1. What is malnutrition?

To define malnutrition, an expert panel of the International Society of Renal Nutrition and Metabolism (ISRNM) has recommended the use of the term “protein-energy wasting” (PEW) to encompass states of undernutrition that could result from a complex interplay of decreased nutrient intake and/or increased catabolism.

2. How is nutritional status examined, and how is malnutrition diagnosed in patients with chronic kidney disease (CKD)?

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  There is no single way to assess nutritional status, which is a consequence of a complex interplay of nutrient intake and catabolism, with significant effect modification by comorbid conditions, especially inflammatory conditions.

  
  
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  PEW can be diagnosed in clinical practice using five different criteria:

  
  
  
  
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    Biochemical measures (serum albumin, prealbumin, transferrin, and cholesterol)

    
    
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    Measures of body mass (body mass index [BMI], unintentional weight loss, and total body fat)

    
    
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    Measures of muscle mass (total muscle mass, mid-arm muscle circumference, and creatinine appearance)

    
    
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    Measures of dietary intake (dietary protein and energy intake)

    
    
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    Integrative nutritional scoring systems (subjective global assessment of nutrition and malnutrition-inflammation score)

  
  
  
  
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  In addition to these readily available measures of PEW, a series of other markers have also been proposed, which could have applicability as research tools; these include measures of appetite, food intake and energy expenditure, other measures of body mass and composition (such as dual energy x-ray absorptiometry [DEXA], bioimpedance, near-infrared interactance, or computed tomography/magnetic resonance imaging of muscle mass) and laboratory measures (such as growth hormone levels, C-reactive protein, interleukin-1, interleukin-6, tumor necrosis factor alpha, serum amyloid-A or peripheral blood cell counts; Box 23.1 ).

  
  
  
  

  Box 23.1.

  
  

  Criteria for the Clinical Diagnosis of Protein-Energy Wasting in Patients With Kidney Disease

  
  

  
  

  Serum chemistry and other laboratory markers

  
  

  
  

  
  
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    Serum albumin <3.8 g/dL (Bromcresol Green)

    
    
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    Serum prealbumin (transthyretin) <30 mg/dL

    
    
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    Serum cholesterol <100 mg/dL

    
    
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    Serum biochemistry: transferrin, urea, triglyceride, bicarbonate

    
    
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    Hormones: leptin, ghrelin, growth hormones

    
    
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    Inflammatory markers: CrP, IL-6, TNF-α, IL-1, SAA

    
    
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    Peripheral blood cell count: lymphocyte count or percentage

  
  

  
  

  Body mass and composition

  
  

  
  

  
  
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    Body mass index <22 kg/m ² (<65 years) <23 kg/m ² (>65 years)

    
    
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    Unintentional weight loss over time: 5% over 3 months or 10% over 6 months

    
    
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    Total body fat percentage <10%

    
    
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    Weight-based measures: weight for height

    
    
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    Total body nitrogen

    
    
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    Total body potassium

    
    
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    Energy-beam based methods: DEXA, BIA, NIR

    
    
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    Underwater weighing and air displacement weighing

    
    
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    14 K Dalton fragment of actomyosin

    
    
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    Microarrays

    
    
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    Muscle fiber size

    
    
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    Relative proportions of muscle fiber types

    
    
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    Muscle alkaline soluble protein

    
    
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    Computed tomography and/or magnetic resonance imaging of muscle mass

  
  

  
  

  Muscle mass

  
  

  
  

  
  
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    Muscle wasting: reduced muscle mass 5% over 3 months or 10% over 6 months

    
    
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    Reduced mid-arm muscle circumference area (>10% of reduction in relation to 50th percentile of reference population)

    
    
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    Urinary creatinine appearance

  
  

  
  

  Dietary intake

  
  

  
  

  
  
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    Unintentional low dietary protein intake: <0.80 g/kg per day for at least 2 months for dialysis patients or <0.6 g/kg per day for patients on CKD stages 2–5

  
  

  
  

  Appetite, food intake, and energy expenditure

  
  

  
  

  
  
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    Appetite assessment questionnaires

    
    
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    Population based dietary assessments: food frequency questionnaires

    
    
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    Measuring energy expenditure by indirect or direct calorimetry

  
  

  
  

  Nutritional scoring systems

  
  

  
  

  
  
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    SGA and its modifications

    
    
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    Malnutrition-Inflammation Score

  
  

  
  

  BIA , bioelectrical impedance analysis; CRP , C-reactive protein; DEXA , dual energy x-ray absorptiometry; IGF-1 , insulin-like growth factor 1; IL , interleukin (e.g., IL-1 and IL-6); NIR , near-infrared interactance; SAA , serum amyloid A; SGA , subjective global assessment of nutritional status; TNF-a a, tumor necrosis factor alpha.

  
  

3. Why is malnutrition associated with mortality in CKD?

Markers of PEW are some of the strongest independent predictors of adverse outcomes in patients with CKD and end-stage kidney disease. The link between PEW and mortality has been established almost exclusively in epidemiologic and observational studies. Thus only an association has been established. Causality needs to be verified in randomized controlled trials of nutritional interventions, even though the association is strong, robust, and consistent. Multiple pathophysiologic mechanisms have been invoked to explain the link between poor nutritional status and mortality in CKD:

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  Lower muscle and adipose mass decrease circulating lipoprotein that normally suppresses circulating endotoxin

  
  
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  Gastrointestinal, hematopoietic, and immune dysfunctions leading to more infections

  
  
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  Micronutrient deficiency leading to oxidative stress and endothelial dysfunction

  
  
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  Inadequate circulating gelsolin to oppose deleterious effects of circulating actin, including platelet activation leading to increased thromboembolic events

  
  
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  The maladaptive activation of the inflammatory and oxidative cascade can potentiate the effects of low nutrient intake by increasing catabolism

  
  
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  Novel factors such as proinflammatory high-density lipoprotein (HDL), myeloperoxidase, and pentraxin may also play important roles

4. What is the obesity paradox in patients with CKD?

Obesity has reached epidemic proportions in the general population and has been linked to increased morbidity and mortality. Several epidemiologic studies have suggested a link between obesity and higher risk of developing incident CKD; the link between obesity and adverse outcomes in the general population is evident from epidemiologic studies showing a linear increase in mortality associated with higher BMI, especially greater than 30 kg/m ² . Studies in patients with moderate to advanced CKD have shown a reversal of this risk factor pattern, with a linear decrease in mortality in those with higher BMI. In fact, patients with BMI levels reaching morbid obesity have shown the best survival, questioning the validity of the obesity paradigm in this patient population. Similar reversals in risk factor patterns, also known as “obesity paradox” or “reverse epidemiology,” have emerged in other patient populations characterized by chronic disease states and a high burden of comorbid conditions (such as those with advanced chronic obstructive pulmonary disease, congestive heart failure, rheumatoid arthritis, malignancies, and liver cirrhosis). The common thread in the populations displaying this phenomenon of reverse epidemiology is their extremely high short-term mortality rate, which probably explains the mechanism whereby obesity appears protective within short periods of time: in such patients the mechanisms responsible for the long-term deleterious effects seen in the general population (metabolic syndrome/insulin resistance/atherosclerosis) are likely overshadowed by the beneficial effects of higher overall nutritional reserves.

5. Can manipulations of weight improve outcomes in patients with CKD?

Interventions aimed at alleviating obesity are advocated in the general population to prevent long-term deleterious consequences. Such interventions are based on robust evidence linking obesity to adverse outcomes. Because descriptive studies in patients on renal replacement therapy suggest that obesity may confer a survival benefit rather than a risk, it may be less likely that interventions validated in the general population can be extrapolated to these patients without critical appraisal of the consequences. There is currently no evidence from clinical trials that have tested the risks versus benefits of weight reduction interventions in dialysis patients. Due to the marked discrepancy between epidemiologic studies of obesity in the general population and in patients on dialysis, any weight loss–based intervention in the latter group would have to proceed with utmost care taken to ensure that no harm is done. There also has to be openness about the possibility that gain in dry (edema free) weight could in fact be beneficial in this patient population because the complex homeostatic changes occurring in the process of increasing lean body mass end even adiposity may entail short-term benefits.