so contribute to oxidative stress , and co-administrated ascorbic acid, given with the goal of mobilizing iron stores, can further stimulate free radical formation, possibly by reduction of Fe (III) ions to more oxidative Fe (II) compounds . ROS and its related compounds can attack lipids, proteins and nucleic acids and alter the structure and function of these macromolecules [4,38]. LDL particles are especially damaged by excessive oxidation and consequently are not recognized by cell LDL receptors. These damaged LDL particles subsequently accumulate in the blood, leading to nutritional derangements.
2.5. Hormonal Derangements
The chronic inflammation in CKD patients decreases anabolism such as protein synthesis, fat mobilization and gluconeogenesis. In addition, metabolic acidosis impairs the action of several anabolic hormones, including GH, thyroid hormone and insulin [40-42]. GH exerts several anabolic actions, and IGF-1 is one of the major mediators of these actions in adults. Hormonal activities by compounds of GH or IGF-1 are disrupted in CKD patients. Uremia is known to be associated with reduced expression of hepatic GH receptor mRNA and hepatic IGF-1 mRNA, as well as a defect in GH signal transduction [40,41]. The abnormalities of this hormonal axis constitute an important factor in the pathogenesis of uremic malnutrition. Uremia is also characterized by insulin resistance. Insulin binding to its receptor seems to be normal in CKD patients, however, a post-receptor defect in tissue insulin responsiveness is observed, resulting in insulin resistance. Decreased food intake can also contribute to insulin resistance.
2.6. Metabolic Acidosis
Metabolic acidosis is noted in a majority of patients when the GFR decreases to less than 20% - 25% of normal , and the degree of acidosis correlates with the severity of CKD. Several adverse consequences are associated with uremic acidosis, including muscle wasting, mineral-bone disease, impaired insulin sensitivity and exacerbation of beta2-microglobulin accumulation . Metabolic acidosis causes an alteration of protein balance, which is shown by an increase in leucine oxidation and/or protein degradation. Inverse correlations between net protein balance and blood bicarbonate are also observed, suggesting that acidosis is responsible for the more negative protein balance [44-46]. Other complications associated with metabolic acidosis in CKD include anorexia, fatigue, impaired function of the cardiovascular system, hyperkalemia, and altered gluconeogenesis and triglyceride metabolism .
2.7. Dialysis-Related Problems
There is a slight difference between CKD not requiring immediate dialysis and ESRD patients maintained on dialysis. Once CKD progress to ESRD and patients initiate maintenance dialysis, their dietary protein intake increases, at least during the first year of therapy [26,47]. Despite increase in dietary protein and energy intake after initiation of dialysis, the high prevalence of a poor nutritional status is developed, which suggests that protein energy malnutrition alone does not explain the poor nutritional status in dialysis patients. The aggravated nutritional status in dialysis patients seems to be associated with the dialysis procedure, as well as with more advanced uremia. During standard HD treatment using high-flux dialyzers, approximately 8 g of free amino acids are removed . In addition, HD is known as a catabolic procedure, which is evidenced by the fact that patients on dialysis days are in negative nitrogen balance, even with high levels of protein intake . A study using stable isotope tracer technique reported that the catabolic effects of HD were limited to amino acid losses. Furthermore, it was reported that increased net whole-body and muscle protein loss persisted for at least 2 hours after completion of an HD treatment .
HD membrane can activate the complement system and contribute to the inflammatory process in HD patients. The use of biocompatible membrane during HD procedure has been recommended because of the beneficial nutritional effects, such as higher concentrations of serum albumin and serum IGF-1, and higher weight gain compared to the use of bioincompatible membranes . However, these derangements have also been observed with the use of biocompatible HD membranes and relatively pure dialysate, suggesting that the HD procedure itself initiates certain metabolic pathways leading to both decreased protein synthesis and increased protein breakdown [37,51]. In addition, REE in ESRD patients is further increased by HD, even using biocompatible membranes . Following HD, diminished carbohydrate and accelerated lipid and amino acid oxidation is also observed.
3. ASSESSMENT OF MALNUTRITION IN PATIENTS WITH CHRONIC KIDNEY DISEASE
Prior to embarking on nutritional intervention, it is important to grasp the nutritional status in CKD and ESRD patients. A variety of tools and techniques available to assess nutritional status in CKD patients are shown in Table 1. An ideal and reliable nutritional marker should either predict clinically important outcomes or identify patients who should receive nutritional management. For many years, nephrologists have been concerned about the validity of the biologic markers used to evaluate nutritional status in CKD and ESRD patients. The most commonly used clinical marker is serum albumin. A large number of studies have shown that serum albumin is a reliable indicator of nutritional status, and that it also displays a notable response to nutritional intervention [53,54]. Differing from normal subjects, CKD and ESRD patients have substantially altered total body water distribution and experience frequent changes in plasma volume, both of which are known to affect albumin turnover and consequently serum albumin concentrations [55,56]. Furthermore, a chronic inflammatory condition in CKD and ESRD patients is known to influence albumin turnover [51,55,56]. Despite inherent limitations, serum albumin is routinely assessed to identify potentially low protein stores and nutritional status in CKD and ESRD patients.
Serum pre-albumin and transferrin can be alternatives to serum albumin as nutritional markers in CKD and ESRD patients. These markers appear to have certain advantages in that they provide an earlier response to nutritional changes and they can be more precisely measured. However, both serum pre-albumin and serum transferrin are also affected by inflammatory conditions. Pre-albumin is excreted through the kidney and transferrin is closely related to iron metabolism. Neither of these has been studied as thoroughly as albumin in CKD and ESRD patients [57-59] and further, it is expensive in some countries to check them regularly.
Plasma homocysteine concentration may reflect nutritional status in ESRD [60,61]. Although hyperhomocysteinemia is present in the majority of CKD and ESRD patients, plasma levels of homocysteine are higher in CKD patients with appropriate nutritional status than in malnourished patients. In addition, the plasma homocysteine level is inversely correlated with SGA and positively correlated with serum albumin and protein intake.
Measurement of somatic protein stores can be used for assessment of nutritional status in ESRD patients. Anthropometrics, lean body mass measurements by dualenergy X-ray absorptiometry (DEXA) or total body nitrogen (TBN) have been studied in this population . DEXA appears to be the most reliable body composition method for evaluating the ESRD population. It relies on fewer assumptions regarding the influence of fluid status on fat mass measurements compared to bioelectrical impedance analysis (BIA) .
BIA has been reported known as an accurate method
Table 1. A variety of tools and techniques available to assess nutritional status in patients with chronic kidney disease.
to measure lean body mass against TBN, which is considered to be a gold standard technique. These techniques are also influenced by ESRD-related limitations .
Subjective global assessment (SGA) has been also introduced for an overall clinical evaluation, including assessment of weight and weight change, dietary intake, gastrointestinal symptoms, and functional status. SGA has been relatively well correlated with objective measures of nutritional status in CKD and ESRD patients [64,65]. However, SGA is not yet a reliable predictor of degrees of uremic malnutrition. Furthermore, to overcome the lack of objectivity, standardization of guidelines and experience are very important for SGA .
4. TREATMENT AND PREVENTION OF CHRONIC KIDNEY DISEASE-RELATED MALNUTRITION
Since uremic malnutrition constitutes the most important factor for poor clinical outcomes in ESRD patients, novel strategies for treatment or prevention must be worked out (Table 2). Considering the complex and multifactorial pathogenesis of uremic malnutrition, the establishment of opinions about the treatment and prevention is not easy.
Inadequate nutritional intake and superimposed medical conditions are thought to play major roles in malnutrition and protein energy wasting, although uremia per se and its treatment modalities can also impair protein metabolism. The amount and/or route of protein and
Table 2. Practical recommendations for preventing or correcting malnutrition in chronic kidney disease.
energy intake should be considered based on renal functional status; unlike predialysis CKD patients, ESRD patients on dialysis are encouraged to maintain an adequate protein and energy intake. Therefore, frequent comprehensive dietary counseling by nephrologists and dietitians is important.
Correction of metabolic acidosis in CKD patients can improve nutritional-related complications, such as nitrogen balance [66,67]. Therapy of uremic acidosis should aim for maintaining a serum bicarbonate level as close to normal as possible, for example 22 - 26 mmol/L. The best way to initiate therapy is with oral sodium bicarbonate (1 tablet 3 times a day) and to increase the dosage as necessary . The usual tablet of 650 mg of sodium bicarbonate contains 7.5 mmol of alkali. For patients who experience gastric discomfort with sodium bicarbonate, Shohl’s solution, a mixture of sodium citrate and citric acid, is useful. In ESRD patients maintained on dialysis, the addition of alkali from the dialysate either as bicarbonate in HD or as lactate in PD may be used . Since endogenous acid production, which depends on diet, is an important factor associated with uremic acidosis, ingestion of vegetables and fruits results in a net production of alkali which tends to delay the progression of uremic acidosis. However, development of hyperkalemia resulting from ingestion of foods containing high potassium content is a concern. Diuretic therapy and subsequent hypokalemia may also delay the development of acidosis, as these tend to stimulate ammonia production.
Once the early signs of uremic malnutrition are detected, active supplementation by an enteral or parenteral route should be considered. Despite conflicting results of oral nutritional supplementation in dialysis patients, oral protein, amino acid tablets or energy supplementation can be tried. According to several reports, oral amino acid supplementation significantly improved serum albumin concentration in HD patients and oral nutritional supplementation improved several nutritional parameters, including serum albumin and serum pre-albumin concentrations, in malnourished HD patients [68,69]. As an adjunctive nutritional therapy in CKD and ESRD patients, appetite stimulants such as megesterol acetate may be also considered, although the appropriate dose and side effect profiles remain to be evaluated in this drug . Novel strategies such as anabolic hormones and anti-inflammatory drugs, along with conventional oral nutritional supplementation, may provide support for multiple patient populations. Recombinant human growth hormone (rhGH) administration has been suggested and has led to significant improvement in nitrogen balance, serum albumin, serum transferrin and IGF-1 concentrations . Recombinant human IGF-1 (rhIGF-1) has also proposed as an anabolic agent, but the side effects of this agent are of concern in CKD patients . As was mentioned above, chronic inflammation is an important catabolic factor and new interventions for blocking the adverse effects of inflammation have been proposed. Since anti-inflammatory drugs such as thalidomide and COX-2 inhibitors would be theoretically helpful through inhibitory actions on TNF-α production and COX-2 expression, such strategies need to be evaluated in the future .
In dialysis patients, an adequate nutritional program can lead to improvement in nutritional status only when an optimal dialytic dose has been established, the catabolic stimulus possibly present has been counteracted, and drugs and procedures that reduce appetite have been avoided . However, increasing the dose or using high-flux dialysis or hemodiafiltration with online regeneration of the ultrafiltrate does not seem to improve nutritional status.
If enteral nutritional supplementation is neither available nor effective, intradialytic parenteral nutrition (IDPN) is recommended for malnourished dialysis patients. Unlike early studies showing conflicting results about the beneficial effects of IDPN, IDPN has recently been reported to promote a robust increase in whole body proteolysis and a significant increase in forearm muscle protein synthesis in chronic HD patients . In malnourished PD patients, conflicting results using amino acid dialysate as a nutritional intervention have been reported. Increases in serum transferrin and total protein concentrations as benefits from amino acid dialysate have been reported . Because an increase in blood urea nitrogen concentration associated with exacerbation of uremic symptoms and metabolic acidosis represents a complication of amino acid dialysate use, these interventions should be considered only in PD patients with severe malnutrition. The use of both IDPN and AAD in ESRD patients need more study to evaluate any longterm beneficial effects. Furthermore, there are no data to show that active nutritional supplementation through the gastrointestinal tract is inferior to parenteral supplementation in dialysis populations . The evidence from large-scale, well-designed nutritional intervention studies in CKD and ESRD patients with uremic malnutrition are very much needed.
Physical activity, as well as total daily protein intake, is the strongest predictor of the amount of lean body mass. Despite conflicting results, exercise appears to bring significant improvements in muscle attenuation, muscle strength, mid-thigh and mid-arm circumference, body weight, and CRP in patients on renal replacement therapy relative to non-exercising patients . Longer training duration or more sensitive analytic techniques are required before such exercise regimens can be recommended as therapy for uremic malnutrition.
Since uremic malnutrition in patients with CKD, nutritional status progressively deteriorates as renal function worsens. The malnutrition in this population is associated with increased morbidity and mortality rates, as well as with numerous pre-existing factors. Therefore, it is vital to identify, treat and prevent conditions associated with poor clinical outcomes.
Despite the better understanding of the pathophysiologic mechanisms of uremic malnutrition and the improvements made in nutritional support, the nutritional condition of CKD and ESRD patients remains a significant cause for concern. Multimodal therapeutic strategies should be considered when the first signs of malnutrition are observed. More importantly, it is necessary to search actively for renal disease because early diagnosis and treatment can improve the prognosis for CKD patients and reduce economic costs connected with treatment.
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Minister of Education, Science and Technology (to C.W. Park; A111055).