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Nutrición Hospitalaria

versión On-line ISSN 1699-5198versión impresa ISSN 0212-1611

Nutr. Hosp. vol.29 no.4 Madrid abr. 2014 



A clinical approach to the nutritional care process in protein-energy wasting hemodialysis patients1-3

Enfoque clínico de atención nutricional en pacientes con desgaste protéico-energético en hemodiálisis



Mar Ruperto1, Francisco J. Sánchez-Muniz1 y Guillermina Barril2

1From Departamento de Nutrición y Bromatología I (Nutrición). Facultad de Farmacia. Universidad Complutense de Madrid.
2Servicio de Nefrología. Hospital Universitario La Princesa. Madrid. Spain.





Introduction: Malnutrition/wasting/cachexia are complex-disease conditions that frequently remain undiagnosed and/or untreated in up to 75% of prevalent hemodialysis (HD) patients. The nutrition care process (NCP) based on assessment, diagnosis, intervention and monitoring of nutritional status is a systematic method that nutrition professionals use to make decisions in clinical practice.
Objective: This review examines from a clinical-nutritional practice point of view: a) nutritional status as a mortality causative factor; b) phenotypic characteristics of malnutri-tion/wasting/cachexia, and c) current trends of NCP with special emphasis on nutritional support and novel nutrient and pharmacologic adjunctive therapies in HD patients.
Method: A literature review was conducted using the Pubmed, Science Direct, Scielo, Scopus, and Medline electronic scientific basis. Studies which assessing nutritional status and nutritional support published from 1990 to 2013 in HD patients were included and discussed.
Results: From all the epidemiological data analyzed, NCP was the suggested method for identifying malnut rition/ wasting or cachexia in clinical practice. Nutrition support as an unimodal therapy was not completely able to reverse wasting in HD patients. Novel experimental therapeutic strategies including the use of appetite stimulants, ghrelin agonist, MC4-R antagonists, anabolic steroids, anti-inflammatory drugs, cholecalciferol, and other components are still under clinical evaluation.
Conclusion: Nutritional status is a strong predictor of morbidity and mortality in HD patients. The terms called malnutrition, wasting and cachexia have different nutritional therapeutics implications. The NCP is a necessary tool for assessing and monitoring nutritional status in the current clinical practice. Novel pharmacological therapies or specific nutrient supplementation interventions studies are required.

Key words: Nutritional care process. Malnutrition. Protein-energy wating. Cachexia. Nutritional support. Hemodialysis.


Introducción: Malnutrición/desgaste proteico-energético (DPE)/caquexia son situaciones patológicas complejas frecuentemente infradiagnosticadas o no tratadas hasta en un 75% de los pacientes prevalentes en hemodiálisis (HD). El proceso de atención nutricional (PAN) basado en la evaluación, diagnóstico, intervención y monitorización del estado nutricional es un método que los profesionales de la nutrición utilizan para tomar decisiones en la práctica clínica.
Objetivo: Esta revisión examina desde la perspectiva de la práctica clínica nutricional: a) el estado nutricional como factor causante de morbi-mortalidad; b) las características fenotípicas de malnutrición, DPE y caquexia y, c) el PAN con especial énfasis en el soporte nutricional y las nuevas terapias nutricionales y farmacológicas en pacientes en HD.
Métodos: Revisión sistemática de la literatura usando las bases científicas electrónicas Pubmed, Science Direct, Scielo, Scopus y Medline. Se incluyeron estudios publicados desde 1990 hasta 2013 que valoraban el estado nutricional y/o el soporte nutricional en pacientes en HD.
Resultados: De todos los datos epidemiológicos analizados, el PAN fue el método sugerido para identificar malnutrición/DPE/caquexia. El soporte nutricional como tratamiento aislado no era capaz de revertir totalmente la malnutrición o el DPE. Nuevas estrategias terapéuticas experimentales incluyendo el uso de estimulantes del apetito, agonistas de grelina, antagonistas MC4-R, esteroides anabólicos, antiinflamatorios y colecalciferol entre otros componentes, están siendo aún evaluados clínicamente.
Conclusiones: El estado nutricional es un predictor de morbilidad y mortalidad en pacientes en HD. Malnutrición, DPE y caquexia son términos con implicaciones terapéuticas diferentes. El PAN es una herramienta necesaria para la evaluación y la monitorización nutricional en la práctica clínica habitual. Estudios con nuevas terapias farmacológicas o intervenciones con suplementación de nutrientes específicos son requeridos.

Palabras clave: Proceso de atención nutricional. Malnutrición. Desgaste protéico-energético. Caquexia. Soporte nutricional. Hemodiálisis.

Non-standards abbreviations
ACE: Angiotensin-converting-enzyme.
BIA: Bioelectrical impedance analysis.
BMI: Body mass index.
CKD: Chronic kidney disease.
CRP: C-reactive protein.
CVD: Cardiovascular disease.
DEI: Dietary energy intake.
DOPPS: Dialysis Outcomes and Practice Patterns Study.
DPE: Desgaste proteico-energético.
DPI: Dietary protein intake.
DXA: Dual-energy x-ray absorptiometry.
EN: Enteral nutrition.
GH: Growth hormone.
IDPN: Intradialytic parenteral nutrition.
IGF-1: Insulin growth factor-1.
KDoqi: Kidney Disease Outcomes Quality Initiative. HD: Hemodialysis.
HDF: Online hemodiafiltration.
HMB: Hydroxyl-methyl-butyrate.
IL-6: Interleukin 6.
ISRM: International Society of Renal nutrition and Metabolism.
Kt/V urea (sp):Single pool urea kinetic model.
MC4-R: Melanocortin-4 receptor antagonists.
MIS: Malnutrition-inflammation score.
NCP: Nutritional care process.
ONS: Oral nutritional supplements.
PA: Phase angle.
PAN: Proceso de atención nutricional.
PEG: Percutaneous endoscopic gastrostomy.
PEJ: Percutaneous endoscopic jejunostomy.
PEW: Protein-energy wasting.
PPAR-γ: Peroxisome proliferator-activated receptor-gamma.
s-albumin: Serum albumin.
SGA: Subjective global assessment. s-prealbumin: Serum prealbumin.
TNF-alpha;: Tumor necrosis factor alpha.
TPN: Total parenteral nutrition.
USRD: United States Renal Data System.



Malnutrition, protein-energy wasting (PEW) and cachexia are prevalent complex conditions that frequently remain undiagnosed and untreated up to three quarters of hemodialysis (HD) patients1-3. Although an improper diet may contribute to malnutrition by itself, others factors including, increase of resting energy expenditure, systemic inflammation, endocrine disorders and metabolic acidosis, might be able to initiate wasting/cachexia syndrome in chronic kidney disease (CKD).

Annual death rates in dialysis patients with wasting/ cachexia are close to 20%4. The Dialysis Outcomes and Practice Patterns Study (DOPPS)5 showed that a reduction of more than 5% in serum albumin (s-albumin) six months after initiation of dialysis was associated with a relative risk of death of 1.96. The NECOSAD study6 reported that wasting, inflammation and cardiovascular disease (CVD) remain as independent risk factors per se, whereas cumulatively they were also death risk factors. A recent spanish study7, showed over 40% of wasting at 24 moths of follow-up in a sample of HD patients. A common pathophysiological link between CVD, inflammation, and wasting was reported68. The wasting/cachexia syndrome was clearly associated as an independent predictor of morbidity and mortality in incident HD patients during the subsequent two years on dialysis9.

Recently, a recent panel of experts suggested that utilizable criteria for clinical diagnosis and treatment of wasting so called, protein-energy wasting (PEW)10,11, and establishes the following question, which nutritional indicators predict clinical outcomes most specifically?"

Current clinical guidelines recommend routine assessment of nutritional status at the early stages of CKD12 and in dialysis patients10,13. However, although a number of nutritional procedures are available, no single indicator can be considered as the ideal and reliable marker of malnutrition or PEW. As nutritional status appears to be a significant mortality prognostic factor, the nutrition care process (NCP)14 method based on assessment, diagnosis, intervention and monitoring might improve clinical outcomes in HD patients.

This review examines current clinical practice in HD patients based on the NCP as follows: a) nutritional status as a cause of morbidity and mortality; b) analysis of phenotypic characteristics of different terms: malnutrition, PEW and cachexia; and c) the current trends in nutritional intervention and monitoring with special emphasis on nutritional support and novel adjunctive strategies.


Causative factors of morbidity and mortality in hemodialysis patients

Most of the identified traditional risk factors of morbidity and mortality in the general population are greatly different in HD patients. Epidemiological data from the United States Renal Data System (USRDS)4 showed that the relative risk of mortality increases in patients with BMI <18.5 kg/m2. The DOPPS cohort study5 reported that each 5 kg/m2 decrease in BMI was associated with 20% higher death risk. Conversely, a higher BMI (>25 kg/m2), due to a phenomenon known as "obesity paradox", was considered as a survival factor in the CKD population in some studies15-17. Fleischmann et al.17 reported that overweight/obese HD patients showed lower rates of hospitalization and higher survival rates than their underweight counter-parts17. In the study of Beddhu et al.18 the protective effect of high BMI was limited to those patients with normal or high muscle mass. In addition, abdominal fat mass has been associated with inflammation, insulin resistance, hyperadipokynaemia, dyslipidaemia and oxidative stress in CKD patients19-22. Postorino et al.23 concluded that waist circumference is an independent predictor of all-cause and CV death from underweight to obesity in HD patients. Abnormal abdominal fat depots assessed by means of a conicity index in a sample of HD patients were linked to both inflammation and wasting as well as mortality risk factor24. Even though these observations do not necessarily imply that principles of vascular pathophysiology differ between overweight/obesity HD patients, recent evidence25,26 indicates that abdominal visceral adiposity intervenes in the classical relationship between CV risk factors, inflammation and wasting compared with observed outcomes in the general population.

Hypoalbuminemia is the strongest predictor of CVD and mortality in dialysis patients when compared with classical risk factors (hypertension, hypercholesterolemia, DM, obesity)27-30 and non-traditional risk factors (anemia, oxidative stress, and dialysis modality)9,31. A drop of 1-g/dL in s-albumin was associated with an increased mortality risk of 47% in HD patients32. Low serum prealbumin (s-prealbumin) concentration is also a recognized predictor of mortality in dialysis patients. Chertow et al.33 reported that HD patients with s-prealbumin levels < 30 mg/dL showed a relative mortality risk of 2.64. Rambod et al.34 found that baseline s-prealbumin concentrations < 20 mg/dL were associated with increased risk of mortality even in normoalbuminemic patients. A drop of 10 mg/dL in dialysis patients with s-prealbumin levels between 20 and 40 mg/dL was also associated with a 37% increase of death risk independent of s-albumin and inflammatory markers34.

Inflammation is an overlapping condition whose prevalence in CKD patients is 30-50%35-38. Serum C-reactive protein (CRP) and interleukin-6 (IL-6) are known inflammation biomarkers and independent predictors of CVD and mortality in dialysis patients39. Some studies38,40 have shown high morbidity and mortality rates associated with increase in acute-phase positive reactants (CRP, fibrinogen) and proinflammatory cytokines (IL-1, IL-6, tumor necrosis factor alpha: TNF-a) in HD patients. Honda et al.38 reported that, in dialysis patients, IL-6 levels were predictors of CVD, while CRP and IL-6 levels were predictors of wasting, and that s-albumin, IL-6, and fetuin A were predictors of mortality. A novel actin-binding prognostic protein mainly secreted by myocytes and defined as plasma gelsolin has been recently involved as a useful biomarker of chronic inflammation, muscle mass, and immunity in CKD patients41. Follistatin, a myostatin binder, was highly increased in wasted and inflamed patients, which suggests a role as a potential mediator of wasting and survival in CKD patients42.

Pro-inflammatory cytokines such as plasma leptin, ghrelin and visfatin have also been involved as potential anorexigens in dialysis patients. A strong negative association exists between appetite and the level of CRP, IL-6, and TNF-α in HD patients43. One third of CKD patients report anorexia or appetite loss; each unit increase in log of CRP levels was associated with a 49% increase in the relative risk of hospitalization and mortality rates over 12-months of clinical observation43. In uremic patients a closed link between high leptin levels with impaired appetite and inflammation44 has been reported. In addition, a higher increase of desacyl ghrelin has been found in anorexic HD patients than in non-anorexic patients45. Patients with low circulating ghrelin concentrations have exhibited an increase of CRP and leptin levels as well as the highest mortality risk from all-cause and CV death risk46. Visfatin a proinflammatory cytokine which is related to anorexia, inflammation and decreased circulating levels of amino acids in advanced CKD patients has been recently reported47;48.


Phenotypic characteristics of Malnutrition/Protein-energy wasting/Cachexia in hemodialysis patients

Different terms and definitions have been used for these conditions associated with substantial loss of body stores, low protein-energy intake and inflammation in CKD patients. The term of malnutrition classified as marasmus or kwashiorkor, respectively is the consequence of a substantial decrease in energy and/or protein intake. Marasmus usually presents a starved appearance with diminished skinfold thickness, body weight loss and is not associated with significant comorbidity or non-inflammatory response (fig. 1) (table I). The classic study in healthy volunteers in Minnesota49 showed that an inadequate intake of food itself does not contribute to wasting or cachexia. Under semi-starvation conditions and despite of 23% body weight loss and muscle wasting, s-albumin concentrations in these subjects dropped only slightly from 4.2 to 3.8 g/dL. In uremic patients on dialysis, Bistrian et al.50 reported that s-albumin concentrations of marasmic patients were within the normal range. In fact, Chazot et al.51 showed that s-albumin and s-prealbumin levels were not sole markers of marasmus in over 20 year-HD patients51. Conversely, kwashiorkor is characterized by a marked hypoalbuminemia and fluid overload. While kwashiorkor s patients respond quickly to nutritional therapy, in marasmic patients it may be slower. It must be taken into account that uremic anorexia, catabolic HD procedure and other related factors could retard the nutritional repletion in marasmus´ patients.

The panel of experts from the International Society of Renal Nutrition and Metabolism (ISRNM)10 has defined the term "protein energy wasting" (PEW) to describe the mild-moderate forms of wasting in uremic patients. According to this definition, PEW is confirmed when at least three of the four features are present:10 a) altered laboratory markers (low s-albumin, prealbumin, or total cholesterol); b) reduced body mass (fat mass depletion or body weight loss); c) reduced muscle mass (muscle wasting or sarcopenia and reduced mid-arm muscle circumference) and, d) inadequate dietary intake (unintentional low dietary protein and energy intake10 (table I) (fig. 2). In contrast to malnutrition, PEW is associated with the elevation of pro-inflammatory cytokines52, endogenous muscle catabolism, hypoalbuminemia53, uremic anorexia43 and elevation of serum CRP54 and CVD55 in dialysis patients. Additionally, the ISRNM10 suggested that the term cachexia be reserved for only the most severe forms of PEW. The emerging concept defined as cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss or decreased of muscle strength with or without loss of fat (corrected for overload volume)56. Cachexia differs in some diagnostic criteria of PEW in CKD patients. BMI < 20 kg/m2 or weight loss of at least 5% ≤ in a period or equal or lower than 12 months and three of the following additional criteria are also required: anorexia, decrease muscle strength, fatigue, low fat-free mass index and altered laboratory parameters [s-albumin < 3.2 g/dL, anaemia (haemoglobin < 12 g/dL), including elevated inflammatory markers such as CRP or IL-6)] (table I). The differences in PEW compared to cachexia is that the latter encompasses only severe forms of metabolic depletion, whereas PEW is referred to mild degrees of depleted fat and muscle body mass.


Nutrition care process as systematic method in clinical practice

The Academy of Nutrition and Dietetics uses the concept Nutritional care process (NCP) as "a systematic problem-solving method that nutrition professionals use to critically think and make decisions to address nutrition-related problems and provide safe and effective quality nutrition care"57,58. This method consists of four consecutive steps: nutrition assessment, diagnosis, intervention, and nutrition monitoring or evaluation. It is a stepwise approach to conducting thorough nutritional assessment to provide tailored nutrition care in renal patients14.

First and Second steps of Nutrition Care process: Nutritional assessment and diagnosis

Nutrition assessment consists of collecting biochemical data, anthropometric measurements, physical examination findings, food/nutrition history and patient history. Guidelines on Nutrition11,13,59 recommend periodic assessment of nutritional status in the absence of malnutrition every 6-12 months in patients younger than 50. Over 5 years on HD and/or aged over 50, it is recommended every 3 months59. The conjoint use of subjective (nutritional screening, clinical history and physical exam) and objective (anthropometrical and laboratory tests) methods to assess and diagnose nutritional status is required.

Nutritional screening is an identification step that is outside the actual care and provides access to the NCP by referral and/or screening of individuals or groups for nutritional risk58 (fig. 2). Subjective global assessment (SGA) has been applied to subjectively evaluate patients at nutritional risk59. A refinement of SGA known as the malnutrition-inflammation score (MIS)60 has been significantly associated with coronary heart disease61, endothelial dysfunction62, poor quality of life63, anorexia43, hyporesponsiveness to erythropoietin64, hospitalization and mortality in dialysis patients60,63. Even though nutritional scoring systems are valuable tools for identifying dialysis patients at risk of malnu-trition/PEW/cachexia, a global assessment of nutritional status should consider a patient´s clinical history together with anthropometrical, biochemical, and inflammatory markers (fig. 3). The Kidney Disease Outcomes Quality Initiative (KDOQI)13 asserts that a single marker by itself does not provide a comprehensive assessment of nutritional status and, thus recommends a collective evaluation of multiple nutritional parameters.

Clinical nutrition history identifies changes in appetite, food intake (likes and dislikes), body weight loss, medication use, and interactions with other pathologies that might justify the modifications in one or several nutritional parameters. Physical examination by identifying clinical signs including changes in adipose tissue and muscle mass, edema and/or ascites, paleness, bruising, and skin lesions are indicators of nutritional risk (fig. 3). Additionally, dry body weight, skinfold thickness and mid-arm muscle circumference provide valuable information longitudinally on nutritional status. Anthropometric measures should be performed immediately after the dialysis session in the non-dominant or free vascular access arm59. More sophisticated methods such as computed tomography, magnetic resonance image scans, and dual-energy X ray absorptiometry (DXA) are used for body composition analysis13.

Bioelectrical impedance analysis (BIA) is a validated method for evaluating hydration status and body composition in CKD and dialysis patients65. Phase angle (PA) emerges as an additional indicator of nutritional status in wasted patients. Thus, the relative mortality risk of patients with PA values < 3o was twice higher than patients with PA ≥ 4o (target)66. A study conducted in 64 HD patients67 analyzed the suitability of the PA as a nutritional-inflammatory indicator. The prevalence of PEW was 81.2% in patients with a PA < 4o and 35% in those with a value ≥ 4o67. Prevalent HD patients with a PA < 4o were shown to be wasted and inflamed67. The conjoint use of BIA measurements, biochemical-nutritional parameters and inflammatory biomarkers may help to estimate dry body weight in hypoalbuminemic patients67. Current clinical practice guidelines10,13,59 do not include inflammatory biomarkers and body composition analysis measured by BIA. The evaluation of s-albumin and s-prealbumin [≥ 3.8 g/dL and ≥ 28 mg/dL, respectively (target)]59 together with one marker of inflammation (e.g. CRP) and management of nutritional status may help to identify HD patients at high risk of mortality who might benefit from nutritional support68.

Nutrition diagnoses list the problem, etiology, signs/symptoms (PES format)14. The problem (P) describes the alterations in the patient´s nutritional status. The etiology (E) or related factors are those factors that contribute to the cause of a particular problem. Finally, the signs and symptoms (S) are the defining characteristics obtained from the objective and subjective nutrition assessment data.

Third step of Nutrition Care Process:

Clinical approach to nutritional intervention

Nutrition intervention is needed for formulating and implementing the plan of nutrition care. There are four categories taken into account that identify the various types of nutrition interventions: a) adequacy of dialysis dose and scheme of hemodialysis (individualized treatment of dialysis: ultrapure water, biocompatible membranes, increasing the frequency-daily HD); b) nutritional counseling and oral nutrition supplementation; c) nutritional support (enteral nutrition and, intra-dialytic parenteral nutrition); d) coordination of nutrition care. In addition, interventions tailored to each one of type (malnutrition/PEW/cachexia) are required (fig. 4).

Adecuacy of dialysis dose and intensified dialysis strategies

Nutrition intervention remarkable factors to take into account in HD patients are the adequacy of the delivered dose (Kt/V urea single pool ≥ 1.2) and vascular access status. Dialysis adequacy is a prerequisite for achieving and/or maintaining nutritional status. In the HEMO study69 no significant differences were found between high-flux and low flux dialysis membranes as well as within high and low dialysis doses as mortality causes. At present, the doses of dialysis that can improve nutritional status are still unknown.

Vascular access is a crucial factor in dialysis as a potential focus of inflammation. A low systemic inflammatory response, maximum biocompatibility of the system, and control of chronic foci of infection should be achieved70. Observational studies71-73 and randomized controlled trials74,75 improving the efficiency of HD, by increasing frequency and duration of HD treatment, demonstrated better volume control and clearance efficiency of uremic toxins, middle molecular weight compounds and improved quality of life. Online hemodiafiltration (HDF) has attracted much attention as a promising optimum modality of HD due to efficient improvement in dialysis adequacy and clearing small and large-size uremic toxins76. Studies on HDF patients showed fewer requirements of phosphate binders, better control of hypertension with fewer use of antihypertensive drugs, less doses of erythropoietin stimulating agents, and iron supplements as a result of abolishing or reducing the inflammatory response77. However, a recent study78 showed that treatment with HDF did not reduce all causes of mortality compared with treatment with low-flux membranes in conventional HD therapy as non-significant differences in s-albumin, s-CRP and s-cholesterol during follow-up were found79. Further studies should be conducted for elucidating this issue.

Daily short or long-nocturnal HD in malnou-rished/PEW/cachectics patients are recommended as adjunctive therapy for 6-12 months59. Daily dialysis results in less fluid overload, fewer medications and dietary restrictions, better blood pressure and phosphate control. Hemodialysis tailored to patient needs should be considered.

Nutritional counseling and oral nutrition supplementation

The recommended dietary energy and protein intakes for HD patients are 30-35 kcal/kg/day and 1.2 g protein/kg/day, respectively13,59,80. Low dietary energy intake (on dialysis and non-dialysis treatment days) has been reported in these patients81. Preventive nutritional strategies include nutritional counseling adapted to each stage of CKD and dialysis modality, might help to reduce and/or prevent malnutrition and some of the PEW conditions. It is important to note, that prolonged and often unnecessary periods of fasting, multiple laboratory tests, missed meals due to dialysis, and restrictive diets during periods of intercurrent diseases are potential precursors of malnutrition and wasting. Periodic reevaluation and nutritional counseling are essential practices even in well-nourished patients. To ensure their nutritional intake HD patients must receive nutritional counseling and routine management of nutritional status82,83. Oral nutrition supplementation (ONS) is the first choice of nutritional support in malnourished/PEW patients whose spontaneous intakes are ≤ 20 kcal/kg/day84. ONS can provide additional 7-10 kcal energy/kg/day and 0.3-0.4 g protein/kg/day to meet dietary recommendations85. Beutler et al.86 compared the results of nutritional counseling alone with supplemented HD patients. S-albumin improved significantly in patients given ONS, but decreased in those who only received nutritional counseling. Seven of the twelve studies listed in table II, are randomized controlled trials reporting significant improvements in nutritional status. Recently, a retrospective matched-large cohort study87 of in-center HD patients with low s-albumin was performed. A total of 5,227 HD patients receiving intra-dialytic ONS with matched-pairs controls were compared. In the intention-to-treat analysis, survival was 9% and up to 34% in the as-treated group when compared with controls. Results of the study support that providing ONS coincident with three-weekly HD sessions in hypoalbuminemic patients may increase protein and energy intakes and improve survival rate87. To achieve protein and energy intakes, ONS should be received two-to-three times a day, preferably one hour after each main meal85 as well as ONS given during dialysis session which increases adherence to the treatment and improves nutritional status88.

Nutritionally complete formulas can be used, either as ONS or even as modular products (carbohydrates, lipids, proteins). Protein modular products may be ineffective in malnourished/PEW patients unless administered together with adequate energy intake. Hence, an ONS with 100% whey protein has a high biological value, and an absence of free phosphorous content may be preferred. Disease-specific formulae for CKD and dialysis patients (high energy density, low potassium, sodium and phosphorus) are tailored for the requirements of these patients. Cockram et al.89 studied the effect of three medical nutritional products (one standard formula and two disease-specific formulas) in well-nourished HD patients. Disease-specific formulas improve serum phosphorus levels and the calcium/phosphorus ratio in comparison to the standard formulae. Fouque et al.90 reported that renal-specific ONS might prevent malnutrition in HD patients without increasing the need for phosphate binders.

A recent randomized controlled trial91, assessed the effect of combined disease-specific formulas with antiinflammatory and antioxidative properties in HD patients during the hemodialysis session. Daily intakes of disease-specific formulas for 3-month observational period were well tolerated and associated with 0.2 g/dL improvement of serum albumin concentration in HD patients.

However, the principal limitations of ONS involve low patient compliance, gastrointestinal intolerance, unpleasant flavor and long-time use of the same formulas. High-energy formula (1.5-2 kcal/mL) to avoid volume overload is recommended92,93. The combination of ONS and nutritional counseling is safe and may be useful in terms of improving nutritional status. To date, ideal ONS (100% whey protein, free from phosphorous, potassium and vitamin A), has not been formulated in HD patients. Current disease-specific formulas with antioxidative and anti-inflammatory components require further considerations.

Nutritional support

The second step of nutrition intervention for malnou-rished/PEW/cachectics patients who do not respond successfully to nutritional counseling and ONS involves: a) intradialytic parenteral nutrition (IDPN), alone or in combination with ONS, and b) enteral nutrition by nasoenteral tube feeding or ostomy (EN) (fig. 4).

IDPN involves the administration of a macro and micronutrient solution through the venous chamber and does not require additional vascular access in HD treatment. The volume administered can be ultrafil-trated during the HD session. As shown in figure 4, PEW/cachectic patients should receive daily nutritional support to achieve the nutritional requirements. Nonetheless, to date, IDPN studies on survival are controversial94. Dezfuli et al.94 demonstrated that s-albumin levels increased 3.5-fold in hypoalbuminemic HD patients receiving IDPN. Joannidis et al.95 found that IDPN increased body weight but did not modify the inflammatory status of 6 patients. Foulks et al.96 reported a body weight gain of at least 10% and a significant reduction of hospitalization and mortality rates in 45 hypoalbuminemic HD patients who received IDPN for 6 months. In a retrospective study, Chertow et al.97 compared 1,679 HD patients who received one or more infusions of IDPN with 22,517 non-IDPN controls. The relative odds ratio for mortality depends highly on the decrease in s-albumin levels of the IDPN patients with ≤ 3.0 g/dL and on their increase in patients with > 4.0 g/dL97. Furthermore, a prospective randomized controlled study98 evaluated the effects of combining IDPN and ONS therapy with respect to the ONS treatment alone in 182 malnourished HD patients over one-year period. These investigators reported that the patients administered with IDPN together with ONS did not improve hospitalization rates, Karnofsky scores, BMI, biochemical parameters on 2-year mortality rates in comparison to patients receiving ONS alone. Multivariate analysis indicated that only the ONS group showed sustained s-albumin and prealbumin improvements after 1-year. Interestingly, s-prealbumin levels of ≥ 30 mg/dL during the first 3 months of ONS were associated with a decrease in the 2-year mortality rate98. IDPN should be considered more of a therapeutic strategy for intravenous nutritional supplementation than a total nutrition support. Clinical guidelines on parenteral nutrition proposed in order to ensure optimal tolerance84: a) IDPN should be infused at a constant rate during 4 h dialysis session; b) IDPN delivery should be progressively increased during the first week to a maximum of 16 mL/kg/day without ever exceeding 1000 mL/per HD session; and, c) ultrafiltration should be controlled and 75 mmol Na+ added per liter of IDPN solution to compensate for sodium losses84. IDPN is recommended whether s-albumin < 3g/dL11.

In addition, IDPN appears to reverse body protein catabolism during the HD session and to normalize the amino acid profile99,100. Losses of 6-8 g of amino acids into the dialysate per dialysis session were reported101. Pupim et al.99,100 investigated the effect of IDPN on protein metabolism in two randomized studies. In the first study99, seven HD patients were randomized with or without IDPN two hours before, during, and two hours after the HD session by using a primed-constant infusion of L-(1-13C) leucine and L (ring-2H5) phenylalanine. IDPN induced a large increase in whole-body protein synthesis and a significant decrease in whole-body protein proteolysis associated with an increase in forearm muscle protein synthesis getting a positive protein balance in whole body and forearm muscle compartments99. In their second study, Pupim et al.100 demonstrated that exercise combined with IDPN doubled forearm muscle essential amino acid uptake and net muscle protein accretion during the HD session. While the anabolic benefits of of IDPN provides only a transient improvement during HD session, ONS resulted in persistent anabolic benefits for muscle protein metabolism in postdialysis when anabolic benefits of IDPN had disappeared102.These results show that IDPN contributes to synthesis rather than catabolism and could counterbalance the catabolic effect of hemodialysis procedure.

PEW/cachectic patients who have spontaneous food intakes < 20 kcal/kg/day or are under stress conditions should receive daily nutritional support by enteral nutrition (EN). Nutritional support by tube feeding is less expensive, produces fewer metabolic and septic complications, and contributes much more to the digestive tract morphology maintenance than intravenous feeding84. EN should be used when nutritional counseling, ONS therapy and IDPN are unable to achieve nutritional requirements92, or when stress conditions are presented84. Enteral nutrition guidelines92 recommend nutritional support in CKD patients with a BMI < 20 kg/m2, body weight loss >10% over the previous 6 months, s-albumin < 3.5 g/dL, and s-prealbumin < 30 mg/dL. EN by tube feeding (nasogastric or nasojejunal tube), or for long-term ostomy [percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ)], are preferred to intravenous nutritional support. Nasojejunal tube feeding is recommended in patients with gastroparesis or in those who are non-responsive to prokinetic drugs92. PEG or PEJ is indicated in PEW or cachectics patients who do not respond to conventional therapy for a period of more than 4 weeks92. Even though the use of specific renal-disease formulas is preferred, standard formulas whose compositions are adapted to the nutritional requirement of the patient, can also be used92. Oligomeric formulas containing partially digested proteins are indicated when dyspepsia and/or malabsorption are involved.

However, when EN cannot meet individual nutritional requirements, or it is contraindicated -due to GI dysfunction or other pathological conditions (peritonitis, intestinal obstruction, ileus, GI ischemia, or enterocutaneous fistulas)-, total parenteral nutrition (TPN) by a central or peripheral vascular access is recommended to allow the digestive tract to recover from the effects of the concomitant condition.

Fourth step of Nutrition Care Process: Nutrition Monitoring and Evaluation

The purpose of monitoring and evaluation is to determine the degree to which progress is being achieved57. It requires and active commitment to measuring and registering the appropriate outcome indicators relevant to the nutritional diagnosis´ signs and symtoms. The re-evaluation of outcomes may also involve additional data collection in order to explore why the nutritional changes have not occurred as expected. Systematic use of these process provides consistency in the practice, adds value and demonstrates effectiveness of nutritional care.


Future adjuctive therapies

Combinations of new and promising therapeutic strategies including the use of appetite stimulants, growth hormone (GH), ghrelin agonist, melacortin-4 receptors (MC4-R) antagonists, anabolic steroids and anti-inflammatory drugs (steroids, pentoxifylline, statins, ACE inhibitors and anticytokine antibodies) are under clinical evaluation. These therapies are based on several studies91;103-117 which are briefly commented on.

Physical exercise activates peroxisome proliferator-activated receptor-gamma (PPAR-γ) and increases insulin-like growth factor type 1 (IGF-1), insulin sensitivity, and protein synthesis103,104. Omega-3 fatty acids can stimulate PPAR-γ by decreasing muscle tissue inflammation103. Fish oil supplementation potentiates the effect of exercise103 and decreases the inflammatory response to the HD procedure105,106. Appetite stimulants (hydralazine sulfate, metoclopramide, prednisolone, megestrol acetate) may also improve nutritional status. Pentoxifylline with or without ONS combination showed a significant improvement in s-albumin concentrations91. Emerging therapeutic strategies with some effective results as thalidomide, COX-2 inhibitors, proteosome inhibitors and anti-myostatin peptibody are still under clinical evaluation. Recombinant human growth hormone (rhGH) and IGF-1 improved protein synthesis in dialysis patients participating in pilot studies with pentoxifylline107,108. Garibotto et al.109 showed significant improvement in net muscle protein balance over a 6-week administration of 50 μg rhGH in cachectic HD patients. Uremia produces peripheral resistance to anabolic hormones (GH, insulin, IGF-I) and their administration has been shown to improve whole-body protein homeostasis. Ghrelin or its analogs may constitute an orexigen therapeutic strategy in CKD patients. In two subsequent studies110,111 subcutaneous ghrelin injection achieved in short-intermediate term induced a sustained positive change in anorexic dialysis patients. Nonetheless, ghrelin infusion induces lipolysis and insulin resistance independently of GH and cortisol112. Further studies are needed to evaluate the adverse side effects and the long-term efficacy of ghrelin in improving appetite and nutritional status. Recently, oral administration of active MC4-R antagonists has been proposed as a promising candidate for the treatment of anorexia and involuntary weight loss in PEW/cachectic patients. In a mouse model of uremic cachexia, Cheung et al.113 demonstrated that intraperitoneal administration of NBI-12i (a MC4-R antagonists) stimulated food intake and increased lean body mass and fat mass in treated uremic mice. However, to date, reports of the effects of MCR4-R antagonists have not been presented in human studies. Antioxidant and anti-inflammatory nutrients as omega-3 fatty acids, gamma-tocopherol and phytoestrogens and physical exercise have been proposed. Cholecalciferol114, gamma-tocopherol and docohexanoic acid115 induced inflammation decrease in HD patients. In addition, nandrolone decanoate in association with exercise increases lean body mass, quadriceps muscle, and knee extensor muscle strength116,117. The combination of aminoacids supplement has been tested. The mixture of hydroxyl-methyl-butyrate, arginine and glutamine was shown to be effective in increasing fat-free mass of middle-aged and elderly patients with advanced-stage cancer118 and in younger subjects with AIDS-associated wasting119,120. The potential benefit of these therapies merits further research. Randomized controlled and large cohort studies are needed to determine the multimodal beneficial effects and clinical outcome of these promising therapeutic strategies.


Conclusions and future remarks

This article has reviewed some issues with regard to NCP (assessment, diagnosis, intervention and monitoring) as well as novel adjunctive therapies to be applied in HD patients. Lastly, clinical research for the prevention and treatment of malnutrition/PEW/ cachexia has been conducted. There is controversy on the development of malnutrition or other conditions such as inflammation or comorbidity related to PEW or cachexia. However, there seems to be less disagreement concerning the consistent association of nutritional status with poor outcomes in dialysis patients. PEW/cachexia is a predictable event in many HD patients, readily diagnosed by assessment of body weight, change in appetite, low albumin and a concomitant increase in bioinflammatory markers. At the onset and throughout the course of illness, HD patients should have access to a nutrition team, to take part in a rehabilitation program tailor-made to their needs and consider the use of specific nutritional support and pharmacologic interventions. As a compromised nutritional status is still a common feature of HD patients, the above simple assessments should form a consistent part of the clinical procedure to diagnoses and treatment as early as possible in order to improve survival and positively affect patients´quality. Furthermore, studies on nutritional status should also incorporate the beneficial role of tailored exercise programs. Novel and complementary therapies such as oral active MC4-R antagonist and proteosome inhibitors may be promising candidates for attenuating disease-associated anorexia and muscle wasting of PEW/cachectics patients. Further studies with nutrients and compounds as hydroxyl-methyl-butyrate and branched chain amino acids with a particular role in protein synthesis should be conducted. From all the epidemiological data analyzed, nutrition support as a unimodal therapy was not completely able to reverse mild PEW and cachexia. Thus, further holistic nutrition-dialysis approaches are required.


Statement of authorship

All authors have significantly contributed to the paper, had access to all the data in the study and approved the final version of the manuscript to be submitted for publication. MR is the corresponding author and guarantor and the paper and has contributed to the design, writing and discussion of the paper. GB and FJS-M have contributed to the critical reading and discussion of the paper.



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Mar Ruperto.
Departamento de Nutrición y Bromatología I (Nutrición).
Facultad de Farmacia.
Plaza Ramón y Cajal, s/n.
Universidad Complutense de Madrid.
28040 Madrid.

Recibido: 20-X-2013.
1.a Revisión: 19-XI-2013.
Aceptado: 18-XII-2013.

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