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Journal of the American College of Nutrition, Vol. 18, No. 5, 481-486 (1999)
Published by the American College of Nutrition

Effects of Severe Protein Restriction with Ketoanalogues in Advanced Renal Failure

Denis Malvy, MD, PhD, Claude Maingourd, MD, Josette Pengloan, MD, Philippe Bagros, MD and Hubert Nivet, MD

Centre René Labusquière and INSERM U.330, Université Victor Segalen Bordeaux 2, Bordeaux, (D.M.)
Service de Néphrologie et Immunologie Clinique, CHU Bretonneau, Tours, (C.M., J.P., H.N.) FRANCE

Address reprint requests to: Dr. Denis MALVY, Centre René Labusquière, INSERM U 330, Université Victor Segalen Bordeaux 2, 146, Rue Léo Saignat, F-33 076 Bordeaux Cedex, FRANCE


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 STATISTICAL METHODS
 RESULTS
 REFERENCES
 
Objective: To compare a severe protein restriction diet supplemented with ketoanalogues to a moderate protein restriction diet in order to limit glomerular filtration rate (GFR) decrease in an advanced renal insufficiency stage.

Design: Prospective randomised study conducted to compare a severe protein restriction diet (0.30 g/kg/day) supplemented with a preparation of ketoanalogues, hydroxyanalogues of aminoacids and aminoacids (Group A) to a moderate protein restriction diet (0.65 g/kg/day) (Group B).

Patients: 50 uremic patients included (25 in each group) with GFR is <20 mL/min/1.73m2.

Results: There were no statistically significant differences between the two dietary regimens for the renal survival. But uremia decreased significantly in Group A (22.7±5.2 to 18.5±6.7 mmol/L) and increased in Group B (26.8±9.0 to 34.9±9.9 mmol/L). Calcemia increased in Group A from 2.28±0.18 to 2.42±0.17 mmol/L, p<0.01 with a stable phosphoremia while calcemia decreased in Group B (2.33±0.18 to 2.25±0.17 mmol/L, p<0.05). At the end of the study, Group A was different from Group B for calcemia (2.42±0.17 vs. 2.25±0.17 mmol/L, p<0.01), phosphoremia (1.39±0.30 vs. 1.80±0.65 mmol/L, p<0.02), alkaline phosphatase (61.42±22.93 vs. 78.8±27.0, p<0.05) and parathormone plasma levels (2.71±1.55 vs. 5.91±1.41 ng/mL, p<0.001).

Comments: Compared to a moderate protein restriction (0.65 g/kg/day), a severe protein restriction (0.3 g/kg/day) supplemented by ketoanologues does not limit GFR decrease when GFR is below 20 mL/min/1.73m2, but improves phosphocalcic plasma parameters.

Key words: uremia, protein restriction, renal failure, ketoanalogues


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 STATISTICAL METHODS
 RESULTS
 REFERENCES
 
In chronic renal failure (CRF), hyperfiltration appears in the remnant glomeruli with subsequent histological lesions and decreased glomerular filtration [1]. In past years, it has been suggested that dietary protein restriction could prevent functional deterioration in both animals [2–5] and humans, due to reduction in glomerular capillary pressure and filtration [6–11]. Previous papers reported that moderate dietary protein restriction is an effective way of delaying functional renal deterioration [12]. Other studies report an improvement in clinical and nutritional status in patients with a low protein diet supplemented by ketoanalogues [13–18]. We report the results of a prospective, randomised, controlled trial undertaken to test the effects of a greater protein restriction in pre-end stage chronic renal failure.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
STATISTICAL METHODS
 RESULTS
 REFERENCES
 
The studied sample was made up of out-patients who attended our Department of Nephrology between January 1, 1983, and May 1, 1987. The inclusion criterion was a creatinine clearance value below 19 mL/min/1.73m2 without lethal disease. Patients with diabetes, cancer, systemic disease, obstructive uropathy and rapidly progressive glomerulonephritis were excluded. Glomerular filtration rate (GFR) was estimated by Cockroft’s formula [19]. Diet history of all patients was studied by a dietitian, and they were asked to adhere to a low-protein diet. After consent was obtained, patients were randomised into two groups: in Group A, patients were allocated to a severe protein restriction diet (0.3 g/kg/day) with a supplement of ketoanalogues and hydroxyanalogues of amino acids, 0.17 g/kg/day) (Table 1); Group B patients were asked to adhere to a 0.65 g/kg/day protein intake.


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  		Table 1. Nutritional Intake Prescription at Input Time (Mean±Standard Deviation)

 
The caloric loss due to the protein restriction was balanced by a rise in carbohydrate and lipid intake. The prescribed energy intake was the amount revealed in the preprotocol period studied by the dietitian. Protein intake was followed by urea nitrogen appearance (UNA) according to Maroni’s formula [20]. All patients received a daily supplement of vitamin D3 (25–50 µg), nicotinic acid (25 mg), vitamin C (70 mg), folate (130 µg) and thiamine (5 mg), riboflavin (5 mg), B6 (1.5 mg) and B12 (3 µg). Calcium (1–4 g per day), and aluminum hydroxide were added depending on calcium and phosphate plasma levels.

The following variables were measured on randomisation, once a month during the first three months, then every three months: body weight, lean body mass and fat body mass by skinfold thickness method [21–22], blood pressure levels, blood cell count, plasma values of electrolytes, urea, creatinine, alkaline phosphatase, calcium, phosphorus, C terminal parathormone, bicarbonate, uric acid, glycemia, cholesterol, triglycerids, albumin, transthyretin-thyroxine binding pre-albumin (TBPA), retinol-binding protein (RBP), aminoacids and urinary expression of creatinine and urea for the clearance evaluation.

At the same frequency, patients were examined by a nephrologist and visited by a dietitian in order to study the diet compliance. Output criteria were a GFR level at 5 mL/min/1.73m2 estimated by the ratio (creatinine clearance + urea clearance)/2 or an uremic intolerance diagnosed by two nephrologists and requiring a dialysis procedure.


   STATISTICAL METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 STATISTICAL METHODS
RESULTS
 REFERENCES
 
Quantitative variables were compared by a t test for paired data and analysis of variance. A Cox regression model was used to evaluate the following variables: age, creatinine, clearance and glomerular filtration rate at onset, type of dietary procedure and etiology of chronic renal failure [23]. First, a univariate analysis was performed on these potential prognostic factors to determine their individual impact. Then, a non-linear multivariate regression was used to determine the best combination of patient characteristics related to renal course [24].

The Kaplan and Meier method was used to calculate actuarial survival curves among patients of group A and group B, and tests of their differences were based on a generalized Wilcoxon test [25].

The statistical package SAS using the procedure PHREG was used for the analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 STATISTICAL METHODS
 RESULTS
REFERENCES
 
Fifty patients entered the study before May 1987, and were followed up for at least three months. At the start of the study, the two groups were similar for age, gender, weight, GFR, renal failure etiologies and blood pressure level (Table 2). The antihypertensive drugs used in both groups were comparable. During the study, six patients refused diet A and two diet B. Four patients died, two in each group.


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  		Table 2. Distribution of Patients at Start of the Study According to Age, Gender, Weight, Glomerular Filtration Rate, Renal Failure Etiology and Blood Pressure

 
There was no statistically significant difference in comparing renal survival of patients between the two dietary regimens (ß=0.108, p=0.713) (Fig. 1). Severe dietary protein restriction did not appear as an efficient procedure in prevention of renal function degradation, compared to moderate protein intake regimen.



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  		Fig. 1. Kaplan-Meier survival curve (months) for the two patient groups, according to output criteria of glomerular filtration rate <5 mL/min/1.73m2 (group A=dashed lines, group B: solid lines).

 
As could be expected, the only two significant variables related to renal survival were onset values of glomerular filtration rate (ß=-0.17, p=0.0007) and clearance of Walser (ß=-0.27, p=0.0004). No other variable remained significant in predicting renal survival, including age (ß=0.013, p=0.25) and chronic renal failure etiology (ß=-0.137, p=0.27).

A significant weight loss was observed in group A between the start and the end of the study (60.3±10.7 kg vs. 57.7±10.6 kg [mean±standard deviation, SD]). This weight loss concerned significantly lean and fat body mass (Table 3). No difference for weight was observed in Group B.


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  		Table 3. Nutritional Anthropometric Measurements (Mean±Standard Deviation)

 
Albumin, TBPA, RBP, aminoacids plasma levels were not different at the end of the study between the two groups and between start and end of the study in each group (Table 4). The valine/glycine ratio decreased between start and end in Group A (1.00±0.35 [mean±SD] vs. 0.63±0.23) and remained stable in B. Uremia decreased significantly in Group A (22.7±5.2 mmol/L to 18.5±6.7 mmol/L) and increased in Group B (26.8±9.0 mmol/L to 34.9±9.9 mmol/L). Moreover at the end of the study, uremia was lower in Group A than in Group B (18.5±6.7 mmol/L vs. 34.9±8.9 mmol/L, p<0.001) (Table 5).


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  		Table 4. Plasma Values for Biochemical Variables (Mean±Standard Deviation) Measured at Start and End of the Study

 

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  		Table 5. Uremia and Urinary Excretion (Mean±Standard Deviation) in both Groups at Start and End of the Study

 
Urinary urea excretion decreased in the two groups at the end of the study, but dramatically in Group A, with a marked difference between the two groups (131.2±69.2 mmol/L in Group A vs. 213.8±67.1 mmol/L in Group B, p<0.001 (Table 5).

Nevertheless, the drop of urinary urea excretion occurred early after the beginning of the study, but remained stable until the end in both groups. The level of protein intake, assessed by urea nitrogen appearance according to Maroni’s formula, showed a 10% difference between urea nitrogen appearance and theoretical nitrogen intake estimation in the two groups (Table 6). As shown in Table 7, calcemia increased in group A from 2.28±0,17 mmol/L to 2.42±0,17 mmol/L, p<0.01. Phosphoremia remained stable. Calcemia decreased in group B from 2.33±0,18 mmol/L to 2.25±0,17 mmol/L, p<0.05. At the end of the study, Group A was different compared to Group B for calcemia (2.42±0,17 mmol/L vs. 2.25±0.17 mmol/L, p<0.01), phosphoremia (1.39±0.3 mmol/L vs. 1.80±0.65 mmol/L, p<0.02), alkaline phosphatase (61.42±22.93 1U/L vs. 78.7±27 1U/L, p<0.05) and parathormone plasma levels (2.71±1.55 ng/mL vs. 5.91±1.41 ng/mL, p<0.001) (Table 8).


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  		Table 6. Protein Intake (g/day) Assessment by Urea Nitrogen Appearance According to Maroni Formula Theoretical Nitrogen Intake Estimation, in Groups A and B, at Start and End of the Study

 

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  		Table 7. Plasma Calcium and Phosphorus Levels (Mean±Standard Deviation) in Groups A and B, at Start and End of the Study

 

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  		Table 8. Plasma Values for Calcium Metabolism Indicators (Mean±Standard Deviation), at the End of the Study

 

   DISCUSSION
 
The diet compliance in both studied groups was good as confirmed by biological results and dietitian interviews. The 10% difference observed between UNA and theoretical protein intake suggests an unknown increase of protein intake in the two groups or a problem in the diet composition tables. This difference remains unclear. The Maroni formula could be quite inappropriate or the nutrition composition tables could be wrong. This severe protein restriction leads to a mild nutritional deficiency revealed by a fall in weight, lean and fat body mass. The only biological nutritional marker altered was the valine/glycine ratio in Group A, despite the ketoanalogue supplement. The lack of disturbances for biological nutritional parameters can be related to their usual inability to assess nutritional status and deficiency among uremic subjects [26].

Phosphorus and calcium metabolism parameters showed the beneficial effects of the Group A diet: calcemia, phosphoremia, alkaline phosphatase and peripheral parathormone levels were within a normal range at the end of the study. At the same time, these parameters were modified in Group B, as usually observed in chronic renal failure. Beneficial results on phosphocalcic parameters have been reported in hemodialysed patients with ketoanalogue supplement [13,27]. This effect could be due either to a direct ketoanalogue impact on parathormone, a chelating role of ketoanalogue for dietary phosphorus or a regulation of the intracellular phosphorus incorporation [28, 15].

In past years, clinical investigators have reported variably beneficial results of dietary protein restriction in human subjects, and their conclusions remained questionable. The first beneficial results of a controlled trial showed a difference in the glomerular filtration decrease between a normal protein intake and a moderate protein restriction in patients with moderate glomerular filtration reduction [12]. They have not been confirmed by the large sample size American study MRDD (Modification of Diet in Renal Diseases) including 585 nondiabetic patients (creatinine clearance >25 mL/min at onset) [29]. Nevertheless the meta-analyses published by Fouque et al. in 1992 [30] and Pedrini et al. in 1996 [31] concluded there was a beneficial effect from the protein restriction diet. We prescribed a greater protein restriction at a GFR level below 20 mL/min/1.73m2. This severe protein restriction did not modify renal survival in our study according to our outset criteria. Nevertheless, we may hypothesize that the severe protein restriction regimen could have reduced uremic toxicity in patients who were near end-stage renal failure, as could suggest the trend of survival curves during the first twenty months according to our output criteria including uremic intolerance requiring a dialysis procedure.

Our results do not justify severe protein restriction with less than 0.6 g protein/kg/day for the limitation of GFR decrease when GFR is below 20 mL/min/1.73m2.

Even if questionable, protein restriction must be prescribed earlier in the renal failure course with the aim of a limitation of GFR decrease, as it has been suggested [10,11], although the optimal level of protein intake and the point at which protein restriction should be introduced remain not clearly determined. Phosphocalcic metabolism benefits of the severe restriction diet were obvious for all patients. Other studies showed a metabolic impact such as improvement in insulin action, glucose tolerance and in leukocytes chemiluminescence [32, 33] with a severe protein restriction diet supplemented with essential aminoacids and ketoanalogues. The specific role and the therapeutic benefit of such a protein restriction and ketoanalogue supplement needs to be specified. Moreover, the metabolic benefit of this type of regimen must be balanced with its cost and related social and familial disturbances.

Received November 1, 1998. Accepted June 1, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 STATISTICAL METHODS
 RESULTS
 REFERENCES
 

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