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Dietary Phosphate Assessment in Dialysis Patients
REVIEW
Dietary Phosphate Assessment in Dialysis Patients Alastair M. Mathewson, PhD,* Denis Fouque, MD, PhD,† and Alex J. Toft* Malnutrition is known to be highly prevalent in patients with kidney disease. It is associated with poor clinical prognosis and can result from restricted dietary protein-energy intake. The issue is also compounded by protein wasting that occurs in dialysis patients. In countering malnutrition, an adequate protein intake is essential but limited by its phosphate content. Therefore, an accurate assessment of nutritional status and intake is an important part of the therapeutic strategy for patients on dialysis. Assessing dietary phosphate intake is not straight forward, with many confounding factors requiring consideration. Interview and diet diaries are the preferred means by which dietary intake can be estimated. However, it is evident that these estimates can vary considerably and are subject to underreporting. Moreover, the use of phosphates as additives and their omission from available nutrient databases are significant contributors to this variation and underestimation. This review highlights the main limitations in assessing dietary phosphate intake and introduces the concept of monitoring changes in dietary habit (appetite) as a proxy for dietary protein and energy intake. This review discusses the use of monitoring dietary habit in trials, with phosphate binders as a simple tool to address the possibility that changes to dietary habits may influence phosphate binder efficacy. Ó 2010 by the National Kidney Foundation, Inc. All rights reserved.
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ALNUTRITION IS KNOWN to be highly prevalent in patients with kidney disease. It is associated with poor clinical prognosis and can result from restricted dietary proteinenergy intake. This is compounded by the protein wasting that occurs in patients on dialysis, partly due to protein and amino acid loss into the dialysate.1 Restricting dietary protein intake may also lead to greater mortality.2,3 The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend a daily protein intake of at least 1.2 g/kg standard body weight,4 and the European Best Practice (EBP) guidelines recommend at least 1.1 g/kg/day.5 However, there is a problem in this: protein is a major source of *INEOS Healthcare Ltd, Warrington, United Kingdom. †Department of Nephrology, Hoˆpital E.Herriot and U870 Inserm, Lyon, France. Address reprint requests to Alastair Mathewson, PhD, INEOS Healthcare Ltd, 4 Liverpool Road, Warrington, WA5 1AQ, United Kingdom. E-mail: [email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.05.014
dietary phosphate, and as dialysis is unable to remove sufficient phosphate to balance daily intake, phosphate accumulation might occur.6,7 Although controlling dietary phosphate intake can help control serum phosphate concentration, care must be taken to ensure adequate nutritional intake, particularly in the form of protein; controlling serum phosphate by reducing protein intake may be detrimental to the patient.2,3 The published data has described that elevated serum phosphate is associated with increased mortality in patients with chronic kidney disease8–11 and more recently it has been found to be associated with increased mortality in the general population.12 The concept of a phosphate-to-protein ratio was proposed in the K/DOQI guidelines in 200313 as a means to aid control of serum phosphate through control of dietary intake, combining and focusing the attention simultaneously on dietary phosphate and protein intake by drawing attention to food with excessive phosphates and little to no protein content. It is evident that most dialysis patients with an adequate protein intake will require oral phosphate binders to prevent a rise in serum phosphate and concomitant rise in serum parathyroid hormone.14
Journal of Renal Nutrition, Vol 20, No 6 (November), 2010: pp 351–358
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Dietary Phosphate Content Phosphorus is found in a wide variety of food and drinks as inorganic phosphates and is also present in drinking water, with a maximum allowed content of 2.2 mg/L in the European Union.15 Estimates of dietary phosphorus intake in European countries are summarized in Table 1, with similar consumption seen in Australia. In the United States, the average phosphate (as phosphorus) intake ranges from 850 to 950 mg/day for women and 1,200 to 1,500 mg/day for men. Mean daily phosphorus intake in Brazil is estimated at 520 mg/1,000 kcal, which equates to 1,196 mg/day, based on an average daily intake of 2,350 kcal.16 Estimates from Japan suggest daily phosphorous intake of 649 6 212 mg, but can be as much as 2,250 mg.17,18 Estimates of dietary phosphorus intake tend to exclude contributions from vitamin and mineral supplements, drinking water, or phosphorous from food additives, and therefore the actual intakes are almost certainly greater than those reported.19 Food additives can contribute more than 30% of the adult phosphorus intake, and are often not taken into account in nutrient composition tables.19 This is of significance because phosphate delivered as additives is more readily absorbed because of its inorganic nature and absence of endogenous chelates, such as phytate, than that found in foods that are naturally high in phosphate.20 This highlights the fact that the source of phosphate is equally as important as the phosphate content of the source. Consideration should be given to the food source when assessing its contribution to bioavailable phosphate.
On average, approximately 60% to 70% of dietary phosphate is absorbed by the gastrointestinal tract. The extent of the absorption depends on the food source. Phosphorus derived from meat sources is reasonably well absorbed, as it exists mostly as intracellular organic compounds that are easily hydrolyzed in the gastrointestinal (GI) tract, resulting in the release of inorganic phosphorus.21 Phosphorus in plant tissue, however, such as that found in bran and seeds, is principally stored in the form of phytates. In nonruminant animals, a lack of phytase results in poor bioavailability of phosphorus from this source,22 unless the food has been supplemented with phytase as a part of its processing, such as the addition of phytase-containing yeast to bread. Bacteria in the gut can also liberate some phosphorus from phytates, provided a complex with cations such as calcium, zinc, or iron has not been formed,23 varying the amount of bioavailable phosphate from individual to individual. It is evident that the phosphate content of supermarket foods can vary significantly, making estimation of phosphate content by patients and dieticians very difficult.24,25 In meats and fish, phosphates are used as a preservative and to help color retention by inhibiting surface oxidation.26 Phosphates are also added to other foodstuffs such as cakes, cheeses, and bread to improve their structural appearance. One limitation with the concept of the phosphate-to-protein ratio is that the total phosphate content of many foods and beverages is not widely available and a means of differentiating between endogenous and added phosphate remains to be established. The hidden phosphate content of a variety of food and drinks
Table 1. Estimates of Daily Intake of Phosphorus in Some EU Countries* Population Italy Household Germany Individual (M) Individual (F) Netherlands Household Sweden Individual (M) Individual (F) UK Individual (M) Individual (F)
N
Method
Mean (mg/day)
97.5 Percentile
2,374
7-day record
1,304
2,076
862 1,144
7-day record 1 food frequency record
1,488 1,188
2,517 1,988
5,958
2-day record
1,480
2,601
1,214
7-day record
1,570 1,290
2,517 1,988
656 803
7-day record
1,493 1,112
2,381 1,763
*Reprinted with permission.15
DIETARY PHOSPHATE ASSESSMENT IN DIALYSIS PATIENTS
has been published in a series of papers.27–29 Differentiation between organic phosphate and added phosphate presents food manufacturers with a significant technical challenge which needs to be overcome before significant advances in food labeling can be addressed.30 KalantarZadeh et al. have recently published a list of phosphate and protein content and their ratio for a range of food and beverages.31 After being calculated for a particular food, these values provide a useful guide to selecting food with a favorable ratio: low in phosphate and high in protein. Examples of food with a high phosphate to protein ratio (.20 mg/g) include sunflower seeds, nuts, milk, and certain cheeses. Food with a low phosphate to protein ratio (,10 mg/g) include fresh meat products such as lamb, beef, pork, fish, and chicken. As mentioned previously, the source of the phosphate needs to be considered because when contained in meat it is more bioavailable as compared with that contained within vegetables and seeds. Despite some considerable variation in phosphorus intake across and within geographical regions, dialysis patients are advised to restrict daily phosphorus intake to no more than 1000 mg/ day (on average, 17 mg/kg body weight), as recommended by K/DOQI13 and EBP guidelines.5 The estimates of daily phosphate intake in dialysis patients taken from weekly dietary recall vary considerably, with mean (6SD) daily intakes estimated at 860 6 300 mg/day and a mean coefficient of variation of 35%.33 Chauveau et al. observed large differences in both the type and amount of food ingested from day to day, particularly from dialysis to nondialysis days.33 A dietician counsels patients on restricting dietary phosphate intake; however, 30% to 50% of patients entering dialysis may not have met a dietician and hence would not have received any counseling.14 Although patients are advised to monitor phosphate intake by reducing the consumption of food high in phosphate, hidden sources of phosphate such as additives are often unaccounted for26 and can contribute significantly to the phosphate burden of dialysis patients34 because of their near complete absorption. The authors reported that restricting the intake of enhanced foods with phosphate containing additives helped decrease phosphate intake.34 The phosphate content of beverages is often not taken into consideration by patients or physicians.35 Savica et al. report that 74% of their patients consumed drinks with a higher phosphate
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content such as red and white wine, cola, and beer, whereas only a minority consumed those with a low phosphate content such as orange juice, lemonade, and mineral water.35 Most beverages contain little to no protein and any phosphate content is almost entirely from additives. As a consequence, patients who consumed beverages with high phosphate content had serum phosphate levels that were higher than the range of phosphate suggested by the K/DOQI guidelines. One of the barriers to controlling dietary phosphorous intake is patient education; there is evidence to suggest that up to 50% of patients receiving treatment at a dialysis unit in the United Kingdom believed that dietary phosphate restriction was no longer necessary when they were taking phosphate binders.36 Indeed, educating patients to avoid foods with phosphate additives can result in a marked reduction in serum phosphate compared with patients not receiving the educational intervention.34 Although nutritional intake was not assessed, the authors suggested that the improvement to serum phosphate was because of change in patients’ behavior regarding food choices, with an increased awareness and reading of food labels and ingredient lists.
Monitoring Nutritional Intake The assessment of the nutritional status of dialysis patients is an important part of their therapeutic strategy, and several methods for assessment are available.14 The K/DOQI has published 21 guidelines on nutrition for dialysis patients detailing methods for evaluating protein-energy nutritional status, managing acid-base balance, ensuring adequate dietary protein and energy intake, and conducting nutrition counseling.4 Of these 21 guidelines, a recent survey of 848 dieticians (National Kidney Foundation Council on Renal Nutrition members) indicated that serum albumin was considered the most important method for evaluating nutritional status in maintenance dialysis.37 It was followed by a change in body weight, and then the dietary intake assessment with diet interviews and/or diaries. However, more than half (57%) of the dieticians reported lack of the necessary tools, such as food models and measuring utensils, personal computer, callipers and stadiometer, as the reason for not implementing some of the guidelines. Monitoring changes in appetite has been proposed as a useful
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aid in the monitoring of nutritional intake38 and has been validated in a large multicenter trial as a proxy for dietary protein and energy intake.39 Dietary assessment is recommended by the EBP guidelines on nutrition as part of a number of assessment tools in the diagnosis of malnutrition.5 The other recommended assessment tools include body mass index, subjective global assessment, anthropometry, normalized protein nitrogen appearance (nPNA), serum albumin and serum prealbumin, serum cholesterol, and various technical investigations (bioimpedancemetry, dual X-ray absorptiometry, near-infrared reactance). Existing methods to assess dietary intake include 24 hours-recall, 3 and 7 days diet diaries, each of which has its own benefits and limitations (Table 2); K/DOQI guidelines recommend periodic 3-day dietary records followed by dietary interviews to calculate nutrient intake as part of the assessment of dietary protein and energy intake.4 In each case, the expertise of a qualified dietician is essential to complete the diaries and ensure accuracy. The EBP guidelines recommend that dietary interviews should be conducted in stable and well-nourished patients every 6 to 12 months, or every 3 months if the patient is aged .50 years or has been on hemodialysis for .5 years.5 Malnourished hemodialysis patients should be assessed more frequently, using at least a 24-hours dietaryrecall method. The guidelines indicate that the use of data obtained from unsupervised food recordings, covering a short period can be incomplete and subjective, and therefore should be used with caution. However, this has to be balanced with the acknowledgement that available food composition tables in books or software programs do not accurately reflect the use of phosphorous as a food additive and preservative.40
Serum Albumin and Prealbumin There is ample evidence that serum albumin and prealbumin are valid and clinically useful indicators of protein-energy nutritional status.4,5 Together with transferrin and other liver-derived proteins, serum albumin and prealbumin are the most commonly used laboratory parameters for routine assessment of nutritional status, with serum albumin being the most commonly used nutritional marker in dialysis patients.14 Changes in albumin and prealbumin are related to changes in dietary protein intake and are thus useful indicators of protein-energy nutritional status and dietary intake in dialysis patients.4 Serum albumin and prealbumin provide a measure of visceral protein pool size and are considered indicators of future mortality risk.41,42 Low serum albumin is considered a sign of uremic anorexia (loss of appetite).1,43 Albumin and prealbumin levels may decrease acutely with inflammation or acute or chronic stress and increase after resolution or recovery. Therefore, a decrease in serum albumin and/or prealbumin must be interpreted in the context of the patient’s clinical status. Reports of infection or signs of infection, such as fever, reported as adverse events during routine clinical monitoring of patients may be used in the interpretation of a fall in albumin and prealbumin. Furthermore, changes in serum albumin and prealbumin can be correlated with phosphate levels. Because of the high phosphate content of dietary protein, changes in serum phosphate mirror changes in dietary protein intake. Thus, a change in serum phosphate and albumin/prealbumin in the same direction provides stronger evidence of a change in dietary (protein) intake than a change in either individually.
Table 2. Comparison of the Main Attributes of Each Method of Collecting Information on Dietary Intake Twenty-Four Hour Dietary Recall
Three Days Food Records
Seven Days Food Records or Diet Diaries
Good starting point revealing major imbalances, dietary inadequacies, and areas of concern Relies on memory and may underestimate actual intake May not represent typical food intake reflecting daily variation
Diary over 3 days may be sufficient when food intake is stable K/DOQI guidelines recommend a 3-day diary covering dialysis, nondialysis, and weekend days Requires teaching patients to measure portions sizes Must account for all food and drink consumed, including snacks
Seven days is the minimum period required to assess protein and energy intake within 10% of the standard error Includes variations in food intake over longer periods Diaries lasting more than 3 days are subject to reduced compliance and accuracy because of reduced motivation
DIETARY PHOSPHATE ASSESSMENT IN DIALYSIS PATIENTS
Appetite One of the most common symptoms in patients with chronic kidney disease suffering from toxic uremia is loss of appetite, or anorexia;43 therefore, appetite assessment has been considered as a practical tool for assessing the relationship between appetite and dietary intake in hemodialysis patients.38 Burrowes et al. described a simple series of questions which can be used to assess appetite and changes in appetite, requiring very little processing by healthcare professionals. Mean levels of protein and energy intake from diet diaries varied significantly by level of appetite rating; when appetite ratings increased, mean energy and protein intakes also increased.38 Burrowes et al. (1996) did not report any significant differences in appetite across comparable intervals, although nutrient intake can vary between dialysis and nondialysis days.33 A single self-report of a patient’s hunger may be easily implemented in any clinic. The questionnaire proposed by Burrowes et al. has been used in a multicenter randomized trial where appetite assessment was validated in a large sample of subjects receiving hemodialysis (N 5 1,846) as a proxy for dietary protein and energy intakes.39 Moreover, Kalantar-Zadeh et al. showed that a simple appetite questionnaire was able to predict mortality at 1-year in a cohort of approximately 300 patients on maintenance hemodialysis in California.44
Diet Interviews and/or Patient Diaries Diet interviews and/or diaries are described by K/DOQI as being valid and clinically useful for measuring dietary protein and dietary energy intake in maintenance of dialysis patients.4 Diet interviews and/or diaries are a useful tool to provide an estimate of nutritional intake. However, it is widely accepted that they underestimate nutrient and fluid intake when compared with energy expenditure,45 which limits their usefulness and interpretability. Livingstone and Black described coefficients of variation of the differences within individuals as 16.5% for 3-day food records, 18.6% for a dietary history, and 28.5% for a foodfrequency questionnaire.45 Diet interviews and/or diaries do not capture phosphorus intake from food additives and can underestimate phosphorus intake by as much as 30%.19 Indeed, available nutrient databases do not account for the variations
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in phosphate additive content, making it extremely difficult for patients and dieticians to accurately estimate phosphate content.34 A linear relationship between dietary phosphate intake and estimated dietary protein intake has been described in the literature after estimating dietary protein and phosphate intake of over 200 patients on maintenance hemodialysis across 2 studies.31,46 The linear relationship accounted for between 83% and 84% variation in dietary phosphorus intake and may be useful in providing rough estimates of dietary phosphate content derived from protein intake. It is unclear whether phosphate additives are accounted for as these tend to be omitted from nutrient composition tables. Trabulsi and Schoeller demonstrated that, regardless of the dietary methodology used to assess dietary habit, true energy intake is consistently underreported, particularly in certain groups within the population.47 These groups present within the population tend to be uncomfortable with their body image and/or consume foods considered to be socially undesirable. An inverse relationship between body mass index and reporting accuracy has been demonstrated, where patients with high body mass index were more likely to underreport.48 Food intake varies widely with time, with a coefficient of variation close to 20% in a 3-day recall and much higher if a 1-day technique or a food frequency questionnaire is used.49 Although 24-hour recall can be a rapid and simple method, it does rely on the patients’ ability to remember how much food was consumed in the previous 24 hours and must be obtained by a trained and skilled dietician. Dietary intake can vary considerably on a daily basis in dialysis patients, with significant decreases in nutrient intake on dialysis days compared with nondialysis days.33 Chauveau et al. recommend a 7-day food record to reliably evaluate qualitative and quantitative aspects of food intake; however, motivational issues can arise when record keeping for over 3 days is required.33 Proper training and direction on how to approximate portion sizes and servings for fluids are difficulties that investigators may come across in assessing dietary intake. Furthermore, literacy and visual impairment among hemodialysis patients is also reported,44 and use of diaries can increase the burden on their caregivers as they might be required to complete the forms, thereby contributing to variation in the diary data generated.
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In a mini-review, Trabulsi and Schoeller indicated that physical and psychological characteristics of study participants can play a significant role in the underreporting bias observed in studies using self-reporting energy intake data.47 Simplifying food choice to ease the reporting burden, embarrassment or guilt of having to record specific foods or quantities, altering their eating pattern during the recording period and stating inconvenience of having to weigh and record their normal diet (selecting foods that were easier to weigh and eating less) as a reason for altering their eating pattern have been recognized as significant limitations of using dietary diaries.45,50 Nutrient intake is only a derived measurement where the primary measure is food intake: differential reporting of nutrients is the inevitable end result of disparity in reporting of foods and meals consumed.45 Diary cards have been used infrequently in the study of nutrient intake in large multinational studies with dialysis patients, as regional variations in diet would require the use of multiple nutrient composition charts. Regional variation in portion size and composition and suitably trained local dieticians to collect and process the results, contribute to data variation. Burrowes et al. reported the results of the only study to evaluate intake in a large cohort (N 5 1,901) of hemodialysis patients, which spanned 7 years and involved 72 hemodialysis units from 15 clinical centers, based in the United States.51 By their own admission, their results were limited by the use of a single 2-day period diet diary assisted recall which provided an estimate of daily energy and protein intake, prone to underestimation. These types of studies are typically restricted to patients attending a limited number of dialysis units, with an attending renal dietician who has the infrastructure to support the time consuming nature of collecting, analyzing, and interpreting the collected information; this infrastructure is not always available.37
Diet and Phosphate Binders Changes in dietary intake during a trial could mask the efficacy of a phosphate binder.32 Increased appetite (because of alleviation of uremic toxicity) and a resultant increase in dietary phosphate intake when trying a new phosphate binder may give the impression of less effective phosphate binding versus comparator. Therefore, it is important to be able to account for any changes in
dietary intake, including phosphates, when assessing the efficacy of a phosphate binder by monitoring nutritional intake. Hutchison et al. performed dietary assessments in a subgroup (N 5 95) of hemodialysis patients (N 5 757) participating in a European multicenter study investigating the efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia.52 Dietary intake of phosphate, calcium, protein, vitamin D, and energy was recorded at 2 time-points during the maintenance phase of the study; however, details of how this assessment was conducted were not provided. The authors indicated that patients’ diets remained constant throughout the study and therefore could not account for the difference in efficacy observed between the 2 investigational compounds. Dietary intake was assessed in a small group of hemodialysis patients (N 5 41) participating in a trial that was investigating the effect of sevelamer HCl on serum phosphorus levels.53 A trained interviewer used the 24-hour recall methods to assess dietary intake on dialysis, nondialysis, and weekend days during the course of the study. There was considerable variability in the measurements, with coefficient of variability of mean daily intakes of dietary nutrients ranging from 31% to 79%. Nevertheless, the authors were able to demonstrate that the dose of sevelamer HCl correlated with dietary phosphate intake. The use of small groups of patients in both these studies is indicative of the difficulties in providing the required support network of adequately trained renal dieticians necessary to gather and interpret the appropriate data.
Conclusion It is evident that an assessment of the nutritional intake of a hemodialysis patient is a necessary part of the physician’s and dietician’s armamentarium to control serum phosphate levels and improve patient outcomes. Furthermore, there have been some developments regarding the assessment of appetite in dialysis patients which are of considerable interest, particularly the fact that the questionnaires are relatively short and simple, and can be performed by staff with little training. Perhaps, monitoring dietary habit in the form of appetite could serve as a simple screening tool, highlighting any changes in dietary habit and thereby in nutritional intake which may require further
DIETARY PHOSPHATE ASSESSMENT IN DIALYSIS PATIENTS
investigation. Changes in dietary habit could act as a preliminary assessment of a change in nutritional intake without the need for a detailed dietary assessment to highlight if there is an issue. Indeed, assessing changes in appetite in trials involving phosphate binders may provide insight as to whether changes in dietary habit are having an effect on efficacy without the need for time consuming estimates of dietary phosphate intake. Nevertheless, there is still a need to assess the actual nutritional intake of a patient and although hampered by significant limitations, particularly in terms of variability, dietary interviews can provide additional data which, provided they are used in combination with various biochemical markers, can contribute to a detailed assessment of the patients’ nutritional status. There is still a need to reduce the variability and cumbersome nature associated with collecting and analyzing data from dietary interviews. Although, in the absence of adequate food labeling, to what extent the shifting use of preservatives and the need for increasing product shelf life may defeat the process remains unclear.
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of patients with chronic kidney disease. Clin J Am Soc Nephrol 5: 519-530, 2010 32. Fouque D: Phosphate intake and the CARE study. Kidney Int 66:2088, 2004 33. Chauveau P, Grigaut E, Kolko A, et al: Evaluation of nutritional status in patients with kidney disease: usefulness of dietary recall. J Ren Nutr 17:88-92, 2007 34. Sullivan C, Sayre S, Leon J, et al: Effect of food additives on hyperphosphatemia among patients with end-stage renal disease. JAMA 301:629-635, 2009 35. Savica V, Calo` LA, Monardo P, et al: Salivary phosphorus and phosphate content of beverages: implications for the treatment of uremic hyperphosphatemia. J Ren Nutr 19:69-72, 2009 36. Ramal G, Chandra L, Harnett P, et al: Assessing knowledge of haemodialysis patients on low phosphate diet and binders. J Ren Nutr 18:S5, 2008 37. Burrowes J, Russell G, Rocco M: Multiple factors affect renal dietitians’ use of the NKF-K/DOQI adult nutritional guidelines. J Ren Nutr 15:407-426, 2005 38. Burrowes J, Powers S, Cockram D, et al: Use of an appetite and diet assessment tool in the pilot phase of a hemodialysis clinical trial: mortality and morbidity in hemodialysis study. J Ren Nutr 6: 229-232, 1996 39. Burrowes JD, Larive B, Chertow GM, et al: Self-reported appetite, hospitalization and death in haemodialysis patients: findings from the Hemodialysis (HEMO) Study. Nephrol Dial Transplant 20:2765-2774, 2005 40. Uribarri J: Phosphorus additives in food and their effect in dialysis patients. Clin J Am Soc Nephrol 4:1290-1292, 2009 41. Goldwasser P, Mittman N, Antignani A, et al: Predictors of mortality in hemodialysis patients. J Am Soc Nephrol 3: 1613-1622, 1993 42. Avram MM, Mittman N, Bonomini L, et al: Markers for survival in dialysis: a seven-year prospective study. Am J Kidney Dis 26:209-219, 1995
43. Carrero JJ: Identification of patients with eating disorders: clinical and biochemical signs of appetite loss in dialysis patients. J Ren Nutr 19:10-15, 2009 44. Kalantar-Zadeh K, Block G, McAllister C, et al: Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients. Am J Clin Nutr 80:299-307, 2004 45. Livingstone MB, Black AE: Markers of the validity of reported energy intake. J Nutr 133:895S-920S, 2003 46. Boaz M, Smetana S: Regression equation predicts dietary phosphorus intake from estimate of dietary protein intake. J Am Diet Assoc 96:1268-1270, 1996 47. Trabulsi J, Schoeller D: Evaluationof dietary assessment instruments against doubly labeled water, a biomarker of habitual energy intake. Am J Physiol Endocrinol Metab 281:E891-E899, 2001 48. Taren D, Tobar M, Hill A, et al: The association of energy intake and bias with psychological scores of women. Eur J Clin Nutr 53:570-578, 1999 49. van Staveren WA, de Boer JO, Burema J: Validity and reproducibility of a dietary history method estimating the usual food intake during one month. Am J Clin Nutr 42:554-559, 1985 50. Macdiarmid J, Blundell J: Dietary under-reporting: what people say about recording their food intake. Eur J Clin Nutr 51:199-200, 1997 51. Burrowes JD, Larive B, Cockram DB, et al: Effects of dietary intake, appetite, and eating habits on dialysis and non-dialysis treatment days in hemodialysis patients: cross-sectional results from the HEMO study. J Ren Nutr 13:191-198, 2003 52. Hutchison A, Maes B, Vanwallegham J, et al: Efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia: a 6 month, randomized, comparative trial versus calcium carbonate. Nephron Clin Pract 100:c8-c19, 2005 53. Goldberg D, Dillon M, Slatopolsky E, et al: Effect of RenaGel, a non-absorbed, calcium- and aluminium-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients. Nephrol Dial Transplant 13:2303-2310, 1998
Dietary Phosphate Assessment in Dialysis Patients Alastair M. Mathewson, PhD,* Denis Fouque, MD, PhD,† and Alex J. Toft* Malnutrition is known to be highly prevalent in patients with kidney disease. It is associated with poor clinical prognosis and can result from restricted dietary protein-energy intake. The issue is also compounded by protein wasting that occurs in dialysis patients. In countering malnutrition, an adequate protein intake is essential but limited by its phosphate content. Therefore, an accurate assessment of nutritional status and intake is an important part of the therapeutic strategy for patients on dialysis. Assessing dietary phosphate intake is not straight forward, with many confounding factors requiring consideration. Interview and diet diaries are the preferred means by which dietary intake can be estimated. However, it is evident that these estimates can vary considerably and are subject to underreporting. Moreover, the use of phosphates as additives and their omission from available nutrient databases are significant contributors to this variation and underestimation. This review highlights the main limitations in assessing dietary phosphate intake and introduces the concept of monitoring changes in dietary habit (appetite) as a proxy for dietary protein and energy intake. This review discusses the use of monitoring dietary habit in trials, with phosphate binders as a simple tool to address the possibility that changes to dietary habits may influence phosphate binder efficacy. Ó 2010 by the National Kidney Foundation, Inc. All rights reserved.
M
ALNUTRITION IS KNOWN to be highly prevalent in patients with kidney disease. It is associated with poor clinical prognosis and can result from restricted dietary proteinenergy intake. This is compounded by the protein wasting that occurs in patients on dialysis, partly due to protein and amino acid loss into the dialysate.1 Restricting dietary protein intake may also lead to greater mortality.2,3 The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend a daily protein intake of at least 1.2 g/kg standard body weight,4 and the European Best Practice (EBP) guidelines recommend at least 1.1 g/kg/day.5 However, there is a problem in this: protein is a major source of *INEOS Healthcare Ltd, Warrington, United Kingdom. †Department of Nephrology, Hoˆpital E.Herriot and U870 Inserm, Lyon, France. Address reprint requests to Alastair Mathewson, PhD, INEOS Healthcare Ltd, 4 Liverpool Road, Warrington, WA5 1AQ, United Kingdom. E-mail: [email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.05.014
dietary phosphate, and as dialysis is unable to remove sufficient phosphate to balance daily intake, phosphate accumulation might occur.6,7 Although controlling dietary phosphate intake can help control serum phosphate concentration, care must be taken to ensure adequate nutritional intake, particularly in the form of protein; controlling serum phosphate by reducing protein intake may be detrimental to the patient.2,3 The published data has described that elevated serum phosphate is associated with increased mortality in patients with chronic kidney disease8–11 and more recently it has been found to be associated with increased mortality in the general population.12 The concept of a phosphate-to-protein ratio was proposed in the K/DOQI guidelines in 200313 as a means to aid control of serum phosphate through control of dietary intake, combining and focusing the attention simultaneously on dietary phosphate and protein intake by drawing attention to food with excessive phosphates and little to no protein content. It is evident that most dialysis patients with an adequate protein intake will require oral phosphate binders to prevent a rise in serum phosphate and concomitant rise in serum parathyroid hormone.14
Journal of Renal Nutrition, Vol 20, No 6 (November), 2010: pp 351–358
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Dietary Phosphate Content Phosphorus is found in a wide variety of food and drinks as inorganic phosphates and is also present in drinking water, with a maximum allowed content of 2.2 mg/L in the European Union.15 Estimates of dietary phosphorus intake in European countries are summarized in Table 1, with similar consumption seen in Australia. In the United States, the average phosphate (as phosphorus) intake ranges from 850 to 950 mg/day for women and 1,200 to 1,500 mg/day for men. Mean daily phosphorus intake in Brazil is estimated at 520 mg/1,000 kcal, which equates to 1,196 mg/day, based on an average daily intake of 2,350 kcal.16 Estimates from Japan suggest daily phosphorous intake of 649 6 212 mg, but can be as much as 2,250 mg.17,18 Estimates of dietary phosphorus intake tend to exclude contributions from vitamin and mineral supplements, drinking water, or phosphorous from food additives, and therefore the actual intakes are almost certainly greater than those reported.19 Food additives can contribute more than 30% of the adult phosphorus intake, and are often not taken into account in nutrient composition tables.19 This is of significance because phosphate delivered as additives is more readily absorbed because of its inorganic nature and absence of endogenous chelates, such as phytate, than that found in foods that are naturally high in phosphate.20 This highlights the fact that the source of phosphate is equally as important as the phosphate content of the source. Consideration should be given to the food source when assessing its contribution to bioavailable phosphate.
On average, approximately 60% to 70% of dietary phosphate is absorbed by the gastrointestinal tract. The extent of the absorption depends on the food source. Phosphorus derived from meat sources is reasonably well absorbed, as it exists mostly as intracellular organic compounds that are easily hydrolyzed in the gastrointestinal (GI) tract, resulting in the release of inorganic phosphorus.21 Phosphorus in plant tissue, however, such as that found in bran and seeds, is principally stored in the form of phytates. In nonruminant animals, a lack of phytase results in poor bioavailability of phosphorus from this source,22 unless the food has been supplemented with phytase as a part of its processing, such as the addition of phytase-containing yeast to bread. Bacteria in the gut can also liberate some phosphorus from phytates, provided a complex with cations such as calcium, zinc, or iron has not been formed,23 varying the amount of bioavailable phosphate from individual to individual. It is evident that the phosphate content of supermarket foods can vary significantly, making estimation of phosphate content by patients and dieticians very difficult.24,25 In meats and fish, phosphates are used as a preservative and to help color retention by inhibiting surface oxidation.26 Phosphates are also added to other foodstuffs such as cakes, cheeses, and bread to improve their structural appearance. One limitation with the concept of the phosphate-to-protein ratio is that the total phosphate content of many foods and beverages is not widely available and a means of differentiating between endogenous and added phosphate remains to be established. The hidden phosphate content of a variety of food and drinks
Table 1. Estimates of Daily Intake of Phosphorus in Some EU Countries* Population Italy Household Germany Individual (M) Individual (F) Netherlands Household Sweden Individual (M) Individual (F) UK Individual (M) Individual (F)
N
Method
Mean (mg/day)
97.5 Percentile
2,374
7-day record
1,304
2,076
862 1,144
7-day record 1 food frequency record
1,488 1,188
2,517 1,988
5,958
2-day record
1,480
2,601
1,214
7-day record
1,570 1,290
2,517 1,988
656 803
7-day record
1,493 1,112
2,381 1,763
*Reprinted with permission.15
DIETARY PHOSPHATE ASSESSMENT IN DIALYSIS PATIENTS
has been published in a series of papers.27–29 Differentiation between organic phosphate and added phosphate presents food manufacturers with a significant technical challenge which needs to be overcome before significant advances in food labeling can be addressed.30 KalantarZadeh et al. have recently published a list of phosphate and protein content and their ratio for a range of food and beverages.31 After being calculated for a particular food, these values provide a useful guide to selecting food with a favorable ratio: low in phosphate and high in protein. Examples of food with a high phosphate to protein ratio (.20 mg/g) include sunflower seeds, nuts, milk, and certain cheeses. Food with a low phosphate to protein ratio (,10 mg/g) include fresh meat products such as lamb, beef, pork, fish, and chicken. As mentioned previously, the source of the phosphate needs to be considered because when contained in meat it is more bioavailable as compared with that contained within vegetables and seeds. Despite some considerable variation in phosphorus intake across and within geographical regions, dialysis patients are advised to restrict daily phosphorus intake to no more than 1000 mg/ day (on average, 17 mg/kg body weight), as recommended by K/DOQI13 and EBP guidelines.5 The estimates of daily phosphate intake in dialysis patients taken from weekly dietary recall vary considerably, with mean (6SD) daily intakes estimated at 860 6 300 mg/day and a mean coefficient of variation of 35%.33 Chauveau et al. observed large differences in both the type and amount of food ingested from day to day, particularly from dialysis to nondialysis days.33 A dietician counsels patients on restricting dietary phosphate intake; however, 30% to 50% of patients entering dialysis may not have met a dietician and hence would not have received any counseling.14 Although patients are advised to monitor phosphate intake by reducing the consumption of food high in phosphate, hidden sources of phosphate such as additives are often unaccounted for26 and can contribute significantly to the phosphate burden of dialysis patients34 because of their near complete absorption. The authors reported that restricting the intake of enhanced foods with phosphate containing additives helped decrease phosphate intake.34 The phosphate content of beverages is often not taken into consideration by patients or physicians.35 Savica et al. report that 74% of their patients consumed drinks with a higher phosphate
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content such as red and white wine, cola, and beer, whereas only a minority consumed those with a low phosphate content such as orange juice, lemonade, and mineral water.35 Most beverages contain little to no protein and any phosphate content is almost entirely from additives. As a consequence, patients who consumed beverages with high phosphate content had serum phosphate levels that were higher than the range of phosphate suggested by the K/DOQI guidelines. One of the barriers to controlling dietary phosphorous intake is patient education; there is evidence to suggest that up to 50% of patients receiving treatment at a dialysis unit in the United Kingdom believed that dietary phosphate restriction was no longer necessary when they were taking phosphate binders.36 Indeed, educating patients to avoid foods with phosphate additives can result in a marked reduction in serum phosphate compared with patients not receiving the educational intervention.34 Although nutritional intake was not assessed, the authors suggested that the improvement to serum phosphate was because of change in patients’ behavior regarding food choices, with an increased awareness and reading of food labels and ingredient lists.
Monitoring Nutritional Intake The assessment of the nutritional status of dialysis patients is an important part of their therapeutic strategy, and several methods for assessment are available.14 The K/DOQI has published 21 guidelines on nutrition for dialysis patients detailing methods for evaluating protein-energy nutritional status, managing acid-base balance, ensuring adequate dietary protein and energy intake, and conducting nutrition counseling.4 Of these 21 guidelines, a recent survey of 848 dieticians (National Kidney Foundation Council on Renal Nutrition members) indicated that serum albumin was considered the most important method for evaluating nutritional status in maintenance dialysis.37 It was followed by a change in body weight, and then the dietary intake assessment with diet interviews and/or diaries. However, more than half (57%) of the dieticians reported lack of the necessary tools, such as food models and measuring utensils, personal computer, callipers and stadiometer, as the reason for not implementing some of the guidelines. Monitoring changes in appetite has been proposed as a useful
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aid in the monitoring of nutritional intake38 and has been validated in a large multicenter trial as a proxy for dietary protein and energy intake.39 Dietary assessment is recommended by the EBP guidelines on nutrition as part of a number of assessment tools in the diagnosis of malnutrition.5 The other recommended assessment tools include body mass index, subjective global assessment, anthropometry, normalized protein nitrogen appearance (nPNA), serum albumin and serum prealbumin, serum cholesterol, and various technical investigations (bioimpedancemetry, dual X-ray absorptiometry, near-infrared reactance). Existing methods to assess dietary intake include 24 hours-recall, 3 and 7 days diet diaries, each of which has its own benefits and limitations (Table 2); K/DOQI guidelines recommend periodic 3-day dietary records followed by dietary interviews to calculate nutrient intake as part of the assessment of dietary protein and energy intake.4 In each case, the expertise of a qualified dietician is essential to complete the diaries and ensure accuracy. The EBP guidelines recommend that dietary interviews should be conducted in stable and well-nourished patients every 6 to 12 months, or every 3 months if the patient is aged .50 years or has been on hemodialysis for .5 years.5 Malnourished hemodialysis patients should be assessed more frequently, using at least a 24-hours dietaryrecall method. The guidelines indicate that the use of data obtained from unsupervised food recordings, covering a short period can be incomplete and subjective, and therefore should be used with caution. However, this has to be balanced with the acknowledgement that available food composition tables in books or software programs do not accurately reflect the use of phosphorous as a food additive and preservative.40
Serum Albumin and Prealbumin There is ample evidence that serum albumin and prealbumin are valid and clinically useful indicators of protein-energy nutritional status.4,5 Together with transferrin and other liver-derived proteins, serum albumin and prealbumin are the most commonly used laboratory parameters for routine assessment of nutritional status, with serum albumin being the most commonly used nutritional marker in dialysis patients.14 Changes in albumin and prealbumin are related to changes in dietary protein intake and are thus useful indicators of protein-energy nutritional status and dietary intake in dialysis patients.4 Serum albumin and prealbumin provide a measure of visceral protein pool size and are considered indicators of future mortality risk.41,42 Low serum albumin is considered a sign of uremic anorexia (loss of appetite).1,43 Albumin and prealbumin levels may decrease acutely with inflammation or acute or chronic stress and increase after resolution or recovery. Therefore, a decrease in serum albumin and/or prealbumin must be interpreted in the context of the patient’s clinical status. Reports of infection or signs of infection, such as fever, reported as adverse events during routine clinical monitoring of patients may be used in the interpretation of a fall in albumin and prealbumin. Furthermore, changes in serum albumin and prealbumin can be correlated with phosphate levels. Because of the high phosphate content of dietary protein, changes in serum phosphate mirror changes in dietary protein intake. Thus, a change in serum phosphate and albumin/prealbumin in the same direction provides stronger evidence of a change in dietary (protein) intake than a change in either individually.
Table 2. Comparison of the Main Attributes of Each Method of Collecting Information on Dietary Intake Twenty-Four Hour Dietary Recall
Three Days Food Records
Seven Days Food Records or Diet Diaries
Good starting point revealing major imbalances, dietary inadequacies, and areas of concern Relies on memory and may underestimate actual intake May not represent typical food intake reflecting daily variation
Diary over 3 days may be sufficient when food intake is stable K/DOQI guidelines recommend a 3-day diary covering dialysis, nondialysis, and weekend days Requires teaching patients to measure portions sizes Must account for all food and drink consumed, including snacks
Seven days is the minimum period required to assess protein and energy intake within 10% of the standard error Includes variations in food intake over longer periods Diaries lasting more than 3 days are subject to reduced compliance and accuracy because of reduced motivation
DIETARY PHOSPHATE ASSESSMENT IN DIALYSIS PATIENTS
Appetite One of the most common symptoms in patients with chronic kidney disease suffering from toxic uremia is loss of appetite, or anorexia;43 therefore, appetite assessment has been considered as a practical tool for assessing the relationship between appetite and dietary intake in hemodialysis patients.38 Burrowes et al. described a simple series of questions which can be used to assess appetite and changes in appetite, requiring very little processing by healthcare professionals. Mean levels of protein and energy intake from diet diaries varied significantly by level of appetite rating; when appetite ratings increased, mean energy and protein intakes also increased.38 Burrowes et al. (1996) did not report any significant differences in appetite across comparable intervals, although nutrient intake can vary between dialysis and nondialysis days.33 A single self-report of a patient’s hunger may be easily implemented in any clinic. The questionnaire proposed by Burrowes et al. has been used in a multicenter randomized trial where appetite assessment was validated in a large sample of subjects receiving hemodialysis (N 5 1,846) as a proxy for dietary protein and energy intakes.39 Moreover, Kalantar-Zadeh et al. showed that a simple appetite questionnaire was able to predict mortality at 1-year in a cohort of approximately 300 patients on maintenance hemodialysis in California.44
Diet Interviews and/or Patient Diaries Diet interviews and/or diaries are described by K/DOQI as being valid and clinically useful for measuring dietary protein and dietary energy intake in maintenance of dialysis patients.4 Diet interviews and/or diaries are a useful tool to provide an estimate of nutritional intake. However, it is widely accepted that they underestimate nutrient and fluid intake when compared with energy expenditure,45 which limits their usefulness and interpretability. Livingstone and Black described coefficients of variation of the differences within individuals as 16.5% for 3-day food records, 18.6% for a dietary history, and 28.5% for a foodfrequency questionnaire.45 Diet interviews and/or diaries do not capture phosphorus intake from food additives and can underestimate phosphorus intake by as much as 30%.19 Indeed, available nutrient databases do not account for the variations
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in phosphate additive content, making it extremely difficult for patients and dieticians to accurately estimate phosphate content.34 A linear relationship between dietary phosphate intake and estimated dietary protein intake has been described in the literature after estimating dietary protein and phosphate intake of over 200 patients on maintenance hemodialysis across 2 studies.31,46 The linear relationship accounted for between 83% and 84% variation in dietary phosphorus intake and may be useful in providing rough estimates of dietary phosphate content derived from protein intake. It is unclear whether phosphate additives are accounted for as these tend to be omitted from nutrient composition tables. Trabulsi and Schoeller demonstrated that, regardless of the dietary methodology used to assess dietary habit, true energy intake is consistently underreported, particularly in certain groups within the population.47 These groups present within the population tend to be uncomfortable with their body image and/or consume foods considered to be socially undesirable. An inverse relationship between body mass index and reporting accuracy has been demonstrated, where patients with high body mass index were more likely to underreport.48 Food intake varies widely with time, with a coefficient of variation close to 20% in a 3-day recall and much higher if a 1-day technique or a food frequency questionnaire is used.49 Although 24-hour recall can be a rapid and simple method, it does rely on the patients’ ability to remember how much food was consumed in the previous 24 hours and must be obtained by a trained and skilled dietician. Dietary intake can vary considerably on a daily basis in dialysis patients, with significant decreases in nutrient intake on dialysis days compared with nondialysis days.33 Chauveau et al. recommend a 7-day food record to reliably evaluate qualitative and quantitative aspects of food intake; however, motivational issues can arise when record keeping for over 3 days is required.33 Proper training and direction on how to approximate portion sizes and servings for fluids are difficulties that investigators may come across in assessing dietary intake. Furthermore, literacy and visual impairment among hemodialysis patients is also reported,44 and use of diaries can increase the burden on their caregivers as they might be required to complete the forms, thereby contributing to variation in the diary data generated.
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In a mini-review, Trabulsi and Schoeller indicated that physical and psychological characteristics of study participants can play a significant role in the underreporting bias observed in studies using self-reporting energy intake data.47 Simplifying food choice to ease the reporting burden, embarrassment or guilt of having to record specific foods or quantities, altering their eating pattern during the recording period and stating inconvenience of having to weigh and record their normal diet (selecting foods that were easier to weigh and eating less) as a reason for altering their eating pattern have been recognized as significant limitations of using dietary diaries.45,50 Nutrient intake is only a derived measurement where the primary measure is food intake: differential reporting of nutrients is the inevitable end result of disparity in reporting of foods and meals consumed.45 Diary cards have been used infrequently in the study of nutrient intake in large multinational studies with dialysis patients, as regional variations in diet would require the use of multiple nutrient composition charts. Regional variation in portion size and composition and suitably trained local dieticians to collect and process the results, contribute to data variation. Burrowes et al. reported the results of the only study to evaluate intake in a large cohort (N 5 1,901) of hemodialysis patients, which spanned 7 years and involved 72 hemodialysis units from 15 clinical centers, based in the United States.51 By their own admission, their results were limited by the use of a single 2-day period diet diary assisted recall which provided an estimate of daily energy and protein intake, prone to underestimation. These types of studies are typically restricted to patients attending a limited number of dialysis units, with an attending renal dietician who has the infrastructure to support the time consuming nature of collecting, analyzing, and interpreting the collected information; this infrastructure is not always available.37
Diet and Phosphate Binders Changes in dietary intake during a trial could mask the efficacy of a phosphate binder.32 Increased appetite (because of alleviation of uremic toxicity) and a resultant increase in dietary phosphate intake when trying a new phosphate binder may give the impression of less effective phosphate binding versus comparator. Therefore, it is important to be able to account for any changes in
dietary intake, including phosphates, when assessing the efficacy of a phosphate binder by monitoring nutritional intake. Hutchison et al. performed dietary assessments in a subgroup (N 5 95) of hemodialysis patients (N 5 757) participating in a European multicenter study investigating the efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia.52 Dietary intake of phosphate, calcium, protein, vitamin D, and energy was recorded at 2 time-points during the maintenance phase of the study; however, details of how this assessment was conducted were not provided. The authors indicated that patients’ diets remained constant throughout the study and therefore could not account for the difference in efficacy observed between the 2 investigational compounds. Dietary intake was assessed in a small group of hemodialysis patients (N 5 41) participating in a trial that was investigating the effect of sevelamer HCl on serum phosphorus levels.53 A trained interviewer used the 24-hour recall methods to assess dietary intake on dialysis, nondialysis, and weekend days during the course of the study. There was considerable variability in the measurements, with coefficient of variability of mean daily intakes of dietary nutrients ranging from 31% to 79%. Nevertheless, the authors were able to demonstrate that the dose of sevelamer HCl correlated with dietary phosphate intake. The use of small groups of patients in both these studies is indicative of the difficulties in providing the required support network of adequately trained renal dieticians necessary to gather and interpret the appropriate data.
Conclusion It is evident that an assessment of the nutritional intake of a hemodialysis patient is a necessary part of the physician’s and dietician’s armamentarium to control serum phosphate levels and improve patient outcomes. Furthermore, there have been some developments regarding the assessment of appetite in dialysis patients which are of considerable interest, particularly the fact that the questionnaires are relatively short and simple, and can be performed by staff with little training. Perhaps, monitoring dietary habit in the form of appetite could serve as a simple screening tool, highlighting any changes in dietary habit and thereby in nutritional intake which may require further
DIETARY PHOSPHATE ASSESSMENT IN DIALYSIS PATIENTS
investigation. Changes in dietary habit could act as a preliminary assessment of a change in nutritional intake without the need for a detailed dietary assessment to highlight if there is an issue. Indeed, assessing changes in appetite in trials involving phosphate binders may provide insight as to whether changes in dietary habit are having an effect on efficacy without the need for time consuming estimates of dietary phosphate intake. Nevertheless, there is still a need to assess the actual nutritional intake of a patient and although hampered by significant limitations, particularly in terms of variability, dietary interviews can provide additional data which, provided they are used in combination with various biochemical markers, can contribute to a detailed assessment of the patients’ nutritional status. There is still a need to reduce the variability and cumbersome nature associated with collecting and analyzing data from dietary interviews. Although, in the absence of adequate food labeling, to what extent the shifting use of preservatives and the need for increasing product shelf life may defeat the process remains unclear.
References 1. Fouque D, Kalantar-Zadeh K, Kopple J, et al: A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int 73:391-398, 2008 2. Shinaberger C, Greenland S, Kopple J, et al: Is controlling phosphorus by decreasing dietary protein intake beneficial or harmful in persons with chronic kidney disease? Am J Clin Nutr 88:1511-1518, 2008 3. Shinaberger CS, Kilpatrick RD, Regidor DL, et al: Longitudinal associations between dietary protein intake and survival in hemodialysis patients. Am J Kidney Dis 48:37-49, 2006 4. National Kidney Foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35:s17-s104, 2000 5. Fouque D, Vennegoor M, Ter Wee P, et al: EBPG guideline on nutrition. Nephrol Dial Transplant 22:ii45-ii87, 2007 6. DeSoi CA, Umans JG: Phosphate kinetics during high-flux hemodialysis. J Am Soc Nephrol 4:1214-1218, 1993 7. Pohlmeier R, Vienken J: Phosphate removal and hemodialysis conditions. Kidney Int 59:S190-S194, 2001 8. Ganesh SK, Stack AG, Levin NW, et al: Association of elevated serum PO4, Ca PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 12:2131-2138, 2001 9. Block GA, Klassen PS, Lazarus JM, et al: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15:2208-2218, 2004 10. Block GA, Hulbert-Shearon T, Levin N, et al: Association of serum phosphorus and calcium x phosphorus product with mortality risk in chronic haemodialysis patients: a national study. Am J Kidney Dis 31:607-617, 1998
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11. Melamed ML, Eustace JA, Plantinga L, et al: Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int 70: 351-357, 2006 12. Abramowitz M, Muntner P, Coco M, et al: Serum alkaline phosphatase and phosphate and risk of mortality and hospitalization. Clin J Am Soc Nephrol 5:1064-1071, 2010 13. National Kidney Foundation: Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42:S1-S201, 2003 14. Locatelli F, Fouque D, Heimburger O, et al: Nutritional status in dialysis patients: a European consensus. Nephrol Dial Transplant 17:563-572, 2002 15. EFSA: Opinion of the scientific panel on dietetic products, nutrition and allergies on a request from the commission related to the tolerable upper intake level of phosphorus. EFSA J 233:1-19, 2005 16. Jansen GR, Jansen NB, Shigetomi CT, et al: Effect of income and geographic region on the nutritional value of diets in Brazil. Am J Clin Nutr 30:955-964, 1977 17. Nishimuta M, Kodama N, Morikuni E, et al: Balances of calcium, magneisum and phosphorus in Japanese young adults. J Nutr Sci Vitaminol 50:19-25, 2004 18. Ueno K, Nakamura K, Nishiwaki T, et al: Intakes of calcium and other nutrients related to bone health in Japanese female college students: a study using the duplicate portion sampling method. Tohoku J Exp Med 206:319-326, 2005 19. Calvo MS, Park YK: Changing phosphorus content of the U.S. diet: potential for adverse effects on bone. J Nutr 126: 1168S-1180S, 1996 20. Uribarri J: Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial 20:295-301, 2007 21. Kayne LH, D’Argenio DZ, Meyer JH, et al: Analysis of segmental phosphate absorption in intact rats. A compartmental analysis approach. J Clin Invest 91:915-922, 1993 22. McCance RA, Widdowson EM: Mineral metabolism of healthy adults on white and brown bread dietaries. J Physiol 101:44-85, 1942 23. Gropper SS, Smith JL, Groff JL: Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing Company, 2008 24. Sherman RA, Mehta O: Phosphorus and potassium content of enhanced meat and poultry products: implications for patients who receive dialysis. Clin J Am Soc Nephrol 4: 1370-1373, 2009 25. Sullivan C, Leon J, Sehgal AR: Phosphorus-containing food additives and the accuracy of nutrient databases: implications for renal patients. J Ren Nutr 17:350-354, 2007 26. Uribarri J, Calvo M: Hidden sources of phosphorus in the typical American diet: does it matter in nephrology? Semin Dial 16:186-188, 2003 27. Murphy-Gutekunst L: Hidden phosphorus in popular beverages: part 1. J Ren Nutr 15:e1-e6, 2005 28. Murphy-Gutekunst L, Barnes K: Hidden phosphorus at breakfast: part 2. J Ren Nutr 15:E1-E6, 2005 29. Murphy-Gutekunst L, Uribarri J: Hidden phosphorusenhanced meats: part 3. J Ren Nutr 15:e1-e4, 2005 30. Murphy-Gutekunst L: Hidden phosphorus: where do we go from here? J Ren Nutr 17:e31-e36, 2007 31. Kalantar-Zadeh K, Gutekunst L, Mehrotra R, et al: Understanding sources of dietary phosphorus in the treatment
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