Relationship between nutritional status and the glomerular filtration rate: results from the MDRD study.

BACKGROUND: The relationship between the protein-energy nutritional status and renal function was assessed in 1785 clinically stable patients with moderate to advanced chronic renal failure who were evaluated during the baseline phase of the Modification of Diet in Renal Disease Study. Their mean +/- SD glomerular filtration rate (GFR) was 39.8 +/- 21.1 mL/min/1.73 m2. METHODS: The GFR was determined by 121I-iothalamate clearance and was correlated with dietary and nutritional parameters estimated from diet records, biochemistry measurements, and anthropometry. RESULTS: The following parameters correlated directly with the GFR in both men and women: dietary protein intake estimated from the urea nitrogen appearance, dietary protein and energy intake estimated from dietary diaries, serum albumin, transferrin, percentage body fat, skinfold thickness, and urine creatinine excretion. Serum total cholesterol, actual and relative body weights, body mass index, and arm muscle area also correlated with the GFR in men. The relationships generally persisted after statistically controlling for reported efforts to restrict diets. Compared with patients with GFR > 37 mL/min/1.73 m2, the means of several nutritional parameters were significantly lower for GFR between 21 and 37 mL/min/1.73 m2, and lower still for GFRs under 21 mL/min/1.73 m2. In multivariable regression analyses, the association of GFR with several of the anthropometric and biochemical nutritional parameters was either attenuated or eliminated completely after controlling for protein and energy intakes, which were themselves strongly associated with many of the nutritional parameters. On the other hand, few patients showed evidence for actual protein-energy malnutrition. CONCLUSIONS: These cross-sectional findings suggest that in patients with chronic renal disease, dietary protein and energy intakes and serum and anthropometric measures of protein-energy nutritional status progressively decline as the GFR decreases. The reduced protein and energy intakes, as GFR falls, may contribute to the decline in many of the nutritional measures.

Factors causing malnutrition in patients with chronic uremia.

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.

The hemodialysis pilot study: nutrition program and participant characteristics at baseline. The HEMO Study Group.

OBJECTIVE: Describe the nutrition program (assessments and interventions) and the participants' baseline nutritional characteristics in the Hemodialysis Pilot Study. DESIGN: Cross sectional survey in which hemodialysis patients were examined during 10 weeks of baseline (BL), before randomization study interventions (dose and flux). SETTING: Four hemodialysis centers (eight dialysis units in total). PATIENTS: Twenty-nine male (mean age, 63 years; range, 34 to 75) and 20 female (mean age, 61 years; range, 29 to 73) hemodialysis patients. INTERVENTIONS: None during BL. MAIN OUTCOME MEASURES: Feasibility of implementing the proposed nutrition program before conducting the full-scale trial, and description of baseline characteristics related to nutrition. RESULTS: A nutrition program was developed to assess nutritional status during BL and follow-up periods and to intervene in patients with weight loss or decreasing serum albumin. Methods for collecting biochemical, dietary and anthropometric data were implemented at four clinical centers. At baseline, mean protein intake estimated by single pool normalized protein catabolic rate was 0.95 +/- 0.21 gm/kg adjusted body weight (ABW) (n = 42) and by diet record assisted recalls (n = 47) 0.94 +/- 0.36 gm/kg ABW/d, respectively. Mean energy intake was 22.8 +/- 8 kcal/kg ABW/day (n = 39). Mean serum albumin concentration using the bromcresol green method was 3.8 +/- 0.4 gm/dL (n = 40). Mean body mass index was within the normal limits of 19-27 kg/m2. Mean skinfold thicknesses in females, but not males, were shifted toward the lower end of usual distributions for healthy individuals. CONCLUSIONS: The goal of designing, developing, and implementing the diet and nutrition component, and related data collection for the HEMO pilot study was accomplished at four separate clinical centers. Baseline mean protein and energy intake were low, suggesting that continuing dietary surveillance is needed. The ongoing full-scale HEMO study will provide the first prospective analysis of dietary intake, nutritional status, and outcome in maintenance hemodialysis patients as a function of dialysis dose and membrane flux.

Nutritional considerations in the treatment of patients with chronic uremia.

Low-protein diets ameliorate uremic symptoms and some of its metabolic complications. These diets can be used successfully to treat patients with chronic renal failure (CRF) because they are able to activate normal compensatory responses when protein intake is restricted and their protein and energy requirements are similar to healthy subjects. However, there has been concern that dietary therapy compromises the nutritional status of CRF patients and that initiating dialysis would be preferable to this type of therapy. Kopple and co-workers have identified the requirements of CRF patients for protein and calories and available evidence indicates that when properly implemented, low-protein diets are safe and can maintain lean body mass even during long-term therapy. Based on the information published by Kopple and co-workers, the strategies for treating CRF patients should include careful analysis of the diet and the nutritional status of the patient.

Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism.

Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.

Nutritional considerations and the indications for dialysis.

Evidence of a reduction in dietary protein intake and some indices of nutritional status in chronic renal failure (CRF) patients consuming unrestricted diets has led some individuals to recommend that low-protein diets be avoided and that dialysis should be initiated if the protein intake declines below 0.8 g protein/kg/day. However, evidence indicates that when properly implemented, low-protein diets are safe and can maintain lean body mass even during long-term therapy. This is because CRF patients are able to activate normal compensatory responses when protein intake is restricted, and their protein and energy requirements are similar to healthy subjects. Because low-protein diets ameliorate uremic symptoms and some of its metabolic complications, dietary therapy should be attempted in all patients with progressive CRF. The recommendation to initiate dialysis when the protein intake declines below 0.8 g/kg/day should be viewed with skepticism because mortality risk is increased in end-stage renal disease (ESRD) patients and dialysis therapy does not improve protein and energy intake or ameliorate malnutrition.

Protein restriction in the pre-end-stage renal disease (ESRD) patient: who, when, how, and the effect on subsequent ESRD outcome.

The protein and energy requirements of patients with chronic renal failure are similar to those of healthy subjects, and evidence indicates that both nephrotic and nonnephrotic chronic renal failure patients can activate normal homeostatic responses allowing them to maintain lean body mass when dietary protein intake is restricted. The benefits of low protein (and phosphorus) diets include the amelioration of uremic symptoms and some of its metabolic complications, and possibly slowing the rate of progression of renal failure. Moreover, there is no evidence that the use of low protein diets (LPD) in the predialysis period results in worse outcomes once dialysis is initiated. When LPD are prescribed, patients should be monitored to assess dietary compliance and to ensure nutritional adequacy. Recent evidence that nutritional indices of patients with progressive chronic renal failure declines when they consume unrestricted diets should not be interpreted as justification against the use of LPD. Rather, it is a compelling argument to institute dietary therapy to minimize complications of renal failure while maintaining nutritional status. Finally, the use of LPD is compatible with "timely" initiation of dialysis in accordance with recommended guidelines.

Impact of chronic renal failure on nitrogen metabolism.

Evidence indicates that both nephrotic and nonnephrotic chronic renal failure (CRF) patients can activate normal compensatory responses when dietary protein intake is restricted and that their protein and energy requirements are similar to normal subjects. When properly implemented, low-protein diets are safe and the benefits include the amelioration of uremic symptoms and some of their metabolic complications and possibly a reduction in the rate of progression of renal failure. To ensure dietary adequacy and compliance, patients should be monitored when treated with low-protein diets. Recent evidence that the protein intake of patients with progressive CRF declines when they consume unrestricted diets should not be considered as an argument against the use of low-protein diets. Rather, it is a persuasive argument in favor of restricting dietary protein intake to minimize the complications of renal failure.

Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study.

The safety of dietary protein and phosphorous restriction was evaluated in the Modification of Diet in Renal Disease (MDRD) Study. In Study A, 585 patients with a glomerular filtration rate (GFR) of 25 to 55 ml/min/1.73 m2 were randomly assigned to a usual-protein diet (1.3 g/kg/day) or a low-protein diet (0.58 g/kg/day). In Study B, 255 patients with a GFR of 13 to 24 ml/min/1.73 m2 were randomly assigned to the low-protein diet or a very-low-protein diet (0.28 g/kg/day), supplemented with a ketoacid-amino acid mixture (0.28 g/kg/day). The low-protein and very-low-protein diets were also low in phosphorus. Mean duration of follow-up was 2.2 years in both studies. Protein and energy intakes were lower in the low-protein and very-low-protein diet groups than in the usual-protein group. Two patients in Study B reached a "stop point" for malnutrition. There was no difference between randomized groups in the rates of death, first hospitalizations, or other "stop points" in either study. Mean values for various indices of nutritional status remained within the normal range during follow-up in each diet group. However, there were small but significant changes from baseline in some nutritional indices, and differences between the randomized groups in some of these changes. In the low-protein and very-low-protein diet groups, serum albumin rose, while serum transferrin, body wt, percent body fat, arm muscle area and urine creatinine excretion declined. Combining patients in both diet groups in each study, a lower achieved protein intake (from food and supplement) was not correlated with a higher rate of death, hospitalization or stop points, or with a progressive decline in any of the indices of nutritional status after controlling for baseline nutritional status and follow-up energy intake. These analyses suggest that the low-protein and very-low-protein diets used in the MDRD Study are safe for periods of two to three years. Nonetheless, both protein and energy intake declined and there were small but significant declines in various indices of nutritional status. These declines are of concern because of the adverse effect of protein calorie malnutrition in patients with end-stage renal disease. Physicians who prescribe low-protein diets must carefully monitor patients' protein and energy intake and nutritional status.

Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet.

UNLABELLED: Clinical experience suggests nephrotic patients are at risk for malnutrition. To determine if nephrotic patients can adapt successfully to a protein-restricted diet, nephrotic (glomerular filtration rate, 52+/-15 ml/min; urinary protein [Uprot.], 7.2+/-2.2 grams/d) and control subjects completed a crossover comparison of diets providing 0.8 or 1.6 grams protein (plus 1 gram protein/gram Uprot.) and 35 kcal per kg per day. Nitrogen balance (BN) was determined and whole body protein turnover measured during fasting and feeding using intravenous -[1-13C]leucine and intragastric -[5,5, 5- 2H3]leucine. BN was positive in both nephrotic and control subjects consuming either diet and rates of whole-body protein synthesis, protein degradation, and leucine oxidation did not differ between groups. In both nephrotic and control subjects anabolism was due to a suppression of whole-body protein degradation and stimulation of protein synthesis during feeding. The principal compensatory response to dietary protein restriction was a decrease in amino acid oxidation and this response was the same in both groups. With the low protein diet leucine oxidation rates during feeding correlated inversely with Uprot. losses (r = -0.83; P < 0. 05). CONCLUSIONS: (a) a diet providing 0.8 gram protein (plus 1 gram protein/gram Uprot.) and 35 kcal per kg per day maintains BN in nephrotic patients; (b) nephrotic patients activate normal anabolic responses to dietary protein restriction (suppression of amino acid oxidation) and feeding (stimulation of protein synthesis and inhibition of protein degradation); (c) the inverse correlation between leucine oxidation and Uprot. losses suggests that proteinuria is a stimulus to conserve dietary essential amino acids.

Role of nutrition in prevention of the progression of renal disease.

In rats with renal disease, low-protein diets slow the decline in renal function, histologic damage, and mortality. Low-protein (and phosphorus) diets can also ameliorate uremic symptoms, secondary hyperparathyroidism, and metabolic acidosis in patients with chronic renal failure. Albeit controversial, evidence also suggests that dietary protein restriction can slow the rate of progression of renal failure and the time until end-stage renal failure. These dietary regimens appear to be safe and patients with chronic renal failure are able to activate normal compensatory mechanisms designed to conserve lean body mass when dietary protein intake is restricted. When low-protein diets are prescribed, patients should be closely monitored to assess dietary compliance and to ensure nutritional adequacy. Evidence that the spontaneous intake of dietary protein decreases in patients with progressive chronic renal failure who consume unrestricted diets should not be construed as an argument against the use of low-protein diets. Rather, it is a persuasive argument to restrict dietary protein intake in order to minimize complications of renal failure while preserving nutritional status.

Protein restriction and malnutrition in renal disease: fact or fiction?

The protein and energy requirements of chronic renal failure (CRF) patients are similar to normal subjects and evidence indicates that both nephrotic and nonnephrotic CRF patients can activate normal homeostatic responses allowing them to achieve a neutral nitrogen balance when dietary protein intake is restricted. The benefits of low-protein (and phosphorus) diets (LPDs) include the amelioration of uremia symptoms and some of its metabolic complications and possibly a slowing of the rate of progression of renal failure. When LPDs are prescribed, patients should be monitored to assess dietary compliance and to ensure nutritional adequacy. Recent evidence that the protein intake of patients with progressive CRF decreases when they consume unrestricted diets should not be interpreted as an argument against the use of LPDs. Rather, it is a persuasive argument to restrict dietary protein intake in order to minimize complications of renal failure while maintaining nutritional status.

How is lean body mass conserved with the very-low protein diet regimen?

Eight CRF patients (GFR = 18.8 +/- 2.7 ml/min) underwent a crossover comparison of a very-low-protein diet (VLPD) providing 0.28 g protein and 35 kcal/kg/day, plus an isomolar mixture of ketoacids (KA) or essential amino acids (EAA). During each dietary period, a 5-day nitrogen balance (BN) was performed and whole-body protein turnover (WBPT) was measured during fasting and feeding using intravenous [1-13C]leucine and intragastric [5,5,5-2H3]leucine. Although the VLPD/KA regimen contained 15% less nitrogen, BN was neutral and did not differ between the regimens. Similarly, rates of WBPT did not differ between the KA or EAA regimens, and neutral BN was achieved by a marked suppression of amino acid oxidation and postprandial inhibition of protein degradation (PD). Participants were then discharged on the VLPD/KA regimen and monitored as outpatients for > or = 1 year. Repeat BN was neutral and rates of WBPT did not differ from baseline values. Thus, the adaptive responses to dietary protein restriction are sustained during long-term therapy.

Long-term adaptive responses to dietary protein restriction in chronic renal failure.

Six patients with chronic renal failure (glomerular filtration rate 18 +/- 2 ml/min) underwent two 10-day admissions separated by at least 1 yr of outpatient therapy with a very low-protein diet (VLPD) providing 0.28 g protein.kg-1.day-1 plus an amino acid-ketoacid supplement. During each Clinical Research Center admission, subjects completed a 5-day nitrogen balance (BN), and whole body protein turnover was measured during fasting and feeding using intravenous [1-13C]leucine and intragastric [5,5,5-2H3]leucine. Outpatient dietary protein compliance was very good (25 vs. 20 g protein/day or 125% goal), whereas energy intake was only 69% of goal (24 vs. 35 kcal.kg-1.day-1). During the 16 +/- 2 mo of dietary therapy, there were no changes in serum proteins or anthropometrics. BN after > or = 1 yr of dietary therapy was neutral and did not differ from initial values (+0.46 +/- 0.20 vs. +0.55 +/- 0.19 g N/day). Similarly, rates of whole body protein synthesis, degradation, and leucine oxidation after long-term therapy with the VLPD regimen did not differ from baseline values, and neutral BN was maintained by a marked suppression of amino acid oxidation and postprandial inhibition of protein degradation. This is the first evidence that the compensatory changes in whole body protein turnover activated in response to dietary protein restriction are sustained during long-term therapy.

Adaptive responses to very low protein diets: the first comparison of ketoacids to essential amino acids.

Eight patients with chronic renal failure (GFR 18.8 +/- 2.7 ml/min) were randomized to a crossover comparison of a very low protein diet (VLPD) containing 0.28 g protein and 35 kcal per kg per day, plus an isosmolar mixture of either ketoacids (KA) or essential amino acids (EAA). Subjects initiated the diets 14 days before hospital admission and following a four-day equilibration, a five-day nitrogen balance (BN) was performed. Whole-body protein turnover (WBPT) was measured during fasting and feeding using intravenous [1-13C]leucine and intragastric [5,5,5-2H3]leucine. Even though the VLPD/KA regimen contained 15% less nitrogen, BN was neutral and did not differ between the regimens. Nitrogen conservation with KA was due to a reduction in urea nitrogen appearance. Rates of WBPT measured during fasting and feeding did not differ between the KA or EAA regimens. During both regimens, feeding decreased protein degradation, whereas protein synthesis was unchanged. Although feeding stimulated leucine oxidation, rates were 50 to 100% lower than reported in CRF patients consuming 0.6 or 1.0 g protein/kg/day. Thus, neutral Bn with the VLPD regimen is achieved by a marked reduction in amino acid oxidation and a postprandial inhibition of protein degradation.

Metabolic responses to nephrosis: effect of a low-protein diet.

To determine whether dietary protein restriction (LPD) causes protein catabolism in adriamycin nephrosis, nephrotic and control rats were paired by weight and gavage fed an 8.5% protein diet for 3 days (protocol 1) or 12 days (protocol 2). Fasting whole body protein turnover was then measured using a constant infusion of L-[1-14C]leucine. After 3 days of LPD, proteinuria decreased slightly and body weight did not change in either group. In contrast, leucine oxidation and urinary urea nitrogen excretion in nephrotic rats decreased by 18% and 37%, respectively (P < or = 0.05). After 12 days of LPD, weight loss did not differ between groups. In contrast to protocol 1, proteinuria decreased by 45% in nephrotic rats fed LPD for 12 days, and leucine oxidation rats increased to the level of control rats. Rates of whole body protein synthesis (PS) and degradation (PD) did not differ between nephrotic and control rats receiving LPD for 3 or 12 days, but were significantly lower than rates measured in rats fed 22% protein. We conclude that 1) proteinuria stimulates protein conservation even when dietary protein intake is restricted; 2) the decrease in amino acid oxidation was dependent on moderate proteinuria, since prolonged LPD ameliorated nephrosis and leucine oxidation rates increased to control levels; and 3) since weight loss and rates of whole body PS and PD in nephrotic and control animals were indistinguishable, moderate proteinuria did not increase protein catabolism.

Vancomycin redistribution: dosing recommendations following high-flux hemodialysis.

Although increased vancomycin clearance has been reported with highly permeable hemodialysis membranes (such as polysulfone), failure to consider post-dialysis redistribution could lead to unnecessary dosage supplementation. In protocol 1, twelve hemodialysis patients admitted for vascular access thrombectomy received 15 mg/kg of vancomycin as surgical prophylaxis. Post-operatively, patients underwent high-flux hemodialysis (HFHD) for two hours using a Fresenius F-80 polysulfone dialyzer (QB = 417 +/- 49, QD = 800 ml/min). Vancomycin's intradialytic clearance increased 13-fold compared to the patient's endogenous clearance (120 +/- 59 vs. 9 +/- 8 ml/min, respectively) yet dialysate recovery indicated that only 17% of body stores were removed (179 +/- 70 mg). Although serum vancomycin levels decreased 33% during HFHD, vancomycin levels increased in all patients following dialysis and the post-rebound values reached 87% of the pre-dialysis concentration. In protocol 2, eight outpatients receiving maintenance HFHD with a F-80 dialyzer (Kt/V = 1.29 +/- 0.08) were given 20 mg/kg of vancomycin immediately following dialysis on Monday; pre- and post-levels were measured during the next three dialysis treatments. The predialysis serum vancomycin levels were > 7.5 micrograms/ml (9.7 +/- 1.0 micrograms/ml; range 8.0 to 11.0) in all patients the following Monday. Thus, vancomycin clearance is increased during HFHD, but redistribution post-HD minimizes changes in serum levels. We recommend a 20 mg/kg i.v. loading dose and subsequent doses of 15 mg/kg every seven days; to account for individual variability, weekly vancomycin levels should be drawn before dialysis.

Mechanisms of adaptation to proteinuria in adriamycin nephrosis.

To evaluate the impact of urinary protein losses on whole body protein turnover (WBPT) independent of acidosis or uremia, we utilized a model of unilateral adriamycin nephrosis. Control rats were matched by weight to nephrotic rats and pair fed 22% protein chow for 14-18 days; urinary urea nitrogen (UUN) was measured on day 12, and leucine turnover measurement was performed on the final day. Growth rates of nephrotic and pair-fed control rats did not differ during the first 2 wk of pair feeding; thereafter, a small difference in growth could be detected. Despite an identical intake of dietary protein, UUN excretion was 29% less in the nephrotic rats (P < or = 0.02). Fasting whole body protein synthesis and degradation did not differ between nephrotic and control rats; in contrast, leucine oxidation decreased by 21% in nephrosis (P < 0.05). On the basis of near normal growth and normal rates of WBPT, we conclude that nephrotic rats fed ad libitum can adapt to the stress of continuous protein losses. A reduction in amino acid oxidation and UUN excretion were the primary mechanisms responsible for protein conservation in experimental nephrosis.