Chapter 21. Chronic Renal Failure & the Uremic Syndrome: Nutritional Issues

• Decline in the glomerular filtration rate.
• Diminished appetite or anorexia.
• Abnormalities in intestinal absorption of some minerals and vitamins.
• Abnormalities in urinary, intestinal, and dermal excretion of nutrients.
• Disorders of nutrient metabolism.

In patients with chronic kidney disease (CKD), as the glomerular filtration rate (GFR) declines, numerous nutritional and metabolic disorders develop, and the dietary requirements for many nutrients are altered. These disorders and alterations include (1) diminished appetite or anorexia; (2) abnormalities in intestinal absorption of certain minerals (eg, calcium) and other nutrients including some trace elements (eg, iron and possibly zinc) and vitamins (eg, riboflavin); (3) abnormalities in urinary, intestinal, and dermal excretion of nutrients; and (4) disorders of nutrient metabolism.

Patients with renal insufficiency also are prone to accumulate toxins that normally are eaten in small amounts and would readily be excreted by the kidneys, such as aluminum. There are alterations in the concentrations and/or composition of certain lipoproteins, with an abnormal proportion of individual lipids and altered structure of some apolipoproteins. Potentially toxic oxidants and reactive carbonyl compounds accumulate in plasma and tissues. Deficiencies of antioxidants, including vitamins C and E and possibly selenium, may increase oxidative stress. Oxidative stress, along with the occurrence of inflammation in renal insufficiency, increases the risk of endothelial injury and atherosclerosis, leading to cardiovascular disease and higher death rates usually observed in patients with advanced CKD.

Malnutrition

Patients with advanced CKD (stages 4 and 5) frequently suffer from protein–energy malnutrition. Protein–energy malnutrition is defined as a state of decreased body protein mass with or without fat depletion or a state of diminished functional capacity due to protein–energy depletion, which is usually caused at least partly by inadequate nutrient intake relative to nutrient demand and/or which is improved by nutritional repletion. In CKD, several conditions may contribute to protein–energy malnutrition or wasting. Because these conditions may be caused by factors in addition to inadequate nutrient intake, the term “wasting” (or protein–energy wasting) can also be used instead of protein–energy malnutrition. It is important to recognize that in advanced chronic renal insufficiency (CRI), ie, stages 4–5 CKD, there are other types of wasting or malnutrition. This is particularly likely to occur for calcium, iron, zinc, and vitamins C, B6, folic acid, and 1,25-dihydroxycholecalciferol.

Approximately one-third to one-half of patients with advanced CKD including those undergoing maintenance dialysis have mild to moderate malnutrition and 5–10% more have severe malnutrition. In malnourished CKD patients, decreased relative body weight or body mass index (BMI, body weight (kg) divided by the square of body height in meters2), skinfold thickness (an estimate of body fat), arm muscle diameter area (a reflection of muscle mass), total body nitrogen and potassium, and increased total body water and extracellular water (Table 21–1) are usually observed. Malnutrition is also manifested by decreased concentrations of many serum proteins including albumin, prealbumin, and transferrin. Serum lipoprotein concentrations including total cholesterol may also be reduced. Low growth rates are observed in children with advanced CKD. Increased levels of proinflammatory cytokines occur frequently.

The Modification of Diet in Renal Disease (MDRD) Study indicated that the dietary protein and energy intake and the nutritional status begin to decline when the GFR is about 25–38 mL/minute/1.73 m2. In a cross-sectional analysis of the baseline data obtained in over 1700 individuals with stage 3–5 CKD, a gradual but persistent decline in serum transferrin and albumin concentrations (Figure 21–1), body weight, mid-arm muscle circumference, and percent body fat was observed parallel to the reduction in the GFR. Decreased energy intake was also observed when the GFR was reduced below about 25–35 mL/minute/1.73 m2.

Causes of Malnutrition and Wasting

Table 21–2 lists potential causes of malnutrition in chronic renal insufficiency.

Inadequate Nutrient Intake

Anorexia, a salient manifestation of CRI, worsens as CKD progresses and is thought to be engendered by uremic toxins. Levels of serum leptin, a hormone known to induce anorexia, are also elevated in uremia. Several studies describe an inverse relationship between serum leptin and dietary protein intake or a direct relationship between serum leptin and weight loss in patients on dialysis. Elevated serum leptin levels in CKD can be caused by impaired degradation by the diseased kidney and possibly also by insulin stimulation of leptin synthesis in CRI patients who are often hyperinsulinemic. Inflammation, which is commonly present in renal insufficiency, is associated with increased levels of proinflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), each of which is known to induce anorexia.

Other reasons for inadequate food intake include the debilitating effects of renal failure and underlying illnesses (eg, diabetes mellitus, lupus erythematosus), the impact of the progressive illness on the patient's ability to eat, and emotional disorders. Also, the fact that physicians and dietitians usually recommend a low protein diet for CKD patients plays a role. Moreover, imposing restrictions on intake of potassium and phosphorus may lead to nutrients that are less palatable to the patient and more difficult to prepare.

Increased Losses of Nutrients

The dialysis procedure itself may promote wasting by removing nutrients. During routine hemodialysis there are losses of about 6–10 g of free amino acids when patients are postabsorptive (fasting) and about 8–10 g when they are postprandial. Approximately 2–3 g of peptides or bound amino acids is also removed. The use of high flux polysulfone hemodialyzers may lead to greater losses of amino acids. During peritoneal dialysis, about 2–3.5 g of free amino acids, 8–9 g of total protein, and 5–6 g of albumin are lost into the dialysate per day. With mild peritonitis, the quantity of protein removed increases to an average of 15 g/day. Peritoneal protein losses as high as 100 g/day have been reported in severe peritonitis. Protein losses fall rapidly with antibiotic therapy but may remain elevated for many days to weeks.

Water-soluble vitamins and other bioactive compounds are also removed by both hemodialysis and peritoneal dialysis. Although these vitamin losses can be theoretically replaced from the diet or by multivitamin supplementations, these measures may be suboptimal in patients with poor nutrient intake due to a myriad of clinical, social, or financial barriers.

Finally, many CRI patients often lose substantial quantities of blood secondary to occult gastrointestinal bleeding, frequent blood sampling for laboratory testing, and the sequestration of blood in the hemodialyzer. Since blood is rich in protein, these blood losses may contribute to additional protein wasting. For example, a person with a hemoglobin of 12 g/dL and a serum total protein of 7 g/dL will lose approximately 16.5 g of protein in each 100 mL of blood removed.

Increased Net Catabolism

CKD patients usually suffer from additional concurrent comorbid conditions, which often induce a hypercatabolic state and also may physically prevent ingestion, gastrointestinal absorption, or assimilation of foods (eg, pancreatitis, gastrointestinal surgery). Hemodialysis per se can enhance net protein breakdown and promote negative nitrogen balance. More bioincompatible hemodialysis membranes, such as cuprophane, are more likely to stimulate the release of interleukins and promote net protein degradation than are more biocompatible membranes. The accumulation of endogenously formed uremic toxins might engender wasting more directly. In renal failure, there are increased plasma or tissue concentrations of probably hundreds of metabolic products. Some of these compounds are bioactive and may have catabolic or antianabolic actions.

Acidemia enhances decarboxylation of branched chain amino acids and engenders protein catabolism in skeletal muscle, bone reabsorption, and negative nitrogen balance. The endocrine disorders of uremia may also promote wasting. Resistance to the actions of insulin and insulin-like growth factor-1 and hyperglucagonemia may promote protein wasting. Parathyroid hormone increases hepatic gluconeogenesis, and may lead ultimately to protein wasting. The findings that 1,25-dihydroxycholecalciferol has pervasive effects on calcium metabolism, that vitamin D deficiency may cause a proximal myopathy, and that 25-hydroxycholecalciferol stimulates muscle protein synthesis in vitro suggest that deficiency of 1,25-dihydroxycholecalciferol might be another cause of muscle protein wasting.

Exogenously derived uremic toxins may cause debility (eg, aluminum) and possibly wasting. Finally, since the kidney synthesizes or degrades many biologically active compounds including certain amino acids, peptide hormones, other peptides, glucose, and fatty acids, it is possible that loss of these metabolic activities of the kidney in renal failure may disrupt the body's metabolism and promote protein–energy wasting.

Inflammation

Advanced CKD and the dialysis treatment process may sustain inflammation and an associated acute phase response with elevation of serum acute phase proteins and reduction in negative acute phase proteins. Potential causes of inflammation in CKD patients are listed in Table 21–3. In patients on maintenance dialysis, indicators of inflammation are correlated with anorexia, wasting, and malnutrition. These findings, together with the known catabolic effects of some proinflammatory cytokines, have bolstered the conclusion that inflammation promotes wasting. With inflammation, serum concentrations of negative acute phase proteins decrease; these include albumin, transferrin, retinol binding protein, transthyretin (prealbumin), and certain lipoproteins. Most surveys suggest that the serum concentration of C-reactive protein (CRP), a marker of inflammation, is increased in about 30–50% of American and European patients on dialysis and perhaps in a lower proportion of Asian patients. It has been argued that these elevated cytokines may promote protein–energy wasting in CKD patients both by inducing anorexia and also by engendering protein catabolism, eg, by activation of proteolytic enzymes released from granulocytes, or by suppressing protein synthesis. Indeed, albumin synthesis is often suppressed when serum CRP is elevated.

Both biocompatible as well as bioincompatible hemodialysis membranes, hemodialysis tubing and filters, both functioning and old thrombosed arteriovenous synthetic grafts, other vascular accesses and peritoneal dialysis catheters, hemodialysate and possibly peritoneal dialysate solutions, and low grade infections, such as caused by Chlamydia, may stimulate the inflammatory response in CKD patients by activating monocytes and/or macrophages. These inflammatory cells then release the cytokines (eg, IL-1, IL-6, and TNF-α) that stimulate the acute phase response. Finally, both oxidants and carbonyl compounds, as well as a deficiency of antioxidants, may cause tissue injury and inflammation and possibly engender a catabolic state.

Malnutrition–Inflammation Complex and Clinical Outcome

Nutritional status is a powerful predictor of morbidity and mortality and quality of life in CKD patients. Low dietary protein intake, decreased body weight for a given height such as BMI, and low serum concentrations of albumin, transthyretin, urea, creatinine, cholesterol, bicarbonate, and phosphorus are also associated with a higher death risk in patients on dialysis. Serum albumin is probably the strongest predictor of mortality in patients on maintenance dialysis (Figure 21–2). Some of these measurements such as daily protein intake [as determined by the normalized protein equivalent of total nitrogen appearance (nPNA)] and serum concentrations of cholesterol, phosphorus, and bicarbonate have a “J” or “U” curve relationship with mortality, in that both low and very high values are associated with a poor survival.

Since obesity and hypercholesterolemia are paradoxically associated with better survival and lower cardiovascular death in patients on maintenance dialysis, a reverse epidemiology of cardiovascular risk factors has been described. This phenomenon is believed to be mostly due to the overwhelming effect of malnutrition and inflammation, both of which are common in CRI. Indeed, according to some investigators, the strong association observed between malnutrition and mortality in CKD patients is the result of the atherogenetic role of inflammation. Because the causes and consequences of malnutrition and inflammation overlap considerably and many of the clinical manifestations of malnutrition and inflammation are identical, the term malnutrition–inflammation complex syndrome (MICS) has been suggested to indicate the close associations between malnutrition and inflammation in CKD patients and their link to clinical outcome (Figure 21–3).

The occurrence of measures indicating the presence of either malnutrition or inflammation in CKD patients or patients on maintenance dialysis has become of great concern to researchers and clinicians, because there is a strong association between the markers of MICS such as hypoalbuminemia, hypocholesterolemia, and underweight, and an increased risk of death. This issue is of particular importance because in patients on maintenance dialysis in the United States the mortality rate, especially due to cardiovascular disease, has remained inappropriately high, over 20% per year, and because traditional cardiovascular risk factors such as hypertension, hypercholesterolemia, and obesity not only do not appear to be associated with this high death risk, but paradoxically show a protective effect, ie, the reverse epidemiology. The time discrepancy between competing risk factors may play a role; it is possible that the deleterious effects associated with undernutrition can be manifested within a much shorter period of time when compared to the consequences of overnutrition, which usually requires a longer time to become manifest. According to this theory, many patients on dialysis may die prematurely of undernutrition before they can experience the cardiovascular consequences of overnutrition.

Assessment of Nutritional Status

Classically, three major lines of inquiries, ie, dietary intake, biochemical measurements, and body composition, are used to assess the protein–energy nutritional status in CKD patients. Composite scores based on assessment measures within these categories are also utilized. These include subjective global assessment (SGA) of nutrition and malnutrition inflammation score (MIS). More technologically based nutritional measures that have been used in CKD patients include dual energy x-ray absorptiometry (DEXA), total body nitrogen or potassium measurements, underwater weighing, bioelectrical impedance analysis, and near infrared interactance. These four categories of nutritional assessment tools are described in Table 21–2. As indicated in Table 21–4, many of these also respond to inflammation and provide a measure of its severity. Hence, the overlap between malnutrition and inflammation exists both at the diagnostic and at the etiologic level. Currently, no uniform approach has been agreed upon for rating the severity of malnutrition in CRI patients.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Procedure Guidelines on Nutrition in Chronic Renal Disease and Renal Failure recommends that nondialyzed CKD patients with a GFR less than 20 mL/minute undergo periodic nutritional assessments by serial measurements of a panel of markers including at least one measure from each of the following clusters: (1) serum albumin, (2) edema-free actual body weight and % standard body weight, (3) SGA, and (4) the nPNA or dietary interviews and diaries.

Assessment of Dietary Protein Intake

In CKD patients dietary protein intake can be estimated by both dietary interviews and diaries and the nPNA, ie, protein equivalent of total nitrogen appearance normalized to the volume of distribution of urea or some other function of body mass; this measure is also known as the normalized protein catabolic rate (nPCR) in patients on dialysis. Since the control of protein intake is central to the nutritional management of patients with renal insufficiency, it is important to accurately monitor nitrogen intake.

A simple and practical method to evaluate the compliance of patient's actual protein intake with the prescribed dietary protein intake is the following formula:

where UUN is urine urea nitrogen measured in a 24-hour urine collection. If the patient's proteinuria is 5 g/day or higher, this quantity needs to be added to the estimated protein intake.

Role of Dietary Protein Intake

Different methods to slow the rate of progression of chronic renal insufficiency in CKD patients are discussed in Chapter 22. Low protein diets are one method. In recent years, three types of low nitrogen diets have primarily been used for the treatment of patients with CRI: (1) A low protein diet providing about 0.55–0.60 g protein/kg body weight/day; (2) a very low protein diet providing approximately 16–20 g/day of protein of miscellaneous quality (ie, about 0.28 g protein/kg/day) supplemented with about 10–20 g/day of the nine essential amino acids; and (3) a similar 16–20 g protein diet generally supplemented with four essential amino acids—histidine, lysine, threonine, and tryptophan—and the ketoacid or hydroxyacid analogs of the other five essential amino acids sometimes with a few other amino acids added.

Several meta-analyses indicate that low protein diets are effective is slowing the rate of progression of CKD to renal replacement therapy (maintenance dialysis or renal transplantation). On average, this effect, although clearcut, is not dramatic and often requires many months of treatment to become evident.

An unresolved issue is whether a low protein diet will retard the progression of renal failure in patients receiving angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). Since dietary protein restriction exerts many of the same hemodynamic and other physiologic effects on the kidney as do ACEIs and ARBs, it is possible that the renal-protective effects of a low protein diet, when combined with ACEIs and ARBs, are replicative, rather than additive.

For CKD stages 1 and 2 (GFR >60 mL/minute) there is almost no information concerning the most desirable dietary protein and phosphorus prescription. Currently protein intake is usually not restricted for these patients except possibly to 0.80–1 g protein and 1200–1400 mg phosphorus/kg/day unless there is evidence that renal function is continuing to decline. Under these circumstances, the patient is treated as indicated below.

For CKD stage 3, low protein, low phosphorus diets may retard progression. A diet providing about 0.60–0.75 g protein/kg/day, of which at least 0.35 g/kg/day is high biologic value protein, is needed to ensure a sufficient intake of the essential amino acids.

For CKD stage 4 and 5, the potential advantages to using a low protein, low phosphorus diet are more compelling. A low protein diet will generate less nitrogenous compounds that are potentially toxic both systemically and to the kidney itself. In addition, it generally contains less phosphorus and potassium, reductions of which are usually imperative at this advanced stage of renal failure. Patients should be prescribed 0.60 g protein/kg/day or, if this is not feasible, up to 0.75 g protein/kg/day. This diet will generally maintain a neutral or positive nitrogen balance as long as the energy intake is not deficient. At least 50% of the protein intake with these low protein diets should be of high biologic value. The protein content of this diet should be increased by 1 g/day of high biologic value protein for each gram of protein excreted in the urine each day. However, only 10–20% of individuals with chronic renal disease are willing and able to adhere to diets providing 0.60 g protein/kg/day or essential amino acid-supplemented very low protein diets.

Dietary Protein Requirements in Patients on Maintenance Dialysis

Some current guidelines including the K/DOQI recommend a nutritional indicator for inaugurating renal replacement therapy. Indeed in patients with stage 5 CKD (GFR <15 mL/minute) who are not undergoing maintenance dialysis, if protein–energy malnutrition develops or persists despite vigorous attempts to optimize protein and energy intake and there is no apparent cause for malnutrition other than low nutrient intake, initiation of maintenance dialysis or a renal transplant is recommended.

Studies in nitrogen balance suggest that most patients on maintenance hemodialysis require more than 1 g protein/kg/day to maintain both protein balance and normal total body protein. The high protein requirement can be due to the fact that patients on maintenance dialysis have increased dietary protein requirements because of the removal of amino acids and peptides by the dialysis procedure and possibly because hemodialysis appears to stimulate protein catabolism by engendering an inflammatory, catabolic response. The K/DOQI Clinical Practice Guidelines currently recommend 1.2 g protein/kg body weight/day for clinically stable patients undergoing maintenance hemodialysis and 1.2–1.3 g protein/kg/day for patients undergoing chronic peritoneal dialysis (PD). At least 50% of the dietary protein should be of high biologic value. It is possible that PD patients who are protein depleted may become more anabolic when they ingest up to 1.4 g protein/kg/day. A recent study showed that the lowest mortality is associated with a protein intake (nPNA) between 0.9 and 1.4 g protein/kg/day (Figure 21–4).

Energy Intake

In nondialyzed CKD patients and patients undergoing maintenance dialysis, energy expenditure, measured by indirect calorimetry, appears to be normal during resting and sitting, following ingestion of a standard meal, and with defined exercise. Studies in nitrogen balance in nondialyzed stage 5 CKD patients ingesting 0.55–0.60 g protein/kg/day indicate that the amount of energy intake necessary to ensure neutral or positive nitrogen balance is approximately 35 kcal/kg/day. However, most studies of the dietary habits of nondialyzed stage 4 and 5 CKD patients and patients on dialysis indicate that their mean energy intakes are lower than this level, usually about 24–27 kcal/kg/day.

The K/DOQI Clinical Practice Guidelines currently recommend that the energy intake for nondialyzed patients with advanced CKD (GFR <25 mL/minute) and for patients on maintenance dialysis should be 35 kcal/kg/day for individuals who are less than 60 years of age and 30–35 kcal/kg/day for those who are 60 years of age or older, who are usually more sedentary (Table 21–5). The same energy intakes are recommended for people with stage 3 or 4 CKD (ie, GFR <60 mL/minute/1.73 m2).

Since energy (and protein) intake seems to decrease when the GFR falls to about 35–50 mL/minute/1.73 m2, to prevent malnutrition, it is important to monitor dietary intake and to treat inadequate intakes, even in clinically stable healthy appearing adults, when the GFR decreases to this level. This low level of GFR may be associated with a serum creatinine as low as 1.5–2.5 mg/dL in some adult patients.

Management of Other Nutritional Factors

The number and magnitude of the changes in the dietary intake for CKD patients are so great that if they were all presented to the patient at one time, the patient could become demoralized and lose the motivation to comply with the diet. It is therefore necessary to prioritize goals for dietary treatment. Usually the importance of controlling the protein, phosphorus, sodium, energy, potassium, and magnesium intake and the need to take calcium and vitamin supplements should be emphasized. However, unless the patient has a lipid disorder or other risk factors that indicate there is a high odds ratio for adverse cardiovascular events, the recommended quantity and types of dietary carbohydrate, fat, and fiber are discussed with the patient, but adherence to these dietary guidelines are not as strongly emphasized. If the patient has complied well with the other, more critical elements of dietary therapy, has a specific lipid disorder that may benefit from dietary therapy, or has expressed an interest in modifying fat, carbohydrate, or fiber intake, then modifications of the dietary intake of these latter nutrients should be explored more intensively.

Lipids

Elevated serum triglyceride levels are common in stage 4–5 CKD. Hypertriglyceridemia is caused primarily by impaired catabolism of triglyceride-rich lipoproteins. The reduced catabolic rate leads to increased quantities of apolipoprotein B (apoB)-containing triglyceride-rich lipoproteins in intermediate-density lipoproteins (IDL) and very low-density lipoproteins (VLDL) and reduced concentrations of high-density lipoproteins (HDL). Since diets for patients with renal failure are usually restricted in protein, sodium, potassium, and water, it is often difficult to provide sufficient energy without resorting to intakes of purified sugars that may increase triglyceride production. In patients on peritoneal dialysis, the glucose load in the peritoneal fluid appears to further increase serum triglycerides and cholesterol. Low serum HDL cholesterol, a common phenomenon in CKD patients, appears to be an independent risk factor for adverse coronary artery disease. Most clinicians recommend treatment of lipid abnormalities in dialysis patients in a manner similar to that used for the general population.

Low fat diets and lipid-lowering medicines retard the rate of progression of renal failure in animal models. In humans, some research suggests that taking supplements rich in omega-3 fatty acid may lower the progression of renal failure in renal transplant patients. A preponderance of studies suggests that omega-3 fatty acids given as fish oil may retard the rate of progression of immunoglobulin A (IgA) nephropathy.

Abnormal carnitine metabolism (see below) has also been implicated as a cause of hypertriglyceridemia in CKD. However, the many studies of treatment of hypertriglyceridemia with carnitine in CKD patients are divided between substantial numbers that show carnitine lowers serum triglycerides and substantial numbers that show no change or, rarely, a rise in serum triglycerides.

At present, there is no consensus as to what dietary fat constellation is the most appropriate for CKD patients. We recommend a Therapeutic Lifestyle Changes (TLC) diet for those with mild to moderate CKD not on maintenance dialysis treatment (Table 21–6). We treat hypertriglyceridemia by dietary modification only when serum triglycerides are greatly elevated (>200 or 300 mg/dL). In this situation, dietary fat intake should not be above 40% of total calories. A high proportion of dietary carbohydrates should be complex. These modifications often lower the palatability of the diet; therefore, the patient's total energy intake must be monitored closely to ensure that it does not fall. With high serum triglyceride values that are unresponsive to dietary therapy, a fibrate (eg, femofibrate) may be tried. l-Carnitine, about 500–1000 mg/day, or for patients on hemodialysis l–carnitine, 10–20 mg/kg/day at the end of each dialysis three times weekly, may be tried if hypertriglyceridemia is severe and unresponsive to these treatments.

Homocysteine

Plasma homocysteine is increased in CKD patients. The mechanism for this increase is unclear but may involve impaired remethylation of homocysteine back to methionine. In the general population, elevated plasma homocysteine is associated with a high incidence of cardiovascular disease. In CRI patients and patients on dialysis, there are contradictory observations pertaining to the association between hyperhomocysteinemia and risk of cardiovascular disease. Most recent studies do not show any association between hyperhomocysteinemia and death in both CRI patients and patients on dialysis.

Vitamin B6 is a cofactor for cystathionine synthetase, which catalyzes the conversion of methionine to cystathionine, and for cystathionase, which converts cystathionine to cysteine. Pyridoxine, given as pyridoxine HCl, a form of vitamin B6, generally does not lower plasma homocysteine in CKD patients. The folate metabolite tetrahydrofolic acid is necessary for the remethylation of homocysteine to reform methionine, and folic acid or folinic acid supplements may decrease plasma homocysteine concentrations in CKD patients, although usually not to normal values.

Carnitine

Carnitine is a naturally occurring compound that is essential for life. It is both synthesized in the body and ingested. Carnitine facilitates the transfer of long-chain (>10 carbon) fatty acids into muscle mitochondria. Since fatty acids are the major fuel source for skeletal and myocardial muscle at rest and during mild to moderate exercise, this activity is considered necessary for normal skeletal and cardiac muscle function.

Patients undergoing maintenance dialysis not infrequently have low serum free carnitine and in some but not all studies, low skeletal muscle free and total carnitine levels. Carnitine deficiency could be due to impaired synthesis of carnitine in vivo, reduced dietary intake of carnitine, and removal of carnitine by dialysis. The weekly loss of free carnitine by dialysis is reported to be approximately equal to the normal weekly urinary excretion of carnitine. However, the finding that serum free carnitine is normal in nondialyzed patients with stage 5 CKD and is low in patients on maintenance dialysis is consistent with the thesis that dialysis of l–carnitine is the major cause of low serum carnitine in patients on maintenance dialysis.

A number of clinical trials in patients with CRI, particularly those undergoing maintenance dialysis therapy, suggest that l-carnitine may provide clinical benefits including (1) increased physical exercise capacity, (2) reduced interdialytic symptoms of skeletal muscle cramps or hypertension, (3) improvement in overall global sense of well being or various symptoms often found in CRI patients, (4) improved response of anemia to erythropoietin treatment, (5) decreased predialysis serum urea, creatinine, and phosphorus, and (6) increased midarm muscle circumference. However, not all clinical trials confirm these findings.

The K/DOQI recommends that l-carnitine can be administered to patients on MHD or PD who suffer from disabling or very bothersome skeletal muscle weakness or cardiomyopathy, skeletal muscle cramps, or hypotension during hemodialysis treatment, severe malaise, or anemia refractory to erythropoietin therapy, and in whom the above conditions do not respond to more standard treatment. The patient can then be given a 3- to 6-month trial of l-carnitine (up to 9 months for refractory anemia). l-Carnitine may be administered orally, intravenously, or into dialysate. Oral l-carnitine is less expensive, but its intestinal absorption may be somewhat unpredictable. A dose of 20 mg/kg at the end of each hemodialysis, three times weekly, can be prescribed.

Sodium and Water

In both normal individuals and people with CKD, about 1–3 mEq/day of sodium is excreted in the feces. In the absence of visible sweating, only a few milliequivalents per day of sodium is lost through the skin. Because both the glomerular filtration and the fractional reabsorption of sodium fall parallel to each other as renal insufficiency progresses in CKD patients, most patients with renal failure are able to maintain sodium balance with a normal sodium intake if they do not have heart or liver failure. Patients with advanced renal failure who receive large loads of sodium, particularly as sodium chloride, may be unable to excrete the quantity of sodium ingested, and they may develop edema, hypertension, and congestive heart failure. This syndrome is particularly likely to occur in stage 4 and 5 CKD. In these patients, hypertension often is more easily controlled when they are sodium restricted, and may be accentuated by an increased sodium intake, probably because of expanded extracellular fluid volume and possibly due to altered intracellular electrolyte composition within arteriolar smooth muscle cells that increase contractility. Moreover, the antiproteinuric effects of ACE inhibitors and probably ARBs are substantially abrogated by even moderate sodium intakes; as urinary sodium excretion rises above about 100 mEq/day, the antiproteinuric effects abate.

In most nondialyzed patients with advanced renal failure, a daily intake of 1000–3000 mg (40–130 mEq) of sodium and 1500–2000 mL of fluid will maintain sodium and water balance. The requirement for sodium and water varies markedly, and each patient must be managed individually. Patients undergoing maintenance dialysis frequently are oliguric or anuric. For patients on hemodialysis, sodium and total fluid intake generally should be restricted to 1000–1500 mg/day and 700–1500 mL/day, respectively. Since sodium and water can be removed easily and continuously with peritoneal dialysis, a more liberal salt and water intake is usually allowed. Indeed, by maintaining a larger dietary sodium and water intake, the quantity of fluid removed from the patient on chronic peritoneal dialysis (CPD) and hence the daily dialysate outflow volume can be increased. This may be advantageous, since with CPD the daily clearance of small- and middle-sized molecules is directly related to the volume of dialysate outflow. Thus for some CPD patients, a higher sodium and water intake (eg, 6–8 g/day of sodium and 3 L/day of water) may enable the patient to use more hypertonic or hyperoncotic dialysate to increase the dialysate outflow volume, thereby increasing dialysate clearances and, if hypertonic glucose is used, energy uptake from the dialysate.

In nondialyzed CKD patients or patients undergoing maintenance dialysis who are not anuric and who have excessive sodium or water retention despite attempts at dietary restriction, a potent loop diuretic, such as furosemide or bumetanide, may be tried to increase urinary sodium and water excretion.

Potassium

Approximately 90% of daily potassium intake is excreted through the kidneys. Potassium excretion occurs mostly in the cortical collecting duct and is regulated by aldosterone and distal nephron sodium delivery. Because of the relative state of fluid overload and the frequent suppression of the renin–angiotensin–aldosterone axis, due to volume expression, diabetes mellitus and/or ACE inhibitors, ARB and aldosterone blockers, potassium tends to be retained in advanced CKD. This is accentuated by diminished distal nephron sodium delivery in the setting of low GFR.

Fecal excretion of potassium is increased due to its enhanced intestinal secretion, and dietary restriction and anorexia can decrease intake. Nonetheless, hyperkalemia is rather universal in patients with advanced CKD not undergoing dialysis, and amounts of urine output prevail. Factors promoting hyperkalemia in CKD include (1) excessive intake of potassium; (2) acidemia; (3) worsening oliguria, eg, due to superimposed acute renal failure; (4) catabolic stress or tissue degradation; (5) possibly hypoinsulinism or hyperglycemia (solvent drag) in patients with diabetes; (6) use of medicines such as ACE inhibitors, aldosterone receptor blockers (eg, spironolactone, epherenone), nonsteroidal anti-inflammatory drugs, and β-receptor blockers.

Patients with stage 4 or 5 CKD (ie, GFR less than 30 mL/minute), including those undergoing MHD, should generally receive no more than 70–75 mEq (about 3 g) of potassium per day. Those with frequent hyperkalemia (>5.5 mEq/L) should restrict their potassium to 1–2 g/day if possible. However, it is important to note that many types of fresh fruits and vegetables and other healthy food contain substantial amounts of potassium. Their restriction by rigid dietary regimens deprive CKD patients, who already have a high risk of cardiovascular disease, from important sources of antiatherogenic foods and neutraceuticals. Patients on peritoneal dialysis are an exception, since they tend to develop hypokalemia due to potassium losses in their peritoneal fluid.

Magnesium

In CKD patients, the difference between dietary intake and fecal excretion of magnesium (net absorption) amounts to about 40–50% of ingested magnesium. Since the absorbed magnesium is excreted primarily by the kidney, hypermagnesemia may occur in CRI. Magnesium also commonly accrues in bone in renal failure and may play a causal role in renal osteodystrophy. The restricted diets of stage 4 or 5 CKD patients are low in magnesium (usually about 100–300 mg/day for a 40-g protein diet). The patients' serum magnesium levels are therefore usually normal or only slightly elevated unless the patient takes substances that are high in magnesium content, such as magnesium-containing antacids and laxatives. Nondialyzed patients with stage 5 CKD require about 200 mg/day of magnesium to maintain neutral magnesium balance. The optimal dietary magnesium allowance for patients on maintenance dialysis has not been well defined. Experience suggests that when the magnesium content is about 1.0 mEq/L in hemodialysate or 0.50–0.75 mEq/L in peritoneal dialysate, a dietary magnesium intake of 200–300 mg/day will maintain the serum magnesium at normal or only slightly elevated levels.

Phosphorus

Renal osteodystrophy and the management of bone disease in CKD are discussed in Chapter 20. Chapter 20 reviews the rationale for controlling dietary phosphorus and the use of gastrointestinal binders of phosphate, hyperphosphatemia, the serum calcium–phosphorus product, calcium phosphate deposition in soft tissue, and hyperparathyroidism. The dietary phosphorus intake and the use of phosphate binders therefore will be discussed here only briefly.

There are inconclusive data concerning the optimal level of phosphorus restriction for retarding progressive renal failure or for minimizing hyperparathyroidism. For both nondialyzed and dialyzed CKD patients, the morning fasting serum phosphorus concentrations should always be maintained at or above 2.5 mg/dL. Lower serum phosphorus levels usually indicate severe malnutrition and have been shown to correlate with high risks of death in patients on maintenance dialysis even after extensive multivariate adjustments for other markers of malnutrition.

Since there is a rough correlation between the protein and phosphorus content of the diet, it is much easier to reduce phosphorus intake if a lower protein diet is used. One approach for patients with moderate CKD (stages 3, 4, and 5) is to maintain phosphorus intake at about 10–15 mg/kg/day. This quantity of phosphorus intake is not overly difficult to attain by patients who are ingesting a 0.60–0.75 g protein/kg/day diet.

The K/DOQI guidelines recommend maintaining serum phosphorus between 3.5 and 5.5 mg/dL in advanced stages of CKD including patients on maintenance dialysis. This often requires the patients to ingest a low phosphorus diet intake of about 800–1000 mg/day, particularly when CKD patients have elevated serum phosphorus concentrations and especially if they have moderate or severe hyperparathyroidism. However, there is the risk that protein–energy malnutrition and hypoalbuminemia also exist with such low amounts of protein intake, especially among patients on maintenance dialysis. Serum phosphorus levels should be monitored monthly following the initiation of dietary phosphorus restriction to ensure that serum phosphorus remains within the target range of each CKD stage.

Without phosphate binders, there is a net intestinal phosphate absorption (diet minus fecal phosphorus) of roughly 60% of the phosphorus intake. Therefore, this level of dietary phosphorus restriction usually will not maintain normal serum phosphorus levels in patients with stage 5 CKD (GFR <15 mL/minute), even with a substantial reduction in the renal tubular reabsorption of phosphorus. Hence, binders of gastrointestinal phosphate are also employed. The recommended phosphorus intake for patients on maintenance dialysis is about 12–15 mg/kg/day or less. This higher upper limit was chosen because with their greater protein intakes, patients on dialysis cannot readily ingest less phosphorus without making the diet too restrictive. Patients on maintenance dialysis almost always require phosphate binders to prevent hyperphosphatemia. Different types of phosphorus binders and their effects on serum phosphorus levels, bone disease, and cardiovascular risk are discussed in Chapter 20.

Calcium

The role of calcium in CKD-associated renal osteodystrophy and the management of bone disease are discussed in detail in Chapter 20. Stages 4 and 5 CKD patients who do not undergo maintenance dialysis usually have an increased dietary requirement for calcium, because they have vitamin D deficiency and resistance to the actions of vitamin D. The risk of calcium deficiency in these patients is enhanced because the diets prescribed for uremic patients are almost always reduced in calcium. Foods high in calcium content are usually high in phosphorus (eg, dairy products) and are therefore restricted for CRI patients. For example, a 40 g protein diet generally provides only about 300–400 mg/day of calcium, whereas the recommended dietary allowances for healthy, nonpregnant, nonlactating adults are about 800–1200 mg/day. Balance studies indicate that nondialyzed stage 5 CKD patients not receiving calcitriol (1,25-dihydroxycholecalciferol) or other vitamin D compounds usually require about 1200–1600 mg/day of calcium for neutral or positive calcium balance.

Low protein diets prescribed to CKD patients may need to be supplemented with approximately 600–1000 mg of elemental calcium daily. Supplemental calcium should not be given unless the serum phosphorus concentration is normal (2.5–5.5 mg/dL) to reduce the risk of calcium phosphate deposition in soft tissues. In addition, frequent monitoring of serum calcium is important because hypercalcemia may develop, particularly if serum phosphorus falls to low-normal or low levels. This is especially likely to occur if the patient also has hyperparathyroidism, a common complication of chronic renal failure.

An adjusted serum calcium range of 8.4–9.5 mg/dL is recommended for CKD stage 5 according to the current K/DOQI guidelines. To calculate the adjusted serum calcium, for each g/dL decrement of serum albumin below 4.0 g/dL, 0.8 mg/dL is subtracted from the measured serum calcium. Treatment with vitamin D analogs will decrease the daily calcium requirement by enhancing intestinal calcium absorption. This will reduce the total daily calcium load for the patient on dialysis who is taking calcium binders of phosphate.

Trace Elements

Trace elements are elements that are present in the body at concentrations <50 mg/kg. Recent advances in analytic methodology allow accurate measurements of trace element levels in body fluids. The main source of body trace elements levels is diet. However, the blood and tissue levels of these elements may be affected by nondietary factors, including renal excretory function, environmental and occupational exposure, duration of renal failure, the concentrations in the fresh dialysate and in flow, and possibly the mode of dialytic therapy. Also, many trace elements are largely protein bound. In CRI, there may be altered serum levels of binding protein levels or increased serum concentrations of compounds that compete for binding sites on these proteins; such factors may also cause a major alteration in serum trace element concentrations independently of the body burden or nutritional needs for these elements. The malnutrition–inflammation complex syndrome in CKD patients may lead to low serum protein concentrations and may be one of the causes of low serum zinc, manganese, and possibly selenium and nickel in CKD patients.

Because many trace elements are present in minuscule amounts in the plasma and are protein bound, losses during dialysis may be minimal. However, substantial amounts of bromide and zinc are removed during hemodialysis because a large proportion of the serum concentrations is not protein bound and because the levels in fresh dialysate are quite low. Conversely, the presence in the dialysate of even minute quantities of certain trace elements may lead to uptake by the body because of the avidity with which some trace elements bind to proteins. This phenomenon has been observed for lead, copper, and zinc. Table 21–7 gives the dietary recommendations for some trace elements in patients on maintenance dialysis.

Zinc

Serum zinc levels are often low, but erythrocyte zinc is often high–normal or elevated in CKD patients. Low levels of serum zinc may be related to removal by dialysis, inadequate dietary intake, and possibly reduced intestinal absorption. Although levels of serum zinc tend to rise at the end of dialysis, this can be attributed entirely to the rise in concentration of carrier proteins due to hemoconcentration. Dysgeusia and impotence in males have been reported to be ameliorated with zinc supplements, but not all studies confirm these findings. Until more definitive studies are conducted concerning dietary zinc requirements, it is recommended that patients on dialysis should receive the recommended dietary allowance for zinc, which is 15 mg/day. Intestinal zinc absorption is not affected by vitamin D metabolites.

Selenium

Selenium is an antioxidant; it is required for the activity of the enzyme glutathione peroxidase. Several studies have indicated low serum levels of selenium in patients with CRI. MICS and its associated poor energy and protein intake along with the restricted diet of CRI patients and patients on dialysis may play a major role in the development of selenium deficiency, especially since meat and fish are rich in selenium. In patients on maintenance dialysis, an association between selenium deficiency and increased oxidative stress has been noted.

Copper

Copper is essential for the activity of many enzymes including cytochrome oxidase and superoxide dismutase. In CKD patients, hypercupremia has been reported more often than copper deficiency. Excessive intake or absorption of copper, especially due to copper tubing used in heating coil for dialysate fluid, has caused hemolytic anemia (also known as Heinz-body-associated anemia) in patients on hemodialysis. The required intake and recommended dietary allowances (RDA) for copper in dialysis patients are currently not known.

Aluminum

Until about a decade ago, aluminum intake was often excessive in patients on dialysis, who regularly took aluminum-containing phosphorus binders such as aluminum hydroxide. Another source of aluminum in patients on hemodialysis is poorly treated fresh dialysate water. In patients on maintenance dialysis, refractory anemia (ie, erythropoietin hyporesponsiveness), osteodystrophy, myopathy, and neurologic disturbances including dementia have been attributed to aluminum toxicity. When nonaluminum–containing phosphorus binders became available, aluminum toxicity was encountered less frequently.

Iron

Iron deficiency is common in patients on maintenance dialysis and is discussed in Chapter 18. The causes include binding of iron to the dialyzer membrane, frequent blood drawing, sequestration of blood in the dialyzer at the termination of a hemodialysis procedure, and intestinal blood loss. Treatment with recombinant human erythropoietin (EPO) may reduce the nonhemoglobin-bound iron stores by enhancing erythropoiesis unless adequate iron supplementation is given. Iron deficiency can be determined by measuring serum iron and total iron binding capacity (TIBC), calculating their ratio, known as transferrin saturation, and assessing serum ferritin levels. Serum TIBC may be affected by the presence of the MICS, since TIBC is a negative acute phase reactant. Hence, its serum level is usually decreased in the setting of MICS. Thus, in CKD patients with evidence of inflammation or malnutrition, the iron saturation ratio (ie, serum iron divided by TIBC) may be erroneously normal or high if the denominator (TIBC) is decreased. Serum ferritin is a positive acute phase reactant and may increase due to non-iron-related factors, such as the MICS.

Vitamin Requirements

CKD patients are at increased risk for deficiencies of several vitamins. The causes for vitamin deficiencies include (1) reduced total food intake due to anorexia; (2) prescription of low-phosphorus, low-potassium diets that restrict intake of nutritionally valuable foods such as fresh fruits and vegetables, dairy products, and other items that are high in vitamins; (3) altered metabolism, as is the case for pyridoxine and possibly folate; (4) impaired synthesis (eg, for 1,25-dihydroxyvitamin D); (5) resistance to the actions of vitamins (eg, vitamin D and possibly folate); (6) decreased intestinal absorption (eg, decreased intestinal absorption of riboflavin, folate, and vitamin D have been described in rats with chronic renal insufficiency); and (7) dialysate losses of water-soluble vitamins.

In some studies, CRI patients who did not receive vitamin supplements generally did not develop signs of vitamin deficiency when followed longitudinally. Based on these findings, the need for vitamin supplementation for patients on maintenance dialysis has been questioned. However, recent reports continue to show that many CKD patients ingest a vitamin intake that provides less than the recommended dietary allowances, and there is a small but persistent prevalence of deficiencies for some water-soluble vitamins (as well as for 1,25-dihydroxyvitamin D) in CRI patients not taking vitamin supplements. At present, it does not seem feasible to identify, a priori, those patients who will develop vitamin deficiencies. Since the intake of water-soluble vitamins at the proposed levels appears to be safe, we propose that these vitamins be supplemented. Table 21–8 shows the dietary recommendations for various vitamins in patients on maintenance dialysis. The RDAs that are proposed for each of the water-soluble vitamins and for vitamin A are similar to those of normal individuals except for higher doses of pyridoxine HCl (10 mg/day, 8.2 mg/day of pyridoxine) and folic acid (about 1 mg/day). Vitamin C is recommended only at the daily allowance levels (70 mg/day) because of the risk of increased oxalate formation at higher intakes. Some studies indicate that vitamin E has an antioxidant effect in patients on chronic dialysis and may protect against cardiovascular events. However, a recent study showed that individuals with no apparent kidney disease who were randomized to receive a vitamin E supplement of 400 units/day had an increased risk of developing heart failure. However, given positive results in CKD patients with CRI, we currently encourage vitamin E administration to all patients with renal insufficiency.

Water-Soluble Vitamins

Some reports indicate that vitamin C supplementation may promote intestinal iron absorption and reduce the incidence of iron deficiency anemia in CKD patients. Serum homocysteine concentrations, a cardiovascular risk factor in the general population, are significantly increased in patients on maintenance dialysis and pharmacologic doses of folic acid may lower plasma total homocysteine levels. However, some recent data indicate that patients on dialysis with a higher plasma homocysteine concentration may paradoxically have a better survival, a phenomenon also known as reverse epidemiology.

Erythrocyte or serum levels of riboflavin (vitamin B2 ), thiamine (vitamin B1 ), niacin, pantothenic acid, and biotin are usually normal in CRI patients. However, case reports of Wernicke's encephalopathy in patients on maintenance dialysis due to thiamine deficiency are occasionally described. Pyridoxine (vitamin B6 ) is removed by hemodialysis; this factor, and probably also altered vitamin B6 metabolism, may account for the increased daily requirement for this vitamin. Vitamin B6 participates in the metabolism of homocysteine, although pyridoxine supplements have not been consistently shown to decrease plasma homocysteine in patients with renal failure.

Lipid-Soluble Vitamins

The lipid-soluble vitamins are D, K, A, and E. Vitamin D is discussed in detail in Chapter 20. Vitamin K levels are usually normal in CKD patients. Administration of a pharmacologic dose of vitamin K (45 mg/day orally) for 1 year was found to prevent loss of bone mass in patients on maintenance dialysis with bone disease characterized by low bone turnover. Several reports describe a relationship between high plasma vitamin K levels and ectopic soft tissue calcification in patients on maintenance dialysis. Since CKD patients generally do not have vitamin K deficiency, vitamin K supplements are not recommended for routine use. However, patients may be at increased risk for vitamin K deficiency if they are not eating, are not given vitamin K by parenteral administration, and are receiving antibiotics that suppress the intestinal bacteria that synthesize vitamin K. Under these conditions, vitamin K supplements should be considered.

There are inconsistent reports about the levels of serum and erythrocyte vitamin E (α-tocopherol) in patients on dialysis. The dialysis procedure does not remove significant amounts of α-tocopherol. These findings may reflect either increased consumption of tocopherol, possibly due to oxidative stress, or a defect in the HDL-mediated transfer of α-tocopherol from plasma to the red blood cell membrane. Since patients on maintenance dialysis often have oxidant stress, several studies have examined the effects on oxidant stress of vitamin E supplementation given orally, during HD treatment utilizing vitamin E-coated dialyzer membranes, or through dialysate (hemolipodialysis). Since chronic renal failure is clearly associated with increased oxidant stress and increased cardiovascular risk, and since vitamin E appears to be rather safe and may be beneficial, it is not unreasonable to consider prescribing a supplement of 400–800 IU/day of vitamin E.

Serum vitamin A concentrations are generally increased in CRI patients, especially among long-term dialysis survivors. Patients on maintenance dialysis who are binephrectomized are reported to have serum retinol levels higher than other CKD patients; this probably reflects the loss of the renal contribution to the degradation of retinal-binding protein (RBP), the carrier protein for vitamin A. Hemodialysis treatment does not change vitamin A levels except possibly by hemoconcentration; indeed losses of vitamin A into dialysate would not be expected because of the relatively large size of the vitamin A–RBP–transthyretin (prealbumin) complex and because vitamin A is lipid soluble. However, β-carotene, ubiquinol, and lycopene have been found to be lower in CKD patients than in individuals without renal insufficiency, and β-carotene and ubiquinol are reported to fall further after a single hemodialysis. It is possible that lipid metabolism may also affect serum vitamin A levels. Evidence suggests that vitamin A may promote erythropoiesis.

Patients with advanced CKD appear to be particularly vulnerable to vitamin A toxicity. Hypercalcemia and elevated serum alkaline phosphatase levels have been described in patients on maintenance dialysis ingesting as little as 7500–15,000 units/day of vitamin A. Therefore, it is recommended that the daily vitamin A intake from foods and supplements combined should not exceed the recommended dietary allowance of 800–1000 μg/day.

Acid–Base Management in Renal Insufficiency

CKD patients with moderate to advanced renal failure frequently develop metabolic acidosis. This is usually associated with a mild to moderate increase in anion gap because of impairment in the ability of the kidney to excrete acidic metabolites. In the earlier stages of renal insufficiency, and occasionally with advanced renal failure, hyperchloremic (nongap) metabolic acidosis may also be caused by excessive renal losses of bicarbonate. Ingestion of low protein diets may prevent or decrease the severity of the acidosis because the endogenous generation of acidic products of protein metabolism will be reduced. Metabolic acidemia may engender oxidation of branched chain amino acids and protein catabolism, impair albumin synthesis, increase β2-microglobulin turnover, cause bone loss, possibly predispose to inflammation, and cause symptoms of weakness and lethargy. The acidemia-induced increased proteolysis in skeletal muscle appears to be caused by enhanced activity of the ATP-dependent ubiquitin–proteosome pathway. Conversely, correction of acidosis has been associated with decreased protein degradation rates and increased plasma branched chain amino acids, serum albumin, body weight, and midarm circumference. It is important to note that epidemiologic studies have shown that in MHD patients, lower predialysis serum bicarbonate and/or higher serum anion gap are associated with a paradoxically greater survival. This is considered to be due to the association of greater appetite and higher protein intake in healthier patients, leading to more acid generation during the interdialytic period.

The K/DOQI Clinical Practice Guidelines for both nutrition in chronic renal failure and bone disease recommend that serum bicarbonate levels should be measured once monthly in all patients on maintenance dialysis and that the predialysis or stabilized serum bicarbonate level should be maintained at or above 22 mmol/L. Because of the safety of giving bicarbonate and the potential advantages of completely eradicating acidemia, serum bicarbonate levels should be maintained in the 23–25 mEq/L range and arterial blood pH should be at 7.36 or higher. A similar recommendation concerning the threshold for treating low serum bicarbonate levels would seem appropriate for nondialyzed patients with any level of renal function.

Since in clinically stable CRI patients, the rate of acid production is usually normal or below normal, alkalinizing medicines are usually very effective for preventing or treating the acidemia. Hence, 35 mg of sodium bicarbonate tablets (4 mEq alkali) or Shohls solution or bicitra (1 mEq alkali/mL) may be given, eg, 650–1300 mg of sodium bicarbonate or citrate twice daily. If the nondialyzed chronically uremic patient is not oliguric and is not likely to develop edema, sodium is usually readily excreted when it is given as sodium bicarbonate or citrate. Since protein metabolism yields acidic products, a low protein diet (eg, 0.60 g protein/kg/day) will also reduce acid production and acidemia. Such a diet can be nutritious for nondialyzed stage 3, 4, and 5 CKD patients, but patients on maintenance dialysis will require more dietary protein (see above). Calcium carbonate may correct mild acidosis, provide needed calcium, and reduce intestinal phosphate absorption. However, the risk of soft tissue and particularly arterial calcification limits the amount of calcium that can be given to CKD patients (see above). However, the non-calcium-containing phosphate binder sevelamer hydrochloride may aggravate acidosis, although there is currently no evidence that this aspect of the medication may be harmful. If the acidosis is more severe, sodium bicarbonate or citrate may be administered intravenously. If acidemia is severe and not controlled by the foregoing measures, hemodialysis or peritoneal dialysis may be employed.

Protein–Energy Malnutrition and Inflammation

There are four goals for the dietary treatment of CKD patients: (1) To maintain good nutritional status, (2) to reduce the risk of cardiovascular disease and to improve survival, (3) to prevent or ameliorate uremic toxicity and the metabolic disorders of renal failure, and (4) if possible, to retard the progression of renal failure. The latter two may appear to contradict the first two goals, since low protein intake is not infrequently recommended to slow the rate of progression of renal insufficiency. Dietary restrictions may remove important sources of antioxidant vitamins such as fresh fruits and vegetables, due to their rich potassium and phosphorus content; the consequences of such limitations are not yet known. Adherence to specialized diets is often a difficult and frustrating endeavor for patients and their families. Patients usually must make fundamental changes in their patterns of behavior. Often, the patients must procure special foods, prepare special recipes, forego or severely limit their intake of favorite foods, or eat foods that they may not like. Demands are made on the patient's time and daily activities and on the emotional support system of the family or close associates. Therefore, it is incumbent on the physician not to prescribe radical changes in the patient's diet unless there is good reason to believe that these modifications may be beneficial.

A number of different modalities have been employed to improve the nutritional or inflammatory status in patients on dialysis, as shown in Table 21–9. A recent study in animal models raises the possibility that protein–energy wasting may lead to inflammation. If this is confirmed in humans, dietary interventions may mitigate inflammation in CKD, as shown in several recent clinical trials in the general population.

Nutritional Supplements

Among more intensive interventions, tube feeding has been reported to be an effective modality, particularly in pediatric, elderly, or disabled individuals. However, according to some, this modality is a cumbersome option that cannot be used in the average (stable and functional) CKD outpatient. Experience with tube feeding in adults with CRI is still limited, probably because many patients and doctors are reluctant to use it.

Parenteral interventions such as intradialytic parenteral nutrition (IDPN) are quite costly and can be employed only during dialysis treatment. Several studies have examined the role of IDPN in improving nutritional status and outcomes in patients on dialysis, and have shown inconsistent results. The cost and strict regulatory criteria of IDPN might have restricted clinical access to these methods. Some retrospective analyses suggest that in patients on dialysis with protein–energy wasting, IDPN may reduce mortality. However, because of these reasons, enthusiasm for providing intensive nutrition modalities such as tube feeding and IDPN is currently limited.

Among simple interventions, hormonal medications may be associated with many side effects such as virilism or the potential for worsening atherosclerosis seen with androgens. However, some other medications, especially appetite stimulants and anti-inflammatory/antioxidant agents, show some promise (see below). Moreover, an increase in energy or protein intake without the concurrent provision of anti-inflammatory or antioxidant nutrients may not be optimally effective and an increased protein intake above 1.4 g/kg/day may be paradoxically associated with decreased survival in MHD patients (see Figure 21–4). Therefore, it is unlikely, although not impossible, to find one single medication to correct MICS. However, oral supplements, especially if they contain a combination of several nutritional and antiin-flammatory agents, are practical and promising treatment modalities.

Anti-Inflammatory and Antioxidant Modalities

Although epidemiologic evidence strongly links inflammation and oxidative stress to each other and to poor outcome in CKD patients, there have been only a few randomized trials that indicate an improvement in outcome with anti-inflammatory or antioxidant treatment. Other treatments (Table 21–10) have been proposed for reducing inflammation or oxidative stress in patients on dialysis but the data supporting the efficacy of these modalities are still inconclusive. One example is the administration of vitamin E, which may be associated with a decreased risk of cardiovascular mortality in patients on dialysis according to some but not all reports (see above).

Statins have been shown to decrease CRP levels irrespective of their effects on lipids, and may be associated with reduced mortality in patients on hemodialysis. However, the issue of worsening hypocholesterolemia in patients on hemodialysis as a result of statins is not resolved.

ACE inhibitors may have anti-inflammatory properties both in the general population with diabetes or hypertension and in those with stage 2–5 CKD including patients on maintenance dialysis. However, many patients on dialysis who already receive these agents continue to have poor outcomes. Acetylcysteine may reduce adverse cardiovascular events in patients on maintenance dialysis. Glitazones are another group of drugs that has been shown to inhibit the activation of inflammatory response genes and promote an immune deviation away from T helper type 1 to T helper type 2 cytokine production. The optimization of dialysis treatment, ultrapure dialysate fluid, and more biocompatible dialysis membranes may improve the inflammatory status in patients on hemodialysis. However, the HEMO Study did not confirm such effects. As discussed above, it is possible that one single agent will not correct MICS, and a combination of nutritional, anti-inflammatory, and antioxidant interventions is needed to do so.

Correction of Anorexia

It has been argued that CRI–associated anorexia is an integral component of the systemic inflammatory response as well as of other factors (see above). Anorexia can be induced by proinflammatory cytokines such as IL-6 and TNF-α and is correlated with all-cause and cardiovascular mortality in patients on dialysis. Consequently, an exploration of the interaction between energy and protein-regulatory mechanisms and proinflammatory cytokines may lead to an effective treatment for MICS-associated anorexia.

Several appetite stimulants have been studied clinically (Table 21–11). Megestrol acetate (MA) is by far the most utilized and best-studied agent. MA, at a dose of 800 mg/day, has been shown to increase appetite and food intake in patients with anorexia due to cancer or AIDS. However, at this dose, it may be associated with side effects, including venous thrombosis, vaginal bleeding, altered liver function, and adrenal insufficiency. The pharmacokinetics of MA have not been evaluated in patients with renal impairment. In addition to improving appetite and food intake, MA has also been found to have significant anti-inflammatory properties (see Table 21–10). MA downregulates the synthesis and release of proinflammatory cytokines and relieves the symptoms of the anorexia–cachexia syndrome based on the modulation of cytokines. There are very few studies concerning MA in patients on dialysis. Our experience with a lower dose of MA (400 mg/day) has been encouraging.

Another potential orexigenic agent for CKD patients is pentoxifylline, which downregulates the local proinflammatory cytokine-mediated nitric oxide synthase pathway, inhibits TNF-α production, and decreases body weight loss and muscle protein wasting in acutely ill patients. There is indirect evidence that pentoxifylline may be an effective treatment for MICS and its clinical consequences including anorexia and erythropoietin resistance. Further research will be necessary to define the role for these agents as therapies for individuals with stage 3–5 CKD.

Nutritional Management of Renal Transplant Patients

Patients who undergo successful renal transplantation often develop normal or even supranormal appetite. Gain in body weight and fat is common. During the first year after transplantation, women may be particularly likely to increase dietary energy and protein intake and gain fat and lean body mass. Several nutritional disorders appear to be related to other factors associated with renal transplantation. These include obesity, insulin resistance and diabetes mellitus, impaired growth in children, protein wasting, altered serum lipid and homocysteine concentrations, and abnormalities in bone, mineral, and vitamin metabolism. Many of these complications are of particular concern because cardiovascular disease is the major cause of morbidity and mortality in renal transplant recipients. Indeed, unlike patients on dialysis, in whom obesity confers survival advantages (reverse epidemiology), obesity has been shown to have a strong association with increased mortality in transplanted patients, hence a so-called “reversal of the reverse epidemiology” is observed.

Lipids

Renal transplant patients often have increased serum triglyceride, VLDL triglyceride, small dense low-density lipoprotein (LDL) cholesterol, and total LDL cholesterol concentrations. HDL cholesterol is often low, and the LDL/HDL cholesterol ratio may be increased. Serum triglyceride levels correlate with the daily dose of prednisone, degree of obesity, and severity of renal insufficiency. These findings are of particular concern because several studies have found a correlation between increased serum lipids and the risk of cardiovascular disease, graft failure, and fatality in renal transplant recipients. Causes of increased serum triglycerides and cholesterol include excessive fat and energy intake, obesity, treatment with glucocorticoids, diuretics, calcinerin inhibitors or rapamycin, nephrotic-range proteinuria, and underlying diseases (eg, diabetes mellitus).

A low cholesterol, high fiber diet with a polyunsaturated:saturated fatty acid ratio greater than 1.0 may lower serum total cholesterol and LDL cholesterol levels in renal transplant recipients. However, the altered lipoprotein pattern may not be affected. A combination of a similar diet with regular exercise may improve the plasma lipid pattern. Fish oil providing 3 g/day of omega-3 fatty acids for 3 months decreased serum triglycerides and VLDL cholesterol in hyperlipidemic renal transplant recipients. However, the effects of diet on the improvement in the serum lipid pattern tend to be modest, and combining dietary therapy with serum 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is generally far more effective in reducing serum total and LDL cholesterol.

The observation that a diet low in carbohydrates and modestly restricted in calories may reduce the cushingoid appearance suggests that such individuals may be given a low carbohydrate intake (1 g/kg/day), which is limited to 28–30 kcal/kg/day. If such a low carbohydrate, moderately restricted energy intake is employed in renal transplant recipients, it should be limited to short periods of time when the prednisone dosage is very high (eg, greater than 40 mg/day). This level of energy intake may not minimize the catabolic response during acute illness and may lead to further wasting. However, the higher protein intake with such diets (eg, 2 g protein/kg/day) may reduce protein malnutrition. Also, given the abnormalities in lipid metabolism in renal transplant recipients, such a high fat diet should not be continued for long periods of time. In general, renal transplant patients should be encouraged to ingest a National Cholesterol Education Program TLC diet as described above for CKD patients. Patients should be encouraged to exercise regularly and to maintain a normal or desirable body weight. For transplant recipients with superimposed catabolic illnesses, 30–40 kcal/kg/day may be prescribed. Other maneuvers to correct abnormal serum lipids are as described for the nontransplant renal failure patient (see above). For renal transplant recipients with serum LDL cholesterol levels above about 70 mg/dL, the TLC diet should be supplemented with statins.

Hyperhomocysteinemia

In patients on maintenance dialysis who have had a successful kidney transplant, plasma homocysteine decreases but remains greater than in nontransplanted individuals with similar levels of renal function. The causes of hyperhomocysteinemia include reduced GFR, which appears to be the most important determinant, low serum folate levels, and possibly calcineurin inhibitor therapy. Folic acid may decrease plasma homocysteine levels in renal transplant recipients, and pyridoxine HCl, 50 mg/day, and vitamin B12 , 0.4 mg/day, may also be added to folic acid, 5 mg/day, to potentiate the treatment.

Vitamins after Renal Transplantation

Low serum folate levels were observed in transplant patients as long as 6 years after transplantation. Serum thiamine and vitamin B12 levels are generally normal in renal transplant patients. After successful renal transplantation, serum vitamin A often remains elevated for extended periods of time and may not fall to normal levels in some patients for several years.

Other Nutritional Issues

Calcineurin inhibitors (cyclosporine A and tacrolimus) as well as sirolimus may increase serum cholesterol, and cause potassium retention with hyperkalemia and urinary magnesium wasting with hypomagnesemia. Moreover, hypophosphatemia is relatively common during the first few months after successful renal transplantation and may occur because of a condition similar to hungry bone syndrome. Hence, judicious phosphorus and magnesium supplementation is imperative to avoid the deleterious effects of hypomagnesemia and hypophosphatemia, which can be profound. Low levels of zinc in plasma and hair and hyperzincuria have also been reported often within 12 months after successful renal transplantation. However, patients who have a functioning renal transplant for more than 12 months after the surgery usually have normal plasma, hair, and urine zinc and normal taste detection and recognition thresholds.