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This paper discusses two of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for nutrition in chronic renal failure. These are the guidelines that recommend a dietary protein intake of 1.2 g protein/kg body weight/day for clinically stable maintenance hemodialysis (MHD) patients (Guideline 15) and 1.2 to 1.3 g protein/kg/day for clinically stable chronic peritoneal dialysis (CPD) patients (Guideline 16). These recommended protein intakes are greater than the usually ingested protein intakes of MHD and CPD patients and are also greater than the recommended protein intakes for healthy, nonpregnant, nonlactating adults. The possible mechanisms that engender these increased protein needs include (1) the substantial quantity of amino acids, peptides, and proteins removed by the dialysis procedure and (2) the protein catabolic or antianabolic state caused by the uremic milieu, the inflammatory state, the oxidative and carbonyl stress, and the bioincompatible dialysis materials to which MHD and CPD patients are exposed. There are a number of nitrogen balance studies that have been performed to identify the dietary protein needs of MHD and CPD patents. The results of this research as well as some of the methodological limitations of these studies are reviewed. The concepts of the average dietary protein intake required to maintain protein balance in MHD or CPD patients and the safe protein intake that will maintain protein balance in virtually all MHD and CPD patients are discussed.

Individuals with chronic renal failure (CRF) have a high prevalence of protein-energy malnutrition. There are many causes for this condition, chief among which is probably reduced nutrient intake from anorexia. In nondialyzed patients with CRF, energy intake is often below the recommended amounts; in maintenance dialysis patients, both dietary protein and energy intake are often below their needs. Although a number of studies indicate that rats with CRF have increased protein catabolism in comparison to control animals, more recent evidence suggests that increased catabolism in CRF rats is largely if not entirely due to acidemia, particularly if these animals are compared to pair-fed control rats. Studies in humans with advanced CRF also indicate that acidemia can cause protein catabolism. Indeed, nitrogen balance studies and amino acid uptake and release and isotopic kinetic studies indicate that in nondialyzed individuals with CRF, who are not acidemic, both their ability to conserve body protein when they ingest low protein diets and their dietary protein requirements appear to be normal. For patients undergoing maintenance hemodialysis or chronic peritoneal dialysis, dietary protein requirements appear to be increased. The increased need for protein is due, in part, to the losses into dialysate of such biologically valuable nitrogenous compounds as amino acids, peptides, and proteins. However, the sum of the dietary protein needs for CRF patients (of about 0.60 g/kg/day) and the dialysis losses of amino acids, peptides and proteins do not equal the apparent dietary protein requirements for most maintenance dialysis patients. This discrepancy may be due to a chronic state of catabolism in the clinically stable maintenance dialysis patient that is not present in the clinically stable nondialyzed individual who has advanced CRF. Possible causes for such a low grade catabolic state include resistance to anabolic hormones (for example, insulin, IGF-1) and a chronic inflammatory state associated with increased levels of pro-inflammatory cytokines.

The published reports of dietary protein and energy intake and protein and energy requirements for maintenance hemodialysis (MHD) patients and chronic peritoneal dialysis (CPD) patients are reviewed. Evidence indicates that the dietary energy intake of patients undergoing MHD or continuous ambulatory peritoneal dialysis (CAPD) is less than normal. Dietary protein intake in various surveys averages approximately 1.0 g/kg/d. The energy expenditure of MHD patients appears to be normal or slightly increased during resting and normal during various other daily activities. Energy expenditure in CAPD patients appears normal. Nitrogen balance and anthropometric studies in MHD or CAPD patients ingesting controlled diets in a metabolic unit research ward also indicate that dietary energy requirements are normal and are approximately 35 to 38 kcal/kg/d in MHD patients. For CAPD patients, total energy requirements (from diet and dialysate) also appear to be 35 to 38 kcal/kg/d. These recommended energy intakes are for adult patients aged approximately 60 years or younger. Thus, the low dietary energy intakes of MHD and CPD patients are maladaptive. Nitrogen balance studies indicate that a safe dietary allowance for protein is approximately 1.2 g/kg/d for MHD patients and 1.2 to 1.3 g/kg/d for CAPD patients. Because the nutritional status of patients at the onset of chronic dialysis therapy is a strong predictor of both their nutritional status during the course of chronic dialysis treatment and their subsequent morbidity and mortality, it is important to maintain good nutritional status in patients with chronic renal failure before their development of end-stage renal disease (ESRD) and establishment on chronic dialysis. Evidence indicates that there is a reduction in dietary protein and energy intake and a gradual deterioration of nutritional status in patients with chronic renal insufficiency as the glomerular filtration rate (GFR) decreases progressively to less than 50 to 60 mL/min/1.73 m2. More studies are needed to assess dietary protein and energy requirements both for MHD and CPD patients who are clinically stable and for those who have sustained comorbid conditions that increase energy expenditure or protein nitrogen appearance.

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.

This study was carried out to examine the mathematical relationships between the urea nitrogen appearance (UNA), total nitrogen appearance (TNA) and dietary nitrogen intake (DNI) in patients with chronic renal failure. Studies were conducted in 20 nondialyzed patients with advanced chronic renal failure (CRF) who were fed 27 constant protein diets for 24.8 +/- 9.5 days (SD) and eight patients undergoing continuous ambulatory peritoneal dialysis (CAPD), who ingested 13 constant protein diets for 20.3 +/- 4.9 days. All patients lived in a hospital research ward throughout the study and underwent full nitrogen balance measurements. Data were analyzed after patients attained equilibrium or near equilibrium with each dietary protein intake. In the CRF patients, using the mean values obtained during the equilibrium phase, there was a direct and precise correlation between the TNA and UNA, where TNA g/day = 1.19 UNA g/day + 1.27 g/day, r = 0.948. The correlation between DNI and UNA was also highly significant, but less precise, with somewhat greater 95% confidence intervals: DNI g/day = 1.20 UNA g/day + 1.74 g/day, r = 0.865. The relationship between DNI and TNA was not much more precise: DNI g/day = 0.97 TNA g/day + 0.65 g/day, r = 0.880. With the CAPD patients, the relationships were as follows: TNA g/day = 0.94 UNA g/day + 5.54 g/day, r = 0.956; DNI g/day = 0.97 UNA g/day + 6.80 g/day, r = 0.705; DNI g/day = 1.07 TNA g/day + 0.63 g/day, r = 0.760. For the CAPD patients, the lowest 95% confidence intervals were also found for the correlation between TNA and UNA. Thus, in both CRF and CAPD patients, the TNA is highly and precisely correlated with the UNA. The DNI is also significantly correlated with UNA and TNA, but the relationship is less precise. In both of these two groups of patients, the difference between the regression equations for TNA versus UNA and DNI versus UNA was, to a substantial degree, accounted for by the intercept.

An increase in plasma insulin-like growth factor I (IGF-I) levels by growth hormone injection or IGF-I infusion can raise renal plasma flow and glomerular filtration rate. However, it is not known whether a more physiological stimulus for IGF-I will also increase IGF-I in the kidney and whether the increase in renal or serum IGF-I is correlated with the increase in renal plasma flow and glomerular filtration rate. Male rats were pair fed either a high-protein (36% protein, N = 9) or a low-protein but isocaloric diet (9% protein, N = 9) for 10 to 14 days. Renal plasma flow and glomerular filtration rate were then estimated by clearance measurements, and IGF-I was measured in extracted serum, liver, renal cortical tissue, and glomeruli. Body weight gain and combined kidney weight were higher in high-protein rats as compared with low-protein animals (0.86 +/- 0.02 SEM versus 0.77 +/- 0.02 g/100 g body wt; P less than 0.05), but liver weights were not different. Serum, liver, and glomerular IGF-I levels were also higher in the high-protein rats as compared with the low-protein animals (serum, 1.12 +/- 0.03 versus 0.80 +/- 0.06 U/mL, P less than 0.05; liver, 183 +/- 17 versus 117 +/- 16 mU/g wet wt, P less than 0.05; glomeruli, 7.43 +/- 0.73 versus 4.81 +/- 0.59 mU/mg of protein, P less than 0.05). In contrast, the renal cortical IGF-I levels were not different in high-protein versus low-protein rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The rates of histidine degradation were investigated in six normal and three chronically uremic men who were not undergoing dialysis therapy. The nine men were studied in the postabsorptive state after they had ingested one or more of the following diets for the indicated periods of time: a 40 g protein diet providing about 1100 mg/day of histidine for 27 +/- 9 SD days (seven studies), an amino acid diet providing only 65 mg/day of histidine (histidine-deficient diet) for 33 +/- 3 days (eight studies), and an amino acid diet providing about 1125 mg/day of histidine (histidine-replete diet) for 32 +/- 7 days (six studies). Diets are listed in the order of administration; five men received all three diets. After fasting overnight, subjects received an intravenous injection of 25 microCi/70 kg body weight of L-[ring-2-14C]-histidine (eight men) or L-carboxyl-14C]-histidine (one man), and expiration of 14CO2 was measured continuously for 2 h. With both tracers, expiration of 14CO2 fell with ingestion of the histidine-deficient diet (p less than 0.005) and then increased with intake of the histidine-replete diet (p less than 0.05). Free histidine in plasma and muscle also decreased with the histidine-deficient diet and rose with the histidine-replete diet. If other tissue free histidine pools changed similarly and protein turnover was not very different with the three diets, then the 14CO2 expiration data and the estimated specific activity of 14C-histidine indicate that histidine degradation fell markedly with the histidine-deficient diet and then increased with the histidine-replete diet. In uremic patients as compared to normal subjects no differences in the magnitude of 14C-histidine degradation or in the pattern of 14CO2 expiration were observed.

Recent studies suggest that patients undergoing continuous ambulatory peritoneal dialysis (CAPD) may be prone to develop protein depletion. This paper reviews data concerning glucose uptake, protein and amino acid losses, and nitrogen and mineral balances in clinically stable adult CAPD patients. Approximately 70% of the glucose instilled with dialysate was absorbed, and the glucose absorbed provided approximately 8 kcal/kg/day to the patient. Serum total protein and albumin losses into dialysate averaged 8.8 +/- (SEM) 0.5 and 5.7 +/- 0.4 g/day, respectively. The quantity of free amino acids removed with dialysis was less, 3.4 +/- 0.3 g/day. The balance studies suggest that a safe dietary protein allowance for clinically stable CAPD patients who are ingesting high energy diets is 1.2 to 1.3 g/kg/day. Tentative dietary allowances for other nutrients in clinically stable CAPD patients are proposed.

Balance studies for nitrogen, potassium, magnesium, phosphorus, and calcium were carried out in eight men undergoing continuous ambulatory peritoneal dialysis (CAPD) to determine dietary protein requirements and mineral balances. Patients were fed high energy diets for 14 to 33 days which provided either 0.98 (seven studies) or 1.44 g (six studies) of primarily high biological value protein/kg body wt/day. Mean nitrogen balance was neutral with the lower protein diet (+0.35 +/- 0.83 SEM g/day) and strongly positive with the higher protein diet (+2.94 +/- 0.54 g/day). With the higher protein diet the balances for potassium, magnesium, and phosphorus were strikingly positive, there was an increase in body weight in all patients, and a rise in mid-arm muscle circumference in five of the six patients. The relation between protein intake and nitrogen balance suggests that the daily protein requirement for clinically stable CAPD patients should be at least 1.1 g/kg/day; to account for variability among subjects 1.2 to 1.3 g protein/kg/day is probably preferable. Potassium balance correlated directly with nitrogen balance (r = 0.81). High fecal potassium losses (19 +/- 1.2 mEq/day) in all patients probably helped maintain normal serum potassium concentrations. Mean serum magnesium was increased (3.1 +/- 0.1 mg/dl), and magnesium balances were positive suggesting that the dialysate magnesium of 1.85 mg/dl is excessive. The net gain of calcium from dialysate was 84 +/- 18 mg/day; this correlated inversely with serum calcium levels (r = -0.90).

Chronically uremic rats weighing approximately 180-200 g and sham-operated controls of similar weight were pair fed diets containing 5, 15 or 23% protein for 10-12 wk. At each level of protein intake, uremic animals gained less weight and had lower protein efficiency ratios than controls. In addition, certain plasma amino acid levels were altered in the uremic animals. These included tyrosine and the tyrosine/phenylalanine ratio, which were decreased, and citrulline, glycine, and the methylhistidines, which were increased. In both uremic and control rats, plasma concentrations of certain amino acids, primarily nonessential ones, varied inversely with protein intake; with the 5% protein diet, the ratio of essential to nonessential amino acids was significantly reduced. These observations indicate that both uremia and reduced protein intake may affect growth and amino acid metabolism in rats with chronic renal failure. The finding that uremic rats utilize protein less efficiently may indicate that marked reductions in protein intake may be particularly hazardous to the nutritional status of the uremic patient.

The mechanism by which keto-acid-supplemented diets may retard the progression of renal failure is not known. We examined whether the protective effect of keto acids may be independent of a low nitrogen intake. Azotemic subtotally nephrectomized Sprague-Dawley rats were pair-fed a 30% casein diet supplemented with a 10% keto acid mixture (n = 10) or 10% cornstarch (n = 10) for 18 weeks. No differences were observed between the two groups of rats with regard to survival, weight gain, plasma urea, blood pressure, albuminuria, or, at the termination of the study, PAH and inulin clearances. Creatinine clearances, measured weekly during the study, were transiently higher in the keto acid group. There was no difference in the incidence or severity of segmental glomerulosclerosis or tubular atrophy in the two groups. These results indicate that the keto acid mixture used did not exert a protective effect against glomerular sclerosis and progressive albuminuria in azotemic rats fed high-protein diets.

Dietary energy requirements were evaluated during 16 studies that were carried out in six clinically stable nondialyzed chronically uremic patients who lived in a clinical research center and were fed diets providing 45, 35, 25 or 15 kcal/kg/day. Each diet was fed for 23.7 +/- 5.7 SD days and provided about 0.55 to 0.60 g protein/kg/day. Nitrogen balance after equilibration and adjusted for changes in body urea nitrogen, and change in body weight each correlated directly with energy intake. Correcting for estimated unmeasured nitrogen losses of about 0.58 g/day, nitrogen balance was negative in one of four patients fed 45 kcal/kg/day, one of five patients receiving 35 kcal/kg/day, three of five patients ingesting 25 kcal/kg/day and both patients fed 15 kcal/kg/day. The urea nitrogen appearance (UNA), the UNA divided by nitrogen intake, and several plasma amino acids, determined after an overnight fast, each correlated inversely with dietary energy intake. Resting energy expenditure measured by indirect calorimetry did not differ from normal and averaged 0.012 +/- 0.0033 kcal/kg/min with the different diets. These observations suggest that although some clinically stable nondialyzed chronically uremic patients ingesting 0.55 to 0.60 g protein/kg/day may maintain nitrogen balance with energy intakes below 30 kcal/kg/day, a dietary intake providing approximately 35 kcal/kg/day may be more likely to maintain neutral or positive nitrogen balance, maintain or increase body mass, and reduce net urea generation.