Calcium Citrate Markedly Enhances Aluminum Absorption From Aluminum Hydroxide Jack W. Coburn, MD, Matthew G. Mischel, MD, William G. Goodman, MD, and Isidro B. Salusky, MD • The effect of calcium citrate on intestinal aluminum absorption, assessed by the increment in urinary aluminum excretion, was evaluated in eight normal men. Baseline urinary aluminum excretion was determined for 2 days; thereafter, subjects ingested aluminum hydroxide for 3 days. In a cross-over study, subjects were given either calcium citrate, 950 mg four times a day, or placebo during the 3 days of aluminum hydroxide ingestion (2.4 g/d). Plasma aluminum levels were measured on the second control day and the third day of aluminum hydroxide ingestion. Baseline urinary aluminum excretion was 0.02 ± 0.004 (6.5 ± 1.1 ",glg creatinine) and 0.03 ± 0.005 ",mollmmol creatinine (7.4 ± 1.3 ",glg creatinine). These values increased during aluminum hydroxide therapy, but values were much greater when calcium citrate was ingested with aluminum hydroxide. On 3 consecutive days, urinary aluminum excretion levels were 11.1 ± 3.23, B.B ± 2.9, and 5.3 ± 0.7 times greater during the administration of calcium citrate with aluminum hydroxide than with aluminum hydroxide alone. Plasma aluminum levels did not differ in the two treatment groups. Thus, calcium citrate markedly enhances the absorption of aluminum from aluminum hydroxide and the two must not be prescribed together in patients with renal failure. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Aluminum absorption; calcium citrate; aluminum hydroxide; normal subjects.
A
MAJOR ROUTE of aluminum loading in patients with renal failure is its absorption from aluminum-containing antacids. \,2 At present, calcium carbonate, calcium acetate, and calcium citrate are recommended as alternatives to aluminum-containing gels to reduce the absorption of dietary phosphorus in patients with chronic renal failure. 38 However, in up to 25% to 50% of dialyzed patients treated with calcium carbonate, aluminum hydroxide is also needed to control the hyperphosphatemia. 4 ,5 Unfortunately, the intake of citric acid and/or sodium citrate can markedly augment intestinal absorption of aluminum. 9 -11 Citrate may also enhance the deposition of aluminum in tissues. 12 These effects of citrate on aluminum metabolism From the Medical and Research Services, West Los Angeles li?terans Administration Center (Wadsworth Division), and Sepulveda li?terans Administration Center; and the Departments of Medicine and Pediatrics, UClA School of Medicine, Los Angeles, CA. Supported in part by US Public Health Service Grants No, DK-35423 and AR-35470, and by research funds of the li?terans Administration, Portions of this work were presented in abstract form at the 21st Annual Meeting of the American Society of Nephrology, San Antonio, IX, December 11-14, 1988, Address reprint requests to Jack W. Coburn, MD, Nephrology Section (W111L) , West Los Angeles li?terans Administration Center, Wilshire and Sawtelle Blvds, Los Angeles, CA 90073, © 1991 by the National Kidney Foundation, Inc, 0272-6386/9111706-0029$3.00/0
708
are not widely recognized by clinicians, and several fatal cases of aluminum-associated encephalopathy have developed in azotemic patients receiving either aluminum hydroxide or aluminum carbonate in conjunction with sodium citrate/citric acid (Shohl's solution or Bicitra [Willen Drug Co, Baltimore, MD]).1O,13 Thus, the augmentation of aluminum absorption by citrate can have serious consequences. It is likely that calcium citrate and aluminumcontaining, phosphate-binding antacids may also be administered together to patients with renal failure. The effect of calcium citrate on intestinal aluminum absorption is not known; if the citrate in calcium citrate augments aluminum absorption, as occurs with sodium citrate/citric acid, the potential for aluminum toxicity would exist. Therefore, we evaluated whether calcium citrate increases the enteral absorption or ingested aluminum in normal man. The results indicate that calcium citrate markedly enhances the absorption of aluminum from aluminum hydroxide. METHODS Studies of aluminum absorption were performed in eight men, ranging in age from 32 to 54 years, who were free of metabolic, renal, or liver diseases. The study protocol was approved by the Human Subjects Review Committee of the Veterans Administration Medical Center, West Los Angeles. Aluminum absorption was indirectly assessed by measuring the urinary excretion of aluminum during a 5-day study period. Baseline urinary aluminum excretion was determined for 2
American Journal of Kidney Diseases, Vol XVII, No 6 (June), 1991: pp 708-711
CA CITRATE RAISES AL ABSORPTION FROM AL(OHh
days; thereafter, subjects ingested aluminum hydroxide for 3 days. The dose of aluminum hydroxide, as Alternagel (Stuart Pharmaceuticals, Washington, DC), 5 mL administered four times daily with meals and at bedtime, provided 2.4 gld of aluminum hydroxide. The study protocol was performed twice in each subject, separated by an interval of 3 to 4 weeks. Subjects were given either calcium citrate, 950 mg four times daily as Citracal (Mission Pharmacal Co, San Antonio, TX), or placebo with the aluminum hydroxide during the 3 days of ingesting the aluminum gel in a "crossed-over" manner. The sequence of administration of placebo and calcium citrate varied for individual. subjects. Twenty-four-hour urine samples were collected in polypropylene containers shown not to produce contamination with aluminum, and aluminum and creatinine concentrations were measured in aliquots of these collections. Plasma samples were collected for aluminum determination on the second control day and on the second day of aluminum hydroxide ingestion. Aluminum levels were measured using electrothermal atomic absorption spectroscopy, '4 and urine creatinine concentrations were determined using the picric acid method." Urinary aluminum excretion is expressed as micromoles of aluminum excreted per millimole creatinine. All results are presented as mean ± SE, and the values were compared using paired and unpaired t tests. 16
RESULTS
Baseline urinary aluminum excretion was 0.02 ± 0.004 (6.5 ± 1.1 JLg/g creatinine) and 0.03 ± 0.005 JLmol/mmol creatinine (7.4 ± 1.3 JLg/g creatinine) for the 2 days immediately before aluminum hydroxide administration, and basal urinary aluminum excretion did not differ between the first and second study for individual patients. The urinary excretion of aluminum increased frof!1 baseline values in each subject given aluminum hydroxide, but the values increased much more when calcium citrate was ingested with aluminum hydroxide (Fig 1). In individual subjects, urinary aluminum excretion rates on the 3 successive days of aluminum ingestion were 11.1 ± 3.23, 8.8 ± 2.9, and 5.3 ± 0.7 times greater, respectively, during the administration of calcium citrate plus aluminum hydroxide than with aluminum hydroxide alone (Fig 1). Plasma aluminum levels did not change after aluminum hydroxide ingestion, and the values did not differ in the two treatment groups. DISCUSSION
The current results indicate that the intestinal absorption of aluminum from aluminum hydroxide, as assessed by the increment in urinary aluminum excretion, increases markedly during the ingestion
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DAYS Fig 1. Urinary and plasma aluminum in eigh.t subjects before (baseline, squares) and during the Ing~s tlon of aluminum hydroxide either alone (0) or With calcium citrate (e). Data are mean ± SE. The increment in urinary aluminum excretion during the ingestion of calcium citrate and aluminum is greater than that with aluminum hydroxide alone, P < 0.02 on days 1 and 2, and P < 0.001 on day 3. To convert renal aluminum/mmol creatinine to I'g aluminum/g creatinine, multiply by 241.
of calcium citrate. Although sodium citrate and/or citric acid have been shown to enhance aluminum . absorption in humans 7.IO and in experimental animals,12.17 the effect of calcium citrate on aluminum metabolism has not previously been documented. Eleven deaths from apparent aluminum toxicity have been reported in patients with renal insufficiency not receiving dialysis who were given aluminum hydroxide for the treatment of hyperphosphatemia and calcium citrate/citric acid (Shohl's solution or Bicitra) for the management of acidosis.lo.13 The current experimental findings suggest that similar concerns about enhanced intestinal aluminum absorption are warranted with the use of calcium citrate. In two subjects from the current study, aluminum excretion exceeded 37 JLmol/d (1,000 JLg/d), quantities similar to the amounts received parenterally by patients who developed aluminum-related bone disease while receiving intravenous nutrition with solutions that were contaminated with aluminum. IS Although urinary aluminum excretion is not an absolute measure of intestinal aluminum absorption, it is a much more sensitive index of aluminum absorption than changes in serum aluminum levels. 19 Studies that have compared
COBURN ET AL
710
oral aluminum loads and much smaller intravenous infusions in rats confirm the value of urinary aluminum excretion as a measure of changes in intestinal absorption when some renal function is maintained. 20 Citrate is unique in its ability to form soluble complexes with aluminum in aqueous solutions or in plasma; indeed, citrate can solubilize aluminum from insoluble complexes such as aluminum phosphate. 21 This chemical property of citrate can increase the intestinal absorption of aluminum, and it may promote the passage of aluminum across biological membranes. Recent observations demonstrated that aluminum citrate can increase the permeability of the intestinal epithelium by opening tight junctions. 22.23 The uptake of soluble complexes of aluminum citrate by tissues may enhance aluminum deposition and augment its toxicity. The marked augmentation of intestinal aluminum absorption produced by citrate, whether taken in the form of citric acid, or its sodium, calcium, or potassium salt, can lead to severe and adverse consequences in patients with advanced renal failure. Several situations might arise whereby patients might inadvertently receive aluminum-containing compounds with a citrate salt. Thus, it is probable that calcium citrate and aluminum gels might be combined in a patient with
advanced renal failure because the calcium citrate, by itself, is inadequate to lower serum phosphorus levels appropriately. 24 The combination of sodium citrate to treat acidosis combined with aluminum gel for hyperphosphatemial0,13 has been noted above. Also, patients with reduced renal function and renal stones might receive potassium citrate 25 with an aluminum gel. Finally, there is always a chance that a nonprescribed aluminum-containing antacid will be taken for dyspepsia or peptic ulcer symptoms by a renal patient who is also taking a citrate salt for one of the reasons noted above or with the citrate ingested unknowingly in AlkaSeltzer (Miles, Inc, Elkhart, IN), an over-the-counter citrate-containing compound. In view of all these possible reasons why citrate and an aluminum gel might be taken together, we strongly' recommend that calcium citrate not be prescribed as a phosphate binder in a renal patient unless calcium carbonate, calcium acetate, and an aluminum gel is each effective or is not tolerated. If calcium citrate must be prescribed, the patient should be aware that aluminum compounds must not be taken concurrently. ACKNOWLEDGMENT W. Van Buren provided excellent technical assistance, Lisa Newman provided assistance in preparing the manuscript.
REFERENCES L Coburn Jw, Norris KC, Nebeker HG: Osteomalacia and bone disease arising from aluminum, Semin Nephrol 6:68-69, 1986 2. Salusky IB, Brill J, Oppenheim W, et al: Features ofrenal osteodystrophy in pediatric patients receiving regular peritoneal dialysis. Semin Nephrol 9:37-42, 1989 3. Salusky m, Coburn Jw, Foley J , et al: Effects of oral calcium carbonate on control of serum phosphorus and changes in plasma aluminum levels after discontinuation of aluminumcontaining gels in children receiving dialysis. J Pediatr 108:767-770, 1986 4. Slatopolsky E, Weerts C, Lopez-Hilker S, et al: Calcium carbonate is an effective phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 315:157-161, 1986 5. Fournier A, Moriniere PH, Sebert JL, et al: Calcium carbonate, an aluminum-free agent for control of hyperphosphatemia, hypocalcemia and hyperparathyroidism in uremia. Kidney Int 29 :S115-S119, 1986 (suppl 18) 6. Cushner HM , Copley lB, Lindberg JS, et al: Calcium citrate, a nonaluminum-containing phosphate-binding agent for treatment of CRE Kidney Int 33 :95-99, 1988 7. Mak RH, Thrner C, Thompson T, et al: Suppression of secondary hyperparathyroidism in children with chronic renal
failure by high dose phosphate binders: Calcium carbonate versus aluminum hydroxide. Br Med J 291 :623-627, 1985 8. Mai ML, Emmett M, Sheikh MS, et al : Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int 36:690-695, 1989 9. Slanina P, Frech W, Ekstrom L, et al : Dietary citric acid enhances absorption of aluminum in antacids. Clin Chern 32:539-541 , 1986 10. Bakir AA, Hryhorczuk DO, Berman E, et al: Acute fatal hyperaluminemic encephalopathy in undialyzed and recently dialyzed uremic patients. Trans Am Soc Artif Intern Organs 32: 171-176, 1986 II. Weberg R, Berstad A: Gastrointestinal absorption of aluminum from single doses of aluminum containing antacids in man. Eur J Clin Invest 16:428-432, 1986 12. Slanina P, Falkeborn Y, Frech W, et al : Aluminum concentrations in the brain and bone of rats fed citric acid, aluminum citrate or aluminum hydroxide. Food Chern Toxicol 22:391-397, 1984 13. Kirschbaum BB, Schoolwerth AC: Acute aluminum toxicity associated with oral citrate and aluminum-containing antacids. Am J Med Sci 297 :9-11 , 1989 14. LeGendre GR, Alfrey AC : Measuring picogram amounts of aluminum in biological tissue by flameless atomic
CA CITRATE RAISES AL ABSORPTION FROM AL(OHh absorption. Clin Chern 22:53-56, 1983 15. Heinegard D, Tidestrom G: Determination of serum creatinine by a direct colorimetric method. Clin Chern Acta 43:305-311, 1973 16. Dixon WJ, Massey FJ: Introduction to Statistical Analysis. New York, NY, McGraw-Hill, 1983 17. Slanina P, Frech W, Bernhardson A, et al: Influence of dietary factors on aluminum absorption and retention in the brain and bone of rats . Acta Pharmacol Toxicol (Copenh) 56:331 -336, 1985 18 . Klein GL, Ott SM, Alfrey AC, et al : Aluminum as a factor in the bone disease of long-term parenteral nutrition . Trans Assoc Am Physicians 95: 155-164, 1982 19. 'Kaehny WD, Hegg P, Alfrey AC: Gastrointestinal absorption of aluminum from aluminum-containing antacids. N Engl J Med 296:1389-1390, 1977 20. Ittel TH, Buddington B, Miller NL , et al: Enhanced gas-
711 trointestinal absorption of aluminum in uremic rats. Kidney Int 32:821-826, 1987 21. Martin RB: The chemistry of aluminum as related to biology and medicine. Clin Chern 32: 1797-1806, 1986 22. Froment DPH, Molitoris BA, Buddington B, et al: Site and mechanism of enhanced gastrointestinal absorption of aluminum by citrate. Kidney Int 36:978-984 , 1989 23 . Molitoris BA, Froment DPH, Mackenzie TA , et al: Citrate: A major factor in the toxicity of orally administered aluminum compounds . Kidney Int 36:949-953 , 1989 24. Sheikh MS, Maguire JA , Emmett M, et al : Reduction of dietary phosphorus binders: A theoretical , in vitro, and in vivo study. J Clin Invest 83:66-73, 1989 25 . Pak CY, Sakhaee K, Fuller C : Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 30:422-428, 1986
A
MAJOR ROUTE of aluminum loading in patients with renal failure is its absorption from aluminum-containing antacids. \,2 At present, calcium carbonate, calcium acetate, and calcium citrate are recommended as alternatives to aluminum-containing gels to reduce the absorption of dietary phosphorus in patients with chronic renal failure. 38 However, in up to 25% to 50% of dialyzed patients treated with calcium carbonate, aluminum hydroxide is also needed to control the hyperphosphatemia. 4 ,5 Unfortunately, the intake of citric acid and/or sodium citrate can markedly augment intestinal absorption of aluminum. 9 -11 Citrate may also enhance the deposition of aluminum in tissues. 12 These effects of citrate on aluminum metabolism From the Medical and Research Services, West Los Angeles li?terans Administration Center (Wadsworth Division), and Sepulveda li?terans Administration Center; and the Departments of Medicine and Pediatrics, UClA School of Medicine, Los Angeles, CA. Supported in part by US Public Health Service Grants No, DK-35423 and AR-35470, and by research funds of the li?terans Administration, Portions of this work were presented in abstract form at the 21st Annual Meeting of the American Society of Nephrology, San Antonio, IX, December 11-14, 1988, Address reprint requests to Jack W. Coburn, MD, Nephrology Section (W111L) , West Los Angeles li?terans Administration Center, Wilshire and Sawtelle Blvds, Los Angeles, CA 90073, © 1991 by the National Kidney Foundation, Inc, 0272-6386/9111706-0029$3.00/0
708
are not widely recognized by clinicians, and several fatal cases of aluminum-associated encephalopathy have developed in azotemic patients receiving either aluminum hydroxide or aluminum carbonate in conjunction with sodium citrate/citric acid (Shohl's solution or Bicitra [Willen Drug Co, Baltimore, MD]).1O,13 Thus, the augmentation of aluminum absorption by citrate can have serious consequences. It is likely that calcium citrate and aluminumcontaining, phosphate-binding antacids may also be administered together to patients with renal failure. The effect of calcium citrate on intestinal aluminum absorption is not known; if the citrate in calcium citrate augments aluminum absorption, as occurs with sodium citrate/citric acid, the potential for aluminum toxicity would exist. Therefore, we evaluated whether calcium citrate increases the enteral absorption or ingested aluminum in normal man. The results indicate that calcium citrate markedly enhances the absorption of aluminum from aluminum hydroxide. METHODS Studies of aluminum absorption were performed in eight men, ranging in age from 32 to 54 years, who were free of metabolic, renal, or liver diseases. The study protocol was approved by the Human Subjects Review Committee of the Veterans Administration Medical Center, West Los Angeles. Aluminum absorption was indirectly assessed by measuring the urinary excretion of aluminum during a 5-day study period. Baseline urinary aluminum excretion was determined for 2
American Journal of Kidney Diseases, Vol XVII, No 6 (June), 1991: pp 708-711
CA CITRATE RAISES AL ABSORPTION FROM AL(OHh
days; thereafter, subjects ingested aluminum hydroxide for 3 days. The dose of aluminum hydroxide, as Alternagel (Stuart Pharmaceuticals, Washington, DC), 5 mL administered four times daily with meals and at bedtime, provided 2.4 gld of aluminum hydroxide. The study protocol was performed twice in each subject, separated by an interval of 3 to 4 weeks. Subjects were given either calcium citrate, 950 mg four times daily as Citracal (Mission Pharmacal Co, San Antonio, TX), or placebo with the aluminum hydroxide during the 3 days of ingesting the aluminum gel in a "crossed-over" manner. The sequence of administration of placebo and calcium citrate varied for individual. subjects. Twenty-four-hour urine samples were collected in polypropylene containers shown not to produce contamination with aluminum, and aluminum and creatinine concentrations were measured in aliquots of these collections. Plasma samples were collected for aluminum determination on the second control day and on the second day of aluminum hydroxide ingestion. Aluminum levels were measured using electrothermal atomic absorption spectroscopy, '4 and urine creatinine concentrations were determined using the picric acid method." Urinary aluminum excretion is expressed as micromoles of aluminum excreted per millimole creatinine. All results are presented as mean ± SE, and the values were compared using paired and unpaired t tests. 16
RESULTS
Baseline urinary aluminum excretion was 0.02 ± 0.004 (6.5 ± 1.1 JLg/g creatinine) and 0.03 ± 0.005 JLmol/mmol creatinine (7.4 ± 1.3 JLg/g creatinine) for the 2 days immediately before aluminum hydroxide administration, and basal urinary aluminum excretion did not differ between the first and second study for individual patients. The urinary excretion of aluminum increased frof!1 baseline values in each subject given aluminum hydroxide, but the values increased much more when calcium citrate was ingested with aluminum hydroxide (Fig 1). In individual subjects, urinary aluminum excretion rates on the 3 successive days of aluminum ingestion were 11.1 ± 3.23, 8.8 ± 2.9, and 5.3 ± 0.7 times greater, respectively, during the administration of calcium citrate plus aluminum hydroxide than with aluminum hydroxide alone (Fig 1). Plasma aluminum levels did not change after aluminum hydroxide ingestion, and the values did not differ in the two treatment groups. DISCUSSION
The current results indicate that the intestinal absorption of aluminum from aluminum hydroxide, as assessed by the increment in urinary aluminum excretion, increases markedly during the ingestion
709 ORAL AI -gels
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DAYS Fig 1. Urinary and plasma aluminum in eigh.t subjects before (baseline, squares) and during the Ing~s tlon of aluminum hydroxide either alone (0) or With calcium citrate (e). Data are mean ± SE. The increment in urinary aluminum excretion during the ingestion of calcium citrate and aluminum is greater than that with aluminum hydroxide alone, P < 0.02 on days 1 and 2, and P < 0.001 on day 3. To convert renal aluminum/mmol creatinine to I'g aluminum/g creatinine, multiply by 241.
of calcium citrate. Although sodium citrate and/or citric acid have been shown to enhance aluminum . absorption in humans 7.IO and in experimental animals,12.17 the effect of calcium citrate on aluminum metabolism has not previously been documented. Eleven deaths from apparent aluminum toxicity have been reported in patients with renal insufficiency not receiving dialysis who were given aluminum hydroxide for the treatment of hyperphosphatemia and calcium citrate/citric acid (Shohl's solution or Bicitra) for the management of acidosis.lo.13 The current experimental findings suggest that similar concerns about enhanced intestinal aluminum absorption are warranted with the use of calcium citrate. In two subjects from the current study, aluminum excretion exceeded 37 JLmol/d (1,000 JLg/d), quantities similar to the amounts received parenterally by patients who developed aluminum-related bone disease while receiving intravenous nutrition with solutions that were contaminated with aluminum. IS Although urinary aluminum excretion is not an absolute measure of intestinal aluminum absorption, it is a much more sensitive index of aluminum absorption than changes in serum aluminum levels. 19 Studies that have compared
COBURN ET AL
710
oral aluminum loads and much smaller intravenous infusions in rats confirm the value of urinary aluminum excretion as a measure of changes in intestinal absorption when some renal function is maintained. 20 Citrate is unique in its ability to form soluble complexes with aluminum in aqueous solutions or in plasma; indeed, citrate can solubilize aluminum from insoluble complexes such as aluminum phosphate. 21 This chemical property of citrate can increase the intestinal absorption of aluminum, and it may promote the passage of aluminum across biological membranes. Recent observations demonstrated that aluminum citrate can increase the permeability of the intestinal epithelium by opening tight junctions. 22.23 The uptake of soluble complexes of aluminum citrate by tissues may enhance aluminum deposition and augment its toxicity. The marked augmentation of intestinal aluminum absorption produced by citrate, whether taken in the form of citric acid, or its sodium, calcium, or potassium salt, can lead to severe and adverse consequences in patients with advanced renal failure. Several situations might arise whereby patients might inadvertently receive aluminum-containing compounds with a citrate salt. Thus, it is probable that calcium citrate and aluminum gels might be combined in a patient with
advanced renal failure because the calcium citrate, by itself, is inadequate to lower serum phosphorus levels appropriately. 24 The combination of sodium citrate to treat acidosis combined with aluminum gel for hyperphosphatemial0,13 has been noted above. Also, patients with reduced renal function and renal stones might receive potassium citrate 25 with an aluminum gel. Finally, there is always a chance that a nonprescribed aluminum-containing antacid will be taken for dyspepsia or peptic ulcer symptoms by a renal patient who is also taking a citrate salt for one of the reasons noted above or with the citrate ingested unknowingly in AlkaSeltzer (Miles, Inc, Elkhart, IN), an over-the-counter citrate-containing compound. In view of all these possible reasons why citrate and an aluminum gel might be taken together, we strongly' recommend that calcium citrate not be prescribed as a phosphate binder in a renal patient unless calcium carbonate, calcium acetate, and an aluminum gel is each effective or is not tolerated. If calcium citrate must be prescribed, the patient should be aware that aluminum compounds must not be taken concurrently. ACKNOWLEDGMENT W. Van Buren provided excellent technical assistance, Lisa Newman provided assistance in preparing the manuscript.
REFERENCES L Coburn Jw, Norris KC, Nebeker HG: Osteomalacia and bone disease arising from aluminum, Semin Nephrol 6:68-69, 1986 2. Salusky IB, Brill J, Oppenheim W, et al: Features ofrenal osteodystrophy in pediatric patients receiving regular peritoneal dialysis. Semin Nephrol 9:37-42, 1989 3. Salusky m, Coburn Jw, Foley J , et al: Effects of oral calcium carbonate on control of serum phosphorus and changes in plasma aluminum levels after discontinuation of aluminumcontaining gels in children receiving dialysis. J Pediatr 108:767-770, 1986 4. Slatopolsky E, Weerts C, Lopez-Hilker S, et al: Calcium carbonate is an effective phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 315:157-161, 1986 5. Fournier A, Moriniere PH, Sebert JL, et al: Calcium carbonate, an aluminum-free agent for control of hyperphosphatemia, hypocalcemia and hyperparathyroidism in uremia. Kidney Int 29 :S115-S119, 1986 (suppl 18) 6. Cushner HM , Copley lB, Lindberg JS, et al: Calcium citrate, a nonaluminum-containing phosphate-binding agent for treatment of CRE Kidney Int 33 :95-99, 1988 7. Mak RH, Thrner C, Thompson T, et al: Suppression of secondary hyperparathyroidism in children with chronic renal
failure by high dose phosphate binders: Calcium carbonate versus aluminum hydroxide. Br Med J 291 :623-627, 1985 8. Mai ML, Emmett M, Sheikh MS, et al : Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int 36:690-695, 1989 9. Slanina P, Frech W, Ekstrom L, et al : Dietary citric acid enhances absorption of aluminum in antacids. Clin Chern 32:539-541 , 1986 10. Bakir AA, Hryhorczuk DO, Berman E, et al: Acute fatal hyperaluminemic encephalopathy in undialyzed and recently dialyzed uremic patients. Trans Am Soc Artif Intern Organs 32: 171-176, 1986 II. Weberg R, Berstad A: Gastrointestinal absorption of aluminum from single doses of aluminum containing antacids in man. Eur J Clin Invest 16:428-432, 1986 12. Slanina P, Falkeborn Y, Frech W, et al : Aluminum concentrations in the brain and bone of rats fed citric acid, aluminum citrate or aluminum hydroxide. Food Chern Toxicol 22:391-397, 1984 13. Kirschbaum BB, Schoolwerth AC: Acute aluminum toxicity associated with oral citrate and aluminum-containing antacids. Am J Med Sci 297 :9-11 , 1989 14. LeGendre GR, Alfrey AC : Measuring picogram amounts of aluminum in biological tissue by flameless atomic
CA CITRATE RAISES AL ABSORPTION FROM AL(OHh absorption. Clin Chern 22:53-56, 1983 15. Heinegard D, Tidestrom G: Determination of serum creatinine by a direct colorimetric method. Clin Chern Acta 43:305-311, 1973 16. Dixon WJ, Massey FJ: Introduction to Statistical Analysis. New York, NY, McGraw-Hill, 1983 17. Slanina P, Frech W, Bernhardson A, et al: Influence of dietary factors on aluminum absorption and retention in the brain and bone of rats . Acta Pharmacol Toxicol (Copenh) 56:331 -336, 1985 18 . Klein GL, Ott SM, Alfrey AC, et al : Aluminum as a factor in the bone disease of long-term parenteral nutrition . Trans Assoc Am Physicians 95: 155-164, 1982 19. 'Kaehny WD, Hegg P, Alfrey AC: Gastrointestinal absorption of aluminum from aluminum-containing antacids. N Engl J Med 296:1389-1390, 1977 20. Ittel TH, Buddington B, Miller NL , et al: Enhanced gas-
711 trointestinal absorption of aluminum in uremic rats. Kidney Int 32:821-826, 1987 21. Martin RB: The chemistry of aluminum as related to biology and medicine. Clin Chern 32: 1797-1806, 1986 22. Froment DPH, Molitoris BA, Buddington B, et al: Site and mechanism of enhanced gastrointestinal absorption of aluminum by citrate. Kidney Int 36:978-984 , 1989 23 . Molitoris BA, Froment DPH, Mackenzie TA , et al: Citrate: A major factor in the toxicity of orally administered aluminum compounds . Kidney Int 36:949-953 , 1989 24. Sheikh MS, Maguire JA , Emmett M, et al : Reduction of dietary phosphorus binders: A theoretical , in vitro, and in vivo study. J Clin Invest 83:66-73, 1989 25 . Pak CY, Sakhaee K, Fuller C : Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 30:422-428, 1986
