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Department of Nephrology and Renal Nutrition, Hospital Edouard Herriot,
Lyon, France.
Laboratoire de Nutrition Humaine, Clermont-Ferrand, France.
Correspondence to Dr. Denis Fouque, Department of Nephrology, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France. Phone: +33-4-72-11-02-60; Fax: +33-4-72-11-02-03; E-mail: denis.fouque{at}chu-lyon.fr
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dietary Assessment
Patients were selected from our regular dietary program, which has been run
in our unit since 1974. A trained dietitian conducted two interviews with each
patient before inclusion. Patients were interviewed at the early diagnosis of
renal failure and before any former diet. They were asked not to modify their
diet and were selected if their dietary protein intake was between 1 and 1.5
g/kg per d and their energy intake was >30 kcal/kg per d. Estimation of the
baseline diet was performed with a 3-d dietary record and a 24-h urea
collection. Patients who were willing to lose weight or who had insulin or
noninsulin diabetes mellitus or progressive renal failure were not included.
After 4 to 6 wk of their usual diet, the patients were admitted to the
metabolic ward for 4 d for the baseline study. Patients were then randomized
to receive a low-protein diet (0.6 g of protein/kg per d with at least half of
the protein being of high biologic value), with or without ketoanalogs of
amino acids. Energy intake was kept constant (31 kcal/kg per d) during the
3-mo period. The dietary survey each month included a 3-d food record and a
24-h urine collection for urea measurement.
Ketoanalogs of Amino Acids
After random allocation, six patients were asked to take a supplement of
ketoacids (Cetolog; Clintec Corp., Velizy, France), 1 tablet/5 kg body wt per
d. Compliance was assessed by pill count; the overall dose per patient was
0.167 ± 0.007 tablets/kg body wt per d for the 3-mo period,
i.e., 84% of prescribed dose. Each 900-mg tablet contained 76 mg of
ketoisoleucine, 97 mg of ketoleucine, 68 mg of ketovaline, 26 mg of
hydroxymethionine, 118 mg of L-ornithine, 129 mg of L-lysine, 26 mg of
L-histidine, 75 mg of L-threonine, 152 mg of L-tyrosine, and 3.4 mg of
calcium. The daily dosage, i.e., 10 to 15 pills, was divided into two
to three doses and taken during meals. No side effect from the ketoanalog
supplement was reported.
Protocol Design
The leucine turnover procedure was carried out on the fourth day of the
metabolic assessment in the Center d'Explorations
Métaboliques. Patients fasted from 8:00 p.m.
the day before the test until 12:00 a.m. the following morning. At 8:00 a.m.,
a 3.5-h intravenous infusion of L[1-13C] leucine (Tracer
Technologies, Inc., Woburn, MA) was started. Blood and expired air samples
were taken at -15 and -5 min to determine the basal 13C enrichment
of plasma 
-ketoisocaproate (KIC) and CO2. Two boluses of
[1-13C] leucine (1 mg/kg) and 13C-sodium bicarbonate (5
mg) were followed by a constant intravenous [1-13C] leucine
infusion of 0.08 µmol/kg per min over the next 3.5 h. Four times during the
last hour of infusion, blood and gas were collected and CO2
production rate (VCO2) was measured by indirect calorimetry
(Deltatrac MBM-100; Datex Instrumentation, Helsinki, Finland).
Analytical Methods and Calculation of Protein Turnover
13CO2 was determined by isotope ratio mass
spectrometry, and plasma KIC enrichment was determined by gas chromatography
mass spectrometry (6). Leucine
fluxes were calculated with the use of the plasma KIC enrichment
(7). Endogenous leucine rate of
appearance, an index of protein breakdown, is then equal to total leucine flux
minus the tracer infusion rate. Leucine oxidation was calculated from the
appearance of 13CO2 in the expired gas divided by the
plasma 13C KIC times 0.90 to correct for retention of
CO2 in the bicarbonate pool. Nonoxidative leucine disposal, an
index of whole-body protein synthesis, was calculated from the difference
between the flux and oxidation of leucine. In the fasting state, total leucine
flux can be assimilated to the leucine appearance from protein
mobilization.
Amino Acid Determination
Plasma was drawn at 7:45 a.m. on the fourth day of the metabolic study,
after an overnight fast. Plasma amino acids were determined with a Jeol
automat (Jeol Corp., Tokyo, Japan) in the research laboratory at Edouard
Herriot Hospital, with the use of a standard liquid chromatography.
Statistical Analyses
Values are reported as mean ± SD. Comparisons between baseline and
the follow-up admission were analyzed with the use of the paired t
test. Comparisons between subgroups at a given period were performed with the
Wilcoxon test on Statview statistical software (Abacus Concept, Berkeley, CA).
Differences were considered significant at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Compliance to the diet was obtained after training with our specialized renal dietitian. Patients were asked not to reduce their energy intake; this was accomplished by increasing slightly the marmalade in breakfast and by increasing to satisfactory levels the daily oil intake mainly in salad dressing. As shown in Table 2 and based on dietary interviews, the energy intake of patients, although not excessive, was kept within acceptable values, e.g., >30 kcal/kg per d. Protein intake was assessed by two different methods. We determined protein nitrogen appearance (PNA) from urinary urea output (Table 2), according to Maroni's formula (8). We also monitored protein intake from the 3-d home dietary records obtained monthly (Table 2). The protein equivalent of the nitrogen content in the ketoanalogs was not included in the estimated dietary protein intake (DPI) and averaged 0.08 ± 0.004 g of protein/kg per d, partly explaining a greater PNA than the DPI (Table 2). Overall, patients gradually reduced their daily protein intake by approximately 40% (diet records), 44% (24-h urinary urea), and 50% (Maroni's estimation; Table 2). Patients did not present body weight or body mass index changes over 3 mo (Table 1).
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Effect of Overall Reduction in Protein Intake on Leucine
Turnover
Because there was no difference between the two groups, results are
presented for all 12 patients (Table
3). The reduction in protein intake induced a decrease in leucine
oxidation by approximately 18% (P < 0.05), associated with a
parallel 8% reduction (P < 0.05) in leucine rate of appearance, an
estimation of protein degradation. There was no change in the nonoxidative
leucine disposal during the low-protein diet period
(Table 3).
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Effects of Ketoanalogs on Leucine Turnover
The effect of ketoanalogs on leucine turnover was estimated from the
comparison of the variation in leucine kinetics from baseline
(Table 3). Although there was a
trend for a reduction for all measurements and these variations seemed to be
more pronounced in the nonketoanalog group, no statistical difference could be
observed between group that received a ketoanalog supplement and group that
did not.
Plasma Amino Acid Pattern
Plasma amino acids were obtained on the fourth day of the metabolic study,
after an overnight fast. There were almost no change from baseline
(Table 4), with the exception
for arginine, which decreased in the nonsupplemented group from 177 ±
37 to 105 ± 33 µmol/L (P < 0.05). In the
ketoanalog-supplemented group of patients, the only significant change was a
14% reduction in plasma tyrosine from baseline (P < 0.05;
Table 4). When we compared the
changes from baseline between groups to test the effects of ketoanalog
supplement, there was no significant difference for any single amino acid,
ratio, or total amino acids. Particularly, plasma branched-chain amino acids
(leucine, isoleucine, and valine) did not change significantly between the
start and the end of the study and between the two groups of patients.
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Discussion |
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Compliance with any diet is the key to success. Renal diets often are complicated by superimposed diseases, chronic medications, spontaneous anorexia, or inappropriate counseling. Furthermore, there is a regular spontaneous reduction in protein and energy intakes after renal function deterioration (9). In the present study, we assessed energy intake by food records and protein intake using a combined food record and urinary nitrogen measurement (8). Table 2 shows the decrease in daily protein intake as estimated by two independent means, i.e., food records and urinary urea nitrogen. The baseline protein intake was 1.13 g/kg per d, slightly lower than the mean protein intake in the French adult population (approximately 1.3 g/kg per d). After the protein restriction was initiated, both protein intake from records and urinary urea decreased to attain statistical significance from baseline at month 3 (Table 2). It is interesting to note that the difference between these two techniques in evaluating actual protein intake is approximately 0.20 to 0.30 g/kg per d during the first two diet interviews but drops to 0.15 g/kg per d after 3 mo of patient training and diet adjustment by the dietitian. These differences likely are explained by the fact that we did not recorded as "protein" the amount of nitrogen in the ketoanalog supplement (approximately 6 g of protein equivalent/d for 6 of the 12 patients), thus explaining a greater nitrogen output than recorded on the diet report (Table 2). In addition, a PNA higher than DPI could be explained by an underestimation of intakes by home diet records because this difference seemed to diminish over time after the number of dietitian interviews was increased (0.19 g of protein/kg per d at month 1, 0.29 at month 2, and 0.15 at month 3; Table 2), whereas patients did not change their ketoanalogs intake during the study. Although none of these differences was statistically significant, we believe that the quality of diet reports can be improved after repeated interviews between patient (and spouse if available) and the specialized renal dietitian. Other reasons for observing a PNA greater than the DPI include acute inflammatory or septic episodes, steroid treatments, or chronic acidosis. None of these conditions occurred during the study, and mean serum bicarbonate was 22.3 and 23.7 mmol/L at baseline and at the end of study, respectively (Table 1).
To avoid a well-described energy limitation associated with the reduction in protein intake (4,10,11), energy intake was monitoring carefully during diet interviews and kept constant during the study. There was no change in actual energy intake of patients during the 3-mo period (Table 2), and this level of energy intake can be considered adequate (12). Generally, energy intake and energy need are less reported than protein intake because it is more difficult to monitor energy needs than to collect urine for urea or nitrogen output measurement. Indeed, sophisticated research techniques, such as direct calorimetry performed in a metabolic chamber or double-labeled water, should be used to assess energy metabolism reliably. A study of 29 women reported that a 7-d diet record underestimated by approximately 20% the true energy needs as estimated by double-labeled water (13). If this were true for patients with CRF, then it may explain partly why such low energy intakes, i.e., 20 to 22 kcal/kg per d, are sometimes reported without concomitant severe malnutrition and/or impaired outcome (14). Another study comparing diet records and weighting food trays at the same time concluded that a diet record underestimated energy intake by <2% (15). In any event, the present energy intake of patients could be considered to be adequate, thus allowing a valid interpretation of the metabolic study (12).
Protein metabolism was assessed by the leucine turnover measurement. This technique has been used extensively in healthy humans. Adaptation to a reduction in protein intake is associated with a decrease in amino acid oxidation during fasting and postprandial states in healthy volunteers (16,17,18,19) and in patients with renal disease and/or renal failure (3,4,5,20,21,22). Table 3 indicates the values obtained before and after 3 mo on a low-protein diet. The fasting leucine rate of appearance (Table 3) and fasting leucine oxidation (Table 3 and Figure 1) decreased by 8% and 18%, respectively (P < 0.05) after reducing protein intake. These facts indicate that a proteinsparing mechanism occurred in response to the reduction of protein intake. The metabolic adaptation, hence, is present in patients with mild CRF, and the magnitude of the amino acid oxidation decrease we observed after 3 mo of protein reduction (- 18%, Table 3 and Figure 1) is suggestive of an important and sustained protein-sparing mechanism.
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Other studies have reported similar findings in CRF patients who were undergoing different types of diet intervention but mostly during shorter studies. Goodship et al. (3) studied six patients with moderate CRF during a short-term (1 wk) regular (1 g of protein/kg per d) or reduced protein intake (0.6 g of protein/kg per d) and energy intakes of 32.5 kcal/kg per d. Fasting leucine oxidation did not change significantly during the lower protein intake, whereas postprandial leucine oxidation decreased by approximately 25% (P < 0.05). Extending a comparable diet up to 3 mo in the present study induced a significant and sustained reduction in fasting leucine oxidation (Table 3). Altogether, these data show that patients with moderate CRF can adapt their protein metabolism during acute and chronic protein intake reductions by reducing amino acid oxidation during both postprandial and fasting states.
More profound protein restrictions reduce amino acid oxidation to a greater magnitude. Masud et al. (5) showed in six predialysis patients that a diet that provided 0.35 g of protein/kg per d supplemented with either ketoacids or essential amino acids for 25 d allowed for maintaining neutral nitrogen balances and body composition. These diets were associated with very low leucine oxidation values, which were not different whether patients were supplemented with ketoanalogs or essential amino acids (5). In a long-term follow-up of these patients (16 mo), the fasting leucine oxidation remained at a low level of 10.0 ± 2.2 µmol/kg per h (4). As compared with the present study (baseline, 16.8 ± 4.2; low-protein diet, 13.8 ± 2.4 µmol/kg per h; Table 3), these amino acid oxidation values seem to be even lower in response to a lower protein intake, thus suggesting a potential "functional reserve" for protein sparing in CRF patients.
The addition of ketoacid supplements to the low-protein diet did not modify the protein metabolism as assessed by leucine turnover measurement (Table 3). Although there was a trend to a greater decrease in turnover values in the nonsupplemented group, none of these changes was significant. It could be argued that the protein restriction that we studied here was not restricted enough to observe the nitrogen-sparing effect of ketoacid administration. Indeed, in other diet intervention studies in uremia, the protein intake was reduced to a greater extent and generally averaged 0.3 to 0.5 g of protein/kg per d (4,5,23).
Amino acids were measured before and after the protein intake reduction (Table 4). Overall, there was almost no change in plasma essential, nonessential, and total amino acids. Branched chain amino acids did not vary between periods and within groups, whether patients received ketoacids or not, as reported by Masud et al. (5). In the ketoanalog-supplemented group, plasma tyrosine decreased by 15% (P < 0.05; Table 4) although tyrosine was included in the ketoanalog supplement (153 mg/pill, corresponding to an intake of 1.2 to 2 g/d). In the low-protein group that was not supplemented with ketoanalogs, arginine decreased by 34% (P < 0.05). More important, the essential/nonessential amino acid ratio (EAA/NEAA) decreased by 23% from 0.47 ± 0.07 to 0.36 ± 0.04 (P < 0.05) as a result of an increase in nonessential amino acids. These values are in agreement with those published by Kopple et al. (11,14). The absence of a comparable decrease of EAA/NEAA in the ketoanalog-supplemented group may be compatible with a better nutritional response. However, the absence of significant essential amino acid decrease in both groups during the study also is an important fact to consider (Table 4).
Finally, another indirect index for an adequate protein metabolism response is that serum insulin-like growth factor-1, a sensitive marker of body protein status (24,25), did not decrease during the 3-mo diet in each group (all patients: baseline, 278 ± 20 µg/L; end, 257 ± 20 µg/L) (26), thus indicating a well-preserved body protein compartment.
In summary, this is the first report of a 3-mo moderate reduction in protein intake in mild CRF patients that shows an adequate metabolic and body composition response. This suggests that under an energy intake >31 kcal/kg per d, a protein intake of 0.7 g/kg per d is metabolically and nutritionally safe. According to the current evidence for prescribing a low-protein diet to patients with mild CRF (27,28,29), this study confirms that such a diet therapy is worth being proposed to patients. Whether patients eventually will accept it certainly may rely more on physicians' beliefs and enthusiasm.
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Acknowledgments |
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We thank Patricia Raton, RD, for patient counseling and diet report analysis; Joelle Goudable, PharmD, for nitrogen measurements; and Georges Richard, PharmD, for amino acid determinations. We are particularly indebted to the nurses of the Renal Unit, Pavillon P, for excellent patient care and technical assistance.
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) or not ([UNK]); *, P < 0.05 from baseline for
all patients (paired t test); no difference between groups at
baseline or at the end of study.