Oral supplementation of branched-chain amino acid improves nutritional status in elderly patients on chronic haemodialysis

Kinya Hiroshige, Toshiyo Sonta, Takeshi Suda, Kaori Kanegae and Akira Ohtani

Renal Division, Social Insurance Chikuho Hospital, Fukuoka, Japan



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Anorexia may be associated with decreased plasma levels of branched-chain amino acids (BCAA). In malnourished elderly haemodialysis (HD) patients, oral BCAA supplementation may improve anorexia, resulting in improved nutritional status.

Methods. Among 44 elderly (age >70 years) patients on chronic HD, 28 patients with low plasma albumin concentration (<3.5 g/dl) were classified as the malnourished group; they also suffered from anorexia. The other 16 patients did not complain of anorexia and were classified as the well-nourished group. We performed a 12-month, placebo-controlled, double-blind study on the malnourished group. Fourteen patients each received daily oral BCAA supplementation (12 g/day) or a placebo in random order in a crossover trial for 6 months. Body fat percentage, lean body mass, plasma albumin concentration, dietary protein and caloric intakes, and plasma amino acid profiles were monitored.

Results. Lower plasma levels of BCAA and lower protein and caloric intakes were found in the malnourished group as compared to the well-nourished group. In BCAA-treated malnourished patients, anorexia and poor oral protein and caloric intakes improved within a month concomitant with the improvement in plasma BCAA levels over the values in well-nourished patients. After 6 months of BCAA supplementation, anthropometric indices showed a statistically significant increase and mean plasma albumin concentration increased from 3.31 g/dl to 3.93 g/dl. After exchanging BCAA for a placebo, spontaneous oral food intake decreased, but the favourable nutritional status persisted for the next 6 months. In 14 patients initially treated with a placebo, no significant changes in nutritional parameters were observed during the first 6 months. However, positive results were obtained by BCAA supplementation during the subsequent 6 months, and mean plasma albumin concentration increased from 3.27 g/dl to 3.81 g/dl.

Conclusions. Normalization of low plasma levels of BCAA by oral supplementation can reduce anorexia and significantly improve overall nutritional status in elderly malnourished HD patients.

Keywords: branched-chain amino acids; dietary intake; elderly patient; haemodialysis; nutrition



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Malnutrition, which is frequently encountered in elderly patients on chronic haemodialysis (CHD), is multifactorial in origin, the contributing causes including ageing itself [13]. It is also generally accepted that nutritional status depends on the dialysis dose delivered, and low dialysis efficacy is associated with higher rates of morbidity and mortality. Anorexia is likely to be a causative factor of malnutrition, especially in elderly patients. Previous studies indicate a possible relationship between plasma levels of branched-chain amino acids (BCAA) and appetite [46]. With or without dialysis, the plasma amino-acid profile in renal failure patients exhibits abnormal patterns, such as reduced essential/non-essential amino acids and lower BCAA level [79]. Therefore in anorectic CHD patients who do not respond to conventional therapies for malnutrition, such as nutritional counselling and diet modification, oral or parenteral BCAA supplementation may be warranted.

In the general population receiving CHD, a few studies have shown no significant benefit of oral essential amino acid supplementation [10,11]. However, in many studies at least some benefit of intradialysis parenteral nutrition containing multiple amino acids was documented to improve visceral protein synthesis, anthropometric measures, and immunocompetence, although these studies could not demonstrate the normalization of impaired plasma amino-acid profile and did not refer to changes in appetite [1215].

In previous studies the amount of BCAA administered orally or parenterally was relatively small (30–50 g/week) because of the use of multiple amino-acid solutions. To clarify the relationship between BCAA and appetite, researchers must normalize the plasma BCAA level by administering relatively large amounts of only BCAA. In general, BCAA granules are used for the treatment for hepatic encephalopathy. Also, numerous controlled trials have used BCAA as a nutritional therapy in patients with chronic liver disease [16]. To our knowledge, there are no other reports concerning the exclusive use of BCAA granules as the strategy for treating malnutrition in dialysis patients. Little investigative effort has been given to studying the nutritional status and treating malnutrition in elderly CHD patients. In this study, we chose the simple method of oral supplementation with commercially available BCAA granules (84 g/week) in elderly CHD patients with anorexia and investigated the effect on spontaneous oral food intake and overall nutritional status.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients population
Fifty-nine patients over 70 years of age undergoing CHD in our unit were assessed for inclusion in this study. Strict inclusion criteria were used: we excluded patients with malnutrition factors unrelated to dialysis. Eight patients with severe complications affecting exercise capacity, such as old cerebral infarction or myocardial infarction, were excluded. Five patients with evidence of underlying disease, such as collagen disease, liver cirrhosis, malignancy, psychological disorders, or endocrinological disorders, were also excluded. Diabetic patients were included, but none received exogenous insulin administration. Two patients who had continuous elevation of carboxyl-terminal parathyroid hormone (c-PTH; >20 ng/ml) were also excluded. Thus 15 patients were excluded for one or more of the reasons mentioned above, and the remaining 44 patients were included in the study. All subjects were outpatients and not employees. Written informed consent from patients was obtained, and the study was conducted in accordance with the principles of the Declaration of Helsinki of the World Medical Association.

All patients were maintained on thrice-weekly CHD treatment using bicarbonate as the buffer solution for appropriately 4 h at a time. The haemodialyser used during the experimental period was polysulphone (PS; Fresenius, Bad Homburg, Germany), which was sterilized by autoclave. The haemodialysers were not reused. All patients were stable, and none had recently undergone surgery. None had significant daily diuresis, which was confirmed by 48-h urine collection of a volume less than 50 ml during the baseline period.

Study design
This study was a 12-month randomized, placebo-controlled, double-blind, crossover trial with a 3-month baseline period prior to the study.

Baseline period
Counselling by a certified dietician was performed monthly for all patients, and the following renal diet was prescribed. The recommended energy intake was 35 kcal/kg body weight/day and that for protein was 1.2 g/kg body weight/day. Nutritional evaluation was performed at the start and the end of the baseline period. Despite the intensive diet counselling, 28 patients with depressed serum albumin (<3.5 g/dl) at the end of the baseline period were classified into the malnourished group; they complained of anorexia to various degrees during the baseline period. Sixteen patients with a normal range of serum albumin (>3.6 g/dl) were classified into the well-nourished group; they did not complain of anorexia. We also studied healthy age- and sex-matched elderly persons for the measurement of nutritional parameters. Plasma amino acid profiles and other biochemical measures such as lipid profile, magnesium, zinc, and c-PTH in plasma were determined at the end of the baseline period in all patients, including the healthy control subjects. C-reactive protein in plasma and bicarbonate concentration in arterial blood were also measured.

Study period
The 28 malnourished patients were randomly assigned to receive either placebo (group 0) or BCAA supplementation (group 1) for the first 6 months and then the opposite treatment for the next 6 months. Three times daily, patients received BCAA granules orally (Livact®, Ajinomoto Co. Ltd, Tokyo, Japan), which consisted of valine (1.1 g), leucine (1.9 g), and isoleucine (1.0 g), at a total dose of 12 g/day. All patients received 4 g BCAA mixed with 2 g dextrose at a time. The placebo containing 6 g dextrose was identical in appearance and taste. Compliance with treatment was evaluated monthly. All patients consumed the BCAA granules exceeding 90% of the prescribed dosage. Sixteen well-nourished CHD patients (group 2) received no nutritional supplementation during the study period. Group demographic characteristics are shown in Table 1Go. No significant differences in age, gender, haemodialysis duration, or underlying disease were observed among the three groups.


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Table 1. Demographic characteristics of patients

 
Nutritional surveys including plasma amino acid profiles were performed at 1, 3, 6, 7, 9, and 12 months after the start of this study for groups 0 and 1. During the study period, including the baseline period, anaemic status was appropriately treated with recombinant human erythropoietin, and the mean haematocrit level in each group ranged from 25 to 30% during the study period. Dialysis efficacy manifested by Kt/V urea was determined every 2 weeks and was maintained at near 1.4, mainly by changing the blood flow rate.

Nutritional survey
Nutritional status was evaluated using plasma albumin concentration, dietary nutrient intake, and anthropometric measures such as body-fat percentage and lean body mass. Dietary protein and caloric intakes were estimated from diet records for 7 consecutive days by a certified dietician. To determine each patient's actual Kt/V urea, we used the urea kinetic modelling formula developed by Daugirdas [17]. Plasma was obtained just before the first dialysis session in a week for the measurements of albumin, amino acid profile, and other biochemical measures.

Height was measured and dry body weight was determined monthly by clinical manifestation and chest X-ray and ultrasonographic readings of the inferior vena cava. Total fat percentage (%) and lean body mass (kg) were determined using bioelectrical impedance analysis in a standard fashion using a four-electrode, single-frequency (50 kHz) impedance plethysmograph (model TBF-410, Tanita Co. Ltd., Tokyo, Japan). All anthropometric measurements were taken after the last dialysis session in a week to minimize any distortion caused by excess tissue fluid.

Laboratory investigation
Blood urea, plasma albumin concentration, and plasma lipid profile were determined by routine methods. Plasma concentrations of zinc were determined by the atomic absorbing method, magnesium by the ultraviolet absorbing method using xylidyl blue, and c-PTH by radioimmunoassay.

Plasma was deproteinized quickly for amino acid analysis by adding 45 mg sulphosalicylic acid/ml plasma, and the precipitate was removed by centrifugation. The supernatant was quickly frozen at -30°C until analysed. Amino acids were measured with a Beckman 121M amino acid analyser (Beckman Instruments, Palo Alto, CA) using a lithium buffer system.

Statistical analysis
All data are expressed as means±standard deviation (SD), unless otherwise indicated. A two-way analysis of variance was used to compare means between groups. Within-group comparisons were made with the Wilcoxon rank-sum test or with a paired Student t-test, as appropriate. A comparison of discrete variables in different groups was performed using a Fisher exact test. Differences were considered significant when a two-sided P value was <0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Baseline nutritional status
During the baseline period, in the 28 anorectic, malnourished patients no significant alterations in nutritional indices were observed, despite intensive diet counselling (Figure 1Go). Therefore, values obtained at the end of the 3-month baseline period (month 0) were taken as baseline values (Table 2Go). As noted, malnourished patients (groups 0 and 1) had a significantly lower mean plasma albumin concentration (3.27±0.22 and 3.31±0.21 g/dl respectively) than well-nourished patients (group 2; mean 3.93±0.26 g/dl). Dry body weight, body-fat ratio, and dietary protein and caloric intakes were significantly lower in groups 0 and 1 than in group 2 (P<0.01). Despite adequate dialysis in these groups, with mean Kt/V urea over 1.4, all patients in groups 0 and 1 complained of anorexia possibly causing poor food intake, which led to a nutritionally depleted state. There were no significant differences in arterial bicarbonate concentration and plasma concentrations of total cholesterol, triglyceride, magnesium, zinc, c-PTH, and C-reactive protein among the 3 groups. Plasma BCAA levels were significantly lower in groups 0 and 1 than in group 2 (Table 3Go). Healthy subjects were better nourished than patients in group 2 and had significantly higher plasma albumin and BCAA levels (Tables 2Go and 3Go).



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Fig. 1. Longitudinal changes in various nutritional parameters in elderly haemodialysis patients with anorexia. In groups 0 and 1, rapid increases in oral protein and caloric intakes after the administration of branched-chain amino acid (BCAA, arrow) granules were followed by increases in serum albumin concentration and anthropometric indices. Closed circles, group 0; open circles, group 1. *P<0.05, **P<0.01 compared to the basal values; {dagger}P<0.05, {dagger}{dagger}P<0.01 compared to the values at 6 months.

 

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Table 2. Baseline nutritional parameters

 

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Table 3. Baseline branched-chain amino acid (BCAA) profile

 

Effect of BCAA supplementation on amino acid profiles
The changes in plasma BCAA levels over time are shown in Figure 2Go. In group 1, after the administration of BCAA granules, rapid increases in plasma BCAA levels were observed within a month, and this favourable change persisted throughout the first 6 months of this study. The same observation was made on group 0 patients, who received BCAA supplements from 6 months after the start of this study, whereas the placebo did not have any influence on BCAA levels during the initial 6-month period. Peak plasma BCAA levels in both groups 0 and 1 became higher than basal values in healthy subjects (Table 3Go). Patients in group 1 showed a rapid decline in plasma BCAA levels after substituting the placebo for BCAA granules; those levels returned to near the baseline values within 3 months. Essential and non-essential amino acids, except BCAA, were not significantly altered by BCAA supplementation during the study period.



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Fig. 2. Longitudinal changes in plasma amino-acid profiles in elderly haemodialysis patients. Branched-chain amino acid (BCAA) concentrations in plasma rapidly increased after oral BCAA supplementation both in groups 0 and 1. After discontinuing BCAA treatment, a rapid reduction in these values was observed in group 1 patients. Closed circles, group 0; open circles, group 1. *P<0.05, **P<0.01 compared to the basal values; {dagger}P<0.05, {dagger}{dagger}P<0.01 compared to the values at 6 months.

 

Effect of BCAA supplementation on nutritional parameters
The time course of nutritional parameters, including oral food intake, are shown in Figure 1Go. All patients in group 1 had a rapidly improved appetite, which resulted in a rapid increase of dietary protein and caloric intakes in parallel with the increase in plasma BCAA levels. These favourable responses persisted throughout the BCAA supplementation period. The mean plasma albumin concentration of 3.31 g/dl at the start significantly improved after 3 months and increased to 3.93 g/dl, which is exactly that in well-nourished patients (group 2; mean 3.93 g/dl). Anthropometric measurements also significantly improved between 3 and 6 months. After discontinuing the BCAA supplementation, spontaneous oral food intake as well as plasma albumin concentration gradually decreased, but never to the baseline values. However, anthropometric indices did not show an apparent decrease. In group 0 patients, no improvement in nutritional parameters was observed during the placebo phase and serum albumin concentration slightly decreased at 6 months. As in group 1, rapid increases in appetite and oral protein and caloric intakes, which were followed by increases in plasma albumin concentration and anthropometric indices, were observed after the BCAA therapy.

Adverse effects
No patients underwent major surgery during the study period or suffered from acute illness at the time of the nutritional evaluation. At 9 months after the start of this study, one patient in group 2 died suddenly from pontine haemorrhage. At 10 months, one patient in group 1 suffered from severe cerebral infarction and was excluded from the rest of the study. During the study period, two patients in group 0 and one patient in group 1 were briefly (less than a week) admitted to the hospital because of common cold and acute bronchitis, and to undergo imaging studies such as a barium enema. During the whole experimental period, BCAA granule supplementation was tolerated well by all patients, except one who had transient diarrhoea for 2 days just after the administration of BCAA granules. No other symptomatic complications related to BCAA granule ingestion were observed in any patients. Serum biochemical analysis revealed that blood urea nitrogen level was insignificantly raised during the amino acid therapy in groups 0 and 1. Blood pH and bicarbonate concentrations were not altered during amino acid therapy in either group (data not shown).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In this study we showed that anorectic, malnourished elderly patients had lower protein and caloric intakes than did well-nourished patients or healthy elderly subjects. It is vital to improve appetite and increase oral food intake as a strategy for improving malnutrition. However, elderly persons may suffer a decline in the senses of smell and taste, dental problems that decrease their ability to chew certain foods, and loss of vision, all of which may make eating less pleasant and lead to a decreasingly low appetite [3]. Therefore, conventional therapies for poor appetite such as dietary counselling and dietary supplementation are less likely to improve poor oral food intake in the elderly. In fact, in this study frequent dietary counselling during the baseline period were ineffective.

In the general population receiving CHD, inadequate dialysis appears to result in impaired appetite and decreased nutritional status [18]. However, a weak positive correlation between dialysis efficacy and spontaneous food intake in elderly CHD patients has been reported in several studies [1,4]. We previously evaluated the effect of prospectively increasing dialysis efficacy as a strategy for improving nutritional status in elderly CHD patients, but could not show any benefit [2]. In fact, in this study dialysis efficacy manifested by Kt/V urea in malnourished patients (groups 0 and 1) was adequate (>1.4) and was quite similar to that in well-nourished patients (group 2).

Chronic inflammation is common especially in elderly CHD patients and may cause atherosclerotic cardiovascular disease such as chronic heart failure, resulting in malnutrition [19]. In this study, patients with vascular diseases such as myocardial infarction and cerebral infarction were excluded. All patients were outpatients and none had chronic heart failure. Also, there were no significant differences in serum C-reactive protein concentrations between the well-nourished and malnourished groups.

Several factors such as leptin, insulin, nitric oxide synthase inhibitors, proinflammatory cytokines, and amino acid imbalances are possibly responsible for appetite suppression in uraemia [2022]. However, a recent report showed a close relationship between the augmentation of appetite and BCAA supplementation. Gill et al. [6] suggested that use of BCAA-enriched parenteral nutrition might minimize the reduction in food intake seen during intravenous nutrition, possibly hastening the return to a normal eating behaviour in healthy subjects. In this study, lower BCAA levels in plasma were documented in elderly anorectic patients compared to well-nourished patients without anorexia; only BCAA was administered in a relatively large dose to normalize the plasma BCAA levels and to exclude the effects of other nutrients such as glucose and lipid emulsion. As a result, plasma BCAA levels increased rapidly in patients receiving BCAA granules and soon became higher than those in healthy subjects. Concomitantly, all anorectic patients showed improved appetite, which led to increases in oral protein and caloric intakes. Good appetite persisted during the BCAA treatment and the plasma BCAA levels were greater than those in healthy subjects; however, after the therapy was stopped, oral food intake decreased, followed by a rapid decrease in plasma BCAA levels. This observation clearly demonstrates a tight correlation of plasma BCAA level with appetite or voluntary food intake.

The mechanisms for the favourable effect of increasing plasma BCAA levels on appetite may be the following: administration of BCAA accentuates the stimulation of respiration by amino acids, possibly by competing with tryptophan for uptake across the blood–brain barrier [23]. This competition may decrease brain uptake of tryptophan, an amino acid that serves as the precursor for serotonin, and thereby decrease the synthesis of brain serotonin, a central respiratory depressant. It may be possible to modify appetite by administering BCAA because serotonin has been implicated as the neurotransmitter that controls food intake [24]. Moreover, the BCAA itself plays a central role in metabolism as a precursor for the synthesis of proteins, fatty acids, metabolic fuel, regulations of protein turnover, and insulin release [25]. Among BCAA, leucine stimulates protein synthesis and its keto analogue inhibits proteolysis due to inhibition of glucocorticoid synthesis. In this regard, normalization of plasma leucine concentration may also benefit nutritional status [26].

Nutritional indices, especially anthropometric measurements, began to improve 3 months after the start of therapy, which is a shorter time span than those in other reports [1215]. Earlier reports showed that any changes in nutritional parameters did not arise until after 6–9 months of intradialysis parenteral nutrition therapy. Rapid improvement of plasma BCAA levels and oral food intake is of potential clinical significance due to the positive effect on protein synthesis, which thereby shortens the required length of time of nutritional treatment. After the cessation of the therapy in group 1, nutritional indices began to decrease, but never to the baseline values. Thus, oral administration of BCAA granules gave rapid and prolonged benefits for nutritional status. Our results of anthropometric measurements using bioelectrical impedance analysis should be interpreted with caution, however, because Di Iorio et al. [27] reported that a significant error might occur in the measurement of body composition from whole-body bioelectrical impedance analysis when performed in certain situations in haemodialysed patients. However, in stable CHD patients, except very obese subjects, Madore et al. [28] reported that bioelectrical impedance analysis is accurate with high sensitivity and specificity for identifying malnourished patients.

Although our results are preliminary, they suggest that there is a strong association between plasma BCAA levels and appetite. Normalization of plasma BCAA levels by oral supplementation was easily and safely achieved and produced prompt and persistent improvement of nutritional indices as well as spontaneous oral food intake in elderly malnourished patients. Modifications of this therapy, such as increasing the length of treatment or providing intermittent treatment on an as-needed basis, may be considered. Certainly, it is too early to recommend this therapy as a routine approach. Additional studies with larger numbers of patients and in conditions of the general haemodialysis population will be required.



   Notes
 
Correspondence and offprint requests to: Kinya Hiroshige MD, Renal Division, Social Insurance Chikuho Hospital, 765-1 Yamabe, Nougata City, 822-0034 Fukuoka, Japan. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 1.12.99
Revision received 17. 4.01.