Brenner and Rector's The Kidney, 8th ed.

CHAPTER 53. Diet and Kidney Disease

Gary C. Curhan   William E. Mitch



Specific Dietary Constituents and Renal Disease, 1817



Energy Intake, 1817



Energy Requirements of Patients with Chronic Kidney Disease, 1818



Sodium Intake, 1819



Potassium Intake, 1819



Protein Intake, 1820



Effects of Modifications in Dietary Lipids, 1823



Gum, 1823



Alcohol, 1823



Caffeine, 1824



Vitamins and Trace Elements in Chronic Kidney Disease, 1824



Herbal Supplements, 1826



Turnover of Nitrogenous Excretory Products in Chronic Kidney Disease, 1826



Urea, 1826



Creatinine, 1826



Uric Acid, 1827



Ammonia, 1828



Other Nitrogenous Compounds in Urine, 1828



Fecal Nitrogen, 1828



Skin Nitrogen Losses, 1828



Total Nonurea Nitrogen Excretion, 1828



Summary, 1829



Assessment of Protein Stores in Chronic Kidney Disease, 1829



Nitrogen Balance, 1829



Urea Nitrogen Appearance Rate, 1830



Serum Albumin and Malnutrition, 1830



Serum Transferrin, Prealbumin, Complement and Insulin-like Growth Factor-1, 1831



Anthropometrics, 1831



Free Plasma Amino Acid and Ketoacid Levels, 1832



Nitrogen Conservation in Severe Chronic Kidney Disease, 1833



Nitrogen Requirements, 1833



Factors Causing Increased Dietary Protein Requirements, 1834



Factors Causing Decreased Dietary Protein Requirements, 1838



Techniques of Nutritional Therapy, 1838



Rationale for Nutritional Therapy, 1838



Compliance, 1839



Comparison of Different Regimens, 1839



Dietary Treatment of Nephrotic Syndrome, 1840



Conclusion, 1841

Dietary factors are important in the development and treatment of renal pati-ents with kidney diseases and complications of renal insufficiency.[1] In this chapter, we focus on dietary components that should be considered when treating patients who have or are at risk for kidney disease. The need to manipulate the diet and the approaches used to accomplish this goal will depend on the patient's level of renal insufficiency.

The determination that there are over 10 million U.S. adults with evidence of chronic kidney disease (CKD) has led to renewed interest in the classification of CKD and the degree of impaired kidney function.[2] The most widely used classification was developed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) committee ( Table 53-1 ). This staging system can be used as a guide to determine when to begin interventions. Even individuals with a reduced risk of progressive kidney damage and a normal GFR (defined as GFR ≥ 60 ml/min/1.73 m2) can develop complications of CKD. In this staging system, kidney damage is defined as persistent abnormal albuminuria on two occasions. GFR can be directly measured but generally is estimated from an equation. The most commonly used equation is that derived from the Modification of Diet in Renal Disease (MDRD) Study.[3] The variables used in this equation to estimate GFR are age, serum creatinine, sex, and race. The accuracy of this equation in determining the true GFR is better when the measured GFR is below 60 ml/min/1.73 m2. Although this staging approach is useful, it has several limitations. First, the equation was derived from individuals in the United States with established kidney disease; thus, it might not apply to patients in other regions of the world. For example, it was shown to be inaccurate when Chinese patients were examined.[4] Second, the accuracy of the MDRD equation is suboptimal for GFR values 60 ml/min/1.73 m2 or higher. For important clinical decisions (e.g., transplant donor evaluation), the GFR should be measured directly. Third, the boundaries for the stages of renal insufficiency in the categories in Table 53-1 are arbitrary. Like other continuous biologic functions, such as blood pressure, there is no absolute threshold. Fourth, certain treatments may acutely reduce the GFR (e.g., starting a diuretic to manage hypertension) causing a shift in the stage of CKD. Clearly, this does not necessarily mean there has been long-term damage to the kidney causing a loss of function. Nonetheless, this classification system is easy to use and should help identify individuals for whom interventions, including dietary modification, might lead to an improvement in their overall health outcomes.

TABLE 53-1   -- Stages of Kidney Dysfunction

CKD Stage


GFR (ml/min/1.73 m2)


Kidney damage (e.g., albuminuria) with normal or increased GFR



Kidney damage (e.g., albuminuria) with mildly reduced GFR



Moderately reduced GFR



Severely reduced GFR



Kidney failure


Adapted from Kidney Disease Outcome Quality Initiative of the National Kidney Foundation (K/DOQI) clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39: S1–266, 2002.

CKD, chronic kidney disease; GFR, glomerular filtration rate.






Energy Intake

In patients entering dialysis therapy, there is a high prevalence of anthropometric abnormalities, including suboptimal body weight. Kopple noted that these findings could result from an inadequate uptake of energy. [5] [6] Because the energy requirement is determined in part by the amount expended during daily activities, the best method of determining energy needs is to measure energy expended during average activity and add the value to the resting energy expenditure (REE). The usual method to obtain the measurement is by indirect calorimetry measured over relatively brief periods and then extrapolating the result to 24 hours; the REE is then multiplied by a factor to account for the individual's activities. The 1981 FAO/WHO/UNU recommendation for energy used a database of approximately 11,000 REE determinations in healthy subjects.[7] It should be recognized that the regression equations used to derive energy requirements published in this report lead to considerable variability. In addition, the estimated REE from indirect calorimetry depends on the consistency and accuracy of the estimated time spent in various physical activities. There also is the issue of adaptation to different calorie intakes. Healthy subjects adapt to decreased nutrient intake by decreasing the value of REE.[8] In semi-starved adults, the REE decreased about 15% over 3 weeks; ultimately, there was loss of lean body mass.[7] This raises the issue of the relationship between an adequate amount of dietary calories and protein.[6] Well-nourished adults can achieve energy balance with only half the usual calorie intake but only if activity is decreased; even in this case, lean body mass may decrease.

Energy Requirements of Patients with Chronic Kidney Disease

Few evaluations of the calorie requirements of CKD patients or their capacity to adapt to a reduced-calorie intake have been published. Monteon and co-workers examined energy expenditure of normal and CKD subjects during rest and exercise.[9] There was no difference between the groups. When calorie intake was reduced, energy expenditure did not fall in either group, indicating that CKD patients do not have any special ability to adapt to a low-calorie intake. Consequently, if energy intake is inadequate, uremic subjects could develop calorie malnutrition and negative nitrogen balance, especially when protein intake is restricted. Monteon and co-workers[9] also concluded that the energy expenditure of dialysis patients is not different from normal subjects. This conclusion is controversial because Ikizler and colleagues[10] noted that 10 hemodialysis patients had a 7% higher than expected level of energy expenditure on both dialysis and nondialysis days. The latter finding suggests that uremia per se increases energy expenditure. In this case, metabolic factors impair-ing energy utilization (e.g., insulin resistance) would contribute to insufficient energy for maintaining body mass. In fact, uremia as well as metabolic acidosis per se causes insulin resistance and would impair energy utilization. [11] [12] On the other hand, a regimen consisting of a low-protein diet in the therapy of CKD patients substantially amelio-rates insulin resistance. Rigalleau and associates[13] examined insulin responses of CKD patients eating 0.3 g protein/kg/day plus a supplement of essential amino acids and ketoacids and found that plasma glucose and insulin levels were significantly lower. They also noted an improvement in glucose oxidation and nonoxidative disposal (mainly glycogen synthesis) and concluded that the low-protein diet did not adversely affect energy balance. In the MDRD Study, the initial values of energy intake were below the recommended levels of 30 to 35kcal/kg/day.[14] During the study (average duration, 2.2 years), energy intake was evaluated by dietary interviews and diaries and it was suggested there was a decline in calories despite intensive dietary counselling; calorie intake ranged from a high value of 26.7 to a low value of 21kcal/kg/day. On the other hand, there are serious questions about the reliability of dietary diaries and interviews in assessing energy intake.[15] Still, low values of energy intake are worrisome because low-protein diets were associated with small decreases in body weight, other anthropometry measures, and serum proteins. The importance of providing sufficient calories is contained in other reports. Hyne and colleagues[16] noted that the nitrogen balance of uremic patients fed a diet of 20 g/day of high-quality protein improved as calorie intake was raised. In studies of normal adults fed diets with barely adequate amounts of essential amino acids, the importance of calorie intake in determining nitrogen balance was demonstrated in the 1950's.[17] Even if the methods of determining calorie intake are questionable,[15] there are several reports indicating that patients with advanced CKD are probably not eating the prescribed amount of calories.[5] [14] [18] The cause of the lower level of calorie intake is unclear but is likely associated with the anorexia of chronic uremia. [19] [20] The contribution of low levels of energy intake in produc-ing abnormalities of nutritional status is unclear. For ex-ample, Bergstrom and associates[21] studied patients with kidney injury who were eating 16 to 20 g/day of protein supplemented with essential amino acids given orally or intravenously and found little or no change in nitrogen balance as energy intake was varied between 22 and 50kcal/kg/day. These data suggest that calorie intake is not so critical if both nitrogen and essential amino acid intake are adequate. Conversely, Kopple and co-workers[22] systematically addressed the question of how calories affect protein conservation when protein intake is minimal. They fed six chronically uremic patients a constant, minimal protein intake of 0.55 to 0.6 g/kg/day and measured nitrogen balance while calorie intake was varied from 15 to 45kcal/kg/day ( Fig. 53-1 ). Extrapolation of their measurements indicates that nitrogen equilibrium can be achieved in all of the patients if the intake is 35kcal/kg/day and hence, that the energy requirements of CKD patients are the same as those of normal adults. Note, however, that only six subjects were studied and the presence of abnormalities in glucose and possibly lipid metabolism could affect these conclusions. Based on the small amount of data,[22] we believe it is advisable to increase calorie intake of CKD patients to 35kcal/kg/day if they are below ideal body weight,[23] especially if the patient is eating a protein-restricted diet. For overweight patients, calories should be restricted.

FIGURE 53-1  The correlation between nitrogen balance and energy intake in six clinically stable, nondialyzed, chronically uremic patients. The open circle and line represents the patient that had the lowest resting energy expenditure. The open circle and solid line is the regression line derived from the individual results.  (From Kopple JD, Monteon FJ, Shaib JK: Effect of energy intake on nitrogen metabolism in nondialyzed patients with chronic renal failure. Kidney Int 29:734–742, 1986.)



Sodium Intake

As CKD progresses, there is an adaptive increase in sodium excretion per nephron, caused in part by the action of atrial natriuretic peptide and other natriuretic peptides; the release of these peptides increases as extracellular volume expands. There also is renal hypoperfusion and an attendant increase in filtration fraction. As renal dysfunction becomes more severe, these hemodynamic changes play an increasingly important role.[24] Hyperaldosteronism often is present, yet aldosterone levels can be stimulated further by posture or by volume depletion.[25] Sodium excretion eventually diminishes and if intake is excessive, edema and hypertension develop and diuretics are required; thus, early sodium restriction should be implemented. As noted in the section on nitrogenous excretory products later, Johnson and colleagues have proposed that a high serum uric acid level is another factor that could contribute to hypertension.[26] Results from experiments in rats suggest that a high uric acid not only contributes to salt-sensitive hypertension but also could cause arteriolar damage in the kidney and other organs. [27] [28] To the extent that these observations apply to CKD patients, those with high serum uric acid levels should be advised to reduce salt intake.

In subjects with hypertension, GFR may[29] or may not[30] vary with salt intake, independently of the renin-angiotensin system. This is a confusing area because salt also affects the degree of insulin resistance in subjects without CKD and insulin resistance in turn is inversely related to GFR.[30] Results from experimental studies have not identified how dietary salt, diabetes, and GFR are related. For example, dietary salt restriction of rats with experimental diabetes acutely reduces hyperfiltration, renal enlargement, and albuminuria,[31] and may paradoxically increase GFR.[32] On the other hand, chronic salt loading may paradoxically decrease GFR.[33]

Our belief is that blood pressure is typically salt sensitive in CKD patients with hypertension (see Chapter 42 ) and hypertension has been associated with more rapid progression.[34] Moreover, a decrease in blood pressure as well as proteinuria occurs in response to salt restriction.[35] The antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II blockers, and nondihydropyridine calcium channel blockers is enhanced by salt restriction, in part owing to a decrease in the filtration fraction. [35] [36] [37] [38] [39] Because the degree of proteinuria is correlated with rate of progression, [40] [41] [42] [43] it follows that salt restriction also may contribute to slowing of progression. Retrospective clinical studies support this inference.[24] Aldosterone has been postulated to play a major role in the progression of chronic renal failure,[44] based in part on studies in experimental animals. [45] [46]Carefully controlled trials are needed before spironolactone can be recommended because of the dangers of producing hyperkalemia.

Sodium intake in the United States and in many parts of the world greatly exceeds daily requirements (designated as “adequate intake”). The importance of sodium is that blood pressure, on average, rises with increasing sodium intake; however, there is substantial heterogeneity in the association between sodium intake and blood pressure. Although individuals are often categorized as “salt-sensitive” or “salt-resistant”, the change in blood pressure in response to changes in sodium intake is not binary. [47] [48] Thus, it is important to remember that as is the case for most biologic variables, there is a continuous distribution within a population for the relation between sodium intake and blood pressure responses. There are certain subgroups in which the blood pressure lowering effects of sodium reduction are more pronounced including African Americans, middle-aged and older persons, and individuals with hypertension, diabetes, or CKD. The response to sodium may also be influenced by GFR, genetic, and other dietary factors. Because the blood pressure and proteinuria of individuals with CKD tends to be more sensitive to salt, dietary sodium restriction is essential for successful control of blood pressure. Even in individuals consuming a higher amount of potassium, which somewhat blunts the sodium-related increase in blood pressure, reducing sodium intake will still lower the blood pressure. Sodium restriction, particularly in more salt-sensitive hypertensive individuals, may reduce evidence of oxidative stress.[49] The most recent recommendations from the Institute of Medi-cine state that for adults daily sodium intake should not exceed 2.3 g (100 mmol), and an intake lower than this is preferable.[50]

We feel that greater sodium restriction should be advised for patients with CKD. Although there are no randomized studies comparing different levels sodium intake in individuals with reduced GFR, we believe it is prudent and clinically beneficial to reduce the sodium intake to less than 2 g/d. Measuring 24-hour urinary sodium excretion may be helpful to quantify actual intake, which tends to be underestimated by most individuals.

Potassium Intake

Recent guidelines from the Institute of Medicine recommend an intake of dietary potassium of 4.7 g/d for the general population.[50] However, it has long been recognized that certain chronic conditions reduce an individual's ability to excrete potassium, including diabetes and CKD.

Potassium regulation is disrupted in individuals with CKD, and these patients may have decreased amounts of total body potassium despite having higher serum potassium levels. The impaired ability to excrete potassium is due to decreased GFR and hormonal changes; the latter defect is frequently associated with drugs commonly used in this population such as angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARBs) and non-steroidal anti-inflammatory agents. There are adaptations that increase the excretion of potassium via both the kidney and gut.[51] This is fortunate because it is difficult to comply with sodium and potassium restriction. We believe before prescribing low-potassium diets, other causes of an increase in serum potassium should be eliminated including modification of drugs affecting potassium excretion, correction of metabolic acidosis, and constipation. There is substantial evidence that diets that are higher in potassium, particularly due to a higher intake of fruits and vegetables, reduce the likelihood of developing a number of chronic diseases, such as coronary heart disease and diabetes. In addition, clinically important reductions in blood pressure have been documented when individuals with normal blood pressure or mild hypertension consume a potassium-rich diet.

Dietary Factors and Blood Pressure

Observational studies suggest that a higher dietary potassium intake would lower blood pressure. However, because of potential confounding factors and the difficulty of assigning effect to a single dietary component, randomized trials were undertaken to answer many of these questions. Fortunately over the past decade well-designed clinical trials have been completed and have greatly expanded our understanding of the relation between specific dietary components and changes in blood pressure.

Several meta-analyses have also concluded that higher potassium intake reduces blood pressure. A meta-analysis by Whelton and colleagues included 32 randomized trials of potassium supplementation. A net increase in urinary potassium excretion of 2 g/d (50 mmol/d) was associated with mean reductions in systolic and diastolic BP associated of 4.4 mm Hg and 2.5 mm Hg in hypertensive and 1.8 mm Hg and 1.0 mm Hg in nonhypertensive individuals.[52] The reductions were greater in those studies in which the sodium intake was high.

One of the most important randomized trials is the DASH (Dietary Approaches to Stop Hypertension) Study. This study did not simply provide potassium supplementation, as had been done in previous studies, but rather looked at modifications in dietary composition. The first DASH Study enrolled 459 adults with systolic blood pressure less than 160 mm Hg and diastolic blood pressure 80 mm Hg to 95 mm Hg.[53] After a 3-week control period in which all subjects were fed a control diet low in fruits, vegetables, and dairy products, and with a typical fat content, they were then randomly assigned to one of three diets for 8 weeks. Participants were assigned to the control diet, a diet rich in fruits and vegetables, or a “combination” diet rich in fruits, vegetables, and low-fat dairy products and with reduced saturated and total fat. For all three groups, sodium intake and body weight were maintained at constant levels. At the end of the study and compared to the control diet, the mean reductions in systolic and diastolic blood pressures for those assigned to the combination diet were 5.5 mm Hg and 3.0 mm Hg. The reductions among the 133 participants with hypertension were more pronounced: 11.4 mm Hg and 5.5 mm Hg for those on the combination diet. In addition, the blood pressure-lowering effects of the DASH diet were substantially greater in black participants (systolic and diastolic BP reductions of 6.9 mm Hg and 3.7 mm Hg) than in white participants (3.3 mm Hg and 2.4 mm Hg).[54] Although this type of study does not directly demonstrate that high potassium intake is beneficial, it does demonstrate that a “potassium-rich” diet is beneficial.

Unfortunately, few of the published studies have included participants with reduced GFR and, especially, patients with advanced CKD. The National Kidney Foundation's expert panel recommended potassium restriction for individuals with more advanced CKD (e.g., stage 4 CKD with an estimated GFR < 30 mL/min/1.73 m2).[55] Clearly, more studies are needed to determine the usefulness and dangers of increasing (or limiting) dietary potassium in patients with CKD.

There are other factors to consider in prescribing the intake of sodium, potassium, and other minerals in addition to blood pressure changes. As mentioned earlier, the major sources of dietary potassium are fruits and vegetables. In these foods, the accompanying anion is typically citrate. Because citrate is converted in the body to bicarbonate, these foods also provide net alkali that may be important because patients with CKD tend to have a reduced ability to excrete acid. In addition to a higher dietary alkali intake favorably impacting overall acid-base balance, this may also directly benefit protein stores and reduce bone loss. As has been detailed in this chapter, metabolic acidosis increases the degradation of essential amino acids and protein in patients with and without CKD. Excess acid is also buffered by bone leading to bone demineralization.

Recommendations for Dietary Potassium

Because of the lack of adequate studies in patients with CKD, firm guidelines cannot be established. We feel it is prudent to encourage patients with CKD to consume a healthy diet that includes fruits and vegetables. This will not only reduce protein intake and hence, the generation of acid and nitrogenous waste products that must be excreted but also will be associated with a lower sodium intake, making hypertension more easily managed. The serum potassium will need to be monitored to avoid clinically important hyperkalemia. The risk of mild hyperkalemia must be balanced against the benefits of higher potassium intake, and clinical recommendations should be tailored to the individual patient.

Protein Intake

Acute Effects of Protein or Amino Acid Loads on Renal Hemodynamics and Proteinuria

Excess dietary protein or intravenous infusion of amino acids leads to a decrease in renal vascular resistance with increases in GFR and RPF, amounting to 11% to 24%. [56] [57] This increment in GFR has been called “functional renal reserve”, although it is not apparent what function it serves. It is seen in children[58] and in the elderly[59] and may or may not be detected in subjects with hypertension.[60] Soy protein does not induce this response.[61]Hyperfiltering diabetics exhibit a markedly blunted renal reserve, unless they are ingesting a low-protein diet. [62] [63] [64] [65] Nonhyperfiltering diabetics, however, respond normally to a protein challenge and may exhibit an exaggerated response to amino acid infusion.[66] Indomethacin treatment prevents this response in healthy subjects but not in diabetics,[67] unless they have received glucagon injections sufficient to restore normal glucagon levels.[63] Heart failure blunts the response, but enalapril treatment restores it.[68]

Both intrarenal and extrarenal mechanisms probably are involved. Evidence for intrarenal mechanisms, such as tubuloglomerular feedback and tubular reabsorption of amino acids and NaCl, were summarized by Woods.[69] Levels of many hormones increase in response to protein loads, including insulin, glucagon, corticosteroids, growth hormone, brain-gut peptides, vasopressin, atrial natriuretic peptide, and dopamine,[70] but nonrenal hormones, at least, do not appear to be essential for the response. [71] [72] Mediators produced within the kidney that are likely to be involved include prostaglandins, kinins, angiotensin II, and nitric oxide.

Angiotensin II appears to play an important role in mediating this response through its inhibitory effect on proximal tubular reabsorption and activation of the tubuloglomerular feedback system.[60] In normal subjects, captopril eliminates the response but nifedipine does not.[73] Renal reserve is attenuated in subjects with essential hypertension who are receiving ACE inhibitors.[74] In diabetics, however, captopril increases the response to amino acid infusion, but salt loading does not increase the response further.[75] Administration of a kinin receptor antagonist abolishes the response.[76] Nitric oxide probably plays a critical role,[77] because administration of L-nitro-arginine methyl ester, an inhibitor of nitric oxide biosynthesis, abolishes it.[78]

Renal nerves also are involved because renal denervation abolishes renal reserve.[79] Dietary phosphorus restriction abolishes the response to oral protein loads but not the response to intravenous amino acids.[80] Although it was initially hoped that the persistence of this response could exclude the presence of harmful hyperfiltration, it was found that neither unilateral renal agenesis[56] nor CKD [56] [69] [81] blunted the response.

Protein loads given to subjects with either microalbuminuria or macroalbuminuria increase the excretion of beta2-microglobulin, retinol-binding protein, and IgG, as well as the excretion of albumin. [56] [82] Even in normal subjects, protein loads increase the excretion of proteins with a molecular radius near 55 angstroms.[83] In type 2 diabetics, a comparison between a chicken-based and meat-based diet revealed that the chicken-based diet or a low-protein diet was associated with lower level of albuminuria and GFR compared to the meat-based diet.[84] In nephrotic patients, proteinuria increases following a meat meal, before or after nifedipine pretreatment, but not after captopril or indomethacin pre-treatment.[85] In children with reflux nephropathy, amino acid infusion augments excretion of albumin and also beta-2-microglobulin.[86]

Effects of Variations in Dietary Protein Intake on Renal Hemodynamics and Proteinuria

In a review, King and Levey[87] noted that the variation of GFR with dietary protein intake occurs in different animal species but is least pronounced in humans, varying from nonsignificant to approximately 20%. The time dependence of this effect has not been examined systematically, but indirect evidence suggests that the response may require months to reach its maximum effect. RPF changes in parallel, but there are also clear-cut structural changes in the kidney, at least in rats, indicating glomerular and tubular hypertrophy, hyperplasia, or both.

In non-nephrotic patients, protein restriction reduces proteinuria. [88] [89] [90] [91] [92] [93] [94] [95] This response and the antiproteinuric effect of ACE inhibition are additive. [96] [97] [98] Studies in rats with Heymann nephritis suggest that high-protein diets aggravate proteinuria by both angiotensin-independent and angiotensin-dependent mechanisms.[99] The response to protein restriction may fail to occur in some diabetics without renal failure, particularly if they do not exhibit hyperfiltration. On the other hand, other diabetics who spontaneously consume relatively high amounts of protein (especially animal protein) are more likely to exhibit microalbuminuria according to some but not all results. [100] [101] When considering low-protein diets for diabetic patients, some caution is needed because there are reports that diabetic patients can not activate the adaptive changes to dietary protein restriction that occur in normal adults and CKD patients (see Fig. 53-5 ). Based on these reports, [94] [102] Aparicio and associates undertook a study of changes in proteinuria and found that proteinuria does not occur in patients with unabated progression despite low-protein diets.[89]

FIGURE 53-5  Intracellular free amino acid concentrations in muscle of chronically uremic patients treated by protein restriction alone. A logarithmic scale is used, so decreases are emphasized as much as increases. Asterisks indicate statistically significant differences.  (Data from Bergström J, Fürst P, Norée L-O, et al: Intracellular free amino acids in muscle tissue of patients with chronic uraemia: Effect of peritoneal dialysis and infusion of essential amino acids. Clin Sci Mol Med 54:51–60, 1978.)



The role of dietary protein restriction in the nephrotic syndrome is considered later.

Nutritional Effect of Protein Restriction in Experimental Renal Disease

Meireles and associates[103] fed rats with CKD diets containing from 8% to 30% protein and measured growth and efficiency of protein use. The lowest protein intake led to the highest efficiency of utilization of protein for growth, but 17% protein was the most efficient in terms of utilization of energy for growth. Diets containing 30% protein caused both metabolic acidosis and anorexia. Both of these responses would lead to loss of protein stores (see later section on nitrogen conservation in CKD).

Protein Restriction and Progression of Renal Disease

There have been a number of studies, some better controlled than others, indicating that protein restriction may slow progression, as well as a few in which no such response was found. Three meta-analyses of these reports have appeared. The first[104] selected six randomized controlled trials for analysis of the frequency of renal death (start of dialysis or death of patient) in control versus treated groups. A total of 890 patients were observed for at least 1 year, half of whom received a low-protein diet. One hundred fifty-six renal deaths occurred, 61 in the low-protein group and 95 in the control group, leading to an odds ratio of 0.54 with a 95% confidence interval of 0.37 to 0.79. The authors concluded that the data strongly support the effectiveness of low-protein diets in delaying the onset of end-stage renal disease. The second study[105] selected five randomized controlled studies, including 1413 patients, with nondiabetic kidney disease, [106] [107] [108] [109] and five studies in type I diabetic nephropathy, [93] [94] [110] [111] [112] including 108 patients. Again, the meta-analysis indicated significantly reduced risk of renal death in the nondiabetics. In the patients with diabetes, protein restriction significantly slowed the increase in proteinuria or the rate of decline of GFR or creatinine clearance. The authors concluded that protein restriction slows the progression of both diabetic and nondiabetic renal disease. One of the studies included in this analysis[109] exemplifies the problems of compliance in interpreting such trials: protein intake estimated from 24-hour urea excretion scarcely differed between experimental and control groups (by only 0.16 g/kg). Not surprisingly, progression rates in the two groups of this study did not differ. A third meta-analysis by Kasiske and co-workers[113] analyzed 24 studies by including 11 in which randomization was not performed; instead, a prospective but not randomly allocated control group was employed or else an evaluation period preceded the treatment period in the same patients. In the randomized trials, the average effect of protein restriction was to slow progression by only 0.53 mL/min/year or about 10%; when the study of Locatelli and colleagues,[109] mentioned previously as showing minimal or no compliance, was excluded, this average effect rose to 0.66 mL/min/year. When nonrandomized and smaller trials were included, greater effects were found, suggesting bias. Thus, these three meta-analyses have led to somewhat varying conclusions.

It should be noted that the two of these meta-analyses [105] [113] included the operational phase of the MDRD Study,[106] which has been viewed by some as having disproven the hypothesis that protein restriction slows progression. This interpretation is clearly incorrect. In a secondary analysis of these results in patients with more advanced disease, [114] [115] it was found that a reduction of 0.2 g/kg/day in achieved protein intake was associated with a 1.15 mL/min/year slower rate of decline in GFR, corresponding to a 41% prolongation of the time to end-stage renal disease.

Controversial results continue to be reported. For example, a study from Denmark[116] documented a reduced risk of ESRD in diabetic patients randomized to mild protein restriction (0.89 g/kg), whereas a report from Italy[117]found no slowing of progression with a 0.6 g/kg protein diet. Type 2 diabetics whose proteinuria diminishes were more likely to exhibit slower progression.[118] In a recent study of patients with all types of renal failure, a low-protein diet, espe-cially if combined with a soy protein isolate, slowed progression.[119]

Combe and colleagues[120] documented the role of compliance in achieving retardation of progression by protein restriction. This finding raises the question about what is the optimal statistical approach for these studies. While intention-to-treat analyses are the gold standard for determining efficacy, analyses that take into account the actual changes made by the intervention group provide information on the effectiveness of the treatment.

In patients with autosomal dominant polycystic kidney disease, Choukroun and co-workers[121] found no effect of protein restriction on progression by multiple regression analysis. However, in the MDRD Study, protein restriction was marginally associated with slower progression in polycystic patients with more advanced disease.[122]

Effect of Protein Restriction in Children with Chronic Kidney Disease

Growth retardation is a major problem in children with CKD and has many causes. [45] [123] Total body nitrogen is characteristically reduced,[124] but the pubertal growth spurt may be normal.[125] No beneficial effect on progression of mild protein restriction (to 0.8 to 1.1 g/kg) has been found using sequential creatinine clearances as a measure of progression. [126] [127]

Vegetable versus Animal Protein

Substitution of vegetable protein for animal protein in normal subjects lowers renal hemodynamics.[128] D'Amico and colleagues [129] [130] [131] [132] fed nephrotic patients a low-fat, vegetarian, soy protein diet for 2 months and observed highly significant decreases in serum lipids and proteinuria. As they noted, it could not be determined whether the change in protein quality, protein quantity, or fat intake was responsible for these effects. Jibani and associates[133] observed a reduction in microalbuminuria after substituting vegetable protein for animal protein in diabetics with early nephropathy. Kontessis and co-workers[61] fed healthy individuals either an animal protein diet or a vegetable protein diet for 3 weeks in random order. GFR, RPF, and fractional clearance of albumin were all greater on the animal protein diet. They also gave acute loads of protein from these two sources, and noted that plasma glucagon and prostaglandin 6 keto-PGFa rose more following the meat load. In nonproteinuric diabetics fed these two diets,[134] similar results were seen; plasma valine and lysine were significantly higher with the meat diet. Soroka and colleagues[135] fed a soy-based, low-protein diet and an animal-based, low-protein diet, in random order, for 6 months each, to patients with CKD. Mean GFR remained constant, as did nutritional status and proteinuria. The vegetarian diet was associated with lower protein and phosphate intakes. Thus, there is suggestive evidence that vegetarian diets may be advantageous in CKD.

Effects of Individual Amino Acids in the Diet


As a substrate for nitric oxide synthesis, arginine has the potential to influence many physiologic processes. L-Arginine supplementation prevents the development of hypertension and nephrosclerosis in the salt-sensitive Dahl/Rapp strain of rats.[136] Dietary supplementation with arginine ameliorated ablative nephropathy and diabetic nephropathy in rats; it also reduced the renal hypertrophy induced by a high-protein diet. [137] [138] Partial inhibition of arginase, induced by administration of a manganese-free diet, slowed the progression of renal failure following subtotal nephrectomy.[139] Dietary arginine supplementation for only 3 days improved renal function in rats with bilateral ureteral obstruction or puromycin aminonucleoside-induced nephrosis.[140] A role of angiotensin II as well as nitric oxide in these responses was suggested by Ashab and associates.[141] They reported that ablative nephropathy (in the rat) was characterized by a reduction in nitrate plus nitrite excretion that was reversed by arginine or captopril administration; there was no additive benefit when both were administered. They concluded that CKD, at least in the rat, is a low nitric oxide production state. Other evidence suggests that the vascular and hormonal effects of arginine administration might involve nonstereospecific responses, as opposed to substrate effects on nitric oxide production (which should be stereospecific).[142] There also is the problem of the arginine paradox: the intracellular arginine concentration is substantially above the Km of nitric oxide synthase, so it is difficult to understand how arginine is serving only as a substrate. There also are unexplained interactions among glutamine, arginine, and endothelial cell nitric oxide production.[143] Finally, some of these responses could be linked to inhibition by arginine effects mediated through ACE; both ACE inhibitors and angiotensin receptor blockers may enhance arginine-induced vasodilatation.[144] Dietary L-arginine (but not D-arginine) protected rats from cyclosporine nephrotoxicity, whereas inhibitors of nitric oxide biosynthesis aggravated it.[145]

Oral or intravenous administration of arginine in normal subjects causes diuresis and lowers blood pressure[146] but may induce microalbuminuria. [147] [148] [149] Urinary cAMP decreases and creatinine excretion increases, but there is little or no change in GFR. In patients with heart failure, 15 g/day of oral arginine reduces endothelin levels and augments the diuretic response to saline loading.[148] In rats with renal ischemia, arginine infusion induces both beneficial and harmful effects.[150]

In contrast to these reports, Narita and associates [151] [152] suggested that the beneficial effects of low-protein diets in renal failure might be attributable to reduced intake of arginine. Dietary restriction of arginine ameliorated antithymocyte serum-induced glomerulonephritis, probably because arginine metabolism to polyamines and proline as well as to nitric oxide was up-regulated in this model of renal failure.[153] Oral arginine in children with CKD and endothelial dysfunction did not induce improvement.[154] A possible explanation of these discordant roles of nitric oxide in renal disease may be that iNOS is chronically stimulated by cytokines, whereas acutely responsive cNOS activity may be depressed.[155] Further work will be needed to resolve these contradictory findings concerning the role of dietary arginine in progression of CKD.


Kaysen and Kropp[156] reported that dietary supplementation with tryptophan prevents the development of hypertension and proteinuria in 7/8 nephrectomized rats. Additional experimental studies of tryptophan supplementation and progression are not available.

The ketoacid/amino acid supplement employed in the feasibility phase of the MDRD Study, as opposed to that used in the operational phase, was tryptophan-free.[156a] This could be relevant because there is a correlation between progression rate and serum-free tryptophan concentration,[157] and the ketoacid supplement used in the feasibility phase appeared to slow progression, whereas that used in the operational phase did not. Profound hypotryptophanemia appeared in some of the patients in the feasibility study,[158] and this could have contributed to their slower progression.

In a series of reports, Niwa and associates [160] [161] [162] documented that indoxyl sulfate, a tryptophan metabolite, is nephrotoxic. Its removal by an orally administered sorbent slows progression of renal failure in patients on a low-protein diet, at least as evidenced by sequential measurements of serum creatinine. A major problem with this scheme is that oral tryptophan administration, rather than increasing indoxyl sulfate levels, leads to a significant decrease in urinary excretion of indoxyl sulphate.[162] Hence, it is not possible to attribute the purported slowing of progression induced by protein restriction to lower intake of tryptophan, thereby reducing indoxyl sulfate production.

Effects of Modifications in Dietary Lipids

Many abnormalities of plasma lipids have been observed in CKD and some of these clearly play a role in progression. [164] [165] [166] Whether progression can be slowed by dietary or pharmacologic modification of lipid levels is less clear. In rats with subtotal nephrectomy, a dietary supplement of linoleic acid did not protect against progression.[166] However, a study of patients on dialysis indicated that those who ate fish tended to survive longer.[167]

Whether based on soy protein, and whether supplemented by essential amino acids, ketoanalogues, or both, protein-restricted vegetarian diets repeatedly have been reported to improve lipid abnormalities of CKD. [132] [169] [170] It has not been established that progression is slowed by these maneuvers. According to Nielsen and co-workers,[170] feeding a diet containing 60% of its fat as monounsaturated fat had no effect on albuminuria in patients with microalbuminuric noninsulin-dependent diabetes mellitus (NIDDM). Conversely, Cappelli and associates[171] gave 3.4 g/day of polyunsaturated fatty acids for 1 year to half of a group of 20 CKD patients. Compared with the control group, treated patients exhibited lower circulating levels of lipids and cytokines, less proteinuria, and slower progression.

Dietary Fat and Coronary Heart Disease

Because of the high risk of developing coronary heart disease (CHD) in patients with CKD, a discussion of the role of dietary fat as a risk factor for CHD is helpful. Different types of dietary fats influence the development of a variety of diseases. Simply reducing the percentage of calories from fat will not reduce the risk of developing CHD. A higher intake of polyunsaturated fat reduces the risk of CHD whereas a higher intake of trans fat and saturated fat increases the risk of CHD.[172] Trans fats are unsaturated fatty acids with at least one double-bond in the trans configuration. Although a small proportion of trans fat occurs naturally, most of the trans fat consumed is purposely generated during the process of partial hydrogenation of vegetable oils. This form of fat is used widely by the food industry because of the longer shelf life and the stability and taste in cooked foods. Consuming trans fatty acids in place of an equal number of calories from saturated or non-trans unsaturated fats raises LDL cholesterol, reduces HDL cholesterol and increases the ratio of total cholesterol to HDL. These changes lead to an increased risk of CHD.[173] Trans fatty acid intake may also increase markers of systemic inflammation, such as IL-6, CRP, and TNF-alpha. Trans fatty acid consumption may also cause endothelial dysfunction, identified by higher levels of ICAM-1, VCAM-1, and E-selectin. Thus, the intake of trans fatty acids should be minimized.

Although the use of antihypertensive or cholesterol lowering medication has been shown to reduce mortality, there is growing evidence that lifestyle changes can further reduce the risk of developing coronary heart disease. For example, a study of over 42,000 men found that a healthy lifestyle (eating a prudent diet, exercising regularly, managing weight, moderate alcohol consumption, and not smoking) could prevent 62% of all coronary events in the whole study population and 57% among those taking antihypertensive or cholesterol-lowering medication.[174] There also are reports of beneficial effects of exercise in dialysis patients leading to an increase in muscle function and potentially, muscle mass. [176] [177] [178] It is clear that even changing lifestyle habits to incorporate more healthy activities can be beneficial. Chiuve and colleagues found that those who adopted at least two additional low-risk lifestyle factors during the study period had a 27% lower risk of CHD.[174] Thus, lifestyle changes that include a healthy diet can reduce the risk of CHD, even among individuals with hypertension or hypercholesterolemia.


Although statins are not a dietary component, these drugs can modify serum cholesterol modification and CHD prevention and, thus, deserve mention. Multiple randomized trials have demonstrated the beneficial effect of statins on reducing LDL cholesterol and CHD. Tonelli and colleagues showed that in individuals with pre-existing CHD, pravastatin given to patients with CKD reduced secondary events just as effectively in individuals without CKD.[178] An important reduction in adverse outcomes was also observed in diabetic patients treated with pravastatin.[178] The greatest absolute reduction in risk was observed in those with both CKD and diabetes, emphasizing the importance of prevention in this high-risk subgroup.

Because of the positive impact on vascular disease, it has been suggested that statins might also reduce the rate of renal function decline and proteinuria. A recent meta-analysis by Sandhu and co-workers included 27 studies and over 39,000 participants.[179] The authors found that overall statin use slowed renal function decline by an average of 1.2 ml/min/yr; however, in subgroup analysis, this benefit was statistically significant only among those with cardiovascular disease but not among participants with renal disease due to diabetes, hypertension, or glomerulonephritis. The authors concluded that statin use might modestly reduce proteinuria.

The impact of statins may vary by patient characteristics. In diabetic patients with hyperlipidemia and nephropathy, statin treatment reduces proteinuria and may slow progression.[180] However, pronounced reduction of plasma total and low-density lipoprotein (LDL) cholesterol and triglycerides by statin therapy failed to alter albuminuria or rate of progression to renal failure in children with steroid-resistant nephrotic syndrome.[181]


Dietary supplementation with gum arabic fiber (50 g/day) increases fecal nitrogen and lowers serum urea nitrogen concentration in patients with CKD, without altering nitrogen balance.[182] Fifteen grams per day of guar gum improves glycemic control and serum lipid levels in patients with NIDDM.[183]


Because of the pervasive consumption of alcohol around the world, it is important to consider the impact of alcohol on renal function. Some experimental animal models have suggested that alcohol may adversely affect renal function. Heavy, chronic alcohol consumption has been associated with hypertension in humans.[184] In contrast, several studies in the cardiovascular literature suggest that alcohol may have a beneficial effect on vascular diseases. Moderate alcohol intake raises HDL cholesterol and reduces hemoglobin A1C and fibrinogen. These changes would explain the reduced risk of developing coronary heart disease that has been observed in several prospective observational studies among men and women, including those with type II diabetes. [186] [187]

Only a few studies have examined the association between alcohol intake and renal function in humans. A case-control study found a non-significant increased likelihood of being on dialysis for individuals who consumed two or more alcoholic beverages per day.[187] However, data from two large prospective cohort studies suggest that moderate alcohol consumption is not harmful and may in fact slightly reduce the rate of renal function decline. [189] [190]Thus, it appears that alcohol intake in moderation is acceptable for individuals with CKD.


Like alcoholic beverages, the intake of caffeinated beverages is extremely common worldwide, but there is little information on the impact on kidney function. In vitro work raised the possibility that caffeine could promote cyst enlargement in patients with polycystic kidney disease, but no data in humans are available.[190] Caffeine has been proposed to increase the risk of analgesic-associated renal disease, but this issue remains unsettled. Earlier studies suggested that the intake of caffeinated beverages may increase the risk of hypertension, but a recent large prospective study found no association between caffeine intake and risk of hypertension.[191] There are reports about the influence of coffee consumption in individuals who already have hypertension. A 2-week study evaluated the impact of changing caffeine intake among 52 individuals with mild hypertension who were regular coffee drinkers.[192]The investigators found that drinking caffeinated coffee over a 2-week period did not adversely influence blood pressure and that abstinence was of no benefit. These findings are consistent with other studies. Thus, at least over the short term, caffeine does not appear to change blood pressure among individuals with mild hypertension. There are no published prospective studies of caffeine intake and change in renal function.

Vitamins and Trace Elements in Chronic Kidney Disease

We do not recommend prescribing a general multivitamin or trace element supplement routinely because patients with CKD have special requirements and limitations in their ability to eliminate and respond to vitamins and trace elements. Vitamins and trace elements are designated as micronutrients because they are required for energy production, organ function, and cell growth and protection (e.g., from oxygen free radicals) but are needed in only small amounts. The diet of patients with CKD can be limited due to anorexia or as part of therapy for advancing renal insufficiency and, therefore, can jeopardize the intake of micronutrient. [1] [19] [194] For this reason, water-soluble vitamins frequently are generally recommended for uremic patients.[194] Other reasons for deficiency of micronutrients include proteinuria with losses of protein-bound elements or decreased intestinal absorption of micronutrients, impaired cellular metabolism, circulating inhibitors, and increased losses with dialysis treatments.[194] The range of factors that could change requirements for micronutrients and the serious methodologic difficulties in measuring them account in large part for the absence of minimum or recommended daily intakes of vitamins in patients with CKD. Few studies have documented the benefits of giving patients supplements of water-soluble vitamins. For example, long-term supplemental vitamin B6 and folate reportedly improve the responses to erythropoietin. [196] [197] Diuretic therapy or hemodialysis can cause accelerated loss of vitamin B1 (thiamine), especially when there is severe restriction of dietary protein or potassium. Unfortunately, there are no long-term evaluations of this problem despite the fact that some of the cardiovascular and neurologic symptoms of thiamine deficiency may mimic complications of advanced CKD. On the other hand, data from hemodialysis patients observed for 1 year after discontinuing routine vitamin supplements revealed that the average concentrations of folate, niacin, and vitamins B1, B6, B12, and C were normal in whole blood and erythrocytes.[197] Because dialysis patients are urged to meet their protein requirements of 1 g/kg/day, there must have been sufficient intake of these vitamins. To avoid complications of deficiency, we recommend that a supplement containing the RDA for water soluble vitamins be prescribed for patients with CKD.

Riboflavin is necessary to maintain levels of the coenzymes flavin mononucleotide and flavin adenine dinucleotide that participate in numerous metabolic pathways of energy utilization. Because it is present in meats and dairy products and these are often restricted for patients with CKD, deficiency may occur. As with thiamine, riboflavin is a water-soluble vitamin and its deficiency can produce problems (sore throat, stomatitis, glossitis) that may be mistaken for uremic symptoms. Folic acid is found in fruits and vegetables but cooking can destroy it. In addition, an overly restrictive intake because of anorexia, hospitalization, or advanced CKD may produce a deficiency. Folic acid is involved in the synthesis of nucleic acids and carbon transfer reactions including those involved in amino acid metabolism (including homocysteine).[194] Folate sufficiency is also necessary for the response to erythropoietin therapy. Vitamin B6, pyridoxine, is critically involved in the metabolism of amino acids via transaminase-catalyzed reactions that transfer nitrogen from amino acids to form glutamate and other amino acids. It is contained in meats, vegetables, and cereal but with restricted diets, pyridoxine deficiency may develop and cause symptoms of a peripheral neuropathy. Because this is also a complication of advanced uremia, a supplement containing the RDA is recommended to avoid a misdiagnosis of the cause of neuropathy.

Vitamin B12 is necessary for the transfer of methyl groups among different metabolic compounds and it is necessary for the synthesis of nucleic acids. The major sources of vitamin B12 are meat and diary products but a deficiency state is unusual because this vitamin is stored in the liver, is protein bound, and its gastrointestinal absorption is carefully regulated. A supplement containing the RDA is recommended even though the likelihood of patients with CKD developing a deficiency state is low.[194] Vitamin B12 can be removed by dialysis, and the recommendation for supplements seems more logical.

Vitamin C or ascorbic acid is used in antioxidant reac-tions and it is involved in hydroxylation of proline during the formation of collagen. It is contained in meat, dairy products, and most vegetables so a deficiency state is unusual. The symptoms of vitamin C are subtle but they are similar to those of advanced uremia including poor wound healing and periodontal disease. Unfortunately, dialysis patients can develop deficiency states when their diet is inadequate.[194] High doses of vitamin C are metabolized to oxalate, which can precipitate in soft tissues (including the kidney). For this reason, vitamin C supplements should not contain more than the RDA.

The remaining water soluble vitamins, biotin, niacin, and pantothenic acid have been less well studied and there is little reason to recommend a supplement unless a specific syndrome develops. Biotin functions as a coenzyme in bicarbonate-dependent carboxylation reactions and is produced by intestinal micro-organisms. Consequently, a deficiency state is unusual. Niacin (nicotinic acid) is an essential component of the nicotinamide adenine dinucleotide phosphate coenzyme. It is synthesized from the essential amino acid, tryptophan, and a deficiency state with diarrhea, dermatitis, or increased triglycerides can develop. Niacin supplements have been used to manage hyperlipidemic conditions such as a low level of high-density lipoprotein cholesterol. Unfortunately, supplements containing niacin can cause flushing symptoms. Pantothenic acid is involved in the function of coenzyme A and hence, in the metabolism of fatty acids, steroid hormones, and cholesterol. Because there has been so little work about the efficacy and consequences of prescribing these vitamins, a supplement is recommended only for deficiency-related syndromes.[194]

Dialysis can impose special requirements for vitamin intake. For example, hemodialysis patients often have elevated blood oxalate levels. They should not be given excess vitamin C in order to limit the increase in serum oxalate concentration. [199] [200] As noted, there is concern about the accumulation of homocysteine in patients with CKD and its association with an increased risk of atherosclerotic, cardiovascular disease.[200] In theory, supplements of vitamins B6, B12, and folic acid could help reduce homocysteine levels,[201] but high doses of folate, vitamins B6, and B12 has not successfully lowered the levels of homocysteine in hemodialysis patients.[202]

In summary, even hemodialysis patients who are urged to eat generous amounts of protein and calories may have an intake that is insufficient to meet the recommended daily allowances for normal subjects.[203] There are too few studies of vitamin intakes to confirm these data in patients with CKD. There is evidence that the requirements for vitamin B6 and folate may be increased in uremia, especially in patients receiving erythropoietin therapy. [196] [197]We conclude that the practice of prescribing a water-soluble vitamin supplement for patients with CKD, including those treated by hemodialysis may be useful and probably does little harm. In view of the reports that peripheral neuropathy and hyperoxalemia can occur with high doses of pyridoxine and vitamin C, respectively, “megavitamin” therapy should be avoided. [199] [205]

The requirements for fat-soluble vitamins also have not been established and there are suggestions that fat-soluble vitamins may participate in some of the complications of CKD. For these reasons, fat-soluble vitamins should be given only when there is a well-defined indication and vitamin supplements providing all vitamins should not be prescribed to avoid the dangers of toxicity. For example, vitamin A (retinol) levels generally are increased in the plasma of patients with CKD because plasma levels of retinol-binding protein are high in uremia, and it is likely that tissue levels are normal or increased even in those patients who have normal levels of unbound or free retinol in plasma.[194] The danger associated with providing supplemental vitamin A is that it is suspected as a contributor to anemia, dry skin, pruritus, and even hepatic dysfunction in uremic patients; vitamin A skin and hepatic toxicity was reported in three patients with CKD who were given parenteral nutrition that contained a multivitamin supplement (including 1500 mg vitamin A).[205] Toxicity in these patients resolved when the vitamin supplement was discontinued indicating that vitamin A should be removed from parenteral nutrition solutions used to treat patients with CKD.

Epidemiologic data also raise potential concerns about prescribing vitamin A for CKD patients. A cross-sectional study using data from over 15,000 participants in NHANES III found that a higher serum vitamin A level was associated with an increased risk of elevated creatinine whereas higher serum vitamin C was associated with a reduced risk.[206] These results suggest that vitamin intake may influence the risk of CKD, but prospective studies are needed.

Vitamin A may have an adverse impact on bone health. A large cohort study of women found that the risk of hip fracture was twice as high in those whose intake of retinol was more than 2000 mg/d compared to less than 500 mg/d.[207] A high intake of vitamin A may impair bone remodeling and retinol appears to interfere with vitamin D-stimulated intestinal absorption of calcium.[208] The impact of vitamin A intake on bone health in CKD requires further study.

The requirements for vitamin E, another fat-soluble vitamin, are also not established. Vitamin E has the potential to suppress the responses to oxidative injury of cells and oxidative injury that might contribute to progression of CKD. In experimental models of CKD, vitamin E reduced the degree of injury in rats with experimental IgA nephropathy or glomerulosclerosis following subtotal nephrectomy or diabetes. There is no evidence for a similar benefit in patients with progressive CKD. Can an inadequate intake of vitamin E (or other antioxidants such as selenium) cause clinical problems? It is suggested that vitamin E might combat the lipid peroxidation and oxidant stress that is in part responsible for an increased red cell turnover in uremia.[209] On the other hand, there are reports that plasma vitamin E levels are normal in uremic patients.[194] In a post-hoc analysis of the HOPE Study that included 993 participants with serum creatinine values 1.4 to 2.3 mg/dL, investigators evaluated the impact of vitamin E supplementation (400IU/day) on cardiovascular and renal outcomes.[210] After an average of 4.5 years of follow-up, vitamin E supplementation had no effect on death, development of cardiovascular disease, or progression of proteinuria. Thus, this dose of vitamin E supplementation had no apparent impact on clinically important outcomes. We do not recommend routinely administering vitamin E to patients with CKD unless clinical conditions can be clearly reversed by vitamin E supplements.

Recommendations for supplemental vitamin D are complex and are discussed in Chapters 52 and 56 .

Recommendations for providing trace element supplements for uremic patients are controversial for several reasons: it is very difficult to determine if body stores are sufficient or excessive, and it is difficult to prove that symptoms are reversed solely by administration of trace elements.[194] Based on postmortem studies, the distribution of trace elements in different tissues of uremic patients is abnormal, but it is not clear that these abnormalities are clinically important. For example, plasma and leukocyte zinc are reported to be decreased and may be associated with endocrine abnormalities such as high plasma prolactin levels.[211] One report suggested that zinc absorption was low in hemodialysis patients and that iron tablets or aluminum hydroxide inhibited zinc absorption.[212] A zinc supplement has been reported to increase B-lymphocyte counts, and improve granulocyte motility, taste, and sexual dysfunction.[194] Another trace element that has been studied more extensively is aluminium because aluminium-containing antacids that have been used to control serum phosphorus and can be associated with the development of bone disease (see Chapter 52 ). Aluminium-based antacids given to critically ill patients increased plasma levels sharply, especially when there was renal insufficiency and this can be considered a complication of hyperalimentation.[213] In stable patients with CKD, the degree of renal insufficiency determined how much aluminium is retained during treatment with aluminium-based antacids. Excess aluminum also can be associated with reduced serum iron stores, which can contribute to resis-tance to the erythropoietin administration. Other trace elements and their beneficial and adverse reactions have been scarcely studied in patients with CKD. There are reports about specific toxic reactions caused by contamination of the dialysate with trace elements and hence, we do not recommend giving supplements of trace elements unless there is documentation (or at least a high degree of suspicion) that trace element deficiency is responsible for a complication. The exception would be patients who are receiving long-term parenteral or enteral nutrition. Finally, the appearance of skin rashes, neurologic abnormalities, or other unexplained problems in dialysis patients should prompt a search for excessive concentrations of trace elements in the dialysate.

Herbal Supplements

Use of complementary medicine is widespread, including the use of herbal supplements. Unfortunately, few of these supplements have been rigorously studied for safety or effectiveness. There have been several reports of nephrotoxicity from different supplements either due to the compounds themselves or contaminants. The potential risk of herbal remedies has recently been reviewed.[214] Based on the absence of information demonstrating benefit and the potential risks involved, we recommend that if the composition and safety of an herbal remedy is unknown, it should not be taken.


Adults in neutral protein balance have equal rates of protein synthesis and protein degradation whereas growing children have a positive protein balance because the rate of protein synthesis exceeds the rate protein degradation. Because it is expensive and technically difficult to measure protein synthesis and degradation, nitrogen balance is frequently calculated and assumed to provide the same information as protein metabolism. Nitrogen balance is calculated as the difference between the intake and excretion of nitrogen in subjects with normal kidney function. In patients with CKD, however, more than the intake and output of nitrogen must be measured. The accumulation of nitrogen-containing products in body fluids must also be measured because these nitrogenous products are not converted into body protein. Instead, their accumulation causes uremic symptoms; this has been demonstrated by reducing their accumulation through restricting dietary protein or by dialysis and observing symptomatic improvement. Thus, CKD is a state of protein intolerance because symptom-producing waste products are generated by the catabolism of dietary protein or body protein stores (or both).


In terms of moles, urea is the major waste product produced from protein. Once produced, urea like other waste products has three fates: it is excreted, accumulates in body fluids, or is degraded. Because protein intake is directly and closely correlated with the production of urea and hence, other nitrogen waste products, the severity of uremia can be estimated from the steady-state concentration of SUN.[215] This is calculated by rearranging the clearance formula so that production of urea minus its degradation divided by the urea clearance yields the steady-state SUN. Alternatively, the steady-state SUN can be estimated from intake of protein, which is 16% nitrogen. If the non-urea nitrogen (0.031 gN/kg/day) is subtracted from dietary nitrogen, this value divided by urea clearance yields the steady-state SUN. The calculation assumes that urea clearance is independent of the plasma concentration, which is reasonable for subjects with CKD. The steady-state SUN is useful because it expresses the severity of renal impairment in relation to the nitrogenous waste products. The key concept is that the steady-state concentration of any nitrogen-containing waste product produced from dietary protein or during protein catabolism will increase in the blood parallel to an increase in the SUN. [217] [218] [219] [220]

Urea is emphasized because it has been known since the classic report of Folin that urea nitrogen excretion by normal subjects varies directly with protein intake.[220] The net production of urea or the urea appearance rate is the principal quantity to consider in prescribing the diet for patients with kidney disease. It is calculated as the sum of urea excreted and accumulated and it provides an estimation of the intake of nitrogen (principally protein) of subjects with and without renal disease. [217] [218] [219] [220] For dialysis patients, this relationship between urea turnover and protein intake has been labelled “urea generation” or “protein catabolic rate (PCR)” by Sargent and co-workers[221]and is calculated as the sum of urea excreted and removed by dialysis plus changes in the body pool of urea. Obviously, this is the same as the urea appearance rate and hence, closely parallels protein in the diet. The name is misleading, however, because the rate of protein catabolism is far greater: the nitrogen flux during the daily processes of protein synthesis and degradation amounts to 45 g to 55 g of nitrogen per day, which is equivalent to 280 g to 350 g of protein or more than 1 kg of muscle (muscle is assumed to be 20% protein). [223] [224] The implication that PCR is a measure of whole body protein catabolism is incorrect, but the principle of conservation of mass indicates that the nitrogen arising from dietary nitrogen plus the difference between whole body protein synthesis and degradation is indeed waste nitrogen production.

Urea Production and Degradation

Rates of urea production and degradation require measuring the plasma disappearance of 14C- or 15N-urea. With this technique, the rate of urea production exceeds the steady-state rate of urea excretion in both normal and uremic subjects. This difference is due to degradation of urea by bacterial ureases in the gastrointestinal tract. The rate of urea degradation in normal adults eating a diet of about 90 g protein/day averages 3.6 g/day of nitrogen; similar values are found in patients with CKD. Another means of evaluating urea degradation is to express it as an extrarenal urea clearance, the rate of urea degradation divided by the plasma concentration of urea. The extrarenal urea clearance of normal subjects averages about 24L/day.[223a] If the same extrarenal clearance was present in CKD patients with a high SUN, the amount of ammonia derived from urea would be very high, but the quantity of ammonia arising from urea is not significantly different from that of healthy subjects.[224] This means that the extrarenal clearance of urea in CKD patients is greatly reduced. For example, in patients being treated with low-protein diets supplemented with amino acids or their α-keto- or α-hydroxy analogues, the extrarenal clearance averaged less than 4L/day. [226] [227] Thus, the amount of nitrogen available from urea degradation is not as large as originally thought presumably because chronic uremia induces a change in the gut mucosa that limits access to bacterial ureases. It remains possible, however, that a rapid elevation of plasma urea, as occurs in patients with acute renal failure, might increase the rate of urea degradation.

Understanding of urea metabolism is critical for prescribing the diet for patients with CKD because a goal is to reduce the accumulation of potential uremic toxins. This will require reducing dietary protein to minimize net urea nitrogen production (i.e., urea appearance). One factor that influences urea metabolism is volume depletion with diuretics,[226] which leads to increased passive reabsorption of urea. Another factor is sodium depletion, which causes urea appearance to rise in both animals and humans. [228] [229] The mechanism for stimulation of urea production with sodium depletion is unknown, but apparently, it does not require glucocorticoids.[227]


Creatinine is formed by a nonenzymatic process that dehydrates creatine and creatine phosphate. The major pool of creatine and creatine phosphate is muscle, which ac cumulates these precursors of creatinine by an active transport system. Because the production of creatine is nonenzymatic, the turnover rate of the creatine pool is only 1.7% per day; a change in the rate of creatinine production does not reach a new steady state for 41 days. [94] [230] The slow turnover is a major reason why the rate of creatinine excretion has been used as an index of lean body mass. Unfortunately, there is considerable variability in creatinine excretion by mechanisms that add to collection errors. To standardize the assessment of lean body mass, the average of three consecutive days of creatinine excretion is required for any reasonably precise estimate of lean body mass. [231] [232] Besides variations in lean body mass, meat in the diet changes creatinine excretion: when the diet is creatine-free, creatinine excretion falls about 15%.[230] The fact that creatinine excretion does not decrease even more with meat-free diets reflects the fact that creatine production is stimulated by low protein or low creatine diets.[231]

Age is an important factor affecting creatinine excretion in normal adults, in addition to dietary creatine/creatinine and lean body mass.[232] In order of descending importance, the relationship between age and creatinine excretion is the result of: (1) a lower lean body mass and hence, muscle as a fraction of weight (aging is associated with increased body fat); and (2) a presumed decrease in meat intake with aging.[230] In patients with advanced CKD, creatinine excretion is lower than predicted by any change in their lean body mass.[228] More importantly, creatinine production in patients with CKD was found to be virtually the same as the rates predicted for normal subjects of the same age, sex, and weight.[233] The explanation for this decrease in creatinine excretion in advanced CKD must be the presence of creatinine degradation.[234]

The first definitive evidence for creatinine degradation was reported by Jones and Burnett, who measured the disappearance of 14C-labeled creatinine administered to uremic patients by injection or by mouth.[235] They detected radioactivity in products of creatinine metabolism including sarcosine, N-methyl hydantoin, creatine, and carbon dioxide. We examined the fate of injected 14C-creatinine in patients with CKD and found that creatinine degradation was correlated positively with the serum creatinine concentration.[233] Therefore, creatinine, like urea, is recycled, to form creatine. Based on the creatinine degradation rates we measured, the extrarenal creatinine clearance was found to average only 0.039L/kg/day. This explains why creatinine metabolism is relevant to total creatinine clearance only when serum creatinine concentration is high. The low extrarenal clearance also could explain why creatinine degradation has not been detected in humans or animals with normal renal creatinine clearances and normal serum creatinine values.

The extrarenal creatinine clearance is most likely due to creatinine degradation by intestinal bacteria because intestinal flora obtained from the intestines of healthy subjects or CKD patients degrade creatinine readily.[236] On the other hand, creatinine metabolism in uremic subjects was not suppressed by oral administration of antibiotics, even though the dose was sufficient to inhibit urea degradation.[233]

Physiologically, creatinine degradation and the decline in creatinine excretion that follows restriction of dietary protein means that creatinine excretion cannot be used as an index of lean body mass in patients with CKD. It also means that judgments about changes in progression of CKD based on serum creatinine cannot be made for 4 months (three half lives of creatine turnover) following a change in dietary protein.[237]

Uric Acid

The fractional clearance of uric acid rises markedly at GFR values below 15 mL/min and the ratio of urate excreted to GFR increases about fivefold because there is increased tubular urate secretion and reduced reabsorption.[238]Besides this adaptation, the steady-state level of uric acid excretion by patients with advanced renal failure falls to about 100 to 300 mg/day (normal rates, 400 to 600 mg/day). Because a serum uric acid level above 10 mg/dL is unusual in patients with CKD, there must be extensive extrarenal degradation of uric acid. In addition, a protein-restricted diet generally is associated with a lower purine intake.[239] This is relevant because protein intake may drop spontaneously in patients with advancing renal insufficiency. Besides decreased uric acid production, CKD probably increases the degradation of uric acid because gastrointestinal bacteria flourish in CKD.[240] Sorensen reported that intravenously injected, radiolabeled uric acid could not be completely recovered in the urine of either healthy subjects or patients with CKD and calculated that extrarenal urate clearance accounts for as much as 65% of uric acid produced by patients with renal insufficiency.[241] Intestinal bacteria probably are responsible for uric acid degradation because the fraction of urate degraded is reduced from 22% to 3% by oral administration of neomycin and streptomycin.[241]

Many compounds that are produced during degradation of uric acid (e.g., ammonia, urea, allantoin) are excreted by the kidney. Consequently, extrarenal clearance of urate or other compounds does not necessarily eliminate nitrogen; it simply may lead to accumulation of other compounds.[242] Still, degradation of urate must contribute to the fact that there is a low incidence of gouty arthritis or renal urate deposits of CRF patients. Uric acid crystals surrounded by inflammatory cells and fibrous tissue may be found in the renal medulla of nongouty patients with long-standing progressive renal insufficiency, but they are unusual. The ability of long-term allopurinol therapy to significantly slow the progression of chronic renal insufficiency in patients with hyperuricemia is controversial. Early studies using less precise measurements of changes in kidney function found no benefit but a recent study did observe slower progression with allopurinol. [245] [246] Pathogenic role for uric acid in producing vascular disease has been proposed.[245] Johnson and colleagues point out that humans have a higher serum uric acid level than other primates or animals, presumably because they have a mutation in uricase (the enzyme that initiates degradation of uric acid). Experimentally, a higher uric acid is associated with the development of hypertension and this in turn seems to be of the “salt-sensitive” type as well as vascular disease. When rats were given oxonic acid in order to block uricase activity, the serum uric acid level increased to about 2 mg/dL producing progressive renal insufficiency, which was linked to the development of glomerular hypertrophy and pathologic changes in arterioles of the kidney.[28] All of these changes were substantially ameliorated by administering allopurinol or a uricosuric diuretic. This association between uric acid and vascular damage has not been appreciated previously, possibly because patients with hypertension were not included in evaluating the effects of a high uric acid. For example, Fessel[246] eliminated patients with severe hypertension in his analysis of the outcome of high levels of uric acid. He examined the clinical course of 113 patients with asymptomatic hyperuricemia and 168 patients with gout, some of whom had mild renal insufficiency. He concluded that, unless serum uric acid exceeded 10 mg/dL in women or 13 mg/dL in men, a high uric acid alone will not affect residual renal function. Thus, the question remains whether patients with hypertension will develop vascular damage and progressive renal insufficiency because their serum uric acid is increased.

Siu and colleagues performed a 12-month prospective, randomized trial of allopurinol versus usual therapy in 54 hyperuricemic individuals in China with CKD. The outcomes evaluated were changes in blood pressure and rate of progression of renal insufficiency.[244] Although serum uric acid levels significantly decreased from 9.8 mg/dL to 5.9 mg/dL in allopurinol treated subjects, there were no significant differences in systolic or diastolic blood pressure at the end of the study. There was a nonsignificant trend toward a lower serum creatinine level in the treatment group. Overall, the combined end point of significant deterioration in renal function and dialysis dependence was reached by 16% of participants in the allopurinol group compared with 46% in the control group (P = 0.02). One participant dropped out due to a skin rash. This study raises the possibility that allopurinol is safe and reduces the rate of renal function decline in individuals with CKD.

Other problems associated with a high serum uric acid are uncommon in patients with CKD. For example, uric acid stones are uncommon; they occurred in only 1.0% to 2.6% of 113 patients with normal renal function and asymptomatic hyperuricemia observed for 8 or more years.[246] Likewise, in nongouty patients with renal insufficiency and hyperuricemia, uric acid stones are rare. Based on these data, the widespread use of allopurinol can not be recommended until other studies document a beneficial effect on progressive renal insufficiency. The safer approach is to reduce dietary protein, which will decrease uric acid production.[247]


The loss of renal mass reduces the capacity to excrete ammonia, even in response to metabolic acidosis (see Chapter 7 ). The major source of blood ammonia is the bacterial degradation of urea, amino acids, peptides, and protein in the intestine; there also is degradation of glutamine to ammonia in the small intestinal mucosa. Fortunately, ammonia transported from the intestine into the liver is readily converted to urea so that blood ammonia levels in patients with renal insufficiency should not be elevated. In one report, there was a slightly high blood ammonia but the mechanisms for this finding and its clinical importance are unknown.[248] There also are isolated cases of hyperammonemia occurring in patients with CKD who have apparently normal liver function.[249] The mechanisms causing hyperammonemia in these cases include partial defects in urea cycle enzymes or other inherited disorders, high-dose chemotherapy, and infections. [251] [252] Urease-producing bacteria in urinary bladders or intestinal abscesses also can cause clinically important hyperammonemia, especially if venous blood from the infected area drains into the vena cava and bypasses the liver.

Other Nitrogenous Compounds in Urine

The difference between total urinary nitrogen and urea nitrogen in urine includes the nitrogen in uric acid, peptides, protein, and creatinine is termed “unmeasured nitrogen”. [217] [220] In patients without proteinuria, unmeasured nitrogen in urine is only 6.2 mg/kg/day when total urinary nitrogen was 10.3 g/day.[220] In patients with proteinuria, albumin clearance as a fraction of GFR varies from 0.3% to 3.0% or more.[251] In general, protein clearance falls as GFR decreases, but the amount excreted depends on factors other than the degree of glomerular damage. [254] [255] For example, raising dietary protein increases proteinuria in nephrotic patients, whereas dietary protein restriction reduces proteinuria. Drugs also affect the degree of proteinuria; it falls when blood pressure is reduced and especially with ACE inhibitors. [43] [89] [96] [97] [256] [257] [258] [259]

Fecal Nitrogen

Patients with chronic kidney disease (CKD) frequently have occult intestinal blood loss; in one study, the average blood loss was 6 mL/day and this may be difficult to detect by the guaiac technique.[258] When the urea appearance exceeds protein nitrogen intake or when the SUN to serum creatinine ratio exceeds 10:1, gastrointestinal bleeding must be considered. Other causes for a change in fecal nitrogen at least in normal adults include variation in dietary roughage, fermentable carbohydrates, and nitrogen. [183] [217] [261] Kopple and colleagues examined rates of nitrogen excretion in nondialysis CKD patients and concluded that fecal nitrogen was correlated with protein intake.[217]In contrast, Maroni and associates concluded that fecal nitrogen varies with body weight but not with protein intake.[216] More recently, results from 52 adult, non-dialysis CKD patients eating various types of diets were examined.[219] In these CKD patients, there was no relationship between dietary nitrogen and fecal nitrogen excretion.

Skin Nitrogen Losses

In otherwise healthy adults, the average loss of nitrogen loss from skin and other unmeasured sources averages 0.5 g nitrogen/day. This amount should be used when calculating nitrogen balance. Because the concentration of urea in sweat is proportional to the plasma urea concentration increased nitrogen loss can occur in uremic individuals during periods of heavy perspiration.

Total Nonurea Nitrogen Excretion

Nonurea nitrogen excretion consists of the nitrogen in feces plus all other forms of nitrogen excreted in urine except urea (i.e., urinary creatinine, uric acid, ammonium, peptides). Maroni and colleagues measured the average nonurea nitrogen excretion of 19 CKD patients who were in neutral or nearly neutral nitrogen balance.[216] The patients were eating varied diets from as much as 94 g/day of protein to low-protein diets supplemented with ketoacids. Despite this large range of intakes, nonurea nitrogen was correlated with body weight and averaged 0.031 g/kg/day of nitrogen. Using this average nonurea nitrogen excretion of 0.031 g N/kg/day, the estimated nitrogen balance did not differ statistically from the measured nitrogen balance. Interestingly, 0.031 g/kg/day of nitrogen ( Fig. 53-2 ) is similar to the value for nonurea urinary nitrogen plus fecal nitrogen excreted by normal subjects or dialysis patients. Consequently, protein intake can be estimated as the sum of urea nitrogen appearance plus an estimate of non-urea nitrogen excretion (i.e., 0.031 g nitrogen/kg body weight/day).

FIGURE 53-2  Calculated values of total nonurea nitrogen excretion (NUN) in normal subjects (▴, &z.cirf;, ▪) and patients with chronic renal failure being treated with nutritional therapy (◆, ⊗,    ,    ,    ) or by hemodialysis or continuous ambulatory peritoneal dialysis (⊠, ⊡).  (From Maroni BJ, Steinman TI, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27:58, 1985.)



The same equation can be used to assess compliance with the amount of prescribed dietary protein. Kopple and associates examined these relationships and reported fecal nitrogen is correlated with nitrogen intake, but also noted that total nonurea nitrogen excretion did not increase with dietary protein intake or body weight.[217] They concluded that nonurea nitrogen excretion is the same for all patients and proposed an equation for dietary protein that is equal to 1.204 times the urea appearance value plus 1.74 g nitrogen per day. As noted, in 80 nitrogen balance measurements performed on 52 CKD patients eating different levels of dietary protein, neither fecal nitrogen nor nonurea nitrogen were found to be correlated with dietary nitrogen.[219] Instead non-urea nitrogen excretion was averaged 0.031 g nitrogen/kg body weight/day. The same analysis of the accuracy of equations for estimating dietary protein showed that the original formula derived by Maroni and co-workers had a somewhat lower error in documenting protein intake. These relationships are emphasized because the equation is needed to assess compliance with the diet and to ensure that it contains the proper amount of protein. The caveats are that the equations for estimating protein intakes are based on the assumption that the patient is in neutral nitrogen balance (i.e., that nitrogen excretion equals nitrogen intake) and that estimates of nonurea nitrogen excretion do not apply to hypercatabolic patients or to patients receiving hyperalimentation or “totally digestible” diets.[260]


Nitrogen excretion by normal individuals or patients with CKD can be categorized as urea nitrogen appearance plus all other forms of nitrogen or nonurea nitrogen. The production of urea nitrogen is closely related to protein intake whereas the excretion of nonurea nitrogen is more closely related to weight. These relationships can be used to estimate dietary protein intake with the caveats that the patient should be in neutral or in nearly neutral nitrogen balance and not receiving intravenous hyperalimentation.


In patients with CKD, the goal of minimizing the accumulation of nitrogenous waste products must be balanced against the need to supply enough essential amino acids in the diet to prevent loss of body protein. The optimal diet is one in which protein synthesis equals protein degradation because in this case, the urea appearance rate approaches zero and hence, the accumulation of nitrogen-containing waste products will be minimal. As discussed, it is difficult to measure the daily rates of protein synthesis and degradation, and they are subject to change by several factors, including an insufficient diet. [216] [224] [263] [264] More importantly, the rates of protein turnover in the body are very high, so even a small increase in protein degradation or decrease in protein synthesis persisting for several weeks can cause a marked loss of lean body mass. Although the “gold standard” for evaluating if protein stores are being maintained is nitrogen balance, it is difficult to calculate, requiring careful measurement of food eaten and all the nitrogen that is excreted and accumulated.[263] Nitrogen balance also does not determine whether protein synthesis or degradation is abnormal and it rarely gives insights into mechanisms that cause loss of protein stores. Other methods of assessing body protein stores also have limitations. For example, hypoalbuminemia is a frequently cited indication that malnutrition is present but albumin stores are affected by many factors including inflammation, acidosis, and losses of albumin. [43] [266] As reviewed later, a major difficulty arising when protein stores are assessed lies in interpreting what the measurements means.

Nitrogen Balance

Nitrogen balance is calculated as the difference between nitrogen intake and excretion plus accumulation of nonprotein nitrogen (principally urea). The half-life of urea disappearance in a normal adult is about 7 hours, so even a large load of urea is mostly excreted within 24 hours. It follows that in normal subjects changes in the urea pool can be ignored when their nitrogen balance is being calculated. In patients with CKD, however, the half-life of urea is prolonged because renal function is impaired. Consequently, the SUN and the body pool of urea nitrogen may not become stable for several days after dietary protein. For this reason, the accumulation or loss of urea nitrogen in the body must be taken into account when the nitrogen balance of patients with CKD is measured. This is possible because the concentration of urea is equal throughout most of body water, so changes in the urea nitrogen pool can be calculated by assuming that the urea space is equivalent to 60% of body weight. Indeed, the average body water in nonedematous uremic patients is ≈60% of body weight. [51] [217] When body water in liters is multiplied by the SUN in g/L, the result is the size of the urea nitrogen pool. It is important to recognize the precision of measuring SUN can dominate the nitrogen balance calculation if only two measurements are made. For example, a change in SUN from 140 to 150 mg/dL, which may be within the laboratory error of measuring the SUN, represents about 4 g of nitrogen in a 70-kg person. Because both a change in weight or in the SUN can affect the nitrogen balance calculation, it is more accurate to estimate the urea space on a given day and then calculate the urea pool size each day (i.e., SUN times the body water plus any change in weight). The daily rate of change in the urea nitrogen pool can then be calculated by linear regression or other curve-fitting techniques. [217] [220] [267] The average change in the size of the urea pool is added to the nitrogen in urea and all other compounds that are excreted to obtain an accurate value of nitrogen balance. This calculation assumes that water accounts for all changes in weight during short periods (i.e., dry weight or body weight minus body water remains constant). It is more precise to measure the urea space using 15N- or 14C-labeled urea. [217] [227] This avoids the error of assuming that all uremic subjects have the same fraction of body weight that is body water because some patients reportedly have a urea space that exceeds body water or even body weight.[224] Notably, measuring the urea space in patients with advanced CKD does not require any correction for loss of the injected, labelled urea in urine as might be necessary in subjects with normal kidney function.

Other sources of nonprotein nitrogen that accumulate in patients with CKD, such as creatinine, can be ignored because even a large increase in serum creatinine has a minimal influence on retained nitrogen. For example, when serum creatinine rises from 10 to 15 mg/dL, it increases the nitrogen retention by only 0.3 g in a 70-kg person.[233] Changes in the pools of nonprotein nitrogenous compounds are not commonly measured because their volumes of distribution are not known. For example, following extensive trauma, the loss of tissue glutamine nitrogen may amount to several grams. Calculating a change in the glutamine pool is difficult because of the large number of assumptions required.[266]

Urea Nitrogen Appearance Rate

Because the principal non-protein source of nitrogen in the body is urea, the accumulation and excretion of urea nitrogen are needed to evaluate protein stores. Both are evaluated within the urea nitrogen appearance rate, which is calculated as the sum of urinary excretion plus accumulation (positive or negative) in the body's pool of urea nitrogen. It should be calculated from several consecutive 24-hour urine collections, daily determinations of weight and SUN, and measurement of the urea space using labelled urea, or 60% of weight in nonedematous subjects. [217] [226] [227]

Knowledge of the urea appearance rate in patients with CKD provides a quantitative measurement of the parameter that nutritional therapy seeks to minimize: a minimal urea appearance value is associated with the most efficient use of dietary protein. For example, Taylor and associates fed low-protein diets containing different amounts of calories to normal young men and women.[266a] Their data reveal a correlation of r = -0.87 between the calculated fraction of dietary protein used for protein synthesis and urea excretion (which is equal to urea appearance in normal subjects). Cottini and associates[218] found that a diet containing 3 to 4 g nitrogen/day was associated with neutral nitrogen balance in patients with chronic renal failure ( Fig. 53-3 ). Clearly, interpretation of the urea nitrogen appearance of patients with CKD requires some knowledge of nitrogen intake because of the close relationship between nitrogen intake and urea appearance.

FIGURE 53-3  Nitrogen balance and urinary urea as a function of nitrogen intake in chronically uremic subjects fed varying quantities of dietary protein. All subjects receiving less than 4 g of nitrogen per day were in neutral or negative nitrogen balance, and urea excretion tends to plateau at a low value. In subjects receiving more than 4 g of nitrogen per day, the steady-state urea nitrogen excretion is equal to the increment in nitrogen intake above the amount required to achieve neutral nitrogen balance.  (From Cottini EP, Gallina DK, Dominguez JM: Urea excretion in adult humans with varying degrees of kidney malfunction fed milk, egg, or an amino acid mixture: Assessment of nitrogen balance. J Nutr 102:11, 1973.)



Serum Albumin and Malnutrition

The concentration of serum albumin is frequently cited as an index of the adequacy of the diet and a low value has been generally used to support a diagnosis of malnutrition.[267] This is erroneous.[268] The serum albumin concentration is the balance between synthesis and degradation of albumin, losses of albumin (e.g., the nephrotic syndrome), and its dilution by body water. When careful measurements of albumin turnover were made in hemodialysis patients, serum albumin was shown to be correlated with body weight and estimates of plasma volume suggesting that variations in albumin synthesis are an important factor controlling serum albumin.[264] Subsequent studies showed that the more important determinant of the serum albumin concentration is variability in albumin catabolism, which is determined by evidence of inflammation. [266] [272] In these studies, metabolic acidosis was unfortunately not evaluated but should be in future studies because it will reduce serum albumin.[270]

Undoubtedly, dietary protein or calories can influence serum albumin but the question is: does malnutrition cause hypoalbuminia? The definition of malnutrition is a complex of abnormalities that are due to an inadequate or unbalanced diet.[268] In fact, there are many metabolic abnormalities in CKD besides the diet that contribute to the “uremic syndrome” that include fatigue, loss of lean body mass, and a decrease in serum albumin and other plasma proteins. Even in conditions that are much more obviously related to malnutrition, changes in serum albumin are small. For example, when patients with anorexia nervosa were compared with age and height-matched subjects, the serum albumin of the patients was not statistically different even though the anorexia nervosa patients had ≈34% lower body weight and 22% lower values of muscle mass.[271] In summary, serum albumin is affected by several factors caused by advanced renal insufficiency besides an inadequate diet.

Many of the abnormalities associated with the loss of protein stores in patients with CKD are in fact ameliorated by restricting dietary protein (e.g., acidosis or insulin resistance). [275] [276] Clinically, low-protein diets do not cause malnutrition. Patients in the MDRD Study who were prescribed the lowest amount of dietary protein had an increase in their serum albumin on average.[14] Secondly, non-acidotic patients eating very low-protein diets supplemented with ketoacids and essential amino acids over periods of at least 1 year had normal values of serum albumin. [275] [277] [278] [279] Other reasons that serum albumin is not reliable index of protein stores is that plasma serum albumin responds relatively slowly to changes in protein stores because it has a half-life of about 20 days. The presence of high values of acute phase reactant proteins suggest that inflammation is a major cause of the morbidity and mortality of patients with CKD. In support of this conclusion, Kaysen and co-workers[264] showed that albumin synthesis falls sharply in subjects with inflammatory illnesses (i.e., albumin functions as a “negative” acute phase reactant). Secondly, many patients with CKD have evidence of inflammation and arteriosclerosis, and there also is an association between the presence of hypoalbuminemia in dialysis patients and higher serum levels of the acute-phase reactant proteins, amyloid A and C-reactive protein (CRP).[277] The interpretation of these results is not clear. Kaysen and colleagues reported that a high CRP level in 1 month did not predict a decrease in serum albumin in the subsequent month,[264] but they did find a relationship between an increase in the blood levels of longer-lived acute-phase reactant proteins and a lower serum albumin.[269] Specifically, high serum levels of the longer-lived acute phase reactant proteins, ceruloplasmin, and alpha-1 acid glycoprotein predicted a lower serum albumin level in the succeeding month. It was concluded that inflammation can cause serum albumin to decrease whereas the diet plays a minimal role in producing hypoalbuminemia in hemodialysis patients.

Several groups have reported high levels of circulat-ing inflammatory cytokines or correlations (or both) between biochemical evidence of inflammation and atherosclerosis in dialysis patients. [270] [280] [281] [282] [283] [284] This result led to the proposal that there is a syndrome of malnutrition, inflammation, and atherosclerosis in patients with CKD: the MIA Syndrome.[267] The implication is that malnutrition may be the cause of this syndrome. However, malnutrition means there are abnormalities caused by an inadequate or unbalanced diet.[268] Consequently, correcting the diet should eliminate or benefit the severity of the syndrome. To date, feeding more protein or calories has not eliminated inflammation or atherosclerosis in patients with CKD. [271] [285] Consequently, it is prudent to avoid linking the loss of body protein stores and fatigue to dietary deficiency. Instead, it is preferable to concentrate on modifying the diet to eliminate uremic toxicity. For example, one factor that is linked to accelerated atherosclerosis in patients with CKD is the accumulation of homocysteine.[283] The cause of high levels of this compound in these patients with CKD is unknown but seems to be linked to abnormal metabolism of sulphur amino acids in patients with CKD.[284] A high homocysteine level may portend a poor prognosis in patients with coronary artery disease.[288] [289] The treatment for this disorder in normal adults is vitamin B6 and folinic acid, but it is only partially successful in patients with CKD.[287] It is possible that this abnormality in amino acid metabolism plus inflammation cause accelerated atherosclerosis.[288]

Serum Transferrin, Prealbumin, Complement, and Insulin-Like Growth Factor-1

Serum transferrin has been used as a marker of protein nutrition because it is sensitive to dietary protein deficiency and has a shorter half-life (≈10 days). Unfortunately, serum transferrin levels, like serum albumin will change with factors other than nutritional status. Serum transferrin may rise when iron stores are depleted and diminish by as much as 50% with chronic inflammatory disorders such as malignant tumors, rheumatoid arthritis, and infections. In contrast, erythropoietin therapy causes no significant change in serum transferrin levels, at least in dialysis patients, nor does erythropoietin cause any major change in nutritional status and no change or minimal improvement in serum albumin, anthropometry, and muscle protein content. [292] [293] Based on these results, there is no persuasive reason to use erythropoietin in predialysis patients solely to improve indices of nutritional status.

The serum concentration of prealbumin has also been touted as an index of nutritional state. It has a half-life of about 2 days and therefore changes more rapidly with variations in nutritional status. Unfortunately, other factors that cause changes in serum albumin (e.g., inflammation) also influence serum prealbumin. Abnormalities in most of the components of serum complement have been found in patients with chronic uremia. Some of these changes may be due to protein malnutrition, because parenteral administration of essential amino acids for a month reportedly corrected most of them.[291]

Insulin-like growth factor-1 (IGF-1) is the major hormone that mediates the effects of growth hormone. IGF-1 has been studied in uremic patients for three reasons. First, administration of growth hormone is associated with a remarkable improvement in the growth of children and it may improve the nutritional status of hemodialysis and CAPD patients. [295] [296] [297] Second, IGF-1 administration has been proposed as a means of augmenting renal function in patients with CKD.[295] Finally, administration of IGF-1 has been proposed as a means of inhibiting catabolism of muscle protein.[296] There is evidence for reduced mRNA levels of IGF-1 but normal or increased levels of IGF-1 and IGF-II in muscle biopsies obtained from hemodialysis patients.[297] This is relevant because acute administration of IGF-1 can improve muscle protein synthesis in normal or uremic patients, suggesting there is reduced responsiveness to IGF-1 in hemodialysis patients, possibly due to a post-receptor defect in the action of IGF-1. [301] [302] This is a complicated area of research because the action of IGF-1 is influenced by the concentration of IGF binding proteins as well as by circulating levels of amino acids. [303] [304] [305] Evidence that circulating IGF-1 levels are influenced by nutritional status, includes the report that a diet containing an insufficient amount of protein reduces IGF-1 levels, as does the presence of chronic malnutrition.[302] In uremic patients, IGF-1 levels change minimally when protein intake is reduced by as much as 40%.[300] Thus, it is difficult to link IGF-1 to nutritional status. However, serum IGF-1 levels do decrease in response to acidosis and there is evidence that a low serum IGF-1 level is associated with a poor outcome in hemodialysis patients. [306] [307] [308] Clearly, more work is needed to understand the metabolic implications of variations in serum IGF-1 levels.


Anthropometry in patients with CKD has limited predictive ability because most reports are based on a single evaluation and the measurements are then compared to the measurements made by investigators who were studying normal adults.[215] For example, serum proteins can be normal in early CKD but anthropometric measurements demonstrated a loss of muscle mass. Bergstrom[306] reviewed several reports and concluded that there is a high prevalence of anthropome-tric abnormalities in virtually all cross-sectional studies of dialysis patients but attributing these abnormalities to malnutrition is questionable. [18] [271] Unfortunately, reading these reports have led some to suggest that dialysis should be initiated early to avoid malnutrition and improve the prognosis of these patients. [310] [311] [312] There are several reasons to reject this conclusion. First, dietary protein intake of patients with uremia may decrease when they have had minimal or no instruction in a sufficient diet. However, in patients enrolled in the MDRD Study, the largest evaluation of the effects of dietary protein restriction, serum albumin increased when dietary protein was limited and proper dietary instruction was provided. Only two patients in the MDRD Study had to stop the trial because of concerns about their nutritional status.[14] Second, long-term results of patients eating low-protein diets indicate that body weight, serum proteins, and blood biochemistry levels are well maintained even when renal function is very impaired. [275] [277] [278] [279] This indicates that a well-planned diet does not cause malnutrition and it can improve values of blood biochemical levels.[1] Without proper dietary education, however, patients with a serum creatinine above 5 mg/dl were reported to have abnormal serum chemistries including bicarbonate below 15 μM, phosphorus above 7 mg/dL, and SUN above 120 mg/dL.[310] Finally, recent analysis of the influence of “early” dialysis on mortality have led to the conclusion that early dialysis does not prolong life. [275] [314] [315] Indeed, patients who begin dialysis with more advanced kidney disease tended to have less mortality even after correcting for age, gender, body weight, diabetes, leukocyte count, dialysis type, or dialysis access. These results indicate why anthropometrics have not been useful in assessing the effectiveness of nutritional therapy for patients with CKD, especially if there were only a single measurement in a cross-sectional analysis of nutritional status.

Free Plasma Amino Acid and Ketoacid Levels

Fasting patients with advanced CKD have many abnormalities of plasma amino acids, including an increase in 3-methylhistidine and 1-methylhistidine, apparently caused by reduced renal clearance of these amino acids. Plasma valine is usually low as are leucine and isoleucine but to a lesser extent. [316] [317] Garibotto and colleagues reported that similar differences in the concentrations of these amino acids occur after a meal.[315] There are at least two mechanisms accounting for low levels of the branched-chain amino acids (BCAA). A low protein intake will contribute to low plasma levels whereas decreased gastrointestinal absorption plays a minimal role.[316] In fact, in rats with experimental CKD, branched-chain amino acids levels in blood were most abnormal in those fed the highest level of protein.[103] In this same experiment, a high protein diet caused metabolic acidosis, a stimulus for accelerated BCAA catabolism. All three BCAA are irreversibly decarboxylated by the same enzyme, branched-chain ketoacid dehydrogenase (BCKAD), and several factors, including metabolic acidosis and glucocorticoids, stimulate the activity of BCKAD in skeletal muscle. [320] [321] [322] In patients, acidosis is also associated with accelerated catabolism of BCAA; dialysis patients exhibit a correlation between plasma bicarbonate levels and the free valine content in skeletal muscle. [323] [324] [325] Additional support for this conclusion is that correction of metabolic acidosis significantly raises the levels of all three BCAA in the muscle of hemodialysis patients.[322]

Other abnormalities of plasma amino acids include an increased citrulline concentration, attributable to impaired conversion of citrulline to arginine by the diseased kidney. However, measurements made in cells or in rats with experimental CKD indicate that the mechanism for a high citrulline level is probably more complex. [326] [327] There also are unexplained increases in cystine, homocysteine, and aspartate; decreased tyrosine, reflecting impaired hydroxylation of phenylalanine; and a high glycine level and a low or low-normal serine level, perhaps related to diminished production of serine from glycine by the diseased kidney. [328] [329] [330] Total tryptophan is low but free tryptophan is normal because of reduced plasma protein binding.[328] Threonine and lysine concentrations are low for unknown reasons. Thus, the essential amino acids, with some exceptions, tend to be reduced in plasma, whereas some of the nonessential amino acids tend to be increased ( Fig. 53-4 ). Decreased essential amino acids are reminiscent of the pattern present in patients with protein malnutrition.[329] But the abnormalities occur even when the patient intake appears to be adequate and many of the same abnormalities persist after a large meal of meat.[315] It has been shown that the low levels of branched-chain amino acids, the essential/nonessential and valine/glycine ratios, as well as the degree of increase in cystine, citrulline, and methyl histidines, all correlate with GFR suggesting they result from metabolic defects caused by CKD.[330] There is growing evidence that the concentrations of sulphur-containing amino acids (i.e., methionine, cysteine, cystine, taurine, homocysteine) are very abnormal in uremic patients, but the mechanisms accounting for these abnormalities have not been defined.[284] There also is evidence that binding of homocysteine to albumin is related to the high cysteine levels and that abnormal intracellular levels of free sulphur-containing amino acids influence the plasma levels. [287] [334] After an intravenous infusion of amino acids in uremic subjects, the removal of valine and phenylalanine were found to be subnormal, whereas histidine removal was increased.[332] It is not known whether this observation contributes to the high plasma levels of histamine found in uremic patients (especially those with pruritus).[333]

FIGURE 53-4  Plasma amino acids in patients with chronic renal failure treated by protein restriction alone. Results are calculated as percentages of normal values. A logarithmic scale is used, so decreases are emphasized as much as increases. The most abnormal values are shown on the left. Statistical significance cannot be evaluated in view of the variety of sources of the data. Note that not all essential amino acids are subnormal.


In general, the severity of amino acid abnormalities is correlated with the degree of renal insufficiency and uremic symptoms.[330] The abnormalities tend to worsen when protein intake is inadequate. An additional problem in interpreting plasma amino acids is that uremia alters the distribution of amino acids between cells and extracellular fluid, except for erythrocytes and the cerebrospinal fluid (CSF). [316] [337] [338] Bergstrom and associates measured the intracellular concentration of amino acids in muscle of undialyzed CRF patients and found abnormalities that differ somewhat from those seen in plasma ( Fig. 53-5 ): the branched-chain amino acids are subnormal; ornithine is low, as is histidine, threonine, lysine, and arginine. [316] [337] In an evaluation of control and undialyzed CKD patients, Divino Filho and colleagues reported that the branched-chain amino acids, valine, isoleucine, and leucine in muscle were normal.[336] The authors point out that metabolic acidosis was almost absent, so they did not expect that the levels would be low as they found with acidotic, dialysis patients. [323] [325]

Metabolites of amino acids, including those containing sulphur such homocysteine as well as a number of small peptides and amines (including polyamines, guanidines, and other nitrogenous compounds), also accumulate in the blood. [236] [340] Abnormalities in these amino acid metabolites are not reviewed because there is no specific therapy for them; generally, their concentrations decrease when protein intake is reduced and urea appearance falls.


Nitrogen Requirements

Nutritional requirements for dietary protein are based primarily on short-term nitrogen balance measurements that were made while CKD patients, who were moderately physically active, were eating a sufficient amount of calories. Most investigators agree that if there is no complicating illness or condition (e.g., metabolic acidosis or inflammation), the nitrogen requirements of CKD patients are not substantially different from those of normal subjects. [7] [341] [342] Consequently, the minimum daily protein requirement for such patients is 0.6 g protein/kg/day. Note that the weight would be based on an edema-free, standard or normal body weight as determined by The National Health and Nutrition Evaluation Survey (NHANES). [343] [344] The standard body weight for an individual is the median body weight of normal Americans of the same height and gender skeletal frame size and age range. This value is used because Americans are becoming more obese and prescribing protein, calories, and salt, based on actual body weight would exceed the capacity of the kidney to excrete the waste products. Accumulation of acid, phosphates, and other waste products would cause uremic symptoms, hyperparathyroidism, aggravated hypertension, and the abnormalities due to acidosis.[1]

When dietary protein is restricted, it is important to provide adequate energy, at least 30kcal/kg standard body weight.[22] With this regimen, a diet containing only the minimal daily protein requirement (i.e., 0.6 g/kg/day) or a supplemented diet containing only 0.3 g protein/kg/day plus a supply of essential amino acids or their nitrogen-free analogues (ketoacids) will achieve nitrogen balance and maintain normal values of nutritional markers during long-term therapy. [275] [277] [278] [345]

As a measure of nutritional adequacy, nitrogen balance has limitations and other methods have been used to evaluate the requirements for groups of subjects of different ages or with various diseases.[215] These methods include measuring the turnover of a labelled amino acid during its constant infusion. The most widely used method is the leucine turnover technique because it is an essential amino acid and its irreversible degradation is easily measured as expired, labelled CO2. The leucine turnover method is sufficiently precise that it can detect the inadequacy of a nutrient before there is any clinical evidence of any deficit and the method can yield estimates of protein synthesis, protein degradation, and the oxidation of leucine throughout the body. Regarding CKD, it been used to identify metabolic responses activated by uremia, by dialysis, or by changes in dietary protein. [324] [346] [347] [348] [349] [350] A limitation of leucine turnover is that it does not measure protein or amino acid metabolism in individual organs.

To interpret results obtained with this method, elements of leucine metabolism should be understood. The initial step in leucine degradation in all cells is transamination to remove the amino group leaving the leucine ketoacid, α-ketoisocaproate. The next step is irreversible decarboxylation of ketoisocaproate releasing labelled CO2 from the 1-position, which can be measured in expired air and used to calculate the rate of amino acid degradation. To measure protein synthesis and degradation, the plasma ratio (enrichment) of unlabeled leucine or its ketoacid (a-ketoisocaproate) by labelled leucine (or labelled α-ketoisocaproate) in plasma is measured. Thus, the leucine turnover technique yields rate of whole-body leucine oxidation, protein synthesis, and protein degradation. For example, the major response to a meal containing more protein than is needed is a sharp increase in the rate of amino acid oxidation ( Fig. 53-6 ). Conversely, when dietary protein is lowered, amino acid oxidation falls ( Fig. 53-7 ). These responses produce more efficient utilization of amino acids in dietary protein and an improvement in protein synthesis. [277] [345] [351] A decrease in amino acid degradation will also reduce the production of urea as well as all potential toxins arising from protein metabolism. A decrease in amino acid oxidation in response to a low-protein diet has been designated as an adaptation: Young determined that an adequate amount of dietary protein is the level of intake that maintains long-term neutral nitrogen, thus a successful adaptation (a decrease in amino acid oxidation) will not change protein synthesis or degradation.[349] There is however, another adaptation when the intake of protein or an essential amino acid falls excessively, and the capacity for amino acid oxidation reaches a limit. When this occurs, both protein synthesis and degradation fall and comprise secondary adaptations. Changes in protein turnover, however are insufficient to achieve protein balance but they do slow the loss of lean body mass. [216] [352] [353] In summary, the amount of protein in the diet initiates metabolic processes that act to defend body protein stores and minimize negative protein balance. The changes in these metabolic processed are detected by measuring amino acid turnover in response to a meal. It is not known how the body recognizes a decrease or increase in dietary protein but it is well established that metabolic acidosis, dialysis procedure, and/or insulin resistance will interfere with these adaptive responses to cause loss of protein stores. [324] [347] [350] [354] [355]

FIGURE 53-6  Metabolic changes that permit successful adaptation to dietary protein restriction. The initial response to lowering dietary protein is a reduction in the oxidation of amino acids (AA oxidation). Amino acid oxidation declines progressively as protein intake is reduced from an excess (>1 g/kg/d) to the recommended daily allowance (RDA) and even further to the minimal daily requirement (MDR) of 0.6 g/kg/d. In contrast, protein degradation (PD) changes minimally until protein intake is reduced to or below the minimal daily requirement. At this level, amino acid oxidation does not decrease further, but protein degradation falls. These considerations only apply to otherwise normal subjects. When there is a catabolic condition such as acidosis or diabetes, infection, etc., the responses can be blunted or blocked and the ability to preserve body protein stores is lost.


FIGURE 53-7  The relationships between different levels of dietary protein and rates of leucine oxidation in normal subjects and CRF patients during fasting (open circles) and feeding (closed circles). There is a significant correlation between the amount of dietary protein and leucine oxidation during both fasting and feeding showing the adaptive response to changes in dietary protein.  (From Tom K, Young VR, Chapman T, et al: Long-term adaptive responses to dietary protein restriction in chronic renal failure. Am J Physiol 268:E668–E677, 1995.)



An important issue is whether kidney disease per se can block adaptation to a low-protein diet. Only a few studies have evaluated the metabolic responses to dietary protein restriction in patients with CKD. Goodship and co-workers studied non acidotic patients with an average serum creatinine of 5 mg/dL by measuring both short-term nitrogen balance and whole-body amino acid oxidation and protein turnover (i.e., leucine turnover) after an overnight fast and during a meal.[343] When the subjects were fed 1 g protein/kg/day, nitrogen balance was neutral or positive and the values of amino acid oxidation and protein synthesis and degradation were indistinguishable from values measured in normal subjects. When dietary protein was reduced to the minimum daily requirement of 0.6 g protein/kg/day, both the patients and normal subjects were in negative nitrogen balance. The reasons why nitrogen balance was negative may have been related to an inadequate time to adapt to the lower protein intake.[342] Regardless, these results demonstrate that the rates of amino acid oxidation and protein turnover activated in normal subjects and patients with CKD eating low-protein diets are identical. Because the presence of catabolic conditions will increase essential amino acid elimination and protein degradation, these adaptive responses will be overcome resulting in loss of body protein stores.

Masud and colleagues examined the adaptive ability of patients with CKD to activate metabolic responses when they were eating only 0.3 g protein/kg/day plus equimolar supplements of essential amino acids or ketoacids.[342] The GFR of the patients averaged 19 mL/min and none of the eight patients was acidotic. The measurements were made after 2 weeks of each diet in order to allow time for adaptation to the new diet. With both regimens, the patients were in neutral nitrogen balance and they exhibited virtually identical changes in amino acid oxidation and protein turnover during feeding and fasting. As might be predicted from the relationships shown in Figure 53-6 , the rates of leucine oxidation during fasting and feeding in patients eating the low-protein supplemented diets were about 50% lower than those measured in patients with CKD ingesting 0.6 or 1.0 g protein/kg/day. Thus, very-low-protein regimens are a powerful stimulus to conserve dietary amino acids and protein stores. The only difference between the ketoacid and essential amino acid regimens was that with ketoacids, patients achieved neutral nitrogen balance despite a 15% lower intake of nitrogen. Interestingly, the differences in nitrogen balance of CKD patients eating the more restrictive diet versus the standard, low-protein diet of 0.6 g protein/kg/day may reflect a longer period of adaptation. On the other hand, neutral balance has been documented when a low-protein diet is abruptly changed to a ketoacid-based regimen and there is evidence that the ketoacid regimen exerts a beneficial effect on protein turnover.[353] Infusion of the ketoacid of leucine will suppress protein breakdown in starving obese individuals and adding this compound to isolated rat muscle decreases protein breakdown. [357] [358]

Patients with the nephrotic syndrome also adapt to a reduction in dietary protein. Maroni and colleagues reported rates of leucine turnover in patients with CKD with varying degrees of proteinuria.[262] The patients were studied while eating two diets: a standard amount of protein (0.8 g protein/kg/day) or an excess of 1.6 g protein/kg/day. With both diets, the patients and control subjects were found to be in neutral or slightly positive nitrogen balance. The major adaptation activated in nephrotic patients was a decrease in the rate of amino acid oxidation. As can be seen in Figure 53-8 , leucine oxidation in nephrotic patients decreased in proportion to the net protein intake (i.e., the actual protein intake minus urinary losses). This metabolic response is clinically important because restricting dietary protein can decrease the degree of proteinuria. Reducing proteinuria is a major goal of treating patients with CKD because it is often associated with slowing the loss of kidney function.[43]

FIGURE 53-8  The relationships between rates of urinary protein losses and leucine oxidation during fasting (open circles) and feeding (closed circles) while nephrotic patients consumed a protein-restricted diet. There was a significant correlation during feeding.  (From Maroni BJ, Staffeld C, Young VY, et al: Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet. J Clin Invest 99:2479–2487, 1997.)



Factors Causing Increased Dietary Protein Requirements

Metabolic Acidosis

Metabolic acidosis is a major stimulus of the catabolism of amino acids and protein in patients with CKD. The metabolic responses to metabolic acidosis will block the ability of the body to adapt successfully to a decrease in protein intake (see earlier discussion) and cause loss of protein stores by activating specific metabolic pathways that increase the activity of branched-chain ketoacid dehydrogenase and the ubiquitin-proteasome system in muscle. Acidosis not only increases the flux through the catabolic pathways but also stimulates the transcription of the genes encoding components of the pathways. Eliminating these responses benefits the nutritional status of healthy individuals and patients with CKD. First, when the acidosis of CKD is corrected, there is a decrease in the loss of branched-chain amino acids leading to increased levels of these amino acids. [323] [325] Second, correction of metabolic acidosis in predialysis patients as well as those treated by hemodialysis or CAPD sharply decreases the degradation of protein. [324] [348] Finally, in a randomized trial of year-long therapy to eliminate acidosis in CAPD patients resulted in weight gain and improved anthropometric indices indicating an increase in muscle mass.[356] Using the same strategy, correction of acidosis was shown to decrease the levels of mRNA encoding ubiquitin in muscle of patients with CAPD.[357] Similar results were initially identified in uremic animals, a sign that acidosis activates the ubiquitin-proteasome pathway (UPP) to degrade protein in muscle. The relevance of these results to nutritional therapy is that CKD patients eating low-protein diets for prolonged periods do not develop metabolic acidosis. [275] [278]

Experimentally, the association between an increase in dietary protein and the development of acidosis is well established. Rats with experimental CKD were fed diets containing 6% protein, 17% or an adequate amount of protein, or an excess of protein (30%). The most efficient use of protein for growth was achieved with 8% protein and rats fed 17% protein grew at the highest rate. CKD rats fed 30% protein developed acidosis and suppressed growth.[103]

Several potential mechanisms have been proposed to explain how acidosis activates catabolic pathways that stimulate the loss of essential amino acids and protein in muscle. Bailey and colleagues[358] measured the intracellular pH in muscle of rats using nuclear magnetic resonance techniques. Rats were made acidotic by intravenous infusion of acid, or by subtotal nephrectomy and in both cases, the serum bicarbonate and blood pH fell sharply, but the pH in muscle did not change. Despite uremia, there also was no abnormality in the recovery of muscle cell pH following a sharp decrease in cell pH induced by nerve stimulation. In rats fed a high acid diet for 5 days there was a small decrease in muscle cell pH but no mechanism for the metabolic changes induced by acidosis was identified.

Another mechanism for the loss of protein stores with acidosis (or several other catabolic conditions) depends on the induction of glucocorticoid production. In normal animals, high doses of glucocorticoids will suppress protein synthesis and accelerate muscle protein breakdown. May and associates[359] noted that in rats with metabolic acidosis and normal renal function there is accelerated protein degradation in muscle but only when glucocorticoid production is increased. The relevance to CKD is that chronically uremic rats with or without metabolic acidosis have high rates of corticosterone (the rodent glucocorticoid) production but by itself, this does not stimulate muscle protein losses. Muscle protein breakdown increases only when acidosis is combined with physiologically high glucocorticoids. [363] [364] Experimentally, the interaction between acidification and glucocorticoids also stimulates the activity of branched-chain ketoacid dehydrogenase to break down branched-chain amino acids. [320] [365] In summary, one complication of CKD, acidosis, increases glucocorticoid production and the degradation of protein and essential amino acids. [366] [367]

Besides stimulating glucocorticoid production, acidosis can exert changes in other hormones. It impairs the ability of growth hormone to stimulate release of IGF-1, the major mediator of growth hormone action.[303] Acidosis reduces thyroid hormones and can stimulate parathyroid hormone release and impair the activation of 1,25 (OH)2 vitamin D3. [368] [369] [370] [371] To avoid these problems, acidosis should be vigorously treated in patients with renal insufficiency.

The Ubiquitin-Proteasome Pathway

Over the past two decades, the ubiquitin-proteasome pathway (UPP) has been identified as the pathway that degrades the bulk of protein in all cells ( Fig. 53-9 ). Its specific relevance to CKD is the sharp rise in UPP activity that occurs in the muscle of animal models of many catabolic conditions including CKD. [224] [372] The activity of the UPP in muscle also increases in response to complications of CKD including metabolic acidosis and decreased action of insulin/IGF-1 and in response to high levels of angiotensin II. [373] [374] [375] [376] [377] [378] There is evidence that the activity of the UPP also increases in the muscle of patients with accelerated muscle atrophy from CKD, cancer, trauma, sepsis, and other catabolic events.[369]

FIGURE 53-9  The ubiquitin(Ub)-proteasome pathway (UPP) of protein degradation. Ub is conjugated to protein substrates by an ATP-dependent process involving three enzymes. When a chain of five Ub molecules are attached, the complex is recognized by the 26S proteasome, the Ubs are removed, the protein is linearlized and injected into the central core of the proteasome. The substrate protein is degraded to peptides, which are degraded to amino acids by peptidases in the cytoplasm or used in antigen presentation.  (From Lecker SH, Goldberg AL, Mitch WE: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819, 2006.)



The UPP consists of concerted actions of three enzymes that link chains of the polypeptide cofactor, ubiquitin (Ub), onto proteins to mark them for degradation. This tagging process leads to their recognition by the 26S proteasome, a very large multicatalytic protease complex that degrades ubiquitinated proteins to small peptides. Three enzymatic components link chains of Ub onto proteins destined for degradation: E1 (Ub-activating enzyme) and E2s (Ub-carrier or conjugating proteins) prepare Ub for conjugation, but the key enzyme in the process is the E3 (Ub-protein ligase). E3 enzymes recognize specific protein substrates and catalyze the transfer of activated Ub to them. Because specificity of the action of the UPP to degrade proteins resides in the E3 enzyme, there are more than one thousand E3's in cells. Proteins conjugated to Ub are recognized and degraded by the 26S proteasome, a large structure found in the nucleus and the cytosol of all cells.[369] The discovery of ubiquitin and the biochemistry of its conjugation to substrate proteins culminated in the awarding of the Nobel Prize in Chemistry in 2004 to Avram Hershko, Aaron Ciechanover and Irwin Rose (

The UPP is involved in critical functions of the body including the regulation of proteins with short half-lives (e.g., regulatory enzymes, transcription factors), immune surveillance processes, and the regulation of muscle protein metabolism. [224] [372] In addition, inhibitors of the UPP have been found to be beneficial for patients with certain types of cancer.[369] Its major relevance to CKD, however, is the increased activity of the UPP in muscle when there are complications of CKD such as acidosis and decreased activity of insulin/IGF-1. In experimental animals and humans with uremia, overall rates of protein synthesis generally are unchanged whereas rates of protein degradation tend to increase. Because the rates of protein turnover in cells are very high (3.5–4.5 g protein/kg/day), even a small increase in proteolysis, with time, will cause marked protein depletion.[223] Most of this acceleration of protein degradation in muscle in disease states occurs via a programmed activation of the UPP. [360] [364] In rodent models, atrophying muscles show accelerated proteolysis via the UPP, higher levels of mRNAs encoding certain components of this proteolytic system, and a similar pattern of changes (both increases or decreases) in the expression of about 100 atrophy-related genes (also termed “atrogenes”).[376] Likewise, humans with these conditions have evidence for activation of the UPP in muscle (e.g., an increase in mRNAs encoding Ub and proteasome subunits). [224] [372] The expression of two critical Ub conjugating E3 enzymes in muscle, atrogin-1 (also known as MAFbx), and MuRF-1, increases dramatically (8–20 fold) in catabolic states ( Fig. 53-10 ). These two E3 enzymes have been shown to regulate the breakdown of protein in animal models of catabolic conditions.[369] The strongest evidence for activation of the UPP muscles of animals undergoing atrophy due to uremia (or other catabolic diseases) is that when studied in vitro, muscles from these models exhibit increased proteolysis, which can be blocked by inhibitors of the proteasome. [364] [374] [380]

FIGURE 53-10  The balance between protein synthesis and degradation determines whether muscles hypertrophy or atrophy. Hypertrophy results when synthesis exceeds degradation because the phosphatidylinositol 3 kinase (PI3K)/Akt pathway stimulates protein synthesis and suppresses caspase-3 while phosphorylating the forkhead (FoxO) transcription factors to prevent expression of enzymes of the UPP. When the PI3K/Akt pathway is suppressed, caspase-3 is activated and FoxO stimulates expression of the E3 enzymes, atrogin-1, and MuRF-1 leading to increased activity of the UPP to degrade protein. Inflammatory cytokines such as TNFa activate NF-kB leading to expression of MuRF1 and increased muscle proteolysis.  (From Lecker SH, Goldberg AL, Mitch WE: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819, 2006.)



Caspase-3 and Muscle Protein Losses

By itself, the UPP attacks myofibrillar proteins (about two thirds of the protein in muscle) only slowly. It is assisted by other proteases, which disassemble the myofibril into its component proteins (actin, myosin, troponin, or tropomyosin) that are rapidly degraded by the UPP. This coordinated activity involves activation of caspase-3 in muscle. Caspase-3 was studied because several catabolic states (e.g., sepsis, renal failure) are characterized by high circulating levels of TNFa or insulin resistance, conditions that induce programmed cell death by activating the caspase cascade. [12] [381] [382] We found that caspase-3 cleaves actomyosin in vitro and in cultured muscle cells yielding substrates that are rapidly degraded by the UPP. In addition, caspase-3 leaves a “footprint” of its action, a 14 kD C-terminal fragment of actin that accumulates in the insoluble fraction of the cell.[380] The same processes occur in the muscle of animals with uremia, diabetes, angiotensin II-induced hypertension, as well as in humans, with muscle atrophy due to disuse from the pain of osteodystrophy and related to either hemodialysis treatment or burn injury. [178] [377] [378] [384]

Signals Triggering Muscle Atrophy

Complications of CKD that trigger the UPP to break down muscle protein include metabolic acidosis, decreased insulin action, increased glucocorticoids, high levels of angiotensin II, and inflammation. [270] [364] [374] [378] Because activation of the UPP involves coordinated changes in the expression of a set of genes in muscle,[376] a common cellular signaling pathway activating the UPP and caspase-3 was sought. In fasting and in other insulin-deficient states, the fall in protein synthesis and the rise in proteolysis are linked events occurring through decreased signaling by the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway. [372] [385] Decreased activity of PI3K causes a decrease in the activity of the serine/threonine kinase, Akt (see Fig. 53-10 ). The reduction in signaling by the PI3K/Akt pathway leads to suppression of synthesis because of reduced mRNA translation and protein production whereas rapid muscle atrophy occurs when there is induction of the E3's, atrogin-1 and MuRF-1 via the forkhead transcription factors.[369]

As noted earlier, glucocorticoids are an essential factor for these catabolic responses because they exert permissive effects that activate the UPP when other catabolic signals are present. For example, activation of muscle proteolysis does not occur in adrenalectomized animals that are starved or treated with NH4Cl to induce metabolic acidosis or made insulin deficient unless the animals are given a physiological dose of glucocorticoids. [375] [386] Similarly, muscle proteolysis induced by angiotensin II or sepsis can be blocked by inhibiting the glucocorticoid receptor. [378] [387] In these experiments, the same physiological levels of cortisol did not stimulate muscle protein degradation unless the animals were also acidosis or made insulin deficient. These complex regulatory interactions actually make “physiological sense” because glucocorticoids integrate stress responses in different tissues: when glucose is needed, an increase in glucocorticoids mobilizes amino acids from muscle protein and induces gluconeogenic enzymes in liver that catalyze conversion of the amino acids to glucose and urea.

Abnormalities in insulin/IGF-1 signaling occur frequently in CKD and are linked to abnormalities in carbohydrate and protein metabolism in muscle.[385] Harter and co-workers[386] suggested that accelerated muscle proteolysis in rats with CKD is linked to diminished responsiveness to insulin. The defect in protein metabolism was most pronounced in rats fed a high-protein diet (a diet that would worsen acidosis); the response to insulin was more normal in CKD rats fed lower amounts of dietary protein. Experimentally, both insulin deficiency or insulin resistance activate the UPP to stimulate protein degradation in muscle. [374] [377] The responses to impaired insulin action include enhanced transcription of the genes that encode components of the UPP system but do not depend on acidosis. [374] [375] However, impaired insulin action, like acidosis, increases glucocorticoid production, which is required to activate the UPP and stimulate muscle protein degradation.[372] Thus, two complications of CKD, resistance to insulin (or diabetes) and metabolic acidosis, will activate protein catabolism in CKD.

A less well documented but still potentially important factor causing loss of protein stores in patients with CKD is their sedentary lifestyle. The hormonal and cellular signaling mechanisms underlying this cause of muscle atrophy are not clear but lack of exercise might suppress the responses to insulin. Davis and co-workers[387] found that exercise training of chronically uremic rats increased the sensitivity of muscle to insulin, thereby improving glucose uptake, glycolysis, and the ability to suppress protein breakdown. Clinical responses of CKD patients to exercise are encouraging. Storer and colleagues[175] found that endurance training (i.e., stationary bicycling) improved muscle function and cardiopulmonary measures in dialysis patients. Johansen and colleagues found that resistance training improved the cross-sectional area of muscle in hemodialysis patients but did not increase lean body mass.[176]Considering these results and the potential for beneficial cardiovascular responses, exercise training should be encouraged. Without exercise, muscle protein loss in CKD involves activation of the UPP and caspase-3. [178] [360] [364] [383] It is unknown how exercise could block this activation but there is information indicating that muscle stretch stimulates the activity of phosphatidylinositol 3-kinase (PI3K) and Akt.[177] We and others have shown that stimulation of PI3K/Akt will block activation of the UPP and caspase-3 in muscle. [384] [391] [392]

There is some evidence that a high level of glucagon stimulates muscle catabolism. Bilbrey and associates[390] demonstrated that plasma glucagon levels are high in uremic subjects and do not decrease normally in response to hyperglycemia. High levels of glucagon given to fasting obese subjects paradoxically decreased urinary urea concentration, but increased urinary ammonia.[391] Others found that humans given large doses of glucagon had an increase in urea excretion.[392] There are no convincing explanations for these observations. Experimentally, muscle proteolysis is unaffected by glucagon except at unphysiologically high levels.[393] In summary, the role of hyperglucagonemia in augmenting nitrogen requirements in uremia is uncertain.

There are more convincing data suggesting that abnormal metabolism of fatty acids stimulates protein breakdown in muscle. Li and Wassner[394] found no abnormalities in muscle protein turnover of rats with mild to moderately severe CKD unless the rats were fasted. With fasting, there was breakdown of myofibrillar muscle protein but no change in protein synthesis; the degree of accelerated muscle protein breakdown was inversely correlated with body fat stores. The pathway activated to degrade muscle protein was not identified.

External Losses of Protein

Digestion of the protein contained in gastrointestinal bleeding will lead to reabsorption of amino acids and augmentation of urea production while depleting body stores of hemoglobin and plasma proteins.[258] The impact of the nephrotic syndrome on body protein stores is discussed subsequently.

Altered Electrolyte Balance

In patients with advanced CKD, defects in ion transport in blood cells have been demonstrated, and there is an increase in intracellular sodium in muscle. In rats with CKD, there are defects in cation transport found in skeletal muscle and adipocytes.[395] Whether acidification or other transport abnormalities directly stimulate catabolism is unknown. For example, depletion of potassium in muscle occurs in CKD patients—even in those with a normal or increased serum potassium concentration.[396] This is relevant because both potassium deficiency[397] and hyperkalemia[398] are intertwined with abnormalities in intracellular acid/base changes as well as abnormalities in the metabolic responses to insulin or IGF-1. It is possible that these abnormalities could increase nitrogen catabolism but this has not been convincingly demonstrated.


Parathyroid hormone (PTH) administration was reported to augment urea production in normal subjects or patients with hyperparathyroidism. Some but not all investigators [402] [403] found that adding PTH to isolated muscle increases the rate of protein degradation. Hyperparathyroidism can also inhibit insulin release and low levels of insulin cause muscle protein degradation in vivo. Still, persuasive evidence for a direct protein effect of PTH on increasing requirements in patients with CKD is not available.

Factors Causing Decreased Dietary Protein Requirements

The principal adaptations that permit a decrease in dietary protein are the body's ability to reduce the destruction of essential amino acids and the breakdown of protein stores (see earlier discussion). The signals and mechanisms that initiate and maintain these adaptive responses have not been identified. The ability to adapt metabolic pathways is robust and these responses act rapidly to produce neutral nitrogen balance and maintain body stores of protein during long-term therapy with low-protein diets. Both normal adults and CKD patients will maintain protein stores as long as there is no complicating disease or disorder. [275] [277] [279] [346]

Calorie intake directly influences the ability of the body to utilize dietary protein optimally when CKD patients are fed protein-restricted diets. Again, the mechanisms underlying this association are poorly understood, but the relationship is clinically important. For example, Kopple and colleagues varied calorie intake while maintaining dietary protein at 0.6 g/kg/day.[22] Nitrogen balance was achieved when calorie intake was 30-35kcal/kg/day. The same group evaluated the effects of varying calorie intake in hemodialysis patients who were eating 1.13 g protein/kg/day.[401] They concluded that 38.5kcal/kg/day is optimal for maintaining nitrogen balance.

Several facts should be kept in mind when assessing calorie intake and requirements. First, the presence of CKD does not seem to increase the resting energy expenditure (REE).[9] The impact of dialysis on REE is more varied, [10] [405] but 35kcal/kg/day will be sufficient for undialyzed or dialyzed patients to maintain protein stores. Second, the prescribed calorie intake should be based on standard body weight; prescribing obese patients a calorie intake based on their actual body weight would be counterproductive, especially if it increases their fat mass. Third, prescribed calorie intake should take into account the physical activity level of the patient, as more active individuals require more calories. Fourth, the assessment of calorie intake is difficult. When the dietary histories of predialysis CKD or hemodialysis patients were examined closely, serious under reporting of calorie intake was uncovered. [15] [406]

Reuse of Urea Nitrogen

Urea can be degraded by the urease present in gut bacteria forming ammonium and carbon dioxide. Initial studies of the efficacy of low-protein diets in CKD patients led to the proposal that there were metabolic pathways that could utilize the nitrogen in urea or ammonia to synthesize amino acids.[404] In support of this conclusion, animal studies show that urea or ammonia can be utilized as a source of non-specific nitrogen and will improve growth.[404a]However, evidence that similar pathways are present in humans is conflicting. It has been reported that 15N in urea or ammonia can be detected in protein[405] but this finding does not prove that ammonium nitrogen stimulates protein synthesis because reversible reactions in which ammonia participates (e.g., the glutamate dehydrogenase reaction), followed by subsequent transamination reactions between glutamate and various ketoacids could cause 15N to appear in amino acids.[406] In this case, there is no net increase in the quantity of amino acids produced; these metabolic pathways are simply exchange reactions. When urea nitrogen utilization was directly examined in studies of CKD patients, ammonia or urea nitrogen was found to be nutritionally unimportant. Varcoe and associates[407] measured the incorporation of labelled urea nitrogen into albumin in both uremic patients and in normal subjects. They concluded that the amount of urea nitrogen used for albumin synthesis is too small to be considered nutritionally significant. Secondly, we suppressed urea degradation to ammonia in patients with CKD who were being treated with low-protein diets or very-low-protein diets plus ketoacids and measured the rates of urea production and degradation using isotopic techniques. [227] [412] The studies were done to determine if blocking the breakdown of urea would change the appearance of the urea. We found no increase in urea nitrogen appearance despite an 85% average reduction in urea degradation and we concluded that urea nitrogen is not used to synthesize amino acids. If urea nitrogen were being used to synthesize amino acids and urea degradation is blocked, then the amount of urea appearing in urine and body fluids should increase. Thus, the results demonstrate that ammonia derived from degradation is simply recycled back into urea.[225] We also found that nitrogen balance improved despite the fact that nitrogen from urea degradation was blocked and, clearly, if urea nitrogen were needed to synthesize amino acids, blocking the breakdown of urea should cause negative nitrogen balance.[408] Still, it remains possible that CKD patients may be able to use urea nitrogen to a minor extent for synthesis of protein because the so-called non-specific nitrogen requirement of normal or malnourished adults can be met by giving urea or ammonia salts to normal or malnourished adults.[409] To date, convincing evidence that the nitrogen arising from urea degradation improves nitrogen conservation in CKD is lacking.


Rationale for Nutritional Therapy

Uncertainty about the benefits of dietary therapy in slowing progression of CKD has obscured a long-established principal: protein restriction ameliorates the signs and symptoms of renal failure. This observation, which dates back at least as far as 1869 has been repeatedly confirmed. [1] [194] [275] [278] [279] [414] In our view, every symptomatic CKD patient should receive instruction and follow-up evaluations from a skilled dietician as well as the nephrologist in order to avoid the complications of CKD including acidosis, hyperphosphatemia, and bone disease and the accumulation of waste products that cause symptoms. Fortunately, there is abundant evidence that a protein-restricted diet does not cause a deficit in the nutritional status of the CKD patient and may even improve it. [1] [14] A recent meta-analysis that included 8 of 40 possible studies involving 1524 non-diabetic individuals found a 31% reduced risk of death in the groups assigned to a lower protein intake.[411] Unfortunately, the variation in the protein prescriptions, the degree of compliance with the diets, and the absence of new studies limits the value of additional meta-analyses.

We note that there continues to be disagreement about the role of dietary protein restriction in slowing progression. Important limitations of most of the previous studies include variations in the degree of adherence to the prescribed level of protein intake, whether there is a differential effect of different types of protein (e.g., vegetable versus animal), the use of multiple drugs that could affect progression (e.g., angiotensin converting enzyme inhibitors), and relatively short follow-up periods in small numbers of individuals with CKD. On the other hand, there is concern about the potential adverse impact on renal function because of the popularity of very high animal protein diets.

Several publications have attempted to address some of these limitations. Levey and colleagues performed secondary analyses of achieved intake in the MDRD study and found that GFR decline was slower by 1.15 ml/min/yr among those who did reduce their protein intake by 0.2 g/kg/day.[412] Knight and co-workers[413] addressed the influence of different levels of protein intake in a study of 1624 women with normal or mildly reduced renal function who were followed over 11 years. Using multivariate analyses, they concluded that a high protein intake was not significantly associated with changes in the estimated GFR using the MDRD formula in women with GFR ≥ 80 ml/min/1.73 m2. However, when women with estimated GFR 56 to 79 ml/min/1.73 m2 were examined, it was found that the GFR fell at a rate of 1.7 ml/min/1.73 m2 faster for each 10 g increase in daily protein intake. Because this was the change over 11 years, the average annual difference would be only 0.15 ml/min/1.73 m2.

It is now widely recognized that different subtypes of fat can have different physiological implications; the same is likely true for the different types of protein. In that same study, Knight and colleagues reported that in women with GFRs of 56 to 79 ml/min/1.73 m2, the GFR fell at a rate of 1.2 ml/min/1.73 m2 faster for each 10 g increase in daily nondairy animal protein intake. No significant associations with rate of GFR decline were observed for dairy or vegetable protein.

The MDRD investigators also reported that protein restriction slowed the rise of urine protein excretion in individuals with moderate CKD.[114] Other studies have documented the beneficial effect of low-protein diets on proteinuria and its additive effect with drugs interrupting the renin-angiotensin system. [89] [96] [97] This is relevant because reducing proteinuria is a major goal in the treatment of CKD patients.[43]

Thus, there remains controversy about the benefit of protein restriction to slow progression of CKD, but the benefits extend beyond simply slowing progression. [1] [416] For these reasons, patients should receive a trial of a protein-restricted diet before initiating dialysis. Arguments against protein restriction that have been put forward, for example by Mehotra and Nolph,[309] obscure this issue in several ways. First, there are problems with dialysis including an adverse psychological impact, inconvenience, and the fact that mortality on dialysis is at least 10 times greater than pre-dialysis mortality (the latter has never been reported to be greater than 3% per annum). [106] [275] [278] [418]Obviously, when the accumulation of waste products, complications of CKD or the inability to maintain body fluids has progressed, dialysis is life saving. But initiating dialysis early has been shown to have no benefits. [314] [315] [419] Second, the argument to start dialysis without trying more conservative therapy fails to consider that it has been demonstrated that pre-dialysis subjects without attention to their diet become hypoalbuminemic related to inflammation and they develop acidosis (among other problems). These problems can be avoided with proper instruction, including a small increase in serum albumin levels. [14] [275]

Why is protein restriction effective in reducing signs and symptoms? A full explanation of this observation is as yet lacking but there are some points to be made. First, with any reduction in protein intake there is a proportionately greater reduction in SUN concentration, with which symptoms are at least weakly correlated.[415a] The greater decrease in SUN occurs because the rate of excretion of nitrogen in forms other than urea is relatively insensitive to nitrogen intake.[219] Second, most of the signs and symptoms of CKD are attributable to the retention of products of protein catabolism, except for anemia and dyslipidemia. Third, protein intake, at least in the United States, averages well above the requirement, so a considerable decrease in intake even to the level of the recommended daily allowance of protein is feasible.[341] Still, a complete explanation of the clinical benefit of protein restriction in chronic kidney disease remains elusive.


The success or failure of nutritional therapy depends largely on patient compliance. Low-protein diets are difficult to adhere to, and some of the complexity in determining their value in terms of progression of CKD is attributable to difficulties in obtaining compliance. [109] [279] Factors affecting compliance with the diet are their relatively high cost, the need for special low-protein products, the time required for separate cooking of meals, poor palatability, monotony, and the required changes in lifestyle for the patients and their families. Cooperation of family members is essential to success as is cooperation of two professionals—the nephrologist and the dietician. According to Rosman and Donker-Willenborg[416] the most important factors determining compliance are (1) dedication of the dietician as well as an involved physician; (2) ongoing and consistent communication among patient, physician, and dietitian; (3) the personal, social, and geographic circumstances of the patient (rural patients were more compliant than urban patients); and (4) the availability of good dietary exchange lists, preferably on the Internet. Compliance is a particularly troublesome problem in evaluating the efficacy of any dietary regimen. If a significant proportion of subjects assigned to the more restrictive diet fail to comply (or if some subjects who are assigned to the less restrictive diet emulate the more restrictive group), a slower rate of progression could be obscured. There also is the possibility that those with more rapid progression will develop CKD symptoms, including anorexia and there is the problem of determining if simply participating in a clinical trial may by itself slow progression. There are several reports indicating that the rate of progression is faster in noncompliant patients. [120] [279] If an analysis by intention-to-treat had been used in such studies, one might have concluded that no significant effect on progression occurred. Thus it is often advisable to employ both intention-to-treat and secondary analyses (which take compliance into consideration) in interpreting such data.

Comparison of Different Regimens

When supplements of essential amino acids or their ketoanalogues are not provided, it is important to be certain that the intake of these carbon skeletons is adequate to ensure that protein metabolism is not impaired. Unfortunately, the requirements of CKD patients for each of the individual essential amino acids have not been examined quantitatively. Circulating levels of amino acids that are particularly low in such patients include the branched-chain amino acids, threonine, and tyrosine. Protein-restricted diets based on an insufficient amount of high-quality protein may not provide enough of these amino acids and a substantial proportion of high-quality protein in the diet is desirable. There have been a few comparative studies of the effects of different dietary regimens in patients with CKD. Di Landro and associates compared the outcome of 3 years treatment with a diet containing 0.6 g/kg of protein in 44 patients with a diet containing 0.3 g/kg protein plus a supplement of essential amino acids and ketoanalogues in 46 patients.[417] Progression, estimated from [Cr]-1 slopes, was significantly slower in the latter group. Parathyroid hormone levels increased in the first group but decreased in the second; serum cholesterol remained elevated in the first group but fell to normal in the second. Teplan and associates randomized CKD patients, all of whom were eating a low-protein diet (0.6 g/kg) and given erythropoietin, to receive a supplement of a ketoacid-amino acid mixture at 0.1 g/kg; controls received no supplement.[418] After 1 to 3 years, GFR fell more in controls; in those receiving the supplement, there was an increase in serum branched chain amino acid and albumin levels while proteinuria and serum concentration of free radicals decreased. Ayli and associates[419] switched 18 CKD patients from a diet containing 0.8 g/kg of protein to one containing 0.4 g/kg, supplemented by a mixture of ketoacids and amino acids. GFR fell less in the second period and LDL cholesterol decreased. Prakash and co-workers randomly assigned 34 CKD patients to a ketoacid-based diet or a placebo. During a 9-month, double-blind, placebo controlled trial, they found significant slowing of the loss of GFR in subjects given the ketoacid regimen.[420] Biochemical parameters did not differ between the groups. The primary results of the Operational Phase of the MDRD Study, with regard to the effects of various levels of protein restriction on progression, were inconclusive.[106] In the 255 patients with advanced renal disease, there was no clearcut benefit (P = .07) of the very-low-protein diet (0.28 g/kg) supplemented with a mixture of amino acids and ketoacids compared to a low-protein diet. Secondary analysis of these results,[114] however, suggested that a lower protein intake was associated with slower progression in both the low- and very-low-protein diets. Each reduction of 0.2 g/kg in protein intake was associated with a slowing of GFR decline by 1.15 mL/min/year or approximately 30%. Lower protein intake also was associated with a delay in the onset of renal failure (P = .001). No benefit could be attributed to the ketoacid supplement. In 585 patients with less severe renal failure, there was no significant difference in overall rate of progression between patients assigned to a low-protein diet (0.58 g/kg) and those assigned to a usual protein diet (1.3 g/kg). However, the low-protein diet led to a decline in GFR during the first few months, followed by a slower rate of decline (P < .01) thereafter. Longer follow-up would therefore be necessary to determine whether protein restriction was beneficial in the long term in this group. In the secondary analysis,[114] no correlation was found between GFR decline and achieved protein intake.

In the Feasibility Phase of the MDRD Study,[421] 66 patients with more advanced CKD were randomly assigned to a low-protein diet (0.575 g/kg), a very-low-protein diet (0.28 g/kg) supplemented by a mixture of essential amino acids, or the same very-low-protein diet supplemented by a mixture of ketoacids and amino acids. This mixture differed substantially from that used in the Operational Phase, but was the same as that used previously by Mitch, Walser, and associates. [427] [428] In the Feasibility Study with an average follow-up of 14 months, progression was significantly slower by intention-to-treat analysis in the group assigned to the ketoacid-based supplement compared with patients assigned to the essential amino acid supplement (P = .028), despite the same protein intake.

Parameters of nutritional status scarcely differed between the diet assignments of the MDRD Study. In the Feasibility Phase, serum albumin and transferrin levels declined in a few patients, but did not become subnormal; no patients became malnourished, even though mean energy intake fell below recommended values. In the full-scale trial,[14] patients assigned to the low- or very-low-protein diets lost about 2 kg and showed a slight decrease in other anthropometric parameters during the first 4 months only, probably because of reduced energy intake ( Fig. 53-11 ). Serum albumin levels rose but transferrin levels fell in patients assigned to the low- or very-low-protein diets ( Fig. 53-12 ). Notably, however, the average serum protein values were within the normal range.[14] A progressive decline in creatinine excretion was observed in the low-protein groups and was probably related to reduced meat intake or increasing degradation of creatinine.[233] Loss of skeletal muscle mass could not have contributed in a major way to the reduction of urinary creatinine excretion because arm muscle area remained the same or decreased only slightly. Importantly, the frequency of hospitalization and the number of patients reaching “stop-points” for nutritional reasons did not differ among the groups.

FIGURE 53-11  Projected changes over 3.2 years in body weight in kg and arm muscle area in cm2 of patients participating in the MDRD Study. Patients with GFR values between 24 and 55 mL/min/1.73 m2 (Study A) were fed 1.3 g protein/kg/day or 0.6 g protein/kg/day; patients in Study B (GFR values between 13 and 24 mL/min/1.73 m2) were fed 0.6 g protein/kg/day or 0.3 g protein/kg/day plus a mixture of ketoacids.  (Data from Kopple JD, Levey AS, Greene T, et al: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease (MDRD) Study. Kidney Int 52:778–791, 1997.)



FIGURE 53-12  Projected changes over 3.2 years in serum albumin in g/dL and serum transferrin in mg/dL of patients participating in the MDRD Study. The dietary-induced changes were small and serum albumin increased.  (Data from Kopple JD, Levey AS, Greene T, et al: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease (MDRD) Study. Kidney Int 52:778–791, 1997.)



Dietary Treatment of Nephrotic Syndrome

Current recommendations for nutritional therapy of the nephrotic syndrome[424] include moderate protein restriction (0.8 to 1.0 g/kg/day), using a soy vegetarian diet. The evidence for a special effect of soy protein comes from studies in rats; in animals with spontaneous hypercholesterolemia, who typically develop glomerular injury, Sakemi, Ikeda, and Shimazu[425] showed that soy protein, added to a conventional casein-based diet, did not have the ability to attenuate glomerular injury, but was less harmful than additional casein.

There have been many reports that dietary protein restriction reduces proteinuria in the nephrotic syndrome. Fourteen studies published up to 1996 were summarized at that time.[256] Protein intake in the control period was usually about 1.2 g/kg; in the treatment period, it was restricted to 0.5 to 0.8 g/kg. The diet generally led to some decrease in proteinuria and some increase in serum albumin concentration, but not one of the 202 patients exhibited normalization of serum albumin level or reduction of proteinuria to sub nephrotic values. In a more recent study,[426] a low-protein diet was associated with a slight increase in serum albumin (6%), but albumin synthesis (which was more than twice normal) decreased.

In contrast to these findings, Walser, Hill, and Tomalis[256] reported that more severe protein restriction (to 0.3 g/kg) plus a supplement of essential amino acids (10–20 g/day) led to complete remission of the nephrotic syndrome in a small number of cases. This regimen generally reduces proteinuria about 50%, mainly in those with the highest degree of proteinuria; serum albumin levels also rise as reported in preliminary form from Japan.[427]

These results are the opposite of conventional wisdom, which holds that protein-restricted diets should not be used in patients with pronounced proteinuria. On the contrary, when proteinuria is most pronounced this regimen can be effective. Fortunately, dietary restriction entails few risks compared to immunosuppressive drugs or high doses of steroids—therapies that are often employed in such patients.


We believe that the most important conclusions to be drawn from the work summarized in this chapter are first, that dietary therapy reduces signs and symptoms of CKD and this therapy should be tried in every case of symptomatic CKD ( Table 53-2 ); second, that dietary therapy of the type described is nutritionally safe. Arguments presented against these conclusions are tenuous: the progressive reduction in voluntary protein intake observed as patients approach end-stage renal failure has led to the suggestion that increasing protein intake can prevent complications.[308] However, the inference that encouraging a high-protein diet will counteract hypoproteinemia is not borne out by experimental evidence. On the contrary, in the largest study of protein-restricted diets, the MDRD Study, it was established that low-protein diets as well as supplemented very-low-protein diets are nutritionally safe.

TABLE 53-2   -- Summary of Dietary Recommendations

Dietary Factor

Impact on GFR Decline

Special Subgroups


Other Comments


Restriction acutely lowers GFR; long term may slow progression


Restriction to 0.8 g protein/kg/day. If symptomatic restrict to 0.6 g protein/kg/day.

Protein-restricted diets should contain ∼50% high-quality protein. Non-dairy animal protein may be most important to restrict.


No impact confirmed


Restrict saturated and avoid transfatty acids

Polyunsaturated fats may reduce risk of CHD


Insufficient data


Avoid refined carbohydrates and simple sugars

Energy needs can be met with sugar polymers


Restriction may slow progression

Elderly, African Americans, diabetics

Intake ≤2 g/d

Most effective for hypertension with higher potassium intake


Insufficient data

Elderly, African Americans, diabetics

Encourage potassium-rich diet as tolerated

Monitor for hyperkalemia

Vitamins and minerals

Insufficient data


Follow recommended dietary allowance

Retinol may adversely affect bone health; vitamin D should be used with care (see Chapter 52 )


GFR, glomerular filtration rate; CHD, coronary heart disease.





1. Mitch WE, Remuzzi G: Diets for patients with chronic kidney disease, still worth prescribing.  J Am Soc Nephrol  2004; 15:234-237.

2. Coresh J, Byrd-Holt D, Astor BC, et al: Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000.  J Am Soc Nephrol  2005; 16:180-188.

3. Levey AS, Coresh J, Greene T, et al: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.  Ann Intern Med  2006; 145:247-254.

4. Zuo L, Ma YC, Zhou YH, et al: Application of GFR-estimating equations in Chinese patients with chronic kidney disease.  Am J Kidney Dis  2005; 45:463-472.

5. Kopple JD, Gao X-L, Oing P-Y: Diet protein and urea and total nitrogen appearance in chronic renal failure patients.  Kidney Int  1997; 52:486-494.

6. Kopple JD: Protein-energy malnutrition in maintenance dialysis patients.  Am J Clin Nutr  1997; 65:1544-1557.

7. FAO/WHO/UNU : Energy and Protein Requirements.  In Technical Report Series 724,  Geneva, World Health Organization, 1985.

8. Leibel RL, Rosenbaum M, Hirsch J: Changes in energy expenditure resulting from altered body weight.  N Engl J Med  1995; 332:621-628.

9. Monteon FJ, Laidlaw SA, Shaib JK, et al: Energy expenditure in patients with chronic renal failure.  Kidney Int  1986; 30:741-747.

10. Ikizler TA, Wingard RL, Sun M, et al: Increased energy expenditure in hemodialysis patients.  J Am Soc Nephrol  1996; 7:2646-2653.

11. Smith D, DeFronzo RA: Insulin resistance in uremia mediated by postbinding defects.  Kidney Int  1982; 22:54-62.

12. DeFronzo RA, Beckles AD: Glucose intolerance following chronic metabolic acidosis in man.  Am J Physiol  1979; 236:E328-E334.

13. Rigalleau V, Combe C, Blanchetier V, et al: Low protein diet in uremia: Effects on glucose metabolism and energy production rate.  Kidney Int  1997; 51:1222-1227.

14. Kopple JD, Levey AS, Greene T, et al: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease (MDRD) Study.  Kidney Int  1997; 52:778-791.

15. Avesani CM, Kamimura MA, Draibe SA, et al: Is energy intake underestimated in nondialyzed chronic kidney disease patients?.  J Renal Nutr  2005; 15:159-165.

16. Hyne BB, Fowell E, Lee HA: The effect of caloric intake on nitrogen balance in chronic renal failure.  Clin Sci  1972; 43:679-687.

17. Rose WC: The amino acid requirements of adult man.  Nutr Abstr Rev  1957; 27:631.

18. Ikizler TA, Greene JH, Wingard RL, et al: Spontaneous dietary protein intake during progression of chronic renal failure.  J Am Soc Nephrol  1995; 6:1386-1391.

19. Bergstrom J: Anorexia in dialysis patients.  Semin Nephrol  1996; 16:222-229.

20. Cheung W, Yu PX, Cone RD, et al: Role of leptin and melanocortin signaling in uremia-associated cachexia.  J Clin Invest  2005; 115:1659-1665.

21. Bergstrom J, Furst P, Ahlberg M, et al: The role of dietary and energy intake in chronic renal failure.   In: Canzler VH, ed. Topical Questions in Nutritional Therapy in Nephrology and Gastroenterology,  Stuttgart: Georg Thieme Verlag; 1978:1-16.

22. Kopple JD, Monteon FJ, Shaib JK: Effect of energy intake on nitrogen metabolism in nondialyzed patients with chronic renal failure.  Kidney Int  1986; 29:734-742.

23. Kerr GR, Sul Lee E, Lam M-KM, et al: Relationships between dietary and biochemical measures of nutritional status in NHANES I data.  Am J Clin Nutr  1982; 35:294-308.

24. Cianciaruso B, Bellizzi V, Minutolo R, et al: Renal adaptation to dietary sodium restriction in moderate renal failure resulting from chronic glomerular disease.  J Am Soc Nephrol  1996; 7:306-313.

25. Berl T, Katz FH, Henrich WL, et al: Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure.  Kidney Int  1978; 14:228-235.

26. Watanabe S, Kang D-H, Feng L, et al: Uric acid, hominoid evolution and the pathogensis of salt-sensitivity.  Hypertension  2002; 40:355-360.

27. Kang D-H, Nakagawa T, Feng L, et al: A role for uric acid in the progression of renal disease.  J Am Soc Nephrol  2002; 13:2888-2898.

28. Mazzali M, Kanellis J, Han H, et al: Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism.  Am J Physiol  2002; 282:F991-F997.

29. Mallamaci F, Leonardis D, Bellizzi V, et al: Does high salt intake cause hyperfiltration in patients with essential hypertension?.  J Hum Hypertens  1996; 10:157-161.

30. Dengel DR, Goldberb AP, Mayuga RS, et al: Insulin resistance, elevated glomerular filtration fraction, and renal injury.  Hypertension  1996; 28:127-132.

31. Allen TJ, Waldron MJ, Casley D, et al: Salt restriction reduces hyperfiltration, renal enlargement and albuminuria in experimental diabetes.  Diabetes  1997; 46:119-124.

32. Vallon V, Wead LM, Blantz RC: Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: Effect of sodium and salt restriction.  J Am Soc Nephrol  1995; 5:1761-1767.

33. Vallon V, Kirschenmann D, Wead LM, et al: Effect of chronic salt loading on kidney function in early and established diabetes mellitus in rats.  J Lab Clin Med  1997; 130:76-82.

34. Peterson JC, Adler S, Burkart JM, et al: Blood pressure control, proteinuria and the progression of renal disease: The Modification of Diet in Renal Disease Study.  Ann Intern Med  1995; 123:754-762.

35. Bakris GL, Weir MR: Salt intake and reductions in arterial pressure and proteinuria: Is there a direct link?.  Am J Hypertens  1996; 9:200S-206S.

36. Bigazzi R, Bianchi S, Baldari D, et al: Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors.  Hypertension  1994; 23:195-199.

37. Weir MR: The influence of dietary salt on the antiproteinuric effect of calcium channel blockers.  Am J Kidney Dis  1997; 29:800-803.

38. Campese VM, Parise M, Karubian F, et al: Abnormal renal hemodynamics in black salt sensitive patients with hypertension.  Hypertension  1991; 18:805-821.

39. Heeg JE, De Jong PE, van der Hem GK, et al: Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril.  Kidney Int  1989; 36:272-279.

40. Rossing P, Hommel E, Smidt UM, et al: Impact of arterial blood pressure and albuminuria on the progression of diabetic nephropathy in IDDM patients.  Diabetes  1993; 42:715-719.

41. Gall MA, Nielsen FS, Smidt UM, et al: The course of kidney function in type-2 (non-insulin-dependent) diabetic patients with diabetic nephropathy.  Diabetologia  1993; 36:1071-1078.

42. Schmitz A: Microalbuminuria, blood pressure, metabolic control, and renal involvement: Longitudinal studies in white non-insulin-dependent diabetic patients.  Am J Hypertens  1997; 10(Suppl S):189S-197S.

43. Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.  J Clin Invest  2006; 116:288-296.

44. Ibrahim HN, Rosenberg ME, Greene EL, et al: Aldosterone is a major factor in the progression of renal disease.  Kidney Int  1997; 63(Suppl 63):S115-S119.

45. Quan ZY, Walser M, Hill GS: Adrenalectomy ameliorates ablative nephropathy in the rat independently of corticosterone maintenance level.  Kidney Int  1992; 41:326-333.

46. Greene EL, Kren S, Hostetter TH: Role of aldosterone in the remnant kidney model in the rat.  J Clin Invest  1996; 98:1063-1068.

47. Sacks FM, Svetkey LP, Vollmar WM, et al: Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet.  N Engl J Med  2001; 344:3-10.

48. Obarzanek E, Proschan MA, Vollmer WM, et al: Individual blood pressure responses to changes in salt intake: results from the DASH-Sodium trial.  Hypertension  2003; 42:459-467.

49. Laffer CL, Bolterman RJ, Romero JC, et al: Effect of salt on isoprostanes in salt-sensitive essential hypertension.  Hypertension  2006; 47:434-440.

50.   Institute of Medicine (U.S.) Panel on Dietary Reference Intakes for Electrolytes and Water: Dietary reference intakes for water, potassium, sodium, chloride and sulfate. In Ch xviii. Washington, DC, National Academies Press, 2005, pp 617.

51. Mitch WE, Wilcox CS: Disorders of body fluids, sodium and potassium in chronic renal failure.  Am J Med  1982; 72:536-550.

52. Whelton PK, He J, Cutler JA, et al: Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials.  JAMA  1997; 277:1624-1632.

53. Appel LJ, Moore TJ, Obarzanek E, et al: A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group.  N Engl J Med  1997; 336:1117-1124.

54. Svetkey LP, Simons-Morton D, Vollmer WM, et al: Effects of dietary patterns on blood pressure: Subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial.  Arch Intern Med  1999; 159:285-293.

55. National Kidney Foundation: K/DOQI Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.  Am J Kidney Dis  2004; 43:S1-S290.

56. de Santo NG, Anastasio P, Spitali L, et al: Renal reserve is normal in adults born with unilateral renal agenesis and is not related to hyperfiltration or renal failure.  Miner Electrolyte Metab  1997; 23:283-286.

57. Thomsen K, Nielsen CB, Flyvbjerg A: Effects of glycine on glomerular filtration rate and segmental tubular handling of sodium in conscious rats.  Clin Exp Pharmacol Physiol  2002; 29:449-454.

58. Anastasio P, Santoro D, Spitali L, et al: Renal functional reserve in children.  Semin Nephrol  1995; 18:454-460.

59. Fliser D, Ritz E, Franek E: Renal reserve in the elderly.  Semin Nephrol  1995; 15:463-467.

60. Gabbai FB: Renal reserve in patients with high blood pressure.  Semin Nephrol  1995; 15:482-487.

61. Kontessis P, Jones S, Dodd R, et al: Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins.  Kidney Int  1990; 38:136-144.

62. Jones SL, Kontessis P, Wiseman M, et al: Protein intake and blood glucose as modulators of GFR in hyperfiltering diabetic patients.  Kidney Int  1992; 41:1620-1628.

63. Fioretto P, Trevisan R, Valerio A, et al: Impaired renal response to a meat meal in insulin-dependent diabetes: Role of glucagon and prostaglandins.  Am J Physiol  1990; 258:F675-F683.

64. Brouhard BH, LaGrone L: Effect of dietary protein restriction on functional renal reserve in diabetic nephropathy.  Am J Med  1990; 89:427-431.

65. Guizar JM, Kornhauser C, Malacara JM, et al: Renal functional reserve in patients with recently diagosed type 2 diabetes mellitus with and without microalbuminuria.  Nephron  2000; 87:223-230.

66. Tuttle KR, Puhlman MF, Cooney SK, et al: Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes.  Am J Physiol  2002; 282:F103-F112.

67. Fioretto P, Trevisan R, Giorato C, et al: Type I insulin-dependent diabetic patients show an impaired renal hemodynamic response to protein intake.  J Diabet Complications  1988; 2:27-29.

68. Juncos LI, Juncos LA, Ferrer MC, et al: Abnormal renal vasodilatation to an amino acid infusion in congestive heart failure: Normalization by enalapril.  Am J Kidney Dis  1999; 33:43-51.

69. Woods LL: Intrarenal mechanisms of renal reserve.  Semin Nephrol  1995; 15:386-395.

70. Ter Wee PM: Renal effects of intravenous amino acid administration in humans with and without renal disease: Hormonal correlates.  Semin Nephrol  1995; 15:426-432.

71. Nair KS, Pabico RC, Truglia JA, et al: Mechanism of glomerular hyperfiltration after a protein meal in humans: Role of hormones and amino acids.  Diabetes Care  1994; 17:711-715.

72. Thomas DM, Coes GA, Williams JD: Dopamine does not mediate protein-induced hyperfiltration.  Exp Nephrol  1994; 2:294-298.

73. Bohler J, Woitas R, Keller E, et al: Effect of nifedipine and captopril on glomerular hyperfiltration in normotensive man.  Am J Kidney Dis  1992; 20:132-139.

74. Tietze IN, Sorensen SS, Ivarsen PR, et al: Impaired renal haemodynamic response to amino acid infusion in essential hypertension during angiotensin converting enzyme inhibitor treatment.  J Hypertension  1997; 15:551-560.

75. Lopes de Faria JB, Friedman R, de Cosmo S, et al: Renal functional response to protein loading in type 1 (insulin-dependent) diabetic patients on normal or high salt intake.  Nephron  1997; 76:411-417.

76. Jaffa AA, Vio CP, Silva RH, et al: Evidence for renal kinins as mediators of amino acid-induced hyperperfusion and hyperfiltration in the rat.  J Clin Invest  1992; 89:1460-1468.

77. King AJ: Nitric oxide and the renal hemodynamic response to proteins.  Semin Nephrol  1995; 15:405-414.

78. El Sayed AA, Haylor J, El Nahas AM: Involvement of renal autocoids in the direct effects of mixed amino acids on the kidney.  Miner Electrolyte Metab  1992; 18:117-119.

79. Muhlbauer B, Spohr F, Schmidt R, et al: Role of renal nerves and endogenous dopamine in amino acid-induced glomerular hyperfiltration.  Am J Physiol  1997; 273:F140-F144.

80. Kraus ES, Cheng L, Sikorski I, et al: Effect of phosphorus restriction on renal response to oral and intravenous protein loads in rats.  Am J Physiol  1993; 264:F752-F759.

81. de Santo NG, Anastasio P, Spitali L, et al: The renal hemodynamic response to an oral protein load is normal in IgA nephropathy.  Nephron  1997; 76:406-410.

82. Hotz P, Mujyabwami F, Roels H, et al: Effect of oral protein load on urinary protein excretion in workers exposed to cadium and to lead.  Am J Ind Med  1996; 29:195-200.

83. Narita R, Kitazto H, Koshimura J, et al: Effects of protein meals on the urinary excretion of various plasma proteins in healthy subjects.  Nephron  1999; 81:398-405.

84. Gross JL, Zelmanovitz T, Moulin CC, et al: Effect of a chicken-based diet on renal function and lipid profile in patients with type 2 diabetes: A randomized crossover trial.  Diabetes Care  2003; 25:645-651.

85. Garini G, Mazzi A, Buzio C, et al: Renal effects of captopril, indomethacin and nifedipine in nephrotic patients after an oral protein load.  Nephrol Dial Transpl  1996; 11:628-634.

86. Coppo R, Porcellini MG, Gianoglio B, et al: Glomerular permselectivity to macromolecules in reflux nephropathy: Microalbuminuria during acute hyperfiltration due to aminoacid infusion.  Clin Nephrol  1993; 40:299-307.

87. King AJ, Levey AS: Dietary protein and renal function.  J Am Soc Nephrol  1993; 3:1723-1737.

88. Wilmer WA, Rovin BH, Hebert CJ, et al: Management of glomerular proteinuria: A commentary.  J Am Soc Nephrol  2003; 14:3217-3232.

89. Aparicio M, Bouchet JL, Gin H, et al: Effect of a low-protein diet on urinary albumin excretion in uremic patients.  Nephron  1988; 50:288-291.

90. Levine SE, D'Elia JE, Bistrian B, et al: Protein-restricted diet in diabetic nephropathy.  Nephron  1989; 52:55-61.

91. Wiseman MJ, Bognetti E, Dodds R, et al: Changes in renal function in response to protein restricted diet in type 1 (insulin-dependent) diabetic patients.  Diabetologia  1998; 30:154-159.

92. Evanoff GV, Thompson CS, Brown J, et al: The effect of dietary protein restriction on the progression of diabetic nephropathy: A 12-month follow-up.  Arch Intern Med  1987; 147:492-495.

93. Walker JD, Dodds RA, Murrells TJ, et al: Restriction of dietary protein and progression of renal failure in diabetic nephropathy.  Lancet  1989; 2:1411-1414.

94. Brodsky IG, Robbins DC, Hiser E, et al: Effects of low-protein diets on protein metabolism in insulin-dependent diabetes mellitus patients with early nephropathy.  J Clin Endocrinol Metab  1992; 75:351-357.

95. Dullaart RP, Beusekamp BJ, Meijer S, et al: Long-term effects of protein-restricted diet on albuminuria and renal function in IDDM patients without clinical nephropathy and hypertension.  Diabetes Care  1993; 16:483-492.

96. Gansevoort RT, De Zeeuw D, De Jong PE: Additive antiproteinuric effect of ACE inhibition and a low-protein diet in human renal disease.  Nephrol Dial Transpl  1995; 10:497-504.

97. Ruilope LM, Casal MC, Praga M, et al: Additive antiporteinuric effect of convert-ing enzyme inhibition and a low protein diet.  J Am Soc Nephrol  1992; 3:1307-1311.

98. deJong P, Navis G, deZeeuw D: Renoprotective therapy: Titration against urinary protein excretion.  Lancet  1999; 354:352-353.

99. Kaysen GA, Webster S, Albander H, et al: High-protein diets augment albuminuria in rats with Heymann nephritis by angiotensin II-dependent and -independent mechanisms.  Miner Electrolyte Metab  1998; 24:238-245.

100. Toeller M, Buyken A, Heitkamp G, et al: Protein intake and urinary albumin excretion rates in the EURODIAB IDDM complications study.  Diabetologia  1997; 40:1219-1226.

101. Jameel N, Pugh JA, Mitchell BD, et al: Dietary protein intake is not correlated with clinical proteinuria in NIDDM.  Diabetes Care  1992; 15:178-183.

102. Hoffer LJ: Adaptation to protein restriction is impaired in insulin-dependent diabetes mellitus.  J Nutr  1998; 128:333S-336S.

103. Meireles CL, Price SR, Pererira AML, et al: Nutrition and chronic renal failure in rats: What is an optimal dietary protein?.  J Am Soc Nephrol  1999; 10:2367-2373.

104. Fouque D, Laville M, Boissel JP, et al: Controlled low protein diets in chronic renal insufficiency: Meta-analysis.  Br Med J  1992; 304:216-220.

105. Pedrini MT, Levey AS, Lau J, et al: The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A meta-analysis.  Ann Intern Med  1996; 124:627-632.

106. Klahr S, Levey AS, Beck GJ, et al: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal failure.  N Engl J Med  1994; 330:878-884.

107. Ihle BU, Becker GJ, Whitworth JA, et al: The effect of protein restriction on the progression of renal insufficiency.  N Engl J Med  1989; 321:1773-1777.

108. Williams PS, Stevens ME, Fass G, et al: Failure of dietary protein and phosphate restriction to retard the rate of progression of chronic renal failure: A prospective, randomized, controlled trial.  Q J Med  1991; 81:837-855.

109. Locatelli F, Alberti D, Graziani G, et al: Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency.  Lancet  1991; 337:1299-1304.

110. Mirtallo JM, Schneider PJ, Mavko K, et al: A comparison of essential and general amino acid infusions in the nutritional support of patients with compromised renal function.  J Parent Ent Nutr  1982; 6:109-113.

111. Zeller KR, Whittaker E, Sullivan L, et al: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus.  N Engl J Med  1991; 324:78-83.

112. Ciavarella A, DiMizio G, Stefoni S, et al: Reduced albuminuria after dietary protein restriction in insulin-dependent diabetic patients with clinical nephropathy.  Diabetes Care  1987; 10:407-413.

113. Kasiske BL, Lakatua JDA, Ma JZ, et al: A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function.  Am J Kidney Dis  1998; 31:954-961.

114. Levey AS, Adler S, Caggiula AW, et al: Effects of dietary protein restriction on the progression of moderate renal disease in the Modification of Diet in Renal Disease Study.  J Am Soc Nephrol  1996; 7:2616-2626.

115. Levey AS, Greene T, Beck GJ, et al: Dietary protein restriction and the progression of chronic renal disease: What have all the results of the MDRD Study shown?.  J Am Soc Nephrol  1999; 10:2426-2439.

116. Hansen HP, Tauber-Lassen E, Jensen BR, et al: Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy.  Kidney Int  2002; 62:220-228.

117. Meloni C, Morosetti M, Suraci C, et al: Severe dietary protein restriction in overt diabetic nephropathy: Benefits or risks?.  J Renal Nutr  2002; 12:96-101.

118. Okada T, Matsumoto H, Nakao T, et al: Effect of dietary protein restriction and influence of proteinuria on progression of type 2 diabetic renal failure.  Nippon Jinzo Gakkai Shi  2000; 42:365-373.

119. Riabov SI, Kucher AG, Grogor'eva ND, et al: Effects of different variants of low-protein diet on progression of chronic renal failure and indices of nutritional status in predialysis stage.  Ter Arkh  2003; 73:10-15.

120. Combe C, Deforges-Lasseur C, Caix J, et al: Compliance and effects of nutritional treatment on progression and metabolic disorders of chronic renal failure.  Nephrol Dial Transpl  1993; 8:412-418.

121. Choukroun G, Itakura Y, Albouze G, et al: Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease.  J Am Soc Nephrol  1995; 6:1634-1642.

122. Klahr S, Breyer JA, Beck GJ, et al: Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease.  J Am Soc Nephrol  1995; 5:2037-2047.

123. Uauy RD, Hogg RJ, Brewer ED, et al: Dietary protein and growth in infants with chronic renal insufficiency: A report from the Southwest Pediatric Nephrology Study Group and the University of California, San Francisco.  Pediatr Nephrol  1994; 8:45-50.

124. Baur LA, Knight JF, Crawford BA, et al: Total body nitrogen in children with chronic renal failure and short stature.  Eur J Clin Nutr  1994; 48:433-441.

125. Polito C, La Manna A, Iovene A, et al: Pubertal growth in children with chronic renal failure on conservative treatment.  Pediatr Nephrol  1995; 9:734-736.

126. Kist-van Holthe tot Echten JE, Nauta J, Hop WC, et al: Protein restriction in chronic renal failure.  Arch Dis Child  1993; 68:371-375.

127. Wingen AM, Fabian-Bach C, Schaefer F, et al: Randomised multicentre study of a low-protein diet on the progression of chronic renal failure in children. European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood.  Lancet  1997; 349:1117-1123.

128. Kitazato H, Fujita H, Shimotomai T, et al: Effects of chronic intake of vegetable protein added to animal or fish protein on renal hemodynamics.  Nephron  2002; 90:31-36.

129. D'Amico G, Gentile MG: Effect of dietary manipulation on the lipid abnormalities and urinary protein loss in nephrotic patients.  Miner Electrolyte Metab  1992; 18:203-206.

130. D'Amico G, Gentile MG, Manna GDW, et al: Effect of vegetarian soy diet on hyperlipidaemia in nephrotic syndrome.  Lancet  1992; 339:1131-1134.

131. D'Amico G, Gentile MG: Influence of diet on liipid abnormalities in human renal disease.  Am J Kidney Dis  1993; 22:151-157.

132. Gentile MG, Fellin G, Cofano F, et al: Treatment of proteinuric patients with a vegetarian soy diet and fish oil.  Clin Nephrol  1993; 40:315-320.

133. Jibani MM, Bloodworth LL, Foden E, et al: Predominantly vegetarian diet in patients with incipient and early clinical diabetic nephropathy: Effects on albumin excretion rate and nutritional status.  Diabetic Med  1991; 8:949-953.

134. Kontessis PA, Bossinakou I, Sarika L, et al: Renal, metabolic, and hormonal responses to proteins of different origin in normotensive, nonproteinuric type I diabetic patients.  Diabetes Care  1995; 18:1233.

135. Soroka N, Silverberg DS, Greemland M, et al: Comparison of a vegetable-based (SOYA) and an animal-based low-protein diet in predialysis chronic renal failure patients.  Nephron  1998; 79:173-180.

136. Chen PY, Sanders PW: L-arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats.  J Clin Invest  1991; 88:1559-1567.

137. Reyes AA, Purkerson ML, Karl I, et al: Dietary supplementation with L-arginine ameliorates the progression of renal disease in rats with subtotal nephrectomy.  Am J Kid Dis  1992; 20:168-176.

138. Reyes AA, Karl IE, Kissane J, et al: L-Arginine administration prevents glomerular hyperfiltration and decreases proteinuria in diabetic rats.  J Am Soc Nephrol  1993; 4:1039-1045.

139. Pisani A, Uccello F, Cesaro A, et al: Progression of chronic renal failure in remnant rats: Role of arginase inhibition.  G Ital Nefrol  2002; 19:278-285.

140. Reyes AA, Porras BH, Chasalow FI, et al: L-arginine decreases the infiltration of the kidney by macrophages in obstructive nephropathy and puromycin-induced nephrosis.  Kidney Int  1994; 45:1346-1354.

141. Ashab I, Peer G, Blum M, et al: Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production.  Kidney Int  1995; 47:1515-1521.

142. MacAllister RJ, Whitley GStJ, Vallance P: Effects of guanidino and uremic compounds on nitric oxide pathways.  Kidney Int  1994; 45:737-742.

143. Arnal J-F, Munzel T, Venema RC, et al: Interactions between L-arginine and L-glutamine change endothelial NO production: An effect independent of NO synthase substrate availability.  J Clin Invest  1995; 95:2565-2572.

144. Komers R, Komersova K, Ruzickova J, et al: Intravenous administration of L-arginine inhibits angiotensin-converting enzyme in humans.  J Hypertension  2000; 18:51-59.

145. Andoh TF, Gardner MP, Bennett WM: Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity.  Transplant  1997; 64:1236-1240.

146. Higashi Y, Oshima T, Ozono R, et al: Effect of L-arginine infusion on systemic and renal hemodynamics in hypertensive patients.  Am J Hypertens  1999; 12:8-15.

147. Bello E, Caramelo C, Lopez MD, et al: Induction of microalbuminuria by L-arginine infusion in healthy individuals: An insight into the mechanisms of proteinuria.  Am J Kidney Dis  1999; 33:1018-1025.

148. Watanabe G, Tomiyama H, Doba N: Effects of oral administration of L-arginine on renal function in patients with heart failure.  J Hypertension  2000; 18:229-234.

149. Herlitz H, Jungersten LU, Wikstrand J, et al: Effect of L-arginine influsion in normotensive subjects with and without a family history of hypertension.  Kidney Int  1999; 56:1838-1845.

150. Tome LA, Yu L, de Castro I, et al: Beneficial and harmful effects of L-arginine on renal ischemia.  Nephrol Dial Transpl  1999; 14:1139-1145.

151. Narita I, Border WA, Ketteler M, et al: L-arginine may mediate the therapeutic effects of low protein diets.  Proc Natl Acad Sci U S A  1995; 92:4552-4556.

152. Narita I, Border WA, Ketteler M, et al: Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis.  Lab Invest  1995; 72:17-24.

153. Ketteler M, Ikegaya N, Brees DK, et al: L-arginine metabolism in immune-mediated glomerulonephritis in the rat.  Am J Kidney Dis  1996; 28:878-887.

154. Bennett-Richards KJ, Kattenhorn M, Donald AE, et al: Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure.  Kidney Int  2002; 62:1372-1378.

155. Blantz RC, Lortie M, Vallon V, et al: Activities of nitric oxide in normal physiology and uremia.  Semin Nephrol  1996; 16:144-150.

156. Kaysen GA, Kropp J: Dietary tryptophan supplementation prevents proteinuria in the seven-eighths nephrectomized rat.  Kidney Int  1983; 23:473-479.

156a. Teschan PE, Beck GJ, Dwyer JT, et al: Effect of a ketoacid-aminoacid-supplemented very low protein diet on the progression of advanced renal disease: A reanalysis of the MDRD Feasibility Study.  Clin Nephrol  1998; 50:273-283.

157. Walser M: Progression of chronic renal failure in man.  Kidney Int  1990; 37:1195-1210.

158. Walser M, Ward L, Hill S: Hypotryptophanemia in patients with chronic renal failure on nutritional therapy.  J Am Soc Nephrol  1991; 2:247.

159. Owada P, Nakao M, Koike J, et al: Effects of oral adsorbent AST-120 on the progression of chronic renal failure—A randomized controlled study.  Kidney Int  1997; 52(Suppl 63):S188-S190.

160. Miyazaki T, Ise M, Hirata M, et al: Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta-1 and progression of renal failure.  Kidney Int  1997; 52(Suppl 63):S211-S214.

161. Niwa T, Tsukushi S, Ise M, et al: Indoxyl sulfate and progression of renal failure—effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.  Miner Electrolyte Metab  1997; 23:179-184.

162. Niwa T, Ise M, Miyazaki T: Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate.  Am J Nephrol  1994; 14:207-212.

163. Keane WF, Guijarro C: Lipids and progressive renal failure.  Contrib Nephrol  1996; 118:17-23.

164. Samuelsson O, Mulec H, Knight-Givson C, et al: Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency.  Nephrol Dial Transpl  1997; 12:1908-1915.

165. Attman PO, Samuelsson O, Alaupovic P: Progression of renal failure—Role of apolipoprotein B-containing lipoproteins.  Kidney Int  1997; 52(Suppl 63):S98-S101.

166. Gregorio SM, Lemos CC, Caldas ML, et al: Effect of dietary linoleic acid on the progression of chronic renal failure in rats.  Braz J Med Biol Res  2002; 35:573-579.

167. Kutner NG, Clow PW, Zhang R, et al: Association of fish intake and survival in a cohort of incident dialysis patients.  Am J Kidney Dis  2002; 39:1018-1024.

168. Monzani G, Bergesio F, Ciuti R, et al: Lp(a) levels-Effects of progressive chronic renal failure and dietary manipulation.  J Nephrol  1997; 10:41-45.

169. Bernard S, Fouque D, Laville M, et al: Effects of low-protein diet supplemented with ketoacids on plasma lipids in adult chronic renal failure.  Miner Electrolyte Metab  1996; 22:143-146.

170. Nielsen S, Hermansen K, Rasmussen OW, et al: Urinary albumin excretion rate and 24-h ambulatory blood pressure in NIDDM with microalbuminuria: Effects of a monounsaturated-enriched diet.  Diabetologia  1995; 38:1069-1075.

171. Cappelli P, Diliberato L, Stuard S, et al: N-3 polyunsaturated fatty acid supplementation in chronic progressive renal disease.  J Nephrol  1997; 10:157-162.

172. Hu FB, Willett WC: Optimal diets for prevention of coronary heart disease.  JAMA  2002; 288:2569-2578.

173. Mozaffarian D, Gottdiener JS, Siscovick DS: Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics.  Am J Cardiol  2006; 97:216-222.

174. Chiuve SE, McCullough ML, Sacks FM, et al: Healthy lifestyle factors in the primary prevention of coronary heart disease among men: Benefits among users and nonusers of lipid-lowering and antihypertensive medications.  Circulation  2006; 114:160-167.

175. Storer TW, Casaburi R, Sawelson S, et al: Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.  Nephrol Dial Transplant  2005; 20:1429-1437.

176. Johansen KL, Painter PL, Sakkas GK, et al: Effects of resistance exercise training and nandrolone decanoate on body composition and muscle function among patients who receive hemodialysis: A randomized, controlled trial.  J Am Soc Nephrol  2006; 17:2307-2314.

177. Workeneh B, Rondon-Berrios H, Zhang L, et al: Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions.  J Am Soc Nephrol  2006; 17:3233-3239.

178. Tonelli M, Keech A, Shepherd J, et al: Effect of pravastatin in people with diabetes and chronic kidney disease.  J Am Soc Nephrol  2005; 16:3748-3754.

179. Sandhu S, Wiebe N, Fried LF, et al: Statins for improving renal outcomes: A meta-analysis.  J Am Soc Nephrol  2006; 17:2006-2016.

180. Lam KSL, Cheng JKP, Janus ED, et al: Cholesterol-lowering therapy may retard the progression of diabetic nephropathy.  Diabetologia  1995; 38:604-609.

181. Sanjad SA, Alabbad A, Alshorafa S: Management of hyperlipidemia in children with refractory nephrotic syndrome—The effect of statin therapy.  J Pediatr  1997; 130:470-474.

182. Bliss DZ, Stein TP, Schleifer CR, et al: Supplementation with gum arabic fiber increases fecal nitrogen excretion and lowers serum urea nitrogen concentration in chronic renal failure patients consuming a low-protein diet.  Am J Clin Nutr  1996; 63:392-398.

183. Groop PH, Aro A, Stenman S, et al: Long-term effects of guar gum in subjects with non-insulin-dependent diabetes mellitus.  Am J Clin Nutr  1993; 58:513-518.

184. Dickinson HO, Mason JM, Nicolson DJ, et al: Lifestyle interventions to reduce raised blood pressure: A systematic review of randomized controlled trials.  J Hypertens  2006; 24:215-233.

185. Solomon CG, Hu FB, Stampfer MJ, et al: Moderate alcohol consumption and risk of coronary heart disease among women with type 2 diabetes mellitus.  Circulation  2000; 102:494-499.

186. Tanasescu M, Hu FB, Willett WC, et al: Alcohol consumption and risk of coronary heart disease among men with type 2 diabetes mellitus.  J Am Coll Cardiol  2001; 38:1836-1842.

187. Perneger TV, Whelton PK, Puddey IB, et al: Risk of end-stage renal disease associated with alcohol consumption.  Am J Epidemiol  1999; 150:1275-1281.

188. Knight EL, Stampfer MJ, Rimm EB, et al: Moderate alcohol intake and renal function decline in women: a prospective study.  Nephrol Dial Transplant  2003; 18:1549-1554.

189. Schaeffner ES, Kurth T, De Jong PE, et al: Alcohol consumption and the risk of renal dysfunction in apparently healthy men.  Arch Intern Med  2005; 165:1048-1053.

190. Belibi FA, Wallace DP, Yamaguchi T, et al: The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease.  J Am Soc Nephrol  2002; 13:2723-2729.

191. Winkelmayer WC, Stampfer MJ, Willett WC, et al: Habitual caffeine intake and the risk of hypertension in women.  JAMA  2005; 294:2330-2335.

192. MacDonald TM, Sharpe K, Fowler G, et al: Caffeine restriction: Effect on mild hypertension.  BMJ  1991; 303:1235-1238.

193. Walser M, Mitch WE, Maroni BJ, et al: Should protein be restricted in predialysis patients?.  Kidney Int  1999; 55:771-777.

194. Masud T: Trace elements and vitamins in renal disease.   In: Mitch WE, Klahr S, ed. Nutrition and the Kidney,  Philadelphia: Lippincott, Williams and Wilkins; 2005:196-217.

195. Mydlik M, Derzsiova K, Zemberova E: Metabolism of vitamin B6 and its requirement in chronic renal failure.  Kidney Int  1997; 52(Suppl 62):S56-S59.

196. Pronai W, Riegler-Keil M, Silberbauer K, et al: Folic acid supplementation improves erythropoietin response.  Nephron  1995; 71:395-400.

197. Ramirez G, Chen M, Boyce HW, et al: Longitudinal follow-up of chronic hemodialysis patients without vitamin supplementation.  Kidney Int  1986; 30:99-106.

198. Ono K: Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients.  Clin Nephrol  1986; 26:239-243.

199. Ott SM, Andress DL, Sherrard DJ: Bone oxalate in a long-term hemodialysis patient who ingested high doses of vitamin C.  Am J Kidney Dis  1986; 8:450-454.

200. Robinson K, Gupta A, Dennis V, et al: Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.  Circulation  1996; 94:2473-2478.

201. Malinow MR, Nieto FJ, Kruger WD, et al: The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes.  Arterioscler Thromb Vasc Biol  1997; 17:1157-1162.

202. Gonin JM, Nguyen H, Gonin R, et al: Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD.  J Nephrol  2003; 16:522-534.

203. Rocco MV, Poole D, Poindexter P, et al: Intake of vitamins and minerals in stable hemodialysis patients as determined by 9-day food food records.  J Renal Nutr  1997; 7:17-24.

204. Schaumburg H, Kaplan J, Winderbank A, et al: Sensory neuropathy from pyridoxine abuse: A new megavitamin syndrome.  N Engl J Med  1983; 309:445-489.

205. Gleghorn EE, Eisenberg LD, Hack S, et al: Observations of vitamin A toxicity in three patients with renal failure receiving parenteral alimentation.  Am J Clin Nutr  1986; 44:107-112.

206. Chen J, He J, Ogden LG, et al: Relationship of serum antioxidant vitamins to serum creatinine in the US population.  Am J Kidney Dis  2002; 39:460-468.

207. Feskanich D, Singh V, Willett WC, et al: Vitamin A intake and hip fractures among postmenopausal women.  JAMA  2002; 287:47-54.

208. Johansson S, Melhus H: Vitamin A antagonizes calcium response to vitamin D in man.  J Bone Miner Res  2001; 16:1899-1905.

209. Taccone-Gallucci M, Giardini O, Ausiello C, et al: Vitamin E supplementation in hemodialysis patients: Effects on peripheral blood mononuclear cells lipid peroxidation and immune response.  Clin Nephrol  1986; 25:81-86.

210. Mann JF, Lonn EM, Yi Q, et al: Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: Results of the HOPE study.  Kidney Int  2004; 65:1375-1380.

211. Caticha O, Norato DY, Tambascia MA, et al: Total body zinc depletion and its relationship to the development of hyperprolactinemia in chronic renal insufficiency.  J Endocrinol Invest  1996; 19:441-448.

212. Abu-Hamdan DK, Mahajan SK, Migdal SD, et al: Zinc tolerance test in uremia: Effect of ferrous sulfate and aluminum hydroxide.  Ann Intern Med  1986; 104:50-52.

213. Ittel TH, Gladziwa U, Muck W, et al: Hyperaluminaemia in critically ill patients: Role of antacid therapy and impaired renal function.  Eur J Clin Invest  1991; 21:93-102.

214. Isnard BC, Deray G, Baumelou A, et al: Herbs and the kidney.  Am J Kidney Dis  2004; 44:1-11.

215. Mitch WE: Dietary requirements of predialysis patients for protein and calories.   In: Mitch WE, Klahr S, ed. Handbook of Nutrition and the Kidney,  Philadelphia: Lippincott-Williams & Wilkins; 2005:115-137.

216. Maroni BJ, Steinman T, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure.  Kidney Int  1985; 27:58-65.

217. Kopple JD, Gao X, Qing DP: Dietary protein, urea nitrogen appearance and total nitrogen appearance in chronic renal failure and CAPD patients.  Kidney Int  1997; 52:486-494.

218. Cottini EP, Gallina DL, Dominguez JM: Urea excretion in adult humans with varying degrees of kidney malfunction fed milk, egg or an amino acid mixture: Assessment of nitrogen balance.  J Nutrition  1973; 103:11-19.

219. Masud T, Manatunga A, Cotsonis G, et al: The precision of estimating protein intake of patients with chronic renal failure.  Kidney Int  2002; 62:1750-1756.

220. Folin O: Laws governing the clinical composition of urine.  Am J Physiol  1905; 13:67-115.

221. Sargent J, Gotch F, Borah M, et al: Urea kinetics: A guide to nutritional management of renal failure.  Am J Clin Nutr  1978; 31:1696-1702.

222. Young VR: Some metabolic and nutritional considerations of dietary protein restriction.   In: Mitch WE, ed. Contemporary Issues in Nephrology: The Progressive Nature of Renal Disease,  New York: Churchill Livingstone; 1986:263-283.

223. Mitch WE, Goldberg AL: Mechanisms of muscle wasting: The role of the ubiquitin-proteasome system.  N Engl J Med  1996; 335:1897-1905.

223a. Walser M, Bodenlos LJ: Urea metabolism in man.  J Clin Invest  1959; 38:1617-1622.

224. Walser M: Urea metabolism in chronic renal failure.  J Clin Invest  1974; 53:1385-1392.

225. Mitch WE, Lietman PS, Walser M: Effects of oral neomycin and kanamycin in chronic renal failure: I. urea metabolism.  Kidney Int  1977; 11:116-122.

226. Dal Canton A, Fuiano G, Conte G, et al: Mechanism of increased plasma urea after diuretic therapy in uraemic patients.  Clin Sci  1985; 68:255-261.

227. Kamm DE, Wu L, Kuchmy BL: Contribution of the urea appearance rate to diuretic-induced azotemia in the rat.  Kidney Int  1987; 32:47-56.

228. Mitch WE, Walser M: A proposed mechanism for reduced creatinine excretion in severe chronic renal failure.  Nephron  1978; 21:248-259.

229. Forbes GB, Bruining GS: Urinary creatinine excretion and lean body mass.  Am J Clin Nutr  1978; 29:1359-1366.

230. Heymsfield SB, Arteaga C, McManus C, et al: Measurement of muscle mass in humans: Validity of the 24-hour urinary creatinine method.  Am J Clin Nutr  1983; 37:478-498.

231. Walker JB: Metabolic control of creatine biosynthesis.  J Biol Chem  1960; 235:2357-2361.

232. Walser M: Creatinine excretion as a measure of protein nutrition in adults of varying age.  J Parent Ent Nutr  1987; 11:73S-77S.

233. Mitch WE, Collier VU, Walser M: Creatinine metabolism in chronic renal failure.  Clin Sci  1980; 58:327-335.

234. Kelly RA, Mitch WE: Creatinine, uric acid and other nitrogenous waste products: Clinical implication of the imbalance between their production and elimination in uremia.  Semin Nephrol  1983; 3:286-294.

235. Jones JD, Burnett PC: Creatinine metabolism in humans with decreased renal function: Creatinine deficit.  Clin Chem  1974; 20:1204-1212.

236. Owens CWI, Albuquerque ZP, Tomlinson GM: In vitro metabolism of creatinine, methylamine and amino acids by intestinal contents of normal and uremic subjects.  Gut  1979; 20:568-574.

237. Maroni BJ, Mitch WE: Role of nutrition in prevention of the progression of renal disease.  Ann Rev Nutr  1997; 17:435-455.

238. Danovitch GM, Weinberger J, Berlyne GM: Uric acid in advanced renal failure.  Clin Sci  1972; 43:331-341.

239. Mitch WE: Getting beyond cross-sectional studies of abnormal nutritional indices in dialysis patients.  Am J Clin Nutr  2003; 77:760-761.

240. Simenhoff ML, Burke JF, Sankkonen JJ, et al: Amine metabolism and the small bowel in uremia.  Lancet  1976; 2:818-822.

241. Sorensen LB: Extrarenal disposal of uric acid.   In: Kelley WN, Weiner IM, ed. Uric Acid, Handbook of Experimental Pharmacology,  Berlin: Springer-Verlag; 1978:325.

242. Mitch WE: Effects of intestinal flora on nitrogen metabolism in patients with chronic renal failure.  Am J Clin Nutr  1978; 31:1594-1600.

243. Rosenfeld JF: Effect of long-term allopurinol administration on serial GFR in normotensive and hypertensive subjects.   In: Sperling O, DeVries A, Wyngaarden JB, ed. Purine Metabolism in Man: Biochemistry and Pharmacology of Uric Acid Metabolism,  New York: Plenum Press; 1974:581-596.

244. Siu YP, Leung KT, Tong MK, et al: Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.  Am J Kidney Dis  2006; 47:51-59.

245. Johnson RJ, Segal MS, Srinivas T, et al: Essential hypertension, progressive renal disease, and uric acid: A pathogenetic link?.  J Am Soc Nephrol  2005; 16:1909-1919.

246. Fessel WJ: Renal outcomes of gout and hyperuricemia.  Am J Med  1979; 67:74-81.

247. Choi HK, Atkinson K, Karlson EW, et al: Purine-rich foods, dairy and protein intake and the risk of gout in men.  N Engl J Med  2004; 350:1093-1103.

248. Defarrari G, Garibotto G, Robaudo C, et al: Brain metabolism of amino acids and ammonia in patients with chronic renal insufficiency.  Kidney Int  1981; 20:505-510.

249. Pimentel L, Brusilow SW, Mitch WE: Unexpected encephalopathy in chronic renal failure: Hyperammonemia complicating acute peritonitis.  J Am Soc Nephrol  1994; 5:1066-1073.

250. Mitchell RB, Wagner JE, Karp JE, et al: Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: Review of nine cases.  Am J Med  1988; 85:662-667.

251. Lavender S, Bennett J, Morse PF, et al: Albumin and creatinine clearances in renal disease.  Clin Sci Mol Med  1974; 46:775-784.

252. Remuzzi A, Perticucci E, Battaglia C, et al: Low-protein diet and glomerular size-selective function in membranous glomerulopathy.  Am J Kidney Dis  1991; 18:317-322.

253. Chan AYM, Cheng ML, Keil LC, et al: Functional response of healthy and diseased glomeruli to a large, protein-rich meal.  J Clin Invest  1988; 81:245-254.

254. D'Amico G, Remuzzi G, Maschio G, et al: Effect of dietary proteins and lipids in patients with membranous nephropathy and nephrotic syndrome.  Clin Nephrol  1991; 35:237-242.

255. Don BR, Kaysen GA, Hutchison FN, et al: The effect of angiotensin-converting enzyme inhibition and dietary protein restriction in the treatment of proteinuria.  Am J Kidney Dis  1991; 17:10-17.

256. Walser M, Hill S, Tomalis EA: Treatment of nephrotic adults with a supplemented, very low-protein diet.  Am J Kidney Dis  1996; 28:354-364.

257. Shichiri M, Nishio Y, Ogura M, et al: Effect of low-protein, very low-phosphorus diet on diabetic renal insufficiency with proteinuria.  Am J Kidney Dis  1991; 18:26-32.

258. Rosenblatt SG, Drake S, Fadem S, et al: Gastrointestinal blood loss in patients with chronic renal failure.  Am J Kidney Dis  1982; 1:232-236.

259. Delaporte C, Jean G, Broyer M: Free plasma and muscle amino acids in uremic children.  Am J Clin Nutr  1987; 31:1647.

260. Loder PB, Kee AJ, Horsburgh R, et al: Validity of urinary urea nitrogen as a measure of total urinary nitrogen in adult patients requiring parenteral nutrition.  Crit Care Med  1989; 17:309-312.

261. Reaich D, Graham KA, Channon SM, et al: Insulin mediated changes in protein degradation and glucose utilization following correction of acidosis in humans with CRF.  Am J Physiol  1995; 268:E121-E126.

262. Maroni BJ, Staffeld C, Young VR, et al: Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet.  J Clin Invest  1997; 99:2479-2487.

263. Rand WM, Scrimshaw NS, Young VR: Conventional (“Long-Term”) nitrogen balance studies for protein quality evaluation in adults: Rationale and limitations.   In: Bodwell CE, Adkins JS, Hopkins DT, ed. Protein Quality in Humans: Assessment and In Vitro Estimation,  Westport: AVI Publishing Co., Inc.; 1981:61-97.

264. Kaysen GA, Dubin JA, Muller HG, et al: Relationships among inflammation nutrition and physiologic mechanisms establishing albumin levels in hemodialysis patients.  Kidney Int  2002; 61:2240-2249.

265. Borah MF, Schoenfeld PY, Gotch FA, et al: Nitrogen balance during intermittent dialysis therapy of uremia.  Kidney Int  1978; 14:491-500.

266. Walser M: Misinterpretation of nitrogen balances when glutamine stores fall or are replenished.  Am J Clin Nutr  1991; 53:1337-1338.

266a. Taylor YSM, Scrimshaw NS, Young VR: The relationship between serum urea levels and dietary nitrogen utilization in young men.  Br J Nutr  1974; 32:407-411.

267. Stenvinkel P, Heimburger O, Paultre F, et al: Strong association between malnutrition, inflammation and atherosclerosis in chronic kidney failure.  Kidney Int  1999; 55:1899-1911.

268. Mitch WE: Malnutrition: A frequent misdiagnosis for hemodialysis patients.  J Clin Invest  2002; 110:437-439.

269. Kaysen GA, Dubin JA, Muller H-G, et al: Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients.  Kidney Int  2004; 65:1408-1415.

270. Movilli E, Zani R, Carli O, et al: Correction of metabolic acidosis increases serum albumin concentration and decreases kinetically evaluated protein intake in hemodialysis patients: A prospective study.  Nephrol Dial Transpl  1998; 13:1719-1722.

271. Smith G, Robinson PH, Fleck A: Serum albumin distribution in early treated anorexia nervosa.  Nutrition  1996; 12:677-684.

272. Aparicio M, Chauveau P, dePrecigout V, et al: Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet.  J Am Soc Nephrol  2000; 11:719-727.

273. Rigalleau V, Blanchetier V, Combe C, et al: A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients.  Am J Clin Nutr  1997; 65:1512-1516.

274. Tom K, Young VR, Chapman T, et al: Long-term adaptive responses to dietary protein restriction in chronic renal failure.  Am J Physiol  1995; 268:E668-E677.

275. Walser M, Hill S: Can renal replacement be deferred by a supplemented very-low protein diet?.  J Am Soc Nephrol  1999; 10:110-116.

276. Aparicio M, Chauveau P, Combe C: Low protein diets and outcome of renal patients.  J Nephrol  2001; 14:433-439.

277. Levey AS, NKF Task Force on Cardiovascular Disease : Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to know? Where do we go from here?.  Am J Kidney Dis  1998; 32(Suppl 3):S1-S199.

278. Herbelin A, Nguyen AT, Zingraff J, et al: Influence of uremia and hemodialysis on circulating interleukin-1 and tumor necrosis factor a.  Kidney Int  1990; 37:116-127.

279. Young GA, Swanepoel CR, Croft MR, et al: Anthropometry and plasma valine, amino acids and proteins in the nutritional assessment of hemodialysis patients.  Kidney Int  1982; 21:492-499.

280. Guilherme A, Czech MP: Stimulation of IRS-1-associated phosphtidylinositol 3-kinase and Akt/protein kinase B but not glucose transport by beta1-integrin signaling in rat adipocytes.  J Biol Chem  1998; 273:33119-33122.

281. Shoji T, Emoto M, Tabata T, et al: Advanced atherosclerosis in predialysis patients with chronic renal failure.  Kidney Int  2002; 61:2187-2192.

282. Stenvinkel P, Heimburger O, Lindholm B: Wasting, but not malnutrition, predicts cardiovascular mortality in end-stage renal disease.  Nephrol Dial Transpl  2004; 19:2181-2183.

283. Bostom AG, Lathrop L: Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerotic outcomes.  Kidney Int  1997; 52:10-20.

284. Suliman ME, Anderstam B, Lindholm B, et al: Total, free, and protein-bound sulphur amino acids in uremic patients.  Nephrol Dial Transpl  1997; 12:2332-2338.

285. Nygard O, Nordrehaug JE, Refsun H, et al: Plasma homocysteine levels and mortality in patients with coronary artery disease.  N Engl J Med  1997; 337:230-236.

286. Selhub J, Jacques PF, Bostom AG, et al: Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.  N Engl J Med  1995; 332:286-299.

287. Bostom AG, Shemin D, Bagley P, et al: Controlled comparison of L-5-methyltetrahydrofolate versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients.  Circulation  2000; 101:2829-2832.

288. Mezzano D, Pais EO, Aranda E, et al: Inflammation not hyperhomocysteinemia is related to oxidative stress and hemostatic and endothelial dysfunction in uremia.  Kidney Int  2001; 60:1844-1850.

289. Eschbach JN, Abdulhadi MH, Brown JK, et al: Recombinant human erythropoietin in uremic patients with end-stage renal disease.  Ann Intern Med  1989; 111:992-1000.

290. Toigo G, Situlin R, Vasile A, et al: Effects of erythropoietin administration on nutritional state and erythrocyte metabolism in maintenance hemodialysis patients.  Contrib Nephrol  1992; 98:79-88.

291. Kult J, Richter U, Scheitza E, et al: Storungen im Komplementsystem bei Niereninsuffizienz und ihre Beeinflussung durch Aminosaurensubstitution.  Dtsch Med Wochenschr  1974; 99:339-342.

292. Mehls O, Haffner D: Treatment of growth retardation in uraemic children.  Nephrol Dial Transpl  1995; 10(Suppl):80-89.

293. Ikizler TA, Wingard RL, Breyer JA, et al: Short-term effects of recombinant human growth hormone in CAPD patients.  Kidney Int  1994; 46:1178-1183.

294. Ikizler TA, Wingard RL, Flakoll PJ, et al: Effects of recombinant human growth hormone on plasma and dialysate amino acid profiles in CAPD patients.  Kidney Int  1996; 50:229-234.

295. Miller SB, Moulton M, O'Shea M, et al: Effects of IGF-1 on renal function in end-stage chronic renal failure.  Kidney Int  1994; 46:207-210.

296. Ziegler TR, Gatzen C, Wilmore DW: Strategies for attenuating protein-catabolic responses in the critically ill.  Annu Rev Med  1994; 45:459-480.

297. Wang H, Casaburi R, Taylor WE, et al: Skeletal muscle mRNA for IGF-IEa, IGF-II, and IGF-I receptor is decreased in sedentary chronic hemodialysis patients.  Kidney Int  2005; 68:352-361.

298. Fryburg DA, Jahn LA, Hill SA, et al: Insulin and insulin-like growth factor-1 enhance human skeletal muscle protein anabolism during hyperaminoacidemia by different mechanisms.  J Clin Invest  1995; 96:1722-1729.

299. Fouque D, Peng SC, Kopple JD: Impaired metabolic response to recombinant insulin-like growth factor-I in dialysis patients.  Kidney Int  1995; 47:876-883.

300. Fouque D, Le Bouc Y, Laville M, et al: Insulin-like growth factor-1 and its binding proteins during a low-protein diet in chronic renal failure.  J Am Soc Nephrol  1995; 6:1427-1433.

301. Garibotto G, Barreca A, Russo R, et al: Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.  J Clin Invest  1997; 99:97-105.

302. Oster MH, Fielder PJ, Levin N, et al: Adaptation of the growth hormone and insulin-like growth factor-1 axis to chronic and severe calorie or protein malnutrition.  J Clin Invest  1995; 95:2258-2265.

303. Brungger M, Hulter HN, Krapf R: Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: New cause of growth hormone insensitivity in humans.  Kidney Int  1997; 51:216-221.

304. Bereket A, Wilson TA, Kolasa AJ, et al: Regulation of the insulin-like growth factor system by acute acidosis.  Endocrinology  1996; 137:2238-2245.

305. Himmelfarb J, Holbrook D, McMonagle E, et al: Kt/V, nutritional parameters, serum cortisol, and insulin growth factor-1 levels and patient outcome in hemodialysis.  Am J Kidney Dis  1994; 24:473-479.

306. Bergstrom J: Why are dialysis patients malnourished?.  Am J Kidney Dis  1995; 26:229-241.

307. Hakim RM, Lazarus JM: Initiation of dialysis.  J Am Soc Nephrol  1995; 6:1319-1320.

308. Anonymous : Clinical Practice Guidelines for Peritoneal Dialysis Adequacy.  Am J Kidney Dis  1997; 30(Suppl 2):S70-S73.

309. Mehrotra R, Nolph KD: Treatment of advanced renal failure: Low-protein diets or timely initiation of dialysis.  Kidney Int  2000; 58:1381-1388.

310. Hakim RM, Lazarus JM: Biochemical parameters in chronic renal failure.  Am J Kidney Dis  1988; 9:238-247.

311. Beddhu S, Samore MH, Roberts MS, et al: Impact of timing of initiation of dialysis on mortality.  J Am Soc Nephrol  2003; 14:2305-2312.

312. Traynor JP, Simpson K, Geddes CC, et al: Early initiation of dialysis fails to prolong survival in patients with end-stage renal failure.  J Am Soc Nephrol  2002; 13:2125-2132.

313. Alvestrand A, Furst P, Bergstrom J: Plasma and muscle free amino acids in uremia: Influence of nutrition with amino acids.  Clin Nephrol  1982; 18:297-305.

314. Young GA, Keogh JB, Parson FM: Plasma amino acids and protein levels in chronic renal failure and changes caused by oral supplements of essential amino acids.  Clin Chim Acta  1975; 61:205-213.

315. Garibotto G, DeFerrari G, Robaudo C, et al: Effects of a protein meal on blood amino acid profile in patients with chronic renal failure.  Nephron  1993; 64:216-225.

316. DeFerrari G, Garibotto G, Robaudo C, et al: Splanchnic exchange of amino acids after amino acid ingestion in patients with chronic renal insufficiency.  Am J Clin Nutr  1988; 48:72-83.

317. May RC, Hara Y, Kelly RA, et al: Branched-chain amino acid metabolism in rat muscle: Abnormal regulation in acidosis.  Am J Physiol  1987; 252:E712-E718.

318. Hara Y, May RC, Kelly RA, et al: Acidosis, not azotemia, stimulates branched-chain amino acid catabolism in uremic rats.  Kidney Int  1987; 32:808-814.

319. England BK, Greiber S, Mitch WE, et al: Rat muscle branched-chain ketoacid dehydrogenase activity and mRNAs increase with extracellular acidemia.  Am J Physiol  1995; 268:C1395-C1400.

320. Bergstrom J, Alvestrand A, Furst P: Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition.  Kidney Int  1990; 38:108-114.

321. Reaich D, Channon SM, Scrimgeour CM, et al: Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation.  Am J Physiol  1993; 265:E230-E235.

322. Lofberg E, Wernerman J, Anderstam B, et al: Correction of metabolic acidosis in dialysis patients increases branched-chain and total essential amino acid levels in muscle.  Clin Nephrol  1997; 48:230-237.

323. Chan W, Wang M, Kopple JD, et al: Citrulline levels and urea cycle enzymes in uremic rats.  J Nutr  1974; 104:678-683.

324. Jansen A, Lewis S, Cattell V, et al: Arginase is a major pathway of L-arginine metabolism in nephritic glomeruli.  Kidney Int  1992; 42:1107-1112.

325. Young GA, Parsons FM: Impairment of phenylalanine hydroxylation in chronic renal insufficiency.  Clin Sci Mol Med  1973; 45:89-92.

326. Wang M, Vhymeister I, Swenseid ME, et al: Phenylalanine hydroxylase and tyrosine aminotransferase activity in chronically uremic rats.  J Nutr  1975; 105:122-127.

327. Tizianello A, DeFerrari G, Garibotto G, et al: Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency.  J Clin Invest  1980; 65:1162-1173.

328. Walser M, Hill SB: Free and protein-bound tryptophan in serum of untreated patients with chronic renal failure.  Kidney Int  1993; 44:1366-1371.

329. Edozien JC: The free amino acids of plasma and urine in kwashiorkor.  Clin Sci  1966; 31:153-166.

330. Dalton RN, Chantler C: The relationship between BCAA and alpha-ketoacids in blood in uremia.  Kidney Int  1983; 24(Suppl 16):S61-S66.

331. Suliman ME, Anderstam B, Bergstrom J: Evidence of taurine depletion and accumulation of cysteinesulfinic acid in chronic dialysis patients.  Kidney Int  1996; 50:1713-1717.

332. Druml W, Fischer M, Liebisch B, et al: Elimination of amino acids in renal failure.  Am J Clin Nutr  1994; 60:418-423.

333. Stockenhuber F, Kurz RW, Sertl K, et al: Increased plasma histamine levels in uraemic pruritus.  Clin Sci  1990; 79:477-482.

334. Bergstrom J, Furst P, Noree L-O, et al: Intracellular free amino acids in muscle tissue of patients with chronic uraemia: Effect of peritoneal dialysis and infusion of essential amino acids.  Clin Sci Mol Med  1978; 54:51-60.

335. Pye IF, McGale EHF, Stonier C: Studies of cerebrospinal fluid and plasma amino acids in patients with steady-state chronic renal failure.  Clin Chim Acta  1979; 92:65-72.

336. Divino Filho JC, Barany P, Stehle P, et al: Free amino-acid levels simultaneously collected in plasma, muscle and erythrocytes of uraemic patients.  Nephrol Dial Transpl  1997; 12:2339-2348.

337. Wilcken DEL, Gupta VJ, Reddy SG: Accumulation of sulphur-containing amino acids including cystine-homocystine in patients on maintenance hemodialysis.  Clin Sci  1980; 58:427-430.

338. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia: I. Nitrogen and potassium.  Medicine  1973; 52:583-594.

339. Mandayam S, Mitch WE: Requirements for protein, calories, and fat in the predialysis patient.   In: Mitch WE, Klahr S, ed. Handbook of Nutrition and the Kidney,  Philadelphia: Lippincott, Williams and Wilkins; 2005:115-137.

340. National Kidney Foundation: National Kidney Foundation K/DOQI clinical practice guidelines for nutrition in chronic renal failure.  Am J Kidney Dis  2000; 35(Suppl 2):S1-S140.

341. Kopple JD: National Kidney Foundation K/DOQI clinical practice guidelines for nutrition in chronic renal failure.  Am J Kidney Dis  2001; 37:S66-S70.

342. Masud T, Young VR, Chapman T, et al: Adaptive responses to very low protein diets: The first comparison of ketoacids to essential amino acids.  Kidney Int  1994; 45:1182-1192.

343. Goodship THJ, Mitch WE, Hoerr RA, et al: Adaptation to low-protein diets in renal failure: Leucine turnover and nitrogen balance.  J Am Soc Nephrol  1990; 1:66-75.

344. Graham KA, Reaich D, Channon SM, et al: Correction of acidosis in hemodialysis decreases whole-body protein degradation.  J Am Soc Nephrol  1997; 8:632-637.

345. Graham KA, Reaich D, Channon SM, et al: Correction of acidosis in CAPD decreases whole body protein degradation.  Kidney Int  1996; 49:1396-1400.

346. Reaich D, Channon SM, Scrimgeour CM, et al: Ammonium chloride-induced acidosis increases protein breakdown and amino acid oxidation in humans.  Am J Physiol  1992; 263:E735-E739.

347. Ikizler TA, Pupim LB, Brouillette JR, et al: Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation.  Am J Physiol  2002; 282:E107-E116.

348. Motil KJ, Matthews DE, Bier DM, et al: Whole-body leucine and lysine metabolism: Response to dietary protein intake in young men.  Am J Physiol  1981; 240:E712-E721.

349. Young VR: 1987 McCollum award lecture. Kinetics of human amino acid metabolism: Nutritional implications and some lessons.  Am J Clin Nutr  1987; 46:709-725.

350. McNurlan MA, Garlick PJ: Influence of nutrient intake on protein turnover.  Diabetes/Metabolism Reviews  1989; 5:165-189.

351. Pupim LB, Heimburger O, Qureshi AR, et al: Accelerated lean body mass loss in incident chronic dialysis patients with diabetes mellitus.  Kidney Int  2005; 68:2368-2374.

352. Pupim LB, Flakoll PJ, Majchrzak KM, et al: Increased muscle protein breakdown in chronic hemodialysis patients with type 2 diabetes mellitus.  Kidney Int  2005; 68:1857-1865.

353. Mitch WE, Abras E, Walser M: Long-term effects of a new ketoacid-amino acid supplement in patients with chronic renal failure.  Kidney Int  1982; 22:48-53.

354. Mitch WE, Clark AS: Specificity of the effect of leucine and its metabolities on protein degradation in skeletal muscle.  Biochem J  1984; 222:579-586.

355. Mitch WE, Walser M, Sapir DG: Nitrogen-sparing induced by leucine compared with that induced by its keto-analogue, alpha-ketoisocaproate, in fasting obese man.  J Clin Invest  1981; 67:553-562.

356. Stein A, Moorhouse J, Iles-Smith H, et al: Role of an improvement in acid-base status and nutrition in CAPD patients.  Kidney Int  1997; 52:1089-1095.

357. Pickering WP, Price SR, Bircher G, et al: Nutrition in CAPD: Serum bicarbonate and the ubiquitin-proteasome system in muscle.  Kidney Int  2002; 61:1286-1292.

358. Bailey JL, England BK, Long RC, et al: Experimental acidemia and muscle cell pH in chronic acidosis and renal failure.  Am J Physiol  1995; 269:C706-C712.

359. May RC, Kelly RA, Mitch WE: Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.  J Clin Invest  1986; 77:614-621.

360. May RC, Kelly RA, Mitch WE: Mechanisms for defects in muscle protein metabolism in rats with chronic uremia: The influence of metabolic acidosis.  J Clin Invest  1987; 79:1099-1103.

361. Bailey JL, Wang X, England BK, et al: The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent, ubiquitin-proteasome pathway.  J Clin Invest  1996; 97:1447-1453.

362. Wang X, Jurkovitz C, Price SR: Regulation of branched-chain ketoacid dehydrogenase flux by extracellular pH and glucocorticoids.  Am J Physiol  1997; 272:C2031-C2036.

363. May RC, Bailey JL, Mitch WE, et al: Glucocorticoids and acidosis stimulate protein and amino acid catabolism in vivo.  Kidney Int  1996; 49:679-683.

364. Isozaki Y, Mitch WE, England BK, et al: Interaction between glucocorticoids and acidification results in stimulation of proteolysis and mRNAs of proteins encoding the ubiquitin-proteasome pathway in BC3H-1 myocytes.  Proc Natl Acad Sci U S A  1996; 93:1967-1971.

365. Brungger M, Hulter HN, Krapf R: Effect of chronic metabolic acidosis on thyroid hormone homeostasis in humans.  Am J Physiol  1997; 272:F648-F653.

366. Graham KA, Reaich D, Channon SM, et al: Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium.  J Am Soc Nephrol  1997; 8:627-631.

367. Krapf R, Vetsch R, Vetsch W, et al: Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate.  J Clin Invest  1992; 90:2456-2463.

368. Wiederkehr MR, Kalogiros J, Krapf R: Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients.  Nephrol Dial Transpl  2004; 19:1190-1197.

369. Lecker SH, Goldberg AL, Mitch WE: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states.  J Am Soc Nephrol  2006; 17:1807-1819.

370. Mitch WE, Medina R, Greiber S, et al: Metabolic acidosis stimulates muscle protein degradation by activating the ATP-dependent pathway involving ubiquitin and proteasomes.  J Clin Invest  1994; 93:2127-2133.

371. Price SR, Bailey JL, Wang X, et al: Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome pathway by a mechanism including gene transcription.  J Clin Invest  1996; 98:1703-1708.

372. Mitch WE, Bailey JL, Wang X, et al: Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting.  Am J Physiol  1999; 276:C1132-C1138.

373. Lecker SH, Solomon V, Price SR, et al: Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats.  J Clin Invest  1999; 104:1411-1420.

374. Wang XH, Hu Z, Hu JP, et al: Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling.  Endocrin  2006; 147:4160-4168.

375. Song Y-H, Li Y, Du J, et al: Muscle-specific expression of insulin-like growth factor-1 blocks angiotensin II-induced skeletal muscle wasting.  J Clin Invest  2005; 115:451-458.

376. Lecker SH, Jagoe RT, Gomes M, et al: Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.  FASEB J  2004; 18:39-51.

377. Tawa NE, Odessey R, Goldberg AL: Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles.  J Clin Invest  1997; 100:197-203.

378. Hotamisligil GS, Peraldi P, Budavari A, et al: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-a- and obesity-induced insulin resistance.  Sci  1996; 271:665-668.

379. Kimmel PL, Phillips TM, Simmens SJ, et al: Immunologic function and survival in hemodialysis patients.  Kidney Int  1998; 54:236-244.

380. Du J, Wang X, Meireles CL, et al: Activation of caspase 3 is an initial step trig-gering muscle proteolysis in catabolic conditions.  J Clin Invest  2004; 113:115-123.

381. Lee SW, Dai G, Hu Z, et al: Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase.  J Am Soc Nephrol  2004; 15:1537-1545.

382. Bodine SC, Stitt TN, Gonzalez M, et al: Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.  Nature Cell Biology  2001; 3:1014-1019.

383. Wing SS, Goldberg AL: Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting.  Am J Physiol  1993; 264:E668-E676.

384. Tiao G, Fagan J, Roegner V, et al: Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.  J Clin Invest  1996; 97:339-348.

385. May RC, Clark AS, Goheer A, et al: Identification of specific defects in insulin-mediated muscle metabolism in acute uremia.  Kidney Int  1985; 28:490-497.

386. Harter HR, Karl IE, Klahr S, et al: Effects of reduced renal mass and dietary protein intake on amino acid release and glucose uptake by rat muscle in vitro.  J Clin Invest  1979; 64:513-523.

387. Davis TA, Klahr S, Karl IE: Insulin-stimulated protein metabolism in chronic azotemia and exercise.  Am J Physiol  1987; 253:F164.

388. Stitt TN, Drujan D, Clarke BA, et al: The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.  Mol Cell  2004; 14:395-403.

389. Sandri M, Sandri C, Gilbert A, et al: Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.  Cell  2004; 117:399-412.

390. Bilbrey GL, Falonna GR, White MG, et al: Hyperglucagonemia of renal failure.  J Clin Invest  1974; 53:841-847.

391. Aoki TT, Muller WA, Brennan MF, et al: Effect of glucagon on amino acid and nitrogen metabolism in fasting man.  Metabolism  1974; 23:805-814.

392. Salter JM, Ezrin C, Laidlaw JC, et al: Metabolic effects of glucagon in human subjects.  Metabolism  1960; 9:753-768.

393. Yoshida Y, Kawamura T, Ikoma M, et al: Effects of antihypertensive drugs on glomerular morphology.  Kidney Int  1989; 36:626-635.

394. Li JB, Wassner SJ: Protein synthesis and degradation in skeletal muscle of chronically uremic rats.  Kidney Int  1986; 29:1136-1143.

395. Druml W, Kelly RA, May RC, et al: Abnormal cation transport in uremia: Mechanisms in adipocytes and skeletal muscle from uremic rats.  J Clin Invest  1988; 81:1197-1203.

396. Bilbrey GL, Carter NW, White MG, et al: Potassium deficiency in chronic renal failure.  Kidney Int  1973; 4:423-430.

397. Hsu FW, Tsao T, Rabkin R: The IGF-1 axis in kidney and skeletal muscle of K deficient rats.  Kidney Int  1997; 52:363-370.

398. Santeusanio F, Faloona GR, Knochel JP, et al: Evidence for a role of endogenous insulin and glucagon in the regulation of potassium homeostasis.  J Lab Clin Med  1973; 81:809-817.

399. Garber AJ: Effect of parathyroid hormone on selected aspects of protein and amino acid metabolism in the rat.  J Clin Invest  1983; 71:1806-1821.

400. Wassner SJ, Li JB: Lack of an acute effect of parathyroid hormone within skeletal muscle.  Int J Pediatri Nephrol  1987; 8:15-20.

401. Slomowitz LA, Monteon FJ, Grosvenor M, et al: Effect of energy intake on nutritional status in maintenance hemodialysis patients.  Kidney Int  1989; 35:704-711.

402. Schneeweiss B, Graninger W, Stockenhuber F, et al: Energy metabolism in acute and chronic renal failure.  Am J Clin Nutr  1990; 52:596-601.

403. Kloppenburg WD, De Jong PE, Huisman RM: The contradiction of stable body mass despite low reported dietary energy intake in chronic haemodialysis patients.  Nephrol Dial Transpl  2002; 17:1628-1633.

404. Giordano C: Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects.  J Lab Clin Med  1963; 62:231-246.

404a. Rose WC, Smith LC, Womack M, Shane M: The utilization of the nitrogen of ammonium salts, urea and certain other compounds in the synthesis of non-essential amino acids in vivo.  J Biol Chem  1949; 181:307-316.

405. Giordano C, de Pascale C, Balestrieri C, et al: Incorporation of urea 15N in amino acids of patients with chronic renal failure on low nitrogen diet.  Am J Clin Nutr  1968; 21:394-404.

406. Walser M: Determinants of ureagenesis with particular reference to renal failure.  Kidney Int  1980; 17:709-721.

407. Varcoe R, Halliday D, Carson ER, et al: Efficiency of utilization of urea nitrogen for albumin synthesis by chronically uremic and normal man.  Clin Sci Mol Med  1975; 48:379-390.

408. Mitch WE, Walser M: Effects of oral neomycin and kanomycin in chronic uremic patients. II. Nitrogen balance.  Kidney Int  1977; 11:123-127.

409. Tripathy K, Klahr S, Lotero H: Utilization of exogenous urea nitrogen in malnourished adults.  Metabolism  1970; 19:253-262.

410. Beale LS: Kidney Diseases, Urinary Deposits and Calculous Disorders; their Nature and Treatment,  Phildelphia, Lindsay and Blakiston, 1869.

411. Fouque D, Laville M, Boissel JP: Low protein diets for chronic renal failure in non-diabetic adults (Cochrane Review).  Cochrane Database Syst Rev  2006;

412. Levey AS, Adler S, Caggiula AW, et al: Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study.  Am J Kidney Dis  1996; 27:652-663.

413. Knight EL, Stampfer MJ, Hankinson SE, et al: The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency.  Ann Intern Med  2003; 138:460-467.

414. Division of Kidney UaHDNN: USRDS 2002 Annual data report: Atlas of end-stage renal disease in the United States,  Bethesda, NIH, 2003.

415. Coresh J, Walser M, Hill S: Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis.  J Am Soc Nephrol  1995; 6:1379-1385.

415a. Johnson WJ, Hagge WH, Wagoner RD, et al: Effects of urea loading in patients with far-advanced renal failure.  Mayo Clinic Proc  1972; 47:21-29.

416. Rosman JB, Donker-Willenborg MA: Dietary compliance and its assessment in the Groningen trial on protein restriction in chronic renal failure.  Contrib Nephrol  1990; 81:95-101.

417. Di Landro D, Dattilo GA, Romagnoli GF: Comparative outcome of patients on a conventional low protein diet versus a supplemented diet in chronic renal failure.  Contrib Nephrol  1990; 81:201-207.

418. Teplan V, Schuck O, Knotek A, et al: Effect of low-protein diet supplemented with ketoacids and erythropoietin in chronic renal failure: A long-term metabolic study.  Am J Kid Dis  2003; 41:S26-S30.

419. Ayli MD, Ayli M, Ensari C, et al: Effect of low-protein diet supplemented with ketoacids on progression of disease in patients with chronic renal failure.  Nephron  2000; 84:288-289.

420. Prakash S, Pand DP, Sharma S, et al: Randomized, double-blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure.  J Renal Nutr  2004; 14:89-96.

421. Teschan PE, Beck GJ, Dwyer JT, et al: Effect of a ketoacid-aminoacid-supplemented very low protein diet on the progression of advanced renal disease: A reanalysis of the MDRD Feasibility Study.  Clin Nephrol  1998; 50:273-283.

422. Walser M, Hill SB, Ward L, et al: A crossover comparison of progression of chronic renal failure: Ketoacids versus amino acids.  Kidney Int  1993; 43:933-939.

423. Mitch WE, Walser M, Steinman TL, et al: The effect of keto acid-amino acid supplement to a restricted diet on the progression of chronic renal failure.  N Engl J Med  1984; 311:623-629.

424. Yeun JY, Kaysen GA: The nephrotic syndrome: nutritional consequences and dietary management.   In: Mitch WE, Klahr S, ed. Handbook of Nutrition and the Kidney,  Philadelphia: Lippincott-Raven; 2002:178-190.

425. Sakemi T, Ikeda Y, Shimazu K: Effect of soy portein added to casein diet on the development of glomerular injury in spontaneous hypercholesterolemic male Imai rats.  Am J Nephrol  2002; 22:548-554.

426. Giordano M, DeFeo P, Lucidi P, et al: Effects of dietary protein restriction on fibrinogen and albumin metabolism in nephrotic patients.  Kidney Int  2001; 60:235-242.

427. Ideura T, Yoshimura A, Shimazui M: Effect of a very low protein diet in nephrotic syndrome.  Wien Klin Wschr  1997; 110:61.