Metabolic Effects of Dietary Treatment in Chronic Renal Failure Guarneri G, Panzetta G, Toigo G (eds): Metabolic and Nutritional Abnormalities in Kidney Disease. Contrib Nephrol. Basel, Karger, 1992, vol 98, pp 157-166
Metabolic Effects of Low-Protein Low-Phosphorus Diet in Patients with Chronic Renal Failure Influence of Compliance M. Aparicio, C. Combe, M.H. Lafage, V. de Precigout, J.L. Bouchet, L. Potaux Service de Néphrologie; Hôpital Pellegrin-Tripode, Bordeaux, France
The mechanisms of the metabolic derangements observed in chronic renal failure (CRF) are not unequivocal. Presence of toxins resulting mainly from protein metabolism, endocrine perturbations or accumulation of compounds preserving homeostasis (tradeoff hypothesis) are all mechanisms which might account for the different metabolic abnormalities commonly seen in uremia. Through different mechanisms, most of the metabolic disorders of CRF can be improved by a low-protein diet (LPD) [1] contributing to the detoxifying effects of nutritional therapy. It has previously been shown that LPD exerts beneficial effects on carbohydrate metabolism in diabetic and nondiabetic uremic patients [2, 3] and on lipid metabolism [4]. In the present study, we have assessed the outcome of bicarbonate, triglyceride and cholesterol serum levels, calcium and phosphorus metabolism and sodium pumps in uremic patients on LPD, and the influence of compliance to LPD on some of the results observed.
Patient Population and Diet Forty ambulatory patients (28 men, 12 women) ranging in age from 22 to 78 years (mean 53.28 ± 14.63 years) with advanced renal failure (glomerular filtration rate (GFR) measured by the urinary clearance of 51Cr-ΕDTA: 15.59 ± 5.41 ml/min/1.73 m2) were studied. Main characteristics of the patients are depicted in table 1.
Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
Patients and Methods
Aparicio/Combe/Lafage/de Precigout/Bouchet/Potaux
158
Before the study, all patients had followed a diet supplying daily between 0.8 and 1 g protein/kg body weight. The patients were proposed a LPD providing daily 0.3 g protein of vegetal origin, 3-5 mg phosphorus/kg body weight and approximately 300 mg calcium. The caloric supply was 35 kcal/kg body weight, carbohydrates furnishing 67 %, lipids 30 % and proteins 3 % From January 1988 to October 1990 (period 1), LPD was supplemented with a mixture of calcium salts of essential amino acids and ketoanalogues in tablet form (Ketosteril, Fresenius Laboratories). The daily dose was 1 tablet for 5 kg body weight, each tablet providing 36 mg nitrogen and 50 mg calcium. From November 1990 to July 1991 (period 2), the patients were given CSW 20-4 tablets (Clintec, France). The mean daily dose was 1 8-2 1 tablets, each tablet providing 75 mg nitrogen and 3.4 mg calcium. Calcium carbonate was given at the dose of 1 g/day (í.e., 400 mg of elemental calcium) during period 1 and at the dose of 2 g/day during period 2 to compensate the lower content of calcium of the second mixture of amino acids, no other phosphate binder was prescribed. All patients were supplemented with iron and received a multivitamin preparation containing vitamin D2 (1,000 IU/day). Compliance with the prescribed diet was assessed by interviews, after a 4-day food record, performed at 3-month intervals and by monthly measurements of urinary urea and phosphorus excretion, the protein intake being estimated by Marini and Mitch's formula. Patients were considered compliant when the calculated intake differed from the prescribed intake by less than ± 20%. Methods The monthly laboratory follow-up consisted of plasma creatinine clearance, blood urea and glucose, serum electrolytes (Na, K, Cl, CO3H), calcium, phosphorus, alkaline phosphatase, osteocalcin, parathyroid hormone (intact hormone), triglycerides, cholesterol, serum protein, serum albumin, blood count, hemoglobin, hematocrit as well as 24hour urine excretion of creatinine, urea, electrolytes, phosphorus and proteins. GFR was measured every 3 months with 51Cr-EDTA clearance. Serum 25-OH-vitamin D and calcitriol were measured by radioimmunoassay every 3 months.
Table 1. Characteristics of patients at the beginning of the study 40 53.28 ±14.63 28:12 411 ± 98.8 15.59 ±5.41 10 11 5 8 6 Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
Patients, n Age, years (mean±SD) Sex, m:f Serum creatinine, µmol/1 (mean±SD) GFR, ml/min/1.73 m2 (mean±SD) Underlying renal disease, n Chronic glomerulonephritis Chronic pyelonephritis Polycystic kidney disease Benign nephrosclerosis Unknown
Dietary Compliance and Correction of Metabolic Disorders of Uremia
159
A histomorphometric study of renal osteodystrophy was performed in a subset of 16 patients. A bone biopsy was taken from an iliac crest using a Meunier drill at the start of the study and from the contralateral iliac crest 12 months later. Previous tetracyclin double labeling permitted a histodynamic evaluation of undecalcified bone. The bone specimen was fixed into a block of methyl-polymethacrylate. Undecalcified 5-µm thick slices were colored using Goldner's technic and with Solochrom-cyanin. An Aluminon coloration was employed to detect aluminum. The dynamic parameters were measured on 20-µm thick uncolored slices. Histomorphometric readings were effectuated with a Zeiss ocular integrator. Static and dynamic parameters were measured. According to these parameters the bone disorders were classified as: pure osteomalacia, pure osteitis fibrosa, mixed osteopathy and normal bone remodeling. Na+ pump activity was assessed in another subset of 20 patients through leukocytic Na+K+ATPase activity which was calculated as the difference between inorganic phosphate released by the action of leukocytes from peripheral venous blood on ATP in the presence and absence of ouabain. This activity was assessed at the start of the study and at 3-month intervals for 1 year. moreover, 86Rb uptake by U937 cells was assessed after the addition of patients' sera at the beginning of the study and 3 months later [5]. During this study, patients were supplemented with 2 g Cl Na not to have their salt intake significantly modified. The different data were analyzed by Student's paired or unpaired t test, or by analysis of variance as appropriate.
Results According to the above-mentioned criteria, 27 patients (67.5%) were considered compliant (C) and 13 patients (32.5 %) noncompliant (NC). At the start of the study, the calculated protein intake was close to 0.8 g/kg body weight in the 2 groups of patients. Distribution of the different renal diseases and GFR were also similar in the 2 groups, as were the different chemical parameters (table 2). Young age and female sex were found more frequently in the NC group without reaching statistical difference. The mean duration of follow-up was identical in the 2 groups: 19.2 ± 7.6 months for the C group and 19.9 ± 8.07 months in the NC group. Table 2. Chemical parameters at the start of the study
C group NC group
Creatinine µmol/1
Bicarbonate Calcium mmol/1 mmol/1
16.13±6.12 383.7±94.7 23.6±3.8 15.02±5.56 428± 126.5 22.2±3.72
Phosphorus PTH mmol/1 pg/ml
2.3±0.11 Ι.48±0.36 Ι36.19±87 2.19±0.14 1.49±0.19 142.46±45.7 Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
GFR ml/min
Aparicio/Combe/Lafage/de Precigout/Bouchet/Potaux
160
At the end of the follow-up, urinary urea excretion was reduced to 80.72 ± 36.54 mmο1/24 h in the C group and to 144.41 ± 54.18 mmol/ 24 h in the NC group. The calculated mean protein intakes were respectively 0.37 ± 0.06 and 0.56 ± 0.15 g/kg/day for the 2 groups. Serum urea decreased dramatically in the C group from 19.77 ± 6.87 to 9.11 ± 2.98 mmol/1 (p < 0.001) and to a lesser extent from 22.04 ± 6.86 to 18.11 ± 7.14 in the NC group (NS). Serum creatinine increased in both groups from 383.7 ± 94.7 to 438.8 ± 176.3 mmol/1 in the C group and from 428 ± 126.5 to 595.4 ± 230.9 in the NC group. Serum triglycerides decreased significantly only in male patients from 2.71 ± 2.44 to 1.89 ± 1.63 mmol/1 (p < 0.003). In the whole group of patients, the mean cholesterol level decreased from 6.05 ± 1.47 to 5.3 ± 1.32 mmol/1 (p < 0.0002). For the whole group of patients, serum bicarbonate increased from 23.12 ± 3.78 to 24.98 ± 3.53 mmol/l, but this increase was only significant for the C group: 23.56 ± 3.8 to 25.81 ± 2.84 mmol/1 (p < 0.0007).
Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
Fig. 1. Influence of compliance to LPD on the evolution of PTH levels. ■ _ C patients; σ = NC patients; ♦ = all patients.
Dietary Compliance and Correction of Metabolic Disorders of Uremia
161
Table 3. Evolution of histological data after a 12-month keto acid-supplemented diet 0 month
12 months
OM/OF (n = 4) Mineralization rate, µm/day Ostenid thickness, µm Bone formation rate, µm2/µm3/day
0.32±0.15 13±2.5 0.005 ± 0.006
0.67±0.02 8±2 0.044 ± 0.02
OF (n = 8) Osteoblastic surfaces, % Osteoclastic surfaces, % Number of osteoclasts/mm Bone formation rate, µm2/µm3/day
8.4±2.6 7.7±2.8 2.5±2.6 0.087±0.43
6±3.1*** 3.1 ±2.2*** 1.04±0.7* 0.044±0.03**
The importance of compliance to LPD is also demonstrated by the outcome of calcium and phosphorus disorders on LPD and the results appear much more convincing in C patients than in NC patients. Serum calcium remained unchanged in both groups but serum phosphorus decreased from 1.48 ± 0.36 to 1.24 ± 0.25 mmol/1 (p < 0.0009) and PTH levels normalized in C patients: 136.19 ± 87 to 76.78 ± 47.06 pg/ml (ρ < 0.0001) while they conversely increased in NC patients (fig. 1). Alkaline phosphatases decreased in both groups, and osteocalcin levels remained unchanged. These results were observed while calcitriol levels were not modified in either group throughout the follow-up and remained at a low normal range for both: 15.68 ± 7.36 pg/ml at the end of the study. In spite of a significant decrease in GFR during the follow-up, bone lesions evolved favorably after 12 months on LPD: Osteomalacic lesions healed in all patients, mineralization and bone formation rate increased whereas osteoid volume decreased. In the patients with initial osteofibrosis, both osteoblastic and osteoclastic surfaces and bone formation rate decreased significantly (table 3). The only 2 patients whose lesions worsened complied very poorly to LPD. The last study dealt with the effect of LPD on the perturbations of the Na pump. At the start of the study, mean leukocytic Na+K+AΤPase activity was significantly reduced when compared with the values obtained from
Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
*p
Metabolic Effects of Low-Protein Low-Phosphorus Diet in Patients with Chronic Renal Failure Influence of Compliance M. Aparicio, C. Combe, M.H. Lafage, V. de Precigout, J.L. Bouchet, L. Potaux Service de Néphrologie; Hôpital Pellegrin-Tripode, Bordeaux, France
The mechanisms of the metabolic derangements observed in chronic renal failure (CRF) are not unequivocal. Presence of toxins resulting mainly from protein metabolism, endocrine perturbations or accumulation of compounds preserving homeostasis (tradeoff hypothesis) are all mechanisms which might account for the different metabolic abnormalities commonly seen in uremia. Through different mechanisms, most of the metabolic disorders of CRF can be improved by a low-protein diet (LPD) [1] contributing to the detoxifying effects of nutritional therapy. It has previously been shown that LPD exerts beneficial effects on carbohydrate metabolism in diabetic and nondiabetic uremic patients [2, 3] and on lipid metabolism [4]. In the present study, we have assessed the outcome of bicarbonate, triglyceride and cholesterol serum levels, calcium and phosphorus metabolism and sodium pumps in uremic patients on LPD, and the influence of compliance to LPD on some of the results observed.
Patient Population and Diet Forty ambulatory patients (28 men, 12 women) ranging in age from 22 to 78 years (mean 53.28 ± 14.63 years) with advanced renal failure (glomerular filtration rate (GFR) measured by the urinary clearance of 51Cr-ΕDTA: 15.59 ± 5.41 ml/min/1.73 m2) were studied. Main characteristics of the patients are depicted in table 1.
Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
Patients and Methods
Aparicio/Combe/Lafage/de Precigout/Bouchet/Potaux
158
Before the study, all patients had followed a diet supplying daily between 0.8 and 1 g protein/kg body weight. The patients were proposed a LPD providing daily 0.3 g protein of vegetal origin, 3-5 mg phosphorus/kg body weight and approximately 300 mg calcium. The caloric supply was 35 kcal/kg body weight, carbohydrates furnishing 67 %, lipids 30 % and proteins 3 % From January 1988 to October 1990 (period 1), LPD was supplemented with a mixture of calcium salts of essential amino acids and ketoanalogues in tablet form (Ketosteril, Fresenius Laboratories). The daily dose was 1 tablet for 5 kg body weight, each tablet providing 36 mg nitrogen and 50 mg calcium. From November 1990 to July 1991 (period 2), the patients were given CSW 20-4 tablets (Clintec, France). The mean daily dose was 1 8-2 1 tablets, each tablet providing 75 mg nitrogen and 3.4 mg calcium. Calcium carbonate was given at the dose of 1 g/day (í.e., 400 mg of elemental calcium) during period 1 and at the dose of 2 g/day during period 2 to compensate the lower content of calcium of the second mixture of amino acids, no other phosphate binder was prescribed. All patients were supplemented with iron and received a multivitamin preparation containing vitamin D2 (1,000 IU/day). Compliance with the prescribed diet was assessed by interviews, after a 4-day food record, performed at 3-month intervals and by monthly measurements of urinary urea and phosphorus excretion, the protein intake being estimated by Marini and Mitch's formula. Patients were considered compliant when the calculated intake differed from the prescribed intake by less than ± 20%. Methods The monthly laboratory follow-up consisted of plasma creatinine clearance, blood urea and glucose, serum electrolytes (Na, K, Cl, CO3H), calcium, phosphorus, alkaline phosphatase, osteocalcin, parathyroid hormone (intact hormone), triglycerides, cholesterol, serum protein, serum albumin, blood count, hemoglobin, hematocrit as well as 24hour urine excretion of creatinine, urea, electrolytes, phosphorus and proteins. GFR was measured every 3 months with 51Cr-EDTA clearance. Serum 25-OH-vitamin D and calcitriol were measured by radioimmunoassay every 3 months.
Table 1. Characteristics of patients at the beginning of the study 40 53.28 ±14.63 28:12 411 ± 98.8 15.59 ±5.41 10 11 5 8 6 Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
Patients, n Age, years (mean±SD) Sex, m:f Serum creatinine, µmol/1 (mean±SD) GFR, ml/min/1.73 m2 (mean±SD) Underlying renal disease, n Chronic glomerulonephritis Chronic pyelonephritis Polycystic kidney disease Benign nephrosclerosis Unknown
Dietary Compliance and Correction of Metabolic Disorders of Uremia
159
A histomorphometric study of renal osteodystrophy was performed in a subset of 16 patients. A bone biopsy was taken from an iliac crest using a Meunier drill at the start of the study and from the contralateral iliac crest 12 months later. Previous tetracyclin double labeling permitted a histodynamic evaluation of undecalcified bone. The bone specimen was fixed into a block of methyl-polymethacrylate. Undecalcified 5-µm thick slices were colored using Goldner's technic and with Solochrom-cyanin. An Aluminon coloration was employed to detect aluminum. The dynamic parameters were measured on 20-µm thick uncolored slices. Histomorphometric readings were effectuated with a Zeiss ocular integrator. Static and dynamic parameters were measured. According to these parameters the bone disorders were classified as: pure osteomalacia, pure osteitis fibrosa, mixed osteopathy and normal bone remodeling. Na+ pump activity was assessed in another subset of 20 patients through leukocytic Na+K+ATPase activity which was calculated as the difference between inorganic phosphate released by the action of leukocytes from peripheral venous blood on ATP in the presence and absence of ouabain. This activity was assessed at the start of the study and at 3-month intervals for 1 year. moreover, 86Rb uptake by U937 cells was assessed after the addition of patients' sera at the beginning of the study and 3 months later [5]. During this study, patients were supplemented with 2 g Cl Na not to have their salt intake significantly modified. The different data were analyzed by Student's paired or unpaired t test, or by analysis of variance as appropriate.
Results According to the above-mentioned criteria, 27 patients (67.5%) were considered compliant (C) and 13 patients (32.5 %) noncompliant (NC). At the start of the study, the calculated protein intake was close to 0.8 g/kg body weight in the 2 groups of patients. Distribution of the different renal diseases and GFR were also similar in the 2 groups, as were the different chemical parameters (table 2). Young age and female sex were found more frequently in the NC group without reaching statistical difference. The mean duration of follow-up was identical in the 2 groups: 19.2 ± 7.6 months for the C group and 19.9 ± 8.07 months in the NC group. Table 2. Chemical parameters at the start of the study
C group NC group
Creatinine µmol/1
Bicarbonate Calcium mmol/1 mmol/1
16.13±6.12 383.7±94.7 23.6±3.8 15.02±5.56 428± 126.5 22.2±3.72
Phosphorus PTH mmol/1 pg/ml
2.3±0.11 Ι.48±0.36 Ι36.19±87 2.19±0.14 1.49±0.19 142.46±45.7 Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
GFR ml/min
Aparicio/Combe/Lafage/de Precigout/Bouchet/Potaux
160
At the end of the follow-up, urinary urea excretion was reduced to 80.72 ± 36.54 mmο1/24 h in the C group and to 144.41 ± 54.18 mmol/ 24 h in the NC group. The calculated mean protein intakes were respectively 0.37 ± 0.06 and 0.56 ± 0.15 g/kg/day for the 2 groups. Serum urea decreased dramatically in the C group from 19.77 ± 6.87 to 9.11 ± 2.98 mmol/1 (p < 0.001) and to a lesser extent from 22.04 ± 6.86 to 18.11 ± 7.14 in the NC group (NS). Serum creatinine increased in both groups from 383.7 ± 94.7 to 438.8 ± 176.3 mmol/1 in the C group and from 428 ± 126.5 to 595.4 ± 230.9 in the NC group. Serum triglycerides decreased significantly only in male patients from 2.71 ± 2.44 to 1.89 ± 1.63 mmol/1 (p < 0.003). In the whole group of patients, the mean cholesterol level decreased from 6.05 ± 1.47 to 5.3 ± 1.32 mmol/1 (p < 0.0002). For the whole group of patients, serum bicarbonate increased from 23.12 ± 3.78 to 24.98 ± 3.53 mmol/l, but this increase was only significant for the C group: 23.56 ± 3.8 to 25.81 ± 2.84 mmol/1 (p < 0.0007).
Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
Fig. 1. Influence of compliance to LPD on the evolution of PTH levels. ■ _ C patients; σ = NC patients; ♦ = all patients.
Dietary Compliance and Correction of Metabolic Disorders of Uremia
161
Table 3. Evolution of histological data after a 12-month keto acid-supplemented diet 0 month
12 months
OM/OF (n = 4) Mineralization rate, µm/day Ostenid thickness, µm Bone formation rate, µm2/µm3/day
0.32±0.15 13±2.5 0.005 ± 0.006
0.67±0.02 8±2 0.044 ± 0.02
OF (n = 8) Osteoblastic surfaces, % Osteoclastic surfaces, % Number of osteoclasts/mm Bone formation rate, µm2/µm3/day
8.4±2.6 7.7±2.8 2.5±2.6 0.087±0.43
6±3.1*** 3.1 ±2.2*** 1.04±0.7* 0.044±0.03**
The importance of compliance to LPD is also demonstrated by the outcome of calcium and phosphorus disorders on LPD and the results appear much more convincing in C patients than in NC patients. Serum calcium remained unchanged in both groups but serum phosphorus decreased from 1.48 ± 0.36 to 1.24 ± 0.25 mmol/1 (p < 0.0009) and PTH levels normalized in C patients: 136.19 ± 87 to 76.78 ± 47.06 pg/ml (ρ < 0.0001) while they conversely increased in NC patients (fig. 1). Alkaline phosphatases decreased in both groups, and osteocalcin levels remained unchanged. These results were observed while calcitriol levels were not modified in either group throughout the follow-up and remained at a low normal range for both: 15.68 ± 7.36 pg/ml at the end of the study. In spite of a significant decrease in GFR during the follow-up, bone lesions evolved favorably after 12 months on LPD: Osteomalacic lesions healed in all patients, mineralization and bone formation rate increased whereas osteoid volume decreased. In the patients with initial osteofibrosis, both osteoblastic and osteoclastic surfaces and bone formation rate decreased significantly (table 3). The only 2 patients whose lesions worsened complied very poorly to LPD. The last study dealt with the effect of LPD on the perturbations of the Na pump. At the start of the study, mean leukocytic Na+K+AΤPase activity was significantly reduced when compared with the values obtained from
Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:47:39 AM
*p
