Factors Affecting Urinary Fluoride Concentrations Among Patients With Renal Dysfunction.

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(1)74. Factors Affecting Urinary Fluoride Concentrations Among Patients With Renal Dysfunction 2. 1. Hsien-Wen Kuo, Chuan-Juan Lin , Li-Li Chen 1. 2. Institute of Environmental Health, and Department of Nursing, China Medical College; Department of Nursing, Hung-Kuang Technology College, Taichung, Taiwan, R.O.C.. Objective. Our objective was to determine the factors that affect urinary fluoride concentrations and to measure fluoride concentrations among subjects with renal function abnormalities. Methods. Ninety subjects were divided into three groups based on creatinine clearance (Ccr). The control group consisted of 31 hospital personnel with normal renal functions and a Ccr > 50 mL/min. The chronic renal failure (CRF) group consisted of 32 subjects with a Ccr < 50 mL/min. The continuous ambulance peritoneal dialysis (CAPD) group included 27 subjects with a Ccr < 10 mL/min. Subjects' basic demographic information and history of fluoride exposure were obtained by questionnaire. Urine samples were collected from the three groups using different procedures. Urine samples were taken over 24-hours and morning urine samples were also collected. Urinary fluoride concentrations were measured using the ion selective electrode method. Creatinine levels, specific gravity levels, and pH values were also measured. Results. Several significant factors affected urinary fluoride concentrations, including renal function, tea consumption, exercise habits, and vegetarianism. After adjusting for age and gender using multiple regression analysis, urinary fluoride concentrations among the control group were found to be 2.25 times higher than the CRF group and 5.5 times higher than the CAPD group. This result suggests that patients in the CRF and CAPD groups display poor fluoride excretion efficiencies which may have lead to fluoride accumulation in the kidney and deterioration of their conditions. Conclusions. It is vital that patients in both the CRF and CAPD groups control their dietary intake of fluoride in order to prevent further deterioration of their conditions. Further research is needed to establish the relationship between fluoride intake and renal abnormalities. ( Mid Taiwan J Med 2001;6:74-81). Key words affecting factors, renal dysfunction, urinary fluoride concentrations. INTRODUCTION. consumption of fluoride can help prevent. In order to determine optimum levels of. dental caries, excessive intake may be harmful. systemic fluoride therapy and to help prevent. to people with renal abnormalities. Since one. fluoride-related diseases, fluoride intake levels. important function of the kidneys is to filter. need to be measured. Although frequent. fluids in the body, they are exposed to relatively high fluoride concentrations. Thus,. Received : August 11, 2000.. Revised : January 5, 2001.. Accepted : March 16, 2001. Address reprint requests to : Hsien-Wen Kuo, Institute of. when fluoride concentrations become too high, acute fluoride toxicity may occur.. Environmental Health, China Medical College, No 91, Hsueh-. Whitford and Taves reported that fluoride,. Shih Road, Taichung 404, Taiwan, R.O.C.. like sodium and chloride, shows a progressive.

(2) Hsien-Wen Kuo, et al.. 75. cortex-to-medulla concentration ratio of. determine the factors affecting urinary. between three and four [1]. Those portions of. fluoride concentrations and to compare. the nephron which are responsible for the. urinary-fluoride. kidney's ability to concentrate urine and. healthy subjects and those with kidney. conserve water in the loops of Henle,. abnormalities.. concentrations. among. collecting ducts, and vasa recta are exposed to the highest fluoride concentrations. Based on a study of renal concentrating functions with prolonged sevoflurane or enflurane anesthesia, Frink et al found a higher peak plasma fluoride ion concentration and greater total inorganic renal exposure with sevoflurane anesthesia [2]. The mitochondria in renal collecting duct cells are targets of fluoride ion toxicity and alterations are partly responsible for the sodium and water disturbances observed. in. halogenated. patients agents. [3].. In. addition,. (methoxyflurane,. enflurane) have been found to induce fluoride dose-related renal dysfunction. For patients with renal dysfunction,. MATERIALS AND METHODS Study Population. All 90 subjects were selected from a teaching hospital in central Taiwan. The healthy group consisted of 31 hospital personnel with normal kidney functions [creatinine clearance (Ccr) > 50 mL/min]. The chronic renal failure (CRF) group included 32 patients with Ccr in urine < 50 mL/min and 27 patients in the continuous ambulance peritoneal dialysis (CAPD) group with Ccr in urine < 10 mL/min. All subjects participated on a volunteer basis and the CRF and CAPD groups signed forms of consent.. excessive fluoride intake can hinder excretion of fluoride, leading to its accumulation and further breakdown by the kidneys. According. METHODS. All subjects were interviewed using a. by the Department of Health. questionnaire administered by a formally. (DOH) in Taiwan, the number of patients. trained nurse. The data collected included the. suffering from renal dysfunction has increased. frequency of use of fluoride-containing. [4]. Thus, it is important. to limit fluoride. toothpaste and vitamins, as well as the. intake levels by controlling consumption of. frequency of consumption of various foods. high-fluoride items such as seafood, tea, and. and drinks containing fluoride, such as tea and. underground water. Because the kidneys are. seafood. For reasons of convenience and. the major route for fluoride excretion. practicality, different procedures and schedules. (approximately 50% of fluoride absorbed from. were used to collect urine samples from all. the GI tract in adults each day is excreted in. subjects during a 24-hour period. One spot. the urine), total fluoride intake can best be. urine sample was collected from each subject. determined by measuring urine-fluoride. in the three groups, usually in the morning.. concentrations. Although less convenient, the. Those in the healthy and CRF groups also. collection of urine samples over a 24-hour. provided samples, which represented total. period is a more accurate indicator of total. urinary output during a 24-hour period. In. fluoride intake than spot samples due to the. addition, subjects in the healthy group. fluctuation of urinary fluoride levels over. provided four consecutive samples at. time. Ding et al reported that the highest. approximately 6-hour intervals and patients in. fluoride levels were found at 10:00 pm and the. the CRF group provided one sample. EDTA. lowest at 2:00 pm. In addition, differences in. was added to all samples in order to prevent. the urinary fluoride concentrations based on. contamination by other metals. Samples were. samples collected in the morning, on the spot,. stored at 4 C for less than 72 hours before. and over 24-hours were not significant [5]. In. urine-fluoride concentrations were measured. the current study, our objective was to. by the ion selective electrode method.. to a. report.

(3) 76. Factors of Urinary Fluoride Concentrations. Fluoride measurements were conducted. and multiple regression [8].. according to the methods described previously [6,7]. Creatinine concentrations in the urine. RESULTS. were measured by Jaffe's Method and specific. The three groups were compared based. gravity levels were measured by a hand. on demographic information and personal. refractometer. A microprocessor pH meter. habits (Table 1). Factors that significantly. (Suntex) measured the pH values.. affected kidney function included age,. For quality control, a calibration curve. education, vegetarianism, vitamin consump-. was set up for each batch. All correlation. tion, use of fluoride toothpaste, and the. coefficients were > 0.999 and relative. frequency of seafood consumption. Among. prediction deviations were < 5%. A total of. the healthy group, education levels and the. seven tests were performed on both a high. number of unmarried subjects were high. (1.25 ppm) and low (0.3125 ppm) urine-fluoride. (over 77% completed college, 45% unmarried). sample in order to determine reproducibility. and their ages were low (< 35 years old =. +. (CV < 1%). The SAS/PC 6.04 package was used. 54.8%). Among the CRF group, the percentage. for all statistical analyses, including frequency. of patients who were vegetarian was high. analysis, univariate analysis, one-way ANOVA,. (34%) and vitamin consumption and use of. Table 1. Basic demographic information and fluoride sources for the three groups Variables. Gender Male Female Age (years) < 35 36 50 51 64 > 65 Vegetarian No Yes Regular activity No Yes Vitamin consumed No Yes Fluoride toothpaste Yes No Unknown Frequency of brewed tea Usually Occasional Seldom No Frequency of tea beverage* Usually Occasional Seldom No. p value. Healthy group. CRF group. CAPD group. (N = 31). (N = 32). (N = 32). n (%). n (%). n (%). 16 ( 51.6) 15 (48.4). 14 (43.8) 13 (56.3). 14 (51.9) 18 (48.1). NS. 1 5 14 7. < 0.01. 17 (54.8) 9 (29.0) 2 (6.5) 3 (9.68). 4 7 7 7. (12.5) (21.8) (21.8) (25.9). ( 3.7) (18.5) (51.9) (25.9). 28 (90.3) 3 (9.7). 14 (43.8) 21 (65.6). 22 (81.5) 5 (18.5). 0.05. 19 (61.3) 12 (38.7). 16 (50.0) 16 (50.0). 16 (59.3) 11 (40.7). NS. 20 (64.5) 11 (35.5). 30 (93.8) 2 (93.8). 8 (29.6) 19 (70.4). < 0.001. 27 (87.1) 2 (6.5) 2 (6.5). 22 (68.8) 2 (6.3) 8 (25.0). 24 (88.9) 3 (11.1) 0 ( 0.0). 0.03. 11 (35.5) 11 (35.5) 2 (6.5) 7 (22.5). 7 8 4 13. (21.9) (25.0) (12.5) (40.6). 3 4 5 15. (11.1) (14.8) (18.5) (55.6). NS. 6 (19.4) 14 (45.2) 8 (25.8) 3 ( 9.7). 12 (37.5) 13 (40.6) 3 (9.4) 4 (12.5). 17 9 1 0. (62.9) (33.3) ( 3.7) ( 0.0). 0.011. *Tea beverages: commercially prepared drinks available in bottles or cartons, usually with a low amount of tea with added ingredients. CRF = chronic renal failure; CAPD = continous ambulance peritoneal dialysis; NS = not significant..

(4) Hsien-Wen Kuo, et al.. 77. Table 2. Comparison of urinary fluoride concentrations, creatinine levels, and pH values from spot urine samples. Urinary fluoride concentration Unadjusted (ppm) Adjusted by cre. (mg/g cre.) Creantine in urine Specific gravity pH value. Healthy group. CRF group. CAPD group. (N = 31). (N = 27). (N = 32). 0.38 0.52 81.70 1.014 5.48. 0.26 0.37 43.96 0.007 1.21. 0.20 0.34 69.84 1.014 4.73. 0.08 0.18 69.09 1.013 4.90. 0.17 0.27 44.30 0.008 1.04. 0.05 0.19 49.51 0.006 1.26. p value. < 0.0115 < 0.01 NS NS NS. NS = not significant.. Table 3. Comparison of urinary fluoride concentrations, creatinine levels, and pH values from 24-hr samples between healthy and CRF groups. Urinary fluoride concentration Unadjusted (ppm) Adjusted by cre. (mg/g cre.) Creantine in urine Specific gravity pH value. Healthy group. CRF group. (N = 31). (N = 27). 0.33 0.47 76.92 1.014 5.00. 0.19 0.29 35.86 0.005 0.91. 0.20 0.47 50.87 1.014 5.26. p value. 0.19 0.38 32.67 0.007 0.96. < 0.01 NS < 0.01 NS NS. NS = not significant.. Table 4. Comparison of urinary fluoride concentrations and creatinine levels from spot urine and 24-hr samples between healthy and CRF groups 24-hour urine Urinary fluoride concentration (unadjusted, ppm) Healthy group CRF group Urinary fluoride concentration (adjusted by creatinine, mg/g cre.) Healthy group CRF group. p value. Morning urine. 0.33 0.20. 0.19 0.19*. 0.38 0.20. 0.26 0.17*. NS NS. 0.47 0.47. 0.29 0.38. 0.52 0.34. 0.37 0.27. NS 0.04. *p < 0.01 and p = 0.03 as compared with the healthy group; NS = not significant.. Table 5. Factors that affect urinary fluoride concentrations based on a multiple regression model Beta (S.E.). Variables Group of Kidney function CRF (Healthy = 1) CAPD (Healthy = 1) Gender (male = 1) Age (< 35 = 1) Use of fluoride toothpaste (no = 1) Freguency of brewed tea (no = 1) Freguency of sea food consumed (no = 1) Habit of vitamin consumed (no = 1) Habit of physical activity (no = 1) Vegetarian (no = 1) 2. 0.13 0.28 0.09 0.001 0.02 0.08 0.04 0.09 0.14 0.18. F = 4.78 (p < 0.01); R = 38.2%; NS = not significant.. (0.09) (0.10) (0.06) (0.002) (0.05) (0.03) (0.04) (0.07) (0.06) (0.08). p value NS < 0.01 NS NS NS < 0.01 NS NS 0.03 0.02.

(5) 78. Factors of Urinary Fluoride Concentrations. T a b le 6. R a t i o o f p r e d i c t e d t o o b s e r v e d v a lue s f o r ur i n a r y f luo r i d e c o n c e n t r a t i o n s ( p p m) b a s e d o n mult i p le regression models (adjusted for age and gender from the healthy group) Variables. N. CRF group CAPD group. 32 27. Observed value (O) 0.20 0.08. Predicted value (E). O/E ratio. 0.45 0.44. 2.25 5.5. 0.17 0.05. fluoride toothpaste were low (6.3% and 68.8%,. adjustment for creatinine, the differences in. respectively). The frequency of tea consump-. urinary fluoride concentrations (mg/g crea.). tion was highest among the healthy group.. were not significant.. The frequency of seafood consumption was. The data shown in Table 4 compare. highest among the CAPD group (> 3. urinary fluoride concentrations based on 24-. times/week = 62.9%). Except for the frequency. hour and spot urine samples from the healthy. of seafood consumption, both the frequency. and CRF groups. Unadjusted for urinary. and number of fluoride sources were highest. fluoride concentrations (ppm), the differences. among the healthy group.. between the two groups for both sets of compare. samples were not significant. However,. urinary fluoride concentrations, creatinine,. The data found in Table 2. unadjusted urinary fluoride concentrations for. specific gravity, and pH values from spot urine. the healthy group were significantly higher. samples from the three groups. Urinary. than for the CRF group. For urinary fluoride. fluoride concentrations and pH values differed. concentrations (mg/g crea.) adjusted for. significantly among the three groups. Overall,. creatinine, there was a significant difference. urinary fluoride concentrations were highest. between the 24-hour and spot urine samples. among the healthy group and lowest among. among the CRF group.. the CAPD group. Both unadjusted and. The data found in Table 5 show the fac-. adjusted for creatinine and specific gravity,. tors affecting urinary fluoride concentrations. urinary fluoride concentrations were also. using multiple regression analysis. Renal. highest among the healthy group. The pH. function was a significant factor, and urinary. values (5.48) in urine were highest among the. fluoride concentrations were higher in the. healthy group and lowest among the CRF. healthy group than in the CRF or CAPD. group (4.73). In the renal dysfunction groups,. groups. As frequency of tea consumption and. urine acidity was highest. Creatinine in urine. excercise. was also highest among the healthy group. vegetarians, urinary floride concentrations also. (81.70 mg/L), but there were no significant. increased. Factors such as gender, age, use of. differences among the three groups. However,. fluoride toothpaste, and consumption of. there was a high degree of variation among. seafood and vitamins were not significant.. the three groups for creatinine in urine.. increased,. especially. among. The data found in Table 6 show predict-. The data found in Table 3 were used to. ed values of urinary fluoride concentrations. compare urinary fluoride concentrations,. between patients in the CRF and CAPD. creatinine, specific gravity, and pH values. groups using a multiple regression model.. based on 24-hour urine samples from the. Adjusted for age and gender (using data from. healthy and CRF groups. Urine-fluoride. the healthy group), the predicted values (E). concentrations (ppm) were higher in the. for the CRF and CAPD groups were 0.45 and. healthy group compared with the CRF group.. 0.44, respectively, whereas the observed values. Creatinine concentrations in the healthy group. (O) were 0.2 and 0.08, respectively. Therefore,. were significantly higher than in the CRF. the urinary fluoride concentrations in the. group since patients in the latter group were. CRF and CAPD groups were 2.25 and 5.5 times. suffering from renal disorders. However, after. (O/E ratio) lower than the healthy group. This.

(6) Hsien-Wen Kuo, et al.. 79. finding suggests that the kidneys of patients in. excretion and greater fluoride accumulation in. the CRF and CAPD groups display poor. the kidneys and blood. Since many of these. fluoride excretion efficiency.. patients have had kidney disorders for long periods of time, a considerable amount of. DISCUSSION. fluoride. may. have. accumulated,. thus. The kidneys are the main target of acute. exacerbating their conditions. Schiffl and. fluoride toxicity. Since fluoride concentrations. Binswanger showed that patients suffering. increase from the cortex to the medulla, those. from chronic renal disease tended to continue. portions of the nephron responsible for. to excrete healthy levels of dietary fluoride. concentrating urine and conserving water are. until the creatinine clearance fell below 25. exposed to the highest fluoride concentrations. ml/min [10]. For the current study, it was. within the kidneys. Fluoride ions are filtered. assumed that all the patients with renal. from the plasma in the glomerular capillaries. dysfunction consumed similar fluoride-rich. into the urinary space of the Bowman's. diets. In these patients, the elevation of the. capsule following variable degrees of tubular. serum fluoride concentrations was delayed. reabsorption. The absorption mechanism may. and was less than might be expected from. involve diffusion of hydrogen fluoride (HF). impairment of the glomerular filtration rate. molecules [9]. When urine is relatively alkaline,. due to diminished tubular reabsorption caused. nearly all of the fluoride exists in the ionic. by expansion of the extracellular fluid. form and remains within the tubule to be. compartment. Further research is needed to. excreted. However, when urine is relatively. establish the relationship between blood-. acidic, proportionately more of the fluoride. fluorine concentrations and urinary fluoride. exists in the undissociated form which. concentrations among CRF and CAPD patients.. increases the transtubular HF concentration. Kono and Spak et al found decreased fluoride. gradient. Factors which alter urinary pH and. clearance levels among both adults and. affect the quantitative features of ion. children with impaired renal functions,. metabolism include: diet, certain metabolic or. indicating that patients with impaired kidney. respiratory diseases, certain drugs, and altitude. functions may have reduced margins of safety. of the subject's residence. In the current study,. for the development of skeletal and dental. the. fluoride. fluorosis compared to subjects with normal. concentrations were vegetarianism, tea. renal functions [11,12]. In Taiwan, a large. consumption and kidney function. These. proportion of the population regularly drinks. results are consistent with those of previous. tea made from fluoride-rich tea leaves. Kuo et. studies which showed that a vegetarian diet. al [13] estimated that the maximum daily. rendered pH values more alkaline, and a meat-. intake of fluoride in the general Taiwanese. rich diet resulted in more acidic pH values [9].. population is 6.326 mg/day, of which 43%. Several metabolic and respiratory disorders. comes from beverages. Walters and Sherlock. (such as diabetes mellitus, renal tubular. reported that among habitual tea drinkers, 1.3. acidosis, asthma and chronic obstructive. mg (72%) of their total daily intake of fluoride. pulmonary disorder) cause disturbances in the. comes from tea consumption [14]. In the. acid-base balance and changes in urinary pH. current study, approximately 22% of the. which may affect the metabolism and. patients with CRF consume tea three or more. biological impact of fluoride.. times daily compared with 11% of patients. factors. affecting. urinary. Urinary pH values among CRF and. among the CAPD group.. CAPD patients in this study were generally. Decreased renal clearance may occur. acidic. This suggests that the increase in the. among patients with impaired renal functions.. rate of diffusion from the tubular tube to the. In the current study, urinary fluoride. interstitial fluid resulted in less fluoride. concentrations for CRF and CAPD patients.

(7) 80. Factors of Urinary Fluoride Concentrations. were 2.25 and 5.5 times (O/E ratio) lower than. order to avoid exacerbating their conditions.. for subjects in the healthy group. It is important to note that this calculation assumes that there was no difference between the. REFERENCES 1.. Whitford GM, Taves DR. Fluoride-induced diuresis:. subjects with regard to fluoride intake. This. renal-tissue solute concentrations, functional,. result suggests that the kidneys of the patients. hemodynamic, and histologic correlates in the rat.. with CRF and CAPD displayed poor fluoride excretion efficiency, which may have resulted. Anesthesiology 1973;39:416-27. 2. Frink EJ Jr, Malan TP Jr, Isner RJ, et al. Renal concentrating function with prolonged sevoflu-. in fluoride accumulation in the kidneys or. rane or enflurane anesthesia in volunteers.. other organs. As such, it is crucial for CRF and. Anesthesiology 1994;80:1019-25.. CAPD patients to control dietary intake of fluoride. in. order. to. prevent. 3. Cittanova ML, Lelongt B, Verpont MC, et al. Fluoride ion toxicity in human kidney collecting duct cells.. further. deterioration of their conditions.. Anesthesiology 1996;84:428-35. 4. Taiwan Department of Health of The Executive. In a study of fluoride metabolism,. Yuan. Public Health in Taiwan, Republic of China,. Spencer et al reported that urine-fluoride. Department of Health, The Executive Yuan, R.O.C.,. excretions ranged from 1.51 to 3.09 mg/day (average 2.26 mg/day) and fecal-fluoride. 1995. 5. Ding CS, Wang G, Chiang CI. Observation of fluoride excretion in urine. [Abstract] Chinese Preventive. excretions ranged from 0.19 to 0.43 mg (avg. 0.29 mg/day), based on an average daily. Medicine 1982:128. 6.. fluoride intake of 4.4 mg, indicating that urine was the primary source of fluoride excretion [15]. The four main sources of fluoride include. fluoride. Anal Chem 1972;44:1693-4. 7. Kuo HW, Chen LL, Wang RY, et al. Effect of fluoride mouth-rinse. diet, toothpaste, dentifrices (mouth rinses), and tablets. It has been reported that the average. source is from tea leaves. Since urinary. program. on. urinary. fluoride. concentrations. Chin Dent J 1998a;17:59-67. 8.. daily intake of fluoride in the Taiwanese population is 1.57 mg [13] and that the primary. Tusl J. Fluoride ion activity electrode as a suitable means for exact direct determination of urinary. SAS/STAT. User's Guide, Release 6.04 Edition, SAS Institute Inc., Cary, N.C., U.S.A., 1986.. 9.. Whitford GM. The physiological and toxicological characteristics of fluoride. [Review] J Dent Res 1990;69:539-49.. fluoride excretions for patients with CRF were. 10. Schiffl HH, Binswanger U. Human urinary fluoride. significantly lower than for patients with. excretion as influenced by renal function. healthy kidney functions, a significantly higher retention of fluoride was noted among CRF patients [15,16]. The results of the current. impairment. Nephron 1980;26:69-72. 11. Kono K. Health effects of fluorine and its compounds. [Review] Nippon Eiseigaku Zasshi 1994;49:852-60.. study are consistent with this finding. If. 12. Spak CJ, Berg U, Ekstrand J. Renal clearance of. subjects with renal dysfunction were exposed. fluoride in children and adolescents. Pediatrics. to high levels of fluoride intake, their conditions. could. further. deteriorate.. Whitford et al showed that patients treated. 1985;75:575-9. 13. Kuo HW, Chang WG, Chang SK, et al. Factors associated with bone quality in central Taiwan communities. J China Medical College 1998b;7:45-54.. with 1.23% APF gel had elevated plasma. 14. Walters CB, Sherlock JC, Evans WH, et al. Dietary. fluoride concentrations and urinary fluoride. intake of fluoride in the United Kingdom and. mol/L or more. fluoride content of some foodstuffs. J Sci Food Agric. concentrations of up to 30. for several hours, which may have resulted in renal concentrating defects [17]. Although APF. 1983;34:523-8. 15. Spencer H, Lewin I, Wistrowski E, et al. Fluoride metabolism in man. Am J Med 1970;49:807-13.. gel is not commonly used in Taiwan, it is still. 16. Malan TP Jr, Kadata Y, Mata H, et al. Renal function. necessary to be aware of fluoride intake since. after sevoflurane or enflurane anesthesia in the. there are many sources of fluoride in the environment. The authors recommend that patients with renal dysfunction regulate their intake of fluoride-rich foods and drinks in. Fisher 344 rat. Anesth Analg 1993;77:817-21. 17. Whitford GM, Allmann DW, Shahed AR. Topical fluoride effects on physiologic and biochemical processes. J Dent Res 1987;66:1072-8..

(8) 81. 2. 1 1. (Ccr) 50 ml/min (CAPD). 32. 90. 31. (CRF) Ccr. 2. Ccr. Ccr 50 ml/min. 27. 10 ml/min 24. (. ). pH. CRF. 2.25. CAPD. 5.5. 2001;6:74-81. 404 8/11/2000 3/16/2001. 9 1/5/2001.

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