular access survival. Am J Kidney Dis inhibition of appetite in the rat. J Am Soc Nephrol 1993;22:2 15-225. 1994:5:488. 93. Goldwasser P. Mittman N, Antignani A, et at.: Predic- 7 1 . Lindsay RM, Spanner E: A hypothesis: The protein tors of mortality in hemodialysis patients. J Am Soc catabolic rate is dependent upon the type and amount Nephrol 1993:3:1613-1622. of treatment in dialyzed uremic patients. Am J Kidney 94. Churchill DN, Taylor DW, Cook RJ, et at.: Canadian Dis 1989; 13:382-389. hemodlalysis morbidity study. Am J Kidney Dis 1992; 72. Lysaght MJ, Pollock CA, Hallet MD, Ibels LS, Farrell 19:214-234. PC: The relevance of urea kinetic modeling to CAPD. 95. Iseki K, Kawazoe N, Fukiyama K: Serum albumin is a Trans Am Soc Artif Intern Organs 1989:35:784-790. strong predictor of death in chronic dialysis patients. 73. Lindsay RM, Spanner E, Heldenheim P, Kortas C, Kidney Int 1993:44:115-119. Blake PG: PCR, Kt/V and membrane. Kidney Int 1993; 96. Collins AJ, Ma JZ, Umen A, Keshaviah P: Urea Index 43[Suppl 4 1 1:S268-S273. and other predictors of hemodialysis patient survival. 74. Movilli E, Mombelloni S, Gagglotti M, Majorca R: Effect Am J Kidney Dis 1994:23:272-282. of age on protein catabolic rate, morbidity, and mortal- 97. Jungers P, ZingraffJ, Albouze G, et at.: Late referral to ity in uraemlc patients with adequate dialysis. Nephrol maintenance dialysis : detrimental consequences. Dial Transplant 1993:8:735-739. Nephrol Dial Transplant l993;8: 1089-1093. 75. Morgenstern A, WinklerJ, Narkis R, et aL: Adequacy of 98. Nor#{233}eLO, Bergstrom J: Treatment of chronic uremic dialysis and nutritional status in hemodialysis pa- patients with protein-poor diet and oral supply of es- tients. Nephron 1994:66:438-441. sential amino acids. Clin Nephrol 1975;3: 195-203. 76. Gotch FA, Sargent JA: A mechanistic analysis of the 99. Walser M: Does prolonged protein restriction preceding National Cooperative Dialysis Study. Kidney Int 1985; dialysis lead to protein malnutrition at the onset of 28:526-534. dialysis? Kidney mt 1993;44: 1139-1144. 77. Harty JC, Boulton H, Curwell J, et aL: The normalized 100. Klein 5: The myth of serum albumin as a measure of protein catabolic rate is a flawed marker of nutrition In nutritional status. Gastroenterology 1990:99:1845- CAPD patients. Kidney mt 1994:45:103-109. 1846. 78. Raja RM, Ijelu G, Goldstein M: Influence of Kt/V and 101 . Lentner C, Ed. Geigy Scientific Tables. Vol. 3. Physical protein catabolic rate on hemodialysis morbidity. A Chemistry, Composition of Blood, Hematology, So- long-term study. ASAIO J 1992;38:M179-180. matometric Data. 8th ed. Basel: Ciba-Geigy Ltd: 1984. 79. Burrowes JD, Lyons TA, Kaufman AM, Levin NW: 102. Kushner I: The phenomenon of the acute phase re- Improvement in serum albumin with adequate hemo- sponse. Ann NY Acad Sd 1982:389:3948.

dialysis. J Renal Nutr 1993:3:171-176. 103. Dinarello CA: Biology of interleukin 1 . FASEB J 1988; 80. Hakim RA, Breyer J, Ismali N, Schulman G: Effects of 2:108-115. dose of dialysis on morbidity and mortality. Am J 104. Castell JV, Andus T, Kunz D, et aL: Interleukin-6, the Kidney Dis 1994:23:661-669. major regulator of acute-phase protein synthesis in

8 1 . United States Renal Data System. 1 994 Annual Data man and rat. Ann NY Acad Sci 1989:557:87-99. Report. Washington, DC: U.S. Department of Health 105. Bailmer PE, Balimer-Hofer K, Repond F, et aL: Acute and Human Services, Health Care Financing Adminis- suppression of albumin synthesis in systemic Inflam- tration, Bureau of Data Management and Strategy; matory disease: An Individually graded response of rat 1994. hepatocytes. J Histochem Cytochem 1992:40:201-206. 82. European Dialysis and Transplant Association- 106. Tullis JL: Albumin 2: Guidelines for clinical use. JAMA European Renal Association. EDTA/ERA Registry Re- 1977:237:460-463. port, Demography of Dialysis and Transplantation in 107. Fleck A, Hawker F, Wallace P1, et at.: Increased vascu- Europe, 1984. Nephroi Dial Transplant 1986; 1:1-8. lar permeability. A major cause of hypoalbumlnaemia 83. Piccoll GB, Salomone M, Bonello F, et at.: Dialysis in disease and injury. Lancet 1985; 1:781-784. choice in the elderly: Cause or effect of relevant clinical 108. Grossman J, Yalow AA, Weston RE: Albumin degrada- problems? Nephrol Dial Transplant 1993:8:1006. tion and synthesis as influenced by hydrocortisone, 84. Harter HR: Review of significant findings from the Na- corticotropin and infection. Metabolism 1960:9:528- tional Cooperative Dialysis Study and recommenda- 550. tions. Kidneylnt l983;23ESuppl 131:107-112. 109. Parving HH, Rasmussen M: Transcaplllary escape rate 85. Gotch FA, Sargent JA: A mechanistic analysis of the of albumin and plasma volume in short- and long-term National Cooperative Dialysis Study. Kidney Int 1985: juvenile diabetics. Scand J Clin Lab Invest 1973:32:8 1- 28:526-534. 87. 86. Parker TF, Reed RB, Lowrie EG: Description of the 1 10. Panting HH, Gyntelberg F: Transcapillary escape rate of participating centers and the patient population in the albumin and plasma volume in essential hypertension. National Cooperative Dialysis Study. Kidney Int 1983; Circ Res 1973:32:643-651.

(Suppl 131:37-41. 1 1 1 . Parving ml, Ranek L, Lassen NA: Increased transcap- 87. Parker TF, Laird NM, Lowrie EG: Comparison of the illary escape rate of albumin in patients with cirrhosis study groups in the National Cooperative Dialysis ofthe liver. Scand J Chin Lab Invest 1977:37:643-648.

1340 Volume 6 . Number 5 ‘ 1995 Bergstrom

1 12. Herrmann FR, Safran C, Levkoff SE, Minaker KL: tients. JPEN 1981:5:463-477. Serum albumin level on admission as a predictor of 1 30. Allman MA, Yau DF, Tiller DJ, et at.: The effect of death, length of stay, and readmission. Arch Intern dietary glucose polymer supplementation on the nutri- Med 1992:152:125-130. tion and plasma amino acids of hemodialysis patients. 1 13. Kaysen GA, Rathorne V. Shearer GC, Depner TA: J Renal Nutr 1992:2:59-66.

Mechanisms of hypoalbuminemia in hemodialysis pa- 131 . Vehe ia, Brown RO, Moore LW, Acchiardo SR, Luther tients. Kidney Int 1995:48:510-516. RW: The efficacy of nutrition support in infected pa- 1 14. Struijk DG, Krediet RT, Koomen GCM, Boeschoten tients with chronic renal failure. Pharmacotherapy EW, Arisz L: The effect of serum albumin at the stat of 1991:11:303-307. continuous ambulatory peritoneal dialysis treatment 132. Foulks CJ, Goldstein J, Kelly MP, Hunt JM: Indica- on patient survival. Peritoneal Dial Int 1994:14:121- tions for the use of intradialytic parenteral nutrition in 126. the malnourished hemodlalysis patients. J Renal Nutr 1 15. Ritz E, Vallance P. Nowicki M: The effect of malnutri- 1991 ;1:23-33. tion on cardiovascular mortality in dialysis patients: is 133. Siskind MS. Lien YHH: Effect of intradialytic paren- L-arginine the answer? Nephrol Dial Transplant 1994; teral nutrition on quality of life in hemodialysis pa- 9:129-130. tients. Int J ArtifOrgans 1993:16:599-603. 1 16. Valiance P, Leone A, Calver A, Coffler J, Moncada 5: 134. Capelli JP, Kushner H, Camiscioli TC, Chen SM, Accumulation ofan endogenous inhibitor ofnitric oxide Torres MA: Effect of intradialytic parenteral nutrition synthesis in chronic renal failure. Lancet 1992:339: on mortality rates In end-stage renal disease care. Am J 572-575. Kidney Dis 1994:23:808-816. 1 17. Anderstam B, Katzarski K, Bergstrom J: Methylargin- 135. Chertow GM, Ling J, Lew NL, Lazarus JM, Lowrie EG: ines in uremia. J Am Soc Nephrol 1994:5:572. The effect of intradialytic paenteral nutrition on sur- 1 18. Alvestrand A, F#{252}rst P. Bergstrom J: Intracellula viral in hemodialysis patients. 1994:24:912-920. amino acids In uremia. Kidney Int 1983:24(Suppl 161: 136. Bilbrey GL: Is intradialytic parenteral nutrition of ben- 59-516. efit in hemodialysis patients? IDPN is beneficial for 1 19. Mattern WD, Hak Li, Lamanna RW, Teasley KM. selected dialysis patients. Semin Dial 1993;6: 168-170. Laffell MS: Malnutrition, altered immune function, and 137. Wolfson M: IDNP is of no proven benefit in hemodialy- the risk of infection in maintenance hemodialysis pa- sis patients. Semin Dial 1993:6:170-173. tients. Am J Kidney Dis 1982:1:206-218. 138. Wilmore DW: Catabolic illness strategies for enhancing 1 20. Keane WF, Maddy MF: Host defenses and infectious complications In maintenance hemodialysis patients. recovery. N Engl J Med 1990:323:56-64. In: Maher JF, Ed. Replacement of Renal Function. 3rd 139. Fine RN, Pyke-Grimin K, Nelson PA, et at.: Recombi- Ed. Boston: Kluwer Academic Publ.; 1989:865-880. nant human growth hormone treatment of children with chronic renal failure: long-term ( 1 to 3 year) 1 2 1 . Ganger DN, Gabel JC, Drake RE, Taylor AE: Physio- logic basis for the clinical use of albumin solutions. outcome. Pediatr Nephrol 1991:5:477-481. Surg Gynecol Obstet 1978; 146:97-104. 140. Tonshoff B, Haffner D, Mehls 0, et at.: Efficacy and 122. Emerson TE: Unique features of albumin: a brief re- safety of growth hormone treatment in short children view. Crit Care Med 1989; 17:690-694. with renal allografts: Three yea experience. Kidney Int 1 23. Gulyassy PF, Depner TA: Impaired binding of drugs 1993:44: 199 -207. and endogenous ligands in renal diseases. Am J Kidney I 4 1 . Ziegler TR, Young LS, Manson JM, Wilmore DW: Met- Dis 1983:2:578-601. abolic effects of recombinant human growth hormone 124. Blackburn GL, Driscoll DF: Time to abandon routine in patients receiving parenteral nutrition. Ann Surg albumin supplementation. Crit Cae Med 1992:20: 1988:208:6-16. 157-158. 142. Schulman G, Wingard RL, Hutchinson RL, Lawrence 125. Parker TF III, Husni L, Huang W, Lew N, Lowrie EG: P, Hakim RM: The effects of recombinant human Survival of hemodialysis patients in the United States growth hormone and intradialytic parenteral nutrition is improved with a greater quantity of dialysis. Am J in malnourished hemodialysis patients. Am J Kidney Kidney Dis 1994:23:670-680. Dis 1993:21:527-534. 126. Bergstrom J: Nutritional requirements of hemodlalysis 143. Kopple J: The rationale for the use of growth hormone patients. In: Mitch WE, Klahr 5, Eds. Nutrition and the or insulin-like growth factor- 1 in adult patients with Kidney. 2nd Ed. Boston: Little, Brown and Company: renal failure. Miner Electrolyte Metab 1992:18:269- 1993:263-289. 275. 127. Cano N, Labastie-Coeyrehourq J, Lacombe P, Ct at.: 144. Peng SC, Fouque D, Kopple JD: Insulin-like growth Perdialytic parenteral nutrition with lipids and amino factor- 1 causes anabolism in malnourished CAPD pa- acids in malnourished hemodialysis patients. Am J tients. J Am Soc Nephrol 1993:4:4 14. Clin Nutr 1990:52:726-730. 145. Fouque D, Peng SC, Kopple JD: Impaired metabolic 128. Toigo G, et aL: Effect of intravenous supplementation response to recombinant insulin-like growth factor- 1 in of a new essential amino acid formulation in hemodial- dialysis patients. Kidney Int 1995:47:876-883. ysis patients. Kidney Int 1989:27:5278. 146. Miller 5, Mouton M, Ace M, Ham.mermann MR: Effects 129. Piralno A.!, Firpo JJ, Powers DV: Prolonged hyperall- of IGF- 1 on renal function in end-stage chronic renal mentation in catabolic chronic dialysis therapy pa- failure. Kidney Int 1994:46:201-207.

Journal of the American Society of Nephrology 1341