Dietary Factors in the Treatment of Chronic Kidney Disease

Sreedhar A. Mandayam

William E. Mitch

Joel D. Kopple

INTRODUCTION

Our goal is to provide the reader with an understanding of how chronic kidney disease (CKD) induces metabolic aberrations and how introducing nutritional factors can improve these metabolic problems. Achieving this goal requires knowledge about how the requirements of different nutrients change with the different stages of CKD. For example, diabetes is the most frequent cause of CKD and the incidence of diabetes is growing. In part, this is occurring because of the increasing prevalence of obesity. Clearly, both diabetes and obesity require the manipulation of the diet to improve health and to prevent adverse outcomes. In addition, diabetes and/or obesity is frequently accompanied by high blood pressure and diffuse vascular complications. If the salt intake of these individuals is not controlled, antihypertensive drugs tend to become ineffective.¹,² There also are the consequences of progressively accumulating waste products leading to uremia (literally, urine in the blood). Because these waste products arise mainly from the metabolism of protein, it is not surprising that symptoms of CKD can be successfully reversed by controlling protein intake.³,⁴,⁵ Besides ensuring that nutrient requirements are met, the nephrologist must understand how to monitor compliance and how to deal with the progressive loss of kidney function. As will be discussed, there remains uncertainty about the influence of dietary modification on the progression of CKD. Regardless, this is not the sole reason to manipulate the diet of a CKD patient.⁶ Other reasons include correcting acidosis, preventing or ameliorating protein-energy wasting (PEW), suppressing uremic bone disease, combating hypertension, and reducing the accumulation of waste products and thereby mitigating uremic syndrome.⁷,⁸ Ignoring these aspects of patient care hastens the need to begin dialysis. But several studies have demonstrated that initiating dialysis earlier (e.g., at glomerular filtration rates [GFR] of about 10 to 12 mL per minute) does not improve the mortality associated with CKD nor does it reduce the complications of CKD.⁹,¹⁰,¹¹,¹² This makes it even more important to use dietary modification to prevent the complications of CKD.

Are there specific problems arising in CKD patients attributable to inadequate attention to nutritional principles? Among such problems, there is uremic bone disease. This complication has become more prominent, in part related to a recent and dramatic increase in phosphate additives to processed food.¹³ In addition, hyperphosphatemia reduces the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in slowing the loss of kidney function.¹⁴ Likewise, adding sodium chloride to foods, particularly processed foods or fast foods, is a major contributor to increasing difficulties in managing hypertensive patients.¹,¹⁵ Another major diet-related problem is the accumulation of waste products when the dietary protein of a CKD patient is unrestricted.⁸,¹⁶ For example, metabolic acidosis arises from the metabolism of amino acids in protein and acid excretion falls as function is lost.⁷ This problem is raised because simply correcting the serum bicarbonate improves protein metabolism, calcium metabolism, and possibly, the progression of CKD.¹⁷,¹⁸,¹⁹,²⁰,²¹,²² Complicating dietary planning are the reports that the average intake of energy, calcium, and a number of vitamins may be inadequate in CKD patients. In short, attention to the diet of patients with CKD is not simply an intellectual exercise; it can produce rapid and sustained benefits as long as the adequacy of the diet is ensured.⁶

The need for and approaches to manipulation of the diet will depend on the degree of renal insufficiency. The most widely used classification of the degree of CKD was developed by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Committee and includes a level signifying an increase in the risk of progressive loss of kidney function (i.e., individuals with an estimated GFR [eGFR], of <60 mL/min/1.73 m²). Notably, those with higher eGFR values can still develop complications of CKD.²³ The variables used in the equations that estimate GFR include age, serum creatinine, sex, and race and the interpretation of the eGFR level has several limitations. First, it was derived from individuals in the United States with established kidney disease but without severe PEW or morbid obesity. Second, there is evidence that the equations are inaccurate for other regions of the world, including Asia and Latin America.²⁴,²⁵,²⁶ Third, the boundaries
for the stages of renal insufficiency are somewhat arbitrary; it seems unlikely there is an absolute threshold identifying all patients who will develop progressive CKD. Fourth, certain activities can acutely reduce GFR (e.g., hypertension therapy with blockers of the renin-angiotensin system [RAS], a very low protein diet). In this case, the stage of CKD can change even though kidney damage has not occurred. Nonetheless, this system can identify patients for whom interventions, including dietary modification, could improve their overall health.

METABOLIC CHANGES IN CHRONIC KIDNEY DISEASE AND TOXINS IN OR DERIVED FROM NUTRIENTS

Although it is possible for one toxin or group of toxins to be responsible for specific signs and symptoms of uremia, the interaction of many toxins more commonly causes the problems of CKD. For example, it was reported that a combination of products of protein metabolism (urea, magnesium, acetoin, 2, 3-butylene-glycol, sulfate, creatinine, T-cresol, and guanidine) impairs oxidative metabolism in slices of the cerebral cortex. When studied at the same concentration but separately, however, none of the potential toxins exerted adverse effects on metabolism.²⁷ There are a large number of potential uremic toxins: in 2003, the European Uremic Toxin Work Group (EUTOX) identified 90 potential toxins that are accumulated in patients with CKD. Proving they are toxic has been difficult. Bergström²⁸ noted that the requirement for identifying a uremic toxin should include: (1) its chemical identity; (2) a concentration higher in tissues or plasma from uremic patients compared to levels in normal subjects; (3) a concentration should correlate with specific uremic signs or symptoms that are improved when the substance is removed; and (4) its toxicity in tissues, cells, etc. should be demonstrable at the concentration present in tissue or fluids from uremic patients. Few putative compounds have met these criteria.

Urea

There is some evidence that urea is toxic, but it is difficult to test for toxicity because the short half-life of urea makes it difficult to maintain a high level in blood and tissues. Nephrectomized dogs were treated with peritoneal dialysis and the serum urea nitrogen (SUN) level was raised to ˜200 mg per deciliter by adding urea to the dialysate; the dogs developed weakness, anorexia, and decreased attentiveness.²⁹ Continued therapy led to vomiting, hemorrhagic diarrhea, hypothermia, and death. In humans undergoing maintenance hemodialysis (MHD), a similar strategy was used to increase the urea concentration in the dialysate: at serum urea nitrogen (SUN) levels of 140 to 200 mg per deciliter most patients developed malaise, lethargy, and some evidence of bleeding.³⁰ Consistent with the idea that urea is toxic at high levels is the recent report that urea can stimulate reactive oxygen species (ROS), leading to insulin resistance.³¹ In patients with CKD, insulin resistance could lead to accelerated muscle wasting (see the following).

Urea toxicity could arise following its decomposition to ammonia or cyanate adducts. Cyanate can condense with NH₂-terminal amino groups and amides, altering the tertiary structure of proteins and, hence, interfering with enzyme activity. For example, a variety of lipids are carbamylated to form toxins, including 3-carboxy-4-methyl-5 propyl-2-furaproprionic carboxy-4methyl-5propyl-2furapropionic (CMPF) acid, a major cause of altered drug protein binding in uremia.³²,³³ Still, the role of protein carbamylation in uremic toxicity is unsettled.³⁴ Finally, urea is converted to ammonia and carbon dioxide largely by bacterial ureases, but this does not raise blood ammonia substantially, at least in patients with normal hepatic function.³⁵ The kidney is another contributor to body ammonium levels but this function is markedly reduced or lost in kidney failure. Thus, hyperammonemia rarely occurs in kidney failure.

LOSS OF NONEXCRETORY KIDNEY FUNCTION AND TOXIC METABOLITES OF PROTEIN

At first glance, many of the manifestations of CKD appear to be due to small, water-soluble toxins that are cleared by hemodialysis or peritoneal dialysis because the removal of urea by dialysis reverses several uremic complications. Besides problems related to urea accumulation, the retention of salt leads to extracellular volume expansion, hypertension, cardiac dilatation, sympathetic nervous system activation, and inflammatory cytokine production. But, the removal of ions or small molecules is only part of the story. First, the loss of metabolic or endocrine functions of the kidney can cause certain complications of CKD. For example, loss of kidney-produced hormones, such as erythropoietin (EPO) or 1,25 hydroxyvitamin D3, can interfere with metabolic functions. Second, the ability to remove larger molecules (so-called middle molecules [0.5 to 3.0 kD] or larger polypeptides including many hormones and cytokines) is progressively diminished as CKD progresses. This interferes with normal cellular metabolism. A more easily understood example is the accumulation of unexcreted acid arising largely from metabolism of sulfur-containing and phosphate-containing proteins and lipids. Acid accumulation causes an increase in the breakdown of protein and essential amino acids. It also causes insulin resistance and abnormalities in endocrine function, including factors affecting bone metabolism.¹⁷,³⁶,³⁷,³⁸,³⁹ Fortunately, these problems are largely prevented when metabolic acidosis is corrected.

Other potentially toxic metabolites of dietary protein can affect kidney function indirectly. For example, phenylalanine metabolites can accumulate when dietary protein is unrestricted; the phenylalanine metabolite, phenyl acetic acid, will inhibit the expression of inducible nitric oxide
synthase (iNOS) and, hence, may contribute to the development of atherosclerosis.⁴⁰

Guanidino-Containing Compounds

Guanidino compounds are potent organic bases that accumulate in the sera and tissues of uremic patients.⁴¹,⁴² Their production rises with excess protein intake. However, the production of guanidinosuccinic acid also increases in renal failure independent of protein intake, thus underscoring the metabolic complexities induced by CKD.⁴³,⁴⁴ The controversy around the identification of uremic toxins such as guanidine compounds arises in part because of the difficulty measuring the plasma and tissue concentrations of guanidino compounds.⁴² In uremic patients, plasma levels may be as high as 8 to 10 mM, but corresponding tissue levels have not been documented. Certain guanidino compounds can have neurotoxic effects: guanidine and methylguanidine are implicated in the development of peripheral neuropathy, and γ-guanidinobutyric acid, taurocyamine, homoarginine, and α-keto-δ-guanidinovaleric acid lower the seizure threshold of experimental animals.⁴⁵ The central nervous system excitatory effects of uremic guanidino compounds may reflect an inhibition of depolarization at γ-aminobutyric acid (GABA) receptors, selective activation of N-methyl-D-aspartate (NMDA) receptors by guanidinosuccinic acid, and an intrinsic depolarizing response.⁴⁶

The Arginine Derivative Asymmetric Dimethylarginine

Asymmetric dimethylarginine (ADMA) derived from arginine can inhibit NOS, and its concentration rises in patients with CKD to decrease nitric oxide (NO) and impair vascular responses.⁴⁷,⁴⁸ In experimental animals, ADMA is associated with concentration-dependent pressor and bradycardic responses and vasoconstriction.⁴⁹ In CKD patients, a decrease in the actions of NO because of a high ADMA level could aggravate hypertension and, possibly, the progression of renal failure.⁵⁰ Despite these intriguing reports, the influence of ADMA on cardiovascular disease is controversial.⁴⁸

Products of Bacterial Metabolism

Uremic toxins can be produced by gut bacteria, and their absorption may be promoted by an increase in the permeability of the gastrointestinal mucosa.⁵¹ The potential of these processes is great because of the huge mass of bacteria (there are more bacterial cells in the colon than in the rest of the human body). Specific uremia-associated problems include bacteria-produced nitrogen-containing waste products and aromatic compounds as well as aliphatic amines (e.g., phenols, indoles, aliphatic amines). With normal kidney function, these compounds do not accumulate because they are rapidly cleared by the kidneys. But, with CKD, some compounds (indoxyl sulfate, hippuric acid, p-cresol, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) initiate toxic reactions in the brain or even contribute to progressive loss of kidney function.

Aromatic Amines

Tryptophan is touted as a major precursor of uremic toxins. It, along with aromatic amines, undergoes deamination and decarboxylation by gut bacteria, yielding metabolites such as indole, indoxyl, skatole, skatoxyl, indican, and indoleacetic acid. Their potential toxicity has been tested by feeding large amounts of the potential toxin and observing changes in organ functions. In the case of indoxyl sulfate, uremic rats were treated with a proprietary resin that absorbs it and other metabolites. The resin not only reduced plasma and urinary levels of indoxyl sulfate, but it also improved metabolism of the kidney and reduced the progression of renal failure.⁵² In the United States, a randomized clinical trial of its effectiveness to retard the progression of CKD has shown promise with minimal toxic reactions.⁵³ This has led to plans for a more extensive trial. Aromatic amines could also exert toxicity by interfering with the binding of drugs to serum proteins yielding abnormal responses at doses used for normal adults. Aromatic amines could also serve as false neurotransmitters.⁵⁴ The infusion of phenol or p-cresol into dogs causes a variety of neurologic symptoms, whereas conjugated phenols can inhibit ATPases and ion transport systems to interfere with cellular metabolism.⁵⁵ p-Cresol can inactivate β-hydroxylase to interfere with the transformation of dopamine into norepinephrine to develop impaired macrophage function.⁵⁶,⁵⁷

Aliphatic Amines

Aliphatic amines such as monomethylamine are derived from the metabolism of creatinine. Alternatively, bacterial metabolism of choline or lecithin produces tertiary methylamines that can then be converted to form secondary methylamines.⁵⁸ Secondary methylamines accumulate in the blood, the cerebrospinal fluid, and brain tissue, but toxicity has not been demonstrated.

In summary, dietary protein is initially broken down into peptides and amino acids. These compounds in turn can be metabolized by bacteria in the gastrointestinal tract generating compounds that are absorbed. There is evidence that sufficiently high levels of these compounds could impair the function of different organs. However, it has been difficult to assign specific toxic reactions to these compounds because of: (1) difficulties in measuring their concentrations in specific tissues; and/or (2) toxic reactions that could be caused by direct interference with cell functions or through indirect actions that decrease organ function.

Nephrotoxic Compounds Derived from Dietary Protein

In 1905, Folin⁵⁹ pointed out that the principal metabolic response to a change in dietary protein intake is a parallel change in urinary urea excretion. This has been confirmed in normal adults and patients with CKD.⁶⁰,⁶¹ Many of the degradation products of dietary protein are excreted primarily by the kidney. Consequently, products arising from the metabolism of protein will accumulate in patients in direct
proportion to the amount of protein eaten and in inverse proportion to the degree of kidney failure. The accumulation of these compounds is in large part responsible for the symptoms and complications of CKD because decreasing dietary protein improves these symptoms.³,⁴,⁵,⁶,⁶² Therefore, dietary counseling should be directed at reducing the SUN, but only following an assurance that adequate amounts of protein and energy are provided.

Illustrative examples of the principle that excess dietary protein participates in the generation of uremic toxicity are indoxyl sulfate and uric acid. Indoxyl sulfate arises from the metabolism of indoles such as dietary tryptophan.⁵² Experimentally, indoxyl sulfate can accelerate kidney damage in models of glomerular sclerosis.⁶³ As indicated previously, a clinical trial was directed at assessing whether removing indoxyl sulfate by ingested activated charcoal will slow the progression of CKD.⁶⁴ Uric acid can contribute to the complications of CKD; a 12-year study of 47,150 previously normal men indicated that diets with high levels of meat or seafood were associated with an increased risk of gout.⁶⁵ This is relevant because Johnson and colleagues³⁰ have described an important association between an increase in uric acid and the development of hypertension. Untreated hypertensive adolescents were found to exhibit a correlation between systolic blood pressure and serum uric acid (r = 0.8).⁶⁶ In some of these adolescents, their hypertension was largely corrected by administering allopurinol. Notably, in CKD patients, serum uric acid does not rise to the level expected from the degree of lost kidney function because there is extensive metabolism of uric acid, presumably by bacteria in the gastrointestinal tract.⁶⁷ The degree to which dietary protein restriction modifies the serum uric acid of CKD patients has not been established, but there is the possibility that allopurinol treatment can help preserve renal function in patients with CKD.

MECHANISMS THAT REGULATE BODY PROTEIN STORES

Robust metabolic mechanisms act to maintain body protein mass following a change in protein intake. These act rapidly and precisely to adjust the rates of amino acid and protein metabolism. Specifically, when dietary protein falls, the major metabolic response is a suppression of the degradation of essential amino acids (EAAs). This response will help to maintain an adequate supply of EAAs for protein synthesis. The ability to decrease EAA degradation, however, is limited, reaching a minimum level when the amount of protein being eaten is at a level that is just adequate for achieving nitrogen balance (i.e., ˜0.6 g protein per kilogram of ideal body weight per day). If dietary protein falls further, there also are adaptive responses that suppress protein degradation (protein synthesis may also increase but is less consistently found compared to a decrease in protein degradation). These responses limit the loss of protein stores and are active in normal adults or CKD patients as long as there are no complications such as acidemia or other catabolic illnesses.⁶⁸,⁶⁹,⁷⁰ Similar adaptive responses are also active in patients with the nephrotic syndrome.⁷¹

Protein Metabolism and Protein Stores

All intracellular and extracellular proteins are continually turning over, being degraded to their constituent amino acids and replaced by the synthesis of new proteins. The rapidity of the turnover of individual proteins varies widely, from minutes for some regulatory enzymes or transcription factors, to days or weeks for proteins like actin and myosin in skeletal muscle and months for hemoglobin in red blood cells. The rate of the degradation of proteins must be specific and highly regulated. Otherwise, countless cellular functions as well as the maintenance of protein stores (e.g., in muscle) would be jeopardized. Evidence that these processes are highly regulated includes the following: (1) The daily rates of protein turnover are enormous (3.7 to 4.7 g/kg/day) and therefore, even a small but sustained decrease in the synthesis of proteins or acceleration of protein degradation would result in marked loss of protein stores.⁷² (2) Precise changes in the levels of proteins are required for the minuteto-minute regulation of transcriptional events or metabolic pathways. It is surprising, therefore, that the majority of intracellular proteins in all tissues is degraded by a single proteolytic system, the ATP-dependent, ubiquitin-proteasome system (UPS).⁷² This specialized system exhibits remarkable specificity by individual proteins for degradation.

The Ubiquitin-Proteasome System

The initial processes of protein degradation by the UPS involve a series of three enzymes that link ubiquitin (Ub) onto proteins.⁷²,⁷³ The single E1 isoform (Ub-activating enzyme) uses ATP to activate Ub and then transfers Ub to one of 20 to 40 isoforms of the E2 Ub-carrier proteins (Fig. 85.1). These reactions provide some specificity for the degradation of substrate proteins; a specific E2 Ub-carrier conjugates with only some of the more than 1,000 different E3 enzymes. This third enzyme, an E3 Ub-protein ligase, is the key determinant of the specificity of proteolysis; a specific E3 Ub-ligase recognizes a specific protein substrate (or possibly specific classes of proteins) and transfers Ub to a lysine in the protein. This process is repeated until the initial Ub is increased to form a chain of four to five Ubs attached to the substrate protein. This poly-Ub chain is recognized by the 26S proteasome. It also uses ATP to degrade the substrate protein. The proteasome is a very large organelle consisting of >60 proteins that create a 20S, barrel-shaped particle with 19S regulatory particles at either or both of its ends. The 19S regulatory particles not only recognize polyubiquitin chains, but when ATP is present, the 26S proteasome also cleaves the poly-Ub chain from the doomed protein and unfolds the protein’s tertiary structure. In the next step, the unfolded substrate protein is translocated through a tunnellike structure into the 20S particle where it is degraded into peptides. The peptides are released into the cytoplasm and
are converted to amino acids by peptidases.⁷³ The importance of these processes is underscored by the awarding of the 2004 Nobel Prize to Avram Hershko, Aaron Ciechanover, and Irwin Rose for discovering this system (http://nobelprize.org/chemistry/laureates/2004/).

FIGURE 85.1 An illustration of the major components of the ubiquitin-proteasome system. (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.)

Recent results have uncovered insights into the proteolytic processes that regulate muscle protein breakdown by the UPS and by mechanisms separate from the UPS. For example, in muscle wasting conditions, the expression of two E3 Ub-conjugating enzymes, Atrogin-1 (also known as MAFbx) and MuRF-1, are critical for the breakdown of muscle proteins.⁷³,⁷⁴ In models of muscle wasting conditions, the expression of Atrogin-1 and MuRF-1 are increased 8- to 20-fold, serving as a sign that muscle protein breakdown is accelerated.⁷⁵,⁷⁶ The signals that activate these E3 Ub-conjugating enzymes have been extensively studied and at least two transcription factors have been identified as regulators of Atrogin-1/MAFbx and MuRF-1 expression: the Forkhead transcription factors (FoxO) and the inflammatory transcription factor, nuclear factor-kappaB (NF-κB).⁷³,⁷⁴

At least five functions of the UPS have been identified as crucial for maintaining normal cellular functions: (1) It permits cells to adapt rapidly to physiologic changes because the UPS rapidly removes proteins to terminate an enzymatic or regulatory process. (2) The UPS can change gene expression by degrading transcription factors or cofactors/inhibitors that regulate transcription (e.g., the UPS degrades I-κB to activate NF-κB and accelerate inflammatory processes).⁷³ (3) The UPS eliminates misfolded or damaged proteins (e.g., the mutant transmembrane conductance regulator protein [CFTR] is selectively degraded by the UPS so it does not reach the epithelial cell surface in patients with cystic fibrosis). (4) The UPS presents antigen to the major histocompatibility complex, class I molecules, thereby participating in immunologic responses. (5) The UPS degrades cellular proteins (including muscle proteins), which are used in gluconeogenesis when energy intake is inadequate or in response to catabolic illnesses.

Chronic Kidney Disease Initiates Mechanisms That Cause a Loss of Muscle Protein

Epidemiologic evidence indicates that CKD is associated with a decrease in muscle and fat mass, which in turn is associated with an increased risk of morbidity and mortality.⁷⁷ The mechanisms causing protein wasting include CKD-induced acceleration of the degradation of proteins due to defective responses to insulin or insulin growth factor 1 (IGF-1) intracellular signaling. Other stimuli causing protein losses include the accumulation of acid (Table 85.1). In addition, an excess of angiotensin (Ang) II, impaired function of muscle precursor cells (i.e., satellite cells), and/or activation of the muscle protein, myostatin, which is synthesized in muscle and modulates muscle growth, stimulate the loss of protein stores. Although there is evidence that each of these factors controls muscle protein metabolism, it is likely that they often act together to cause a loss of muscle mass.

When is a loss of muscle mass suspected? Besides a loss of body weight, the principal evidence for subnormal protein stores has been hypoalbuminemia. The finding of hypoalbuminemia in CKD patients is generally presumed to be attributable to protein malnutrition.⁷⁸,⁷⁹ However, malnutrition is defined as abnormalities related to an insufficient amount of protein, energy, or other nutrients in the diet or to an imbalance among dietary nutrients.⁸⁰ There are at least two reasons that the muscle wasting associated with CKD is not caused
by malnutrition per se: first, if protein malnutrition were the cause of defects in protein stores, then the abnormalities should be corrected by simply altering the diet. This hypothesis has been examined and found to be wanting: Ikizler et al.⁸¹ measured rates of protein synthesis and degradation in fasting hemodialysis patients using labeled amino acid turnover techniques. They studied three protocols and in each instance measured protein metabolism before, during, and at 2 hours after completing dialysis.⁸²,⁸³. When dialysis was performed in fasting patients, protein degradation exceeded protein synthesis demonstrating that over days to weeks, these responses would produce a significant loss of body protein stores. In the second protocol, they tested the influence of intravenous parenteral nutrition (IDPN) given during hemodialysis.⁸² IDPN did improve both protein synthesis and degradation measured during dialysis, but the increase in protein
degradation persisted at 2 hours following the completion of dialysis. In the third protocol, they tested the effects of an oral nutritional supplement versus IDPN. As before, protein balance improved with both supplements but at 2 hours after completing dialysis, protein balance was still negative.⁸³ Thus, abnormalities in protein metabolism were not eliminated by simply increasing the intake of protein and calories during dialysis. Others report similar conclusions: in a randomized, controlled trial of responses to IDPN, hemodialysis patients were compared to other hemodialysis patients who were not given a dietary supplement. After 2 years, the supplement had not improved mortality, body mass index, laboratory markers of nutritional status, or the rate of hospitalization.⁸⁴ Even though the excessive morbidity and mortality occurring in patients with CKD may not be corrected simply by changing the diet or correcting hypoalbuminemia, it is critical to plan the diet of CKD patients in order to ensure that they receive an adequate amount of protein and energy.⁷⁸,⁸⁰ It is also necessary to avoid an excess of dietary protein because the accumulation of waste products will contribute to complications of CKD, especially in the nondialyzed patient with advanced CKD.⁸

TABLE 85.1 Evidence That Metabolic Acidosis Induces Protein and Amino Acid Catabolism in Normal Infants and Children as Well as Chronic Kidney Disease Patients

Subjects Investigated	Measurements of Effectiveness	Outcome of Trial
Infants²²⁶	Low birth weight, acidotic infants were given NaHCO₃ or NaCl	NaHCO₃ supplement improved growth
Children²²⁷ with CKD	Children with CKD had protein degradation measured	Protein loss was ˜twofold higher when HCO₃ was <16 mM compared to >22.6 mM
Normal adults²²⁸	Induced acidosis and measured amino acid and protein metabolism	Acidosis increased amino acid and protein degradation
Normal adults¹⁰⁸	Induced acidosis and measured nitrogen balance and albumin synthesis	Acidosis induced negative nitrogen balance and suppressed albumin synthesis
CKD²²⁹	Nitrogen balance before and after treatment of acidosis	NaHCO₃ improved nitrogen balance
CKD²²	2 years NaHCO₃ therapy vs standard care	Slowed loss of creatinine clearance and improved nutritional status
CKD¹⁷	Essential amino acid and protein degradation before and after treatment of acidosis	NaHCO₃ suppressed amino acid and protein degradation
CKD²³⁰	Muscle protein degradation and degree of acidosis	Proteolysis was proportional to acidosis and blood cortisol
CKD²³¹	Nitrogen balance before and after treatment of acidosis	NaHCO₃ reduced urea production and nitrogen balance
CKD²²	Protein stores after NaHCO₃ treatment to slow progression	Serum proteins and weight improved
Hemodialysis¹⁰³	Protein degradation before and after treatment of acidosis	NaHCO₃ decreased protein degradation
Hemodialysis¹⁰⁹	Serum albumin before and after treatment of acidosis	NaHCO₃ increased serum albumin
CAPD¹⁰⁴	Protein degradation before and after treatment of acidosis	NaHCO₃ decreased protein degradation
CAPD¹⁰⁶	Weight and muscle gain before and after treatment of acidosis	Raising dialysis buffer increased weight and muscle mass
CKD, chronic kidney disease; CAPD, continuous ambulatory peritoneal dailysis.

What are the signals in CKD that enhance a loss of protein stores? Recent studies in rodent models of CKD have established that the accelerated muscle wasting involves cellular mechanisms that are similar to those causing muscle wasting in other catabolic conditions, such as cancer cachexia, starvation, insulin deficiency/resistance, or sepsis.⁷²,⁷³ Common to each of these catabolic states is an acceleration of proteolysis via the UPS, which is presumably augmented by higher levels of messenger RNAs (mRNAs) encoding certain components of the UPS.³⁶ There are also increases or decreases in the expression of about 100 atrophy-related genes called atrogenes. The latter responses indicate that the mRNAs of atrophy-related genes in muscle wasting states are due to changes in gene transcription yielding a common transcriptional program that involves various growth-related genes in atrophying muscle.⁸⁵ The strongest evidence for the activation of the UPS in muscles of animals undergoing CKD-induced atrophy from catabolic diseases is that inhibitors of the proteasome block the increase in protein degradation in muscles isolated from rodent models of catabolic diseases.³⁶,⁸⁶,⁸⁷

In CKD, abnormalities identified as signals that stimulate protein degradation in muscle include the development of metabolic acidosis, defects in insulin/IGF-1 intracellular signaling, or an increase in Ang II levels.⁸⁸,⁸⁹,⁹⁰ All three conditions cause muscle atrophy in rodents. Finally, CKD patients frequently have high circulating levels of inflammatory cytokines and this has been shown to cause accelerated muscle protein degradation at least in part by impairing insulin or IGF-1 signaling in muscles.⁹¹,⁹²

Caspase-3 and Muscle Wasting in Chronic Kidney Disease

Muscle atrophy in catabolic conditions specifically affects contractile proteins, which comprise about two-thirds of the protein in muscle. Notably, the ubiquitin protease system (UPS) readily degrades major components of the myofibril (actin, myosin, troponin, or tropomyosin). But when these same proteins are present in complexes or in intact myofibrils, they are degraded very slowly by the UPS.⁹³ Therefore, other proteases must initially cleave proteins to break down the complex structure of muscle. The protease functioning in this fashion is caspase-3.⁹⁴ Notably, caspase-3 cleaves actomyosin in vitro, and it is stimulated in cultured muscle cells, where myofibrillar proteins are cleaved and subsequently degraded by the UPS. Caspase-3 activation produces a footprint of its activity, a 14kD C-terminal fragment of actin that is found in the insoluble fraction of muscle.⁹⁴ For example, accumulation of the 14-kD actin fragment is found in muscles of animals with accelerated protein degradation due to acidosis, diabetes, and Ang II-induced hypertension.⁸⁹,⁹⁴,⁹⁵ Likewise, the 14-kD actin fragment can be found in muscles of patients with CKD or other causes of muscle wasting. The level of the 14-kD actin fragment in muscle of CKD patients was found to decrease in response to an exercise program directed at increasing the patient’s endurance. The level of the fragment was also highly correlated (r = 0.78) with the measured rate of protein degradation in muscles of patients undergoing hip replacement for osteoarthritis. Finally, the 14-kD actin fragment that was present in unburned muscle of patients who had a major burn injury to another area of the body was sharply increased.⁹⁶ Thus, the level of the 14-kD fragment seems to be closely related to the rate of protein degradation and is present in specific disorders characterized by muscle wasting. Additional testing will be needed to determine if this method could serve as a biomarker of accelerated muscle protein degradation in other conditions causing muscle wasting.

Signals Triggering Muscle Wasting in Chronic Kidney Disease or Other Catabolic States

CKD is associated with several complications that can trigger the UPS to degrade muscle protein, and there is evidence that these complications can function in concert to cause muscle wasting. Metabolic acidosis stimulates muscle protein breakdown by the UPS, but only when there is a concomitant increase in glucocorticoid production and development of insulin resistance.⁹⁷,⁹⁸ Glucocorticoids are also required for the accelerated protein degradation that occurs in models of diabetes, high levels of Ang II, and sepsis.⁹⁰,⁹⁹,¹⁰⁰

Impaired insulin/IGF-1 intracellular signaling is another stimulus for accelerated muscle protein breakdown. The mechanism involves the decreased activation of the phosphatidylinositol 3-kinase(PI3K)/Akt pathway.⁸⁹ Specifically, when insulin or IGF-1 signaling is low, PI3K activity falls, reducing the production of phosphadidylinositol-3,4,5 phosphate, the active product of PI3K. This results in decreased phosphorylation and activity of the serine/threonine kinase, Akt, leading to decreased phosphorylation of downstream kinases, gycogen synthase kinase 1 (GSK1) and mTOR/S6kinase, and suppression of protein synthesis.
Decreased PI3K/Akt signaling is a key step that stimulates protein degradation in muscle. Decreased PI3K/Akt signaling induces the expression of caspase-3 and the E3 Ub conjugating enzymes, Atrogin-1 and muscle ring finger protein 1 (MuRF-1), to enhance muscle protein degradation.⁸⁹ Expression of these E3 enzymes occurs because there is decreased phosphorylation of the Forkhead family of transcription factors (FoxO1, 3, 4). When these factors are not phosphorylated, they migrate into the nucleus to stimulate the transcription of Atrogin-1 and, potentially, other genes involved in muscle metabolism.⁸⁹,¹⁰¹,¹⁰² Insulin or IGF-1 blocks this process by stimulating the PI3K/Akt pathway to suppress the expression of Atrogin-1. Together, these results provide evidence that muscle wasting in response to the complications of CKD is due to a common signaling pathway that alters key enzymes modulating protein synthesis and degradation.

Are there methods for correcting the abnormalities in muscle protein metabolism that occur in CKD? In a mouse model of CKD, the mice were paired for SUN and weight and treated with either a humanized antibody or peptibody against myostatin or the diluent.⁷⁶ Peptibody treatment increased body and muscle weight while raising muscle protein synthesis and suppressing protein degradation. Interestingly, these beneficial responses were accompanied by an increase in the phosphorylation of Akt and a decrease in the circulating levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). These results suggest that methods could be developed to prevent muscle wasting in CKD patients.

This brief review of changes in muscle protein metabolism caused by progressive CKD emphasizes that activities of caspase-3 and the UPS participate in the turnover of the bulk of proteins in the body. Because the daily turnover of protein is high, even a small but persistent increase in protein breakdown would cause muscle wasting. Specific complications of kidney disease coordinate the activity of proteolytic systems (i.e., caspase-3 and the UPS) to degrade muscle proteins. These responses involve defects in insulin/IGF-1 intracellular signaling pathways and decreased PI3K/Akt signaling, which are initiated by metabolic acidosis or inflammation. In addition, glucocorticoids play a permissive role in stimulating muscle wasting. Understanding these regulatory mechanisms could blunt the muscle wasting that occurs in different catabolic conditions.

Factors Stimulating Loss of Muscle Mass in Chronic Kidney Disease

Abundant clinical evidence indicates that acidemia is an important cause of protein losses (Table 85.1). Reaich et al.¹⁷ found that the rate of protein degradation in acidemic CKD patients is high, but when they were given sodium bicarbonate, protein degradation decreased by 28%. It increased again when the patients developed acidemia in response to eating an equimolar amount of sodium chloride. The stimulatory effect of metabolic acidosis on protein breakdown is also present in hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) patients.¹⁰³,¹⁰⁴,¹⁰⁵ At least in CAPD patients, increased muscle proteolysis was found to be related to activation of the UPS.¹⁰⁶,¹⁰⁷ In normal adults, induction of metabolic acidemia not only increased insulin resistance but also caused negative nitrogen balance and reduced the rate of albumin synthesis.³⁸,¹⁰⁸ Changes in albumin metabolism induced by metabolic acidemia also occur in hemodialysis patients; correcting their serum bicarbonate levels was found to increase serum albumin levels.¹⁰⁹ Despite these reports documenting the catabolic effects of metabolic acidemia, a cross-sectional analysis of dialysis patients suggested there is no relationship between acidemia and hypoalbuminemia, weight loss, etc.¹¹⁰ There are several problems with this conclusion. First, a cause and effect relationship cannot be evaluated from results of a cross-sectional study.¹¹¹ Second, a single serum bicarbonate measurement is not sufficient to define the presence of acidemia, and there are technical problems with measuring serum bicarbonate: a delay in measuring the serum bicarbonate concentration allows for the escape of carbon dioxide, which lowers the bicarbonate artificially.¹¹² Third, there are many impaired hormonal responses in patients with metabolic acidemia, including the impaired function of growth hormone, the thyroid hormone, and the conversion of vitamin D to its most active form, 1, 25 (OH)2 cholecalciferol.¹¹³,¹¹⁴,¹¹⁵ All of these could interact and impair the ability of CKD patients to maintain protein stores by indirect mechanisms.

SPECIFIC DIETARY CONSTITUENTS FOR PATIENTS WITH CHRONIC KIDNEY DISEASE

Energy Intake

In patients entering dialysis therapy, anthropometric abnormalities, including suboptimal body weight, could result from an inadequate energy intake.¹¹⁶,¹¹⁷,¹¹⁸ Unfortunately, such caloric deficits are difficult to measure; estimates from the resting energy expenditure (REE) may underestimate or overestimate a patient’s average activity. Moreover, indirect calorimetry measured during brief periods can yield erroneous conclusions when extrapolated to 24 hours. Estimates of energy intake based on dietary histories or questionnaires can lead to erroneous conclusions.¹¹⁹,¹²⁰

The 1981 Food and Agricultural Organization (FAO)/World Health Organization (WHO)/United Nations (UN) recommended energy requirements based on 11,000 REE determinations made in healthy subjects.¹²¹ But, the regression equations used to derive energy requirements had considerable variability. Extrapolating REE measurements to all activities with this degree of variability suggests caution is required in making decisions based on those types of measurements. Besides these issues, the individual can adapt to different calorie intakes: healthy adults eating an inadequate nutrient intake will decrease their REE value.¹²² When normal adults ate diets with barely adequate amounts of EAA, their nitrogen balance improved when energy intake
increased.¹²³ Well-nourished adults achieve energy balance but only by decreasing their activity. With this adaptation, lean body mass can be lost.¹¹⁸ Nonetheless, virtually all studies of REE by indirect calorimetry as well as studies based on nitrogen balances indicate that both CKD and maintenance dialysis patients have at least normal energy expenditures during resting or with a variety of activities. Patients with advanced kidney failure and those undergoing MHD or CPD usually have decreased daily physical activity. In normal sedentary adults, total daily physical activity is estimated to account for only about 15% to 25% of total daily energy expenditure. Thus, the reduced physical activity of advanced kidney failure or chronic dialysis patients generally does not result in a major reduction in daily energy expenditure in comparison to sedentary normal people without CKD.

Energy Requirements of Chronic Kidney Disease Patients

Unfortunately, there have been few evaluations of the energy requirements of CKD patients or their responses to a reducedcalorie intake. In one landmark study, the energy expenditure of normal subjects, CKD patients, and hemodialysis patients during rest and exercise revealed no differences among the three groups.¹²⁴ Notably, when calorie intake was reduced, energy expenditure did not fall, indicating that CKD patients do not develop a special ability to adapt to a low-calorie intake. Thus, an inadequate energy intake when coupled to dietary protein restriction could cause negative nitrogen balance (i.e., a loss of protein stores).⁸ Most studies of energy expenditure in CKD and MHD patients support the thesis that energy expenditure is normal, but one group of investigators reported that energy expenditure on both dialysis and nondialysis days was 7% higher in hemodialysis patients compared to normal adults.¹²⁴,¹²⁵ If, indeed, uremia increases energy expenditure, impaired energy use (e.g. insulin resistance) could cause a loss of lean body mass. This is relevant because patients with serum creatinine values >2.4 mg per deciliter or those who are obese or those with metabolic acidosis can develop insulin resistance and impaired energy use.²,³⁸,¹²⁶,¹²⁷ Fortunately, a low protein diet can actually improve insulin resistance.³,⁵,¹²⁸,¹²⁹ Regarding this conclusion, energy intake in patients with moderate renal insufficiency in the MDRD study was below 30 to 35 kcal/kg/day yet the loss of body mass was infrequent and only a few patients were withdrawn from the trial because of nutritional considerations.¹³⁰ On the other hand, the MDRD study used dietary interviews and diaries to estimate energy intake, methods that can give erroneous results, particularly in CKD or MHD patients.¹¹⁹,¹²⁰ Regardless, if a patient is losing weight and there is a history of a low energy intake, additional calories are needed. Intake from such a supplement must be monitored closely because it may lead to an increase in body fat rather than larger stores of protein.¹³¹

The contribution of a low energy intake to nutritional deficiencies in CKD patients is unclear: CKD outpatients who were eating 16 to 20 g per day of protein plus a supplement of EAA had no change in nitrogen balance when their energy intake was varied between 22 and 50 kcal/kg/day.¹³² On the other hand, Kopple et. al.¹³³ fed six CKD patients a constant, minimal protein intake of 0.55 to 0.60 g/kg/day and measured nitrogen balance while calorie intake was varied from 15 to 45 kcal/kg/day. They concluded that the dietary energy requirement for nitrogen equilibrium for CKD patients who are eating low protein diets should be 35 kcal/kg/day in order to maximize dietary protein use. If CKD patients are at or below their ideal body weight, we believe their energy intake should be 35 kcal/kg/day.¹³⁴ For overweight patients, energy intake should be restricted to reduce obesity because obesity causes insulin resistance and impairs the use of protein and calories.²,¹²⁰,¹³¹

Protein Requirements

Nitrogen balance (Bn) is a measurable index of changes in body protein stores and serves as the gold standard for assessing dietary protein requirements. A neutral or positive Bn indicates that the body’s protein stores are maintained or increased. For healthy adults engaging in moderate physical activity and eating sufficient calories, the World Health Organization (WHO) used Bn values to conclude that the average requirement for protein of mixed biologic value is approximately 0.6 g of protein per kilogram of body weight per day. This average dietary protein requirement plus 2 standard deviations was assigned as the “safe level of intake,” or 0.75 g/kg/d; this value should meet the protein requirements of 97.5% or more of healthy adults.¹²¹ There are two caveats: first, not all normal adults will require this amount of dietary protein, but some will need more than 0.75 g/kg/day. Second, for CKD patients, an increase in dietary protein will increase the production of urea and other waste products. If these compounds are not excreted, uremia will develop.⁷²,¹³⁵ Adaptive metabolic responses are activated when dietary protein is restricted (see previous). The presumed origin of these metabolic responses is a decrease in plasma insulin leading to the conversion of body protein stores (principally, skeletal muscle) into amino acids, which are converted to glucose in the liver. Insulin is likely to be one of the most potent mediators of these changes in protein turnover because it suppresses protein degradation in normal or diabetic subjects.¹³⁶,¹³⁷ This could explain why diabetic patients (including those with insulin resistance) being treated by hemodialysis are at increased risk of developing an accelerated loss of lean body mass.¹³⁸ Because insulin resistance can be present in patients with serum creatinine levels as low as 2.4 mg per deciliter and because metabolic acidosis can cause insulin resistance, insulin-initiated mechanisms could be a key factor regulating whole body protein metabolism.³⁸,¹²⁷ In summary, healthy adults successfully adapt to dietary protein restriction by: (1) suppressing the catabolism of EAA and, possibly, NEAA; and (2) suppressing protein degradation while stimulating protein synthesis. A principal mediator of these changes is likely to be insulin.

Protein Requirements for Chronic Kidney Disease Patients

Patients with advanced CKD that is uncomplicated by metabolic acidemia or inflammation, etc. are remarkably efficient at adapting to dietary protein restriction.⁶⁸ In response to the limitation of dietary protein from 1.0 to 0.6 g/kg/day, they reduce amino acid oxidation and protein degradation as well as normal adults. The same adaptive responses occur if the diet is restricted to only 0.3 g/kg/day plus a supplement of essential amino acids or their nitrogen-free analogs (ketoacids). These diets are associated with the maintenance of indices of adequate nutrition during more than 1 year of observation.⁶⁹,⁷⁰ Clinically, it must be recognized that compensatory responses will not fully compensate for an inadequate diet and the diet will cause loss of lean mass. Moreover, diabetic patients may not activate adaptive changes to dietary protein restriction as efficiently as do normal adults or CKD patients. Finally, if CKD is complicated by acidemia or inflammatory or chronic illnesses, patients may not be able to activate an adaptive response to dietary restriction.

Protein Requirements for Nephrotic Patients

Patients who are excreting more than 3 to 5 g of protein per day could be at increased risk for protein wasting because their protein intake may not meet minimal requirements. This does not mean that prescribing an excess of protein will improve protein stores. Unfortunately, a high protein diet actually raises the degree of proteinuria in CKD patients.¹³⁹,¹⁴⁰ This problem is emphasized because patients eating a well-designed low-protein diet can experience a decrease in proteinuria and an increase in serum albumin concentrations compared to patients fed excessive amounts of protein (see the following). The other problem is that feeding a high protein diet increases the likelihood of developing complications of CKD. The other reason to emphasize this problem is the consensus that the degree of proteinuria is closely related to the risk for progressive kidney and cardiovascular diseases.¹⁴¹ The other factor to consider regarding dietary protein prescriptions for nephrotic patients is that it can activate the same adaptive responses as CKD patients or normal subjects.⁷¹ This ability leads to neutral Bn of nephrotic patients fed 0.8 or 1.6 g/kg/day (plus 1 g of dietary protein for each gram of proteinuria) and 35 kcal/kg/day of energy. There is evidence that even less dietary protein (<0.6 g/kg/day) may not increase the risk of protein wasting in patients with the nephrotic syndrome.¹⁴² In summary, patients with uncomplicated CKD, including those with nephrotic range proteinuria, activate normal compensatory responses to dietary protein restriction by suppressing EAA oxidation and reducing protein degradation. These responses lead to the preservation of lean body mass during long-term dietary therapy. When nephrotic patients excrete ≥10 g of protein per day, there are no clear guidelines for manipulating their dietary protein and calories.

Dietary Sodium and Chloride

Normal adults maintain an extracellular fluid volume that changes by < 1 L (1 kg of body weight) and only have minimal changes in blood pressure despite wide variations in daily salt intake. But, if blood pressure rises when sodium chloride intake increases, a patient is labeled salt sensitive and salt balance occurs only slowly. Notably, salt sensitivity can precede established hypertension and it constitutes a cardiovascular risk factor, complicates antihypertensive therapy, contributes to a progressive loss of kidney function in patients with CKD, exacerbates proteinuria, and diminishes the antiproteinuric responses of patients with kidney disease.¹⁴³,¹⁴⁴ For these reasons, regulating sodium chloride intake is essential for the treatment of patients who have or who are at risk for high blood pressure, for those with kidney disease, and/or for those with cardiovascular risk factors. Treatment with diuretics generally fails in patients who have no dietary guidelines for salt intake because salt intake can cancel the effectiveness of diuretics.¹⁴⁵ Unfortunately, regulating sodium chloride intake is difficult because salt is added to so many foods; it is estimated that, generally, >80% of daily sodium intake is already an integral part of foods.¹⁴⁶,¹⁴⁷

A sodium intake of 2 g per day or 84 mEq per day is widely recommended for patients with hypertension or cardiovascular and kidney diseases. It is important to specify this amount because a no-added-salt diet contains about 4 g of sodium or 168 mEq.¹,¹⁴⁸ This level of salt intake exacerbates blood pressure and edema in many CKD patients. Fortunately, a diet of 2 g of sodium per day can be achieved with skilled diet planning.

Salt-sensitive patients with CKD and hypertension can be detected by determining if their blood pressure rises >10% when a low salt diet is switched to a high salt diet. The frequency of salt-sensitive individuals (with the exception of some patients with primary interstitial kidney disease) increases with age, especially when renal function is declining.¹⁴⁷,¹⁴⁹,¹⁵⁰ Salt restriction is especially important in the treatment of hypertensive CKD patients because antihypertensive agents, with the possible exception of calcium channel blockers, are less effective when sodium intake is unrestricted.¹⁵¹ Because it is an achievable goal, the ideal sodium intake for hypertensive patients is 2 g per day. A decrease in dietary salt can transiently reduce GFR but this usually reverses within a week. Because most dietary salt is already in foods, especially in prepared or fast foods, it is difficult to predict salt intake. Because ˜95% of sodium ingested is excreted by the kidneys, the sodium content of a 24-hour urine sample is the best indicator of sodium intake. With fever, strenuous exercise, or diarrhea, and especially in patients with an ileostomy, there can be significant extrarenal sodium losses. To monitor salt intake, CKD patients should weigh themselves daily and record their weight; if weight is declining, it is most likely due to a loss of extracellular salt and water, and contrariwise, if weight is increasing, it is most likely due to an accumulation
of salt and water. In such cases, the diet should be reviewed to determine the source of the unwanted salt. Monitoring body weight is emphasized because sodium excretion fluctuates widely during the day, and a “spot” urine for measurement of the sodium/creatinine ratio does not provide reliable insights into the assessment of dietary salt. Fortunately, even patients accustomed to a high sodium chloride intake experience salt cravings, and they should be reassured that the craving will disappear after a few weeks.¹⁴⁶,¹⁵²

In summary, a cornerstone of designing diets for CKD patients is to establish appropriate goals for blood pressure and sodium intake. Home blood pressure recording or ambulatory 24-hour blood pressure recordings are the most reliable in assessing the effectiveness of therapy. Compliance with dietary salt restriction must be monitored by 24-hour urine collections for sodium content. Fortunately, this same collection can be used to determine creatinine clearance and to estimate protein intake from urea excretion (see the following) and the presence of microalbuminuria and other minerals. If sodium excretion is excessive and blood pressure increases, education by the nutritionist and repeated measurements of 24-hour urine sodium collections will make dietary planning easier.

Dietary Potassium

Guidelines from the Institute of Medicine recommend a potassium intake of 4.7 g per day.¹⁵³ Fortunately, the ability to excrete this amount of potassium is usually retained until renal insufficiency is very advanced.¹⁵⁴ The ability to eliminate potassium is maintained by increased potassium excretion by both the gut and kidney, making the design of diets to restrict both dietary salt and potassium possible.¹⁵⁴ If hyperkalemia is present, a search is needed to determine if there is acidemia, defects in aldosterone actions, or if treatment has been changed to include nonsteroidal anti-inflammatory drugs (NSAIDs) or blockers of the renin-angiotensinaldosterone system (RAAS). If these changes are required, dietary potassium must be restricted. The diet is limited to ˜1.5 g per day; compliance is monitored from the 24-hour urinary excretion of potassium.

It is fortunate that the ability to excrete potassium is maintained because diets rich in potassium (e.g., fruits and vegetables) reduce the likelihood of developing chronic diseases, such as coronary heart disease and diabetes. Moreover, clinically important reductions in blood pressure have been documented to occur when adults with normal blood pressure or mild hypertension consume a potassium-rich diet. For example, in the DASH (Dietary Approaches to Stop Hypertension) Study,¹⁵⁵ potassium was increased in the diet but a potassium supplement was not supplied. Adults with systolic blood pressures <160 mm Hg and diastolic blood pressure 80 to 95 mm Hg were fed a standard Western diet high in saturated fat and low in fruits and vegetables and calcium. They were then randomly assigned to the same diet, which included a diet rich in fruits and vegetables versus a combined diet rich in fruits, vegetables, and with low-fat dairy products. This last diet had a reduced content of saturated and total fat. For all three groups, sodium intake and body weight were maintained at constant and at similar levels. Systolic and diastolic blood pressures decreased with the fruit and vegetable diet, and a more pronounced reduction in systolic and diastolic pressures occurred with the combination of high fruit and vegetable, and low-fat dairy product diet (-11.4 and -5.5 mm Hg, respectively). The changes in blood pressures were substantially greater in African American participants as compared to Caucasians.¹⁵⁶ This study did not address the effects of these diets in CKD patients but may be applicable because of the adaptations in potassium excretion.

Regarding CKD patients, the National Kidney Foundation’s expert panel¹⁵⁷ recommended the restriction of dietary potassium in adults with CKD at stage 4 (estimated GFR <30 mL/min/1.73 m²). The regulation of the serum potassium concentration at the desired level is complicated because patients with advanced CKD generally have low values of total body potassium, even when the serum potassium is high.¹⁵⁸ More studies are needed to determine the usefulness and dangers of increasing (or limiting) dietary potassium in patients with CKD.

VITAMINS AND TRACE ELEMENTS IN RENAL DISEASE

Micronutrients, vitamins, and trace elements are required for energy production, organ function, and cell growth and protection (e.g., from oxygen free radicals). Consequently, they should be included when planning diets for CKD patients.¹⁵⁹ Besides an insufficient intake, losses of protein-bound elements with proteinuria, decreased intestinal absorption of micronutrients, cellular metabolic changes or circulating inhibitors, and medicines that antagonize some vitamins can cause micronutrient deficiency syndromes. Unfortunately, there is very little information concerning the minimum requirements or the recommended daily allowances (RDA) for these nutrients in CKD patients. For CKD patients, supplements of water-soluble vitamins are routinely prescribed because meat and diary products are routinely restricted in their diets and there can be benefits of a daily supplemental vitamin. The long-term administration of vitamin B6 and folate can improve responses to EPO.¹⁶⁰ Vitamin B1 (thiamine) losses can occur with diuretic therapy or hemodialysis, potentially causing problems when the diet is restricted. However, there are no long-term evaluations detailing the incidence of thiamine deficiency even though some of its cardiovascular and neurologic symptoms can mimic complications of advanced CKD. For MHD patients, the average concentrations of folate, niacin, and vitamins B1, B6, B12, and C in whole blood and erythrocytes are often normal, presumably because the diet protein requirement of 1 g/kg/day is being eaten.¹⁶¹ However, low or borderline low levels of certain vitamins, particularly vitamins B6 and C, folic acid, and 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol, are often reported.¹⁶² The need for some vitamins is
increased in kidney failure, so we recommend that a supplement containing the RDA for water-soluble vitamins be prescribed for CKD, hemodialysis, and CAPD patients.

Riboflavin is necessary for normal energy use because it is used to maintain levels of the coenzymes flavin mononucleotide and flavin adenine dinucleotide. Riboflavin is present in meat and dairy products and its deficiency can produce sore throats, stomatitis, or glossitis, which may be mistaken for uremic symptoms. Folic acid is found in fruits and vegetables, but cooking can destroy it, and hence, it could become deficient in patients with restricted diets. Because folic acid is required for adequate EPO treatment and for the synthesis of nucleic acids and for methyl group transfer reactions and because it may decrease homocysteine production, it should be provided as a supplement. Vitamin B6 (pyridoxine) is necessary for many metabolic reactions involving amino acids via transaminase-catalyzed reactions. It is contained in meats, vegetables, and cereals. A deficiency can produce symptoms of a peripheral neuropathy or altered immune function, or host resistance may develop. Because these problems could complicate advanced uremia, a daily pyridoxine HCl supplement providing 5 mg per day for stage 4 and 5 CKD patients and 10 mg per day for MHD and CPD patients is recommended. Vitamin B12 is required for the transfer of methyl groups among metabolic compounds and for the synthesis of nucleic acids. Its major sources are meat and diary products. A deficiency state is unusual because this vitamin is stored in the liver. Also, little vitamin B12 is removed during hemodialysis because its molecular weight is rather high (1,355 Da), and it is largely protein bound in plasma. A daily supplement containing the RDA is recommended even though the likelihood of CKD, MHD, or CPD patients developing a deficiency state is low.¹⁵⁹

Vitamin C or ascorbic acid protects against antioxidant reactions and is involved in the hydroxylation of proline during collagen formation. It also is contained in meat, dairy products, and most vegetables so a deficiency state is unusual. Unfortunately, dialysis readily removes vitamin C, so a deficiency state can develop in patients eating an inadequate diet. Since high doses of vitamin C are metabolized to oxalate which can precipitate in soft tissues (including the kidney), vitamin C supplements should contain only the RDA amount.

The remaining water soluble vitamins, including biotin, niacin, and pantothenic acid, have been less well studied. Biotin functions as a coenzyme in bicarbonate-dependent carboxylation reactions and is produced by intestinal microorganisms. Consequently, a deficiency state is unusual. Niacin (nicotinic acid) is used as a nicotinamide adenine dinucleotide phosphate coenzyme. It is synthesized from the essential amino acid, tryptophan; a deficiency produces diarrhea, dermatitis, or increased triglycerides. Pantothenic acid is involved in the function of coenzyme A and, hence, in the metabolism of fatty acids, steroid hormones, and cholesterol. Although there is minimal information about the efficacy and consequences of these vitamins in renal disease, a supplement of the RDA of these vitamins appears to be quite safe, and we also recommend supplements, but only at amounts equivalent to the RDA.

In summary, patients eating restricted diets are at risk for developing vitamin-deficiency syndromes. Even MHD and chronic peritoneal dialysis (CPD) patients who are urged to eat generous amounts of protein and energy are at risk for ingesting less than the RDA of vitamins established for normal subjects and the daily requirements at least for vitamin B6 and folate appear to be increased in these patients.¹⁶³ We conclude that CKD as well as chronic dialysis patients should have a water-soluble vitamin supplement because it may prevent certain problems from developing and probably does little harm. Because hyperoxaluria and possibly peripheral neuropathy can occur with high doses of vitamin C and pyridoxine, respectively, megavitamin therapy should be avoided.¹⁶⁴

The requirements for fat-soluble vitamins in patients with CKD have not been established, and there are reasons to suspect that some of these vitamins may even cause complications of CKD. We recommend that fat-soluble vitamins should be given only when there is a well-defined indication. Because many multivitamin preparations contain fat-soluble vitamins, these preparations should be avoided unless there is evidence for a deficiency condition. Notably, plasma vitamin A (retinol) levels are usually increased in CKD patients because the level of retinol-binding protein is high, making it likely that tissue levels are normal or increased.¹⁵⁹ Supplemental vitamin A can contribute to anemia, dry skin, pruritus, bone resorption, and hepatic dysfunction in uremic patients.¹⁶⁵

The requirements for vitamin E, another fat-soluble vitamin, are not established. Vitamin E has been given in experimental models of CKD, providing some reduction in the degree of renal injury in rats with experimental immunoglobulin A (IgA) nephropathy or glomerulosclerosis following a subtotal nephrectomy or diabetes.¹⁶⁶ Although plasma vitamin E levels are generally reported to be normal in uremic patients, the question of supplementing vitamin E to suppress lipid peroxidation/oxidant stress has not been settled. Vitamin E may reduce the rate of progression of carotid artery stenosis in MHD patients with a history of vascular disease. Other studies have not confirmed a beneficial effect of vitamin E on atherosclerosis in patients with CKD. Another factor to be considered is that vitamin E supplements may be hazardous. The Heart Outcomes Prevention Evaluation (HOPE) Study was carried out in older people who were at a high risk for adverse cardiovascular events; there was no restriction to the presence or absence of CKD. Patients treated with daily vitamin E (400 IU) developed a delayed and significantly increased risk for heart failure and hospitalization for heart failure.¹⁶⁷ The RDA for vitamin E is 15 mg per day, and lower doses of vitamin E could be given to CKD or maintenance dialysis patients. Indeed, some multivitamins contain quantities of vitamin E that are less than the RDA and are provided largely to ensure that the daily vitamin E intake meets the RDA. Although vitamin E might reduce oxidant stress, it is controversial whether routine vitamin E supplements should be given to CKD patients.

The vitamin D analogs, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol, are bound to an alphalike globulin and may be lost in the urine in nephrotic patients.¹⁶⁸ This can lead to decreased ionized and total calcium, and bone disease in some patients and patients with the nephrotic syndrome should have regular surveillance of vitamin D levels. Recommendations for supplemental vitamin D are discussed in Chapter 73.

The need to supplement most trace element supplements for CKD and maintenance dialysis patients is not clear. The controversy arises because of difficulties in determining if body stores are insufficient, adequate, or excessive. A deficiency may not be reversed solely if only more trace elements are supplied.¹⁵⁹ Aluminum has been studied extensively because aluminum-containing antacids have been used to control serum phosphorus and, in the past, dialysates were contaminated with aluminum. Aluminum accumulation can cause bone disease, especially osteomalacia, a progressive dementia, proximal muscle weakness, impaired immune function, and anemia.¹⁶⁹,¹⁷⁰ Aluminum retention also can reduce serum iron stores, contributing to resistance to erythropoetin (EPO) therapy.¹⁷¹ Plasma and leukocyte zinc levels are reportedly decreased and may be associated with endocrine abnormalities such as high plasma prolactin levels.¹⁷² In patients with advanced CKD, the urinary excretion of zinc or fecal zinc may be decreased.¹⁷³ Some reports indicate that dysgeusia, poor food intake, and impaired sexual function, which are common problems of uremic patients, may be improved by giving patients zinc supplements.¹⁷⁴ Other studies, however, have not confirmed these results.¹⁷⁵ A zinc supplement has been reported to increase B-lymphocyte counts, granulocyte motility, and taste and sexual dysfunction.¹⁵⁹

The finding that serum selenium is low in dialysis patients has raised the question of supplementing selenium because selenium participates in the defense against oxidative damage of tissues, which may be increased with kidney failure.¹⁷⁶ The relationship among other trace elements and the occurrence of beneficial or adverse reactions has not been well studied in CKD patients. Hence, with the possible exception of the nephrotic syndrome, we do not recommend routinely giving supplements of trace elements unless there is documentation that trace element intake is low or a deficiency is present. This may be the case for iron, zinc, and selenium. The exception would be patients who are receiving long-term parenteral or enteral nutrition without supplements of trace elements; these individuals should routinely be given trace elements. Finally, the appearance of skin rashes, neurologic abnormalities, or other unexplained problems in maintenance dialysis patients should prompt a search for excessive concentrations of trace elements in the dialysate.

Assessment of Dietary Compliance

The classic report of Folin⁵⁹ pointed out that urea excretion is the principal change in urinary nitrogen that occurs when dietary protein changes. This has been repeatedly confirmed and provides a firm foundation for assessing compliance with low-protein diets.⁶⁰,⁶¹,¹⁷⁷ The rate of urea production exceeds the steady-state rate of urea excretion in both normal and uremic subjects because there is an extrarenal clearance of urea. This extrarenal removal of urea is due to its degradation by bacterial ureases present in the gastrointestinal tract.¹⁷⁸,¹⁷⁹,¹⁸⁰ In the past, it was believed that urea degradation to ammonia contributes substantially to amino acid synthesis in the liver and, hence, improves the nutritional status of uremic patients.¹⁸¹ This is incorrect; the ammonia nitrogen is simply used to synthesize urea by reincorporating it into urea.¹⁷⁹,¹⁸⁰ Fortunately, the rate of net urea production closely parallels dietary nitrogen⁶⁰,¹⁷⁷ and net production (i.e., urea appearance [UNA]) is easily calculated because the concentration of urea is equal throughout body water.¹⁵⁴,¹⁷⁹ Because water represents ˜60% of body weight in nonedematous patients, changes in the urea nitrogen pool can be calculated by multiplying 60% of nonedematous body weight in kilograms by the SUN concentration in grams per liter. The UNA is calculated as the change in the urea nitrogen pool (positive or negative) plus urinary urea nitrogen excretion. If the SUN and weight are stable, urea nitrogen accumulation is zero and UNA equals the excretion rate (Table 85.2).

Nonurea Nitrogen

Unlike urea nitrogen, nonurea nitrogen excretion (i.e., the nitrogen excreted in feces and in urinary uric acid, creatinine, and unmeasured nitrogenous products) does not vary greatly over a large range of dietary protein.⁶⁰,⁶¹ The nonurea nitrogen excretion averages 0.031 g of nitrogen per kilogram of ideal body weight per day (Fig. 85.2

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