I. Adult guidelines

Article Outline

• A. Maintenance dialysis
  • 1. Evaluation of protein-energy nutritional status
    • Guideline 1. Use of panels of nutritional measures
    • Guideline 2. Panels of nutritional measures for maintenance dialysis patients
    • Guideline 3. Serum albumin
    • Guideline 4. Serum prealbumin
    • Guideline 5. Serum creatinine and the creatinine index
    • Guideline 6. Serum cholesterol
    • Guideline 7. Dietary interviews and diaries
    • Guideline 8. Protein equivalent of total nitrogen appearance (Pna)
    • Guideline 9. Subjective global nutritional assessment (Sga)
    • Guideline 10. Anthropometry
    • Guideline 11. Dual energy x-ray absorptiometry (Dxa)
    • efGuideline 12. Adjusted edema-free body weight (Abw)
  • 2. Management of acid-base status
    • Guideline 13. Measurement of serum bicarbonate
    • Guideline 14. Treatment of low serum bicarbonate
  • 3. Management of protein and energy intake
    • Guideline 15. Dietary protein intake (Dpi) in maintenance hemodialysis (Mhd)
    • Guideline 16. Dietary protein intake (Dpi) for chronic peritoneal dialysis (Cpd)
    • Guideline 17. Daily energy intake for maintenance dialysis patients
  • 4. Nutritional counseling and follow-up
    • Guideline 18. Intensive nutritional counseling with maintenance dialysis (Md)
    • Guideline 19. Indications for nutritional support
    • Guideline 20. Protein intake during acute illness
    • Guideline 21. Energy intake during acute illness
  • 5. Carnitine
    • Guideline 22. L-carnitine for maintenance dialysis patients
• B. Advanced chronic renal failure without dialysis
  • Guideline 23. Panels of nutritional measures for nondialyzed patients
  • Guideline 24. Dietary protein intake for nondialyzed patients
  • Guideline 25. Dietary energy intake (Dei) for nondialyzed patients
  • Guideline 26. Intensive nutritional counseling for chronic renal failure (Crf)
  • Guideline 27. Indications for renal replacement therapy
• C. Appendices (Adult guidelines)
  • Appendix I. Methods for measuring serum albumin
  • Appendix II. Methods for calculation and use of the creatinine index
  • Appendix III. Dietary interviews and diaries
  • Appendix IV. Role of the renal dietitian
  • Appendix V. Rationale and methods for the determination of the protein equivalent of nitrogen appearance (PNA)
  • Appendix VI. Methods for performing subjective global assessment
  • Appendix VII. Methods for performing anthropometry and calculating body measurements and reference tables
  • Appendix VIII. Serum transferrin and bioelectrical impedance analysis
  • Appendix X. Potential uses for L-carnitine in maintenance dialysis patients
• References

Back to Article Outline

A. Maintenance dialysis 

1. Evaluation of protein-energy nutritional status 

Guideline 1. Use of panels of nutritional measures 

RATIONALE

Optimal monitoring of protein-energy nutritional status for maintenance dialysis (MD) patients requires the collective evaluation of multiple parameters, particularly using measures that assess different aspects of protein-energy nutritional status. No single measure provides a complete overview of protein-energy nutritional status. Each of the valid indicators described in Guidelines 2 and 23 has a role in the overall nutritional assessment of dialysis patients.

There are ample data suggesting that complementary indicators of nutritional status exhibit independent associations with mortality and morbidity in maintenance hemodialysis (MHD) and chronic peritoneal dialysis (CPD) patients. For example, the serum albumin, serum creatinine, and body weight-for-height are independently associated with survival.¹⁴ Data from theUSRDS confirm these findings, using the serum albumin and body mass index (BMI; kg/m²).¹⁵ In the CANUSA study, both the serum albumin and SGA were independent predictors of death or treatment failure.¹⁶ A discussion of why serum transferrin concentrations and bioelectrical impedance studies are not recommended for the nutritional assessment of MD patients in clinical practice is given in Appendix VIII.

RECOMMENDATIONS FOR RESEARCH

1. Studies are needed to determine the most effective combination of measures of nutritional status for evaluating protein-energy malnutrition.

Guideline 2. Panels of nutritional measures for maintenance dialysis patients 

Table 1. Recommended Measures for Monitoring Nutritional Status of Maintenance Dialysis Patients

RATIONALE

The advantages to using these individual nutritional measures are discussed in Guidelines 3 and 8 through 10 and in Appendices III, V, and VII. The combination of these measurements provides an assessment of visceral and somatic protein pools, body weight and hence fat mass, and nutrient intake.

Serum albumin is recommended for routine measurement because there is a large body of literature that defines the normal serum albumin values, characterizes the nutritional and clinical factors affecting serum albumin concentrations, and demonstrates the relationship between serum albumin concentrations and outcome. Body weight, adjusted for height, is proposed because of the clear association between body weight and body fat mass and because body weight is correlated with clinical outcome. SGA is recommended because it gives a comprehensive overview of nutritional intake and body composition, including a rough assessment of both muscle mass and fat mass, and because it is correlated with mortality rates. Assessment of nutrient intake is essential for assessing the probability that a patient will develop PEM, for evaluating the contribution of inadequate nutrient intake to existing PEM, and for developing strategies to improve protein-energy nutritional status. Also, nutrient intake is correlated with clinical outcome. nPNA provides an independent and less time consuming assessment of dietary protein intake (DPI). Dietary interviews and diaries can be used to assess intake not only of protein and energy but also of a variety of other nutrients as well as the pattern and frequency of meals (information that may aid in identifying the cause of inadequate nutrient intake). A low predialysis or stabilized serum urea level may indicate a low intake of protein or amino acids.

RECOMMENDATIONS FOR RESEARCH

1. Research is necessary to identify and validate the following:

(a) The optimal panel of measures to screen for disorders in nutritional status.

(b) The optimal panel of measures for a comprehensive assessment of nutritional status.

(c) The optimal frequency with which these nutritional measures should be employed.

2. More information is needed concerning the appropriate parameters to be used for assessment of body composition (eg, for expressing dual energy x-ray absorptiometry [DXA] measurements, anthropometry, and the creatinine index).

3. Patient subgroups should be identified (eg, elderly, obese, severely malnourished, or physically very inactive individuals) for whom the use of specialized combinations of body composition measures are beneficial.

Guideline 3. Serum albumin 

RATIONALE

Serum albumin levels have been used extensively to assess the nutritional status of individuals with and without chronic renal failure (CRF).¹⁷ Malnutrition is common in the end-stage renal disease (ESRD) population,¹⁸ and hypoalbuminemia is highly predictive of future mortality risk when present at the time of initiation of chronic dialysis as well as during the course of maintenance dialysis (MD).¹⁴, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷ It follows that nutritional interventions that maintain or increase serum albumin concentrations may be associated with improved long-term survival, although this has not been proven in randomized, prospective clinical trials. Serum albumin levels may fall modestly with a sustained decrease in dietary protein and energy intake and may rise with increased protein or energy intake.²⁸ Conversely, serum albumin levels may fall acutely with inflammation or acute or chronic stress and increase following resolution or recovery.

Despite their clinical utility, serum protein (eg, albumin, transferrin, and prealbumin) levels may be insensitive to changes in nutritional status, do not necessarily correlate with changes in other nutritional parameters, and can be influenced by non-nutritional factors.²⁹, ³⁰, ³¹, ³² Some of these non-nutritional factors, which are frequently present in this population, include infection or inflammation, hydration status, peritoneal or urinary albumin losses, and acidemia.³³, ³⁴, ³⁵, ³⁶ Hence, hypoalbuminemia in MD patients does not necessarily indicate protein-energy malnutrition (PEM). The patient's clinical status (eg, comorbid conditions, dialysis modality, acid-base status, degree of proteinuria) must be examined when evaluating changes in the serum albumin level. Serum albumin concentrations are inversely correlated with serum levels of positive acute-phase proteins.³³, ³⁴, ³⁷ An elevated C-reactive protein has been reported to negate the positive relationship between serum albumin and nPNA.³⁴ However, some studies suggest that serum albumin is independently affected by both inflammation and nutritional intake.³⁴

As indicated above, positive acute-phase proteins (eg, C-reactive protein [CRP], alpha-1 acid glycoprotein [a1-AG], ferritin, and ceruloplasmin) are not nutritional parameters but may be used to identify the presence of inflammation³⁸ in individuals with low serum albumin or prealbumin (Guideline 4) levels and possibly for predicting outcome. a1-AG may be more specific than CRP for detecting inflammation in MD patients.³⁷ Serial monitoring of serum concentrations of positive acute-phase proteins (CRP, a1-AG) during episodes of inflammation in MD patients indicate that serum levels follow patterns similar to those found in acutely ill individuals who do not have CRF.³⁹

Although no single ideal measure of nutritional status exists, the serum albumin concentration is considered to be a useful indicator of protein-energy nutritional status in MD patients. The extensive literature, in individuals with orwithout renal failure, relating serum albumin to nutritional status, and the powerful association between hypoalbuminemia and mortality risk in the MD population, strongly support this contention. In addition, the measurement of serum albumin levels is inexpensive, easy to perform, and widely available. Methods for measuring serum albumin are discussed in Appendix I.

RECOMMENDATIONS FOR RESEARCH

1. More information is needed concerning the relative contributions of nutritional intake and inflammatory processes to serum albumin concentrations.

2. There is a need for a better understanding of the mechanisms by which hypoalbuminemia or the factors causing hypoalbuminemia lead to increased morbidity and mortality in MD patients.

3. Studies are needed to assess whether and under what conditions nutritional intervention increases serum albumin concentrations in hypoalbuminemic MD patients.

4. Will an increase in serum albumin levels induced by nutritional support reduce morbidity and mortality in persons undergoing MD?

Guideline 4. Serum prealbumin 

RATIONALE

Serum prealbumin (transthyretin) has been used in individuals with or without CRF as a marker of protein-energy nutritional status.⁴⁰ It has been suggested that serum prealbumin may be more sensitive than albumin as an indicator of nutritional status, since it has a shorter half-life than albumin (~2 to 3 days versus ~20 days, respectively).²⁵, ⁴¹ However, prealbumin is limited by many of the same factors described for albumin. Prealbumin may not correlate with changes in other nutritional parameters³¹, ³² and it is a negative acute-phase reactant (ie, serum levels decline in response to inflammation or infection⁴³). In addition, recommendations for the routine use of serum prealbumin levels as a marker are tempered by the fact that prealbumin levels are increased in renal failure, presumably due to impaired degradation by the kidney.¹⁷, ⁴² Although fewer studies have been published relating prealbumin levels to outcomes in MD patients than have been published regarding albumin levels, several studies have demonstrated that prealbumin levels less than 30 mg/dL are associated with increased mortality risk and correlate with other indices of PEM.²⁵, ⁴¹, ⁴², ⁴⁴

Based on available evidence, serum prealbumin is considered to be a valid measure of protein-energy nutritional status in individuals undergoing MD. There is insufficient evidence to conclude that prealbumin is a more sensitive or accurate index of malnutrition than is serum albumin. If the predialysis or stabilized serum prealbumin level is used to monitor nutritional status, it is recommended that the outcome goal for prealbumin is a value greater than or equal to 30 mg/dL.

RECOMMENDATIONS FOR RESEARCH

1. What range of serum prealbumin concentrations is associated with optimal outcome?

2. More information is needed concerning the relative contributions of nutritional intake and inflammatory processes to serum prealbumin levels.

3. Data are needed concerning the mechanisms by which low serum levels of prealbumin lead to increased mortality in MD patients.

4. Will nutritional intervention in malnourished hypoprealbuminemic MD patients increase serum prealbumin concentrations?

5. Will an increase in serum prealbumin levels induced by nutritional support reduce morbidity and mortality in individuals undergoing MD?

Guideline 5. Serum creatinine and the creatinine index 

RATIONALE

In MHD patients with little or no renal function who are receiving a constant dose of dialysis, the predialysis serum creatinine level will be proportional to dietary protein (muscle) intake and the somatic (skeletal muscle) mass.¹⁷, ⁴⁵, ⁴⁶ In chronic peritoneal dialysis (CPD) patients with little or no residual renal function, the stabilized serum creatinine level with a given dialysis dose will be proportional to skeletal muscle mass and dietary muscle intake. Thus, a low predialysis or stabilized serum creatinine level in an MD patient with negligible renal function suggests decreased skeletal muscle mass and/or a low dietary protein intake (DPI).¹⁷ Among nonanuric individuals, this relationship persists, but the magnitude of the urinary creatinine excretion must be considered when interpreting the predialysis or stabilized serum creatinine as a nutritional parameter. This is particularly relevant to CPD patients, who are more likely to maintain residual renal function for longer periods.

The creatinine index is used to assess creatinine production and, therefore, dietary skeletal muscle protein intake and muscle mass. The creatinine index estimates fat-free body mass rather accurately in individuals with ESRD.⁴⁶, ⁴⁸ Appendix II discusses creatinine metabolism in greater detail and describes methods for calculating the creatinine index and, from this value, the fat-free body mass.

In individuals in whom loss of skeletal muscle mass is suspected on the basis of low or declining serum creatinine levels, this observation may be confirmed using the creatinine index. Direct relationships between serum creatinine and the serum albumin²⁹, ³³, ⁴² and prealbumin concentrations^42a are reported. Among individuals undergoing CPD, the creatinine index is lower in individuals with protein-energy malnutrition as determined by a composite nutritional index.³⁰

Serum creatinine and the creatinine index are predictors of clinical outcome. In individuals undergoing maintenance HD (MHD), predialysis serum creatinine¹⁴, ²⁵, ⁴², ⁴⁴, ⁴⁵, ⁴⁹, ⁵⁰, ⁵¹, ⁵² and the molar ratio of serum urea to creatinine are both predictive of and inversely related to survival. This relationship persists even after adjusting for patient characteristics (age, sex, diagnosis, and diabetic status) and dialytic variables.¹⁴, ²⁵, ⁴⁴, ⁴⁵, ⁵⁰, ⁵² The serum creatinine at the onset of MHD distinguishes between short-term (< 12 months) and long-term (> 48 months) survival in incident patients.²⁵ In longitudinal studies of PD patients, initial serum creatinine levels are inversely related to mortality.²⁵, ⁴⁴, ⁵² The creatinine index is directly related to the normalized protein equivalent of total nitrogen appearance (nPNA) and independent of the dialysis dose (Kt/V_urea ).⁵³ A low or declining creatinine index correlates with mortality independently of the cause of death, although people with catabolic diseases may have larger and faster declines in the creatinine index before death.⁵³ Some research has not shown a clear association between the serum creatinine concentration and outcome.²³, ⁴², ⁵⁴

The serum creatinine concentration that indicates malnutrition has not been well defined. The mortality risk associated with low serum creatinine increases at levels below 9 to 11 mg/dL in individuals on MHD or PD.¹⁴, ²⁵, ³⁰, ⁴⁴, ⁵¹ In individuals with negligible urinary creatinine clearance (CrCl), the nutritional status of individuals undergoing MHD or CPD who have a predialysis or stabilized serum creatinine of less than approximately 10 mg/dL should be evaluated.

RECOMMENDATIONS FOR RESEARCH

1. The degree of correlation of the serum creatinine and creatinine index with skeletal muscle mass and DPI, and the sensitivity to change in these parameters of creatinine metabolism, need to be better defined.

2. The relationship between the creatinine index and the edema-free lean body mass or skeletal muscle protein mass needs to be defined for ESRD patients.

3. The rate of creatinine degradation in ESRD patients needs to be defined more precisely.

4. The level of serum creatinine and the creatinine index associated with optimal nutritional status and lowest morbidity and mortality rates need to be defined.

5. The relationships between other markers of protein-energy nutritional status (eg, serum albumin, prealbumin, or anthropometry) and serum creatinine or creatinine index are limited, somewhat contradictory, and need to be further examined.

6. Whether nutritional interventions that increase serum creatinine or creatinine index will improve morbidity or mortality in malnourished MD patients should be tested.

7. The effects of age, gender, race, and size of skeletal muscle mass on the relationship between the serum creatinine and the creatinine index on morbidity and mortality need to be examined.

Guideline 6. Serum cholesterol 

RATIONALE

The predialysis or stabilized serum cholesterol concentration may be a useful screening tool for detecting chronically inadequate protein-energy intakes. Individuals undergoing MHD who have a low-normal (less than approximately 150 to 180 mg/dL) nonfasting serum cholesterol have higher mortality than do those with higher cholesterol levels.¹⁴, ²⁵, ⁴⁷, ⁵⁰, ⁵⁵ As an indicator of protein-energy nutritional status, the serum cholesterol concentration is too insensitive and nonspecific to be used for purposes other than for nutritional screening, and MD patients with serum cholesterol concentrations less than approximately 150 to 180 mg/dL should be evaluated for nutritional deficits as well as for other comorbid conditions.

Serum cholesterol is an independent predictor of mortality in MHD patients.¹⁴, ¹⁹, ⁴⁷, ⁵⁵ The relationship between serum cholesterol and mortality has been described as either “U-shaped” or “J-shaped,” with increasing risk for mortality as the serum cholesterol rises above the 200 to 300 mg/dL range¹⁴ or falls below approximately 200 mg/dL.¹⁹, ²⁵, ⁴⁷, ⁵⁰ The mortality risk in most studies appears to increase progressively as the serum cholesterol decreases to, or below, the normal range for healthy adults (≤200 mg/dL).¹⁴, ¹⁹, ²⁵, ⁵⁰, ⁵⁵ Not all studies of MHD patients show that serum cholesterol levels predict mortality, however.¹⁹, ²³, ⁴² The relationship between low serum cholesterol and increased mortality is not observed in the CPD population,¹⁴, ²⁵, ⁴², ⁴⁴, ⁵² possibly because sample sizes in studies of individuals undergoing CPD are smaller and possibly due to confounding by greater energy (glucose intake) and/or hypertriglyceridemia. In one study, higher serum cholesterol concentrations (>250 mg/dL) were associated with increased mortality in CPD patients.⁵⁶

Predialysis serum cholesterol is generally reported to exhibit a high degree of collinearity with other nutritional markers such as albumin,⁴² prealbumin,⁴² and creatinine,⁴⁴ as well as age.⁴⁴ In MHD patients, the predialysis serum cholesterol level measured may be affected by non-nutritional factors. Cholesterol may be influenced by the same comorbid conditions, such as inflammation, that affect other nutritional markers (eg, serum albumin).⁴² In one study there was no difference in serum cholesterol in CAPD patients whose serum albumin level was less than 3.5 g/dL as compared with those with levels ≥3.5 g/dL.³³

RECOMMENDATIONS FOR RESEARCH

1. What are the conditions under which serum cholesterol is a reliable marker of protein-energy nutrition? What can be done to increase the sensitivity and specificity of the serum cholesterol as an indicator of protein-energy nutritional status?

2. The relationships between other markers of protein-energy nutritional status (eg, serum albumin or anthropometry) and serum cholesterol are limited, somewhat contradictory, and need to be better defined.

3. How does nutritional intervention in malnourished MD patients affect their serum cholesterol concentrations?

4. Recent data suggest that serum cholesterol exhibits a negative acute-phase response to inflammation.⁴² The relationship among serum cholesterol, nutritional status, and inflammation needs to be further investigated.

5. Why does mortality increase when the serum cholesterol falls outside the 200 to 250 mg/dL range?

6. More information is needed about the patterns of morbidity and mortality associated with abnormal serum cholesterol concentrations in MD patients. For example, in these individuals, is cardiovascular mortality directly related to the serum cholesterol level and are malnutrition and mortality from infection inversely related to the serum cholesterol level?

7. Additional data investigating the relationships among serum cholesterol, protein-energy nutritional status, morbidity, and mortality are needed for persons undergoing CPD.

Guideline 7. Dietary interviews and diaries 

RATIONALE

Patients undergoing MHD or CPD frequently have low protein and energy intake. Evidence indicates that for patients ingesting low protein or energy intakes, increasing dietary protein or energy intake improves nutritional status.⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰ It is important, therefore, to monitor the dietary protein and energy intake of MHD and CPD patients. A number of studies in individuals without renal disease indicate that dietary diaries and interviews provide quantitative information concerning intake of protein, energy, and other nutrients.⁶¹, ⁶² It is recommended, therefore, that individuals undergoing MHD or CPD periodically maintain 3-day dietary records followed by dietary interviews conducted by an individual trained in conducting accurate dietary interviews and calculating nutrient intake from the diaries and interviews, eg, a registered dietitian, preferably with experience in renal disease (see Appendices III and IV). When staffing conditions limit the time available to conduct more formal assessments of nutritional intake, a 24-hour dietary recall may be substituted for dietary interviews and/or diaries in nutritionally stable patients.

RECOMMENDATIONS FOR RESEARCH

1. Techniques to improve the reliability and precision of dietary interviews or diaries for MD patients are needed.

2. Other less laborious and more reliable methods to estimate nutrient intake, particularly energy intake, are needed.

Guideline 8. Protein equivalent of total nitrogen appearance (Pna) 

RATIONALE

During steady-state conditions, nitrogen intake is equal to or slightly greater than nitrogen assessed as total nitrogen appearance (TNA).⁶³ TNA is equal to the sum of dialysate, urine, fecal nitrogen losses, and the postdialysis increment in body urea-nitrogen content. Because the nitrogen content of protein is relatively constant at 16%, the protein equivalent of total nitrogen appearance (PNA) can be estimated by multiplying TNA by 6.25 (PNA is mathematically identical to the protein catabolic rate or PCR). In the clinically stable patient, PNA can be used to estimate protein intake. Because protein requirements are determined primarily by fat-free, edema-free body mass, PNA is usually normalized (nPNA) to some function of body weight (eg, actual, adjusted, or standardized [NHANES II] body weight [SBW] or body weight derived from the urea distribution space [V_urea /0.58]).⁶³ Because urea nitrogen appearance (UNA; ie, the sum of urea nitrogen in urine and dialysate and the change in body urea nitrogen) is highly correlated with TNA and measurement of total nitrogen losses in urine, dialysate, and stool is inconvenient and laborious, regression equations to estimate PNA from measurements of urea nitrogen in serum, urine, and dialysate have been developed. The estimation of PNA from measurements of urea nitrogen is readily performed from the routine urea kinetic modeling session in HD patients and, at least in theory, should be subject to less measurement error than dietary diaries and recall. The equations used to estimate PNA are discussed in Appendix V.

There are several important limitations to PNA as an estimate of DPI. First, PNA approximates protein intake only when the patient is in nitrogen equilibrium (steady-state).⁶³ In the catabolic patient, PNA will exceed protein intake to the extent that there is net degradation and metabolism of endogenous protein pools to form urea. Conversely, when the patient is anabolic (eg, growth in children, recovering from an intercurrent illness, or during the last trimester of pregnancy) dietary protein is utilized for accrual of new body protein pools, and PNA will underestimate actual protein intake. Second, UNA (and hence PNA) changes rapidly following variations in protein intake. Hence, PNA may fluctuate from day to day as a function of protein intake, and a single PNA measurement may not reflect usual protein intakes. Third, when DPI is high, TNA underestimates protein intake (ie, nitrogen balance is unrealistically positive).⁶⁴, ⁶⁵ This is probably caused by increased nitrogen losses through unmeasured pathways of excretion (eg, respiration and skin).⁶⁶ Fourth, PNA may overestimate DPI when the protein intake is less than 1 g/kg/d (possibly due to endogenous protein catabolism).⁶⁷, ⁶⁸, ⁶⁹ Finally, normalizing PNA to body weight can be misleading in obese, malnourished, and edematous patients. Therefore, it is recommended that for individuals who are less than 90% or greater than 115% of SBW, the adjusted edema-free body weight (aBW_ef ) be used when normalizing PNA to body weight (Guideline 12).

Notwithstanding these limitations, when consideration is given to the caveats discussed above, the nPNA is a valid and useful method for estimating protein intake. However, PNA should not be used to evaluate nutritional status in isolation, but rather as one of several independent measures when evaluating nutritional status.

RECOMMENDATIONS FOR RESEARCH

1. There are still a number of technical problems with measuring PNA in individuals undergoing HD or peritoneal dialysis that engender errors and increase the costs of measurement. Research to decrease these sources of error would be useful.

2. The mathematical relationship between PNA and protein intake in MHD patients has not been well defined. A larger database to examine these relationships more precisely would be useful.

3. More research into optimal methods for normalizing PNA to body mass would be valuable.

Guideline 9. Subjective global nutritional assessment (Sga) 

RATIONALE

Subjective global assessment (SGA) is a reproducible and useful instrument for assessing the nutritional status of MD patients.¹⁶, ²⁹, ⁷⁰, ⁷¹, ⁷² It is a simple technique that is based on subjective and objective aspects of the medical history and physical examination. SGA was initially developed to determine the nutritional status of patients undergoing gastrointestinal surgery⁷³, ⁷⁴ and subsequently was applied to other populations.¹⁶, ²⁹, ⁷⁰, ⁷¹, ⁷², ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷

Among the benefits of using the SGA are that it is inexpensive, can be performed rapidly, requires only brief training, and gives a global score or summation of protein-energy nutritional status. Disadvantages to the SGA include the fact that visceral protein levels are not included in the assessment. SGA is focused on nutrient intake and body composition. It is subjective, and its sensitivity, precision, and reproducibility over time have not been extensively studied in MHD patients.

Many cross-sectional studies have used the SGA to assess nutritional status in individuals undergoing CPD.¹⁶, ²⁹, ⁷¹, ⁷⁵, ⁷⁸ Correlations among SGA and other measures of protein-energy nutritional status are well described.²⁹, ⁷¹ SGA has been less well studied in MHD patients.⁷² In the Canada-USA (CANUSA) study, a prospective cohort study of 680 continuous ambulatory peritoneal dialysis (CAPD) patients, SGA was modified to four items (weight loss, anorexia, subcutaneous fat, and muscle mass). Subjective weightings were assigned to each of the four items representing nutritional status (eg, 1 to 2 represented severe malnutrition; 3 to 5, moderate to mild malnutrition; and 6 to 7, normal nutrition).¹⁶

It is recommended that SGA be determined by the 4-item, 7-point scale used in the CANUSA Study,¹⁶ because this method may provide greater sensitivity when assessing nutritional status and more predictive power in MD patients than the original 3-point ordinal scale.⁷³, ⁷⁴ The CANUSA study, using the 7-point scale, showed with multivariable analysis that a higher SGA score was associated with a lower relative risk of death and fewer hospitalized days per year.¹⁶ Also, small changes in the SGA score correlated with clinical outcomes.⁷⁹ Methods for performing SGA are discussed in Appendix VI.

RECOMMENDATIONS FOR RESEARCH

1. The most effective technique for performing SGA needs to be identified. Is the currently recommended 4-item scale optimal? Should visceral proteins (eg, serum albumin, transferrin, and/or prealbumin) be added to the SGA? Should a standard reference of body mass be included (eg, BMI or %SBW)?

2. The technique of SGA needs greater validation with regard to sensitivity, specificity, accuracy, intraobserver and interobserver variability, correlation with other nutritional measures, and predictability of morbidity, mortality, or other clinical outcomes.

Guideline 10. Anthropometry 

RATIONALE

Anthropometry quantifies body mass, provides a semiquantitative estimate of the components of body mass, particularly the bone, muscle, and fat compartments, and gives information concerning nutritional status.³¹, ⁸⁰, ⁸¹, ⁸², ⁸³ The anthropometric parameters that are generally assessed include body weight, height, skeletal frame size, skinfold thickness (an indicator of body fat), mid-arm muscle circumference (MAMC; an indicator of muscle mass), area, or diameter, or percent of the body mass that is fat, percent of usual body weight (%UBW), percent of standard (NHANES II ) body weight (%SBW), and BMI. The various anthropometric measures provide different information concerning body composition; therefore, there are advantages to measuring all of the parameters indicated above. Hence, the emphasis given to different anthropometric parameters and their relative precision should be taken into consideration. Anthropometry requires precise techniques of measurement and the use of proper equipment to give accurate, reproducible data; otherwise, the measurements may give quite variable results.⁸² Some measures of anthropometry are more precise, such as %UBW, %SBW, and BMI, than are skinfold thickness and MAMC. Methods for performing anthropometry and calculating body composition from these measurements and reference tables are presented in Appendix VII.

In adult MD patients, height is not a valid method for measuring protein or energy nutritional status. However, it must be measured because it is used in height-adjusted reference tables for weight (including SBW and BMI). Because height may decrease with aging, particularly in MD patients who have bone disease, height should be measured annually. Skeletal frame size must also be determined to calculate an individual's %SBW (see Appendix VII).

Muscle area, diameter, or circumference is used to estimate muscle mass and, by inference, the fat-free mass and somatic protein pool. Significant changes in these measurements reflect changes in body muscle and somatic protein mass and may indicate a nutritionally compromised state. Anthropometry has been used to assess nutritional status in MHD and CPD patients.²⁹, ³¹, ³², ⁷¹, ⁷⁵, ⁸⁴ These studies indicate that muscle mass is decreased, often markedly, in many, if not the majority, of MD patients.

Anthropometric monitoring of the same patient longitudinally may provide valuable information concerning changes in nutritional status for that individual. The desirable or optimal anthropometric measures for MD patients have not been defined. There is evidence that MHD patients who have larger body-weight-for-height (eg, BMI) measurements are more likely to survive, at least for the subsequent 12 months.¹⁵, ⁵⁰, ⁸⁵, ⁸⁶ Patients in the lower 50th percentile of weight-for-height clearly have a reduced survival rate.¹⁵, ⁸⁵, ⁸⁶, ⁸⁷ One study indicates that MHD patients who are in the upper 10th percentile of body weight-for-height have the greatest 12-month survival rate.⁸⁵

In contrast to these findings, virtually all studies of normal populations indicate that low weight-for-height measures are associated with greater survival, especially if the analyses are adjusted for the incidence of cigarette smoking in individuals with low BMI.⁸⁸ Interpretation of these disparate findings among individuals undergoing MD and the normal population is also confounded by the lack of interventional trials in which a change in anthropometric measurements is correlated with clinical outcome.

Anthropometric measurements in MD patients can be compared with normal values obtained from the NHANES II data⁸⁹ or with values from normal individuals who have the greatest longevity.⁸⁸, ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ⁹⁵, ⁹⁶, ⁹⁷ Anthropometric norms for patients treated with HD are published and generally are similar to the values available for the general population.⁹⁸ Differences in anthropometric measurements among MD patients and normal individuals may indicate a nutritional disorder or other clinical abnormality (eg, edema or amputation). The use of currently available anthropometric norms obtained from MD patients is of questionable value since age-, sex-, and race- or ethnicity-specific reference data are not available for this population. Furthermore, it has not been shown that the norms for MHD patients are desirable or healthy values.

RECOMMENDATIONS FOR RESEARCH

1. Age-, sex-, and race- or ethnic-specific desirable reference values for anthropometry obtained in large numbers of MD patients are needed.

2. The risk of morbidity and mortality associated with different anthropometric measurements in MD patients should be determined.

3. To determine whether anthropometry might be an acceptable intermediate outcome in nutrition intervention trials.

4. Will improvement in anthropometric values through nutritional intervention be associated with decreased morbidity and mortality and enhanced quality of life in individuals undergoing MD?

Guideline 11. Dual energy x-ray absorptiometry (Dxa) 

RATIONALE

Assessment of body composition, particularly with serial evaluation, can provide information concerning the long-term adequacy of protein-energy nutritional intake.⁵⁸, ⁹⁹ Most clinically useful techniques for measuring body composition are not very precise unless obtained by trained anthropometrists using standardized methods, such as in Guideline 10. Whole body dual energy x-ray absorptiometry (DXA) is a reliable, noninvasive method to assess the three main components of body composition (fat mass, fat-free mass, and bone mineral mass and density). The accuracy of DXA is less influenced by the variations in hydration that commonly occur in ESRD patients.¹⁰⁰, ¹⁰¹, ¹⁰² In vivo precision and accuracy of fat mass estimates by DXA are approximately 2% to 3% and 3%, respectively, in MHD¹⁰¹ and CPD patients. Studies of DXA in CRF, MHD, and CPD patients have demonstrated the superior precision and accuracy of DXA as compared with anthropometry, total body potassium counting, creatinine index, and bioelectrical impedance (BIA).⁸⁰, ¹⁰⁰, ¹⁰¹, ¹⁰²

DXA scanning utilizes an x-ray source that produces a stable, dual-energy photon beam.⁸⁰, ¹⁰⁰, ¹⁰¹, ¹⁰² These beams are projected through the body by scanning in a rectilinear raster pattern. Various tissues (fat, fat-free mass, and bone) attenuate the x-ray beams to different extents. Body composition is computed from the ratios of the natural logarithms of the attenuated and unattenuated beams.

The main limitations to DXA are the substantial cost of acquiring the instrument, the requirement for dedicated space to house it, the costs for the DXA measurement, and the fact that individuals may need to travel to the DXA facility for the measurements. DXA also does not distinguish well between intracellular and extracellular water compartments. However, DXA scanners are becoming increasingly common in metropolitan settings. Where precise estimates of body composition and bone mineral density are required, use of DXA is preferred over traditional anthropometric techniques or BIA. However, the routine use of DXA is not recommended.

RECOMMENDATIONS FOR RESEARCH

1. The sensitivity and specificity of DXA as a marker of protein-energy nutritional status, and specifically body composition, need to be defined more precisely.

2. Careful studies of the relationships between changes in more traditional markers of protein-energy nutritional status (eg, albumin, prealbumin, or anthropometry) and changes in body composition by DXA are needed.

3. Whether DXA assessment of body composition might be an acceptable intermediate outcome in nutrition intervention trials needs to be determined.

4. Whether DXA measurements correlate with morbidity and mortality in MD patients needs to be determined.

_efGuideline 12. Adjusted edema-free body weight (Abw) 

RATIONALE

The wide range in body weight and body composition observed among dialysis patients seriously limits the use of the actual body weight for assessment or prescription of nutritional intake. The use of the actual or unadjusted body weight to assess the actual nutrient intake or to prescribe the intake of energy and protein can be hazardous when individuals are very obese or very underweight. On the other hand, it may be hazardous to ignore the effects of the patient's body size on dietary needs and tolerance in individuals who are markedly underweight or overweight. It is recognized that the determination of the patient's edema-free body weight is often difficult and not precise. Clinical judgement based on physical examination and, if necessary, body composition measurements are used to estimate the presence or absence of edema.

The following equation can be used to calculate the edema-free adjusted body weight (aBW_ef )⁶³: aBW_ef = BW_ef + [(SBW − BW_ef ) × 0.25] where BW_ef is the actual edema-free body weight and SBW is the standard body weight as determined from the NHANES II data.⁸⁹ Since interdialytic weight gain (IDWG) can be as high as 6 to 7 kg in HD patients, and peritoneal dialysate plus intraperitoneal ultrafiltrate can reach 2 to 5 kg, the aBW_ef should be calculated based on postdialysis values for HD patients and post-dialysate drain measurements for peritoneal dialysis patients.

Equation 1 takes into account the fact that the metabolic needs and dietary protein and energy requirements of adipose tissue in obese individuals is less than that of edema-free lean body mass and also that very underweight individuals are less likely to become metabolically overloaded if they are prescribed diets based on their aBW_ef as compared with the standard (normal) body weight for individuals of similar age, height, gender, and skeletal frame size. Since the volume of distribution of urea and other protein metabolites is reduced in smaller individuals, a reduced protein prescription based on the aBW_ef , as compared with the standard weight, should lead to a lesser rate of accumulation of these metabolites in the body. On the other hand, use of the aBW_ef instead of the actual body weight of an underweight individual may provide the additional nutrients necessary for nutrient repletion. The use of the aBW_ef for prescribing protein or energy intake should be considered as a starting point. As always, clinical judgment and longitudinal assessment of body weight and other nutritional measures should be used to assess the response to dietary therapy and for making further decisions concerning dietary management.

The use of the aBW_ef may not be required for all patients. Clinical experience suggests that the actual edema-free body weight may be used effectively for nutritional assessment and nutritional prescription when the BW_ef is between 95% and 115% of the SBW as determined from the median body weights obtained from the NHANES II data.⁸⁹

RECOMMENDATIONS FOR RESEARCH

1. The use of the aBW_ef for assessment and prescription of nutritional intake must be validated.

2. More precise and practical methods are needed for assessing the size of body water compartments and, in particular, undesirable increases or reductions in total body water, intracellular water, or extracellular or intravascular water.

2. Management of acid-base status 

Guideline 13. Measurement of serum bicarbonate 

Guideline 14. Treatment of low serum bicarbonate 

RATIONALE

Acidemia refers to abnormally increased hydrogen ion concentrations in the blood. Acidosis refers to the existence of one or more conditions that promote acidemia. Acidemia, as measured by serum bicarbonate and/or blood pH, is common in individuals who have CRF or who are undergoing MD. Low serum bicarbonate concentrations in a MD patient almost always indicate metabolic acidosis. Questions concerning the presence or severity of acidemia can be resolved by measuring arterial blood pH and gases. Acidemia due to metabolic acidosis is associated with increased oxidation of branched chain amino acids (valine, leucine, and isoleucine),¹⁰³ increased protein degradation¹⁰⁴ and PNA,¹⁰⁵, ¹⁰⁶ and decreased albumin synthesis.¹⁰⁷ Levels of plasma branched chain amino acids have been described to be low in CRF, and a significant direct correlation between plasma bicarbonate levels and free valine concentrations in muscle has been reported in MD patients.¹⁰⁸ Similarly, a direct correlation between serum bicarbonate and albumin concentrations has been observed in MHD patients.¹⁰⁵, ¹⁰⁹ Acidemia may have detrimental effects on vitamin D synthesis and bone metabolism and may increase beta-2 microglobulin turnover.¹¹⁰

Normalization of the predialysis or stabilized serum bicarbonate concentration can be achieved by higher basic anion concentrations in the dialysate and/or by oral supplementation with bicarbonate salts. Higher concentrations of bicarbonate in hemodialysate (>38 mmol/L) has been shown to safely increase predialysis serum bicarbonate concentrations.⁴⁵, ¹⁰⁴, ¹¹¹, ¹¹², ¹¹³ An oral dose of sodium bicarbonate, usually about 2 to 4 g/d or 25 to 50 mEq/d, can be used to effectively increase serum bicarbonate concentrations.¹⁰⁹, ¹¹², ¹¹⁴, ¹¹⁵, ¹¹⁶ In individuals undergoing CPD, higher dialysate lactate or bicarbonate levels and oral sodium bicarbonate may each raise serum bicarbonate levels.¹¹⁴, ¹¹⁷, ¹¹⁸

Correction of acidemia due to metabolic acidosis has been associated with increased serum albumin,¹¹⁹ decreased protein degradation rates,¹¹³, ¹¹⁴, ¹²⁰ and increased plasma concentrations of branched chain amino acids and total essential amino acids.¹¹⁶, ¹¹⁹, ¹²¹ It has been proposed that eradication of acidemia increases cellular influx and decreases cellular efflux of branched chain amino acids.¹²¹ An increase in plasma bicarbonate levels may promote greater body weight gain and increased mid-arm circumference¹¹⁷; a rise in triceps skinfold (TSF) thickness is also reported but is not a consistent finding.¹¹³, ¹¹⁷ In one long-term study of CPD patients, raising the serum bicarbonate level was associated with fewer hospitalizations and shorter hospital stays.¹¹⁷ Rapid correction of acidemia by bicarbonate infusion has been associated with an increase in serum 1,25(OH)₂ D₃ concentrations¹²² and a decrease in osteocalcin, suggesting an improvement in osteoblast function.¹²³

A few studies have not found any detrimental effects of mild metabolic acidemia, and some investigators found that small increases in serum bicarbonate concentrations were not associated with significant improvements in nutritional or clinical status.¹²⁴, ¹²⁵, ¹²⁶ Indeed, some epidemiological studies report that a slightly increased anion gap, unadjusted for serum creatinine or albumin, is associated with a lower risk of mortality. This latter relationship may be due to greater appetites and protein intake in healthier people. However, most trials report that normalizing the predialysis or stabilized serum bicarbonate concentrations is beneficial for protein, amino acid and bone metabolism, and protein-energy nutritional status.³⁶ Thus, the serum bicarbonate should be monitored regularly at monthly intervals and correction of metabolic acidemia by maintaining serum bicarbonate at or above 22 mmol/L should be a goal of the management of individuals undergoing MD.

There are several technical problems with measuring bicarbonate. The techniques of blood collection and transportation and the assay methods can each influence the measured values. Serum bicarbonate (as total CO₂ ) was found to be significantly lower (about 4 mmol/L) in a reference laboratory when measured by enzymatic assay as compared with when it was measured directly by an electrode.¹²⁷ Introduction of air into the collecting tube, the technique of removal of blood for assay, and long delays in the measurement can each adversely affect the results. For more accurate values, blood should not be allowed to have contact with air, delays in processing of the sample should be avoided, and the same laboratory and methods of analysis should be used for serial measurements.

RECOMMENDATIONS FOR RESEARCH

1. The optimum serum bicarbonate and blood pH levels for MD patients need to be defined. There are data from individuals without renal insufficiency indicating that mid-normal or high normal blood pH range maintains better nutritional status than does the low-normal range.

2. More research is needed on the long-term effects of correcting acidemia on clinical outcomes and particularly on intermediate nutrition-related outcomes as well as morbidity and mortality.

3. The effect of correction of acidemia on muscle function and on beta-2 microglobulin metabolism needs more investigation.

3. Management of protein and energy intake 

Guideline 15. Dietary protein intake (Dpi) in maintenance hemodialysis (Mhd) 

RATIONALE

The findings from many studies that MHD patients have a high incidence of PEM underscores the importance of maintaining an adequate nutrient intake.¹²⁸, ¹²⁹ Although there are numerous causes for malnutrition, decreased nutrient intake is probably the most important. Causes of poor nutrient intake include anorexia from uremia itself, the dialysis procedure, intercurrent illness, and acidemia. Inadequate intake is also caused by comorbid physical illnesses affecting gastrointestinal function, depression, other psychiatric illness, organic brain disease, or socioeconomic factors. Removal of amino acids (about 10 to 12 g per HD),¹³⁰, ¹³¹, ¹³² some peptides,¹³³ low amounts of protein (≤1 to 3 g per dialysis, including blood loss), and small quantities of glucose (about 12 to 25 g per dialysis if glucose-free dialysate is used) may contribute to PEM. Hypercatabolism from a chronic inflammatory state, associated illnesses, the dialysis procedure itself, or acidemia may also induce malnutrition.¹³⁴, ¹³⁵, ¹³⁶, ¹³⁷

DPI is often reported to be low in MHD patients. A number of publications have described the mean DPI of individuals treated with MHD to vary from about 0.94 to 1.0 g protein/kg/d.⁵⁷, ¹³⁸, ¹³⁹, ¹⁴⁰ Hence, approximately half of MHD patients ingest less than this quantity of protein. Few studies have directly assessed the dietary protein requirements for MHD patients. No prospective long-term clinical trials have been conducted in which patients are randomly allocated to different dietary protein levels and the effects of protein intake on morbidity, mortality, or quality of life have been assessed.

Several prospective nutritional-metabolic studies have compared the effects of different levels of DPI on nutritional status. Most of these latter studies have been carried out in in-hospital clinical research centers, and hence, the numbers of patients studied have been small.⁵⁷, ⁵⁸, ¹³⁷, ¹³⁹ Taken together, these studies suggest that a DPI of about 1.2 g/kg/d is necessary to ensure neutral or positive nitrogen balance in most clinically stable MHD patients. At least 50% of the protein ingested should be of high biological value. Protein of high biological value has an amino acid composition that is similar to human protein, is likely to be an animal protein, and tends to be utilized more efficiently by humans to conserve body proteins. The increased efficiency of utilization of high biological value protein is particularly likely to be observed in individuals with low protein intakes.

Retrospective studies analyzing the relationships between DPI and such outcomes as nutritional status¹³⁸ or morbidity and mortality have also been conducted.¹⁴¹, ¹⁴², ¹⁴³ Protein intake in these studies has been estimated from dietary histories obtained from patient recall or estimated from the protein equivalent of total nitrogen appearance (PNA or PCR; see Appendix V for discussion of these methods). In two retrospective studies of MHD patients, protein intakes of less than 1.2 g/kg/d were associated with lower serum albumin levels and higher morbidity.¹⁴⁰, ¹⁴¹ On the other hand, not every epidemiological study found a significant relationship between morbidity or mortality and normalized PNA (nPNA or nPCR).¹⁴², ¹⁴³

In summary, a number of studies have shown a relationship between DPI and such measures of nutritional status as levels of serum albumin, prealbumin and transferrin, body weight, morbidity, and mortality. DPI also correlates with nitrogen balance. Protein intakes of less than 0.75 g/kg/d are inadequate for most MHD patients. Ingestion of 1.1 g of protein/kg/d (with at least 50% of the protein of high biological value) may maintain good protein nutrition in some MHD patients but is not sufficient to maintain good nutrition in the great majority of clinically stable patients ingesting 25 or 35 kcal/kg/d.⁵⁸ It is therefore recommended that a safe DPI that will maintain protein balance in almost all clinically stable MHD patients is 1.2 g protein/kg BW/d; at least 50% of the protein should be of high biological value.

It is difficult for some MHD patients to maintain this level of daily protein intake. Techniques must be developed to ensure this level of intake for all patients. Education and dietary counseling should be the first steps in attempting to maintain adequate protein intake. If this approach is unsuccessful, nutritional support, such as that outlined in Guideline 19, should be considered. These techniques include food supplements, tube feeding, and intravenous nutrition. It should be recognized that foods containing protein are major sources of phosphorus, hydrogen ions, cholesterol (in the case of animal protein), and dietary fats. When increasing dietary protein intake, adjustments in therapy (eg, dialysis dose, phosphate binders, bicarbonate supplementation, and cholesterol management) should be considered.

RECOMMENDATIONS FOR RESEARCH

1. More studies are needed on the relationship between the quantity and type of DPI and nutritional status, morbidity, mortality, and quality of life in MHD patients. Long-term, randomized, prospective clinical trials would be particularly helpful in addressing these questions. To reduce the large costs for such studies, innovative investigational tools are needed.

2. Information concerning dietary protein requirements of special subsets of MHD patients is needed. Such subsets include individuals with PEM or low dietary energy intake (DEI), obese individuals, and the elderly.

Guideline 16. Dietary protein intake (Dpi) for chronic peritoneal dialysis (Cpd) 

RATIONALE

The fact that patients with ESRD treated with CPD often have PEM emphasizes the importance of maintaining an adequate intake of protein.²⁹, ³⁰, ³³ Many of the causes of malnutrition in CPD patients are similar to those in MHD patients. However, protein losses into peritoneal dialysate are almost invariably higher than are protein losses into hemodialysate. Peritoneal protein losses average about 5 to 15 g/24 hours, and during episodes of peritonitis, dialysate protein may be considerably higher.¹⁴⁴ Peritoneal amino acid losses average about 3 g/d,¹⁴⁵ and some peptides are dialyzed. Anorexia due to glucose absorption from dialysate may also contribute to reduced dietary intake and malnutrition. These factors result in a requirement for dietary protein that is higher than in the normal population. Compounding these factors and predisposing to malnutrition is the finding that DPI is often rather low, less than 1.0 g/kg/d. As with MHD patients, malnutrition in peritoneal dialysis patients is associated with poor outcome.¹⁶, ¹⁹, ⁴⁴, ¹⁴⁵, ¹⁴⁷

Several studies have examined nitrogen balances in CPD patients consuming various levels of dietary protein. These studies indicate that DPIs of 1.2 g/kg/d or greater are almost always associated with neutral or positive nitrogen balance.⁵⁹, ⁶⁰, ¹⁴⁸ A number of studies show a relationship between DPI and such nutritional parameters as serum albumin, total body protein and nitrogen balance in patients undergoing CPD.⁵⁹, ⁶⁰, ¹⁴⁸ Based on these considerations, it is recommended that a safe DPI that will maintain protein balance in almost all clinically stable CPD patients is at least 1.2 g protein/kg body weight/d. A DPI of 1.3 g/kg/d probably increases the likelihood that adequate protein nutrition will be maintained in almost all clinically stable individuals. At least 50% of the protein should be of high biological value. The nPNA for a 70-kg man ingesting 1.2 g and 1.3 g protein/kg body weight/d, based on the Bergstrom and Blumenkrantz data, is estimated to be 1.02 and 1.14 g protein/kg/d.¹⁴⁹, ¹⁵⁰ It is recognized that some CPD patients will maintain good protein nutritional status with somewhat lower dietary protein intakes. The current guideline is recommended to provide assurance that almost all clinically stable CPD patients will have good protein nutrition.

Patients who do not have an adequate DPI should first receive dietary counseling and education. If DPI remains inadequate, oral supplements should be prescribed. If the oral supplements are not tolerated or effective and protein malnutrition is present, consideration should be given to use of tube feedings to increase protein intake. Amino acids may be added to dialysate to increase amino acid intake and to replace amino acid losses in dialysate.¹⁵¹, ¹⁵²

RECOMMENDATIONS FOR RESEARCH

1. The research recommendations for management of DPI for patients treated with maintenance peritoneal dialysis are similar to those for patients treated with MHD.

2. Studies to determine the optimum protein intake should be undertaken in subsets of CPD patients, including those who are elderly, malnourished, obese, or who have a low energy intake or catabolic illness such as peritonitis.

Guideline 17. Daily energy intake for maintenance dialysis patients 

RATIONALE

Longitudinal and cross-sectional data indicate that MD patients frequently have low energy intake and are underweight, often despite receiving apparently adequate dialysis therapy.¹²⁸, ¹⁵³ Low body weights (adjusted for height, age, and gender) are associated with increased mortality rates in MD patients.¹⁵, ⁵⁰, ⁸⁵, ⁸⁶ Hence, it would seem important to aggressively attempt to maintain adequate energy intakes.

Dietary energy requirements have been studied in MHD patients under metabolic balance conditions. Dietary energy requirements were examined in six MHD patients while they ingested diets providing 25, 35, and 45 kcal/kg/d and a DPI of 1.13 g/kg/d for 21 days each. These studies indicated that the mean energy intake necessary to maintain both neutral nitrogen balance and unchanging body composition was about 35 kcal/kg/d.⁵⁸ The finding that energy expenditure in MHD and CPD patients appears to be normal corroborates the observations from the aforementioned nitrogen balance and body composition studies.¹⁵⁴, ¹⁵⁵, ¹⁵⁶, ¹⁵⁷

Based on the aforementioned studies, it is recommended that MHD patients consume a diet with a total daily energy intake of 35 kcal/kg body weight/d. For CPD patients, the recommended total daily energy intake, including both diet and the energy intake derived from the glucose absorbed from peritoneal dialysate, should be 35 kcal/kg/d. Most of the patients who participated in these studies were younger than 50 years of age, and this recommendation is therefore made only for individuals less than 60 years of age. Because older age may be associated with reduced physical activity and lean body mass, a daily energy intake of 30 to 35 kcal/kg/d for older patients with more sedentary lifestyles is acceptable. These recommendations are approximately the same as those for normal adults of the same age who are engaged in mild daily physical activity as indicated in the Recommended Dietary Allowances (RDA).¹⁵⁸

Many patients will be unable to attain these recommended energy intakes. For individuals who are unable to consume an adequate energy intake, intensive education and dietary counseling by a trained dietitian should be undertaken. If this strategy is unsuccessful, oral nutritional supplements that are high in energy are recommended. Tube feedings and parenteral nutrition may also be considered (Guideline 19). Obese patients may not require as much energy per kilogram of body weight as nonobese patients (Guideline 12).

RECOMMENDATIONS FOR RESEARCH

1. Few studies have examined energy requirements of persons undergoing MHD or CPD. Hence, there is a great need for more research in this area. It would be of particular value to conduct both carefully controlled metabolic studies, as well as long-term, randomized outpatient clinical trials, particularly in which patients are randomly assigned to different energy intakes. It would be helpful to relate daily energy intake to morbidity, mortality, and quality of life scales, as well as to nutritional measures. To reduce the high cost and length of time to collect such data, innovative investigative tools to address these issues are needed.

2. Studies are needed to assess the optimal energy requirements of subsets of MD patients (eg, individuals with PEM, patients with superimposed catabolic illnesses, obese individuals, and elderly patients).

3. Studies are needed to examine whether increasing energy intake of MD patients with protein or energy malnutrition would be beneficial to the patients.

4. Assessment of energy intake is laborious, time-consuming, and therefore expensive. Developmental studies to create accurate and less costly methods for assessing energy intake are greatly needed.

4. Nutritional counseling and follow-up 

Guideline 18. Intensive nutritional counseling with maintenance dialysis (Md) 

RATIONALE

The high incidence of PEM and the strong association between measures of malnutrition and mortality rate in individuals undergoing MD suggests the need for careful nutritional monitoring and treatment of these individuals. Whether or not such intervention prevents or improves nutritional status has not been examined, but evidence clearly suggests that inadequate nutritional intake is an important contributor for PEM in these patients.¹⁵⁹ Moreover, evidence from large multicenter trials utilizing nutrition intervention indicates that frequent nutrition counseling results in compliance with the intervention and improved outcomes.¹⁶⁰, ¹⁶¹, ¹⁶², ¹⁶³ Although similar studies have not been performed in MD patients, it is reasonable to assume that similar results would occur with the ESRD patient population.

The dietitian-performed nutrition assessment includes the development of a plan of care that incorporates all aspects of the nutrition evaluation (nutritional status assessment, nutrition history, patient preferences, and the nutritional prescription). These are incorporated into an active plan that is then implemented by the medical team. This care plan should be updated on a quarterly basis. The nutrition care plan should be incorporated into a continuous quality improvement plan. This plan of care should be implemented and reviewed in a multidisciplinary fashion that includes the patient and/or caregiver (often the patient's spouse) and the physician, nurse, social worker, and dietitian.

Conditions in which the patient's nutritional status may deteriorate rapidly may dictate more frequent evaluation of the nutrition care plan. Examples of such conditions are unexplained reductions in energy or protein intake, depression, deterioration in other measures of protein-energy status, pregnancy, acute inflammatory or catabolic illnesses particularly in the elderly, hospitalization, diabetes mellitus, large or prolonged doses of glucocorticoid or other catabolic medications, and post-renal transplant allograft loss. Under these circumstances, monthly or weekly updates to the nutrition plan of care and more intensive nutrition counseling may be necessary.

RECOMMENDATIONS FOR RESEARCH

1. A better understanding of the effects of nutrition intervention counseling methods (including quality of life scales) on nutritional intake, nutritional status, morbidity, and mortality should be evaluated in MD patients.

Guideline 19. Indications for nutritional support 

RATIONALE

Many apparently well-dialyzed patients consume approximately 80% or less of their recommended energy intake,¹⁶⁴ even when counseled by an experienced renal dietitian. Inadequate nutrient intake may have a variety of causes, including anorexia, inadequate nutritional training, inability to procure or prepare food, psychiatric illnesses, superimposed acute or chronic diseases, mechanical impairments to food intake (eg, lack of dentures), cultural food preferences, and the uremic state, sometimes intensified by underdialysis.¹⁶⁵ Hospitalized MD patients often ingest even lower amounts (eg, as low as 66% and 50%, respectively) of protein and energy,¹³⁸, ¹⁵⁰ even though protein and energy needs of patients often increase during acute illness. Even in individuals who consumed an adequate diet prior to an illness, food intake may fall to inadequate levels. In the acutely ill hospitalized patient, prescription of an oral diet is often unlikely to improve the intake to a level that maintains neutral or positive nitrogen balance.¹³⁸, ¹⁵⁰ These considerations underscore the need for nutrition support for MD patients who sustain inadequate nutrient intake for extended periods of time. There are no large-scale, randomized, prospective clinical trials evaluating the effects of nutrition support in MD patients. Recommendations are therefore based on the experience in nonrenal patients as well as current information regarding nutrition and metabolism of ESRD patients.

Published guidelines and available recommendations suggest that counseling to increase dietary protein and energy intake, nutritional supplements, and tube feeding should be considered before attempting forms of parenteral nutrition in MD patients.¹⁶⁶, ¹⁶⁷, ¹⁶⁸, ¹⁶⁹ If the intestinal tract is functional, enteral tube feeding is traditionally considered the first line of nutritional therapy in the hospitalized patient who is unable to eat adequately. It has been used successfully to provide nutritional support to infants and children who are receiving MD.¹⁷⁰, ¹⁷¹, ¹⁷² Adult MHD patients have been nourished exclusively with oral supplements.¹⁷³ There is no reason to suspect that malnourished adult MD patients would differ from infants or children or that acutely ill adult MD patients would differ from acutely ill nondialysis patients in their response to enteral feedings, except for a greater need to restrict the water, mineral, and possibly protein loads in these feedings.¹⁷³

Advantages to enteral feeding include its ability to provide a patient's total nutritional needs chronically and on a daily basis, to provide balanced nutrients, to administer specialized formulas, to provide a smaller water load than intravenous feedings, to constitute a lower risk of infection than total parenteral nutrition (TPN), and to be less expensive than TPN or IDPN.¹⁷⁴, ¹⁷⁵ Risks of enteral feeding include pulmonary aspiration, fluid overload, reflux esophagitis, and other complications of enteral feeding devices.

MHD patients who satisfy each of the following three criteria may benefit from IDPN:

1. Evidence of protein or energy malnutrition and inadequate dietary protein and/or energy intake.¹⁷⁶

2. Inability to administer or tolerate adequate oral nutrition, including food supplements or tube feeding.

3. The combination with oral or enteral intake which, when combined with IDPN, will meet the individual's nutritional needs.

Previously published studies support the use of IDPN for selected MHD patients who are malnourished and eating poorly.¹⁶⁹, ¹⁷⁵, ¹⁷⁷ Advantages of IDPN as compared to tube feeding or TPN include the following: no need for a dedicated enteral feeding tube or vascular access, ultrafiltration during dialysis (which reduces the risks of fluid overload), and no demands on the time or effort of the patient. Disadvantages to IDPN include provision of insufficient calories and protein to support longterm daily needs (ie, IDPN is given during dialysis for only 3 days out of 7), it does not change patients' food behavior or encourage them to eat more healthy meals, and it is expensive.¹⁷⁸

IPAA may increase protein balance in clinically stable, malnourished CPD patients who have low protein intakes.¹⁵¹, ¹⁵², ¹⁷⁹, ¹⁸⁰, ¹⁸¹, ¹⁸², ¹⁸³, ¹⁸⁴, ¹⁸⁵ The net infusion of 2 L of peritoneal dialysate containing 1.1% amino acids with a peritoneal dwell time of 5 to 6 hours is associated with a retention of about 80% of the amino acids. The amount retained varies directly with peritoneal transport characteristics as determined by peritoneal equilibrium testing.¹⁸⁷ Hence, the administration of a single 2-L exchange of 1.1% amino acid dialysate for 5 to 6 hours provides a net uptake of about 17 to 18 g of amino acids, which is greater than the quantity of both protein (about 9 g) and amino acids (about 3 g) removed each day by peritoneal dialysis.¹⁸⁷

IPAA may also reduce the infused daily carbohydrate load by about 20%, thereby reducing the risk of hyperglycemia and the tendency to hypertriglyceridemia.¹⁸⁸ Most studies of IPAA were not randomized or controlled and used an open (before-after) or crossover design. Intermediate nutrition-related outcome variables (eg, nitrogen-protein balance, serum proteins, and anthropometry) were used in all studies. No study of IPAA has evaluated patient survival, hospitalization, or other clinical outcomes (eg, health-related quality of life). The long-term effects of IPAA on nutritional status and clinical outcomes are unknown. In some patients given IPAA, a mild metabolic acidosis may occur that is readily treatable.

CPD patients who satisfy each of the following three criteria may benefit from IPAA:

1. Evidence of protein malnutrition and an inadequate DPI.

2. Inability to administer or tolerate adequate oral protein nutrition, including food supplements, or enteral tube feeding.

3. The combination of some oral or enteral intake which, when combined with IPAA, will meet the individual's nutritional goals.

Also, in some patients who have difficulty with control of hyperglycemia, hypercholesterolemia, or hypertriglyceridemia that is related to the extensive carbohydrate absorption from peritoneal dialysate, IPAA might reduce serum glucose and lipid levels.

RECOMMENDATIONS FOR RESEARCH

1. Conduct a randomized clinical trial comparing oral nutritional supplements, tube feeding, and IDPN in malnourished MD patients. Outcomes should include survival, morbidity, and quality of life as well as nutritional status.

2. Research is needed to define the optimal composition of oral supplements, enteral nutrition, and IDPN formulas for MD patients.

3. Conduct studies of the indications for nutritional support in MD patients.

4. Determine the optimal timing for IPAA administration (eg, daytime CAPD versus nighttime with cycler).

5. Evaluate the effects of IPAA on physical function, hospitalization, and other clinical outcomes.

6. Examine the clinical value and cost-effectiveness of nutritional support through hemodialysate.¹³⁰

Guideline 20. Protein intake during acute illness 

Guideline 21. Energy intake during acute illness 

RATIONALE

For the purposes of this guideline, acutely ill refers to an acute medical or surgical illness associated with a state of increased catabolism. Such events would be expected to increase the protein and energy requirements. Hospitalization is not a prerequisite for this definition.

Few data exist on the protein requirements of acutely ill MD patients.¹³⁸, ¹⁵⁰, ¹⁸⁹, ¹⁹⁰ There are no published data of the energy requirements of acutely ill MD patients. Septic patients with acute renal failure have an increased resting energy expenditure (REE).¹⁵⁵ There is no reason to assume that the protein requirements of the acutely ill MD patient is less than that needed by the clinically stable MD patient.⁶⁰, ¹³⁸, ¹⁴⁸, ¹⁵⁰, ¹⁹⁰, ¹⁹¹ The recommended safe protein intake for MHD and CPD patients is considered to be 1.2 g/kg/d and 1.3 g/kg/d, respectively (Guidelines 15 and 16). The recommended daily energy intake for both MHD and CPD patients with light to moderate physical activity is 35 kcal/kg/d for those less than 60 years of age and 30 to 35 kcal/kg/d for those 60 years of age or older (Guideline 17).

Acutely ill, hospitalized MD patients often ingest less than 1.2 or 1.3 g protein/kg/d and are usually in negative nitrogen balance.¹³⁸, ¹⁵⁰ On the other hand, hospitalized dialysis patients who were given a mean protein intake of 1.3 g/kg/d or greater, with a non-protein energy intake of 34 ± 6 kcal/kg/d, were able to improve biochemical markers of nutritional status.¹⁸⁹ A protein intake of 0.79 g/kg/d or less and an energy intake of 18 ± 8 kcal/d or less is associated with neutral or negative nitrogen balance in hospitalized MHD patients.¹³⁸ In CAPD patients, hypoalbuminemia is more likely to occur when the protein intake is less than 1.3 g/kg/d and is significantly associated with an increased incidence of peritonitis and more prolonged hospital stays.¹⁹⁰ Protein intakes of 1.5 g/kg/d or greater appear to be well tolerated in CPD patients.⁶⁰, ¹⁹²

Hospitalized MD patients frequently have a decreased energy intake that, in one study, averaged 50% of recommended levels, and this was associated with negative nitrogen balance.¹³⁸ Hospitalized infected MD patients displayed an increase in serum proteins when their energy intake was 34 kcal/kg/d, and the increase in their serum prealbumin concentrations was directly correlated with the cumulative non-protein energy intake (r = 0.37, P < 0.01).¹⁸⁹

For acutely ill individuals without renal disease, greater DPIs, as high as 1.5 to 2.5 g/kg/d, are often recommended.¹⁶⁶ It is proposed that these higher protein intakes may preserve or even replete body protein more effectively than lower protein intakes.¹⁶⁶, ¹⁶⁷ These considerations raise the possibility that protein intakes greater than 1.2 or 1.3 g/kg/d may also benefit the catabolic, acutely ill MHD or CPD patient. However, there are no data as to whether these benefits will occur in acutely ill MD patients. Moreover, DPIs in this range, and the attendant increase in water and mineral intake, often will not be well tolerated by MD patients unless they are undergoing more intensive HD with increased dialysis dose (ie, more than three times per week or continuous venovenous hemofiltration with HD [CVVHD]).¹⁹³, ¹⁹⁴ Thus, MD patients who receive more intensive dialysis treatment may tolerate protein intakes greater than 1.2 to 1.3 g protein/kg/d. Amino acid losses and, hence, amino acid requirements may increase with more intensive HD (about 10 to 12 g of amino acids removed with each HD)¹³⁰, ¹³¹, ¹³² or with CVVHD (an average of about 5 to 12 g of amino acids per day removed with CVVHD in patients receiving nutritional support).¹⁹⁴

Because acutely ill MD patients are generally very inactive physically, their energy needs will be diminished by the extent to which their physical activity has been decreased. In rather sedentary individuals, however, physical activity accounts for only roughly 3% of total daily energy expenditure. In acutely ill nonrenal patients, REE may increase modestly, and daily energy requirements are not increased over normal. Thus, energy intakes of 30 to 35 kcal/kg/d are recommended for acutely ill MHD and CPD patients. The energy provided by the uptake of dextrose or other energy sources from dialysate should be included when calculating energy intake.

It is emphasized that many acutely ill individuals are not able to ingest this quantity of protein or energy,¹³⁸, ¹⁵⁰ and tube feeding, IDPN, or TPN may be necessary (Guideline 19). Hospitalized dialysis patients who have evidence of malnutrition at the time of admission may require more immediate nutrition support depending on the adequacy of their nutrient intake. For some patients in whom an extended period of inadequate nutrient intake can be projected, nutritional support should be instituted immediately. These recommendations refer to the acutely ill MD patient. The appropriate nutritional management of the acutely ill patient with acute renal failure may be quite different.¹⁹⁵

RECOMMENDATIONS FOR RESEARCH

1. Studies to define the optimal protein intake for the MD patients who are acutely ill are needed.

2. The effects of different levels of protein intake on patient outcome and on nutritional markers are needed. Because increasing protein intake may alter dialysis requirements, the effect of higher levels of protein intake on the optimal dose of dialysis should be defined.

3. The energy needs of acutely ill MD patients should be better defined. It would be particularly valuable to define how energy needs may vary with different protein and amino acid intakes.

4. The development of simple and inexpensive methods for determining the energy expenditure in individual acutely ill patients would be very helpful.

5. The optimal mixes of energy sources (ie, protein, amino acids, carbohydrates, and fat) for acutely ill MD patients should be defined.

6. Studies are needed that examine which energy intakes are associated with the most optimal clinical outcomes.

5. Carnitine 

Guideline 22. L-carnitine for maintenance dialysis patients 

RATIONALE

The use of L-carnitine in MD patients is attractive on the theoretical level, because it is well known that patients undergoing MD usually have low serum free L-carnitine concentrations and that skeletal muscle carnitine is sometimes decreased. Because L-carnitine is known to be an essential co-factor in fatty acid and energy metabolism, and patients on dialysis tend to be malnourished, it might follow that repletion of L-carnitine by the intravenous or oral route could improve nutritional status, particularly among patients with low dietary L-carnitine intakes. L-carnitine has been proposed as a treatment for a variety of metabolic abnormalities in ESRD, including hypertriglyceridemia, hypercholesterolemia, and anemia. It has also been proposed as a treatment for several symptoms or complications of dialysis, including intradialytic arrhythmias and hypotension, low cardiac output, interdialytic and post-dialytic symptoms of malaise or asthenia, general weakness or fatigue, skeletal muscle cramps, and decreased exercise capacity or low peak oxygen consumption. Studies using L-carnitine for each of these potential indications were reviewed. Randomized clinical trials were given particular consideration, although the evidence was not restricted to these studies, many of which are summarized in Appendix X.

There was complete agreement that there is insufficient evidence to support the routine use of L-carnitine for MD patients. In selected individuals who manifest the above symptoms or disorders and who have not responded adequately to standard therapies, a trial of L-carnitine may be considered. In reaching these conclusions, we considered the strength of available evidence as well as the alternative therapies available for each potential indication.

RECOMMENDATIONS FOR RESEARCH

1. Additional clinical trials in the area of erythropoietin-resistant anemia, carefully accounting for anticipated differences in response based on factors such as iron stores and the level of inflammatory mediators.

2. Further definition of the L-carnitine response by taking an “outcomes” approach to patients treated with L-carnitine. Can patient subgroups be identified who are likely to respond to L-carnitine for one or more of its proposed indications? Are certain individuals uniform “responders” across indications (a “carnitine-deficient” phenotype) or do certain patient characteristics predict specific responses?

3. A randomized clinical trial of L-carnitine in MD patients with cardiomyopathy and reduced ejection fraction.

4. A randomized clinical trial of L-carnitine for the treatment of hyperlipidemia, restricted to patients with preexisting hyperlipidemia.

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B. Advanced chronic renal failure without dialysis 

Guideline 23. Panels of nutritional measures for nondialyzed patients 

RATIONALE

Deterioration of nutritional status often begins early in the course of CRI, when the GFR is as high as 28 to 35 mL/min/1.73 m² or greater.¹⁹⁶, ¹⁹⁷, ¹⁹⁸ As a result, frank PEM is frequently present at the time that individuals commence MD therapy.¹⁶, ²³, ¹²⁸ Malnutrition in patients commencing MD is a strong predictor of poor clinical outcome.²², ²³, ⁷⁹, ¹⁹⁹ Thus, it is important to prevent or correct PEM in patients with progressive CRF, although randomized prospective clinical trials to test this hypothesis are not available. Methods for estimating or measuring GFR are discussed in Appendix IX.

The use of effective techniques to monitor nutritional status is an essential component of protocols to prevent or treat malnutrition in individuals with progressive CRI or CRF. Serum albumin, a measure of body weight-for-height (eg, %SBW), SGA, and assessment of dietary intake are all recommended because of the extensive experience with these indices and each is predictive of future morbidity and mortality in individuals with CRI or CRF or patients on MD. Serum albumin and prealbumin are indicators of visceral protein mass as well as inflammatory status and have been used extensively in persons with or without renal disease to assess nutritional status.¹⁷, ⁴² Moreover, hypoalbuminemia and low serum prealbumin at the initiation of dialysis are predictive of increased mortality risk.¹⁹, ⁴², ⁴⁴, ¹⁴⁵, ¹⁹⁹

For the nondialyzed patient with chronic renal failure, there are much more data relating serum albumin rather than serum prealbumin concentrations to outcome. Also, since serum prealbumin levels are affected by the GFR,¹⁷ variations in renal function may confound the results. Therefore, although either measurement could be used to assess the nutritional or inflammatory status of the CRI or CRF patient, the serum albumin may be the preferred measurement.

Reduction in body weight below reference values correlates with the loss of somatic protein, as well as increased risk of hospitalization, postoperative complications, and mortality.¹⁵, ⁸⁵ In MD patients, evidence of moderate to severe malnutrition as determined by SGA is associated with increased mortality.¹⁶, ⁷⁹, ²⁰⁰, ²⁰¹ Measurements of dietary interviews/diaries and nPNA are recommended because these measures can detect inadequate nutrient intake, which predicts poor outcome and is also a key cause of PEM (see Appendices III, V, and VI ).

RECOMMENDATIONS FOR RESEARCH

1. More sensitive and specific measures of protein-energy nutritional status in CRI/CRF patients need to be developed.

2. Studies are needed to test whether monitoring nutritional status in individuals with progressive CRI/CRF by a combination of measures is beneficial for detecting and preventing malnutrition.

3. Additional research is needed to define more accurately the combination of measures that provides the most useful information concerning the nutritional status of individuals with CRI/CRF.

Guideline 24. Dietary protein intake for nondialyzed patients 

RATIONALE

There are several potential advantages to prescribing a carefully designed low-protein diet (eg, about 0.60 g protein/kg/d) for the treatment of individuals with progressive CRF. Low-protein diets reduce the generation of nitrogenous wastes and inorganic ions, which cause many of the clinical and metabolic disturbances characteristic of uremia. Moreover, low-protein diets can diminish the ill effects of hyperphosphatemia, metabolic acidosis, hyperkalemia, and other electrolyte disorders. Although the main hypothesis of the Modification of Diet in Renal Disease Study was not proven,²⁰² post hoc analyses indicated that low protein diets retarded the progression of renal failure.²⁰³, ²⁰⁴ Three meta-analyses each indicate that such diets are associated with retardation of the progression of renal failure or a delay in the onset of renal replacement therapy.²⁰⁵, ²⁰⁶, ²⁰⁷ It is also possible that in patients with higher levels of GFR, possibly as great as 50 mL/min/1.73 m², a planned low protein diet may retard progression of renal failure. There has been much confusion in the nephrology community regarding the collective results of these studies.

A decline in protein and energy intake and in indices of nutritional status have been documented in patients with a GFR below about 50 mL/min/1.73 m² who have been consuming uncontrolled diets.¹⁹⁶, ¹⁹⁷, ¹⁹⁸ Indeed, patients who are allowed to eat ad libitum diets may ingest inadequate energy and, occasionally, insufficient protein rather than too much. In contrast, both metabolic balance studies as well as clinical trials suggest that the preponderance of CRF patients ingesting a controlled low-protein diet providing 0.60 g protein/kg/d will maintain nutritional status,⁵⁷, ⁹⁹, ²⁰⁸, ²⁰⁹, ²¹⁰ particularly if they receive higher energy intakes (ie, 35 kcal/kg/d).²¹¹

DPIs providing somewhat larger quantities of protein have been recommended based on the findings that adherence is easier with such diets and actual protein intakes of 0.75 g/kg/d or lower were all associated with similar rates of progression of renal failure in patients with a GFR of 25 mL/min/1.73 m² or lower.²⁰³ Thus, for individuals who are unwilling or unable to ingest 0.60 g protein/kg/d or are unable to maintain adequate energy intakes with this dietary regimen, a diet providing up to 0.75 g protein/kg/d may be prescribed. Such diets must be carefully implemented by personnel with expertise and experience in dietary management (Appendix IV), and individuals prescribed such a diet must be carefully monitored (Guidelines 1 and 26 and Appendix III). Methods for measuring or estimating GFR are discussed in Appendix IX.

RECOMMENDATIONS FOR RESEARCH

1. Which subpopulations of patients with progressive chronic renal disease are particularly likely or unlikely to display slowing in the decline of their GFR with dietary protein restriction?

2. Are there any additive benefits to prescribing both low protein diets and angiotensin converting enzyme inhibitors for patients with progressive chronic renal disease?

Guideline 25. Dietary energy intake (Dei) for nondialyzed patients 

RATIONALE

In patients with CRF who are not receiving dialysis therapy, energy expenditure (and hence energy requirements) when measured at rest, while sitting quietly, during prescribed exercise, or after ingesting a meal of a defined composition is similar to that of healthy subjects.¹⁵⁴, ¹⁵⁵ Available evidence indicates that a diet providing about 35 kcal/kg/d is necessary to maintain neutral nitrogen balance, to promote higher serum albumin concentrations and more normal anthropometric parameters, and to reduce the UNA (ie, to improve protein utilization).²¹¹ These energy needs are similar to those described in the USRDA for normal adults of similar age.¹⁵⁸ In CRF patients 60 years of age or older, who tend to be less physically active, an energy intake of 30 to 35 kcal/kg/d may be sufficient, although energy requirements of CRF patients in this age range have not been well studied. This latter recommendation is based, in part, on the recommended dietary allowances of older normal adults (US Recommended Dietary Allowances).¹⁵⁸

The recommendation for this energy intake for individuals with GFR less than 25 mL/min is based on findings of low energy intakes in clinically stable individuals with this level of renal insufficiency and evidence that these patients often show signs of nutritional deterioration.¹⁹⁶ Methods for measuring or estimating GFR are discussed in Appendix IX.

It may be difficult (or impossible in some circumstances) for patients to achieve this energy goal with dietary counseling alone. However, inadequate energy intake is considered to be one of the principal reversible factors contributing to malnutrition in the ESRD population. To facilitate compliance with the energy prescription, creative menu planning is encouraged, taking into consideration the patient's food preferences. Foods, beverages, and nutritional supplements with high energy density may be used. If sufficient energy intake to maintain nutritional status cannot be attained by these techniques, supplemental tube feeding may be considered.

RECOMMENDATIONS FOR RESEARCH

1. Studies are needed to assess why spontaneous DEI is reduced in persons with CRF who are not undergoing MD.

2. More data are needed on the energy requirements of clinically stable patients with CRI. There are very few data in this area.

3. Data are also needed on the energy requirements of individuals with CRF who are obese or malnourished or who have associated catabolic illnesses.

4. What techniques can be used to increase energy intake in individuals with CRI and CRF?

Guideline 26. Intensive nutritional counseling for chronic renal failure (Crf) 

RATIONALE

PEM is common in people with ESRD and several studies indicate that it is often present at the time that MD therapy is initiated, indicating that deterioration in nutritional status often predates the onset of renal replacement therapy.¹⁶, ²¹, ⁷⁵, ¹²⁸, ²⁰¹ Indeed, research indicates that patients with CRI who are not receiving nutritional management often demonstrate evidence of deterioration in nutritional status before dialysis therapy is initiated.¹⁹⁶, ¹⁹⁸ Moreover, biochemical and anthropometric indicators of PEM present at the initiation of dialysis are predictive of future morbidity and mortality risk.²², ²³, ²⁵, ⁴², ⁵², ¹⁹⁹, ²⁰¹, ²¹² A progressive decline in dietary protein and energy intake, anthropometric values, and biochemical markers (eg, serum albumin, transferrin, cholesterol, and total creatinine excretion) of nutritional status has been documented in patients with progressive CRF consuming uncontrolled diets. The decline in spontaneous protein and energy intake, serum proteins, and anthropometric values is evident when the GFR falls below 50 mL/min and is particularly notable below a CrCl of about 25 mL/min.¹⁹⁶, ¹⁹⁷ In one prospective observational study, for each 10 mL/min decrease in CrCl, DPI decreased by 0.064 ± 0.007 g/kg/d, weight declined by 0.38% ± 0.13% of initial weight, and serum transferrin decreased by 16.7 ± 4.1 mg/dL.¹⁹⁶ A positive correlation between energy intake and GFR has also been reported, independent of the prescribed protein intake.¹⁹⁷

In summary, evidence of PEM may become apparent well before there is a requirement for renal replacement therapy. Interventions that maintain or improve nutritional status are likely to be associated with improved long-term survival, although this has not been proven in randomized, prospective clinical trials. Therefore, it is recommended that regular monitoring of the patient's nutritional status should be a routine component of predialysis care.

RECOMMENDATIONS FOR RESEARCH

1. Why do apparently clinically stable patients with creatinine clearances under 50 mL/min often have decreased dietary protein and energy intakes and evidence of deteriorating nutritional status?

2. What interventions are likely to prevent or reverse the developing PEM in these individuals?

3. Will interventions that improve nutritional status reduce morbidity and mortality in these individuals?

Guideline 27. Indications for renal replacement therapy 

RATIONALE

It is well documented that mortality and morbidity are increased in individuals with ESRD who begin dialysis therapy with overt evidence of PEM. Accumulating evidence also indicates that initiation of dialysis more in line with current NKF-DOQI practice guidelines (ie, GFR ~10.5 mL/min) results in improved patient outcomes compared with when dialysis is delayed until the GFR is <5 mL/min and symptomatic uremia and associated medical complications are present.²¹³, ²¹⁴, ²¹⁵ Furthermore, there is evidence that initiating maintenance dialysis under these circumstances, and when there has been nutritional deterioration, results in an improvement in nutritional indices.²¹⁵, ²¹⁶, ²¹⁷, ²¹⁸, ²¹⁹, ²²⁰ There is no evidence that earlier initiation of dialysis leads to improved nutritional status among patients without overt uremia. Moreover, it has not been established that improved nutritional status at the initiation of dialysis directly leads to improved survival or fewer dialysis-related complications. Despite the lack of evidence from controlled clinical trials, interventions that maintain or improve nutritional status before the requirement for renal replacement therapy are likely to result in improved long-term survival.

There is ample evidence that the survival of patients with ESRD is closely associated with their nutritional status (Guidelines 3 through 6, 8, 18, and 23). These findings have been demonstrated not only in large, diverse populations of prevalent MD patients, but also in patients commencing MD therapy.²³, ⁷⁹, ²²¹ Hypertension, pre-existing cardiac disease, and low serum albumin concentrations were independently associated with diminished long-term survival in 683 ESRD patients who started dialysis during 1970 through 1989.²²¹ In 1,982 HD patients, a low serum albumin concentration at the initiation of dialysis was associated with a significant increase in the relative risk of death.²³ A direct relation between serum albumin and survival and an independent association between modified SGA and survival was observed in 680 incident CPD patients.⁷⁹ In contrast, in one study no significant associations were found between serum albumin, creatinine, and urea concentrations and survival in incident HD patients.²²² The sample size in the latter study was relatively small (n = 139), and 94% of the study sample were Black (83%) or Hispanic (11%).²²² No studies have specifically examined the relations among other nutritional indicators (eg, %SBW, PNA, and DXA) and survival in incident HD or peritoneal dialysis patients.

Low-protein (eg, 0.60 g protein/kg/d), high-energy (35 kcal/kg/d) diets may retard the rate of progression of chronic renal disease²⁰⁶, ²⁰⁷ and should maintain patients with chronic renal disease in good nutritional status (Guidelines 24 and 25).⁵⁷, ⁹⁹, ²⁰⁸, ²⁰⁹, ²¹¹ However, it is recognized that such low-protein diets may not maintain adequate nutritional status in all patients, particularly if an adequate energy intake is not maintained (Guideline 25).⁹⁹, ²¹¹ Furthermore, there is evidence that the spontaneous intake of protein and energy, and other indicators of nutritional status, tend to diminish in patients with progressive CRI who are consuming unregulated diets.¹⁹⁶ Therefore, patients with CRI need to undergo nutritional assessment at frequent intervals so that any deterioration in nutritional status can be detected early (Guidelines 23 and 26 and Appendix IV). The plan of care and nutritional interventions outlined in Guideline 18 for the nutritional management of the dialysis patient is also appropriate for patients with progressive CRI.

Because of the association between PEM and poor outcome, it is recommended that MD be initiated or renal transplantation performed in patients with advanced CRF (ie, GFR <20 mL/min) if there is evidence of deteriorating nutritional status or frank PEM, no other apparent cause for the malnutrition, and efforts to correct the nutritional deterioration or PEM are unsuccessful, despite the absence of other traditional indications for dialysis (eg, pericarditis or hyperkalemia). Although the following criteria are not considered rigid or definitive, initiation of renal replacement therapy should be considered if, despite vigorous attempts to optimize protein and energy intake, any of the following nutritional indicators show evidence of deterioration: (1) more than a 6% involuntary reduction in edema-free usual body weight (%UBW) or to less than 90% of standard body weight (NHANES II) in less than 6 months; (2) a reduction in serum albumin by greater than or equal to 0.3 g/dL and to less to than 4.0 g/dL (Guideline 3), in the absence of acute infection or inflammation, confirmed by repeat laboratory testing; or (3) a deterioration in SGA by one category (ie, normal, mild, moderate, or severe; Guideline 9 and Appendix VI).

RECOMMENDATIONS FOR RESEARCH

1. Studies to assess the optimal timing and indications for commencing renal replacement therapy are needed.

2. Serial evaluations of nutritional status in the course of these studies will help to determine whether initiation of dialysis indeed improves nutritional status.

3. Studies should be conducted to determine whether any GFR level can be used to indicate when maintenance dialysis should be initiated.

4. Whether earlier initiation of renal replacement therapy can prevent the development or worsening of PEM and its attendant complications needs to be evaluated in a controlled study.

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C. Appendices (Adult guidelines) 

Appendix I. Methods for measuring serum albumin 

Most laboratories utilize a colorimetric method for the measurement of the serum albumin concentration and particularly the bromcresol green (BCG) assay. If another assay is utilized, the normal range specific to that assay should be used. Research that reports the serum albumin should specify the assay used and its normal range.

Nephelometry and the electrophoretic method²²³ are very specific for the determination of the serum albumin concentration. However, these methods are time-consuming, expensive, and not generally used in clinical laboratories. The BCG colorimetric method is rapid, reproducible, and has been automated.²²⁴ This method uses small aliquots of plasma, has a low coefficient of variation (5.9%), and is not affected by lipemia, salicylates, or bilirubin. With values in the normal electrophoretic range of 3.5 to 5.0 g/dL, the BCG method gives values that are comparable to the values obtained by electrophoresis. The normal range for the serum albumin by the BCG method is 3.8 to 5.1 g/dL.²²⁴ The BCG method differs from the electrophoretic method by about 0.3 g/dL.²²³ The BCG method underestimates albumin in the high normal range and overestimates albumin below the normal range with an overall mean overestimation of approximately 0.61 g/dL.²²⁵

Some laboratories use the bromcresol purple (BCP) colorimetric method to measure the serum albumin concentration.²²³ Although this method is more specific for albumin and has specificity similar to electrophoretic methods, clinically it has proved to be less reliable than the BCG method. BCP has been shown to underestimate serum albumin in pediatric HD patients with a mean difference of 0.71 g/dL.²²⁶ Maguire and Price²²⁷ have demonstrated similar results in CRF patients.

Serum albumin concentrations obtained by the BCG method in HD patients were virtually identical to the values obtained using nephelometry. Values obtained by the BCP assay underestimated the nephelometric values by 19%. Agreement between BCG and BCP with the nephelometric values in CAPD patients showed less variation; however, the BCG values were not different from the nephelometric values.²²⁸

Chronic dialysis units often have little influence over the method used by their reference laboratories. If the BCG method is available, it should be requested. If the BCP method must be used, then the normal range for that laboratory should serve as the reference. Additionally, less clinical weight might be given to serum albumin concentrations measured by the BCP method and other markers of malnutrition in ESRD patients might be more heavily weighted.

Appendix II. Methods for calculation and use of the creatinine index 

The creatinine index is defined as the creatinine synthesis rate. The creatinine index is used to assess the dietary skeletal muscle protein intake and skeletal muscle mass. The creatinine index is determined primarily by the size of the skeletal muscle mass and the quantity of skeletal (and cardiac) muscle ingested (ie, the intake of creatine and creatinine). Hence, creatinine production is approximately proportional to skeletal muscle mass in stable adults who are neither anabolic nor catabolic and who have a constant protein intake.⁴⁶, ¹⁰², ²³⁴ In normal individuals, dietary intake of creatine and creatinine from skeletal (and cardiac) muscle is associated with increased urinary excretion of creatinine.⁵³, ²²⁹ In clinically stable individuals undergoing MD, creatinine is synthesized and levels rise in plasma at a rate that is approximately proportional to somatic protein (skeletal muscle) mass and dietary muscle (protein) intake.¹⁷, ⁴⁶, ¹⁰² In CPD patients, the stabilized serum creatinine and creatinine index are also proportional to skeletal muscle mass and dietary muscle intake.

The creatinine index is measured as the sum of creatinine removed from the body (measured from the creatinine removed in dialysate, ultrafiltrate, and/or urine), any increase in the body creatinine pool, and the creatinine degradation rate.⁴⁸

The equation for calculating the creatinine index is as follows: Creatinine index (mg/24 h) = dialysate (or ultrafiltrate) creatinine (mg/24 h) + urine creatinine (mg/24 h) + change in body creatinine pool (mg/24 h) + creatinine degradation (mg/24 h) The change in the body creatinine pool is calculated as follows: Change in body creatinine pool (mg/24 h) = [serum creatinine (mg/L)_f − serum creatinine (mg/L)_i ] × [24/h/(time interval between the i and f measurements)] × [body weight (kg) × (0.50 L/kg)] where i and f are the initial and final serum creatinine measurements (usually separated by about 20 to 68 hours), body weight is the time averaged body weight between the initial and final serum creatinine measurements, and 0.50 L/kg is the estimated volume of distribution of creatinine in the body.²³⁰, ²³¹

The change in the body creatinine pool when body weight varies can be calculated from the following equation: Change in creatinine pool (mg/24 h) = [[serum creatinine (mg/L)_f × (body weight (kg)_f × 0.5 L/kg)] − [serum creatinine (mg/L)_i × (body weight (kg)_i × 0.5 L/kg)]] × (24 h/time interval between the i and f measurements) The creatinine degradation rate is estimated as follows: Creatinine degradation (mg/24 h) = 0.38 dL/kg/24 h × serum creatinine (mg/dL) × body weight (kg)²³⁰ The creatinine index can be used to estimate dietary skeletal muscle protein or mass and edema-free lean body mass.²³², ²³³ The relation between the creatinine index and edema-free lean body mass may be estimated as follows: Edema-free lean body mass (kg) = (0.029 kg/mg/24 h) × creatinine index (mg/24 h) + 7.38 kg²³⁴ The constant used in this last equation (0.029 kg/mg/24 h) was derived from individuals without renal disease²³⁴ and should be reevaluated for ESRD patients; at least one study suggests that this constant is also applicable for MD patients.²³² Skeletal or cardiac muscle protein intake as well as total protein intake can affect the creatinine index,²³⁵, ²³⁶ and marked variations in these nutrients may therefore have major effects on the creatinine index. Thus, until the relationships between total protein intake and muscle intake and the creatinine index are well defined for ESRD patients, some caution must be exercised in interpreting the creatinine index, particularly if the diet of the individual in question is particularly high or low in these nutrients.

Appendix III. Dietary interviews and diaries 

There are several methods for estimating dietary nutrient intake.¹⁵³, ²³⁷ The most common methods are food intake records and dietary recalls. The dietary recall (usually obtained for the previous 24 hours) is a simple, rapid method of obtaining a crude assessment of dietary intake. It can be performed in approximately 30 minutes, does not require the patient to keep records, and relies on the patient's ability to remember how much food was eaten during the previous 24 hours. Accurate quantification of the amounts of foods eaten is critical for the 24-hour recall. Various models of foods and measuring devices are used to estimate portion sizes. Advantages to the recall method are that respondents usually will not be able to modify their eating behavior in anticipation of a dietary evaluation and they do not have to be literate. Disadvantages of the 24-hour recall include its reliance on memory (which may be particularly limiting in the elderly), that the responses may be less accurate or unrepresentative of typical intakes, and that it must be obtained by a trained and skilled dietitian.

Dietary diaries are written reports of foods eaten during a specified length of time. A food-intake record, lasting for several days (3 to 7 days), provides a more reliable estimate of an individual's nutrient intake than do single-day records. Records kept for more than 3 days increase the likelihood of inaccurate reporting because an individual's motivation has been shown to decrease with increasing number of days of dietary data collection, especially if the days are consecutive.²³⁸ On the other hand, records maintained for shorter times may not provide accurate data on usual food and nutrient intakes. The actual number of days chosen to collect food records should depend on the degree of accuracy needed, the day-to-day variability in the intake of the nutrient being measured, and the cooperation of the patient. When food records are chosen to estimate dietary energy and DPI in MD patients, it is recommended that 3-day food records be obtained for accuracy and to minimize the burden on the patient and/or his family. Records should include at least one weekday and one weekend day, in addition to dialysis and nondialysis days for MHD patients, so that variability in food intake can be estimated more accurately.

The validity and reliability of the dietary interviews and diaries depend on the patient's ability to provide accurate data and the ability of the nutritionist to conduct detailed, probing interviews. The intake of nutrients is generally calculated using computer-based programs. Food records must be maintained meticulously to maximize the accuracy of the diary. Food intake should be recorded at the time the food is eaten to minimize reliance on memory. Special data collection forms and instructions are provided to assist the individual to record adequate detail. Recording error can be minimized if instructions and proper directions on how to approximate portion sizes and servings of fluid are provided.

Food models are also helpful for instruction. The food record should indicate the time of day of any intake (both meals and snacks), the names of foods eaten, the approximate amount ingested, the method of preparation, and special recipes or steps taken in the food preparation. The dietitian should carefully review the food record with the patient for accuracy and completeness shortly after it is completed.

Calculation and Expression of Protein and Energy Intake

DPI can be expressed in absolute units such as grams of protein per day (g/d) or as a function of the patient's actual or adjusted body weight (eg, g/kg/d; Guideline 12). Dietary energy intake (DEI) refers to the energy yielded from ingestion of protein, carbohydrates, fat, and alcohol. DEI can be expressed in absolute units such as kilocalories per day (kcal/d) or as a function of the patient's actual or adjusted body weight per day (kcal/kg/d). Consideration should be given to using the adjusted edema-free body weight (aBW_ef , Guideline 12) to express DPI or DEI in individuals who are less than 95% or greater than 115% of SBW.

In CPD patients with normal peritoneal transport capacity, approximately 60% of the daily dialysate glucose load is absorbed, resulting in a glucose absorption of about 100 to 200 g of glucose per 24 hours.²³⁹, ²⁴⁰ Another method ofestimating the quantity of glucose absorbed is the following formula²⁴⁰: Glucose absorbed (g/d) = 0.89x (g/d) − 43 where x is the total amount of dialysate glucose instilled each day. Both of the methods described above are based on the observation that (anhydrous) glucose in dialysate is equal to about 90% of the glucose listed. For example, dialysate containing 1.5% glucose actually contains about 1.30 g/dL of glucose and 4.25% glucose in dialysate actually contains 3.76 g/dL of glucose.²⁴⁰ It is probable that the relationship between dialysate glucose concentration and glucose absorbed may be different with automated peritoneal dialysis.

The net glucose absorption from dialysate should be taken into consideration when calculating total energy intake for PD patients.

Appendix IV. Role of the renal dietitian 

Implicit in many of the guidelines in this document is the availability to the patient of an individual with expertise in renal dietetics. Implementation of many of the guidelines concerning nutritional assessment (anthropometry, subjective global assessment, dietary interviews and diaries, and integration of the results of nutritional measurements) and nutritional therapy (developing a plan for nutritional management, counseling the patient and his/her family on appropriate dietary protein and energy intake, monitoring nutrient intake, educational activities, and encouragement to maximize dietary compliance) is best performed by an individual who is trained and experienced in these tasks. Although occasionally a physician, nurse, or other individual may possess the expertise and time to conduct such activities, a registered dietitian, trained and experienced in renal nutrition, usually is best qualified to carry out these tasks. Such an individual not only has undergone all of the training required to become a registered dietitian, including, in many instances, a dietetic internship, but has also received formal or informal training in renal nutrition. Such a person, therefore, is particularly experienced in working with MD patients as well as individuals with CRF.

There appears to be a general sense among renal dietitians, based on experience, that an individual dietitian should be responsible for the care of approximately 100 MD patients but almost certainly no more than 150 patients to provide adequate nutritional services to these individuals.²⁴¹, ²⁴² Because, in many dialysis facilities, the responsibilities of the renal dietitian are expanded beyond the basic care described in these guidelines (eg, monitoring protocols and continuous quality improvement), these facilities should consider a higher ratio of dietitians to patients. Randomized prospective controlled clinical trials have not been conducted to examine whether this is the maximum number of patients at which dietitians are still highly effective.

Appendix V. Rationale and methods for the determination of the protein equivalent of nitrogen appearance (PNA) 

The reader is referred to previously published guidelines and to the works of primary investigators in the field for a more in-depth explanation of urea modeling and kinetics. The DOQI Nutrition Work Group endorses the previous DOQI recommendations concerning Kt/V and offers new material concerning eKt/V and a new recommendation for the normalization of PNA (nPNA). The Work Group recognizes that dialysis units may use a variety of methods for determining Kt/V and nPNA. These may range from the use of previously published nomograms and simple, noniterative formulas to the use of iterative urea kinetic modeling. The Work Group does not propose that one method is superior to another, but only that the formulas listed in this Appendix are preferable for the uses indicated. The term nPNA will be substituted for normalized protein catabolic rate (nPCR) when the latter term was used in earlier equations and published reports.

RATIONALE

The results of the National Cooperative Dialysis Study (NCDS) led to a mechanistic analysis of dialysis adequacy based on solute clearance.²⁴³ Two important concepts emerged from these analyses: urea clearance (a measure of dialysis dose not related to protein catabolism) and nPNA (a measure of protein nitrogen appearance unrelated to dialysis dose). Some have pointed out that Kt/V and nPNA may be mathematically interrelated, because they share some common parameters.²⁴⁴ Potential causes of coupling including error coupling, calculation bias, and confounding variables.²⁴⁴ Certain study designs are sensitive to specific errors due to these types of mathematical coupling. For example, cross-sectional studies may suffer from all three types of errors. Nonrandomized longitudinal studies may be affected by calculation bias and confounding variables; and randomized, prospective trials are subject to calculation bias. The prospective, randomized HEMO trial should help to determine the physiological relationship between Kt/V and nPNA.²⁴⁴ Current data suggest that there is little relationship clinically between Kt/V and nPNA.²⁴⁵ nPCR did not differ between the Kt/V = 1.0 and Kt/V = 1.4 groups, but did increase with a higher protein diet group (1.3 versus 0.9 g/kg/d). The presence of these three types of error in the determination and interpretation of Kt/V and nPNA must be recognized by the clinician if Kt/V and nPNA are to be correctly interpreted.

nPNA may be affected by protein intake, by anabolic and catabolic factors such as corticosteroids or anabolic hormones, and possibly by other factors that are currently unrecognized. nPNA is closely correlated with DPI only in the steady state; ie, when protein and energy intake are relatively constant (< 10% variance), when there are little or no internal or external stressors, when there is no recent onset or cessation of anabolic hormones, and, when calculated by the two-BUN method, the dose of dialysis is constant. In the individual patient who is in a stable steady-state and who has none of the previously mentioned conditions that would interfere with the interpretation of the nPNA, it may be reasonable to assume that nPNA reflects the DPI. As has been done in the HEMO study, it is advisable to independently check the DPI (derived from nPNA) by intermittently obtaining dietary histories.

The terminology for PCR has recently been questioned. It has been argued that, although it represented a useful concept, it was a misnomer, because intact proteins, peptides, and amino acids are lost in dialysate and urine and are not catabolized. Moreover, protein catabolism in nutrition and metabolic literature refers to the absolute rate of protein breakdown that commonly requires measurement of isotopically labeled amino acids. The absolute rate of protein breakdown is much greater than the net degradation of exogenous and endogenous proteins that result in urea excretion.⁶³ Instead of PCR, the term “protein equivalent of total nitrogen appearance” (PNA) has been suggested,⁶³ which is in keeping with the original definition suggested by Borah et al.¹³⁷ The DOQI Nutrition Work Group prefers the use of PNA instead of PCR and recommends its acceptance by the dialysis community, because it is more precise and is a term that better reflects the actual physiology.

PNA may be normalized (nPNA) to allow comparison among patients over a wide range of body sizes. The most convenient index of size is the urea distribution volume (V), because it is calculated from urea modeling, is equivalent to body water volume, and is highly correlated with fat free or lean body mass. Total body weight is a poor index of PNA because nitrogen appearance is not affected by body fat. However, because V is an index that is unfamiliar to clinicians and not readily available, it is customary to convert V to a normalized body weight by dividing by 0.58, its average fraction of total body weight. The resulting nPNA is expressed as the equivalent number of grams of protein per kilogram of body weight per day, but it is important to note that body weight in the denominator is not the patient's actual body weight but instead is an idealized or normalized weight calculated from V/0.58. For example, to calculate DPI (for a patient who satisfies the previously discussed criteria for steady state), one must not multiply nPNA by the patient's actual body weight but instead multiply by V/0.58.

The Work Group believes that ideal body weight (aBW_ef ), which correlates very closely with body water volume, is a good denominator for normalizing PNA. Ideal weight may be more appropriate than V/0.58 in patients who are emaciated or edematous. Like many physiologic variables, PNA may correlate better with body surface area, but because water volume is highly correlated with surface area within the range of adult body sizes, urea volume is a reasonable substitute.

The methods used to determine the PNA (PCR) differ between maintenance hemodialysis and chronic peritoneal dialysis because of the differences in calculating total nitrogen appearance (TNA). TNA is the sum of all outputs of nitrogen from the body including skin, feces, urine, and dialysate. The technique for the measurement of TNA is expensive, labor intensive, and impractical for routine clinical use. In metabolically stable patients, the nitrogen output in feces (including flatus) and skin (including nails and hair) is constant and can be ignored for the sake of simplifying the calculation. The TNA is very strongly correlated with UNA.¹³⁷, ¹⁵⁰, ²⁴⁶, ²⁴⁷, ²⁴⁸ Although this correlation is strong, the 95% confidence limits are ±20% of the mean.²⁴⁹ The regression equations used to estimate TNA from UNA may not be accurate if a patient has unusually large protein losses into dialysate, has high urinary ammonium excretion, or is in marked positive or negative nitrogen balance.⁶³

The formulas used to calculate the single-pool Kt/V (spKt/V) and PNA (PCR) can be divided into two separate groupings: those that depend on a three-BUN measurement, single-pool, variable-volume kinetic model and those that depend on a two-BUN measurement, single-pool, variable-volume model.

The two-BUN method is more complex than the three-BUN method, because it requires computer iteration over an entire week of dialysis to arrive at G (urea generation rate). The three-BUN method calculates the urea generation rate (G) from the end of the first dialysis to the beginning of the second dialysis and is primarily determined by the difference between the two-BUN values (post- to pre-). It also requires iteration and a computer but only over the time span of a single dialysis and a single interdialysis interval. The two-BUN method calculates G from the absolute value of the predialysis BUN (C₀ ) and Kt/V. Because C₀ is determined both by G and by Kt/V, if Kt/V is known (calculated from the fall in BUN during dialysis), then G can be determined from the absolute value of C₀ (by the complicated iteration scheme over an entire week). Note that the absolute value of C₀ is not used to calculate Kt/V, which is determined by the log ratio of C₀ /C. Comparing the two methods, although the three-BUN method is mathematically simpler, it is actually more difficult to do because it requires waiting 48 to 72 hours before the third BUN can be drawn. It is also a more narrow measure of G because it is constrained to the single interdialysis period and can be manipulated by the patient who becomes aware that the measurement will be done when the first two blood samples are drawn. Fortunately, graphical nomograms have been developed and validated that allow the calculation of PNA based on predialysis and postdialysis BUN samples from the same dialysis session.²⁵⁰

Equations for the Determination of spKt/V, V, and PNA (PCR) in HD and Peritoneal Dialysis Patients

Hemodialysis. Two-BUN, single-pool, variable-volume model: Beginning of week PNA (PCR) = C₀ /[36.3 + (5.48)(spKt/V) + ((53.5)/(spKt/V))] + 0.168 Midweek PNA (PCR) ; = C₀ /[25.8 + ((1.15)/(spKt/V)) + (56.4)/(spKt/V)] + 0.168 End of week PNA (PCR) ; = C₀ /[16.3 + (4.3)(spKt/V) + (56.6)/(spKt/V) + 0.168 where C₀ is the predialysis BUN. C₀ is adjusted upward in patients who have significant remaining GFR according to the formula: C₀ ′ = C₀ [1 + (0.79 + (3.08)/(Kt/V))Kr/V] Kr is residual urinary urea clearance in mL/min, C₀ ′ and C₀ are in mg/dL, and V is in L. Because these formulas introduce errors ranging from 3.7% (end of week) to 8.39% (beginning of week) and the r ranges from 0.9982 to 0.9930, the Work Group believes that they represent an excellent approach to the simplified measurement of PNA (PCR).

The DOQI Hemodialysis Adequacy Work Group has recommended the use of the natural log formula to calculate Kt/V: spKt/V = −Ln(R − 0.008 × t) + (4 − (3.5 × R)) × UF/W where R is the postdialysis/predialysis BUN ratio, t is the dialysis session in hours, UF is the ultrafiltration volume in liters, and W is the postdialysis weight in kilograms.²⁵¹ Multiple errors can occur that will affect the calculated PCR, Kt/V, and UNA. To decrease errors in the timing of the collection of BUN and to standardize the measurement, the BUN should be drawn using the Stop Flow/Stop Pump technique recommended by the DOQI Hemodialysis Adequacy Work Group. A complete discussion of the sampling techniques, problems, and trouble shooting can be found in the Clinical Practice Guidelines.²⁵², ²⁵³

The DOQI Hemodialysis Adequacy Work Group has recommended the following formulas for UKM using a single pool, three-sample model. These should be determined using already available computer software and should be utilized by those dialysis units that have formal UKM available to them. These formulas assume thrice-weekly HD. V_t = (QF) (t) [[1 − [(G − (C_t )(K + Kr − Qf))/(G − (C₀ )(K + Kr − Qf))]^{((Qf)/(K+Kr−Qf))}]⁻¹ − 1] PNA (G) = (Kr + a) × [C₀ − C_t ((Vt + a(theta))/Vt)^{−(Kr + a)} where Vt is the postdialysis volume; Qf is the rate of volume contraction during dialysis (difference in pre and post weights divided by length of dialysis); G is the interdialytic urea generation rate (PNA); K and Kr are the dialyzer and renal urea clearances; C_t and C₀ are the BUN concentrations at the end and beginning of dialysis; a is the rate of interdialytic volume expansion and it is calculated by the total IDWG divided by the length of the interdialytic period (theta); and C_0′ is the predialysis BUN of the subsequent dialysis session. An initial estimate of Vt is obtained from the use of an anthropometric or regression formula found in the Clinical Practice Guidelines.²⁵⁴

It is important to recognize that spKt/V overestimates the actual delivered dose of dialysis because of urea disequilibrium. The spKt/V actually measures the dialyzer removal of urea, not the actual patient clearance of urea. As dialysis time is shortened and the intensity of dialysis increases, the error in the estimation of the delivered dose of dialysis increases, because the effects of urea equilibrium are accentuated. Urea disequilibrium may occur because of diffusion disequilibrium between body water compartments (membrane dependent), flow disequilibrium because of differences of blood flow in various tissues and organs, and disequilibrium caused by cardio-pulmonary recirculation of blood. The latter type of disequilibrium is only seen in patients undergoing arterio-venous hemodialysis and not those undergoing veno-venous HD. Membrane, flow, and recirculation disequilibrium errors are magnified as dialysis time is shortened and the intensity of the session increased (eg, increasing Qb). For these reasons, a more accurate description of the delivered dose of dialysis has been developed that uses the equilibrated postdialysis BUN and bypasses the necessity of keeping the patient in the dialysis unit for an hour to obtain the true equilibrated postdialysis BUN sample.²⁵⁵ The work group recommends that this measurement of the effective patient clearance of urea (eKt/V) be utilized instead of spKt/V. eKt/V = spKt/V − (0.6)(K/V) + 0.03 where K/V is expressed in hours⁻¹. K/V = (spKt/V)/t

Peritoneal dialysis. The formulas for calculation of PNA (PCR) in CPD patients have been validated for CAPD. However, they are generally applied to all CPD patients. In CPD patients the following formulas apply (yielding grams per 24 hours): PNA (PCR) = 15.7 + (7.47 × UNA)²⁵⁶ PNA (PCR) = 34.6 + (5.86 × UNA)⁶⁰ PNA (PCR) = 10.76 × (0.69 × UNA + 1.46)²⁵⁷ PNA (PCR) = 20.1 + (7.50 × UNA)¹⁴⁹ The UNA is calculated by measuring the 24-hour urea excretion by peritoneal dialysate and residual renal urea excretion and adding the change in total body urea nitrogen (calculated as BUN change over time): UNA = (Vd × DUN + Vu × UUN)t + (d(body urea nitrogen))/t where Vd and Vu are dialysate and urine volumes in L, t is the time of collection, and DUN and UUN are dialysate and urine concentrations of urea nitrogen. Because daily changes in daily BUN in CPD patients are negligible, the formula can be shortened to UNA = ((Vd × DUN) + (Vu × UUN)/t)⁶³

Normalization of PNA for HD and Peritoneal Dialysis Patients

The PNA should be normalized or adjusted to a specific body size. The most common normalization and the one recommended by the DOQI Hemodialysis Work Group is to normalize to V/0.58²⁵¹: nPNA (nPCR) (g/kg/d) = (PNA)/(V/0.58)) There are no data to support other normalization techniques, but normalization to edema-free aBW (aBW_ef ) may be the preferred normalization technique.⁶³ The DOQI Nutrition Work Group recommends the use of the following normalization formula (Guideline 12): nPNA = (PNA)/aBW_ef where aBW_ef is the actual edema-free body weight.

Calculation of V²⁵²

Anthropometric determination of urea distribution volume.

Watson formula: Males: TBW = 2.447 − (0.09156 × age) + (0.1074 × height) + (0.3362 × weight) Females: TBW = −2.097 + (0.1069 × height) + (0.2466 × weight)

Hume-Weyer formula:

Males: TBW = (0.194786 × height) + (0.296785 × weight) − 14.012934 Females: TBW = (0.34454 × height) + (0.183809 × weight) − 35.270121 where TBW = total body water (V).

The Watson and Hume-Weyer formulas were derived from analyses of healthy individuals and their applicability to ESRD patients has been questioned. When compared with TBW calculated by BIA, the TBWs calculated from these formulas underestimate TBW by about 7.5%.

TBW by BIA Formula

TBW = −0.07493713 × age − 1.01767992 × male + 0.12703384 × ht − 0.04012056 × wt + 0.57894981 × diabetes − 0.00067247 × wt² − 0.0348146 × (age × male) + 0.11262857 × (male × wt) + 0.00104135 × (age × wt) + 0.00186104 (ht × wt) where wt and ht represent the patient's weight and height and male = 1 and diabetes = 1. If not male or not diabetic, then these values = 0.²⁵⁸

Appendix VI. Methods for performing subjective global assessment 

Healthcare professionals (eg, physicians, dietitians, and nurses) should undergo a brief training period before using SGA. This training is recommended to increase precision and skill in using SGA. The four items currently used to assess nutritional status are weight change over the past 6 months, dietary intake and gastrointestinal symptoms, visual assessment of subcutaneous tissue, and muscle mass.

Weight change is assessed by evaluating the patient's weight during the past 6 months. A loss of 10% of body weight over the past 6 months is severe, 5% to 10% is moderate, and less than 5% is mild. This is a subjective rating on a scale from 1 to 7, where 1 or 2 is severe malnutrition, 3 to 5 is moderate to mild malnutrition, and 6 or 7 is mild malnutrition to normal nutritional status. If the weight change was intentional, the weight loss would be given less subjective weight. Edema might obscure greater weight loss. Dietary intake is evaluated and includes a comparison of the patient's usual and recommended intake to current intake. Duration and frequency of gastrointestinal symptoms (eg, nausea, vomiting, and diarrhea) are also assessed. The interviewer rates this component of SGA on the 7-point scale with higher scores indicative of better dietary intake, better appetite, and the absence of gastrointestinal symptoms.

The physical examination includes an evaluation of the patient's subcutaneous tissue (for fat and muscle wasting) and muscle mass. Subcutaneous fat can be assessed by examining the fat pads directly below the eyes and by gently pinching the skin above the triceps and biceps. The fat pads should appear as a slight bulge in a normally nourished person but are “hollow” in a malnourished person. When the skin above the triceps and biceps is gently pinched, the thickness of the fold between the examiner's fingers is indicative of the nutritional status. The examiner then scores the observations on a 7-point scale. Muscle mass and wasting can be assessed by examining the temporalis muscle, the prominence of the clavicles, the contour of the shoulders (rounded indicates well-nourished; squared indicates malnutrition), visibility of the scapula, the visibility of the ribs, and interosseous muscle mass between the thumb and forefinger, and the quadriceps muscle mass. These are also scored on a 7-point scale, with higher scores indicating better nutritional status. The scores from each of these items are summated to give the SGA rating. It is recommended that SGA be used to measure and monitor nutritional status periodically in both MHD and peritoneal dialysis patients.

Appendix VII. Methods for performing anthropometry and calculating body measurements and reference tables 

Anthropometry comprises a series of noninvasive, inexpensive, and easy-to-perform methods for estimating body composition. However, they are operator dependent and, to be useful clinically, must be performed in a precise, standardized, and reproducible manner. It is recommended that any individual who performs the measurements should first undergo training to increase precision and skill. Without such training, considerable variance will occur both within and between observers in obtaining and interpreting the measurements. Standardized methods for collecting anthropometric data are available and should be utilized.

The anthropometric measurements that are valid for assessing protein-energy nutritional status in MD patients include skinfold thickness, midarm muscle area or circumference, %UBW, and %SBW. An estimate of skeletal frame size is also necessary for evaluating an individual's anthropometric measurements. Therefore, a brief description of the methodology and reference tables for evaluating frame size in addition to other measures are provided.

Skeletal Frame Size

Measurement of elbow breadth is a rough estimate of an individual's skeletal frame size. Frame size estimates of small, medium, and large for males and females are available and presented in Table 2.⁸⁹

Table 2. Frame Size by Elbow Breadth (cm) of US Male and Female Adults Derived From the Combined NHANES I and II Data Sets

The 10th and 90th percentiles, respectively, represent the predicted mean ± 1.282 times the SE. Similarly, the 15th and 85th percentiles are the predicted mean minus and plus, respectively, 1.036 times the SE of the regression equation. There were significant black-white population differences in weight and body composition when age and height were considered. However, when the comparisons were made with reference to age, height, and frame size, there were only minor interpopulation differences. For this reason, all races (white, black, and other) included in the NHANES I and II surveys were merged together for the purpose of calculating percentiles of anthropometric measurements.

Adapted and reprinted with permission from Frisancho.⁸⁹

Method for Estimating Skeletal Frame Size

Equipment. Sliding bicondylar caliper.

Method. Ask the patient to stand erect, with feet together facing the examiner. Ask the patient to extend either arm forward until it is perpendicular to the body. Flex the patient's arm so that the elbow forms a 90° angle with the fingers pointing up and the posterior part of the wrist is toward the examiner. Hold the small sliding caliper (bicondylar caliper) at a 45° angle to the plane of the long axis of the upper arm and find the greatest breadth across the epicondylis of the elbow. Measure to the nearest 0.1 cm twice with the calipers at a slight angle (this may be necessary because the medial condyle is more distal than the lateral condyle). An average of the two measurements is used (Table 2).⁸⁹

Percent of Usual Body Weight (%UBW)

UBW is obtained by history or from previous measurements. A stable weight in adult dialysis patients may be an indicator of good nutritional status, because adults normally are expected to maintain their body weight. The formula below for percent of UBW is appropriate for patients whose weight has been stable for most of their lives. Percent of UBW = ([actual weight ÷ UBW] × 100) Weight loss over time is a simple and useful longitudinal measure to monitor nutritional status because it is a risk factor for malnutrition. Even if the patient is overweight or obese, a significant weight loss in a short period of time may indicate malnutrition and predict increased morbidity and mortality.

Percent of Standard Body Weight (%SBW)

SBW is the patient's actual weight (postdialysis) expressed as a percentage of normal body weight for healthy Americans of similar sex, height, and age range and skeletal frame size. %SBW = (actual weight ÷ SBW) × 100 For individuals in the United States, these data are usually obtained from the National Health and Nutrition Evaluation Survey (NHANES). The third and most recent NHANES study indicates that the average American has gained about 7% in body weight.⁹⁷ This was considered a compelling argument for using the NHANES II data rather than data from NHANES III. However, individuals undergoing MHD who are in the upper 50th percentile or greater of body weight-for-height have an increased odds ratio for survival.⁹⁷ Patients who are less than 90% of normal body weight are considered to be mildly to moderately malnourished, and those who are less than 70% of normal body weight are considered severely malnourished.⁸⁵ Individuals who are 115% to 130% of SBW are considered mildly obese, those between 130% and 150% are moderately obese, and those above 150% of SBW are considered to be severely obese.²⁵⁹ Therefore, it is recommended that a target body weight for maintenance dialysis patients is between 90% and 110 % of SBW. At present, it is recommended that the NHANES II data be used for the reference source (Tables 3 through 8).

Table 4. Selected Percentiles of Weight, Triceps and Subscapular Skinfolds, and Bone-Free Upper Arm Muscle Area (AMA) for US Men and Women With Medium Frames (25 to 54 Years Old)

*Values estimated through linear regression equation.

†Numbers refer to percentiles of the normal population from the NHANES study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard.

Adapted and reprinted with permission from Frisancho.⁸⁹

Table 5. Selected Percentiles of Weight, Triceps and Subscapular Skinfolds, and Bone-Free Upper Arm Muscle Area (AMA) for US Men and Women With Large Frames (25 to 54 Years Old)

*Values estimated through linear regression equation.

†Numbers refer to percentiles of the normal population from the NHANES study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard.

Adapted and reprinted with permission from Frisancho.⁸⁹

Table 6. Selected Percentiles of Weight, Triceps and Subscapular Skinfolds, and Bone-Free Upper Arm Muscle Area (AMA) for US Men and Women With Small Frames (55 to 74 Years Old)

*Values estimated through linear regression equation.

†Numbers refer to percentiles of the normal population from the NHANES study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard.

Adapted and reprinted with permission from Frisancho.⁸⁹

Table 3. Selected Percentiles of Weight, Triceps and Subscapular Skinfolds, and Bone-Free Upper Arm Muscle Area (AMA) for US Men and Women With Small Frames (25 to 54 Years Old)

*Values estimated through linear regression equation.

†Numbers refer to percentiles of the normal population from the NHANES study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard.

Adapted and reprinted with permission from Frisancho.⁸⁹

Table 7. Selected Percentiles of Weight, Triceps and Subscapular Skinfolds, and Bone-Free Upper Arm Muscle Area (AMA) for US Men and Women With Medium Frames (55 to 74 Years Old)

*Values estimated through linear regression equation.

†Numbers refer to percentiles of the normal population from the NHANES study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard.

Adapted and reprinted with permission from Frisancho.⁸⁹

Table 8. Selected Percentiles of Weight, Triceps and Subscapular Skinfolds, and Bone-Free Upper Arm Muscle Area (AMA) for US Men and Women With Large Frames (55 to 74 Years Old)

*Values estimated through linear regression equation.

†Numbers refer to percentiles of the normal population from the NHANES study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard.

Adapted and reprinted with permission from Frisancho.⁸⁹

Body Mass Index (BMI)

BMI is a useful and practical method for assessing the level of body fatness. BMI is calculated by dividing weight (in kilograms) by height squared (in meters). Based on epidemiological data,⁸⁵ it is recommended that the BMI of MD patients be maintained in the upper 50th percentile, which would be BMIs for men and women of at least approximately 23.6 and 24.0 kg/m², respectively. Notwithstanding the greater unadjusted survival data for men and women in the upper 10th percentile of body weight for height,¹⁵, ⁸⁵ the large numbers of epidemiological data in normal individuals suggest that persons who are severely obese (eg, %SBW greater than 120 or BMI greater than 30 kg/m²) should be placed on weight reduction diets. Shorter survival also suggests that obese MD patients should also be placed on weight reduction diets, but no studies have been performed in MD patients to determine the safety and efficacy of this theory.

Skinfold Thickness

Skinfold anthropometry is a well-established clinical method for measuring body fat.²⁶⁰ Subcutaneous fat measurement is a rather reliable estimate of total body fat in nutritionally stable individuals. About one-half of the body's fat content is found in the subcutaneous layer.⁸³ Measurement of skinfold thickness at only one site is a relatively poor predictor of the absolute amount of body fat and the rate of change in total body fat because each skinfold site responds differently relative to changes in total body fat.⁸³ Measuring skinfold thickness at four sites (triceps, biceps, subscapular, and iliac crest) that quantify subcutaneous adipose tissue thickness on the limbs and trunk can make an accurate assessment of body fat.⁸⁶, ²⁶¹, ²⁶² Equations have been developed for estimating total body fat from these skinfold thicknesses,²⁶⁰ although these equations have been developed from people without renal failure. Table 2, Table 7 give normal values for triceps and subscapular skinfold thicknesses.⁸⁹ Nonetheless, measuring skinfold thickness should be considered a semiquantitative measure of the amount or rate of change in total body fat.

In a study that measured four-site skinfold anthropometry, a reduction in percent total body fat was observed in a group of MHD patients when compared with controls.²⁶¹ Loss of fat from subcutaneous stores occurs proportionally. Therefore, repeated measures in the same patient over time may provide useful information on trends of fat stores.⁸³

Methods for Performing Skinfold Thickness

Measuring Upper Arm Length

Equipment. Flexible, nonstretchable (eg, metal) tape measure.

Method. (1) Ask the patient to stand erect with his/her feet together. (2) Stand behind the patient. (3) Ask the patient to flex his/her right arm 90° at the elbow with the palm facing up. (4) Mark the uppermost edge of the posterior border of the acromion process of the scapula with a cosmetic pencil. (5) Hold the tape measure at this point and extend the tape down the posterior surface of the arm to the tip of the olecranon process (the bony part of the mid-elbow). (6) Keep the tape in position and find the distance halfway between the acromion and the olecranon process that is the midpoint of the upper arm. (7) Mark a (+) at the midpoint on the posterior surface (back) of the arm. (8) Mark another (+) at the same level on the anterior (front) of the arm.

Measuring Skinfold Thickness (Biceps, Triceps, Subscapular, and Iliac Crest)

Equipment. Skinfold calipers.

Method: triceps skinfold (TSF). (1) Ask the patient to stand with his/her feet together, shoulders relaxed, and arms hanging freely at the sides. (2) Stand to the patient's right side. (3) Locate the point on the posterior surface of the right upper arm in the same area as the marked midpoint for the upper arm circumference. (4) Grasp the fold of skin and subcutaneous adipose tissue gently with your thumb and forefingers, approximately 1.0 cm above the point at which the skin is marked, with the skinfold parallel to the long axis of the upper arm. (5) Place the jaws of the calipers at the level that has been marked on the skin with the marking pencil. The jaws should be perpendicular to the length of the fold. (6) Hold the skinfold gently and measure the skinfold thickness to the nearest 1 mm. (7) Record the measurement. If two measurements are within 4 mm of each other, record the mean. If the measurements are more than 4 mm apart, take four measurements and record the mean of all four.

Method: biceps skinfold. (1) Follow the same procedure as for the TSF, but with the measurement of the biceps skinfold at the front of the upper arm (instead of the back, as with the triceps). The level is the same as for the triceps and arm circumference, and the location is in the midline of the anterior part of the arm. (2) Ask the patient to stand with his/her feet together, shoulders relaxed, and arms hanging freely at the sides. (3) Stand behind the patient's right side. (4) Rotate the right arm so that the palm is facing forward. (5) Locate the point on the anterior surface of the right upper arm in the same area as the marked midpoint for the upper arm circumference. (6) Grasp the fold of skin and subcutaneous adipose tissue on the anterior surface of the upper arm, in the midline of the upper arm, and about 1.0 cm above the marked line on the middle of the arm. (7) Measure the skinfold thickness to the nearest 1 mm while you continue to hold the skinfold with your fingers. (8) Record the measurement. If two measurements are within 4 mm of each other, record the mean. If the measurements are more than 4 mm apart, take four measurements and record the mean of all four.

Method: subscapular skinfold. (1) Ask the patient to stand erect, with relaxed shoulders and arms. (2) Open the back of the examination gown or garment. (3) Palpate for the inferior angle of the right scapula. (4) Grasp a fold of skin and subcutaneous adipose tissue directly below (1.0 cm) and medial to the inferior angle. This skinfold forms a line about 45° below the horizontal, extending diagonally toward the right elbow. (5) Place the jaws of the caliper perpendicular to the length of the fold, about 1.0 cm lateral to the fingers, with the top jaw of the caliper on the mark over the inferior angle of the scapula. (6) Measure the skinfold thickness to the nearest 1 mm while the fingers continue to hold the skinfold. (7) Record the measurement. If two measurements are within 4 mm of each other, record the mean. If the measurements are more than 4 mm apart, take four measurements and record the mean of all four.

Method: suprailiac skinfold. (1) Ask the patient to stand erect, with feet together and arms hanging loosely by the sides. If necessary, arms may be abducted slightly to improve access to the site. This measurement can be taken in the supine position for those unable to stand. The suprailiac skinfold is measured in the midaxillary line immediately superior to the iliac crest. (2) Palpate for the iliac crest. (3) Grasp the skin at an oblique angle, just posterior to the midaxillary line below the natural cleavage lines of the skin. Align the skinfold inferomedially at 45° to the horizontal. (4) Gently apply the caliper jaws about 1 cm from the fingers holding the skinfold. (5) Record the skinfold to the nearest 0.1 cm. If two measurements are within 4 mm of each other, record the mean. If the measurements are more than 4 mm apart, take four measurements and record the mean of all four.

The suprailiac skinfold, as well as the biceps skinfold, may be more useful in the research setting than in most clinical settings. It may be more difficult to obtain the suprailiac skinfold than the other skinfold measurements due to the potential reluctance of patients to expose that site. However, the Tables 9 and 10 are provided for those who may wish to incorporate these measurements as a component of the anthropometric assessment of MD or CRF patients.

Table 9. Equivalent Fat Content, as Percentage of Body Weight, for a Range of Values for the Sum of Four Skinfold Measurements

Biceps, triceps, subscapular and suprailiac of men and women of different ages.

Adapted and reprinted with permission from Durnin and Womersley.²⁶⁰

The method for estimating body fat from these four skinfold measurements is shown below.

Table 10. Equations for Estimating Body Density From the Sum of Four Skinfold Measurements

Four skinfolds are biceps, triceps, subscapular, and suprailiac.

*Σ = sum of 4 skinfolds (biceps, triceps, subscapular, suprailiac).

Data from Durnin and Womersley²⁶⁰ and reprinted with permission from Wright and Heymsfield (eds): Nutritional Assessment, 1984, Blackwell Science, Inc.

Estimating Body Fat and Fat-Free Mass According to the Method of Durnin and Wormersley²⁶⁰

Method. (1) Determine the patient's age and weight (in kilograms). (2) Measure the following skinfolds (in millimeters): biceps, triceps, subscapular, and suprailiac. (3) Compute the sum (Σ) by adding the four skinfolds. (4) Compute the logarithm of the sum (Σ). (5) Apply one of the equations from Table 10 (age- and sex-adjusted) to compute body density (D, g/mL). (6) Fat mass is calculated as follows: Fat mass (kg) = body weight (kg) × [(4.95/D) − 4.5] where D is obtained from the formulas shown in Table 10. (7) Fat-free body mass (FFM) is calculated as follows: FFM (kg) = body weight (kg) − fat mass (kg)

Mid-Arm Muscle Area, Diameter, and Circumference

Anthropometric measures of skeletal muscle mass are an indirect assessment of muscle protein. Approximately 60% of total body protein is located in skeletal muscle—the body's primary source of amino acids in response to poor nutritional intake.⁸³

Estimates of muscle mass in an individual, for comparison with a reference population, eg, NHANES, is made by measuring the arm at the midpoint from the acromion to the olecranon. From measurements of both the mid-arm circumference (MAC) and the triceps skinfold (TSF), a calculated estimate of the mid-arm muscle circumference (MAMC) (that includes the bone) can be made using the following formula (Table 11)⁸³: MAMC (cm) = MAC (cm) − (π × TSF (cm)) A more accurate assessment of muscle mass is obtained by estimating bone-free arm muscle area (AMA).

Table 11. Mid-Arm Muscle Circumference for Adult Men and Women in the United States (18 to 74 Years)

Numbers refer to percentiles of the normal population from the NHANES I study. In general, the body weights of normal individuals at the 50th percentile who have the same height, gender, age range, and skeletal frame size as the patient in question are used as the standard. Measurements made in the right arm.

*Values are in units of cm.

Adapted and reprinted with permission from Bishop et al.³¹⁷

Corrected AMA may be calculated from TSF thickness and MAC using the following formulas²⁶³: AMA (corrected for males) = [(MAC (cm) − π × TSF (cm))²/4π] − 10 AMA (corrected for famales) = [(MAC (cm) − π × TSF (cm))²/4π] − 6.5 AMA estimates may be inaccurate in obese and elderly subjects (Table 3, Table 8).⁸⁹

Methods for Performing Mid-Arm Muscle Area, Diameter, and Circumference

Equipment. Flexible, nonstretchable (eg, metal) tape measure.

Method. (1) Ask the patient to stand with his/her elbow relaxed, with the right arm hanging freely to the side. (2) Place the tape around the upper arm, directly over the pencil mark at the midpoint on the posterior aspect (back) of the upper arm. Keep the tape perpendicular to the shaft of the upper arm. (3) Pull the tape just snugly enough around the arm to ensure contact with the medial side of the arm and elsewhere. Make sure that the tape is not too tight that it causes dimpling of the skin. (4) Record the measurement to the nearest millimeter. (5) Check to see if the two measurements are within 0.4 cm of each other. If they are not, take two more measurements and record the mean of all four.

Appendix VIII. Serum transferrin and bioelectrical impedance analysis 

Two indicators of protein-energy status (serum transferrin and bioelectrical impedance analysis) were not deemed valid measures of nutritional status in MD patients by the a priori definition (median panel rating 7 or above), but were considered by the Work Group to be worthy of brief discussion. Both were limited by a lack of specificity as nutritional indicators.

Serum Transferrin

Serum transferrin has been used extensively as a marker of nutritional status, and particularly the visceral protein pools, in individuals with or without CRF.¹⁷ It has been suggested that serum transferrin may be more sensitive than albumin as an indicator of nutritional status, possibly because transferrin has a shorter half-life than albumin (~8 versus ~20 days, respectively).¹⁷ Transferrin is a negative acute-phase reactant and is limited by many of the same conditions that limit albumin and prealbumin as indicators of nutritional status. Moreover, the serum transferrin concentration is affected by iron status (ie, serum transferrin increases in iron deficiency and declines following iron loading). Thus, increased iron requirements induced by chronic blood loss from sequestration of blood in the hemodialyzer, blood drawing, or gastrointestinal bleeding and by erythropoietin therapy and the frequent intravenous administration of iron may complicate interpretation of serum transferrin levels.

There is insufficient evidence that serum transferrin is a more sensitive index of PEM than serum albumin in MD patients. Furthermore, its lesser degree of specificity renders it less clinically useful than other serum proteins in this population. Serum transferrin may be more useful in nondialyzed patients with advanced CRF who are less likely to have increased blood loss and who are not receiving erythropoietin or iron therapy.⁸⁵

Bioelectrical Impedance Analysis (BIA)

BIA is an attractive tool for nutritional assessment of individuals undergoing MD because it is relatively inexpensive to perform, noninvasive and painless, requires minimal operator training, and provides input data that has been correlated with several aspects of body composition.²⁶¹ Numerous population-based studies have shown a strong direct correlation (r > 0.9) between BIA (height-adjusted resistance) and total body water (TBW). The estimation of other, more complex body compartments (eg, edema-free lean body mass and body cell mass) has proved more difficult, in part because of the relative unavailability of gold standards for estimating compartment sizes. Population-specific regression equations for edema-free lean body mass and body cell mass have not been developed in ESRD. Therefore, systematic bias might magnify the error obtained using regression models derived from nonrenal populations. Errors may compound if multiple compartments are estimated (eg, body cell mass = lean body mass − extracellular water). Therefore, using regression-adjusted BIA parameters (resistance and reactance) to estimate body composition is not sufficiently reliable or valid to recommend its use in MD patients, in contrast to DXA (Guideline 11).

A more compelling argument for the use of BIA is the evidence linking phase angle*with survival in hemodialysis patients.²⁰⁰, ²⁶⁴ Although phase angle has been shown to correlate with some nutritional variables (eg, SGA, anthropometric measures, nPNA, and serum albumin, prealbumin, and creatinine), the physiologic basis for the correlation between phase angle and protein-energy nutritional status is not clearly established.²⁰⁰ As with other nutritional indicators (eg, serum albumin; Guideline 3, Rationale), it is not clear that the relation between phase angle and survival is related to nutritional status.

Exploring the link between reactance, resistance, and derivations thereof (eg, phase angle), survival, and nutritional status represents an exciting area of inquiry. If BIA is to be used in the clinical setting, it is recommended that focus be placed on these direct impedance parameters, rather than on regression estimates of edema-free lean body mass or other body compartments.

Appendix IX. Estimation of Glomerular Filtration Rate

Several guideline statements refer to glomerular filtration rates (GFR) below which certain monitoring strategies or therapies should be instituted. The inulin clearance is considered to be the most accurate measure of the GFR. However, it is a laborious and rather expensive measurement. We describe here recommended methods for determining GFR that are more useful under clinical conditions.

GFR can be estimated from the serum creatinine concentration and other factors, or determined more precisely using either timed urine collections or radioisotope elimination methods.²⁶⁵, ²⁶⁶, ²⁶⁷ For the purposes recommended in these guidelines, the estimated GFR will usually be sufficient to provide a useful “ballpark” value for the GFR (ie, <25 mL/min). Direct urinary clearance measurements will be more useful in determining the degree of renal dysfunction at lower levels of clearance, when the need for renal replacement therapy is entertained.

The most widely used method for estimating GFR is the Cockcroft-Gault equation.²⁶⁶ This equation considers the effects of age, sex, and body weight on creatinine generation (ie, on average, increased age, female sex, and decreased weight associated with reduced creatinine generation; Guideline 5), thereby adjusting serum creatinine values to more accurately reflect creatinine clearance. GFR = [(140 − age) × body weight (kg) × 0.85 if famale] ÷ [72 × serum creatinine (mg/dL)] More recently, an equation was derived from data obtained from the MDRD study, GFR measured by iothalamate clearances as the standard of measurement.²⁶⁷ In addition to incorporating the influence of age and gender, the effects of race, and three (rather than one) biochemical measures are included: GFR = 170 × serum creatinine^−0.999 × age^−0.176 × female^0.762 × (1.18 × black race) × SUN^−0.17 × serum albumin^0.318 Timed urine collections are considered by most investigators to be valuable, albeit flawed measurements of GFR. Creatinine clearance is the value most frequently employed. As the GFR falls, however, the creatinine clearance progressively overestimates GFR, to a degree that may approach twice the true GFR value (<15 to 20 mL/min). At these levels of renal function, a more valid approximation of the GFR can be obtained using an average of the creatinine and urea clearances. Others have advocated the use of a creatinine clearance after administration of cimetidine, a drug known to block creatinine secretion. The accuracy of the timed urine collection is dependent on the integrity of the collection (among other factors). The creatinine index (Guideline 5) is often used to confirm whether a collection is appropriate, insufficient, or in excess. Radioisotope elimination methods (eg, ethylenediaminetetraaceticacid [EDTA], iothalamate) can be more accurate, but are limited by time constraints and expense.

Appendix X. Potential uses for L-carnitine in maintenance dialysis patients 

Prior Evaluation and Therapy of Proposed Indications

Although there is evidence that L-carnitine administration may favorably affect the management of anemia (see below), it is essential that other potential issues be resolved before proceeding with L-carnitine therapy. For example, patients with persistent anemia despite the provision of erythropoietin should be thoroughly investigated for causes of erythropoietin resistence, including iron, folate, and vitamin B12 deficiency, chronic infection or inflammatory disease, advanced secondary hyperparathyroidism, and underdialysis. Efforts to correct these abnormalities (eg, iron supplementation, increase in dialysis dose) should be implemented before L-carnitine is used to treat anemia.

Intradialytic hypotension should be managed with meticulous attention to the dialysis procedure, and modification of the dialysis procedure should be considered. Prolongation of dialysis time, ultrafiltration profiling, sodium modeling, modification of dialysate sodium and calcium concentrations, and modification of dialysate temperature are among the changes in management that could be considered.

Causes of low cardiac output in ESRD patients should be thoroughly investigated. Pericarditis with tamponade is a life-threatening complication that can be diagnosed by careful physical examination and echocardiography. Left ventricular dysfunction should be managed with agents that provide afterload reduction (eg, angiotensin converting enzyme inhibitors) and have been shown to enhance survival in non-ESRD patients.²⁶⁸ Other agents proven effective in cardiomyopathy (eg, β-adrenergic antagonists) should also be considered.²⁶⁹ Symptoms of heart failure with normal or high cardiac output may be seen with conditions such as severe anemia, hyperthyroidism, and large or multiple arteriovenous shunts.

Malaise, asthenia, weakness, fatigue, and low exercise capacity are more complex entities, with few broadly effective therapies. Before considering L-carnitine for these conditions, underdialysis, abnormalities of thyroid function, primary neurologic diseases, sleep disturbances (including restless legs syndrome), depression, and other nutrient deficiencies should be considered and treated if present.

Specific Indications

For most potential indications, there was insufficient evidence from carefully conducted clinical trials to provide strong support for the use of L-carnitine. What follows below is a description of the evidence used by the Work Group to reach is conclusions. The level of detail provided roughly corresponds to the quantity and quality of available evidence.

Elevated serum triglycerides. The Work Group agreed that there was insufficient evidence to support or refute the use of L-carnitine for dialysis-associated hypertriglycedemia. Thirty-two studies were reviewed.²⁷⁰, ²⁷¹, ²⁷², ²⁷³, ²⁷⁴, ²⁷⁵, ²⁷⁶, ²⁷⁷, ²⁷⁸, ²⁷⁹, ²⁸⁰, ²⁸¹, ²⁸², ²⁸³, ²⁸⁴, ²⁸⁵, ²⁸⁶, ²⁸⁷, ²⁸⁸, ²⁸⁹, ²⁹⁰, ²⁹¹, ²⁹², ²⁹³, ²⁹⁴, ²⁹⁵, ²⁹⁶, ²⁹⁷, ²⁹⁸, ²⁹⁹, ³⁰⁰, ³⁰¹ Among 681 subjects, 55 maintenance hemodialysis patients served as controls. Thirty-one studies evaluated the serum triglycerides alone and one also reported on serum total cholesterol levels. L-carnitine treatment allocation was randomly assigned in 9 studies.²⁷⁰, ²⁷², ²⁷⁴, ²⁷⁵, ²⁷⁶, ²⁷⁷, ²⁷⁹, ²⁸⁰, ³⁰¹ L-carnitine was administered intravenously in 17 studies,^{270, 272, 275, 277, 280, 281, 284, 286, 287, 289-291, 294, 296, 297, 299, 301} orally in 13 studies,^{271,273,276,279,285,288,289,292,293,295,296,298, 300} and via the dialysate in 7 studies.²⁷⁴, ²⁷⁸, ²⁸², ²⁸³, ²⁸⁷, ²⁹², ²⁹⁸ Peritoneal dialysis patients were studied in one report.²⁹⁰ The average number of subjects was 21 per study (range, 6 to 97). The duration of L-carnitine treatment was heterogeneous, ranging from 1 week to 12 to 15 months, with the mean duration being 3 to 6 months. When administered intravenously, the dose of L-carnitine ranged from 1 mg/kg body weight to 2 g at the end of each dialysis session, usually thrice weekly. Oral L-carnitine was administered in one to three daily doses, from 10 mg/kg body weight per day to 3 g per day. When L-carnitine was added into the dialysate, the final dialysate L-carnitine concentration was approximately 75 μmol/L or 150 μmol/L, corresponding to 2 g or 4 g of L-carnitine for each dialysis session, respectively.

There was no significant change in serum triglycerides in 23 of 32 studies. In a single study in which 3 g per day of oral L-carnitine were administered, there was a significant increase in serum triglycerides (+ 22%) over a 5-week time period. A decrease in serum triglycerides was observed in seven studies; in some of these, the significant decrease was observed in patient subgroups only, based on dialysate buffer,²⁷⁸ starting HDL concentrations,²⁹¹ or the final dose of L-carnitine.²⁸⁰ The small sample sizes, heterogeneity in L-carnitine route of administration and dose, variable durations of study and methods of analysis, and the inclusion of patients with normal triglyceride levels in most studies make interpretation of these data difficult.

Cardiac function and arrhythmias. Cardiac and skeletal muscle myocyte metabolism is largely oxidative and dependent on free fatty acid delivery and mitochondrial transport. Moreover, the myocyte has one of the highest intracellular carnitine concentrations in the body. Experimental models of cardiomyopathy have been corrected with the administration of L-carnitine, and primary carnitine deficiency has been associated with left ventricular hypertrophy in animal models.

Cardiovascular disease accounts for approximately 50% of deaths in the ESRD population, and complications of left ventricular dysfunction and left ventricular hypertrophy lead to considerable morbidity.³⁰² For these reasons, L-carnitine therapy has been explored as a treatment for cardiovascular disease in ESRD.

Two studies of L-carnitine treatment evaluated ejection fraction as an index of left ventricular function.³⁰³, ³⁰⁴ Van Es et al³⁰³ showed a statistically significant increase in ejection fraction among 13 patients (mean, 48.6% versus 42.4%) after 3 months of L-carnitine therapy (1 g IV after each hemodialysis session). The patients had all undergone hemodialysis for greater than 1 year, using high-flux, bicarbonate dialysis, with hematocrit >30% and with no change in hemodialysis frequency or time over the course of the study. The study was not randomized, and there was no concurrent control. Fagher et al³⁰⁴ conducted a 6-week, randomized placebo-controlled trial in 28 hemodialysis patients, who received either 2 g IV of L-carnitine or placebo after each hemodialysis session. There was no difference in ejection fraction comparing baseline and posttreatment values and no difference between L-carnitine and placebo groups. Furthermore, there was no difference in heart volumes. Although randomized and placebo-controlled, the study was short-term, and the patients included did not have evidence of myocardial dysfunction (mean ejection fraction, 62%).

As part of a multicenter, long-term (6 months), double-blind, placebo-controlled randomized clinical trial of 82 maintenance hemodialysis patients (see below),²⁷² Holter monitoring was performed during a single dialysis period during the baseline (nontreatment) period, during the treatment period, and at the end of the treatment phase. Individual data were not available for review, but the authors noted that there were very few arrythmias at baseline in their study subjects, and no significant change in dialysis-associated arrhythmias was observed.

Malaise, asthenia, muscle cramps, weakness, and fatigue. Seven studies reported the effects of L-carnitine on either postdialysis fatigue,^{276, 305-308} muscle weakness,³⁰⁶ muscle cramps,²⁷⁷ or well-being.²⁷⁷, ³⁰⁹ Only the study reported by Sloan et al³⁰⁹ included a well-accepted scale of health-related quality of life (the Medical Outcomes Study Short Form-36 instrument). The duration of treatment ranged from 2 to 6 months. The dose and route of delivery was widely variable, making comparison across studies difficult (Table 12).

Table 12. Studies Evaluating the Effect of L-Carnitine Administration on Dialysis-Related Symptoms

In a double-blind, randomized, placebo-controlled study, Ahmad et al³⁰⁵ showed significant improvement over time in postdialysis asthenia in both L-carnitine–and placebo-treated patients; there was no significant difference in the response to treatment between the groups. However, it was only among the L-carnitine–treated patients that the authors found a significant reduction in intradialytic muscle cramps and hypotension. Sakurauchi et al³⁰⁶ reported that symptoms of fatigue were reduced in 14 of 21 patients, and muscle weakness improved in 14 of 24 patients (P < 0.05) after 3 months of L-carnitine treatment. There was no control group, and the methods of symptom assessment were neither adequately described nor validated. Sohn et al²⁷⁷ reported significant improvements in muscle cramps and sense of well-being comparing L-carnitine to placebo in 30 hemodialysis patients, although their methods of assessment were likewise not described. Casciani et al³⁰⁷ performed an 18-patient, nonrandomized cross-over study, and showed a significant improvement in asthenia after 2 months of L-carnitine administration, regardless of the order of drug administration. Bellinghieri et al²⁷⁶ evaluated muscle fatigability immediately postdialysis and during the interdialytic interval. They showed that postdialysis asthenia was markedly reduced as early as 15 days after commencing L-carnitine therapy, whereas intradialytic asthenia was only improved after 30 days of treatment. When L-carnitine was stopped, asthenia resumed within 15 to 30 days.²⁷⁶ By contrast, Fagher et al³⁰⁸ found no subjective improvement in fatigue in 14 patients treated with L-carnitine for 6 weeks.

Sloan et al³⁰⁹ provided oral L-carnitine (1 g before and 1 g after each dialysis treatment) to 101 maintenance hemodialysis patients and evaluated their health-related quality of life with the SF-36. In this study, oral L-carnitine had a perceived positive effect on the SF-36 general health (P < 0.02) and physical function (P < 0.03) subscales, although the effects were not sustained after 6 months of treatment.

In summary, although most studies of “subjective” symptoms suggest a beneficial effect of L-carnitine supplementation for maintenance dialysis patients, the Work Group concluded that the heterogeneity of study design, and the difficulty in measuring these and related symptoms in an unbiased manner render the available evidence in this area inconclusive. Nevertheless, several members of the Work Group felt that a short-term trial of L-carnitine was reasonable in selected patients with these symptoms who are unresponsive to other therapies, in light of its favorable side effect profile, lack of alternative effective therapies, and the findings from some studies of improvement in these symptoms with L-carnitine therapy.

Exercise capacity. Correction of anemia, hyperparathyroidism, and 1, 25-OH vitamin D3 deficiency and provision of adequate dialysis do not fully restore muscle function and exercise capacity in ESRD patients. Carnitine is abundant in skeletal muscle, and muscle carnitine content has been reported to decrease with dialysis vintage.²⁷⁷ Therefore, provision of L-carnitine might help to restore muscle mass and function. Five studies describing various aspects of physical activity were reviewed in detail. Physical activity was assessed by a patient activity score,³¹⁰ exercise time, maximal oxygen consumption and mid arm muscle area,³⁰⁵ a measurement of maximum strength,³⁰⁸ exercise workload,³⁰⁸ and subjective muscle strength.²⁸⁰

The duration of treatment ranged from 1 to 6 months. L-carnitine was administered either IV at the end of each dialysis session, 2 g for 6 weeks³⁰⁷ or 6 months,³¹¹ 20 mg/kg for 6 months,³⁰⁵ or PO 0.9 g/d for 2 months²⁹⁸ and 3 g/d for 30 days.²⁸⁰

Each study assessed physical activity in a different manner. Siami et al³¹⁰ observed a trend (P = 0.07) toward improvement in subjective physical activity (on a scale from 1 [normal] to 5 [total incapacity]) after dosing L-carnitine, 2 g IV after dialysis for 6 months. Ahmad et al³⁰⁵ reported a significant increase in mid-arm muscle area (P = 0.05) in carnitine-treated patients and no change in placebo-treated patients. In the L-carnitine–treated patients, there was a significant increase in the maximal oxygen consumption (mean increase, 111 mL/min; P < 0.03) and a trend toward increased exercise time. Fagher et al³⁰⁸ observed an improvement in maximum muscular strength from baseline (P < 0.01) only in the group receiving L-carnitine 2 g IV after dialysis for 6 weeks, although there was no significant difference between treatment and placebo arms in this study. Mioli et al²⁹⁸ reported an increase in maximum work load after 45 days of oral L-carnitine administration that was sustained after 60 days of treatment (P < 0.05). Finally, Albertazzi³¹¹ reported a subjective improvement in physical activity (not quantified) in 10 patients receiving 3 g L-carnitine PO per day for 30 days and no change in 10 control subjects.

In summary, as with the more subjective symptoms of malaise, asthenia, muscle cramps, weakness and fatigue, there is inconclusive evidence regarding the role of L-carnitine supplementation on muscle function in ESRD. Although most of the published studies suggest a modest beneficial effect, relatively few studies are well-controlled, the methods of assessment are not validated, and assessment may be insensitive to important changes induced by a variety of therapies, including L-carnitine itself. The Work Group members were also concerned about the effect of publication bias on the available medical literature. In other words, it might be less likely for investigators to submit studies with a nil effect, and less likely that journal editors would publish such papers. The Work Group agreed that there was insufficient evidence to support the use of L-carnitine to enhance muscle strength or exercise capacity in patients on dialysis. However, the Work Group agreed that a short-term trial of L-carnitine (3 to 4 months) was reasonable in selected patients to enhance muscle strength and exercise capacity, in light of its favorable side effect profile, lack of alternative effective therapies, and benefits shown in several studies. More research is required in this area.

Anemia. It has been proposed that carnitine deficiency might reduce erythrocyte half-life, by adversely influencing the integrity of the erythrocyte membrane. Kooistra et al³¹² showed a relation between anemia and erythropoietin requirements and low serum free carnitine levels in dialysis patients. Despite the availability of recombinant erythropoietin and the more liberal use of intravenous iron dextran in recent years, a large proportion of maintenance dialysis patients continue to suffer from anemia or require large doses of erythropoietin to maintain blood hemoglobin concentrations within the recommended range. Epidemiologic studies have consistently shown a mortality advantage among patients with hematocrits in the 30% to 36% range, and the NKF-DOQI Work Group on Anemia Management recommended a target hematocrit of 33% to 36% based on the expert panels' detailed literature review.

Ten studies involving carnitine and anemia were reviewed in detail. Four studies²⁷², ³¹⁴, ³¹⁵, ³¹⁶ (36 patients total) compared hemoglobin or hematocrit at baseline and after about 2 months of L-carnitine treatment (three studies using oral L-carnitine and one study using a combination of oral and intravenous L-carnitine). A fifth study²⁹² was a nonrandomized trial in which 12 patients were treated with oral L-carnitine (1 g per day) and 11 patients were dialyzed against a bath supplemented with L-carnitine (concentration, ~100 μmol/L) for 6 months. Although three of the five studies showed significant improvement in blood hemoglobin or hematocrit, the Work Group discounted these studies due to flaws in design. A single cross-over study was performed.²⁷⁶ In only one of the two sequences was there a significant increase in hematocrit. There were 14 patients overall (7 in each sequence). The rather small sample size limited statistical power, and there was no consideration given to blood loss, iron status, or other clinical factors. It is noteworthy that in none of the six studies cited above were the hematologic effects of L-carnitine the primary outcome of interest.

Four randomized, placebo-controlled clinical trials²⁷², ²⁷⁵, ³¹⁵, ³¹⁶ were conducted in which the effect of L-carnitine on hemoglobin concentration or hematocrit was evaluated. In three of the four studies,²⁷², ³¹⁴, ³¹⁶ treatment of anemia was the primary focus of the work. The total number of patients studied was 109. Nillson-Ehle et al²⁷⁵ treated 28 patients for 6 weeks with L-carnitine 2 g IV after each dialysis session. There were no significant differences in hemoglobin concentration in either group. No mention was made of serum levels or intake of iron, vitamins, or other factors known to affect management of this condition. In a randomized, placebo-controlled, double-blind trial, Labonia²⁷² treated 13 patients with L-carnitine 1 g IV after each dialysis session for 6 months and compared the results with 11 patients given a placebo control. Inclusion criteria included a stable dialysis regimen, “normal” iron status, “usual” treatment with folic acid and vitamin B12, and the absence of “severe” hyperparathyroidism. In each patient, efforts were made to periodically reduce the dose of erythropoietin, but any reduction in the erythropoietin dose was maintained only if the hematocrit did not decrease. The target hematocrit was 28% to 33% throughout the study, and a protocol for erythropoietin dosing was established. There were defined, accepted criteria for the provision of iron supplements. The hematocrit remained stable in the L-carnitine–treated group, but dropped slightly (and significantly) in the placebo group (mean, 29.5% to 27.9%; P < 0.05). The erythropoietin dose requirements were reduced by 38% in the L-carnitine–treated patients and unchanged in the placebo-treated group. Roughly the same proportion of patients received iron during the course of the study, although the ferritin concentration (a marker of iron stores and of inflammation) was higher on average in the placebo group. There were no changes in endogenous erythropoietin or in erythrocyte osmotic fragility; thus, there was not a clear mechanism for what appeared to be a large clinical effect.

Trovato et al³¹⁵ showed even more dramatic results in a placebo-controlled randomized study conducted before the availability of erythropoietin. In the control group, the mean hematocrit was 24.0% at baseline and dropped to 21.8% after 12 months. In the L-carnitine group, the mean hematocrit was 25.5% and increased to 37.4% after 12 months. All patients received folic acid, vitamin B12, and sodium ferrigluconate at the end of each dialysis session.

Finally, Caruso et al³¹⁶ led a placebo-controlled randomized clinical trial in 31 hemodialysis patients, looking at erythropoietin dose and hematocrit. Patients received 1 g of L-carnitine IV after each dialysis session. The overall study results showed no significant effect of L-carnitine. When examining the subgroup of patients older than 65 years of age (n = 21), there were significant increases in hematocrit (mean, 32.8% versus 28.1%) and lowering of the erythropoietin dose (mean, 92.8 versus 141.3 U/kg) in the L-carnitine–treated patients compared with placebo-treated controls. It is worth noting that the Trovato et al³¹⁵ and Caruso et al³¹⁶ studies both employed per protocol analyses, compared with the more conventional “intent to treat” methods.

Some members of the Work Group felt that an empiric trial of oral or intravenous L-carnitine (~1 g after dialysis) was reasonable in selected patients with anemia and/or very large erythropoietin requirements. A 4-month trial was considered to be of sufficient length to reliably assess the response to L-carnitine.

E. Index of Equations and Tables (Adult Guidelines)

Abbreviations: HD, hemodialysis; Kt/V, measure of dialysis where K is the membrane clearance, t is the time on dialysis, and V is the volume of urea distribution; CPD, chronic peritoneal dialysis; PNA, protein equivalent of total nitrogen appearance; GFR, glomerular filtration rate.

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• * *A predialysis serum measurment is obtained from an individual immediately before the initiation of a hemodialysis or intermittent peritoneal dialysis treatment. A stabilized serum measurement is obtained after the pwtient has stabilized on a given dose of CAPD.
• * *Phase angle reflects the relative contributions of fluid (resistance, or R) and cell membranes (reactance, or Xc) to the observed impedance in a biological system. Mathematically, phase angle equals the arc tangent of Xc/R.²⁶⁴