Mechanisms and Treatment of Anorexia in End-Stage Renal Disease Patients on Hemodialysis

Mechanisms and Treatment of Anorexia in End-Stage Renal Disease Patients on Hemodialysis Maurizio Bossola, MD, Luigi Tazza, MD, and Giovanna Luciani, MD Anorexia, defined as the loss of the desire to eat, is relatively common in hemodialysis patients, occurring in one third of such cases. The pathogenesis is essentially unknown. It has been proposed that uremic toxins such as middle molecules, inflammation, altered amino acid pattern, leptin, ghrelin, and neuropeptide Y are involved. Anorexia reduces oral energy and protein intakes, thus contributing to the development of malnutrition and cachexia. Unquestionably, it contributes to poor quality of life. The clinical relevance of anorexia as an independent prognostic factor in hemodialysis is debated. The treatment of this debilitating condition is based on a therapeutic strategy that may include daily dialysis sessions and nutritional counseling. Normalization of plasma branched chain amino acids through branched chain amino acid supplementation may decrease anorexia and improve energy and protein intake. The role of megestrol acetate as an appetite stimulant needs to be validated through adequate randomized trials. Subcutaneous ghrelin administration and melanocortin-receptor antagonists appear to be promising therapeutic interventions. Ó 2009 by the National Kidney Foundation, Inc. All rights reserved.

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NOREXIA, DEFINED AS THE loss of the desire to eat, is relatively common in endstage renal disease patients receiving chronic hemodialysis, occurring in about one third of cases.1–5 Anorexia reduces oral energy and protein intakes, thus contributing to the development of malnutrition and cachexia.1–3 In addition, poorer appetite is unequivocally associated with increased hospitalisation rates, poor quality of life and with an increased risk of morbidity and mortality.4 The presence of anorexia and its degree can be evaluated through the first three questions of the Appetite and Diet Assessment Tool (ADAT).5,6 The responses to the first question, During the past week, how would you rate your appetite?, adhered to a 5-point Likert scale: (1) very good, (2) good, (3) fair, (4) poor, and (5) very poor. The second and third questions ask whether there had been a change in appetite in the past week and, if so,

whether had appetite increased, remained the same, or decreased.

Pathogenesis The pathogenesis of anorexia in hemodialysis patients is essentially unknown. It has been proposed that uremic toxins such as middle molecules, inflammation, altered amino acid pattern, hormones (e.g., leptin and ghrelin), and neuropeptides (e.g., neuropeptide [NPY]) are involved.1–3,7

Middle-Size Molecules

Istituto di Clinica Chirurgica, Universita` Cattolica del Sacro Cuore, Roma, Italia. Address requests for reprints to Maurizio Bossola, Istituto di Clinica Chirurgica, Universita` Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy. E-mail: [email protected] Ó 2009 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/09/1901-0002$36.00/0 doi:10.1053/j.jrn.2008.10.003

In 1996, Anderstam and colleagues8 demonstrated that intraperitoneal injection of uremic plasma ultrafiltrate into normal rats inhibits ingestive behavior. The effect was not specific for one type of nutrient but was seen to affect the intakes of carbohydrate, protein, and a mixed nutritional solution to about the same extent. The absence of an effect on ingestive behavior of the nonuremic plasma ultrafiltrate supported the conclusion that the inhibition of the uremic ultrafiltrate is a feature of uremic intoxication. The observation that the ingestion of sucrose and the mixed nutritional solution were reduced after the injection of ultrafiltrate of normal urine suggests that one or more toxic factors that are normally eliminated from the body by urinary excretion accumulate in the body

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fluids of patients. Uremic plasma and urine fractions with the strongest dose-dependent anorexic activity had a molecular weight of 1 to 5 kDa. In a subsequent study, Abdel-Hafiz Mamoun et al.9 demonstrated that an intracerebroventricular injection of 5 or 10 mL of urine middle molecule fraction inhibited carbohydrate intake by 13.4% and 41.6%, respectively, and that an injection of 5 or 10 mL of uremic plasma ultrafiltrate middle molecule fraction inhibited carbohydrate intake by 22.6% and 49.5%, respectively. However, the physiological effect of middle molecules on the brain is unknown, and as yet little is known about their exact molecular weight and availability to the brain.

Inflammation A strong and consistent association between anorexia and high levels of inflammatory markers has been shown by Kalantar-Zadeh et al.4 in a cohort of 331 hemodialysis patients. Serum concentrations of C-reactive protein, interleukin-6, and tumor necrosis factor (TNF)-a increased significantly with diminishing appetite. Aguilera et al.10 found high TNF-a plasma levels in 97.6% of 42 peritoneal dialysis patients and showed that anorectic patients had higher TNFa levels than nonanorectic patients. Nonanorectic patients with other gastrointestinal symptoms also had higher levels of TNf-a than asymptomatic patients.10 Indeed, it is well known that cytokines are able to inhibit appetite both in healthy conditions and in various diseases (cancer, sepsis, cardiac cachexia, chronic obstructive pulmonary disease).11,12 It has been extensively demonstrated that cytokines induce anorexia by acting meal size, meal duration, and meal frequency differentially; that specific cytokines may be transported from the periphery to the brain and cytokines generate mediators that can act on peripheral and/or brain target sites; and that cytokines act directly on hypothalamic neurons proposed to participate in feeding.11,12

Altered Amino Acid Pattern The amino acid profile in end-stage renal disease with or without dialysis exhibits abnormal patterns, such as reduced essential/nonessential amino acids ratio and lower branched chain amino acid (BCAA) levels.13 It is well known that BCAA deficiency is involved in anorexia at the brain level.14 Recently, it has been proposed that the low neutral

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and BCAA plasma and cerebrospinal fluid concentrations permit a high level of tryptophan transport across the blood-brain barrier, causing an increase in the synthesis of serotonin responsible for appetite inhibition.15 However, this hypotheses is still unproved in hemodialysis patients. Recently, we measured the circulating levels of free tryptophan and the trypthophan/large neutral amino acid ratio in 51 hemodialysis patients in our laboratory without observing significant differences between patients with good, fair,or poor appetite.16

Leptin, Grelin, and Neuropeptide Y Under normal conditions, energy intake is controlled by the hypothalamus where peripheral signals convey information on energy and adiposity status.17 In the hypothalamus, the arcuate nucleus contains specific neuronal populations that transduce these inputs into neuronal responses and, via second-order neuronal signaling pathways, into behavioral responses.17 Some signals coming from the periphery (adipose tissue and gastrointestinal tract), such as leptin and ghrelin, are perturbed in hemodialysis patients.1–3 In fact, both plasma levels of leptin and ghrelin are significantly higher in hemodialysis patients than in control subjects.18,19 Leptin, a hormone secreted from adipose tissue as a product of the ob gene expressed predominantly by adipocytes, influences energy homeostasis and immune and neuroendocrine function. Leptin decreases appetite, in part, by inhibiting neurons that produce the NPY and the agoutirelated peptide (AgRP), which are orexigenic peptides, while stimulating neurons in the arcuate-nucleus region of the hypothalamus to produce melanocortins, that are anorexigenic.18 On the basis of the observation that ESRD patients with or without dialysis have inappropriately high serum leptin levels, it has been speculated that hyperleptinemia in ESRD patients may be one of the factors mediating anorexia and wasting.18 Moreover, through an elegant experimental study, Cheung et al.20 have shown that leptin receptor2deficient (db/db) mice, undergoing subtotal nephrectomy and consequently showing elevated circulating leptin levels, resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. However, although some clinical studies have demonstrated that leptin contributes to malnutrition, others have failed to demonstrate any

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relationships between serum leptin and different nutritional markers and intakes.21–25 Moreover, Bossola et al.26 confirmed that hemodialysis patients have higher levels of serum leptin than do healthy subjects and demonstrated that serum leptin levels and the serum leptin/body mass index ratio were not different in anorexic and in nonanorexic hemodialysis patients. It is possible that a state of relative leptin resistance may occur in ESRD patients receiving hemodialysis as in obese patients that does not respond to these increased leptin levels with reduced food intake.27,28 Ghrelin, an orexigenic peptide released primarily from the oxyntic cells of the stomach, regulates feeding and body weight regulation through stimulation of hypothalamic appetite centers and coordination of energy balance.17 A common observation is that plasma ghrelin levels are markedly increased in hemodialysis patients with respect to control subjects.29,30 Chang et al.30 have determined the profile of plasma ghrelin levels over 24 hours in nondiabetic hemodialysis patients showing a unique diurnal change without an obvious plasma ghrelin rise before each meal time or a rapid fall after eating. They also found that the average level of plasma ghrelin in hemodialysis patients was one-fifth higher than that in the healthy control group at most sampling times during the day, except between 10 P.M. and 2 A.M. According to the authors of the study, these observations suggest that there is a resistance to ghrelin action in end-stage renal disease patients, either peripheral or central, or both. The detection of high plasma ghrelin levels in hemodialysis patients is in contrast with the strong tendency of hemodialysis patients to be anorexic. Interestingly, no association was found between plasma ghrelin levels and estimated protein intake (nPNA) in hemodialysis patients.29 Recently, we measured the circulating levels of ghrelin in 51 hemodialysis patients in our laboratory, detecting higher levels in patients with very poor or poor appetite. Overall, it seems that the available data do not allow definitive and clear considerations on the significance of high plasma ghrelin level as well as on its role in the perturbation of feeding behavior that occurs in many hemodialysis patients. A recent study showed that desacyl ghrelin levels were significantly higher in anorexic than in nonanorexic hemodialysis patients, suggesting that desacyl ghrelion may be involved in the pathogenesis of uremic anorexia.31 However, this

study raises the question of how desacyl ghrelin may induce anorexia in hemodialysis patients.32 Indeed, there is strong evidence that desacyl ghrelin, like ghrelin, functions as orexigenic peptides in the hypothalamus.33 NPY is the most potent orexigen factor known.10 Unfortunately, there are no studies in hemodialysis patients that have evaluated the plasma NPY levels and have correlated them with the presence of anorexia and with nutritional parameters. Lower than normal NPY plasma values have been shown in 22% of peritoneal dialysis patients, normal values in 66%, and high values in 12%.10 NPY values were lower in anorexic (43.2 6 27.5 pg/mL) than in nonanorexic patients (64.9 6 25.5; P , .05).10

Current Therapy The treatment of anorexia in hemodialysis patients is based on a therapeutic strategy that may include frequent dialysis sessions, nutritional counseling, and nutritional and pharmacological approaches (Table 1).

Increase in Number of Dialysis Sessions As shown in Table 2, the increase in the number of dialysis sessions through short daily hemodialysis (SDHD) or nocturnal hemodialysis has been shown to improve appetite and food intake as well as nutritional status. Moreover, it seems that daily hemodialysis significantly increases serum albumin and cholesterol levels and dry body weight.31–35 In one study, an improvement of lean body mass has also been demonstrated.33 This is probably due to a general feeling of well-being, increased physical activity, fewer dietetic restrictions, decreased dose of medications such as phosphate, potassium binders, and antihypertensive drugs, body composition, and nutritional status. It has also been suggested that daily hemodialysis increases the clearance of potential anorexic factors.31–39 In the study of Liakopoulos et al.,40 the increase of dialytic dose in 104 peritoneal dialysis patients has been shown to improve uremic symptoms and particularly fatigue and anorexia.

Nutritional Counseling A comprehensive nutritional, diet, and appetite assessment to identify whether nutritional status is

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ANOREXIA IN ESRD PATIENTS ON HEMODIALYSIS Table 1. Actual Therapeutic Interventions for Anorexia of Dialysis Patients: Results of Clinical Studies With Different Types of Dialysis Author (Year)

No. of Patients

O’Sullivan et al., 5 (Hemodialysis) 1998 Galland et al., 10 (Hemodialysis) 2001 Spanner et al., 45 (Hemodialysis) 2003

Type of Intervention/Treatment LNHD

Duration

Effects

8 weeks

Increase number of dialysis sessions SDHD (n 5 11), LNHD (n 5 12), cHD (n 5 22) Switch from cHD to SDHD

Galland et al., 2004

17 (Hemodialysis)

Liakopoulos V et al., 2004

104 (Peritoneal dialysis) Increase daily dialysate volume

Significant increase of dietary intake 23 months Weight gain and lean body mass increase 18 months Increased nPNA, serum albumin levels, and arm muscle area with SDHD 39 months* Increase of daily calorie-protein intake, serum albumin and prealbumin levels, body weight with SDHD Decrease of anorexia prevalence

SDHD, short daily hemodialysis; LNHD, long nocturnal hemodialysis; cHD, conventional thrice-weekly hemodialysis; nPNA, protein equivalent of nitrogen appearance. *Mean.

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 issues that could affect food intake. Two studies have shown that dietary counseling aimed at correcting reduced or unhealthy nutrient intake, performed by a nutritionist, has been shown to be useful in improving serum albumin levels and maintaining a stable weight.41,42

Appetite Stimulants Megestrol acetate (MA) is a synthetic, orally active derivate of the naturally occurring hormone progesterone that may induce appetite via stimulation of NPY in the hypothalamus, modulation of calcium channels in the ventromedial hypothalamus, a well-known satiety center, and inhibition of the activity of proinflammatory cytokine such as interleukin-1, interleukin-6, and TNF-a.1 MA has been found to improve appetite, caloric intake, and nutritional status in cancer patients.43 Four studies that have included a total of 64 hemodialysis patients and with MA doses ranging between 40 to 800 mg/daily have shown an improvement of appetite, weight gain, and an increase of serum albumin.44–47 However, all these studies are single arm, not controlled, and not randomized. On these bases, MA cannot be recommended in the routine clinical practice for the treatment of anorexia of hemodialysis patients. Nevertheless, it cannot be underestimated that

many side effects such as headaches, dizziness, confusion, diarrhea, hyperglycemia, and thromboembolic phenomena may be observed. Large, randomized, controlled trials are warranted to define the exact role of MA in preventing and treating anorexia in hemodialysis patients.

Oral BCAA Supplementation Hiroshige et al.48 randomly assigned 28 malnourished patients with anorexia and low plasma albumin levels to receive BCAA supplementation (12 g/day) or placebo. In patients receiving BCAA supplementation, anorexia and poor oral and protein and caloric intakes improved within a month concomitant with the improvement in plasma BCAA levels over the values in well-nourished patients. After 6 months of BCAA supplementation, anthropometric indices showed a statistically significant enhancement and serum albumin levels increased from 3.3 g/dL to 3.9 g/dL. After exchanging BCAA for placebo, spontaneous oral food intake decreased, although the favorable nutritional status persisted for the next 6 months. These data, although preliminary, suggest that normalization of plasma BCAA levels may decrease anorexia and improve energy and protein intake in hemodialysis patients. However, they need to be validated in larger trials.

Perspectives Ghrelin In experimental cachexia models, administration of ghrelin has shown to ameliorate anorexia,

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Table 2. Actual Therapeutic Interventions for Anorexia of Dialysis Patients: Dietary Counseling, Megestrol Acetate, and Oral Branched Chain Amino Acids Author (Year) Akpele and Bailey, 2004 Bossola et al., 2008 Lien et al., 1996

Burrowes et al., 1999

No. of Patients

Type of Intervention/ Treatment

Dose

Duration

40 (Hemodialysis)

Dietary counseling

—

14 months

64 (Hemodialysis)

Dietary counseling

—

36 months

16 (12 Peritoneal dialysis and 4 Hemodialysis) 1 (Hemodialysis)

Megestrol acetate

40 mg/day

Megestrol acetate

320 mg/day 24 weeks

Boccanfuso et al., 2000

17 (Hemodialysis)

Costero et al., 2004

32 (Peritoneal dialysis)

Rammohan et al., 2005

10 (Hemodialysis)

Hiroshige et al., 2001

28 (Hemodialysis)

Effects Serum albumin increase Serum albumin increase Serum albumin increase

Improvement of reported appetite, increase of energy and protein intakes, fat mass increase, decrease of fatfree mass Megestrol acetate 800 mg/day 6 months Improvement of appetite and weight gain Megestrol acetate 160 mg/day 5.9 months Improvement of appetite and weight gain Megestrol acetate 400 mg/day Increase of weight, body mass index, serum albumin, energy-protein intakes, quality of life Oral 12 g/day 12 months Appetite and dietary supplementation intake of branched chain improvement. amino acids Increase in serum albumin levels and anthropometric indices

induce weight gain, and reduce proinflammatory cytokine expression.8 In humans, intravenous or subcutaneous ghrelin administration has been demonstrated to be safe and well tolerated at dosages up to 10 mg/kg and to increase food intake.49–51 Ghrelin administration seems to be effective in stimulating appetite also in wasting diseases. such as cachectic chronic obstructive pulmonary disease52 and cancer cachexia.53 Subcutaneous ghrelin administration has been shown to enhance short-term food intake in dialysis patients.54 In fact, in the study of Wynne et al.,16 nine peritoneal dialysis patients with mild to moderate malnutrition were administered subcutaneous ghrelin (3.6 nmol/kg) and saline placebo

in a randomized, double-blind, crossover protocol, and the administration of subcutaneous ghrelin significantly increased the group mean absolute energy intake, compared with placebo, during the study meal (690 6 190 versus 440 6 250 kcal; P 5 .0062). When expressed as proportional energy increase for each individual, ghrelin administration resulted in immediate doubling of energy intake (204% 6 120% versus 100%; P 5 .0319). Recently, a ghrelin splice variant and isoxazole carboxamide derivatives as ghrelin receptor modulators were designed, tested, and patented.54 Their efficacy and safety in human beings remain to be evaluated through adequate, randomized, controlled studies.

ANOREXIA IN ESRD PATIENTS ON HEMODIALYSIS

Melanocortin-4 Receptor Antagonists The central melanocortin system, one of the central feeding circuits, has been recognized as an important regulator of energy balance for several years.55,56 It is composed of a network of neurons located in the arcuate nucleus that contains pro-opiomelanocortin (POMC), which is the precursor of a-melanocyte2stimulating hormone (a-MSH); type 3 melanocortin recptors (MC3-R), located on POMC neurons and within other areas of the hypothalamus; and type 4 melanocortin receptors (MC4-R), which are distributed widely throughout the brain and receive input from POMC synapses.55,56 Pharmacologic manipulation has shown that agonizing the MC4-R causes weight loss and antagonizing the MC4-R produces weight gain.57–59 Cheung et al.60 have shown that intraperitoneal administration of NBI-12i, a small molecule MC4-R antagonist with high affinity and selectivity that penetrates the central nervous system after peripheral administration, stimulated food intake and weight gain in uremic mice. Furthermore, NBI12i2treated uremic mice gained lean body mass and fat mass and had a lower basal metabolic rate compared to vehicle-treated and diet-supplemented uremic mice.60 Interestingly, in the past few years, numerous classes of MC4-R small molecule antagonists have been reported and patented such as phenylpiperazines and pyridinylpiperazines, pyrrolidinones, acylguanidine derivatives, benzimidazole derivatives, arginine analogues, and piperazine derivatives.16

Conclusion Anorexia, relatively common in hemodialysis patients, has detrimental effects on the nutritional status, the quality of life, and survival. The therapeutic armamentarium is relatively poor, with most drugs and nutritional tools necessitating further trials to be completely validated. Of promise seems to be the role of ghrelin and melanocortin receptor antagonists. However, further studies are urgently needed to better understand the pathogenic mechanisms of hemodialysis-related anorexia and to define if amelioration of anorexia and improvements in energy intake would result in a long-term benefit in terms of increased quality of life and reduced morbidity and mortality.

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in patients on chronic peritoneal dialysis with declining renal function. Int Urol Nephrol 36:437-443, 2004 41. Akpele L, Bailey JL: Nutrition counselling impacts serum albumin levels. J Ren Nutr 14:143-148, 2004 42. 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 43. Pascual Lo´pez A, Roque´ i Figuls M, Urru´tia Cuchi G, et al: Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom Manage 27: 360-369, 2004 44. Lien YH, Ruffenach SJ: Low dose megestrol increases serum albumin in malnourished dialysis patients. Int J Artif Organs 19:147-150, 1996 45. Boccanfuso JA, Hutton M, McAllister B: The effects of megestrol acetate on nutritional parameters in a dialysis population. J Ren Nutr 10:36-43, 2000 46. Costero O, Bajo MA, del Peso G, et al: Treatment of anorexia and malnutrition in peritoneal dialysis patients with megestrol acetate. Adv Periton Dial 20:209-212, 2004 47. Rammohan M, Kalantar-Zadeh K, Liang A, et al: Megestrol acetate in a moderate dose for the treatment of malnutritioninflammation complex in maintenance dialysis patients. J Ren Nutr 15:345-355, 2005 48. Hiroshige K, Sonta T, Suda T, et al: Oral supplementation of branched chain amino acid improves nutritional status in elderly patients on chronic hemodialysis. Nephrol Dial Transplant 16: 1856-1862, 2001 49. Wren AM, Seal LJ, Cohen MA, et al: Ghrelin enhances appetite and increases food intake in humans. J Endocrinol Metab 86:5992-5995, 2001 50. Schmid DA, Held K, Ising M, et al: Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls. Neuropsychopharmacology 30:1187-1192, 2005 51. Druce MR, Neary NM, Small CJ, et al: Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int J Obes 30:293-296, 2006 52. Nagaya N, Itoh T, Murakami S, et al: Treatment of cachexia with ghrelin in patients with COPD. Chest 128: 1187-1193, 2005 53. Neary NM, Small CJ, Wren AM, et al: Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrin Metab 89:2832-2836, 2004 54. 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 55. Marks DL, Ling N, Cone RD: Role of the central melanocortin system in cachexia. Cancer Res 61:1432-1438, 2001 56. Adan RA, Tiesjema B, Hillebrand JJ, et al: The MC4 receptor and control of appetite. Br J Pharmacol 149:815-827, 2006 57. Sutton GM, Josephine Babin M, et al: A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally. Peptides 29: 104-111, 2008 58. Joppa MA, Ling N, Chen C, et al: Central administration of peptide and small molecule MC4 receptor antagonists induce hyperphagia in mice and attenuate cytokine-induced anorexia. Peptides 26:2294-2301, 2005

ANOREXIA IN ESRD PATIENTS ON HEMODIALYSIS 59. Markison S, Foster AC, Chen C, et al: The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology 146:2766-2773, 2005

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60. Cheung WW, Kuo HJ, Markison S, et al: Peripheral administration of the melanocortin-4 receptor antagonist NBI12i ameliorates uremia-associated cachexia in mice. J Am Soc Nephrol 18:2517-2524, 2007