- Email: [email protected]
Interventions to Counteract Anorexia in Dialysis Patients
REVIEW
Interventions to Counteract Anorexia in Dialysis Patients Maurizio Bossola, MD, Stefania Giungi, MD, Giovanna Luciani, MD, and Luigi Tazza, MD The treatment of anorexia in chronic hemodialysis patients is based on a therapeutic strategy which includes optimal dialysis dose (through daily or nocturnal dialysis), support of food intake (through nutritional counseling and oral nutritional supplements), counteractive action to anorexic agents (e.g., inflammatory cytokines and low levels of branched chain amino acids), stimulation of appetite (ghrelin), and attention to associated symptoms (e.g., symptoms of depression and anxiety, fatigue, other comorbidities). However, the fact remains that the studies so far conducted are insufficient both in terms of number and quality to provide guidelines for clinical and research purposes. Randomized, controlled trials are needed in the future to define the best strategy to counteract anorexia in maintenance dialysis patients. Ó 2011 by the National Kidney Foundation, Inc. All rights reserved.
A
NOREXIA, PRESENT IN about one-third of dialysis patients, reduces oral energy and protein intake thereby contributing to the development of malnutrition and cachexia, is associated with increased mortality risk and the hospitalization rates, and contributes to poor quality of life.1 The pathogenesis of anorexia in dialysis patients is essentially unknown. It has been proposed that uremic toxins including middle molecules, inflammation, altered amino acid patterns, hormones (e.g., leptin and ghrelin), and neuropeptides (e.g., neuropeptide Y) are involved.1 In addition, the clinical condition of the dialysis patients plays a significant role in the development of uremic anorexia, in particular, through the associated symptoms (fatigue, gastrointestinal symptoms, symptoms of depression, and anxiety) and by the comorbid conditions. The treatment of anorexia in dialysis patients continues to be a challenge for the nephrologists. In the absence of appropriate guidelines, the
Hemodialysis Service, Department of Surgery, Catholic University, Rome, Italy. Address reprint requests to Maurizio Bossola, MD, Istituto di Clinica Chirurgica, Universita Cattolica del Sacro Cuore, Largo A.Gemelli, 8 , 00168 Roma, Italia. E-mail: [email protected] Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.10.003
16
treatment of anorexia in dialysis patients might include the following measures: 1. Increase in number of dialysis sessions 2. Supporting food intake 3. Counteracting possible anorexic agents 4. Appetite stimulants 5. Attention to associated symptoms
Increase in Number of Dialysis Sessions The increase in the number of dialysis sessions through short daily hemodialysis or nocturnal hemodialysis (HD) has been shown to improve appetite and food intake.2–5 This is probably because of a general feeling of well-being, increased physical activity, fewer dietetic restrictions, decreased dose of medications such as phosphate and potassium binders, and anti-hypertensive drugs. In peritoneal dialysis, it has been shown that the increase in the daily dialysate volume leads to a significant reduction in the frequency of anorexia.6
Supporting Food Intake It might be necessary to support food intake and increase the daily calorie and protein intakes for an anorexic patient. This aim might be achieved by undertaking the measures described in the following paragraphs: Journal of Renal Nutrition, Vol 21, No 1 (January), 2011: pp 16–19
ANOREXIA IN DIALYSIS PATIENTS
Nutritional Counseling A comprehensive nutritional, dietary, and appetite assessment to identify whether nutritional stores are too low is mandatory, as well as definition of problems related to self-feeding, access to food, gastrointestinal distress, and eventually, identification of active psychic, social, medical, dialytic, or medicinal related issues that could affect food intake.7,8 Dietary counseling to correct reduced or unhealthy nutrient intake, performed by a nutritionist, has been reported to be useful. Akpele and Bailey7 have recently shown in stable HD patients with inadequate dietary intake that the rate of change in serum albumin level was significantly greater among patients randomized to receive intensive nutritional counseling than among those who received oral supplements. On average, the serum albumin level increased 0.06 g/dL per month for patients randomized to the dietary counseling and decreased 0.04 g/dL per month for those randomized to the dietary supplement group. Similarly, Bossola et al. have shown through a 36-month prospective, pilot study that when HD patients optimized their whole-food consumption through routine intensive dietary counseling, serum albumin level body weight, and total cholesterol improved over time.8 Oral Nutritional Supplements Oral nutritional supplements (ONS) specific for HD patients have been designed to provide adequate energy, protein, vitamins, and minerals, and limited amounts of potassium, phosphate, and fluids. They are available as energy or protein sources or combination of both. Supplements are in the form of solid food, powders, or liquid formulations. Numerous cross-over or nonrandomized controlled or randomized controlled studies have been conducted in the last 2 decades. Overall, it seems that ONS might improve serum albumin levels and/or other nutritional parameters in HD patients, whereas there are insufficient data to assess their effect on clinical outcome. In addition, poor compliance might be a key limiting factor for ONS efficacy.9 Intradialytic Parenteral Nutrition Intradialytic parenteral nutrition (IDPN) has the advantage of providing calories and proteins during HD treatment without the need for
17
establishing a central venous line. The nutrients are infused into the blood returning from the dialyser to the patient. In most studies, IDPN is associated with improvement of protein and energy homeostasis, increase of body weight, and/or improvement of nutritional parameters.9 In terms of survival, 3 retrospective trials have shown that it is improved by IDPN, whereas a large randomized study has shown that IDPN associated with ONS (93 patients) compared with ONS alone (93 patients) did not improve 2-year mortality, hospitalization rate, Karnofsky score, body mass index (BMI), or laboratory nutritional parameters.9
Counteracting Possible Anorexic Agents Anorexia has been associated with higher serum levels of cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-61 and lower plasma concentrations of branched chain amino acids (BCAAs).10 Thus, a possible treatment of anorexia in dialysis patients is to counteract these anorexic agents. Till date, no evidence of studies that have evaluated the efficacy of anti-cytokine and/or anti-inflammatory agents in the treatment of anorexia of dialysis patients has been reported. The studies that have investigated the safety and efficacy of anti-cytokine therapies, such as antiTNF-a agents, in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis or pentoxifylline and thalidomide as inhibitors of TNF-a production, and/or secretion in cancer-related anorexia, and cachexia might provide an explanation. However, 2 recent trials with oral amino acids supplements have led to interesting results. Eustace et al.11 have shown that oral amino acid supplements in hypoalbuminemic HD patients resulted in a significant improvement of serum albumin levels, grip strength, and short form health survey (SF-12) mental health score but not in serum amino acid levels, SF-12 physical health score, or anthropometric measures. Hiroshige et al.12 randomized 28 malnourished patients to receive daily BCAA supplementation (12 g/day) or placebo. After 6 months, anthropometric indices and serum albumin levels showed a statistically significant increase in the BCAA group. After exchanging BCAA for placebo, spontaneous oral food intake decreased, although the favorable nutritional status persisted for the next 6 months, suggesting that the
18
BOSSOLA ET AL
normalization of plasma BCAA levels can reduce anorexia and improve energy and protein intakes in HD patients.
Appetite Stimulants Megestrol acetate has been found to improve appetite, caloric intake, and nutritional status in cancer patients. Of the few studies which have been conducted in dialysis patients, none have been randomized or controlled.1 Till date, it seems that the use of megestrol acetate in the clinical practice cannot be recommended. Large, randomized, and controlled trials are warranted to define the exact role of megestrol acetate in preventing and treating anorexia in HD patients. There is evidence that ghrelin administration significantly enhances food intake, both in patients receiving peritoneal dialysis and HD.13,14 In the study performed by Wynne et al., ghrelin was administered subcutaneously in 9 peritoneal dialysis patients with mild to moderate malnutrition (3.6 nmol/kg) and saline placebo in a randomized, double-blind, crossover protocol13 Ghrelin administration significantly increased the mean absolute energy intake of the group and resulted in immediate doubling of energy intake. More recently, Ashby et al. have reported that ghrelin administration increased ghrelin levels in circulation and immediately increased the appetite significantly, with an increase in energy intake noted at the first study meal.14 Interestingly, persistence of this effect throughout the week was confirmed with food diaries and final study meals. It seems that manipulation of appetite with ghrelin or its analogues represents an attractive and promising therapeutic strategy in anorexia of dialysis patients.
Attention to Associated Symptoms When compared with other chronic diseases such as cancer, sepsis, chronic obstructive pulmonary disease, and heart failure, anorexia does not appear to be an isolated symptom but part of a symptom complex that includes pain, gastrointestinal symptoms, and also symptoms of depression, anxiety, and fatigue.15 In addition, it has been well described that anorexic dialysis patients have higher frequency of comorbidities with respect to nonanorexic ones (47) It is possible that the reduction of the symptom burden frequently associated with anorexia might significantly
Table 1. Level of Evidence on the Basis of the Type Study Design Type of Indication Adequate and/or more dialysis dose Support food intake Nutritional counselling Oral nutritional supplements Intradialytic parenteral nutrition Counteraction of anorexic agents Anti-cytokine drugs Anti-inflammatory drugs Administration branched chain amino acids Appetite stimulants Megestrol acetate Ghrelin Attention to associated symptoms Reduction of pain Reduction of fatigue Reduction of symptom of depression and/or anxiety
Evidence B
B B None None None A
None B
To be assessed To be assessed To be assessed
Adapted from Oxford Centre for Evidence-based medicine.
improve appetite. To this regard, it seems that adequate, randomized, controlled studies are necessary.
Conclusion The adequate and/or increased dialysis dosage through daily or nocturnal dialysis, the support of food intake through nutritional counseling and ONS, the counteractive action to anorexic agents such as the administration of branched chain amino acids, and the stimulation of appetite by the administration of ghrelin have been proven to improve anorexia in dialysis patients (evidence A or B) (Table 1). However, it seems that further randomized controlled studies are needed to better define the role of these therapeutic strategies in the treatment of anorexia of dialysis patients, and their effects on more established nutritional markers and on hard clinical outcomes. Eventually, these studies will provide the basis for appropriate nutritional guidelines in dialysis patients.
References 1. Bossola M, Tazza L, Giungi S, et al: Anorexia in hemodialysis patients: an update. Kidney Int 70:417-422, 2006 2. O’Sullivan DA, MsCharty JT, Kumar R, et al: Improved biochemical variables, nutrient intake, and hormonal factors in slow nocturnal hemodialysis: a pilot study. Mayo Clin Proc 73: 1035-1045, 1998
ANOREXIA IN DIALYSIS PATIENTS 3. Galland R, Traeger J, Arkouche W, et al: Short daily hemodialysis and nutritional status. Am J Kidney Dis 37(1 Suppl 2): S95-S98, 2001 4. Spanner E, Suri R, Heidenheim AP, et al: The impact of quotidian hemodialysis on nutrition. Am J Kidney Dis 42(Suppl 1):S30-S35, 2003 5. Galland R, Traeger J, Arkouche W, et al: Short daily hemodialysis rapidly improves nutritional status in hemodialysis patients. Kidney Int 60:1555-1560, 2001 6. Liakopoulos V, Krishnan M, Stefanidis I, et al: Improvement in uremic symptoms after increasing daily dialysate volume in patients on chronic peritoneal dialysis with declining renal function. Int Urol Nephrol 36:437-443, 2004 7. Akpele L, Bailey JL: Nutrition counselling impacts serum albumin levels. J Ren Nutr 14:143-148, 2004 8. Bossola M, La Torre G, Giungi S, et al: Serum albumin, body weight and inflammatory parameters in chronic hemodialysis patients: a three-year longitudinal study. Am J Nephrol 28:405-412, 2008 9. Bossola M, Tazza L, Giungi S, et al: Artificial nutritional support in chronic hemodialysis patients: a narrative review. J Ren Nutr 20:213-223, 2010
19
10. Bossola M, Scribano D, Colacicco L, et al: Anorexia and plasma levels of free tryptophan, branched chain amino acids, and ghrelin in hemodialysis patients. J Ren Nutr 19:248-255, 2009 11. Eustace JA, Coresh J, Kutchey C, et al: Randomized double-blind trial of oral essential amino acids for dialysisassociated hypoalbuminemia. Kidney Int 57:2527-2538, 2000 12. Hiroshige K, Sonta T, Suda T, et al: Oral supplementation of branched chain amino acid improves nutritional status in elderly patients on chronic HD. Nephrol Dial Transplant 16:1856-1862, 2001 13. Wynne K, Giannitsopoulou K, Small CJ, et al: Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 16:2111-2118, 2005 14. Ashby DR, Ford HE, Wynne KJ, et al: Sustained appetite improvement in malnourished dialysis patients by daily ghrelin. Kidney Int 76:199-206, 2009 15. Davison SN, Jhangri GS: Impact of pain and symptom burden on the health-related quality of life of hemodialysis patients. J Pain Symptom Manage 39:477-485, 2010
Interventions to Counteract Anorexia in Dialysis Patients Maurizio Bossola, MD, Stefania Giungi, MD, Giovanna Luciani, MD, and Luigi Tazza, MD The treatment of anorexia in chronic hemodialysis patients is based on a therapeutic strategy which includes optimal dialysis dose (through daily or nocturnal dialysis), support of food intake (through nutritional counseling and oral nutritional supplements), counteractive action to anorexic agents (e.g., inflammatory cytokines and low levels of branched chain amino acids), stimulation of appetite (ghrelin), and attention to associated symptoms (e.g., symptoms of depression and anxiety, fatigue, other comorbidities). However, the fact remains that the studies so far conducted are insufficient both in terms of number and quality to provide guidelines for clinical and research purposes. Randomized, controlled trials are needed in the future to define the best strategy to counteract anorexia in maintenance dialysis patients. Ó 2011 by the National Kidney Foundation, Inc. All rights reserved.
A
NOREXIA, PRESENT IN about one-third of dialysis patients, reduces oral energy and protein intake thereby contributing to the development of malnutrition and cachexia, is associated with increased mortality risk and the hospitalization rates, and contributes to poor quality of life.1 The pathogenesis of anorexia in dialysis patients is essentially unknown. It has been proposed that uremic toxins including middle molecules, inflammation, altered amino acid patterns, hormones (e.g., leptin and ghrelin), and neuropeptides (e.g., neuropeptide Y) are involved.1 In addition, the clinical condition of the dialysis patients plays a significant role in the development of uremic anorexia, in particular, through the associated symptoms (fatigue, gastrointestinal symptoms, symptoms of depression, and anxiety) and by the comorbid conditions. The treatment of anorexia in dialysis patients continues to be a challenge for the nephrologists. In the absence of appropriate guidelines, the
Hemodialysis Service, Department of Surgery, Catholic University, Rome, Italy. Address reprint requests to Maurizio Bossola, MD, Istituto di Clinica Chirurgica, Universita Cattolica del Sacro Cuore, Largo A.Gemelli, 8 , 00168 Roma, Italia. E-mail: [email protected] Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.10.003
16
treatment of anorexia in dialysis patients might include the following measures: 1. Increase in number of dialysis sessions 2. Supporting food intake 3. Counteracting possible anorexic agents 4. Appetite stimulants 5. Attention to associated symptoms
Increase in Number of Dialysis Sessions The increase in the number of dialysis sessions through short daily hemodialysis or nocturnal hemodialysis (HD) has been shown to improve appetite and food intake.2–5 This is probably because of a general feeling of well-being, increased physical activity, fewer dietetic restrictions, decreased dose of medications such as phosphate and potassium binders, and anti-hypertensive drugs. In peritoneal dialysis, it has been shown that the increase in the daily dialysate volume leads to a significant reduction in the frequency of anorexia.6
Supporting Food Intake It might be necessary to support food intake and increase the daily calorie and protein intakes for an anorexic patient. This aim might be achieved by undertaking the measures described in the following paragraphs: Journal of Renal Nutrition, Vol 21, No 1 (January), 2011: pp 16–19
ANOREXIA IN DIALYSIS PATIENTS
Nutritional Counseling A comprehensive nutritional, dietary, and appetite assessment to identify whether nutritional stores are too low is mandatory, as well as definition of problems related to self-feeding, access to food, gastrointestinal distress, and eventually, identification of active psychic, social, medical, dialytic, or medicinal related issues that could affect food intake.7,8 Dietary counseling to correct reduced or unhealthy nutrient intake, performed by a nutritionist, has been reported to be useful. Akpele and Bailey7 have recently shown in stable HD patients with inadequate dietary intake that the rate of change in serum albumin level was significantly greater among patients randomized to receive intensive nutritional counseling than among those who received oral supplements. On average, the serum albumin level increased 0.06 g/dL per month for patients randomized to the dietary counseling and decreased 0.04 g/dL per month for those randomized to the dietary supplement group. Similarly, Bossola et al. have shown through a 36-month prospective, pilot study that when HD patients optimized their whole-food consumption through routine intensive dietary counseling, serum albumin level body weight, and total cholesterol improved over time.8 Oral Nutritional Supplements Oral nutritional supplements (ONS) specific for HD patients have been designed to provide adequate energy, protein, vitamins, and minerals, and limited amounts of potassium, phosphate, and fluids. They are available as energy or protein sources or combination of both. Supplements are in the form of solid food, powders, or liquid formulations. Numerous cross-over or nonrandomized controlled or randomized controlled studies have been conducted in the last 2 decades. Overall, it seems that ONS might improve serum albumin levels and/or other nutritional parameters in HD patients, whereas there are insufficient data to assess their effect on clinical outcome. In addition, poor compliance might be a key limiting factor for ONS efficacy.9 Intradialytic Parenteral Nutrition Intradialytic parenteral nutrition (IDPN) has the advantage of providing calories and proteins during HD treatment without the need for
17
establishing a central venous line. The nutrients are infused into the blood returning from the dialyser to the patient. In most studies, IDPN is associated with improvement of protein and energy homeostasis, increase of body weight, and/or improvement of nutritional parameters.9 In terms of survival, 3 retrospective trials have shown that it is improved by IDPN, whereas a large randomized study has shown that IDPN associated with ONS (93 patients) compared with ONS alone (93 patients) did not improve 2-year mortality, hospitalization rate, Karnofsky score, body mass index (BMI), or laboratory nutritional parameters.9
Counteracting Possible Anorexic Agents Anorexia has been associated with higher serum levels of cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-61 and lower plasma concentrations of branched chain amino acids (BCAAs).10 Thus, a possible treatment of anorexia in dialysis patients is to counteract these anorexic agents. Till date, no evidence of studies that have evaluated the efficacy of anti-cytokine and/or anti-inflammatory agents in the treatment of anorexia of dialysis patients has been reported. The studies that have investigated the safety and efficacy of anti-cytokine therapies, such as antiTNF-a agents, in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis or pentoxifylline and thalidomide as inhibitors of TNF-a production, and/or secretion in cancer-related anorexia, and cachexia might provide an explanation. However, 2 recent trials with oral amino acids supplements have led to interesting results. Eustace et al.11 have shown that oral amino acid supplements in hypoalbuminemic HD patients resulted in a significant improvement of serum albumin levels, grip strength, and short form health survey (SF-12) mental health score but not in serum amino acid levels, SF-12 physical health score, or anthropometric measures. Hiroshige et al.12 randomized 28 malnourished patients to receive daily BCAA supplementation (12 g/day) or placebo. After 6 months, anthropometric indices and serum albumin levels showed a statistically significant increase in the BCAA group. After exchanging BCAA for placebo, spontaneous oral food intake decreased, although the favorable nutritional status persisted for the next 6 months, suggesting that the
18
BOSSOLA ET AL
normalization of plasma BCAA levels can reduce anorexia and improve energy and protein intakes in HD patients.
Appetite Stimulants Megestrol acetate has been found to improve appetite, caloric intake, and nutritional status in cancer patients. Of the few studies which have been conducted in dialysis patients, none have been randomized or controlled.1 Till date, it seems that the use of megestrol acetate in the clinical practice cannot be recommended. Large, randomized, and controlled trials are warranted to define the exact role of megestrol acetate in preventing and treating anorexia in HD patients. There is evidence that ghrelin administration significantly enhances food intake, both in patients receiving peritoneal dialysis and HD.13,14 In the study performed by Wynne et al., ghrelin was administered subcutaneously in 9 peritoneal dialysis patients with mild to moderate malnutrition (3.6 nmol/kg) and saline placebo in a randomized, double-blind, crossover protocol13 Ghrelin administration significantly increased the mean absolute energy intake of the group and resulted in immediate doubling of energy intake. More recently, Ashby et al. have reported that ghrelin administration increased ghrelin levels in circulation and immediately increased the appetite significantly, with an increase in energy intake noted at the first study meal.14 Interestingly, persistence of this effect throughout the week was confirmed with food diaries and final study meals. It seems that manipulation of appetite with ghrelin or its analogues represents an attractive and promising therapeutic strategy in anorexia of dialysis patients.
Attention to Associated Symptoms When compared with other chronic diseases such as cancer, sepsis, chronic obstructive pulmonary disease, and heart failure, anorexia does not appear to be an isolated symptom but part of a symptom complex that includes pain, gastrointestinal symptoms, and also symptoms of depression, anxiety, and fatigue.15 In addition, it has been well described that anorexic dialysis patients have higher frequency of comorbidities with respect to nonanorexic ones (47) It is possible that the reduction of the symptom burden frequently associated with anorexia might significantly
Table 1. Level of Evidence on the Basis of the Type Study Design Type of Indication Adequate and/or more dialysis dose Support food intake Nutritional counselling Oral nutritional supplements Intradialytic parenteral nutrition Counteraction of anorexic agents Anti-cytokine drugs Anti-inflammatory drugs Administration branched chain amino acids Appetite stimulants Megestrol acetate Ghrelin Attention to associated symptoms Reduction of pain Reduction of fatigue Reduction of symptom of depression and/or anxiety
Evidence B
B B None None None A
None B
To be assessed To be assessed To be assessed
Adapted from Oxford Centre for Evidence-based medicine.
improve appetite. To this regard, it seems that adequate, randomized, controlled studies are necessary.
Conclusion The adequate and/or increased dialysis dosage through daily or nocturnal dialysis, the support of food intake through nutritional counseling and ONS, the counteractive action to anorexic agents such as the administration of branched chain amino acids, and the stimulation of appetite by the administration of ghrelin have been proven to improve anorexia in dialysis patients (evidence A or B) (Table 1). However, it seems that further randomized controlled studies are needed to better define the role of these therapeutic strategies in the treatment of anorexia of dialysis patients, and their effects on more established nutritional markers and on hard clinical outcomes. Eventually, these studies will provide the basis for appropriate nutritional guidelines in dialysis patients.
References 1. Bossola M, Tazza L, Giungi S, et al: Anorexia in hemodialysis patients: an update. Kidney Int 70:417-422, 2006 2. O’Sullivan DA, MsCharty JT, Kumar R, et al: Improved biochemical variables, nutrient intake, and hormonal factors in slow nocturnal hemodialysis: a pilot study. Mayo Clin Proc 73: 1035-1045, 1998
ANOREXIA IN DIALYSIS PATIENTS 3. Galland R, Traeger J, Arkouche W, et al: Short daily hemodialysis and nutritional status. Am J Kidney Dis 37(1 Suppl 2): S95-S98, 2001 4. Spanner E, Suri R, Heidenheim AP, et al: The impact of quotidian hemodialysis on nutrition. Am J Kidney Dis 42(Suppl 1):S30-S35, 2003 5. Galland R, Traeger J, Arkouche W, et al: Short daily hemodialysis rapidly improves nutritional status in hemodialysis patients. Kidney Int 60:1555-1560, 2001 6. Liakopoulos V, Krishnan M, Stefanidis I, et al: Improvement in uremic symptoms after increasing daily dialysate volume in patients on chronic peritoneal dialysis with declining renal function. Int Urol Nephrol 36:437-443, 2004 7. Akpele L, Bailey JL: Nutrition counselling impacts serum albumin levels. J Ren Nutr 14:143-148, 2004 8. Bossola M, La Torre G, Giungi S, et al: Serum albumin, body weight and inflammatory parameters in chronic hemodialysis patients: a three-year longitudinal study. Am J Nephrol 28:405-412, 2008 9. Bossola M, Tazza L, Giungi S, et al: Artificial nutritional support in chronic hemodialysis patients: a narrative review. J Ren Nutr 20:213-223, 2010
19
10. Bossola M, Scribano D, Colacicco L, et al: Anorexia and plasma levels of free tryptophan, branched chain amino acids, and ghrelin in hemodialysis patients. J Ren Nutr 19:248-255, 2009 11. Eustace JA, Coresh J, Kutchey C, et al: Randomized double-blind trial of oral essential amino acids for dialysisassociated hypoalbuminemia. Kidney Int 57:2527-2538, 2000 12. Hiroshige K, Sonta T, Suda T, et al: Oral supplementation of branched chain amino acid improves nutritional status in elderly patients on chronic HD. Nephrol Dial Transplant 16:1856-1862, 2001 13. Wynne K, Giannitsopoulou K, Small CJ, et al: Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 16:2111-2118, 2005 14. Ashby DR, Ford HE, Wynne KJ, et al: Sustained appetite improvement in malnourished dialysis patients by daily ghrelin. Kidney Int 76:199-206, 2009 15. Davison SN, Jhangri GS: Impact of pain and symptom burden on the health-related quality of life of hemodialysis patients. J Pain Symptom Manage 39:477-485, 2010