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.
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.
Table 21–6. Nutrient Composition of the Therapeutic Lifestyle Changes (TLC) Diet. ||Download (.pdf)
Table 21–6. Nutrient Composition of the Therapeutic Lifestyle Changes (TLC) Diet.
<7% of total calories
Up to 10% of total calories
Up to 20% of total calories
25–35% of total calories
50–60% of total calories
Approximately 15% of total calories
Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain
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.
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 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.
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.
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.
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.
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.
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 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.
Table 21–7. Recommended Dietary Intake of Trace Elements for Adult Patients with Advanced Chronic Kidney Disease (CKD). ||Download (.pdf)
Table 21–7. Recommended Dietary Intake of Trace Elements for Adult Patients with Advanced Chronic Kidney Disease (CKD).
Daily requirement in chronic renal insufficiency
Toxicity reported with excessive intake
Dependent on erythropoietin treatment and other factors
No data available in CKD
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 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 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.
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 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.
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.
Table 21–8. Recommended Dietary Intake of Selected Vitamins for Adult Patients with Advanced Chronic Kidney Disease. ||Download (.pdf)
Table 21–8. Recommended Dietary Intake of Selected Vitamins for Adult Patients with Advanced Chronic Kidney Disease.
Toxicity reported with excessive intake
Vitamin B6 (pyridoxine)
400–800 IU (optional, see text)
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.
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.
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