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Factors causing malnutrition in patients with chronic uremia
Factors Causing Malnutrition in Patients With Chronic Uremia William E. Mitch, MD, and Bradley J. Maroni, MD ● There is abundant evidence that patients with chronic renal failure (CRF), including those treated by hemodialysis or peritoneal dialysis, have evidence of malnutrition with decreased body weight and subnormal values of serum proteins (suggesting a loss of visceral protein stores). Potential causes of an abnormal nutritional status that have been identified include an inadequate intake of protein or calories, an inability to activate the metabolic responses that are needed to achieve nitrogen and protein balance, or the presence of a disease that prevents activation of these metabolic responses or acts to stimulate the breakdown of body protein stores. Three critical metabolic responses to a limited protein intake have been identified: a reduction in the irreversible degradation of amino acids and the degradation of protein breakdown and an increase in protein synthesis in response to a meal. Metabolic acidosis blocks the first two responses and hence contributes to malnutrition in patients with chronic uremia. Other factors that could contribute to malnutrition include an inadequate intake because of anorexia or hormonal imbalances that impair protein turnover. In evaluating CRF patients with malnutrition, the first task is to ensure an adequate intake and to eliminate factors that impair the ability to achieve nitrogen balance. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic uremia; nitrogen balance; protein degradation; anorexia.
T
HERE HAS BEEN intensive interest in the nutritional state of patients with chronic renal failure (CRF) because of the excessive morbidity and high mortality of patients treated by dialysis and the link between a low serum albumin and the risk of death in dialysis patients.1,2 Several factors can contribute to the impaired nutritional status of patients with chronic uremia, including those who are being treated by dialysis. The first is an inadequate intake of calories and protein (Table 1). Dietary protein restriction is a time-honored method of improving the symptoms of uremia; the diets are effective therapeutically because they lead to reduced levels of uremic toxins, most of which result from the breakdown of protein. Consequently, a low-protein diet can ameliorate metabolic acidosis, renal osteodystrophy, hyperkalemia, and hypertension because the diets are restricted in sulfates, phosphates, potassium, and sodium. Although controversial, there also is evidence that low-protein diets can slow the progressive loss of renal function.3 Regardless, it is important to document that the dietary requirements are being achieved to treat patients successfully. The diet From the Renal Division, Emory University School of Medicine, Atlanta, GA. Received September 11, 1998; accepted in revised form September 14, 1998. Address reprint requests to William E. Mitch, MD, Emory University Renal Division, 338 WMB/1639 Pierce Dr, Atlanta, GA 30322. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3301-0030$3.00/0 176
must contain the required amounts of protein and calories, because an inadequate diet can jeopardize a patient’s nutritional status. DIETARY REQUIREMENTS OF CHRONICALLY UREMIC PATIENTS
Careful nitrogen balance studies by Kopple and Coburn4 showed that patients with CRF in the predialysis stage of their disease have the same minimal daily requirement for protein (0.6 g/kg/d) as normal adults.4 An assessment of the adequacy of the diet and nutritional status is needed regularly and includes periodic estimates of protein intake5 plus measurements of weight, mid-arm muscle circumference, and serum proteins.6 With this type of monitoring, low-protein diets are nutritionally sound in CRF patients without complicating diseases. This conclusion is consistent with results from the Modification of Diet in Renal Disease Study.7 In an analysis of the nutritional status of patients in that study, it was found that anthropometric measurements scarcely changed while serum albumin values actually increased in patients eating the lowprotein diets. It is known that excessive dietary protein increases the degree of proteinuria and that dietary protein restriction can reduce the degree of proteinuria.8 However, the protein requirements of patients with the nephrotic syndrome have not been examined as extensively. Recently, Maroni et al9 measured the nitrogen balance of patients with the nephrotic syndrome while they ate 0.8 g protein/kg/d plus 1 g protein for each gram lost
American Journal of Kidney Diseases, Vol 33, No 1 (January), 1999: pp 176-179
MALNUTRITION IN CHRONIC UREMIA
177
Table 1. Dietary Requirements of Patients With Chronic Kidney Disease
Healthy adults CRF patients Nephrotic patients Hemodialysis patients CAPD patients
Protein (g/kg/d)
Calories* (kcal/kg/d)
0.6 0.6 0.6 1.0 1.2
30-35 30-35 30-35 30-35 30-35
*Energy requirement may be increased depending on activity level. Abbreviations: CRF, chronic renal failure; CAPD, continuous ambulatory peritoneal dialysis.
in the urine.9 Nitrogen balance was uniformly positive, and serum albumin was unchanged. These results indicate that dietary protein restriction can be used safely if nephrotic patients are monitored carefully. The protein requirement for patients being treated by dialysis is even higher: For hemodialysis patients, it is 1 g protein/kg/d, whereas for continuous ambulatory peritoneal dialysis (CAPD) patients, it is 1.2 g protein/kg/d.10,11 The protein requirements for hemodialysis patients is high in part because there are losses of amino acids, plus the dialysis procedure itself may be catabolic.1 During CAPD, there is loss of protein as well as amino acids, accounting in part for the increased protein requirement. Note that the amount of protein lost cannot be replaced by an equivalent amount of dietary protein because protein lost in the nephrotic syndrome or by CAPD patients (ie, protein synthesis) does not occur with 100% efficiency. Dietary protein cannot be considered in isolation, however, because it also is important that adequate calories are consumed (Table 1). An adequate calorie supply is critical for CRF patients who are eating proteinrestricted diets as well as those being treated by dialysis.6,12 FACTORS IMPAIRING THE NUTRITIONAL STATUS
If protein and calorie requirements are not provided in the diet, patients are at risk for losing protein stores. The mechanism underlying loss of protein stores is unclear, but there are important adaptive responses that occur whenever nitrogen intake is limited (Table 2). Normal subjects fed a low-protein diet activate the following adaptive
mechanisms to promote neutral nitrogen balance: (1) As dietary protein is reduced, there is a reduction in amino acid oxidation allowing more efficient utilization of dietary essential amino acids; (2) when dietary protein approaches 0.6 g/kg/d, another response is activated and protein degradation is suppressed, especially in response to a meal. In the latter case, there often is an increase in protein synthesis but the magnitude of this response is less than the limitation in protein degradation.13 It is clear that patients with uncomplicated CRF can activate the same metabolic responses to dietary protein restriction, even when the patients are eating only approximately 0.3 g protein/kg/d plus a supplement of ketoacids.13 Recently, Maroni et al9 showed that these responses are also activated in CRF patients with the nephrotic syndrome9; in this case, the results are even more fascinating. The adaptive decrease in amino acid oxidation was determined by the net amount of protein eaten (ie, the difference between protein intake and urinary protein losses); the degree of suppression of amino acid oxidation was greatest in those with the least net protein intake. Ultimately, this adaptive response yields more efficient utilization of dietary protein. Even though these adaptive responses are intact in patients with CRF, at least in the predialyTable 2. Metabolic Adaptations to Dietary Protein Restriction
Response
Suppression of amino acid oxidation
Suppression of protein degradation
Stimulation of protein synthesis
Determinants of the Response
Related to the amount of dietary protein as well as with urinary protein losses Activated if dietary protein is below the minimum daily requirement; also activated by feeding
Increased by feeding
Benefit
Promotes the utilization of dietary essential amino acids
1) Minimizes loss of lean body mass when dietary protein intake inadequate 2) Promotes anabolism during feeding Replaces protein lost during fasting
178
MITCH AND MARONI
Table 3. Factors Impairing Nutritional Status of Patients With Chronic Renal Failure Condition
Anorexia Metabolic acidosis Infection/Inflammatory illness Diabetes
Mechanism
Inadequate protein or calorie intake Stimulation of amino acid and protein degradation Stimulation of protein degradation Stimulation of protein degradation and suppression of protein synthesis
sis phase of their disease (the responses have not been assessed in dialysis patients), an inadequate intake of protein and calories will impair the nutritional status (Table 3). This is important because CRF patients can develop anorexia. The causes of anorexia in uremia have been largely unexplored, although there are a number of potential causes (Table 4). Recently, Anderstam et al14 used a rodent model to assess the spontaneous food intake and determined that substances in the plasma of uremic patients can suppress appetite. Attempts to determine the chemical composition of this factor(s) indicate that it probably falls in the ‘‘middle molecule’’ size and may be a peptide. Clearly, isolation and characterization of these compounds will be a very important step toward understanding one of the major complications of uremia. Other factors in chronic uremia impair nutritional responses. Metabolic acidosis impairs the adaptive metabolic responses in two ways: it stimulates the degradation of the essential, branched-chain amino acids and the degradation Table 4. Potential Cause of Anorexia in Chronic Uremia Accumulation of an ‘‘anorectic factor’’ Gastropathy–enteropathy in diabetes Inflammation, infection Medications Psychosocial factors: Depression, poverty, alcohol/ drugs Hemodialysis Cardiovascular instability Postdialysis fatigue Peritoneal dialysis Abdominal distension Absorption glucose Peritonitis
of protein in muscle.15,16 Mechanisms for these catabolic responses to acidosis involve stimulation of the rate-limiting enzyme in branchedchain amino acid degradation, branched-chain ketoacid dehydrogenase, and activation of the ubiquitin-proteasome pathway. Although these catabolic changes were initially described in rats, they have been confirmed in normal subjects and CRF patients, including those eating a lowprotein diet.17-20 Metabolic acidosis also suppresses albumin synthesis.21 In short, metabolic acidosis blocks the ability of CRF patients to adapt to a low-protein diet. Infections or other inflammatory illnesses and poorly controlled diabetes mellitus also activate the ubiquitin-proteasome pathway, causing accelerated protein degradation in muscle.22 These factors contribute to the catabolic effects of chronic kidney disease. In summary, the dietary requirements for patients with CRF uncomplicated by metabolic acidosis or a catabolic illness are known. Anorexia or problems associated with dialysis can limit the ability of a patient to achieve the proper dietary intake. If the intake is sufficient, then patients with chronic renal disease will activate adaptive metabolic responses to maintain nitrogen balance and protein stores. At least one catabolic condition that impairs the ability of CRF patients to activate these responses is metabolic acidosis, but there could be other problems, including infections. Research is needed to uncover the mechanisms causing anorexia and those impairing adaptive metabolic responses. Another major advance will occur when we understand the mechanisms underlying the adaptive responses because activation of these responses could improve the nutritional status of patients with kidney diseases and other catabolic illnesses. REFERENCES 1. Bergstrom J: Nutrition and mortality in hemodialysis. J Am Soc Nephrol 6:1329-1341, 1995 2. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of the death rate differences among facilities. Am J Kidney Dis 15:458-482, 1990 3. Maroni BJ, Mitch WE: Role of nutrition in prevention of the progression of renal disease. Annu Rev Nutr 17:435455, 1997 4. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia: I. Nitrogen and potassium. Medicine 52:583-594, 1973
MALNUTRITION IN CHRONIC UREMIA
5. Maroni BJ, Steinman T, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27:58-65, 1985 6. Maroni BJ: Requirements for protein, calories, and fat in the predialysis patient, in Mitch WE, Klahr S (eds): Nutrition and the Kidney (ed 2). Boston, MA, Little, Brown, 1993, pp 185-212 7. Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman J, Hollinger DL, Maroni BJ, Merrill D, Scherch LK, Shulman G, Wang SR, Zimmer GS: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease (MDRD) Study. Kidney Int 52:778-791, 1997 8. Kaysen GA, Gambertoglio J, Jimenez I, Jones H, Hutchison FN: Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int 29:572-577, 1986 9. Maroni BJ, Staffeld C, Young VR, Manatunga A, Tom K: Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet. J Clin Invest 99:2479-2487, 1997 10. Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, Wolfson M, Humphreys MH: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 14:491-500, 1978 11. Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW: Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis. Kidney Int 21:849-861, 1982 12. Monteon FJ, Laidlaw SA, Shaib JK, Kopple JD: Energy expenditure in patients with chronic renal failure. Kidney Int 30:741-747, 1986 13. Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: Protein and amino acid metabolism. Semin Nephrol 14:232-237, 1994
179
14. Anderstam B, Mamoun A-H, Bergstrom J, Sodersten P: Middle-sized molecule fractions isolated from uremic ultrafiltrate and normal urine inhibit ingestive behavior in the rat. J Am Soc Nephrol 7:2453-2460, 1996 15. Hara Y, May RC, Kelly RA, Mitch WE: Acidosis, not azotemia, stimulates branched-chain amino acid catabolism in uremic rats. Kidney Int 32:808-814, 1987 16. Bailey JL, Wang X, England BK, Price SR, Ding X, Mitch WE: The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent, ubiquitinproteasome pathway. J Clin Invest 97:1447-1453, 1996 17. Reaich D, Channon SM, Scrimgeour CM, Daley SE, Wilkinson R, Goodship THJ: Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 265:E230-E235, 1993 18. Williams B, Hattersley J, Layward E, Walls J: Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int 40:779-786, 1991 19. Stein A, Moorhouse J, Iles-Smith H, Baker R, Johnstone J, James G, Troughton J, Bircher G, Walls J: Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int 52:1089-1095, 1997 20. Lofberg E, Wernerman J, Anderstam B, Bergstrom J: Correction of metabolic acidosis in dialysis patients increases branched-chain and total essential amino acid levels in muscle. Clin Nephrol 48:230-237, 1997 21. Ballmer PE, McNurlan MA, Hulter HN, Anderson SE, Garlick PJ, Krapf R: Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 95:39-45, 1995 22. Mitch WE, Goldberg AL: Mechanisms of muscle wasting: The role of the ubiquitin-proteasome system. N Engl J Med 335:1897-1905, 1996
T
HERE HAS BEEN intensive interest in the nutritional state of patients with chronic renal failure (CRF) because of the excessive morbidity and high mortality of patients treated by dialysis and the link between a low serum albumin and the risk of death in dialysis patients.1,2 Several factors can contribute to the impaired nutritional status of patients with chronic uremia, including those who are being treated by dialysis. The first is an inadequate intake of calories and protein (Table 1). Dietary protein restriction is a time-honored method of improving the symptoms of uremia; the diets are effective therapeutically because they lead to reduced levels of uremic toxins, most of which result from the breakdown of protein. Consequently, a low-protein diet can ameliorate metabolic acidosis, renal osteodystrophy, hyperkalemia, and hypertension because the diets are restricted in sulfates, phosphates, potassium, and sodium. Although controversial, there also is evidence that low-protein diets can slow the progressive loss of renal function.3 Regardless, it is important to document that the dietary requirements are being achieved to treat patients successfully. The diet From the Renal Division, Emory University School of Medicine, Atlanta, GA. Received September 11, 1998; accepted in revised form September 14, 1998. Address reprint requests to William E. Mitch, MD, Emory University Renal Division, 338 WMB/1639 Pierce Dr, Atlanta, GA 30322. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3301-0030$3.00/0 176
must contain the required amounts of protein and calories, because an inadequate diet can jeopardize a patient’s nutritional status. DIETARY REQUIREMENTS OF CHRONICALLY UREMIC PATIENTS
Careful nitrogen balance studies by Kopple and Coburn4 showed that patients with CRF in the predialysis stage of their disease have the same minimal daily requirement for protein (0.6 g/kg/d) as normal adults.4 An assessment of the adequacy of the diet and nutritional status is needed regularly and includes periodic estimates of protein intake5 plus measurements of weight, mid-arm muscle circumference, and serum proteins.6 With this type of monitoring, low-protein diets are nutritionally sound in CRF patients without complicating diseases. This conclusion is consistent with results from the Modification of Diet in Renal Disease Study.7 In an analysis of the nutritional status of patients in that study, it was found that anthropometric measurements scarcely changed while serum albumin values actually increased in patients eating the lowprotein diets. It is known that excessive dietary protein increases the degree of proteinuria and that dietary protein restriction can reduce the degree of proteinuria.8 However, the protein requirements of patients with the nephrotic syndrome have not been examined as extensively. Recently, Maroni et al9 measured the nitrogen balance of patients with the nephrotic syndrome while they ate 0.8 g protein/kg/d plus 1 g protein for each gram lost
American Journal of Kidney Diseases, Vol 33, No 1 (January), 1999: pp 176-179
MALNUTRITION IN CHRONIC UREMIA
177
Table 1. Dietary Requirements of Patients With Chronic Kidney Disease
Healthy adults CRF patients Nephrotic patients Hemodialysis patients CAPD patients
Protein (g/kg/d)
Calories* (kcal/kg/d)
0.6 0.6 0.6 1.0 1.2
30-35 30-35 30-35 30-35 30-35
*Energy requirement may be increased depending on activity level. Abbreviations: CRF, chronic renal failure; CAPD, continuous ambulatory peritoneal dialysis.
in the urine.9 Nitrogen balance was uniformly positive, and serum albumin was unchanged. These results indicate that dietary protein restriction can be used safely if nephrotic patients are monitored carefully. The protein requirement for patients being treated by dialysis is even higher: For hemodialysis patients, it is 1 g protein/kg/d, whereas for continuous ambulatory peritoneal dialysis (CAPD) patients, it is 1.2 g protein/kg/d.10,11 The protein requirements for hemodialysis patients is high in part because there are losses of amino acids, plus the dialysis procedure itself may be catabolic.1 During CAPD, there is loss of protein as well as amino acids, accounting in part for the increased protein requirement. Note that the amount of protein lost cannot be replaced by an equivalent amount of dietary protein because protein lost in the nephrotic syndrome or by CAPD patients (ie, protein synthesis) does not occur with 100% efficiency. Dietary protein cannot be considered in isolation, however, because it also is important that adequate calories are consumed (Table 1). An adequate calorie supply is critical for CRF patients who are eating proteinrestricted diets as well as those being treated by dialysis.6,12 FACTORS IMPAIRING THE NUTRITIONAL STATUS
If protein and calorie requirements are not provided in the diet, patients are at risk for losing protein stores. The mechanism underlying loss of protein stores is unclear, but there are important adaptive responses that occur whenever nitrogen intake is limited (Table 2). Normal subjects fed a low-protein diet activate the following adaptive
mechanisms to promote neutral nitrogen balance: (1) As dietary protein is reduced, there is a reduction in amino acid oxidation allowing more efficient utilization of dietary essential amino acids; (2) when dietary protein approaches 0.6 g/kg/d, another response is activated and protein degradation is suppressed, especially in response to a meal. In the latter case, there often is an increase in protein synthesis but the magnitude of this response is less than the limitation in protein degradation.13 It is clear that patients with uncomplicated CRF can activate the same metabolic responses to dietary protein restriction, even when the patients are eating only approximately 0.3 g protein/kg/d plus a supplement of ketoacids.13 Recently, Maroni et al9 showed that these responses are also activated in CRF patients with the nephrotic syndrome9; in this case, the results are even more fascinating. The adaptive decrease in amino acid oxidation was determined by the net amount of protein eaten (ie, the difference between protein intake and urinary protein losses); the degree of suppression of amino acid oxidation was greatest in those with the least net protein intake. Ultimately, this adaptive response yields more efficient utilization of dietary protein. Even though these adaptive responses are intact in patients with CRF, at least in the predialyTable 2. Metabolic Adaptations to Dietary Protein Restriction
Response
Suppression of amino acid oxidation
Suppression of protein degradation
Stimulation of protein synthesis
Determinants of the Response
Related to the amount of dietary protein as well as with urinary protein losses Activated if dietary protein is below the minimum daily requirement; also activated by feeding
Increased by feeding
Benefit
Promotes the utilization of dietary essential amino acids
1) Minimizes loss of lean body mass when dietary protein intake inadequate 2) Promotes anabolism during feeding Replaces protein lost during fasting
178
MITCH AND MARONI
Table 3. Factors Impairing Nutritional Status of Patients With Chronic Renal Failure Condition
Anorexia Metabolic acidosis Infection/Inflammatory illness Diabetes
Mechanism
Inadequate protein or calorie intake Stimulation of amino acid and protein degradation Stimulation of protein degradation Stimulation of protein degradation and suppression of protein synthesis
sis phase of their disease (the responses have not been assessed in dialysis patients), an inadequate intake of protein and calories will impair the nutritional status (Table 3). This is important because CRF patients can develop anorexia. The causes of anorexia in uremia have been largely unexplored, although there are a number of potential causes (Table 4). Recently, Anderstam et al14 used a rodent model to assess the spontaneous food intake and determined that substances in the plasma of uremic patients can suppress appetite. Attempts to determine the chemical composition of this factor(s) indicate that it probably falls in the ‘‘middle molecule’’ size and may be a peptide. Clearly, isolation and characterization of these compounds will be a very important step toward understanding one of the major complications of uremia. Other factors in chronic uremia impair nutritional responses. Metabolic acidosis impairs the adaptive metabolic responses in two ways: it stimulates the degradation of the essential, branched-chain amino acids and the degradation Table 4. Potential Cause of Anorexia in Chronic Uremia Accumulation of an ‘‘anorectic factor’’ Gastropathy–enteropathy in diabetes Inflammation, infection Medications Psychosocial factors: Depression, poverty, alcohol/ drugs Hemodialysis Cardiovascular instability Postdialysis fatigue Peritoneal dialysis Abdominal distension Absorption glucose Peritonitis
of protein in muscle.15,16 Mechanisms for these catabolic responses to acidosis involve stimulation of the rate-limiting enzyme in branchedchain amino acid degradation, branched-chain ketoacid dehydrogenase, and activation of the ubiquitin-proteasome pathway. Although these catabolic changes were initially described in rats, they have been confirmed in normal subjects and CRF patients, including those eating a lowprotein diet.17-20 Metabolic acidosis also suppresses albumin synthesis.21 In short, metabolic acidosis blocks the ability of CRF patients to adapt to a low-protein diet. Infections or other inflammatory illnesses and poorly controlled diabetes mellitus also activate the ubiquitin-proteasome pathway, causing accelerated protein degradation in muscle.22 These factors contribute to the catabolic effects of chronic kidney disease. In summary, the dietary requirements for patients with CRF uncomplicated by metabolic acidosis or a catabolic illness are known. Anorexia or problems associated with dialysis can limit the ability of a patient to achieve the proper dietary intake. If the intake is sufficient, then patients with chronic renal disease will activate adaptive metabolic responses to maintain nitrogen balance and protein stores. At least one catabolic condition that impairs the ability of CRF patients to activate these responses is metabolic acidosis, but there could be other problems, including infections. Research is needed to uncover the mechanisms causing anorexia and those impairing adaptive metabolic responses. Another major advance will occur when we understand the mechanisms underlying the adaptive responses because activation of these responses could improve the nutritional status of patients with kidney diseases and other catabolic illnesses. REFERENCES 1. Bergstrom J: Nutrition and mortality in hemodialysis. J Am Soc Nephrol 6:1329-1341, 1995 2. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of the death rate differences among facilities. Am J Kidney Dis 15:458-482, 1990 3. Maroni BJ, Mitch WE: Role of nutrition in prevention of the progression of renal disease. Annu Rev Nutr 17:435455, 1997 4. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia: I. Nitrogen and potassium. Medicine 52:583-594, 1973
MALNUTRITION IN CHRONIC UREMIA
5. Maroni BJ, Steinman T, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27:58-65, 1985 6. Maroni BJ: Requirements for protein, calories, and fat in the predialysis patient, in Mitch WE, Klahr S (eds): Nutrition and the Kidney (ed 2). Boston, MA, Little, Brown, 1993, pp 185-212 7. Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman J, Hollinger DL, Maroni BJ, Merrill D, Scherch LK, Shulman G, Wang SR, Zimmer GS: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease (MDRD) Study. Kidney Int 52:778-791, 1997 8. Kaysen GA, Gambertoglio J, Jimenez I, Jones H, Hutchison FN: Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int 29:572-577, 1986 9. Maroni BJ, Staffeld C, Young VR, Manatunga A, Tom K: Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet. J Clin Invest 99:2479-2487, 1997 10. Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, Wolfson M, Humphreys MH: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 14:491-500, 1978 11. Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW: Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis. Kidney Int 21:849-861, 1982 12. Monteon FJ, Laidlaw SA, Shaib JK, Kopple JD: Energy expenditure in patients with chronic renal failure. Kidney Int 30:741-747, 1986 13. Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: Protein and amino acid metabolism. Semin Nephrol 14:232-237, 1994
179
14. Anderstam B, Mamoun A-H, Bergstrom J, Sodersten P: Middle-sized molecule fractions isolated from uremic ultrafiltrate and normal urine inhibit ingestive behavior in the rat. J Am Soc Nephrol 7:2453-2460, 1996 15. Hara Y, May RC, Kelly RA, Mitch WE: Acidosis, not azotemia, stimulates branched-chain amino acid catabolism in uremic rats. Kidney Int 32:808-814, 1987 16. Bailey JL, Wang X, England BK, Price SR, Ding X, Mitch WE: The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent, ubiquitinproteasome pathway. J Clin Invest 97:1447-1453, 1996 17. Reaich D, Channon SM, Scrimgeour CM, Daley SE, Wilkinson R, Goodship THJ: Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 265:E230-E235, 1993 18. Williams B, Hattersley J, Layward E, Walls J: Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int 40:779-786, 1991 19. Stein A, Moorhouse J, Iles-Smith H, Baker R, Johnstone J, James G, Troughton J, Bircher G, Walls J: Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int 52:1089-1095, 1997 20. Lofberg E, Wernerman J, Anderstam B, Bergstrom J: Correction of metabolic acidosis in dialysis patients increases branched-chain and total essential amino acid levels in muscle. Clin Nephrol 48:230-237, 1997 21. Ballmer PE, McNurlan MA, Hulter HN, Anderson SE, Garlick PJ, Krapf R: Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 95:39-45, 1995 22. Mitch WE, Goldberg AL: Mechanisms of muscle wasting: The role of the ubiquitin-proteasome system. N Engl J Med 335:1897-1905, 1996