Centre de Rein Artificiel, Tassin, France
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Abstract |
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Methods. Ten patients (59.5 years old; 4F/6M; HD treatment for 304 months; group A) underwent an extensive nutritional examination and were compared to a control group of 10 patients treated with HD for an average of 51 months and strictly matched for age (58.6 years old), gender, and height (group B). The patients were treated on a similar basis (long-duration HD, cellulosic membranes, Daugirdas index >2).
Results. The body weight (BW) in group A had decreased gradually from the 11th year of HD treatment, whereas it had increased by an average of 1.9±4.4% since the beginning of the HD treatment in group B. The body mass index (BMI) was lower in group A (19.3±2.3 vs 21.4±2.8 kg/m2; P=0.05). The arm-muscle circumference (AMC), the arm-muscle area (AMA), and triceps skinfold (TSF) were lower in group A than in group B. The fat mass assessed with anthropometry (10.8±4.0 vs 14.8±4.2 kg) was significantly lower in group A. The deviation of actual BW from ideal BW (IBW) was significantly lower in group A than in group B (80.6±10.7% vs 89.6±9.0%; P=0.028); The deviations of actual BW, TSF, and AMA from standard values of the NHANES II study were more marked in group A than in group B. On the other hand, daily energy and protein intakes (DEI and DPI) were identical in both groups and met the recommendations for dialysis patients when normalized to the actual BW. When normalized to the IBW, the DEI appeared low. Energy expenditure was not different between groups, and not different from the resting metabolism calculated from the Harris and Benedict formula. Average albumin, prealbumin, and IgF-1 were normal and not different between groups. Branched-chain amino acids (BCAA), and especially leucine, were correlated with BMI in group A but not in group B. Serum total and free carnitine were low in both groups. Three patients had ascorbic acid deficiency in group A but none in group B.
Conclusions. Hence, despite adequate dialysis dose and protein intake, patients treated with HD for a long period of time became malnourished, whereas the classical nutritional markers remained in normal ranges. Among the potential causes leading to malnutrition, inadequate energy intake and micronutrient deficiencies were found in these patients.
Keywords: amino acids; anthropometrics; carnitine; haemodialysis; malnutrition; serum albumin; survivors
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Introduction |
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Subjects and methods |
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Nutrition work-up
The 20 patients of groups A and B underwent the following investigations:
1. Body weight evolution
The body weight (BW) was patient dry weight, as previously defined [3]. In group A, the BW was recorded at each HD onset calendar anniversary and expressed as a percentage of the BW at the end of the first year of HD treatment. This calculation was possible for all but one patient who arrived in the unit after 48 months of HD treatment. For this patient, the reference BW was the BW after 48 months of HD treatment.
2. Anthropometric data
These were collected by the same investigator (C. Blanc) at the end of the midweek HD treatment. The body mass index (BMI) was calculated according to the formula BMI=BW/(height)2. The frame size was estimated from the elbow breadth measured with a Harpenden stadiometer. For each patient, the deviation (%) of the BW from the ideal BW (IBW) was calculated. The IBW was obtained from the Metropolitan Life Insurances data [4]. The triceps, biceps, subscapular, and supra-iliac skinfolds (TSF, BSF, SSSF and SISF) were assessed using a TannerWhitehouse caliper (Seritex, Carlstadt, NJ). For each patient, the deviation (%) of the BW and TSF from the standard value were calculated. The standard BW and TSF (StdBW and StdTSF) were determined as the fiftieth percentile value of the BW and TSF distributions in the National Health and Nutrition Examination Survey (NHANES) II population, according to age, gender, and elbow breadth [5].
3. Body composition
Fat mass and arm-muscle area (AMA), derived from arm-muscle circumference (AMC) and TSF, were calculated according to Durnin and Womersley (in reference [6]). The deviation (%) of the AMA from the standard values (StdAMA [5]) was calculated. Moreover, the patients underwent a total body dual-energy X-ray absorptiometry (DEXA) examination (Hologic 1000W, Boston, MA) that displays total body and regional fat and lean body masses. Regional body composition was measured on the superior limb without blood access. This examination was taken on a midweek day without dialysis, or the morning of the dialysis day if the patient was treated at night.
4. Food intake
A 3-day food questionnaire was filled out by the patient and was used to estimate the daily protein and energy intakes from the Bilnut 3 software (La Membrolle, France). The normalized protein nitrogen appearance (nPNA), estimating the protein intake, was calculated as previously reported [7].
5. Energy expenditure (EE)
The fasting patients underwent (in supine position) the measurement of energy expenditure for two or three 30-min periods under a canopy with the DeltaTrac II® device (Datex Engström, Sweden). The resting EE was derived from this data according to the O2 and CO2 volumes measured by the device. It was compared to the basal metabolism values calculated from the Harris and Benedict formula (given in Figure 3).
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Statistical analyses
Results are expressed as mean±SD, except in Figures 13
in which SEM is used. For the body weight evolution study, ANOVA for repeated measures and paired t-test were used. Groups A and B were compared with the unpaired t test or Wilcoxon rank test according to the normality of data distribution. A P value <0.05 was considered as significant, except for the comparisons of the plasma amino acids. In this case, Bonferroni adjustment was applied and the significant P value was 0.0002. Bilateral t test was used to compare the deviations of BW from IBW and BW, TSF, and AMA from the standard values of NHANES study [5] for these parameters. Correlations and multiple regression adjusted for age were calculated between biochemical and anthropometric data (Solo 6.0.4, BMDP®).
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Results |
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Body weight evolution
In Figure 1 is displayed the BW evolution in group A. The nadir of BW was reached at the 11th year of treatment. Then it decreased and a statistical significant difference from the nadir was reached at the 16th year of HD treatment and thereafter. In group B, from the beginning of the HD treatment to June 1997, the BW has increased by 1.9±4.4% of the predialysis BW at the first HD treatment (extremes, -3.9% to +9.1%).
Anthropometry and body composition
Data are reported in Table 2 and Figure 2
. The BMI was lower in group A than in group B. Four patients in group A and one patient in group B had a BMI<18.5 kg/m2. The AMC, AMA, and TSF measured by anthropometry were significantly lower in patients of group A than in group B. The deviation of BW from the ideal BW was significantly lower than 100% in both groups, but it was significantly larger in group A than in group B. Deviations of BW from StdBW were significantly lower than 100% in both groups, and significantly larger in group A. The TSF and AMA deviations from standard TSF and standard AMA were significantly lower in group A than in group B and lower than 100% in group A, but not in group B. The fat mass was lower in group A than in group B, but the difference was statistically significant only when total body fat mass was calculated from anthropometry. However, the upper limb fat mass from DEXA was significantly lower in group A than in group B. The fat proportion using this method was identical in both groups. Also the total and regional lean body mass assessed from DEXA were lower in group A than in group B but the differences did not reach significance.
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Food intake
The amount of daily energy intake (DEI) was similar in groups A and B (respectively 1864.2±521.2 and 1820.6±554.9 kcal/day). The normalization of DEI to the actual BW was respectively 35.1±8.3 and 31.0±9.5 kcal/kg/day, and 27.7±5.2 and 27.4±6.8 kcal/kg/day when IBW was used. The daily protein intake (DPI) was not different between both groups, 80.2±24.3 g/day in group A and 70.4±20.6 g/day in group B (respectively 1.53±0.48 and 1.19± 0.33 g/kg/day when normalized to actual BW, and 1.20±0.3 and 1.07±0.3 g/kg/day when normalized to IBW). The nPNA was 1.33±0.51 in group A and 1.29±0.72 g/kg/day in group B.
Energy expenditure
The fasting energy expenditure measured with the DeltaTrac® device was not different between groups and closely related to the resting energy expenditure calculated from the HarrisBenedict formula (Figure 3). The respiratory quotient was 0.84±0.03 in group A and 0.87±0.05 in group B.
Biochemical data
These are reported in Table 3. The average values of usual nutritional markers such as albumin, pre-albumin, cholesterol, and apolipoprotein A were in the normal ranges and there was no difference between the two groups. Serum albumin had no significant correlations with anthropometric data in group A and was correlated with BMI in group B (Table 4
). The bicarbonate level was significantly higher in group A. C-reactive protein was slightly higher in group A, but the difference with the other group did not reach significance.
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No difference was found between groups for PTH, insulin, glucagon, and cortisol plasma levels. Fasting insulin was higher than the upper normal range in 4/10 patients in group A and 5/10 in group B. Plasma leptin was widely distributed in both groups (Table 3). Leptin level was normal in males of group A, but increased in females of both groups and males of group B (Table 3
). In group A, leptin was not correlated with any of the anthropometric markers. In group B, leptin was correlated with proportion of body fat assessed by DEXA and TSF (Table 4
). In both groups, leptin was strongly correlated with plasma insulin (r=0.78, P=0.007 in group A and r=0.94, P=0.00006 in group B).
The aminograms are listed in Table 5. The average values of several amino acids were higher than the upper normal range in both groups (phenylalanine, proline, ornithine, glutamic acid, citrulline, aspartic acid) and only in group B for glycine and arginine. The average values of serine (group A) and cystine (group B) were lower than the lower normal range. In group A, leucine was significantly correlated with the BMI (Table 4
; Figure 4
), and with standard TSF deviation in group B (Table 4
).
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The average vitamin B6 plasma level was in the normal ranges (Table 3). Three patients in group A and four patients in group B were beneath the lower range for vitamin B6. The average plasma acid ascorbic level was significantly lower in group A than in group B (Table 3
). Three patients in group A were deficient in ascorbic acid, whereas all the patients in group B were in the normal range for ascorbic acid.
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Discussion |
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The selection of a control group for nutritional comparison is difficult, but appeared necessary to emphasize the malnutrition of long-term survivors. Each long-term survivor was matched with a control patient of the same gender, age, and height. Some of these patients had yet spent a long period of HD treatment (average: 51 months, maximum of 98.4 months). However, we think control patients were suitable for comparisons because in our experience, as demonstrated in Figure 1, the BW is stable for a long period of time, longer than the higher duration of treatment of any of the patients in the control group.
These long-term survivors display a significant and progressive decrease of BW beginning after the 11th year and significant from the 16th year of HD treatment. This evolution is also present in the long-term survivors that were not included in the study. We expressed the body weight as a percentage of the dry weight at the end of the first year of treatment because we expect that, at that time, the patient has probably got rid of fluid overload. In 24 long-term survivors, Bazzi et al. [10] did not find evidence of malnutrition, and particularly, there was no deviation of BW from IBW; this was quite different from our data. Nevertheless, the average duration of treatment was lower in their patients than in our study (222±23 vs 304±35 months, an average difference of almost 7 years) and it is possible that malnutrition was not yet significantly pronounced. These authors did not find a difference between the body weight at the beginning of HD treatment and at the 18th year of treatment. In our experience the body weight increases till a nadir reached in the 1012th year of treatment and then begins to slowly decrease. In our study, the body weight was identical at the first and the 15th year of treatment.
Whereas time on dialysis has been recently found a strong predictor of malnutrition [9], no extensive nutritional study has been reported yet in these long-term survivors. The average BMI of these patients was low and four of them had a BMI less than 18.5 kg/m2. This value of BMI has been proposed as the cut-off point for proteincalorie malnutrition [6]. Even a value less than 22 kg/m2 has been proposed as an indicator of reduced AMC [11]. The BW, TSF, and AMA were much lower than the standard values from NHANES anthropometric data, but these results have to be cautiously interpreted because the European anthropometric standards might be different from the North American ones. Marcén et al. [9] have reported lower values of TSF and AMC in the Spanish population than in North American people. However, the deviations from standard weight, TSF, and AMA were larger in the long-term survivors than in the control group and it argues for malnutrition among these patients. The DEXA data for body fat and lean body mass were not statistically different between the two groups. We can argue that the small number of patients was responsible for that, as a clear trend was present for both of these parameters.
Whereas malnutrition estimated from anthropometric measurements was obvious, it is noteworthy that the classical markers of malnutrition were normal in the HD long-term survivors. Visceral proteins like serum albumin, prealbumin, and apolipoprotein A were normal and no difference was found with the control group. It then appears that these patients have developed marasmus after a prolonged period of HD treatment. Also, serum IGF-1 was in the normal ranges for all the studied patients. However, serum IGF-1 may be higher in HD patients than in normal subjects, as shown by Himmelfarb et al. [12] in 52 HD patients. Moreover, resistance to the anabolic effect of IGF-1 in this setting is well documented [13]. So the significance of a normal serum level is unknown. Among the long-term survivors and the control group, IGF-1 was not correlated with AMA [14] or TSF [15]. The correlation of leucine with BMI in the group of long-term survivors was strong in a small number of patients. Hence, in these patients plasma leucine appears a good marker of the nutritional status. Such relationship between BCAA and anthropometrics has been previously reported [11,15,16].
Serum total and free carnitine were low in both groups of patients of the study. Carnitine status in HD patients is controversial [17]. Altered synthesis and perdialytic losses influence serum total carnitine levels in HD patients. Also, we have previously reported a correlation between protein intake and serum total carnitine level in 194 HD patients [18]. In the current study, however, this correlation was found only in the control group, but not in the long-term survivors. It is not known if carnitine supplementation in the long-term survivors may improve their nutritional status.
Leptin, an appetite suppressor produced by adipocytes, was higher than normal in the patients of both groups. Heimbürger et al. [19], using the same radioimmunoassay to assess leptin concentrations, have reported a threefold increase of leptin in HD patients. One of the reasons for the increase of leptin in this setting could be the failure of the kidney to clear leptin in ESRD [20]. Moreover, the correlation between leptin and insulin indicates that insulin resistance of dialysis patients may influence the leptin level, as reported previously by Stenvinkel et al. [21] in advanced chronic renal failure. The normal level of serum leptin in male long-term survivors argues against the involvement of leptin in the malnutrition of these patients.
The causes of malnutrition in the long-term survivors do not clearly emerge from the study. The age at start of HD treatment was 34.5 years. Getting older, even for 2 decades, may not explain the BW evolution and the malnutrition. Cross-sectional studies of nutritional surveys show that the body weight and skin folds increase from the 2nd to the 6th decade [2,4,5]. The food intake was not different between the two groups of patients. In group A, the average protein intake met the usual recommendation in this setting [22]. It may partly explain the maintained levels of serum albumin and prealbumin. Regarding the energy intake, the recommended daily amount is 35 kcal/kg/day [23]. The average energy intake normalized to the actual BW in group A matched exactly this value (35.1 kcal/kg/day). However, when ideal BW was used, the amount of energy daily ingested was much lower (27.5±5.2 kcal/kg/day), and low energy intake may participate in malnutrition. However, normal values of serum IGF-1 may favour the hypothesis of an adequate food intake, as shown by Oster et al. [24]. But it has been reported that a low food intake may impair IGF-1 bioavailability (expressed as the ratio IGF-1/IGFBP-3) rather than basal level of IGF-1 [25] and IGFBP-3 was not available in this study.
Metabolic acidosis, a frequent condition in HD patients, is a major factor of muscle catabolism in this setting [26]. In our study, the group of long-term survivors had a higher level of serum bicarbonates than the control group. However, this value is only cross-sectional. A nutritional effect of long-term exposure to mild metabolic acidosis cannot be ruled out. Moreover, most of the long-term survivors were under a low amount of steroids (usually 4 mg/day of methylprednisolone) for amyloidosis-related joint pains. Even if the catabolic effect of such a low dose of steroids has not been demonstrated, it is known that the interaction of acidosis and steroids enhances muscle catabolism [27]. The combination of both factors in long-term survivors could favour the lean body mass depletion. Also, we did not assess the physical activity in these patients. It is possible that its limitation related to joint amyloidosis deposits may contribute to muscle wasting in these patients. However, in a retrospective analysis of 26 patients treated for 20 years with HD treatment, no difference in weight loss was found in patients receiving or not receiving steroids or in relation to the extent of amyloidosis (personal data).
Resting energy expenditure (REE) measured on a non-dialysis day was not different between groups, and slightly lower than the expected value of REE calculated from the HarrisBenedict formula that provides a theoretical value matched for age, weight, height, and gender. The increase of REE on a non-dialysis day in HD patients is controversial. Whereas Montéon et al. [28] did not find an increase of REE, Ikizler et al. [29] reported an 8% increase of REE in HD patients on a non-dialysis day when compared to healthy subjects. However, increased REE on non-dialysis day does not appear as a main factor of malnutrition in the long-term survivors. The role of the dialysis procedure itself as a cause of malnutrition may be cited for several reasons. Ikizler et al. [29] have reported a 7.7% increase of REE during the HD session, maximum during the first 2-h, whatever the membrane used. Hence, the length of the session and the cellulosic membrane used in these patients do not appear to affect the risk of increased REE during the dialysis. Amino-acid release from the leg during the dialysis session by the interaction of blood and membrane has been reported with cellulosic but not with biocompatible dialysers [30]. The nutritional impact of the various membranes used has been studied on a short-term basis and remains controversial. Locatelli et al. [31] reported no significant variation of the post-dialysis body weight and serum albumin level after 2 years of treatment with cellulosic or biocompatible membranes, whereas Parker et al. [32] found an increase of the post-dialysis body weight and serum albumin only in patients treated with biocompatible membranes. The long-term effect of the nutritional impact of the membrane remains to be studied.
In conclusion, the patients treated for a long period of time with HD are at risk of malnutrition despite apparent adequate protein intake, absence of increased energy expenditure on non-dialysis day, and a large dose of dialysis. Usual nutritional visceral markers are normal. No definitive cause of malnutrition arises from this study. It appears important to optimize the energy intake and the acidbase status, and to monitor and adequately supplement micronutrients.
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Acknowledgments |
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Notes |
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References |
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