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The effects of zinc supplementation on serum zinc concentration and protein catabolic rate in hemodialysis patients
The Effects of Zinc Supplementation on Serum Zinc Concentration and Protein Catabolic Rate in Hemodialysis Patients Nancy A. Jern, MS, RD, LD,* Anne D. VanBeber, PhD, RD, LD,† Mary Anne Gorman, PhD, RD, LD, FADA,‡ Cynthia G. Weber, PhD, RD, LD,§ George U. Liepa, PhD,\ and Carolyn C. Cochran, MS, RD, LD¶ Objective: To examine the effect of zinc sulfate supplementation on serum zinc concentrations and protein catabolic rate (PCR) in hemodialysis (HD) patients. Design: Randomized, double-blind, before-after trial. Setting: Outpatient dialysis center in a large metropolitan city. Patients: Twenty-eight maintenance HD patients were selected. Twenty (15 women, 5 men) subjects completed the study. Subjects were identified for inclusion in the study by the following criteria: a history of low PCR (⬍0.09 g/kg body weight), HD treatment for a minimum of 6 months, no signs of gastrointestinal disorders, and no record of hospitalizations for reasons other than access complication within the last 3 months. Interventions: Patients consumed 7.7 µmol zinc sulfate (2,200 µg) or a cornstarch placebo capsule daily for 90 days. In addition, patients completed a 2-day food record representative of 1 dialysis day and 1 nondialysis day. Main outcome measure: Fasting, predialysis serum samples were collected on days 0, 40, and 90 to determine serum zinc concentration and PCR. Dietary parameters including intake of zinc, protein, and energy were analyzed on Days 0 and 90. Results: Initial analysis at Day 0 of serum zinc concentration indicated subjects were below the normal range for serum zinc standards (12.2 µmol/L [80 µg/dL]). After supplementation, subjects in the zinc-supplemented group showed significant increases in serum zinc concentrations from 12.2 µmol/L (80 µg/dL) at Day 0 to 15.3 µmol/L (100 µg/dL) at Day 90. A significant positive correlation (r ⫽ ⫹0.61) was shown between PCR and serum zinc concentrations at the end of the study. Reported dietary protein intake did not change with zinc supplementation. Conclusion: Low serum zinc concentrations are reversible with zinc supplementation. Improvement in serum zinc concentration increases the PCR of HD patients. r 2000 by the National Kidney Foundation, Inc.
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ENAL DISEASE affects approximately 8 million people in the United States.1 Individuals with chronic renal failure require renal replacement therapy, such as maintenance dialysis or transplantation, to sustain life. The goal of diet therapy for the dialysis population is to minimize uremia and other metabolic disorders while maintaining adequate nutritional status.2
One complicating factor of uremia is zinc deficiency.3 During the past 2 decades, an increased number of diet- and disease-induced human zinc deficiency cases have been reported worldwide.4-6 Some chronic renal failure patients exhibit inordinately low concentrations of plasma zinc because of increased metabolic demands and are at higher risk for developing zinc deficiency. It
*Clinical Dietitian, Presbyterian Hospital of Dallas, Dallas, TX. †Associate Professor and Chair, Department of Nutrition and Dietetics, Texas Christian University, Fort Worth, TX. ‡Professor, Department of Nutrition and Dietetics, Texas Christian University, Fort Worth, TX. §Nutrition Consultant, Spa at the Crescent, Dallas, TX. \Professor and Department Head, Department of Human, Environmental and Consumer Resources, Eastern Michigan State University, Ypsilanti, MI.
¶Renal Dietitian, Dallas Nephrology Associates, Dallas, TX. Work conducted at Texas Woman’s University, Department of Nutrition and Food Science, Denton, TX. Address reprint requests to Anne D. VanBeber, PhD, RD, LD, Associate Professor and Chair, Department of Nutrition and Dietetics, Texas Christian University, Box 298600, Fort Worth, TX 76129. r 2000 by the National Kidney Foundation, Inc. 1051-2276/00/1003-0006$3.00/0 doi:10.1053/jren.2000.7413
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Journal of Renal Nutrition, Vol 10, No 3 ( July), 2000: pp 148-153
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is widely known that clinical signs of zinc deficiency include taste and smell dysfunction and impaired wound healing. Zinc supplementation may benefit this population by relieving a variety of symptoms, including hypogeusia and anorexia. The adult recommended dosage of elemental zinc for healthy subjects is 1 mg/kg/d, with the recommended daily allowance (RDA) for adults ranging from 1.5 to 7.7 µmol/d (100 to 150 µg/d).4,7 Serum concentrations of zinc in healthy subjects have been reported to peak 4 weeks after administration of a daily zinc supplement of 2.3 to 7.7 µmol/d (150 to 500 µg/24 h) and then decrease to initial values after ceasing supplementation.3 Toxic effects of zinc therapy have rarely been reported. A potential toxic effect, however, is zinc-induced copper deficiency anemia that has been reported in subjects administered 23.0 µmol/d (1,500 µg/24 h) zinc for 14 to 24 months.3 Zinc absorption from a supplement administered 3 or more hours after ingestion of a meal has been shown to range between 40% and 90%, while a supplement administered with a meal results in an absorption rate of 8% to 38%.8 Urea kinetic modeling is a technique used to calculate a hemodialysis (HD) patient’s protein catabolic rate (PCR; grams per kilogram body weight per day).9 The target PCR for HD patients is approximately 1.2 g/kg/24 h.10 PCRs, which reflect the patient’s metabolic status and are associated with protein intake, are used to direct/ plan patient nutrition education programs.11 Ureakinetic modeling PCR determinations are used to assess the protein status and malnutrition of HD patients.12,13 The model is based on the assumption that the requirement of dialysis is proportional to the patient’s PCR (g/kg) relative to lean body mass.14 The model uses urea, a measurable product of protein catabolism, to define and monitor dialysis treatment. The purpose of this study was to determine if zinc sulfate supplementation would increase PCR in HD patients to a desired value of 1.2 g/kg/24 h.
Methods Subjects Criteria for selection of subjects to participate in the present study included: a history of low PCR (⬍0.9 g/kg body weight), HD treatment for a minimum of 6 months, no signs of gastroin-
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testinal disorders, and no record of hospitalization for reasons other than access complication within the last 3 months. Twenty-eight subjects (22 women and 6 men) undergoing long-term HD 3 times/week at the Southwestern Dialysis Center, Dallas, TX agreed to participate in the study. Subjects were from various economic backgrounds, and each was given medical clearance by his/her attending physician. Signatures of consent were obtained from all participants after they were given both verbal and written descriptions of the research protocol.
Experimental Design and Sample Determination Randomization of participants in the supplemented and placebo groups was completed by the pharmacist at Parkland Memorial Hospital, Dallas, TX, to insure that the researcher would not know whether the subjects were receiving the zinc supplement or the placebo. The 28 subjects were randomly selected to receive 1 capsule daily containing either 2,200 µg zinc sulfate (7.7 µmol; N ⫽ 14) or cornstarch (N ⫽ 14). Subjects were instructed to consume the supplement for 90 days, 3 or more hours after ingestion of an evening meal and without food or other medications. At the beginning of the study, each subject was administered a supply of 100 capsules. To monitor compliance, capsules were counted at midpoint (Day 40) and the end (Day 90) of the study to determine the actual number of pills consumed by the patient. Subjects were also visited during regular dialysis treatments on a weekly basis to monitor compliance. Predialysis serum samples were collected at the beginning (Day 0), midpoint (Day 40), and end (Day 90) of the study, after a minimal 5-hour fast, during the patients’ routine visit to the dialysis center. Whole blood samples (10 mL) were collected in plastic, zinc-free vacutainer tubes. Blood was allowed to clot for 1 hour at room temperature and then centrifuged for 30 minutes at 3,500 rpm using a clinical centrifuge (Dynac, model #0151; Needham Heights, MA). Three milliliters of serum were removed using a plastic pipette and frozen at 0.0°C. The serum samples were analyzed within 24 hours. Serum zinc concentrations were determined using atomic absorption spectrophotometry (Varian SpectrAA 40; Varian, Inc, Mulgrave, Victoria, Australia)
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according to the procedures outlined by Hackley et al.15 Each subject’s initial, midpoint, and endpoint PCR (g/kg body weight/24 h) was determined using the Southwestern Dialysis Center routine screenings of kinetic modeling. Kinetic modeling was performed during the second week of every other month using the procedures of Sargent and Gotch.16 Subjects were instructed to keep a 2-day food record, including 1 dialysis day and 1 nondialysis day, at the beginning (Day 0) and end (Day 90) of the study. A 2-day food record length was chosen to improve patient compliance and because patients received HD treatments at 2-day intervals. Written and verbal instructions regarding the maintenance of food records were given to each subject, and all subjects received a plastic measuring cup to be used for measuring portion sizes. Dietary records were analyzed using the 24-Hour Recall Computer Program (Nova Services, Dallas, TX) and Nutritionist IV, 1999 nutrient data bank (N-Squared Computing, Salem, OR). Intake of total energy, dietary protein, phosphorus, and zinc was calculated at the beginning and end of the study. Dry body weight was recorded at Days 0, 40, and 90.
Statistical Analysis An analysis of variance with repeated measures design was used to assess changes in serum dependent variables over time. A dependent t test was used to assess changes in dietary parameters from the time of initial supplementation to the end of the supplementation period. The statistical package used was the Statistical Package for Social Sciences-Series X (SPSSX, Chicago, IL).
Results Twenty participants (15 women, 5 men) completed the study. Twelve were African-American, 4 were white, and 4 were Hispanic. Three female subjects experienced adverse reactions (nausea, difficulty swallowing) to the supplements and were withdrawn from the study. Two women were unable to complete the study because of hospitalization; 1 woman was removed from the study after a myocardial infarction. Two subjects (1 man, 1 woman) did not complete the study because of noncompliance with prescribed behavior. A total of 8 subjects (7 women, 1 man) were eliminated from the analysis. Mean age of the participants was 56.5 years (range, 23 to 80 years). Body weight ranged from 54.5 to 137.0 kg. Mean length of time that subjects had undergone dialysis treatment was 4 years, 2 months (range, 9 months to 13 years).
Effects of Dietary and Supplementary Zinc Intake and Serum Zinc Concentration Initial mean serum zinc concentrations for participants in the placebo group and the supplement group were not significantly different. By day 90, serum zinc concentrations of subjects receiving the zinc supplement were 15.3 µmol/L (100 µg/dL), significantly higher than the serum zinc concentration of 10.7 µmol/L (70 µg/dL) seen among subjects receiving the placebo (Fig 1; P ⬍ .05). Serum zinc concentrations for participants in the zinc-supplemented group increased significantly (P ⬍ .05) from 12.2 µmol/L (80 µg/dL) at Day 0, to 13.8 µmol/L (90 µg/dL) at Day 40, to
Figure 1. Effect of zinc supplementation on mean serum zinc concentrations in HD patients.
ZINC SUPPLEMENTATION IN HEMODIALYSIS PATIENTS
15.3 µmol/L (100 µg/dL) at Day 90. Serum zinc concentrations for participants in the placebo group remained stable from Day 0 (12.2 µmol/L [80 µg/dL]) to Day 90 (10.7 µmol/L [70 µg/dL]; Fig 1). A significant difference in reported dietary zinc intake was observed between participants in the 2 groups from the beginning to the end of the study (P ⬍ .05; Fig 1). Participants in the placebo group showed a mean increase in nonsupplemented dietary zinc consumed from .55 µmol/d to .78 µmol/d (36 µg/24 h to 51 µg/24 h; P ⬍ .05), while participants in the zinc-supplemented group showed a decrease in the nonsupplemented dietary zinc consumed, from .63 µmol/d to .37 µmol/d (41 µg/24 h to 24 µg/24 h; P ⬍ .05).
Effects of Dietary and Supplementary Zinc Intake on Protein and Calorie Intake and Body Weight Reported dietary protein intake increased significantly (P ⬍ .05) from 50 g/24 h at day 0 to 59 g/24 h at day 90 among participants in the placebo group. Participants in the treatment group showed a non-insignificant increase in dietary protein intake from 50 g/24 h to 51 g/24 h from the beginning to the end of the study. However, participants in the zinc-supplemented group showed a significant (P ⬍ .05) increased intake of 1,256 kJ/24 h (300 kcal/d), from 5,799 kJ/24 h (1,385 kcal/d) at Day 0 to 7,042 kJ/24 h (1,682 kcal/d) at Day 90. No significant difference in energy intake was observed in participants in the placebo group from Day 0 (5,196 kJ/24 h [1,241 kcal/d]) to Day 90 (5,723 kJ/24 h [1,367 kcal/d]). No significant differences were observed between the participants in either group for body weight from the
Figure 2. Effect of zinc supplementation on mean PCR in HD patients.
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beginning, to the midpoint, or the end of the study.
Effect of Dietary and Supplementary Zinc Intake on PCR The effect of dietary and supplementary zinc intake on PCRs is represented in Fig 2. Initial mean PCR was similar in both the zincsupplemented group (0.85 g/kg/24 h) and the placebo group (0.85 g/kg/24 h). After an initial rise in PCR by both groups at day 40, a significant difference (P ⬍ .05) in PCR was observed by Day 90 when the zinc-supplemented group exhibited a PCR of 0.91 g/kg/24 h and the placebo group exhibited a PCR of 0.85 g/kg/24 h.
Correlations Between Serum Zinc Concentrations and PCR There were no significant correlations found between PCR and serum zinc concentrations for the zinc-supplemented group at the beginning and midpoint of the study. However, a positive significant correlation did exist between PCR and serum zinc concentration among participants in the zinc-supplemented group by the end of the study (r ⫽ ⫹0.61, P ⬍ .05).
Correlations Between Dietary Protein Intake and PCR Although subjects were randomly selected for inclusion in either the placebo or experimental group for the duration of the study, a significant negative correlation existed between the reported dietary protein intake of the placebo group subjects and PCR (r ⫽ ⫺0.69, P ⬍ .01). By the end of the study, participants in the placebo group did not exhibit this significant negative correlation,
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whereas dietary protein intake and PCR showed a significant negative correlation (r ⫽ ⫺0.67, P ⬍ .01) for the zinc-supplemented group of subjects.
Discussion The average daily intake of zinc in a wellbalanced American diet is approximately 1.8 to 2.3 µmol/d (120 to 150 µg/24 h), assuming a 40% absorption rate from food.5 However, the exact daily requirement needed to prevent zinc deficiency in HD patients is unknown. Because of the variables affecting zinc absorption, dietary requirements are contingent upon food habits of a particular population. Zinc is most available for absorption from protein-rich food from animals. Other factors affecting zinc absorption include body size, the level of zinc in the diet, the amount of zinc in the body, and the presence of other potential interfering substances in the diet.5
Effects of Zinc Supplementation on Serum Zinc Concentrations Controversy remains in the literature as to the effects of zinc deficiency on uremic patients undergoing maintenance HD. The results of the present double-blind study indicated that HD patients showed subnormal serum zinc concentrations, which after zinc supplementation returned to the normal range. This is consistent with findings of Mahajan et al17 and Atkin-Thor et al,7 who showed subnormal serum zinc concentrations in their HD population and improvements after zinc supplementation. The results of the present study indicate that low serum zinc concentrations in HD patients may be reversible with zinc supplementation.
Correlations Between Serum Zinc Concentrations and PCR The urea kinetic modeling–derived PCR can be used to measure malnutrition and protein status in HD patients. This measurement correlates with patient outcome and is used by medical staff to assess protein balance and plan medical nutrition therapy.18,19 Several medical benefits of an improved PCR have been observed, including improved nutritional status, decreased number of hospitalizations, and decreased length of dialysis therapy.20,21
In the present study, a positive correlation was observed between serum zinc concentrations and PCR. These results show that supplementing the diet of HD patients with zinc may lead to an improvement in PCR. An accurate PCR value is considered to be an indicator of actual dietary protein consumed. Nutritional benefits associated with an increased PCR are thought to include improved nitrogen balance and improved dietary protein intake.18,20 An observed relationship between dialysis dose and protein intake reflects enhanced nutritional status with improvement of uremic symptoms. Furthermore, Ohri-Vachaspati and Sehgal22 reported that a low PCR was independently associated with decreased physical function scores. Medical benefits from an improved PCR are seen by a decreased number of hospitalizations, as reported by Yang et al.20 The positive correlation between serum zinc concentration and PCR could be used in the medical management of HD patients as one indicator of zinc repletion.
Effects of Zinc Supplementation on Energy Intake The results of this study showed significant increases in the ‘‘reported energy intake’’ of the zinc-supplemented patients, whereas no significant improvements were observed in the subjects who received the placebo. Data presented in the literature show that zinc deficiency affects taste acuity.7 Mahajan et al23 observed improvement in taste acuity, and Atkin-Thor et al7 observed improvement in taste acuity, as well as an increase in the patients’ energy and protein intake when increased dietary zinc was provided. The results from the present study support these findings of Atkin-Thor et al7 regarding reported energy intake. However, statistical differences were not found between participants in the 2 groups for reported dietary zinc or protein intakes. It should be noted that the 2-day food record used in the present study may have limited the ability to identify large variances in dietary intake. In addition, the sample size and length of the study may not have provided enough statistical power to detect differences in dietary factors. Nevertheless, these results are supported by Brown et al,24 who showed that there was no correlation between dietary protein and dietary zinc intakes in patients with renal
ZINC SUPPLEMENTATION IN HEMODIALYSIS PATIENTS
disease before dialysis. Brown et al24 also reported that patients with renal disease on a 40-g protein diet consumed approximately 50% of the RDA for zinc, which is considered less than the amount necessary to prevent negative zinc balance. The results from the dietary analysis of the present study showed that HD patients consumed approximately 30% of their RDA for zinc. With the low dietary zinc intake reported by these HD patients, it is possible that they may be in a steady state of negative zinc balance. The results of the present study are also in agreement with those reported by O’Nion et al,25 who noted low intakes of dietary zinc (25% to 65% RDA) in HD patients. The etiology of zinc deficiency in this population may be partly explained by the reported low levels of dietary zinc consumed in both groups. Additional research is warranted regarding zinc deficiency and its effect on protein metabolism in HD patients. The present study used serum zinc concentration as the measure of zinc status. Other dietary and nondietary factors alter serum zinc concentration. It would be prudent to quantify serum albumin concentration and its correlation with serum zinc concentration, because albumin is the primary carrier of zinc in serum. The change in protein status observed in the zincsupplemented subjects suggests that serum albumin may have changed. This, in turn, may have also influenced the alteration of zinc in the circulation. In addition, future studies with HD patients should examine the effect of zinc supplementation on other parameters of urea kinetic modeling.
References 1. Burge J, Schemmel R, Park H, et al: Taste acuity and zinc status in chronic renal disease. J Am Diet Assoc 84:1203-1206, 1984 2. Kopple J: Nutritional management of chronic renal failure. Nutr MD 6:1-8, 1980 3. Wilson P, Greene H: Importance of zinc in human nutrition. Nutr MD 2:1-8, 1984 4. Prasad A: Nutritional zinc today. Nutr Today 16:1-4, 1981 5. Prasad A: Clinical and biochemical manifestations of zinc deficiency in human subjects. J Am Coll Nutr 4:65-72, 1985 6. Blendis L, Mercedes A, Wilson D, et al: The importance of
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dietary protein in the zinc deficiency of uremia. Am J Clin Nutr 34:2658-2661, 1981 7. Atkin-Thor E, Goddard B, O’Nion J, et al: Hypogeusia and zinc depletion in chronic dialysis patients. Am J Clin Nutr 31:1948-1951, 1978 8. Mertz W (ed): Zinc in Trace Elements in Human and Animal Nutrition. New York, NY, Academic, 1986 9. Canaud B, Leblanc M, Garred LJ, et al: Protein catabolic rate over lean body mass ratio: A more rational approach to normalize the protein catabolic rate in dialysis patients. Am J Kidney Dis 30:672-679, 1997 10. Sargent J: Nutrition and treatment of the acutely ill patient using urea kinetics. Dial Transplant 10:314-316, 1983 11. Kopple T: Nutritional therapy in kidney failure. Nutr Rev 39:193-206, 1981 12. Kerr PG, Strauss BJ, Atkins RD: Assessment of the nutritional state of dialysis patients. Blood Purif 14:382-387, 1996 13. Hakim RM, Levin N: Malnutrition in hemodialysis patients. Am J Kidney Dis 21:125-137, 1993 14. Gotch F: A quantitive evaluation of small and middle molecule toxicity in therapy of uremia. Dial Transplant 9:183189, 1980 15. Hackley B, Smith J, Halstead J: A simplified method for plasma zinc determination by atomic absorption spectrophotometry. Clin Chem 14:1-5, 1968 16. Sargent J, Gotch F: The analysis of concentration dependence of uremic lesions in clinical studies. Kidney Int 7:S35-S44, 1975 (suppl 2) 17. Mahajan S, Prasad A, Rabbani P, et al: Zinc deficiency: A reversible complication of uremia. Am J Clin Nutr 36:11771183, 1982 18. Canaud B, Garred LJ, Argiles A, et al: Creatinine kinetic modeling: A simple and reliable tool for the assessment of protein nutritional status in haemodialysis patients. Nephrol Dial Transplant 10:1405-1410, 1995 19. Depner TA, Daugiradas JT: Equations for normalized protein catabolic rate based on two-point modeling of hemodialysis urea kinetics. J Am Soc Nephrol 7:780-785, 1996 20. Yang CS, Chen SJ, Leu SW, et al: Nutritional status and clinical outcome of uremic patients after high doses of hemodialysis. J Formos Med Assoc 94:23-29, 1995 21. Sehgal AR, Leon J, Soinski JA: Barriers to adequate protein nutrition among hemodialysis patients. J Ren Nutr 4:179-187, 1998 22. Ohri-Vachaspati P, Sehgal AR: Quality of life implications of inadequate protein nutrition among hemodialysis patients. J Ren Nutr 1:9-13, 1999 23. Mahajan S, Prasad A, Lambrijon J, et al: Improvement of uremic hypogeusia by zinc: A double blind study. Am J Clin Nutr 33:1517-1521, 1980 24. Brown E, McGuckin M, Wilson M: Zinc in selected hospital diets. J Am Diet Assoc 69:632-635, 1976 25. O’Nion J, Atkin-Thor E, Rother S, et al: Effect of zinc supplementation on red blood cell zinc, serum zinc, taste acuity, and dietary intake in zinc deficient dialysis patients. Dial Transplant 7:1208-1210, 1978
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ENAL DISEASE affects approximately 8 million people in the United States.1 Individuals with chronic renal failure require renal replacement therapy, such as maintenance dialysis or transplantation, to sustain life. The goal of diet therapy for the dialysis population is to minimize uremia and other metabolic disorders while maintaining adequate nutritional status.2
One complicating factor of uremia is zinc deficiency.3 During the past 2 decades, an increased number of diet- and disease-induced human zinc deficiency cases have been reported worldwide.4-6 Some chronic renal failure patients exhibit inordinately low concentrations of plasma zinc because of increased metabolic demands and are at higher risk for developing zinc deficiency. It
*Clinical Dietitian, Presbyterian Hospital of Dallas, Dallas, TX. †Associate Professor and Chair, Department of Nutrition and Dietetics, Texas Christian University, Fort Worth, TX. ‡Professor, Department of Nutrition and Dietetics, Texas Christian University, Fort Worth, TX. §Nutrition Consultant, Spa at the Crescent, Dallas, TX. \Professor and Department Head, Department of Human, Environmental and Consumer Resources, Eastern Michigan State University, Ypsilanti, MI.
¶Renal Dietitian, Dallas Nephrology Associates, Dallas, TX. Work conducted at Texas Woman’s University, Department of Nutrition and Food Science, Denton, TX. Address reprint requests to Anne D. VanBeber, PhD, RD, LD, Associate Professor and Chair, Department of Nutrition and Dietetics, Texas Christian University, Box 298600, Fort Worth, TX 76129. r 2000 by the National Kidney Foundation, Inc. 1051-2276/00/1003-0006$3.00/0 doi:10.1053/jren.2000.7413
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Journal of Renal Nutrition, Vol 10, No 3 ( July), 2000: pp 148-153
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is widely known that clinical signs of zinc deficiency include taste and smell dysfunction and impaired wound healing. Zinc supplementation may benefit this population by relieving a variety of symptoms, including hypogeusia and anorexia. The adult recommended dosage of elemental zinc for healthy subjects is 1 mg/kg/d, with the recommended daily allowance (RDA) for adults ranging from 1.5 to 7.7 µmol/d (100 to 150 µg/d).4,7 Serum concentrations of zinc in healthy subjects have been reported to peak 4 weeks after administration of a daily zinc supplement of 2.3 to 7.7 µmol/d (150 to 500 µg/24 h) and then decrease to initial values after ceasing supplementation.3 Toxic effects of zinc therapy have rarely been reported. A potential toxic effect, however, is zinc-induced copper deficiency anemia that has been reported in subjects administered 23.0 µmol/d (1,500 µg/24 h) zinc for 14 to 24 months.3 Zinc absorption from a supplement administered 3 or more hours after ingestion of a meal has been shown to range between 40% and 90%, while a supplement administered with a meal results in an absorption rate of 8% to 38%.8 Urea kinetic modeling is a technique used to calculate a hemodialysis (HD) patient’s protein catabolic rate (PCR; grams per kilogram body weight per day).9 The target PCR for HD patients is approximately 1.2 g/kg/24 h.10 PCRs, which reflect the patient’s metabolic status and are associated with protein intake, are used to direct/ plan patient nutrition education programs.11 Ureakinetic modeling PCR determinations are used to assess the protein status and malnutrition of HD patients.12,13 The model is based on the assumption that the requirement of dialysis is proportional to the patient’s PCR (g/kg) relative to lean body mass.14 The model uses urea, a measurable product of protein catabolism, to define and monitor dialysis treatment. The purpose of this study was to determine if zinc sulfate supplementation would increase PCR in HD patients to a desired value of 1.2 g/kg/24 h.
Methods Subjects Criteria for selection of subjects to participate in the present study included: a history of low PCR (⬍0.9 g/kg body weight), HD treatment for a minimum of 6 months, no signs of gastroin-
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testinal disorders, and no record of hospitalization for reasons other than access complication within the last 3 months. Twenty-eight subjects (22 women and 6 men) undergoing long-term HD 3 times/week at the Southwestern Dialysis Center, Dallas, TX agreed to participate in the study. Subjects were from various economic backgrounds, and each was given medical clearance by his/her attending physician. Signatures of consent were obtained from all participants after they were given both verbal and written descriptions of the research protocol.
Experimental Design and Sample Determination Randomization of participants in the supplemented and placebo groups was completed by the pharmacist at Parkland Memorial Hospital, Dallas, TX, to insure that the researcher would not know whether the subjects were receiving the zinc supplement or the placebo. The 28 subjects were randomly selected to receive 1 capsule daily containing either 2,200 µg zinc sulfate (7.7 µmol; N ⫽ 14) or cornstarch (N ⫽ 14). Subjects were instructed to consume the supplement for 90 days, 3 or more hours after ingestion of an evening meal and without food or other medications. At the beginning of the study, each subject was administered a supply of 100 capsules. To monitor compliance, capsules were counted at midpoint (Day 40) and the end (Day 90) of the study to determine the actual number of pills consumed by the patient. Subjects were also visited during regular dialysis treatments on a weekly basis to monitor compliance. Predialysis serum samples were collected at the beginning (Day 0), midpoint (Day 40), and end (Day 90) of the study, after a minimal 5-hour fast, during the patients’ routine visit to the dialysis center. Whole blood samples (10 mL) were collected in plastic, zinc-free vacutainer tubes. Blood was allowed to clot for 1 hour at room temperature and then centrifuged for 30 minutes at 3,500 rpm using a clinical centrifuge (Dynac, model #0151; Needham Heights, MA). Three milliliters of serum were removed using a plastic pipette and frozen at 0.0°C. The serum samples were analyzed within 24 hours. Serum zinc concentrations were determined using atomic absorption spectrophotometry (Varian SpectrAA 40; Varian, Inc, Mulgrave, Victoria, Australia)
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according to the procedures outlined by Hackley et al.15 Each subject’s initial, midpoint, and endpoint PCR (g/kg body weight/24 h) was determined using the Southwestern Dialysis Center routine screenings of kinetic modeling. Kinetic modeling was performed during the second week of every other month using the procedures of Sargent and Gotch.16 Subjects were instructed to keep a 2-day food record, including 1 dialysis day and 1 nondialysis day, at the beginning (Day 0) and end (Day 90) of the study. A 2-day food record length was chosen to improve patient compliance and because patients received HD treatments at 2-day intervals. Written and verbal instructions regarding the maintenance of food records were given to each subject, and all subjects received a plastic measuring cup to be used for measuring portion sizes. Dietary records were analyzed using the 24-Hour Recall Computer Program (Nova Services, Dallas, TX) and Nutritionist IV, 1999 nutrient data bank (N-Squared Computing, Salem, OR). Intake of total energy, dietary protein, phosphorus, and zinc was calculated at the beginning and end of the study. Dry body weight was recorded at Days 0, 40, and 90.
Statistical Analysis An analysis of variance with repeated measures design was used to assess changes in serum dependent variables over time. A dependent t test was used to assess changes in dietary parameters from the time of initial supplementation to the end of the supplementation period. The statistical package used was the Statistical Package for Social Sciences-Series X (SPSSX, Chicago, IL).
Results Twenty participants (15 women, 5 men) completed the study. Twelve were African-American, 4 were white, and 4 were Hispanic. Three female subjects experienced adverse reactions (nausea, difficulty swallowing) to the supplements and were withdrawn from the study. Two women were unable to complete the study because of hospitalization; 1 woman was removed from the study after a myocardial infarction. Two subjects (1 man, 1 woman) did not complete the study because of noncompliance with prescribed behavior. A total of 8 subjects (7 women, 1 man) were eliminated from the analysis. Mean age of the participants was 56.5 years (range, 23 to 80 years). Body weight ranged from 54.5 to 137.0 kg. Mean length of time that subjects had undergone dialysis treatment was 4 years, 2 months (range, 9 months to 13 years).
Effects of Dietary and Supplementary Zinc Intake and Serum Zinc Concentration Initial mean serum zinc concentrations for participants in the placebo group and the supplement group were not significantly different. By day 90, serum zinc concentrations of subjects receiving the zinc supplement were 15.3 µmol/L (100 µg/dL), significantly higher than the serum zinc concentration of 10.7 µmol/L (70 µg/dL) seen among subjects receiving the placebo (Fig 1; P ⬍ .05). Serum zinc concentrations for participants in the zinc-supplemented group increased significantly (P ⬍ .05) from 12.2 µmol/L (80 µg/dL) at Day 0, to 13.8 µmol/L (90 µg/dL) at Day 40, to
Figure 1. Effect of zinc supplementation on mean serum zinc concentrations in HD patients.
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15.3 µmol/L (100 µg/dL) at Day 90. Serum zinc concentrations for participants in the placebo group remained stable from Day 0 (12.2 µmol/L [80 µg/dL]) to Day 90 (10.7 µmol/L [70 µg/dL]; Fig 1). A significant difference in reported dietary zinc intake was observed between participants in the 2 groups from the beginning to the end of the study (P ⬍ .05; Fig 1). Participants in the placebo group showed a mean increase in nonsupplemented dietary zinc consumed from .55 µmol/d to .78 µmol/d (36 µg/24 h to 51 µg/24 h; P ⬍ .05), while participants in the zinc-supplemented group showed a decrease in the nonsupplemented dietary zinc consumed, from .63 µmol/d to .37 µmol/d (41 µg/24 h to 24 µg/24 h; P ⬍ .05).
Effects of Dietary and Supplementary Zinc Intake on Protein and Calorie Intake and Body Weight Reported dietary protein intake increased significantly (P ⬍ .05) from 50 g/24 h at day 0 to 59 g/24 h at day 90 among participants in the placebo group. Participants in the treatment group showed a non-insignificant increase in dietary protein intake from 50 g/24 h to 51 g/24 h from the beginning to the end of the study. However, participants in the zinc-supplemented group showed a significant (P ⬍ .05) increased intake of 1,256 kJ/24 h (300 kcal/d), from 5,799 kJ/24 h (1,385 kcal/d) at Day 0 to 7,042 kJ/24 h (1,682 kcal/d) at Day 90. No significant difference in energy intake was observed in participants in the placebo group from Day 0 (5,196 kJ/24 h [1,241 kcal/d]) to Day 90 (5,723 kJ/24 h [1,367 kcal/d]). No significant differences were observed between the participants in either group for body weight from the
Figure 2. Effect of zinc supplementation on mean PCR in HD patients.
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beginning, to the midpoint, or the end of the study.
Effect of Dietary and Supplementary Zinc Intake on PCR The effect of dietary and supplementary zinc intake on PCRs is represented in Fig 2. Initial mean PCR was similar in both the zincsupplemented group (0.85 g/kg/24 h) and the placebo group (0.85 g/kg/24 h). After an initial rise in PCR by both groups at day 40, a significant difference (P ⬍ .05) in PCR was observed by Day 90 when the zinc-supplemented group exhibited a PCR of 0.91 g/kg/24 h and the placebo group exhibited a PCR of 0.85 g/kg/24 h.
Correlations Between Serum Zinc Concentrations and PCR There were no significant correlations found between PCR and serum zinc concentrations for the zinc-supplemented group at the beginning and midpoint of the study. However, a positive significant correlation did exist between PCR and serum zinc concentration among participants in the zinc-supplemented group by the end of the study (r ⫽ ⫹0.61, P ⬍ .05).
Correlations Between Dietary Protein Intake and PCR Although subjects were randomly selected for inclusion in either the placebo or experimental group for the duration of the study, a significant negative correlation existed between the reported dietary protein intake of the placebo group subjects and PCR (r ⫽ ⫺0.69, P ⬍ .01). By the end of the study, participants in the placebo group did not exhibit this significant negative correlation,
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whereas dietary protein intake and PCR showed a significant negative correlation (r ⫽ ⫺0.67, P ⬍ .01) for the zinc-supplemented group of subjects.
Discussion The average daily intake of zinc in a wellbalanced American diet is approximately 1.8 to 2.3 µmol/d (120 to 150 µg/24 h), assuming a 40% absorption rate from food.5 However, the exact daily requirement needed to prevent zinc deficiency in HD patients is unknown. Because of the variables affecting zinc absorption, dietary requirements are contingent upon food habits of a particular population. Zinc is most available for absorption from protein-rich food from animals. Other factors affecting zinc absorption include body size, the level of zinc in the diet, the amount of zinc in the body, and the presence of other potential interfering substances in the diet.5
Effects of Zinc Supplementation on Serum Zinc Concentrations Controversy remains in the literature as to the effects of zinc deficiency on uremic patients undergoing maintenance HD. The results of the present double-blind study indicated that HD patients showed subnormal serum zinc concentrations, which after zinc supplementation returned to the normal range. This is consistent with findings of Mahajan et al17 and Atkin-Thor et al,7 who showed subnormal serum zinc concentrations in their HD population and improvements after zinc supplementation. The results of the present study indicate that low serum zinc concentrations in HD patients may be reversible with zinc supplementation.
Correlations Between Serum Zinc Concentrations and PCR The urea kinetic modeling–derived PCR can be used to measure malnutrition and protein status in HD patients. This measurement correlates with patient outcome and is used by medical staff to assess protein balance and plan medical nutrition therapy.18,19 Several medical benefits of an improved PCR have been observed, including improved nutritional status, decreased number of hospitalizations, and decreased length of dialysis therapy.20,21
In the present study, a positive correlation was observed between serum zinc concentrations and PCR. These results show that supplementing the diet of HD patients with zinc may lead to an improvement in PCR. An accurate PCR value is considered to be an indicator of actual dietary protein consumed. Nutritional benefits associated with an increased PCR are thought to include improved nitrogen balance and improved dietary protein intake.18,20 An observed relationship between dialysis dose and protein intake reflects enhanced nutritional status with improvement of uremic symptoms. Furthermore, Ohri-Vachaspati and Sehgal22 reported that a low PCR was independently associated with decreased physical function scores. Medical benefits from an improved PCR are seen by a decreased number of hospitalizations, as reported by Yang et al.20 The positive correlation between serum zinc concentration and PCR could be used in the medical management of HD patients as one indicator of zinc repletion.
Effects of Zinc Supplementation on Energy Intake The results of this study showed significant increases in the ‘‘reported energy intake’’ of the zinc-supplemented patients, whereas no significant improvements were observed in the subjects who received the placebo. Data presented in the literature show that zinc deficiency affects taste acuity.7 Mahajan et al23 observed improvement in taste acuity, and Atkin-Thor et al7 observed improvement in taste acuity, as well as an increase in the patients’ energy and protein intake when increased dietary zinc was provided. The results from the present study support these findings of Atkin-Thor et al7 regarding reported energy intake. However, statistical differences were not found between participants in the 2 groups for reported dietary zinc or protein intakes. It should be noted that the 2-day food record used in the present study may have limited the ability to identify large variances in dietary intake. In addition, the sample size and length of the study may not have provided enough statistical power to detect differences in dietary factors. Nevertheless, these results are supported by Brown et al,24 who showed that there was no correlation between dietary protein and dietary zinc intakes in patients with renal
ZINC SUPPLEMENTATION IN HEMODIALYSIS PATIENTS
disease before dialysis. Brown et al24 also reported that patients with renal disease on a 40-g protein diet consumed approximately 50% of the RDA for zinc, which is considered less than the amount necessary to prevent negative zinc balance. The results from the dietary analysis of the present study showed that HD patients consumed approximately 30% of their RDA for zinc. With the low dietary zinc intake reported by these HD patients, it is possible that they may be in a steady state of negative zinc balance. The results of the present study are also in agreement with those reported by O’Nion et al,25 who noted low intakes of dietary zinc (25% to 65% RDA) in HD patients. The etiology of zinc deficiency in this population may be partly explained by the reported low levels of dietary zinc consumed in both groups. Additional research is warranted regarding zinc deficiency and its effect on protein metabolism in HD patients. The present study used serum zinc concentration as the measure of zinc status. Other dietary and nondietary factors alter serum zinc concentration. It would be prudent to quantify serum albumin concentration and its correlation with serum zinc concentration, because albumin is the primary carrier of zinc in serum. The change in protein status observed in the zincsupplemented subjects suggests that serum albumin may have changed. This, in turn, may have also influenced the alteration of zinc in the circulation. In addition, future studies with HD patients should examine the effect of zinc supplementation on other parameters of urea kinetic modeling.
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dietary protein in the zinc deficiency of uremia. Am J Clin Nutr 34:2658-2661, 1981 7. Atkin-Thor E, Goddard B, O’Nion J, et al: Hypogeusia and zinc depletion in chronic dialysis patients. Am J Clin Nutr 31:1948-1951, 1978 8. Mertz W (ed): Zinc in Trace Elements in Human and Animal Nutrition. New York, NY, Academic, 1986 9. Canaud B, Leblanc M, Garred LJ, et al: Protein catabolic rate over lean body mass ratio: A more rational approach to normalize the protein catabolic rate in dialysis patients. Am J Kidney Dis 30:672-679, 1997 10. Sargent J: Nutrition and treatment of the acutely ill patient using urea kinetics. Dial Transplant 10:314-316, 1983 11. Kopple T: Nutritional therapy in kidney failure. Nutr Rev 39:193-206, 1981 12. Kerr PG, Strauss BJ, Atkins RD: Assessment of the nutritional state of dialysis patients. Blood Purif 14:382-387, 1996 13. Hakim RM, Levin N: Malnutrition in hemodialysis patients. Am J Kidney Dis 21:125-137, 1993 14. Gotch F: A quantitive evaluation of small and middle molecule toxicity in therapy of uremia. Dial Transplant 9:183189, 1980 15. Hackley B, Smith J, Halstead J: A simplified method for plasma zinc determination by atomic absorption spectrophotometry. Clin Chem 14:1-5, 1968 16. Sargent J, Gotch F: The analysis of concentration dependence of uremic lesions in clinical studies. Kidney Int 7:S35-S44, 1975 (suppl 2) 17. Mahajan S, Prasad A, Rabbani P, et al: Zinc deficiency: A reversible complication of uremia. Am J Clin Nutr 36:11771183, 1982 18. Canaud B, Garred LJ, Argiles A, et al: Creatinine kinetic modeling: A simple and reliable tool for the assessment of protein nutritional status in haemodialysis patients. Nephrol Dial Transplant 10:1405-1410, 1995 19. Depner TA, Daugiradas JT: Equations for normalized protein catabolic rate based on two-point modeling of hemodialysis urea kinetics. J Am Soc Nephrol 7:780-785, 1996 20. Yang CS, Chen SJ, Leu SW, et al: Nutritional status and clinical outcome of uremic patients after high doses of hemodialysis. J Formos Med Assoc 94:23-29, 1995 21. Sehgal AR, Leon J, Soinski JA: Barriers to adequate protein nutrition among hemodialysis patients. J Ren Nutr 4:179-187, 1998 22. Ohri-Vachaspati P, Sehgal AR: Quality of life implications of inadequate protein nutrition among hemodialysis patients. J Ren Nutr 1:9-13, 1999 23. Mahajan S, Prasad A, Lambrijon J, et al: Improvement of uremic hypogeusia by zinc: A double blind study. Am J Clin Nutr 33:1517-1521, 1980 24. Brown E, McGuckin M, Wilson M: Zinc in selected hospital diets. J Am Diet Assoc 69:632-635, 1976 25. O’Nion J, Atkin-Thor E, Rother S, et al: Effect of zinc supplementation on red blood cell zinc, serum zinc, taste acuity, and dietary intake in zinc deficient dialysis patients. Dial Transplant 7:1208-1210, 1978