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Optimum dietary protein requirement in nondiabetic maintenance hemodialysis patients
Optimum Dietary Protein Requirement in Nondiabetic Maintenance Hemodialysis Patients Sakae Ohkawa, PhD, Yukiko Kaizu, PhD, Mari Odamaki, PhD, Naoki Ikegaya, MD, Ikuo Hibi, MD, Kunihiko Miyaji, MD, and Hiromichi Kumagai, MD ● Background: There is controversy about whether the dietary protein requirement of 1.2 g/kg/d for hemodialysis (HD) patients, in the nutritional guidelines recommended by the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI), is reasonable. Methods: A cross-sectional study was conducted in 129 stable HD patients without diabetes (84 men, 45 women) to investigate the association between the protein equivalent of nitrogen appearance normalized by ideal body weight (nPNAibw), an index of protein intake, and skeletal muscle mass or other metabolic consequences. Patients were divided into 5 groups according to nPNAibw index. Midthigh muscle area (TMA), midthigh subcutaneous fat area (TSFA), abdominal muscle area (AMA), abdominal subcutaneous fat area (ASFA), and visceral fat area (AVFA) were measured using computed tomography, and various nutritional parameters were compared among these groups. Results: TMA and AMA values increased with increasing dietary protein intake from less than 0.7 g/kg/d to 0.9-1.1 g/kg/d and showed a plateau at greater than 0.9 to 1.1 g/kg/d of dietary protein intake. Conversely, fat mass, including TSFA, ASFA, and AVFA, and serum potassium concentration increased with graded protein intake, and no plateau was formed. Patients with nPNAibw greater than 1.3 g/kg/d satisfied the criterion of visceral obesity. Although serum prealbumin levels showed a trend similar to that of muscle mass, there was no significant difference in serum albumin levels among the study groups. Conclusion: Optimal dietary protein requirement for patients undergoing maintenance HD in a stable condition appears to be less than the level recommended by the NKF-KDOQI nutritional guidelines. Am J Kidney Dis 43:454-463. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Protein requirement; hemodialysis (HD); muscle mass; computed tomography (CT); fat mass.
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ROTEIN-ENERGY malnutrition has been observed frequently in hemodialysis (HD) patients and has been recognized as an important risk factor for increased morbidity and mortality.1,2 The current nutritional guidelines of the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommend 1.2 g/kg/d of dietary protein for HD patients (guideline 15).3 This figure is based on results of nitrogen-balance studies4,5 and was supported by results from studies examining the relationship between dietary protein intake and frequency of hospitalization or mortality.6 However, the recommended protein intake of 1.2 From the Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, Miyaji Hospital, Shizuoka, Japan. Received July 22, 2003; accepted in revised form October 28, 2003. Supported in part by grant aid from Shizuoka Research and Education Foundation, Shizuoka, Japan. Address reprint request to Hiromichi Kumagai, MD, Associate Professor, Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. E-mail: kumagai@ u-shizuoka-ken.ac.jp © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4303-0007$30.00/0 doi:10.1053/j.ajkd.2003.10.042 454
g/kg/d was set at the safe level for approximately 95% of patients; therefore, this level might exceed physiological requirements for most people. Opinions that advised lowering the recommended level of protein intake for HD patients have appeared recently.7,8 The reason for these proposals is that an excessive intake of dietary protein might cause such problems as hyperphosphatemia and accumulation of uremic toxins. Furthermore, increased protein intake usually is accompanied by overingestion of other nutrients9 and thus might be associated with fat accumulation, hyperkalemia, and interdialytic weight gain. The studies on which the recommended dose of protein intake was determined were performed approximately 20 years ago.4,5 Recent improvements in the performance of dialysis membranes have made it possible to increase the dialysance of both small- and medium-molecularweight substances associated with uremic toxicity. However, a high-performance membrane can result in the loss of a substantial amount of medium-molecular-weight proteins, such as albumin.10 Under these circumstances, the effect of dietary protein intake on protein nutritional status needs to be investigated again. Although protein nutritional status usually has
American Journal of Kidney Diseases, Vol 43, No 3 (March), 2004: pp 454-463
PROTEIN REQUIREMENT IN HD PATIENTS
been evaluated by concentrations of such somatic proteins as albumin, prealbumin, and other serum proteins because of their easy accessibility, the proportion of these proteins in the amount of whole-body protein is relatively small. Because more than 60% of total-body protein is included in muscles, skeletal muscle mass would be a better indicator of protein nutritional status.11 However, there have been few useful methods available for the practical evaluation of muscle mass in HD patients. We recently showed measurement of thigh muscle area (TMA) using computed tomography (CT) to be a good indicator of muscle mass in HD patients.12,13 Furthermore, the method of CT can provide information about fat accumulation and its distribution in the body. In an attempt to determine the most appropriate dietary protein intake, the current study was conducted to evaluate the effect of ingested dietary protein on muscle mass and other metabolic consequences in HD patients without diabetes. PATIENTS AND METHODS
Patients A cross-sectional study was conducted on maintenance HD patients to investigate the association between dietary protein intake and skeletal muscle mass or other metabolic consequences. Subjects were recruited from both daytime and nighttime HD patients at Miyaji Hospital (Shizuoka, Japan). Study inclusion criteria were patients who had been on HD therapy for more than 6 months and out-patients without diabetes with a clinically stable condition. Bedbound patients were excluded because their muscles might have fallen into atrophy because of lack of physical activity. Patients also were excluded if they participated in heavy work or organized exercise programs, which could considerably affect muscle mass. Any patient whose body weight had changed by more than 3% in 6 months also was excluded from the study. HD was performed for 4 to 5 hours 3 times/wk using hollow-fiber dialyzers and bicarbonate-buffered dialysate (Kindaly AF-3P; Fuso, Osaka, Japan). Blood flow rate was in the range of 150 to 250 mL/min, with a dialysate flow rate of 500 mL/min; these are the standard values in Japan. Most patients were administered a phosphate binder to avoid hyperphosphatemia. Patients had been educated by dietitians at the start of dialysis therapy to restrict their sodium chloride (⬃7 g/d), potassium (⬃1,500 mg/d), phosphorus (⬃700 mg/d), and fluid intake and to ingest 35 kcal/kg/d of energy and 1.2 g/kg/d of protein. However, energy and protein intake ultimately was under the control of patients. Blood samples were drawn at the start and end of the first dialysis session of the week. Serum was immediately sepa-
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rated and stored at ⫺82°C until analyzed. The study protocol was approved by the Ethics Committee of Miyaji Hospital.
Anthropometric Measurements Body weight was measured before and after each dialysis session, and postdialysis body weight was used as the dry weight (DW). Body mass index (BMI) was calculated as DW in kilograms divided by the square of the height in meters.
Measurement of Muscle and Fat Areas by CT Axial CT images of the thigh and abdomen were obtained at the midpoint of a line extending from the superior border of the patella to the greater trochanter of the femur and at the level of the third lumbar spine, respectively.12 Each patient was examined in the supine position with thigh muscles relaxed. The thickness of a slice was 10 mm. Radiographic images were digitally scanned for analysis by a personal computer. Adipose-tissue–free TMA, thigh subcutaneous fat area (TSFA), intermuscular fat area in the thigh, abdominal muscle area (AMA), abdominal subcutaneous fat area (ASFA), and visceral fat area (AVFA) were measured with use of the public domain planimetry program, The National Institutes of Health IMAGE (written by Wayne Rasband, The National Institutes of Health, Bethesda, MD).
Protein Equivalent of Nitrogen Appearance Normalized by Ideal Body Weight The protein equivalent of nitrogen appearance (PNA), which is widely accepted as a measure of dietary protein intake in a stable condition, was calculated by the formula published by the KDOQI Hemodialysis Adequacy Work Group.3 Data collected during a beginning-of-the-week dialysis session were used for these calculations. HD dose was evaluated using the following formula: spKt/V ⫽ ⫺Ln(R ⫺ 0.008 ⫻ t) ⫹ (4 ⫺ [3.5 ⫻ R]) ⫻ UF/W where spKt/V is single-pool Kt/V, R is the ratio of postdialysis to predialysis serum urea nitrogen, t is time of dialysis in hours, UF is the amount of ultrafiltration in liters, and W is postdialysis body weight in kilograms. Normalized PNA (nPNA) was evaluated using the following formula: nPNA (g/kg/d) ⫽ C0/[36.3 ⫹ 5.48(spKt/V) ⫹ 53.5/(spKt/V)] ⫹ 0.168 where C0 is the predialysis concentration of serum urea nitrogen in milligrams per deciliter. To evaluate whether a patient had ingested an appropriate amount of protein, body weight in the denominator of the equation for nPNA should be the nutritionally ideal body weight, rather than actual postdialytic body weight or DW.14 For example, if the patient has a lower body weight than the ideal body weight because of undernutrition, nPNA (PNA divided by DW) can overestimate protein intake. Therefore, nPNA was normalized to the ideal body weight (nPNAibw) using the following equation:
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Fig 1. Representative CT images of (A, C) the thigh and (B, D) abdomen in patients with nPNAibw (A, B) less than 0.7 g/kg/d and (C, D) greater than 1.3 g/kg/d. TMA, AMA, TSFA, ASFA, and AVFA are greater in patients with an nPNAibw greater than 1.3 g/kg/d than in those with an nPNAibw less than 0.7 g/kg/day, although bone areas are similar.
nPNAibw ⫽ nPNA ⫻ postdialysis body weight (kg)/ideal body weight (kg) where ideal body weight was determined from the height and a BMI of 22 kg/m2, the preferred value from a study examining the relationship between BMI and morbidity in Japanese men and women.15 nPNAibw was calculated once a month, and the average for 3 months is shown in the results.
Analytical Procedures Serum albumin, creatinine, urea nitrogen, potassium, phosphorus, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using an automatic analyzer and standard laboratory techniques. Serum prealbumin and C-reactive protein (CRP) levels were determined by laser nephelometry. Serum interleukin-6 (IL-6) concentration was measured by using an enzyme-linked immunoassay (Ultrasensitive human IL-6 immunoassay kit; R&D Systems, Minneapolis, MN).
Statistical Analyses Each data value is presented as mean ⫾ SD. Differences among groups were evaluated by an analysis of variance (ANOVA) and subsequent Bonferroni test. A simple regression analysis was used to examine relationships among variables. P less than 0.05 is considered statistically significant. All statistical analyses were performed using GBSTAT software (Dynamic Microsystems, Silver Spring, MD).
RESULTS
One hundred seventy-five patients were assessed for eligibility according to our inclusion and exclusion criteria. Forty-eight patients were excluded because of diabetes (n ⫽ 21), recent start of dialysis therapy (n ⫽ 12), unstable DW (n ⫽ 12), bedbound (n ⫽ 1), regular muscle training (n ⫽ 1), and heavy work (n ⫽ 1). Thus, 127 patients (82 men, 45 women; mean age, 60.0 ⫾ 12.0 years; range, 21 to 82 years) were
PROTEIN REQUIREMENT IN HD PATIENTS Table 1.
Variable
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Patient Characteristics Men (n ⫽ 82)
Women (n ⫽ 45)
Age (y) 59.4 ⫾ 11.1 60.9 ⫾ 13.7 Duration of HD (mo) 66.9 ⫾ 52.5 77.2 ⫾ 59.9 Height (cm) 163.3 ⫾ 6.3 150.7 ⫾ 5.6* DW (kg) 55.2 ⫾ 7.4 46.1 ⫾ 7.0* 20.7 ⫾ 2.3 20.3 ⫾ 2.6 BMI (kg/m2) PNA (g/d) 57.5 ⫾ 12.5 51.6 ⫾ 10.4* nPNAibw (g/kg/d) 1.01 ⫾ 0.19 1.13 ⫾ 0.20* Kt/Vurea 1.12 ⫾ 0.08 1.26 ⫾ 0..10* Serum Albumin (g/dL) 3.96 ⫾ 0.34 3.91 ⫾ 0.31 Prealbumin (mg/dL) 34.6 ⫾ 7.7 34.1 ⫾ 7.0 Urea nitrogen (mg/dL) 78.1 ⫾ 12.4 81.3 ⫾ 14.0 Creatinine (mg/dL) 13.0 ⫾ 2.4 11.2 ⫾ 1.7* Potassium (mEq/L) 5.14 ⫾ 0.65 5.38 ⫾ 0.60† Phosphorus (mg/dL) 4.68 ⫾ 0.91 5.17 ⫾ 1.16† Total cholesterol (mg/dL) 151 ⫾ 32 174 ⫾ 30† HDL cholesterol (mg/dL) 47.0 ⫾ 12.5 53.0 ⫾ 13.6† Triglycerides (mg/dL) 125 ⫾ 76 137 ⫾ 60 IL-6 (pg/mL) 5.90 ⫾ 6.03 6.00 ⫾ 6.04 CRP (mg/L) 4.9 ⫾ 8.7 3.6 ⫾ 4.7 CT data 104.1 ⫾ 22.0 76.0 ⫾ 14.8* TMA (cm2) TSFA (cm2) 30.8 ⫾ 13.3 52.3 ⫾ 24.8* IMFA (cm2) 8.3 ⫾ 3.4 8.9 ⫾ 4.8 AMA (cm2) 120.1 ⫾ 20.0 81.4 ⫾ 17.9* ASFA (cm2) 96.3 ⫾ 44.5 116.2 ⫾ 66.5 AVFA (cm2) 81.7 ⫾ 52.3 83.0 ⫾ 43.2 NOTE. Values expressed as mean ⫾ SD. To convert albumin in g/dL to g/L, multiply by 10; urea nitrogen in mg/dL to mmol/L, multiply by 0.357; creatinine in mg/dL to mol/L, multiply by 88.4; potassium in mEq/L to mmol/L, multiply by 1; phosphorus in mg/dL to mmol/L, multiply by 0.3229; cholesterol in mg/dL to mmol/L, multiply by 0.0259; triglycerides in mg/dL to mmol/L, multiply by 0.0113. Abbreviations: Kt/Vurea, amount of dialysis delivered to a patient per treatment; IMFA, intermuscular fat area. *P ⬍ 0.01, significantly different from men. †P ⬍ 0.05, significantly different from men.
included in the study. Representative CT images of the thigh and abdomen of HD patients are shown in Fig 1. The advantage of a CT image is that the contours of a muscle can be precisely traced, and intermuscular fat mass can be discriminated from muscle bulk. Patient characteristics and various nutritional indices, including muscle and fat areas, are listed in Table 1. BMI of patients was no different from the average BMI of Japanese dialysis patients (21.0 ⫾ 3.6 kg/m2 for men, 20.2 ⫾ 3.4 kg/m2 for women),16 whereas these values were significantly less than those of the general Japanese
population (23.0 ⫾ 2.9 kg/m2 for men, 22.8 ⫾ 3.4 kg/m2 for women).17 Serum albumin and prealbumin concentrations were 3.94 ⫾ 0.28 g/dL (39.4 ⫾ 2.8 g/L) and 34.3 ⫾ 6.9 mg/dL, respectively, suggesting that nutritional status had been fairly well maintained in this population. Mean age, duration of HD therapy, BMI, and serum albumin, prealbumin, urea nitrogen, and triglyceride levels were not significantly different between men and women. Height, DW, PNA, and serum creatinine levels were significantly greater in men than women, whereas Kt/ Vurea, nPNAibw, and serum potassium, phosphorus, total cholesterol, and HDL cholesterol levels were significantly greater in women than men. TMA and AMA were significantly greater in men than women, whereas TSFA was significantly greater in women than men. The intramuscular fat area of the thigh and ASFA and AVFA did not differ between men and women. Patients were divided into 5 groups according to nPNAibw value: less than 0.7, 0.7 to 0.9, 0.9 to 1.1, 1.1 to 1.3, and greater than 1.3 g/kg/d. Clinical variables are compared among these groups in Tables 2 and 3, and muscle and fat areas of the thigh and abdomen are shown in Figs 2 (men) and 3 (women). Mean age, height, and serum phosphorus, total cholesterol, and HDL cholesterol levels were not significantly different among the groups for men and women. Body weight, BMI, and blood urea nitrogen level increased significantly with increasing nPNAibw in both men and women. TMA in both men and women and AMA in men were significantly lower in the groups with nPNAibw less than 0.7 and 0.7 to 0.9 g/kg/d than in the groups with nPNAibw greater than 0.9 to 1.1 g/kg/d. TMA and AMA increased with increasing nPNAibw from less than 0.7 g/kg/d to 0.9 to 1.1 g/kg/d and showed a plateau in the groups with nPNAibw greater than 0.9 to 1.1 g/kg/d. The relationship between nPNAibw and serum creatinine level, an index of whole-body muscle mass, was similar to that with TMA. Conversely, TSFA, ASFA, and AVFA progressively increased with increasing nPNAibw without saturation. AVFA in patients with nPNAibw greater than 1.3 g/kg/d was greater than 100 cm2, a level satisfying the criterion for visceral obesity defined by the Japanese Society for the Study of Obesity.18
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OHKAWA ET AL Table 2.
Comparison of Clinical Variables for nPNAibw in Men nPNAibw (g/kg/d)
⬍0.7 (n ⫽ 5)
0.7-0.9 (n ⫽ 22)
0.9-1.1 (n ⫽ 30)
1.1-1.3 (n ⫽ 18)
⬎1.3 (n ⫽ 7)
ANOVA P
Age (y) 67.2 ⫾ 6.1 57.8 ⫾ 14.4 60.2 ⫾ 11.1 57.9 ⫾ 7.6 59.1 ⫾ 8.6 0.50 Duration of HD (mo) 53.8 ⫾ 62.5 44.5 ⫾ 29.8 75.4 ⫾ 57.2 88.4 ⫾ 59.3* 55.4 ⫾ 43.8 0.05 Height (cm) 162.4 ⫾ 7.1 162.5 ⫾ 6.4 163.9 ⫾ 4.5 163.6 ⫾ 7.6 163.1 ⫾ 9.8 0.94 DW (kg) 45.9 ⫾ 6.7 50.7 ⫾ 4.7 56.3 ⫾ 4.5†‡ 58.2 ⫾ 8.1†‡ 64.1 ⫾ 8.4†‡§㛳 0.001 17.3 ⫾ 1.7 19.2 ⫾ 1.7¶ 21.0 ⫾ 1.5†‡ 21.7 ⫾ 2.0†‡ 24.0 ⫾ 1.1†‡§# 0.0001 BMI (kg/m2) Kt/Vurea 1.11 ⫾ 0.07 1.09 ⫾ 0..09 1.11 ⫾ 0.08 1.15 ⫾ 0.08 1.10 ⫾ 0.07 0.27 Serum Albumin (g/dL) 3.63 ⫾ 0.07 3.99 ⫾ 0.45 3.93 ⫾ 0.29 4.01 ⫾ 0.31 4.02 ⫾ 0.24 0.21 Prealbumin (mg/dL) 28.9 ⫾ 3.8 32.1 ⫾ 8.2 35.3 ⫾ 7.2 37.2 ⫾ 6.7 37.4 ⫾ 9.8 0.09 Urea nitrogen (mg/dL) 55.7 ⫾ 3.6 70.3 ⫾ 9.4† 77.9 ⫾ 7.8†‡ 87.8 ⫾ 8.1†‡§ 94.5 ⫾ 4.0†‡§ 0.0001 Creatinine (mg/dL) 8.5 ⫾ 1.5 12.2 ⫾ 2.2† 13.3 ⫾ 2.2† 14.3 ⫾ 1.4*† 13.9 ⫾ 1.2† 0.0001 Potassium (mEq/L) 4.58 ⫾ 0.58 5.13 ⫾ 0.74 5.11 ⫾ 0.60 5.14 ⫾ 0.46 5.73 ⫾ 0.73¶ 0.05 Phosphorus (mg/dL) 4.66 ⫾ 0.98 4.63 ⫾ 0.74 4.68 ⫾ 0.91 4.63 ⫾ 1.30 4.93 ⫾ 0.47 0.96 Total cholesterol (mg/dL) 154 ⫾ 58 150 ⫾ 40 148 ⫾ 23 158 ⫾ 24 132 ⫾ 32 0.52 HDL cholesterol (mg/dL) 46 ⫾ 12 51 ⫾ 12 47 ⫾ 13 40 ⫾ 12 47 ⫾ 9 0.15 Triglycerides (mg/dL) 97 ⫾ 30 104 ⫾ 39 124 ⫾ 61 171 ⫾ 123 119 ⫾ 107 0.11 IL-6 (pg/mL) 16.5 ⫾ 9.5 6.9 ⫾ 12.9 7.2 ⫾ 6.8 7.1 ⫾ 5.6 5.0 ⫾ 4.8 0.14 CRP (mg/L) 2.41 ⫾ 0.70 0.67 ⫾ 1.41† 0.26 ⫾ 0.17† 0.38 ⫾ 0.38† 0.23 ⫾ 0.03† 0.0005 NOTE. Values expressed as mean ⫾ SD. See Table 1 for SI conversion factors. *P ⬍ 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d. †P ⬍ 0.01 versus nPNAibw less than 0.7 g/kg/d. ‡P ⬍ 0.01 versus nPNAibw of 0.7 to 0.9 g/kg/d. §P ⬍ 0.01 versus nPNAibw of 0.9 to 1.1 g/kg/d. 㛳P ⬍ 0.05 versus nPNAibw of 1.1 to 1.3 g/kg/d. #P ⬍ 0.01 versus nPNAibw of 1.1 to 1.3 g/kg/d. ¶P ⬍ 0.05 versus nPNAibw less than 0.7 g/kg/d.
Prealbumin levels showed a trend similar to that of muscle mass in relation to increasing nPNAibw. However, there was no significant difference in serum albumin levels among all nPNAibw groups. CRP levels were significantly greater in the nPNAibw group of less than 0.7 g/kg/d than in the other groups for men. IL-6 levels also were greater in the lowest nPNAibw group than in the other groups, although the difference was not statistically significant. Serum potassium level correlated significantly with nPNAibw (r ⫽ 0.29; P ⬍ 0.001). Mean serum potassium level exceeded 5.5 mEq/L (mmol/L) in the nPNAibw group of greater than 1.3 g/kg/d in both men and women. DISCUSSION
Results of the present cross-sectional study show that muscle mass increased with increasing dietary protein intake from less than 0.7 g/kg/d to 0.9 to 1.1 g/kg/d and showed a
plateau in the groups with greater than 0.9 to 1.1 g/kg/d of dietary protein intake. Because a determination of protein intake at the point at which body protein synthesis levels out (forms a plateau) may be a useful indicator of protein requirements,19 0.9 to 1.1 g/kg/d of dietary protein is considered the minimum level for maintaining adequate protein nutritional status in HD patients. This optimal level of protein intake is almost similar to values previously examined by leucine turnover and nitrogen balance studies in both sedentary healthy subjects (0.89 g/kg/d)20 and maintenance HD patients (0.9 to 1.0 g/kg/d).21 An excessive protein intake greater than the optimal level does not appear to have resulted in an increase in muscle mass. However, this level of dietary protein intake is substantially less than the recommended protein requirement in the nutritional guidelines from the NKF-KDOQI (1.2 g/kg/d)3 and the Japanese
PROTEIN REQUIREMENT IN HD PATIENTS Table 3.
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Comparison of Clinical Variables for nPNAibw in Women nPNAibw (g/kg/d)
Age (y) Duration of HD (mo) Height (cm) DW (kg) BMI (kg/m2) Kt/Vurea Serum Albumin (g/dL) Prealbumin (mg/dL) Urea nitrogen (mg/dL) Creatinine (mg/dL) Potassium (mEq/L) Phosphorus (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) IL-6 (pg/mL) CRP (mg/L)
⬍0.7 (n ⫽ 0)
0.7-0.9 (n ⫽ 6)
0.9-1.1 (n ⫽ 16)
— — — — — —
68.3 ⫾ 11.4 110.5 ⫾ 90.4 150.9 ⫾ 6.9 40.7 ⫾ 5.9 18.0 ⫾ 1.2 1.20 ⫾ 0.08
62.1 ⫾ 14.7 78.9 ⫾ 65.5 151.7 ⫾ 6.2 44.5 ⫾ 6.1 19.3 ⫾ 2.0 1.29 ⫾ 0.12
— — — — — — — — — — —
3.81 ⫾ 0.23 28.4 ⫾ 6.4 60.2 ⫾ 11.9 9.3 ⫾ 0.1 4.90 ⫾ 0.64 5.67 ⫾ 0.87 176 ⫾ 48 55 ⫾ 18 122 ⫾ 86 9.3 ⫾ 6.5 0.48 ⫾ 0.41
3.88 ⫾ 0.29 32.8 ⫾ 6.1 76.0 ⫾ 9.5* 10.9 ⫾ 1.9§ 5.39 ⫾ 0.77 4.99 ⫾ 0.98 171 ⫾ 34 50 ⫾ 11 145 ⫾ 52 6.1 ⫾ 6.5 0.46 ⫾ 0.68
1.1-1.3 (n ⫽ 13)
58.5 ⫾ 14.7 66.2 ⫾ 43.8 149.8 ⫾ 5.5 45.5 ⫾ 6.1 20.3 ⫾ 2.5 1.26 ⫾ 0.09 3.95 ⫾ 0.34 37.2 ⫾ 5.9 88.1 ⫾ 11.2*† 12.1 ⫾ 1.4* 5.52 ⫾ 0.43 5..08 ⫾ 0.83 176 ⫾ 30 56 ⫾ 17 138 ⫾ 81 7.5 ⫾ 6.8 0.39 ⫾ 0.49
⬎1.3 (n ⫽ 10)
ANOVA P
58.0 ⫾ 13.2 68.8 ⫾ 48.5 150.1 ⫾ 6.0 52.7 ⫾ 6.4*†‡ 23.2 ⫾ 1.9*†‡ 1.27 ⫾ 0.11
0.44 0.49 0.84 0.018 0.0001 0.32
3.94 ⫾ 0.34 36.3 ⫾ 8.1§ 90.6 ⫾ 9.4*† 11.4 ⫾ 1.5§ 5.48 ⫾ 0.51 5.28 ⫾ 1.64 178 ⫾ 18 52 ⫾ 14 133 ⫾ 51 4.7 ⫾ 2.9 0.25 ⫾ 0.13
0.79 0.05 0.0001 0.01 0.19 0.67 0.94 0.71 0.89 0.56 0.69
NOTE. Values expressed as mean ⫾ SD. See Table 1 for SI conversion factors. *P ⬍ 0.01 versus nPNAibw of 0.7-0.9 g/kg/d. †P ⬍ 0.01 versus nPCRibw of 0.9 to 1.1 g/kg/d. ‡P ⬍ 0.01 versus nPCRibw of 1.1 to 1.3 g/kg/d. §P ⬍ 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d.
Society of Nephrology (1.0 to 1.2 g/kg/d).22 These guidelines were determined considering that HD patients experience such catabolic stress as blood-membrane interaction,23 dialysate amino acid and protein loss,10 acidosis,24 and inflammation25 and thus are recommended to maintain a higher dietary protein intake than healthy subjects. It recently was proposed that the protein requirement for dialysis patients in the NKFKDOQI nutrition guidelines should be modified to a lower level.7,8 One reason for this proposal is that the evidence for increased HD-induced protein breakdown has not been shown in patients by continuously measuring leucine flux before, during, and after HD with a cuprophane membrane.21 The introduction of a biocompatible membrane and bicarbonate dialysate to recent HD protocols might have resulted in additional suppression of the blood-membrane interaction and acidosis. Another reason is that even if amino acid and protein losses into the dialysate reach 6 to 12 g/HD session, the estimated additional protein need would be only 0.04 to 0.08 g/kg/d.26
The background to the argument that the protein requirement for HD patients shown in the NKF-KDOQI nutrition guidelines might be too high is that high protein loading might lead to some adverse effects in HD patients. A highprotein diet induces an increase in blood urea nitrogen levels, accumulation of uremic metabolites, hyperphosphatemia, and hyperkalemia. An increase of more than 5.5 mEq/L (mmol/L) in serum potassium levels was found in patients with an nPNAibw greater than 1.3 g/kg/d in the present study. Furthermore, patients with greater protein intake often also have high energy intake,9 and the protein excess above the needs is oxidized as energy, rather than stored in the muscle.27 As a result, fat mass, including subcutaneous fat, intramuscular fat, and visceral fat, increased with graded protein intake, and no plateau was observed in our HD patients. Accumulation of fat, especially in the visceral area, might be associated with atherosclerosis and increased morbidity and mortality.28 Serum albumin level is a powerful indicator of protein nutritional status. However, it is notewor-
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Fig 2. Comparison of TMA and fat areas versus nPNAibw between (left) men and (right) women. aP < 0.05 versus nPNAibw less than 0.7 g/kg/d; bP < 0.01 versus nPNAibw less than 0.7 g/kg/d; cP < 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d; dP < 0.01 versus nPNAibw of 0.7 to 0.9 g/kg/d; eP < 0.05 versus nPNAibw of 0.9 to 1.1 g/kg/d; fP < 0.01 versus nPNAibw of 0.9 to 1.1 g/kg/d; gP < 0.05 versus nPNAibw of 1.1 to 1.3 g/kg/d; hP < 0.01 versus nPNAibw of 1.1 to 1.3 g/kg/d.
thy that serum albumin levels were not significantly different among the groups in our current study. A kinetic study reported that when dietary protein intake was deficient, both albumin synthetic and catabolic rates decreased, resulting in preservation of serum albumin level.29 Castaneda et al30 showed in elderly women that serum albumin levels remained unchanged after a 9-week study of adaptation to a low-protein diet, whereas muscle mass and muscle function were both significantly reduced. Serum albumin level therefore does not appear to be a good indicator of marginal protein deficiency compared with muscle mass. Inflammation is another factor for the wasting of muscle mass in addition to a low dietary protein intake. Tumor necrosis factor (TNF) and
IL-1 have both been reported to have an important role in protein catabolism in the muscle of animals with sepsis and chronic inflammatory states.31,32 These cytokines can directly enhance protein degradation in skeletal muscle, probably through the ubiquitin-proteasome pathway.33 Furthermore, because TNF sequentially induces the production of IL-6,34 some metabolic effects of TNF are thought to be mediated by IL-6. IL-6 recently has been recognized as a direct muscle proteolysis-inducing factor in cancer cachexia.35 However, from results of the current study, anorexia might be a main mediator for muscle wasting associated with inflammation36 because CRP levels were significantly greater in the group with the lowest dietary protein intake than in the other groups, and IL-6 levels showed a similar
PROTEIN REQUIREMENT IN HD PATIENTS
461
Fig 3. Comparison of AMA and fat areas versus nPNAibw in (left) men and (right) women. aP < 0.05 versus nPNAibw less than 0.7 g/kg/d; bP < 0.01 versus nPNAibw less than 0.7 g/kg/d; cP < 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d; dP < 0.01 versus nPNAibw of 0.7 to 0.9 g/kg/d; eP < 0.05 versus nPNAibw of 0.9 to 1.1 g/kg/d; fP < 0.01 versus nPNAibw of 0.9 to 1.1 g/kg/d; gP < 0.05 versus nPNAibw of 1.1 to 1.3 g/kg/d; hP < 0.01 versus nPNAibw of 1.1 to 1.3 g/kg/d.
trend. When dietary protein is not adequate to meet metabolic demands, the muscle acts as an amino acid supplier, and as a result, muscle wasting develops. TNF and IL-1 have been reported to be directly involved in the brain to produce anorexia.36 These results suggest that suppression of cytokine production seems to be important for improving the appetite and preventing muscle wasting in malnourished patients undergoing HD. A sedentary lifestyle also might affect muscle wasting and fat deposition in HD patients. Increased dietary intake can improve nutritional status in maintenance HD patients.37 However, as shown by healthy subjects, it is difficult to increase muscle mass without exercise or physical loading, even if nutritional intake is suffi-
cient. Fat mass might be accumulated rapidly in the visceral area during the weight-relapse period of obese patients after weight loss despite no return of the fat-free mass.38 Aerobic exercise and muscle strength training during HD sessions recently have been reported to be effective for improving exercise capacity and muscle strength.39 Additional study is required to explore the metabolic consequence of physical exercise and define optimal exercise regimens for HD patients. There are some limitations of this study. First, although nitrogen balance is affected by both energy intake and protein intake, dietary energy intake was not taken into account in this study. It is possible that inadequate energy intake could have accelerated muscle wasting in patients with
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low protein intake. Moreover, the relative contribution of protein and energy intakes to fat deposition was not shown clearly in patients with a protein overload in the current study. However, the Hemodialysis Study showed a strong correlation between dietary protein intake and dietary energy intake in HD patients (r ⫽ 0.74; P ⬍ 0.001),9 suggesting that energy intake can be roughly predicted from the level of nPNAibw. Second, it is not known whether the plateau level of muscle mass attained by subjects with 0.9 to 1.1 g/kg/d of protein intake was similar to that of healthy subjects. The normal level of TMA matched for race, age, sex, and physical activity has not yet been determined, and this needs to be done in a subsequent study. In summary, protein intake of 0.9 to 1.1 g/kg/d brought muscle mass to a plateau level, and any additional increase in dietary protein did not appear to result in increased muscle mass in HD patients without diabetes. An excessive protein intake of more than 1.3 g/kg/d, probably accompanied by energy overloading, induced such adverse effects as visceral obesity and an increase in serum potassium level. Therefore, the optimal dietary protein intake is likely to be less than the level recommended in the nutritional guidelines from the NKF-KDOQI and Japanese Society of Nephrology in such patients as ours, in whom nutritional status had been maintained fairly well, suggested by serum albumin level. Considering that HD patients are always exposed to catabolic stress and tend to be anorexic, the recommended level might still be within the reasonable range for most HD patients. REFERENCES 1. Bergstrom J: Nutrition and mortality in hemodialysis. J Am Soc Nephrol 6:1329-1341, 1995 2. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 329:1001-1006, 1993 3. National Kidney Foundation: KDQOI Clinical Practice Guidelines for Nutrition in Chronic Renal Failure. Am J Kidney Dis 35:S17-S104, 2000 (suppl 2) 4. Borah MF, Schoenfeld PY, Gotch FA, et al: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 14:491-500, 1978 5. Slomowitz LA, Monteon FJ, Grosvenor M, Laidlaw SA, Kopple JD: Effect of energy intake on nutritional status in maintenance hemodialysis patients. Kidney Int 35:704711, 1989 6. Acchiardo SR, Moore LW, Latour PA: Malnutrition as
the main factor in morbidity and mortality of hemodialysis patients. Kidney Int 24:199-203, 1983 7. Lim VS, Flanigan MJ: Protein intake in patients with renal failure: Comments on the current NKF-DOQI guidelines for nutrition in chronic renal failure. Semin Dial 14:150-152, 2001 8. Block G, Uribarri J, Coladonato JA, et al: How should hyperphosphatemia be managed in dialysis patients? Semin Dial 15:315-328, 2002 9. Rocco MV, Paranandi L, Burrowes JD, et al: Nutritional status in the HEMO study cohort at baseline. Am J Kidney Dis 39:245-256, 2002 10. Ikizler TA, Flakoll PJ, Parker RA, Hakim RM: Amino acid and albumin losses during hemodialysis. Kidney Int 46:830-837, 1994 11. Goldstein-Fuchs DJ: Assessment of nutritional status in renal disease, in Mitch WE, Klahr S (eds): Nutrition and the Kidney. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 42-92 12. Ohkawa S, Odamaki M, Yoneyama T, Hibi I, Miyaji K, Kumagai H: Standardized thigh muscle area measured by computed axial tomography as an alternate muscle mass index for nutritional assessment of hemodialysis patients. Am J Clin Nutr 71:485-490, 2000 13. Kaizu Y, Ohkawa S, Kumagai H: Muscle mass index in haemodialysis patients: A comparison of indices obtained by routine clinical examinations. Nephrol Dial Transplant 17:442-448, 2002 14. Marcen R, Teruel JL, de la Cal MA, et al: The impact of malnutrition in morbidity and mortality in stable haemodialysis patients. Nephrol Dial Transplant 12:2324-2331, 2002 15. Tokunaga K, Matsuzawa Y, Kotani K, et al: Ideal body weight estimated from the body mass index with the lowest morbidity. Int J Obes 15:1-5, 1991 16. Japanese Society for Dialysis Therapy: An Overview of Regular Dialysis Treatment in Japan [Japanese]. Tokyo, Japan, Japanese Society for Dialysis Therapy, 2000, p 222 17. Ministry of Health, Labour and Welfare: The National Nutrition Survey in Japan [Japanese]. Tokyo, Japan, Dai-Ichi, 1999, p 104 18. The Examination Committee of Criteria for Obesity Disease in Japan, Japan Society for the Study of Obesity: New criteria for “obesity disease” in Japan. Circ J 66:987992, 2002 19. Young VR, Bier DM, Pellett PL: A theoretical basis for increasing current estimates of the amino acid requirements in adult man, with experimental support. Am J Clin Nutr 50:80-92, 1989 20. Tarnopolsky MA, Atkinson SA, MacDougall JD, et al: Evaluation of protein requirements for trained strength athletes. J Appl Physiol 73:1986-1995, 1992 21. Lim VS, Bier DM, Flanigan MJ, Sum-Ping ST: The effect of hemodialysis on protein metabolism. A leucine kinetic study. J Clin Invest 91:2429-2436, 1993 22. The Japanese Society of Nephrology: Guidelines for life style and dietary therapy for kidney diseases. Nippon Jinzo Gakkai Shi 39:1-37, 1997 23. Cheung AK: Biocompatibility of hemodialysis membranes. J Am Soc Nephrol 1:150-161, 1990 24. Mitch WE, Maroni BJ: Factors causing malnutrition
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in patients with chronic uremia. Am J Kidney Dis 33:176179, 1999 25. Kaysen GA, Chertow GM, Adhikarla R, Young B, Ronco C, Levin NW: Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. Kidney Int 60:333-340, 2001 26. Wolfson M, Jones MR, Kopple JD: Amino acid losses during hemodialysis with infusion of amino acids and glucose. Kidney Int 21:500-506, 1982 27. Pi-Sunyer FX: Obesity, in Shils ME, Olson JA, Shike M, Ros AC (eds): Modern Nutrition in Health and Disease. Baltimore, MD, Lippincott Williams & Wilkins, 1999, pp 1395-1418 28. Matsuzawa Y: Pathophysiology and molecular mechanisms of visceral fat syndrome: The Japanese experience. Diabetes Metab Rev 13:3-13, 1997 29. Kelman L, Saunders SJ, Frith L, Wicht S, Corrigal A: Effects of dietary protein restriction on albumin synthesis, albumin catabolism, and the plasma aminogram. Am J Clin Nutr 25:1174-1178, 1972 30. Castaneda C, Charnley JM, Evans WJ, Crim MC: Elderly women accommodate to a low-protein diet with losses of body cell mass, muscle function, and immune response. Am J Clin Nutr 62:30-39, 1995 31. Siegel SA, Shealy DJ, Nakada MT, et al: The mouse/ human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 7:15-25, 1995
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32. Zamir O, Hasselgren PO, O’Brien W, Thompson RC, Fischer JE: Muscle protein breakdown during endotoxemia in rats and after treatment with interleukin-1 receptor antagonist (IL-1ra). Ann Surg 216:381-385, 1992 33. Mitch WE, Price SR: Mechanisms activated by kidney disease and the loss of muscle mass. Am J Kidney Dis 38:1337-1342, 2001 34. Libert C, Brouckaert P, Shaw A, Fiers W: Induction of interleukin 6 by human and murine recombinant interleukin 1 in mice. Eur J Immunol 20:691-694, 1990 35. Strassmann G, Fong M, Kenney JS, Jacob CO: Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681-1684, 1992 36. Tisdale MJ: Cancer anorexia and cachexia. Nutrition 17:438-442, 2001 37. Mehrotra R, Berman N, Alistwani A, Kopple JD: Improvement of nutritional status after initiation of maintenance hemodialysis. Am J Kidney Dis 40:133-142, 2002 38. Froidevaux F, Schutz Y, Christin L, Jequier E: Energy expenditure in obese women before and during weight loss, after refeeding, and in the weight-relapse period. Am J Clin Nutr 57:35-42, 1993 39. DePaul V, Moreland J, Eager T, Clase CM: The effectiveness of aerobic and muscle strength training in patients receiving hemodialysis and EPO: A randomized controlled trial. Am J Kidney Dis 40:1219-1229, 2002
P
ROTEIN-ENERGY malnutrition has been observed frequently in hemodialysis (HD) patients and has been recognized as an important risk factor for increased morbidity and mortality.1,2 The current nutritional guidelines of the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommend 1.2 g/kg/d of dietary protein for HD patients (guideline 15).3 This figure is based on results of nitrogen-balance studies4,5 and was supported by results from studies examining the relationship between dietary protein intake and frequency of hospitalization or mortality.6 However, the recommended protein intake of 1.2 From the Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, Miyaji Hospital, Shizuoka, Japan. Received July 22, 2003; accepted in revised form October 28, 2003. Supported in part by grant aid from Shizuoka Research and Education Foundation, Shizuoka, Japan. Address reprint request to Hiromichi Kumagai, MD, Associate Professor, Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. E-mail: kumagai@ u-shizuoka-ken.ac.jp © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4303-0007$30.00/0 doi:10.1053/j.ajkd.2003.10.042 454
g/kg/d was set at the safe level for approximately 95% of patients; therefore, this level might exceed physiological requirements for most people. Opinions that advised lowering the recommended level of protein intake for HD patients have appeared recently.7,8 The reason for these proposals is that an excessive intake of dietary protein might cause such problems as hyperphosphatemia and accumulation of uremic toxins. Furthermore, increased protein intake usually is accompanied by overingestion of other nutrients9 and thus might be associated with fat accumulation, hyperkalemia, and interdialytic weight gain. The studies on which the recommended dose of protein intake was determined were performed approximately 20 years ago.4,5 Recent improvements in the performance of dialysis membranes have made it possible to increase the dialysance of both small- and medium-molecularweight substances associated with uremic toxicity. However, a high-performance membrane can result in the loss of a substantial amount of medium-molecular-weight proteins, such as albumin.10 Under these circumstances, the effect of dietary protein intake on protein nutritional status needs to be investigated again. Although protein nutritional status usually has
American Journal of Kidney Diseases, Vol 43, No 3 (March), 2004: pp 454-463
PROTEIN REQUIREMENT IN HD PATIENTS
been evaluated by concentrations of such somatic proteins as albumin, prealbumin, and other serum proteins because of their easy accessibility, the proportion of these proteins in the amount of whole-body protein is relatively small. Because more than 60% of total-body protein is included in muscles, skeletal muscle mass would be a better indicator of protein nutritional status.11 However, there have been few useful methods available for the practical evaluation of muscle mass in HD patients. We recently showed measurement of thigh muscle area (TMA) using computed tomography (CT) to be a good indicator of muscle mass in HD patients.12,13 Furthermore, the method of CT can provide information about fat accumulation and its distribution in the body. In an attempt to determine the most appropriate dietary protein intake, the current study was conducted to evaluate the effect of ingested dietary protein on muscle mass and other metabolic consequences in HD patients without diabetes. PATIENTS AND METHODS
Patients A cross-sectional study was conducted on maintenance HD patients to investigate the association between dietary protein intake and skeletal muscle mass or other metabolic consequences. Subjects were recruited from both daytime and nighttime HD patients at Miyaji Hospital (Shizuoka, Japan). Study inclusion criteria were patients who had been on HD therapy for more than 6 months and out-patients without diabetes with a clinically stable condition. Bedbound patients were excluded because their muscles might have fallen into atrophy because of lack of physical activity. Patients also were excluded if they participated in heavy work or organized exercise programs, which could considerably affect muscle mass. Any patient whose body weight had changed by more than 3% in 6 months also was excluded from the study. HD was performed for 4 to 5 hours 3 times/wk using hollow-fiber dialyzers and bicarbonate-buffered dialysate (Kindaly AF-3P; Fuso, Osaka, Japan). Blood flow rate was in the range of 150 to 250 mL/min, with a dialysate flow rate of 500 mL/min; these are the standard values in Japan. Most patients were administered a phosphate binder to avoid hyperphosphatemia. Patients had been educated by dietitians at the start of dialysis therapy to restrict their sodium chloride (⬃7 g/d), potassium (⬃1,500 mg/d), phosphorus (⬃700 mg/d), and fluid intake and to ingest 35 kcal/kg/d of energy and 1.2 g/kg/d of protein. However, energy and protein intake ultimately was under the control of patients. Blood samples were drawn at the start and end of the first dialysis session of the week. Serum was immediately sepa-
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rated and stored at ⫺82°C until analyzed. The study protocol was approved by the Ethics Committee of Miyaji Hospital.
Anthropometric Measurements Body weight was measured before and after each dialysis session, and postdialysis body weight was used as the dry weight (DW). Body mass index (BMI) was calculated as DW in kilograms divided by the square of the height in meters.
Measurement of Muscle and Fat Areas by CT Axial CT images of the thigh and abdomen were obtained at the midpoint of a line extending from the superior border of the patella to the greater trochanter of the femur and at the level of the third lumbar spine, respectively.12 Each patient was examined in the supine position with thigh muscles relaxed. The thickness of a slice was 10 mm. Radiographic images were digitally scanned for analysis by a personal computer. Adipose-tissue–free TMA, thigh subcutaneous fat area (TSFA), intermuscular fat area in the thigh, abdominal muscle area (AMA), abdominal subcutaneous fat area (ASFA), and visceral fat area (AVFA) were measured with use of the public domain planimetry program, The National Institutes of Health IMAGE (written by Wayne Rasband, The National Institutes of Health, Bethesda, MD).
Protein Equivalent of Nitrogen Appearance Normalized by Ideal Body Weight The protein equivalent of nitrogen appearance (PNA), which is widely accepted as a measure of dietary protein intake in a stable condition, was calculated by the formula published by the KDOQI Hemodialysis Adequacy Work Group.3 Data collected during a beginning-of-the-week dialysis session were used for these calculations. HD dose was evaluated using the following formula: spKt/V ⫽ ⫺Ln(R ⫺ 0.008 ⫻ t) ⫹ (4 ⫺ [3.5 ⫻ R]) ⫻ UF/W where spKt/V is single-pool Kt/V, R is the ratio of postdialysis to predialysis serum urea nitrogen, t is time of dialysis in hours, UF is the amount of ultrafiltration in liters, and W is postdialysis body weight in kilograms. Normalized PNA (nPNA) was evaluated using the following formula: nPNA (g/kg/d) ⫽ C0/[36.3 ⫹ 5.48(spKt/V) ⫹ 53.5/(spKt/V)] ⫹ 0.168 where C0 is the predialysis concentration of serum urea nitrogen in milligrams per deciliter. To evaluate whether a patient had ingested an appropriate amount of protein, body weight in the denominator of the equation for nPNA should be the nutritionally ideal body weight, rather than actual postdialytic body weight or DW.14 For example, if the patient has a lower body weight than the ideal body weight because of undernutrition, nPNA (PNA divided by DW) can overestimate protein intake. Therefore, nPNA was normalized to the ideal body weight (nPNAibw) using the following equation:
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Fig 1. Representative CT images of (A, C) the thigh and (B, D) abdomen in patients with nPNAibw (A, B) less than 0.7 g/kg/d and (C, D) greater than 1.3 g/kg/d. TMA, AMA, TSFA, ASFA, and AVFA are greater in patients with an nPNAibw greater than 1.3 g/kg/d than in those with an nPNAibw less than 0.7 g/kg/day, although bone areas are similar.
nPNAibw ⫽ nPNA ⫻ postdialysis body weight (kg)/ideal body weight (kg) where ideal body weight was determined from the height and a BMI of 22 kg/m2, the preferred value from a study examining the relationship between BMI and morbidity in Japanese men and women.15 nPNAibw was calculated once a month, and the average for 3 months is shown in the results.
Analytical Procedures Serum albumin, creatinine, urea nitrogen, potassium, phosphorus, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using an automatic analyzer and standard laboratory techniques. Serum prealbumin and C-reactive protein (CRP) levels were determined by laser nephelometry. Serum interleukin-6 (IL-6) concentration was measured by using an enzyme-linked immunoassay (Ultrasensitive human IL-6 immunoassay kit; R&D Systems, Minneapolis, MN).
Statistical Analyses Each data value is presented as mean ⫾ SD. Differences among groups were evaluated by an analysis of variance (ANOVA) and subsequent Bonferroni test. A simple regression analysis was used to examine relationships among variables. P less than 0.05 is considered statistically significant. All statistical analyses were performed using GBSTAT software (Dynamic Microsystems, Silver Spring, MD).
RESULTS
One hundred seventy-five patients were assessed for eligibility according to our inclusion and exclusion criteria. Forty-eight patients were excluded because of diabetes (n ⫽ 21), recent start of dialysis therapy (n ⫽ 12), unstable DW (n ⫽ 12), bedbound (n ⫽ 1), regular muscle training (n ⫽ 1), and heavy work (n ⫽ 1). Thus, 127 patients (82 men, 45 women; mean age, 60.0 ⫾ 12.0 years; range, 21 to 82 years) were
PROTEIN REQUIREMENT IN HD PATIENTS Table 1.
Variable
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Patient Characteristics Men (n ⫽ 82)
Women (n ⫽ 45)
Age (y) 59.4 ⫾ 11.1 60.9 ⫾ 13.7 Duration of HD (mo) 66.9 ⫾ 52.5 77.2 ⫾ 59.9 Height (cm) 163.3 ⫾ 6.3 150.7 ⫾ 5.6* DW (kg) 55.2 ⫾ 7.4 46.1 ⫾ 7.0* 20.7 ⫾ 2.3 20.3 ⫾ 2.6 BMI (kg/m2) PNA (g/d) 57.5 ⫾ 12.5 51.6 ⫾ 10.4* nPNAibw (g/kg/d) 1.01 ⫾ 0.19 1.13 ⫾ 0.20* Kt/Vurea 1.12 ⫾ 0.08 1.26 ⫾ 0..10* Serum Albumin (g/dL) 3.96 ⫾ 0.34 3.91 ⫾ 0.31 Prealbumin (mg/dL) 34.6 ⫾ 7.7 34.1 ⫾ 7.0 Urea nitrogen (mg/dL) 78.1 ⫾ 12.4 81.3 ⫾ 14.0 Creatinine (mg/dL) 13.0 ⫾ 2.4 11.2 ⫾ 1.7* Potassium (mEq/L) 5.14 ⫾ 0.65 5.38 ⫾ 0.60† Phosphorus (mg/dL) 4.68 ⫾ 0.91 5.17 ⫾ 1.16† Total cholesterol (mg/dL) 151 ⫾ 32 174 ⫾ 30† HDL cholesterol (mg/dL) 47.0 ⫾ 12.5 53.0 ⫾ 13.6† Triglycerides (mg/dL) 125 ⫾ 76 137 ⫾ 60 IL-6 (pg/mL) 5.90 ⫾ 6.03 6.00 ⫾ 6.04 CRP (mg/L) 4.9 ⫾ 8.7 3.6 ⫾ 4.7 CT data 104.1 ⫾ 22.0 76.0 ⫾ 14.8* TMA (cm2) TSFA (cm2) 30.8 ⫾ 13.3 52.3 ⫾ 24.8* IMFA (cm2) 8.3 ⫾ 3.4 8.9 ⫾ 4.8 AMA (cm2) 120.1 ⫾ 20.0 81.4 ⫾ 17.9* ASFA (cm2) 96.3 ⫾ 44.5 116.2 ⫾ 66.5 AVFA (cm2) 81.7 ⫾ 52.3 83.0 ⫾ 43.2 NOTE. Values expressed as mean ⫾ SD. To convert albumin in g/dL to g/L, multiply by 10; urea nitrogen in mg/dL to mmol/L, multiply by 0.357; creatinine in mg/dL to mol/L, multiply by 88.4; potassium in mEq/L to mmol/L, multiply by 1; phosphorus in mg/dL to mmol/L, multiply by 0.3229; cholesterol in mg/dL to mmol/L, multiply by 0.0259; triglycerides in mg/dL to mmol/L, multiply by 0.0113. Abbreviations: Kt/Vurea, amount of dialysis delivered to a patient per treatment; IMFA, intermuscular fat area. *P ⬍ 0.01, significantly different from men. †P ⬍ 0.05, significantly different from men.
included in the study. Representative CT images of the thigh and abdomen of HD patients are shown in Fig 1. The advantage of a CT image is that the contours of a muscle can be precisely traced, and intermuscular fat mass can be discriminated from muscle bulk. Patient characteristics and various nutritional indices, including muscle and fat areas, are listed in Table 1. BMI of patients was no different from the average BMI of Japanese dialysis patients (21.0 ⫾ 3.6 kg/m2 for men, 20.2 ⫾ 3.4 kg/m2 for women),16 whereas these values were significantly less than those of the general Japanese
population (23.0 ⫾ 2.9 kg/m2 for men, 22.8 ⫾ 3.4 kg/m2 for women).17 Serum albumin and prealbumin concentrations were 3.94 ⫾ 0.28 g/dL (39.4 ⫾ 2.8 g/L) and 34.3 ⫾ 6.9 mg/dL, respectively, suggesting that nutritional status had been fairly well maintained in this population. Mean age, duration of HD therapy, BMI, and serum albumin, prealbumin, urea nitrogen, and triglyceride levels were not significantly different between men and women. Height, DW, PNA, and serum creatinine levels were significantly greater in men than women, whereas Kt/ Vurea, nPNAibw, and serum potassium, phosphorus, total cholesterol, and HDL cholesterol levels were significantly greater in women than men. TMA and AMA were significantly greater in men than women, whereas TSFA was significantly greater in women than men. The intramuscular fat area of the thigh and ASFA and AVFA did not differ between men and women. Patients were divided into 5 groups according to nPNAibw value: less than 0.7, 0.7 to 0.9, 0.9 to 1.1, 1.1 to 1.3, and greater than 1.3 g/kg/d. Clinical variables are compared among these groups in Tables 2 and 3, and muscle and fat areas of the thigh and abdomen are shown in Figs 2 (men) and 3 (women). Mean age, height, and serum phosphorus, total cholesterol, and HDL cholesterol levels were not significantly different among the groups for men and women. Body weight, BMI, and blood urea nitrogen level increased significantly with increasing nPNAibw in both men and women. TMA in both men and women and AMA in men were significantly lower in the groups with nPNAibw less than 0.7 and 0.7 to 0.9 g/kg/d than in the groups with nPNAibw greater than 0.9 to 1.1 g/kg/d. TMA and AMA increased with increasing nPNAibw from less than 0.7 g/kg/d to 0.9 to 1.1 g/kg/d and showed a plateau in the groups with nPNAibw greater than 0.9 to 1.1 g/kg/d. The relationship between nPNAibw and serum creatinine level, an index of whole-body muscle mass, was similar to that with TMA. Conversely, TSFA, ASFA, and AVFA progressively increased with increasing nPNAibw without saturation. AVFA in patients with nPNAibw greater than 1.3 g/kg/d was greater than 100 cm2, a level satisfying the criterion for visceral obesity defined by the Japanese Society for the Study of Obesity.18
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OHKAWA ET AL Table 2.
Comparison of Clinical Variables for nPNAibw in Men nPNAibw (g/kg/d)
⬍0.7 (n ⫽ 5)
0.7-0.9 (n ⫽ 22)
0.9-1.1 (n ⫽ 30)
1.1-1.3 (n ⫽ 18)
⬎1.3 (n ⫽ 7)
ANOVA P
Age (y) 67.2 ⫾ 6.1 57.8 ⫾ 14.4 60.2 ⫾ 11.1 57.9 ⫾ 7.6 59.1 ⫾ 8.6 0.50 Duration of HD (mo) 53.8 ⫾ 62.5 44.5 ⫾ 29.8 75.4 ⫾ 57.2 88.4 ⫾ 59.3* 55.4 ⫾ 43.8 0.05 Height (cm) 162.4 ⫾ 7.1 162.5 ⫾ 6.4 163.9 ⫾ 4.5 163.6 ⫾ 7.6 163.1 ⫾ 9.8 0.94 DW (kg) 45.9 ⫾ 6.7 50.7 ⫾ 4.7 56.3 ⫾ 4.5†‡ 58.2 ⫾ 8.1†‡ 64.1 ⫾ 8.4†‡§㛳 0.001 17.3 ⫾ 1.7 19.2 ⫾ 1.7¶ 21.0 ⫾ 1.5†‡ 21.7 ⫾ 2.0†‡ 24.0 ⫾ 1.1†‡§# 0.0001 BMI (kg/m2) Kt/Vurea 1.11 ⫾ 0.07 1.09 ⫾ 0..09 1.11 ⫾ 0.08 1.15 ⫾ 0.08 1.10 ⫾ 0.07 0.27 Serum Albumin (g/dL) 3.63 ⫾ 0.07 3.99 ⫾ 0.45 3.93 ⫾ 0.29 4.01 ⫾ 0.31 4.02 ⫾ 0.24 0.21 Prealbumin (mg/dL) 28.9 ⫾ 3.8 32.1 ⫾ 8.2 35.3 ⫾ 7.2 37.2 ⫾ 6.7 37.4 ⫾ 9.8 0.09 Urea nitrogen (mg/dL) 55.7 ⫾ 3.6 70.3 ⫾ 9.4† 77.9 ⫾ 7.8†‡ 87.8 ⫾ 8.1†‡§ 94.5 ⫾ 4.0†‡§ 0.0001 Creatinine (mg/dL) 8.5 ⫾ 1.5 12.2 ⫾ 2.2† 13.3 ⫾ 2.2† 14.3 ⫾ 1.4*† 13.9 ⫾ 1.2† 0.0001 Potassium (mEq/L) 4.58 ⫾ 0.58 5.13 ⫾ 0.74 5.11 ⫾ 0.60 5.14 ⫾ 0.46 5.73 ⫾ 0.73¶ 0.05 Phosphorus (mg/dL) 4.66 ⫾ 0.98 4.63 ⫾ 0.74 4.68 ⫾ 0.91 4.63 ⫾ 1.30 4.93 ⫾ 0.47 0.96 Total cholesterol (mg/dL) 154 ⫾ 58 150 ⫾ 40 148 ⫾ 23 158 ⫾ 24 132 ⫾ 32 0.52 HDL cholesterol (mg/dL) 46 ⫾ 12 51 ⫾ 12 47 ⫾ 13 40 ⫾ 12 47 ⫾ 9 0.15 Triglycerides (mg/dL) 97 ⫾ 30 104 ⫾ 39 124 ⫾ 61 171 ⫾ 123 119 ⫾ 107 0.11 IL-6 (pg/mL) 16.5 ⫾ 9.5 6.9 ⫾ 12.9 7.2 ⫾ 6.8 7.1 ⫾ 5.6 5.0 ⫾ 4.8 0.14 CRP (mg/L) 2.41 ⫾ 0.70 0.67 ⫾ 1.41† 0.26 ⫾ 0.17† 0.38 ⫾ 0.38† 0.23 ⫾ 0.03† 0.0005 NOTE. Values expressed as mean ⫾ SD. See Table 1 for SI conversion factors. *P ⬍ 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d. †P ⬍ 0.01 versus nPNAibw less than 0.7 g/kg/d. ‡P ⬍ 0.01 versus nPNAibw of 0.7 to 0.9 g/kg/d. §P ⬍ 0.01 versus nPNAibw of 0.9 to 1.1 g/kg/d. 㛳P ⬍ 0.05 versus nPNAibw of 1.1 to 1.3 g/kg/d. #P ⬍ 0.01 versus nPNAibw of 1.1 to 1.3 g/kg/d. ¶P ⬍ 0.05 versus nPNAibw less than 0.7 g/kg/d.
Prealbumin levels showed a trend similar to that of muscle mass in relation to increasing nPNAibw. However, there was no significant difference in serum albumin levels among all nPNAibw groups. CRP levels were significantly greater in the nPNAibw group of less than 0.7 g/kg/d than in the other groups for men. IL-6 levels also were greater in the lowest nPNAibw group than in the other groups, although the difference was not statistically significant. Serum potassium level correlated significantly with nPNAibw (r ⫽ 0.29; P ⬍ 0.001). Mean serum potassium level exceeded 5.5 mEq/L (mmol/L) in the nPNAibw group of greater than 1.3 g/kg/d in both men and women. DISCUSSION
Results of the present cross-sectional study show that muscle mass increased with increasing dietary protein intake from less than 0.7 g/kg/d to 0.9 to 1.1 g/kg/d and showed a
plateau in the groups with greater than 0.9 to 1.1 g/kg/d of dietary protein intake. Because a determination of protein intake at the point at which body protein synthesis levels out (forms a plateau) may be a useful indicator of protein requirements,19 0.9 to 1.1 g/kg/d of dietary protein is considered the minimum level for maintaining adequate protein nutritional status in HD patients. This optimal level of protein intake is almost similar to values previously examined by leucine turnover and nitrogen balance studies in both sedentary healthy subjects (0.89 g/kg/d)20 and maintenance HD patients (0.9 to 1.0 g/kg/d).21 An excessive protein intake greater than the optimal level does not appear to have resulted in an increase in muscle mass. However, this level of dietary protein intake is substantially less than the recommended protein requirement in the nutritional guidelines from the NKF-KDOQI (1.2 g/kg/d)3 and the Japanese
PROTEIN REQUIREMENT IN HD PATIENTS Table 3.
459
Comparison of Clinical Variables for nPNAibw in Women nPNAibw (g/kg/d)
Age (y) Duration of HD (mo) Height (cm) DW (kg) BMI (kg/m2) Kt/Vurea Serum Albumin (g/dL) Prealbumin (mg/dL) Urea nitrogen (mg/dL) Creatinine (mg/dL) Potassium (mEq/L) Phosphorus (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) IL-6 (pg/mL) CRP (mg/L)
⬍0.7 (n ⫽ 0)
0.7-0.9 (n ⫽ 6)
0.9-1.1 (n ⫽ 16)
— — — — — —
68.3 ⫾ 11.4 110.5 ⫾ 90.4 150.9 ⫾ 6.9 40.7 ⫾ 5.9 18.0 ⫾ 1.2 1.20 ⫾ 0.08
62.1 ⫾ 14.7 78.9 ⫾ 65.5 151.7 ⫾ 6.2 44.5 ⫾ 6.1 19.3 ⫾ 2.0 1.29 ⫾ 0.12
— — — — — — — — — — —
3.81 ⫾ 0.23 28.4 ⫾ 6.4 60.2 ⫾ 11.9 9.3 ⫾ 0.1 4.90 ⫾ 0.64 5.67 ⫾ 0.87 176 ⫾ 48 55 ⫾ 18 122 ⫾ 86 9.3 ⫾ 6.5 0.48 ⫾ 0.41
3.88 ⫾ 0.29 32.8 ⫾ 6.1 76.0 ⫾ 9.5* 10.9 ⫾ 1.9§ 5.39 ⫾ 0.77 4.99 ⫾ 0.98 171 ⫾ 34 50 ⫾ 11 145 ⫾ 52 6.1 ⫾ 6.5 0.46 ⫾ 0.68
1.1-1.3 (n ⫽ 13)
58.5 ⫾ 14.7 66.2 ⫾ 43.8 149.8 ⫾ 5.5 45.5 ⫾ 6.1 20.3 ⫾ 2.5 1.26 ⫾ 0.09 3.95 ⫾ 0.34 37.2 ⫾ 5.9 88.1 ⫾ 11.2*† 12.1 ⫾ 1.4* 5.52 ⫾ 0.43 5..08 ⫾ 0.83 176 ⫾ 30 56 ⫾ 17 138 ⫾ 81 7.5 ⫾ 6.8 0.39 ⫾ 0.49
⬎1.3 (n ⫽ 10)
ANOVA P
58.0 ⫾ 13.2 68.8 ⫾ 48.5 150.1 ⫾ 6.0 52.7 ⫾ 6.4*†‡ 23.2 ⫾ 1.9*†‡ 1.27 ⫾ 0.11
0.44 0.49 0.84 0.018 0.0001 0.32
3.94 ⫾ 0.34 36.3 ⫾ 8.1§ 90.6 ⫾ 9.4*† 11.4 ⫾ 1.5§ 5.48 ⫾ 0.51 5.28 ⫾ 1.64 178 ⫾ 18 52 ⫾ 14 133 ⫾ 51 4.7 ⫾ 2.9 0.25 ⫾ 0.13
0.79 0.05 0.0001 0.01 0.19 0.67 0.94 0.71 0.89 0.56 0.69
NOTE. Values expressed as mean ⫾ SD. See Table 1 for SI conversion factors. *P ⬍ 0.01 versus nPNAibw of 0.7-0.9 g/kg/d. †P ⬍ 0.01 versus nPCRibw of 0.9 to 1.1 g/kg/d. ‡P ⬍ 0.01 versus nPCRibw of 1.1 to 1.3 g/kg/d. §P ⬍ 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d.
Society of Nephrology (1.0 to 1.2 g/kg/d).22 These guidelines were determined considering that HD patients experience such catabolic stress as blood-membrane interaction,23 dialysate amino acid and protein loss,10 acidosis,24 and inflammation25 and thus are recommended to maintain a higher dietary protein intake than healthy subjects. It recently was proposed that the protein requirement for dialysis patients in the NKFKDOQI nutrition guidelines should be modified to a lower level.7,8 One reason for this proposal is that the evidence for increased HD-induced protein breakdown has not been shown in patients by continuously measuring leucine flux before, during, and after HD with a cuprophane membrane.21 The introduction of a biocompatible membrane and bicarbonate dialysate to recent HD protocols might have resulted in additional suppression of the blood-membrane interaction and acidosis. Another reason is that even if amino acid and protein losses into the dialysate reach 6 to 12 g/HD session, the estimated additional protein need would be only 0.04 to 0.08 g/kg/d.26
The background to the argument that the protein requirement for HD patients shown in the NKF-KDOQI nutrition guidelines might be too high is that high protein loading might lead to some adverse effects in HD patients. A highprotein diet induces an increase in blood urea nitrogen levels, accumulation of uremic metabolites, hyperphosphatemia, and hyperkalemia. An increase of more than 5.5 mEq/L (mmol/L) in serum potassium levels was found in patients with an nPNAibw greater than 1.3 g/kg/d in the present study. Furthermore, patients with greater protein intake often also have high energy intake,9 and the protein excess above the needs is oxidized as energy, rather than stored in the muscle.27 As a result, fat mass, including subcutaneous fat, intramuscular fat, and visceral fat, increased with graded protein intake, and no plateau was observed in our HD patients. Accumulation of fat, especially in the visceral area, might be associated with atherosclerosis and increased morbidity and mortality.28 Serum albumin level is a powerful indicator of protein nutritional status. However, it is notewor-
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Fig 2. Comparison of TMA and fat areas versus nPNAibw between (left) men and (right) women. aP < 0.05 versus nPNAibw less than 0.7 g/kg/d; bP < 0.01 versus nPNAibw less than 0.7 g/kg/d; cP < 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d; dP < 0.01 versus nPNAibw of 0.7 to 0.9 g/kg/d; eP < 0.05 versus nPNAibw of 0.9 to 1.1 g/kg/d; fP < 0.01 versus nPNAibw of 0.9 to 1.1 g/kg/d; gP < 0.05 versus nPNAibw of 1.1 to 1.3 g/kg/d; hP < 0.01 versus nPNAibw of 1.1 to 1.3 g/kg/d.
thy that serum albumin levels were not significantly different among the groups in our current study. A kinetic study reported that when dietary protein intake was deficient, both albumin synthetic and catabolic rates decreased, resulting in preservation of serum albumin level.29 Castaneda et al30 showed in elderly women that serum albumin levels remained unchanged after a 9-week study of adaptation to a low-protein diet, whereas muscle mass and muscle function were both significantly reduced. Serum albumin level therefore does not appear to be a good indicator of marginal protein deficiency compared with muscle mass. Inflammation is another factor for the wasting of muscle mass in addition to a low dietary protein intake. Tumor necrosis factor (TNF) and
IL-1 have both been reported to have an important role in protein catabolism in the muscle of animals with sepsis and chronic inflammatory states.31,32 These cytokines can directly enhance protein degradation in skeletal muscle, probably through the ubiquitin-proteasome pathway.33 Furthermore, because TNF sequentially induces the production of IL-6,34 some metabolic effects of TNF are thought to be mediated by IL-6. IL-6 recently has been recognized as a direct muscle proteolysis-inducing factor in cancer cachexia.35 However, from results of the current study, anorexia might be a main mediator for muscle wasting associated with inflammation36 because CRP levels were significantly greater in the group with the lowest dietary protein intake than in the other groups, and IL-6 levels showed a similar
PROTEIN REQUIREMENT IN HD PATIENTS
461
Fig 3. Comparison of AMA and fat areas versus nPNAibw in (left) men and (right) women. aP < 0.05 versus nPNAibw less than 0.7 g/kg/d; bP < 0.01 versus nPNAibw less than 0.7 g/kg/d; cP < 0.05 versus nPNAibw of 0.7 to 0.9 g/kg/d; dP < 0.01 versus nPNAibw of 0.7 to 0.9 g/kg/d; eP < 0.05 versus nPNAibw of 0.9 to 1.1 g/kg/d; fP < 0.01 versus nPNAibw of 0.9 to 1.1 g/kg/d; gP < 0.05 versus nPNAibw of 1.1 to 1.3 g/kg/d; hP < 0.01 versus nPNAibw of 1.1 to 1.3 g/kg/d.
trend. When dietary protein is not adequate to meet metabolic demands, the muscle acts as an amino acid supplier, and as a result, muscle wasting develops. TNF and IL-1 have been reported to be directly involved in the brain to produce anorexia.36 These results suggest that suppression of cytokine production seems to be important for improving the appetite and preventing muscle wasting in malnourished patients undergoing HD. A sedentary lifestyle also might affect muscle wasting and fat deposition in HD patients. Increased dietary intake can improve nutritional status in maintenance HD patients.37 However, as shown by healthy subjects, it is difficult to increase muscle mass without exercise or physical loading, even if nutritional intake is suffi-
cient. Fat mass might be accumulated rapidly in the visceral area during the weight-relapse period of obese patients after weight loss despite no return of the fat-free mass.38 Aerobic exercise and muscle strength training during HD sessions recently have been reported to be effective for improving exercise capacity and muscle strength.39 Additional study is required to explore the metabolic consequence of physical exercise and define optimal exercise regimens for HD patients. There are some limitations of this study. First, although nitrogen balance is affected by both energy intake and protein intake, dietary energy intake was not taken into account in this study. It is possible that inadequate energy intake could have accelerated muscle wasting in patients with
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low protein intake. Moreover, the relative contribution of protein and energy intakes to fat deposition was not shown clearly in patients with a protein overload in the current study. However, the Hemodialysis Study showed a strong correlation between dietary protein intake and dietary energy intake in HD patients (r ⫽ 0.74; P ⬍ 0.001),9 suggesting that energy intake can be roughly predicted from the level of nPNAibw. Second, it is not known whether the plateau level of muscle mass attained by subjects with 0.9 to 1.1 g/kg/d of protein intake was similar to that of healthy subjects. The normal level of TMA matched for race, age, sex, and physical activity has not yet been determined, and this needs to be done in a subsequent study. In summary, protein intake of 0.9 to 1.1 g/kg/d brought muscle mass to a plateau level, and any additional increase in dietary protein did not appear to result in increased muscle mass in HD patients without diabetes. An excessive protein intake of more than 1.3 g/kg/d, probably accompanied by energy overloading, induced such adverse effects as visceral obesity and an increase in serum potassium level. Therefore, the optimal dietary protein intake is likely to be less than the level recommended in the nutritional guidelines from the NKF-KDOQI and Japanese Society of Nephrology in such patients as ours, in whom nutritional status had been maintained fairly well, suggested by serum albumin level. Considering that HD patients are always exposed to catabolic stress and tend to be anorexic, the recommended level might still be within the reasonable range for most HD patients. REFERENCES 1. Bergstrom J: Nutrition and mortality in hemodialysis. J Am Soc Nephrol 6:1329-1341, 1995 2. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 329:1001-1006, 1993 3. National Kidney Foundation: KDQOI Clinical Practice Guidelines for Nutrition in Chronic Renal Failure. Am J Kidney Dis 35:S17-S104, 2000 (suppl 2) 4. Borah MF, Schoenfeld PY, Gotch FA, et al: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 14:491-500, 1978 5. Slomowitz LA, Monteon FJ, Grosvenor M, Laidlaw SA, Kopple JD: Effect of energy intake on nutritional status in maintenance hemodialysis patients. Kidney Int 35:704711, 1989 6. Acchiardo SR, Moore LW, Latour PA: Malnutrition as
the main factor in morbidity and mortality of hemodialysis patients. Kidney Int 24:199-203, 1983 7. Lim VS, Flanigan MJ: Protein intake in patients with renal failure: Comments on the current NKF-DOQI guidelines for nutrition in chronic renal failure. Semin Dial 14:150-152, 2001 8. Block G, Uribarri J, Coladonato JA, et al: How should hyperphosphatemia be managed in dialysis patients? Semin Dial 15:315-328, 2002 9. Rocco MV, Paranandi L, Burrowes JD, et al: Nutritional status in the HEMO study cohort at baseline. Am J Kidney Dis 39:245-256, 2002 10. Ikizler TA, Flakoll PJ, Parker RA, Hakim RM: Amino acid and albumin losses during hemodialysis. Kidney Int 46:830-837, 1994 11. Goldstein-Fuchs DJ: Assessment of nutritional status in renal disease, in Mitch WE, Klahr S (eds): Nutrition and the Kidney. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 42-92 12. Ohkawa S, Odamaki M, Yoneyama T, Hibi I, Miyaji K, Kumagai H: Standardized thigh muscle area measured by computed axial tomography as an alternate muscle mass index for nutritional assessment of hemodialysis patients. Am J Clin Nutr 71:485-490, 2000 13. Kaizu Y, Ohkawa S, Kumagai H: Muscle mass index in haemodialysis patients: A comparison of indices obtained by routine clinical examinations. Nephrol Dial Transplant 17:442-448, 2002 14. Marcen R, Teruel JL, de la Cal MA, et al: The impact of malnutrition in morbidity and mortality in stable haemodialysis patients. Nephrol Dial Transplant 12:2324-2331, 2002 15. Tokunaga K, Matsuzawa Y, Kotani K, et al: Ideal body weight estimated from the body mass index with the lowest morbidity. Int J Obes 15:1-5, 1991 16. Japanese Society for Dialysis Therapy: An Overview of Regular Dialysis Treatment in Japan [Japanese]. Tokyo, Japan, Japanese Society for Dialysis Therapy, 2000, p 222 17. Ministry of Health, Labour and Welfare: The National Nutrition Survey in Japan [Japanese]. Tokyo, Japan, Dai-Ichi, 1999, p 104 18. The Examination Committee of Criteria for Obesity Disease in Japan, Japan Society for the Study of Obesity: New criteria for “obesity disease” in Japan. Circ J 66:987992, 2002 19. Young VR, Bier DM, Pellett PL: A theoretical basis for increasing current estimates of the amino acid requirements in adult man, with experimental support. Am J Clin Nutr 50:80-92, 1989 20. Tarnopolsky MA, Atkinson SA, MacDougall JD, et al: Evaluation of protein requirements for trained strength athletes. J Appl Physiol 73:1986-1995, 1992 21. Lim VS, Bier DM, Flanigan MJ, Sum-Ping ST: The effect of hemodialysis on protein metabolism. A leucine kinetic study. J Clin Invest 91:2429-2436, 1993 22. The Japanese Society of Nephrology: Guidelines for life style and dietary therapy for kidney diseases. Nippon Jinzo Gakkai Shi 39:1-37, 1997 23. Cheung AK: Biocompatibility of hemodialysis membranes. J Am Soc Nephrol 1:150-161, 1990 24. Mitch WE, Maroni BJ: Factors causing malnutrition
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in patients with chronic uremia. Am J Kidney Dis 33:176179, 1999 25. Kaysen GA, Chertow GM, Adhikarla R, Young B, Ronco C, Levin NW: Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. Kidney Int 60:333-340, 2001 26. Wolfson M, Jones MR, Kopple JD: Amino acid losses during hemodialysis with infusion of amino acids and glucose. Kidney Int 21:500-506, 1982 27. Pi-Sunyer FX: Obesity, in Shils ME, Olson JA, Shike M, Ros AC (eds): Modern Nutrition in Health and Disease. Baltimore, MD, Lippincott Williams & Wilkins, 1999, pp 1395-1418 28. Matsuzawa Y: Pathophysiology and molecular mechanisms of visceral fat syndrome: The Japanese experience. Diabetes Metab Rev 13:3-13, 1997 29. Kelman L, Saunders SJ, Frith L, Wicht S, Corrigal A: Effects of dietary protein restriction on albumin synthesis, albumin catabolism, and the plasma aminogram. Am J Clin Nutr 25:1174-1178, 1972 30. Castaneda C, Charnley JM, Evans WJ, Crim MC: Elderly women accommodate to a low-protein diet with losses of body cell mass, muscle function, and immune response. Am J Clin Nutr 62:30-39, 1995 31. Siegel SA, Shealy DJ, Nakada MT, et al: The mouse/ human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 7:15-25, 1995
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32. Zamir O, Hasselgren PO, O’Brien W, Thompson RC, Fischer JE: Muscle protein breakdown during endotoxemia in rats and after treatment with interleukin-1 receptor antagonist (IL-1ra). Ann Surg 216:381-385, 1992 33. Mitch WE, Price SR: Mechanisms activated by kidney disease and the loss of muscle mass. Am J Kidney Dis 38:1337-1342, 2001 34. Libert C, Brouckaert P, Shaw A, Fiers W: Induction of interleukin 6 by human and murine recombinant interleukin 1 in mice. Eur J Immunol 20:691-694, 1990 35. Strassmann G, Fong M, Kenney JS, Jacob CO: Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681-1684, 1992 36. Tisdale MJ: Cancer anorexia and cachexia. Nutrition 17:438-442, 2001 37. Mehrotra R, Berman N, Alistwani A, Kopple JD: Improvement of nutritional status after initiation of maintenance hemodialysis. Am J Kidney Dis 40:133-142, 2002 38. Froidevaux F, Schutz Y, Christin L, Jequier E: Energy expenditure in obese women before and during weight loss, after refeeding, and in the weight-relapse period. Am J Clin Nutr 57:35-42, 1993 39. DePaul V, Moreland J, Eager T, Clase CM: The effectiveness of aerobic and muscle strength training in patients receiving hemodialysis and EPO: A randomized controlled trial. Am J Kidney Dis 40:1219-1229, 2002