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Calcium Acetate Control of Serum Phosphorus in Hemodialysis Patients
Calcium Acetate Control of Serum Phosphorus in Hemodialysis Patients Michael Emmett, MD, Maryella D. Sirmon, MD, Wanda G. Kirkpatrick, MD, Charles R. Nolan, MD, Gunther W. Schmitt, MD, and Mark vB. Cleveland, PhD • Calcium acetate has many characteristics of an ideal phosphorus binder. It is a readily soluble salt that avidly binds phosphorus in vitro at pH 5 and above. One-dose/one-meal balance studies show it to be more potent than calcium carbonate or calcium citrate. We studied chronic (3-month) phosphorus binding with calcium acetate in 91 hyperphosphatemic dialysis patients at four different centers. All phosphorus binders were stopped for 2 weeks. Calcium acetate at an Initial dose of 8.11 mmol (325 mg Ca2 +) per meal was then used as the only phosphorus binder. Dose was adjusted to attempt control of predlalysls phosphorus level less than 1.78 mmollL (5.5 mgl100 mL). Final calcium acetate dose was 14.6 mmol (586 mg) Ca2 + per meal. Sixteen patients developed mild transient hypercalcemia (mean, 2.84 mmollL [11.4 mg/dLJ. Initial phosphorus values in mmollL (mg/dL) were 2.39 (7.4); at 1 month, 1.91 (5.9); and at 3 months, 1.68 (5.2). Initial calcium values In mmollL (mg/dL) were 2.22 (8.9); at 1 month, 2.37 (9.5); and at 3 months, 2.42 (9.7). Initial aluminum values in I'mollL (JLg/L) were 2.99 (80.7); and at 3 months were 2.54 (68.4). Initial C-terminal parathyroid hormone (C-PTH) values In ng/mL were 14.6; at 1 month, 11.9; and at 3 months, 13.2. Sixty-nine patients then entered a double-blind study. Phosphorus binders were stopped for 1 week. Calcium acetate (at a dose established in a prior study) or placebo was then administered for 2 weeks. Next, patients were crossed to the opposite regimen for 2 weeks. Initial phosphorus was 2.36 mmollL (7.3 mg/100 mL) and calcium 2.22 mmollL (8.9 mg/100 mL). Calcium acetate reduced phosphorus to 1.91 mmollL (5.9 mg/100 mL) and Increased calcium to 2.37 mmollL (9.5 mgl100 mL) (both P<0.01). Placebo had no effect. Calcium acetate at an average dose of 14.6 mmol (586 mg) Ca 2 + per meal controlled serum phosphorus in an unselected group of dialYSis patients. Aluminum and C-PTH levels decreased. The drug was well tolerated. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: calcium acetate; hyperphosphatemia; renal osteodystrophy; phosphorous binders; aluminum.
P
ATIENTS WITH chronic renal failure absorb 50% to 60% of ingested phosphorus, regardless of their vitamin D status, and most develop positive phosphorus balance and hyperphosphatemia. 1 Severe dietary phosphorus restriction is not practical, therefore phosphorus binders are prescribed for the majority of these patients. Aluminum salts have been used primarily; however, because of their toxicity, they are being rapidly displaced by calcium salts.2-6 Unfortunately, calcium salts are also not ideal phosphorus
From the Nephrology/Metabolism Division, Baylor University Medical Center, and the Dallas Kidney Disease Center, Dallas, TX.; Nephrology Division, University of South Alabama Medical Center, Mobile , AL; Nephrology Service, Wilford Hall US Air Force Medical Center, Lackland AFB, San Antonio, TX.; Nephrology Division, ~terans Administration Medical Center, Boston, MA; and Braintree Laboratories, Braintree, MA. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of De· fense or other departments of the United States government. Supported by a grant from Braintree Laboratories, Braintree, MA, and the Renal Research and Education Fund, Baylor University Medical Center, Dallas, TX.. Address reprint requests to Michael Emmett, MD, Nephrology/Metabolism Division, Baylor University Medical Center, 3500 Gaston, Dallas, TX. 75246. © 1991 by the National Kidney Fountlation, Inc. 0272-6386/9111705-0007$3.00/0
544
binders. Very large doses are often necessary and frequently calcium salts must be combined with aluminum to adequately control serum phosphorus. 4 •5 When calcium carbonate, the most commonly used calcium salt, is ingested, a large fraction (20 % to 30 %) is absorbed. 1 This produces significant hypercalcemia in about one third of treated patients. 5 .6 Even when the serum calcium concentration remains normal, the large load of absorbed calcium may contribute to soft tissue and vascular calcification. Some calcium salts may bind phosphorus more effectively than others. Calcium acetate, a very soluble salt, binds phosphorus more rapidly than calcium carbonate in vitro.7 The relative advantage of calcium acetate compared with calcium carbonate increases in the 6.0 to 8.0 pH range. 7 One-dose/one-meal balance studies in normal subjects and patients with chronic renal failure show calcium acetate to bind twice as much phosphorus as equivalent amounts of calcium carbonate. 7.8 Furthermore, with calcium acetate, less calcium is absorbed per unit phosphorus bound. With calcium acetate, 2.27 mEq of calcium is absorbed per 1 mEq phosphate bound, compared with 6.25 mEq of calcium absorbed per 1 mEq phosphate bound with calcium carbonate. 8
American Journal of Kidney Diseases, Vol XVII, No 5 (May), 1991 : pp 544-550
545
CALCIUM ACETATE PHOSPHORUS BINDING
All published studies of calcium acetate used as a phosphorus binder have either been in vitro or one-dose/one-meal balance experiments. The present study evaluates long-term (3 month) serum phosphorus control with calcium acetate in a group of hemodialysis outpatients. Serum calcium, Ca x P products, aluminum, and parathyroid hormone (PTH) levels were also monitored. This was followed by a 2-week cross-over study comparing calcium acetate with placebo using a randomized double-blind protocol. Four dialysis centers participated in this study. METHODS The participating centers were the Dallas Kidney Disease Center, Dallas, TX; the Mobile Providence West Dialysis Center, Mobile, AL; the Nephrology Service, Wilford Hall US Air Force Medical Center, Lackland AFB, TX; and Boston Veterans Administration Hospital Dialysis Unit, Boston, MA. All patients had chronic renal failure and were maintained on hemodialysis three times a week. Patients selected for study required phosphorus-binding drugs to reduce serum phosphorus. Patients were excluded if they were pregnant (or intended to become pregnant), mentally unstable, unable to comply with the study protocol, or had persistent hypercalcemia (>2.74 mmollL [11 mg/l00 mLD. Patients were not excluded on the basis of poor phosphorus control with standard phosphorus-binding drugs. Dialysis treatment times ranged between 3 and 4 hours (most patients were dialyzed using time-averaged urea concentrations and protein catabolic rates to determine treatment duration). Dialysate calcium concentrations between 1.5 mmol/L (3.0 mEq/L) and 1.75 mmollL (3.5 mEq/L) were used. (Most patients were treated with a 1.625 mmollL [3.25 mEq/L] calcium dialysate.) Bicarbonate dialysate was used in 77 of the 91 patients, while 14 were dialyzed with an acetate bath. No attempt was made to alter dietary intake during the period of study. All phosphorus-binding drugs were discontinued for 2 weeks. It was necessary for the serum phosphorus concentration to increase to 1.81 mmollL (5.6 mgllOO mL) or greater to qualify for study. The study was approved by the Human Studies Research Review Committee at each study site and was conducted in compliance with Good Laboratory Practice Regulations and Code of Federal Regulations parts 56 and 50.
Part A Qualified patients received calcium acetate (Phos-Lo, Braintree Laboratories, Braintree, MA) at an initial dose of two tablets per meal (one before and one after the meal). Each tablet contained 4.22 mmol (667 mg) of calcium acetate (equivalent to 4.22 mmol [169 mg] elemental calcium). The dose was subsequenty adjusted every 2 weeks, attempting to maintain the predialysis serum phosphorus concentration between 1.45 mmollL (4.5 mg/l00 mL) and 1.78 mmollL (5.5 mg/dL).
Predialysis blood samples were collected following the 2week qualification period (off all phosphorus binders) and then
every 2 weeks during part A. Samples were analyzed for sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, uric acid, albumin, calcium, and phosphorus by local laboratories at each study site. At 4-week intervals, aluminum, and C-terminal and N-terminal PTH levels were measured (Nichols Institute, San Juan Capistrano, CA). Patients remained in study part A for 3 months unless forced to drop out (hospitalization, kidney transplant, severe intercurrent illness, or death).
Part B Each patient completing part A was requalified by discontinuing calcium acetate for 1 to 2 weeks and demonstrating that the serum phosphorus concentration increased to at least 1. 81 mmol/L (5.6 mg/l00 mL). Qualified patients were randomized with a computer-generated random number table. They received either calcium acetate or placebo (lactose) using a double-blind crossover protocol. Each patient's drug dose was identical to the dose of calcium acetate received by that patient at the conclusion of study part A. After 2 weeks of therapy, patients were crossed over to the alternative treatment (placebo or calcium acetate). Weekly predialysis blood samples were collected for measurement of sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, uric acid, albumin, calcium, and phosphorus. Aluminum and C-terminal and N-terminal PTH levels were measured on entry and every 2 weeks (Nichols Institute). Part B duration was 4 weeks (2 weeks of placebo and 2 weeks of calcium acetate).
Data Analysis Patients entered in part A were included for data analysis if they completed at least 50% (6 weeks) of the study. Patients entered in part B were included for analysis only if they completed the entire 4-week protocol. Site comparisons, treatment order effects, and changes in laboratory values over time were analyzed by repeated measures analysis of variance. 9 In the event of a significant difference, means were compared by Fisher's least significant difference. \0 Differences with P values less than or equal to 0.05 were considered significant. All computers and programs used were validated with a standard data set. All data are reported as mean ± SEM unless otherwise stated.
RESULTS
Part A One hundred three patients entered study part A. Ninety-one completed at least 6 weeks of the study and 85 completed the entire 12-week protocol. Reasons for drop out included intercurrent illness, renal transplantation, etc. Nine serious and/or fatal events that occurred are listed in Table 1. Calcium acetate therapy was not thought to have contributed to any of these events. The calcium and phosphorus concentrations measured before each event is shown in Table 1.
546
EMMETT ET AL Table 1.
Serious or Unexpected Adverse Events: Part A Calcium-
Age/Sex
68/M
Reaction
59/M
Diagnosed terminal cancer, initiated after study Death due to eVA Death due to eVA Death due to MI Death due to surgical complications Foot infection
59/F
ehest pains
61/M
Foot ulcer, nausea, vomiting Atrial flutter
39/F 48/F 71/M 28/F
411F
Conclusions and Outcome
mmol/L
Phosphorus mmollL
(mg/l00 mL)
Unrelated to study: completed study
2.42
(9.7)
2.39
(7.4)
Unrelated Unrelated Unrelated Unrelated
2.12 2.27 2.15 2.15
(8.5) (9.1) (8.6) (8.6)
1.71 1.91 2.32 1.94
(5.3) (5.9) (7.2) (6.0)
2.52
(10.1)
1.45
(4.5)
2.47
(9.9)
1.84
(5.7)
2.35
(9.4)
2.61
(8.1)
2.52
(10.1)
1.87
(5.8)
to to to to
study study study study
Unrelated to study: medication discontinued Unrelated to study: resolved, completed study Unrelated to study: resolved Unrelated to study: resolved
(mg/l00 mL)
Abbreviations: eVA, cerebrovascular accident; MI, myocardial infarction. * Last measurement before the event.
The 91 patients completing at least 6 weeks of study part A included 48 men and 43 women. Their average age was 54 ± 5 years. Seventy-five percent of these patients had been using aluminum salts (alone or together with calcium salts) before the study, while 25 % had used calcium salts without aluminum. Ten patients were using vitamin D preparations (eight by mouth, two parenteral) and they were continued. During the 3-month study period, the average calcium acetate dose increased from the initial two tablets (8.43 mmol [338 mg]) elemental calcium per meal, to 3.5 tablets (14.8 mmol [592 mg]) elemental calcium per meal, as shown in Table 2. Dose titration had largely been accomplished by the end of the second month. The effect of calcium acetate treatment on biochemical parameters is shown in Table 3. Mean serum phosphorus concentration decreased from 2.39 mmollL (7.4 mg/loo mL) to 1.68 mmollL (5.2 mg/loo mL). The greatest decrease in phosphorus concentration occurred during the first month of therapy. Mean serum calcium concentration increased from 2.22 mmollL (8.9 mg/too Table 2. Time (wk) Tablets Elemental calcium, mmol (mg)
mL) to 2.42 mmollL (9.7 mg/too mL). Again, the increase in calcium concentration was greatest during the first month of therapy. Phosphorus and calcium concentrations did not change significantly during the final month of therapy. Throughout the study, the decrease in phosphorus exceeded the increase in calcium. Therefore, the calcium X phosphorus product, which was initially 66.1, decreased to 50.6 after 12 weeks of calcium acetate therapy. Aluminum levels decreased significantly from an initial level of2.99 jtmollL (80.7 jtg/L) to 2.54 jtmollL (68.4 jtg/L) after 12 weeks of therapy. Although N-terminal and C-terminal PTH levels both decreased, only the decrease in C-PTH was statistically significant (P
Prescribed Dose of Calcium Acetate per Meal: Part A
o 2 8.43 (338)
4 2.4 ± 0.1 10.2 ± 2.50 (406 ± 10)
8
3.2 ± 0.1 13.5 ± 5.00 (541 ± 20)
12 3.5 ± 0.1 14.8 ± 5.94 (592 ± 22)
547
CALCIUM ACETATE PHOSPHORUS BINDING Table 3.
Laboratory Measurements: Part A Time (wk)
Normal Range No. of patients Phosphorus, mmol/L (mg/100 mL) Calcium, mmol/L (mg/100 mL) Ca x P Aluminum, J.lmol/L (J.lg/L) N-PTH, pg/mL C-PTH, ng/mL Sodium, mmol/L Potassium, mmol/L Chloride, mmol/L Bicarbonate, mmol/L BUN, mmollL (mg/100 mL) Creatinine, mmol/L (mg/100 mL) Uric acid, mmol/L (mg/100 mL) Albumin (g/100mL)
0
103 .81-1.36 (2.5-4.2) 2.12-2.62 (8.5-10.5) <1.48 «40) 8-24 .05-.33 136-145 3.5-5.0 96-106 24-30 3.6-10.0 (10-28) 88-132 (1-1.5) 130-458 (2.2-7.7) 3.0-5.5
2.30 (7.4 2.22 (8.9 66.1 2.99 (80.7 80.1 14.6 138.0 4.6 99.4 21.7 26.0 (72.7 1,308 (14.8 470 (7.9 3.7
± .06 ± .17) ± .02 ± .09) ± 1.7 ± .21 ± 5.6) ± 6.6 ± 1.6 ± .04 ± .07 ± .06 ± 0.5 ± 0.7 ± 1.9) ± 35 ± 0.4) ±6 ± 0.1) ± .04
3.17 mmollL [12.7 mg/loo mLl), hypercalcemia was mild and did not exceed 3.0 mmollL (12 mg/ 100 mL). The hypercalcemic episodes resolved either spontaneously (7/16), or following a calcium acetate dose reduction (9/16). The 16 patients who became hypercalcemic had a calcium concentration at entry into part A of 2.32 ± 0.07 mmollL (9.3 ± 0.3 mg/loo mL). This was not statistically different from the initial calcium concentration of the entire study group, 2.22 ± 0.02 mmol/L (8.9 ± 0.1 mg/loo mL). The hypercalcemic group included two of the 10 patients using vitamin D preparations. Seven patients complained of nausea and/or vomiting. Patients did not complain of new onset, or worse, constipation. Indeed, many patients spontaneously expressed their preference for calcium acetate compared with aluminum salts because the former was not constipating. Analysis showed only minor differences between study centers with respect to prestudy chemical parameters or response to therapy. Part B
Sixty-nine patients who completed part A discontinued phosphorus binders for 1 to 2 weeks and then entered study part B. Thirty-eight were men and 31 were women, with an average age of 55.5
95 1.91 (5.9 2.37 (9.5 55.9
70.9 11.9 138.0 4.9 100.5 21.3 26.7 (74.9 1,343 (15.2 487 (8.2 3.8
± ± ± ± ±
p
12
8
4
.05 .16) .02 .10) 1.5
± 6.5 ± 1.3 ± 0.4 ± .09 ± 0.5 ± 0.5 ± 0.8 ± 2.2) ± 35 ± 0.4) ± 12 ± 0.2) ± .04
89 1.81 ± (5.6 ± 2.42 ± (9.7 ± 53.2 ± 69.3 12.6 138.0 4.8 99.9 21.6 26.9 (75.4 1,326 (15.0 476 (8.0 3.8
.06 .17) .02 .10) 1.6
± 6.6 ± 1.6 ± 0.4 ± .08 ± 0.5 ± 0.5 ± 0.9 ± 2.4) ± 35 ± 0.4) ± 12 ± 0.2) ± .04
85 1.68 ± .06 (5.2 ± .17) 2.42 ± .02 (9.7 ± .10) 50.6 ± 1.4 2.54 ± 1.8 (68.4 ± 4.8) 65.8 ± 6.3 13.2 ± 1.8 139.0 ± 0.4 4.8 ± .09 101.7 ± 0.5 20.0 ± 0.5 27.1 ± 0.9 (75.9 ± 2.5) 1,317 ± 35 (14.9 ± 0.4) 476 ± 12 (8.0 ± 0.2) 3.8 ± .04
Value
<0.01 <0.01 <0.001 <0.01 NS
<0.01 NS
<0.01 <0.01 NS NS NS NS NS
years. There were no important differences between study centers with respect to prestudy chemical parameters or response to therapy. Patients were randomly assigned to treatment with either calcium acetate or placebo. The drug (or placebo) dose used in each subject was based on the calcium acetate dose required by each patient during study part A. After 2 weeks, subjects were crossed over to the alterative treatment (placebo or calcium acetate). Table 4 shows the part B results. Patients initially receiving calcium acetate (group I) had a reduction in serum phosphorus from 2.42 mmollL (7.5 mg/loo mL) to 1.90 mmollL (5.9 mg/lOO mL), while serum calcium increased from 2.20 mmollL (8.8 mg/loo mL) to 2.35 mmol/L (9.4 mg/loo mL). When placebo replaced calcium acetate, serum phosphorus and calcium concentrations returned to baseline levels. The group initially receiving placebo (group II) showed a similar response when switched to calcium acetate. Treatment order effects were not detected. Therefore, group I and group II results were pooled as shown in Fig 1. The changes in serum phosphorus, calcium, and calcium X phosphorus product were all significant. Five episodes of transient mild hypercalcemia occurred during calcium acetate treatment (range, 2.79 mmollL [11.2 mg/loo mL] to 2.89 mmollL
548
EMMETI ET AL
Table 4.
Calcium and Phosphorus Measurements: Part B Baseline
Group I (n = 36) Phosphorus, mmollL (mg/100 mL) Calcium, mmol/L (mg/100 mL)
2.42 (7.5 2.20 (8.8
± .09 ± .27) ± .03 ± .14)
Baseline
Group II (n = 32) Phosphorus, mmol/L (mg/100 mL) Calcium, mmol/L (mg/100 mL)
2.29 (7.1 2.25 (9.0
± ± ± ±
.08 .24) .04 .16)
2 Weeks Calcium Acetate
1.90 (5.9 2.35 (9.4
± ± ± ±
.09* .29)* .04* .17)*
2 Weeks Placebo
2.52 (7.8 2.20 (8.8
± ± ± ±
.11 .34) .03 .14)
2 Weeks Placebo
2.55 (7.9 2.17 (8.7
± ± ± ±
.12 .38) .04 .18)
2 Weeks Calcium Acetate
1.90 (5.9 2.35 (9.4
± ± ± ±
.08* .25)* .05* .19)*
NOTE. Group I received calcium acetate first; group II received placebo first. *P<0.01 compared with baseline.
[11.6 mg/100 mL]). None of these patients had developed hypercalcemia during part A. Each hypercalcemic episode quickly resolved after calcium acetate was discontinued (as planned after 2 weeks) . No other adverse reactions were asso-
10
Baseline
Placebo
Calcium Acetate
9 Ul
:l
eo
-a Ul
8
o .c
a..
o
E
7
:l
'0
~ 6 E o
o ~ E
5 4
3L--U~
Cax P
__~__-J~~-L____~aL~L
65.0
68.6
56.0
Fig 1. Combined data-part B (n 69 patients). Following 2 weeks of calcium acetate, the reduction in serum phosphorus, increase in serum calcium, and reduction in Ca x P product are significantly different from the effect of placebo (P
ciated with calcium acetate therapy during study part B. DISCUSSION
The use of calcium salts to bind dietary phosphorus may be limited by excessive calcium absorption and hypercalcemia. High calcium concentrations in the gastrointestinal tract drive passive calcium absorption. II Therefore, patients with chronic renal failure absorb 20% to 30% of large oral calcium loads, even if they are vitamin D-deficient. II Vitamin D supplementation further increases calcium absorption. (1\\'0 of the 10 patients who were receiving vitamin D supplementation developed transient hypercalcemia.) Ingested calcium salts can reduce serum phosphorus via several mechanisms. First, calcium will bind ingested phosphorus within the gastrointestinal tract and reduce its absorption. Second, absorbed calcium can increase systemic calcium concentrations and precipitate phosphorus in the skeleton, as well as soft tissues.2.12-15 Third, increased calcium concentrations decrease PTH levels. This may decrease skeletal phosphorus release. 16 Therefore, a reduction in serum phosphorus concentration following calcium salt ingestion does not prove that intestinal phosphorus binding has occurred. Gastrointestinal balance studies are needed to prove that ingested compounds bind and decrease the absorption of dietary phosphorus. Balance studies have shown that calcium acetate binds about twice as much dietary
CALCIUM ACETATE PHOSPHORUS BINDING
phosphorus as equivalent quantities of calcium carbonate. 7.8 An average calcium acetate dose of 3.5 tablets (14.8 mmol [592 mg]) elemental Ca2 + per meal decreased the mean predialysis serum phosphorus concentration from 2.39 mmollL (7.4 mg/IOO mL) to 1.68 mmollL (5 .2 mg/IOO mL) over the 3month treatment period. The reduction in phosphorus was largely achieved during the first month of treatment, although there was a trend toward further reduction over the next 2 months. The decrease in phosphorus was accompanied by an increase in serum calcium from 2.22 mmollL (8.9 mg/lOO mL) to 2.42 mmollL (9.7 mg/l00 mL). However, the reduction in phosphorus exceeded the increase in calcium so that the calcium X phosphorus product decreased. Hypercalcemia developed in 17 % of the patients, but was mild and readily reversed. The crossover trial (part B) showed that calcium acetate significantly reduced phosphorus and increased calcium concentrations within 2 weeks of initiation of therapy. Again, the calcium x phosphorus product decreased during calcium acetate therapy. Phosphorus and calcium concentrations returned to baseline within 2 weeks of substituting placebo for calcium acetate. Recently, Slatopolsky et al reported that calcium carbonate, at an average dose of 84.8 mmol (3,400 mg) elemental calcium per day, controlled phosphorus concentrations in most dialysis patients. 5 However, despite this relatively high calcium dose, 30% of the patients required supplemental aluminum salts to achieve acceptable phosphorus control. Calcium carbonate therapy produced hypercalcemia in 35 % of the patients over the 2month study period. A 1.625-mmollL (3 .25-mEq/ L) calcium dialysis bath was used. Although the dialysate calcium concentration can be reduced to permit the use of even larger doses of calcium carbonate,17.18 this may exacerbate secondary hyperparathyroidism in some patients. 19 Assuming three meals per day (most likely an overestimation), our patients ingested 41.92 mmol (1,680 mg) elemental calcium as calcium acetate per day to control serum phosphorus. This is about one half the calcium carbonate dose reported by Slatopolsky et al. 5 During the 3-month study, 17% of our patients developed hypercalcemia. This
549
compares favorably with the reported hypercalcemic frequency of 35 % produced by calcium carbonate over a shorter study period. 4.5 Patients with chronic renal failure may be hypochlorhydric or achlorhydric . 20.21 They frequently receive antacids and inhibitors of gastric acid secretion. Impaired gastric acidification will slow calcium carbonate dissolution and may decrease its phosphorus-binding efficacy; by contrast, calcium acetate is an excellent phosphorus binder at relatively high pH. 7 Plasma aluminum levels decreased from 2.99 /LmollL (80.7 /Lg/L) to 2.54 /LmollL (68.4 /Lg/L) after 3 months of calcium acetate therapy (P < 0.01). Although unstimulated plasma aluminum levels may not accurately reflect the total aluminum burden, the observed decrease suggests aluminum intoxication will be ameliorated, or prevented, by conversion to calcium acetate. The 15 % decrease in serum aluminum levels was less dramatic than the reductions reported in prior studies of calcium salt substitution. However, 25 % of our patients were not using any aluminum salts before entry in the study, and most had used both aluminum and calcium salts . Therefore, their basal exogenous aluminum load was smaller. PTH levels decreased slightly over the 3-month study period in response to increased blood calcium concentrations. However, the reduction in PTH levels was probably blunted by declining aluminum levels. Aluminum suppresses PTH secretion and lower aluminum levels will produce less suppression. The acetate load ingested by our patients was relatively small, averaging less than 30 mmol per meal. Although the fraction absorbed is unknown, there was no detectable increase in serum bicarbonate concentrations. Large, rapidly infused loads of acetate may have adverse hemodynamic and lipid effects, but it is unlikely that the relatively small amounts of acetate ingested by our patients would have such effects. Calcium citrate is known to markedly increase gastrointestinal aluminum absorption.22 In contrast, calcium acetate has no such effect.23 Therefore, if serum phosphorus cannot be controlled with calcium acetate alone, aluminum binders can be added without additional stimulation of aluminum absorption.
EMMETT ET AL
550
This study shows that calcium acetate can be used to control serum phosphorus in hemodialysis outpatients on a long-term basis. Calcium acetate is well tolerated and accepted by patients. The lower dose requirements and low frequency of hypercalcemia are consistent with one-meal/onedose balance data, which showed that calcium acetate bound phosphorus more efficiently, and was
associated with less calcium absorption than calcium carbonate. ACKNOWLEDGMENT The authors wish to thank Karen McGregor, PA-C, and Lezlie Miller, PA-C, for their valuable assistance in the completion of this study, and Ann Drew for the excellent preparation of the manuscript.
REFERENCES 1. Ramirez lA, Emmett M, White MG, et al: The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 30:753-759, 1986 2. Meyrier A, Marsac 1, Richet G: The influence of a high calcium carbonate intake on bone disease in patients undergoing hemodialysis. Kidney Int 4:146-153, 1973 3. Fournier A, Moriniere P, Sebert lL, et al: Calcium carbonate, an aluminum-free agent for control of hyperphosphatemia, hypocalcemia, and hyperparathyroidism in uremia. Kidney Int 29:S114-S119, 1986 (suppl) 4. Gonella M, Calabrese G, Vagelli G, et al: Effects of high CaC0 3 supplements on serum calcium and phosphorus in patients on regular hemodialysis treatment. Clin Nephrol24: 147150, 1985 5. Slatopolsky E, Weerts C, Lopez-Hilker S, et al: Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing hemodialysis. N Engl 1 Med 315:157-161, 1986 6. Hercz G, Kraut lA, Andress DA, et al: Use of calcium carbonate as a phosphate binder in dialysis patients. Miner Electrolyte Metab 12:314-319, 1986 7. Sheikh MS, Maguire lA, Emmett M, et al: Reduction of dietary phosphorus absorption by phosphorus binders: A theoretical, in vitro, and in vivo study. 1 Clin Invest 83:66-73, 1989 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. Winer BI: Statistical Principles in Experimental Design (ed 2). New York, NY, McGraw-Hill, 1971 10. Millikin GA, lohnson DE: Analysis of Messy Data, vol I, Designed Experiments. Belmont, CA, Lifetime Learning, 1984 II. Sheikh MS, Ramirez A, Emmett M, et al: Role of vitamin D-dependent and vitamin D-independent mechanisms in absorption of food calcium. 1 Clin Invest 81: 126-132, 1988
12. Clarkson EM, McDonald Sl, de Wardener HE: The effect of a high intake of calcium carbonate in normal subjects
and patients with chronic renal failure. Clin Sci 30:425-438, 1966 13. Gipson RM, Coburn lW, Adams AA, et al: Calciphylaxis in man: A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 136: 1273-1280, 1976 14. Renaud H, Atik A, Herve M, et al: Evaluation of vascular calcinosis risk factors in patients on chronic hemodialysis: Lack of influence of calcium carbonate. Nephron 48:28-32, 1988 15. Campistol 1M, Almirall 1, Martin E, et al: Calcium carbonate-induced calciphylaxis. Nephron 51:549-550, 1989 16. Massry SG, Cobern lW, Popovtzer MM, et al: Secondary hyperparathyroidism in chronic renal failure. Arch Intern Med 124:431-441, 1969 17. Slatopolsky E, Weerts C, Norwood K, et al: Long-term effects of calcium carbonate and 2.5 mEq/liter calcium dialysate on mineral metabolism. Kidney Int 36:897-903, 1989 18. Mactier RA, Van Stone 1, Cox A, et al: Calcium carbonate is an effective phosphate binder when dialysate calcium concentration is adjusted to control hypercalcemia. Clin Nephrol 28:222-226, 1987 19. Wens R, Bergmann P, Dratwa M, et al: Variations of intact PTH levels during hemodialysis: Effects of dialysate calcium. Kidney Int 37:324, 1990 (abstr) 20. Milito G, Taccone-Gallucci M, Brancaleone C, et al: Assessment of the upper gastrointestinal tract in hemodialysis patients awaiting renal transplantation. Am 1 Gastroenterol 78:328-331, 1983 21. Gold CH, Morley IE, Viljoen M, et al: Gastric acid secretion and serum gastrin levels in patients with chronic renal failure on regular hemodialysis. Nephron 25:92-95, 1985 22. Molitoris BA, Froment DH, MacKenzie TA, et al: Citrate: A major factor in the toxicity of orally administered aluminum compounds. Kidney Int 36:949-953, 1989 23. Nolan CR, Califano lR, Butzin CA: Influence of calcium acetate or calcium citrate on intestinal aluminum absorption. Kidney Int 38:937-941, 1990
P
ATIENTS WITH chronic renal failure absorb 50% to 60% of ingested phosphorus, regardless of their vitamin D status, and most develop positive phosphorus balance and hyperphosphatemia. 1 Severe dietary phosphorus restriction is not practical, therefore phosphorus binders are prescribed for the majority of these patients. Aluminum salts have been used primarily; however, because of their toxicity, they are being rapidly displaced by calcium salts.2-6 Unfortunately, calcium salts are also not ideal phosphorus
From the Nephrology/Metabolism Division, Baylor University Medical Center, and the Dallas Kidney Disease Center, Dallas, TX.; Nephrology Division, University of South Alabama Medical Center, Mobile , AL; Nephrology Service, Wilford Hall US Air Force Medical Center, Lackland AFB, San Antonio, TX.; Nephrology Division, ~terans Administration Medical Center, Boston, MA; and Braintree Laboratories, Braintree, MA. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of De· fense or other departments of the United States government. Supported by a grant from Braintree Laboratories, Braintree, MA, and the Renal Research and Education Fund, Baylor University Medical Center, Dallas, TX.. Address reprint requests to Michael Emmett, MD, Nephrology/Metabolism Division, Baylor University Medical Center, 3500 Gaston, Dallas, TX. 75246. © 1991 by the National Kidney Fountlation, Inc. 0272-6386/9111705-0007$3.00/0
544
binders. Very large doses are often necessary and frequently calcium salts must be combined with aluminum to adequately control serum phosphorus. 4 •5 When calcium carbonate, the most commonly used calcium salt, is ingested, a large fraction (20 % to 30 %) is absorbed. 1 This produces significant hypercalcemia in about one third of treated patients. 5 .6 Even when the serum calcium concentration remains normal, the large load of absorbed calcium may contribute to soft tissue and vascular calcification. Some calcium salts may bind phosphorus more effectively than others. Calcium acetate, a very soluble salt, binds phosphorus more rapidly than calcium carbonate in vitro.7 The relative advantage of calcium acetate compared with calcium carbonate increases in the 6.0 to 8.0 pH range. 7 One-dose/one-meal balance studies in normal subjects and patients with chronic renal failure show calcium acetate to bind twice as much phosphorus as equivalent amounts of calcium carbonate. 7.8 Furthermore, with calcium acetate, less calcium is absorbed per unit phosphorus bound. With calcium acetate, 2.27 mEq of calcium is absorbed per 1 mEq phosphate bound, compared with 6.25 mEq of calcium absorbed per 1 mEq phosphate bound with calcium carbonate. 8
American Journal of Kidney Diseases, Vol XVII, No 5 (May), 1991 : pp 544-550
545
CALCIUM ACETATE PHOSPHORUS BINDING
All published studies of calcium acetate used as a phosphorus binder have either been in vitro or one-dose/one-meal balance experiments. The present study evaluates long-term (3 month) serum phosphorus control with calcium acetate in a group of hemodialysis outpatients. Serum calcium, Ca x P products, aluminum, and parathyroid hormone (PTH) levels were also monitored. This was followed by a 2-week cross-over study comparing calcium acetate with placebo using a randomized double-blind protocol. Four dialysis centers participated in this study. METHODS The participating centers were the Dallas Kidney Disease Center, Dallas, TX; the Mobile Providence West Dialysis Center, Mobile, AL; the Nephrology Service, Wilford Hall US Air Force Medical Center, Lackland AFB, TX; and Boston Veterans Administration Hospital Dialysis Unit, Boston, MA. All patients had chronic renal failure and were maintained on hemodialysis three times a week. Patients selected for study required phosphorus-binding drugs to reduce serum phosphorus. Patients were excluded if they were pregnant (or intended to become pregnant), mentally unstable, unable to comply with the study protocol, or had persistent hypercalcemia (>2.74 mmollL [11 mg/l00 mLD. Patients were not excluded on the basis of poor phosphorus control with standard phosphorus-binding drugs. Dialysis treatment times ranged between 3 and 4 hours (most patients were dialyzed using time-averaged urea concentrations and protein catabolic rates to determine treatment duration). Dialysate calcium concentrations between 1.5 mmol/L (3.0 mEq/L) and 1.75 mmollL (3.5 mEq/L) were used. (Most patients were treated with a 1.625 mmollL [3.25 mEq/L] calcium dialysate.) Bicarbonate dialysate was used in 77 of the 91 patients, while 14 were dialyzed with an acetate bath. No attempt was made to alter dietary intake during the period of study. All phosphorus-binding drugs were discontinued for 2 weeks. It was necessary for the serum phosphorus concentration to increase to 1.81 mmollL (5.6 mgllOO mL) or greater to qualify for study. The study was approved by the Human Studies Research Review Committee at each study site and was conducted in compliance with Good Laboratory Practice Regulations and Code of Federal Regulations parts 56 and 50.
Part A Qualified patients received calcium acetate (Phos-Lo, Braintree Laboratories, Braintree, MA) at an initial dose of two tablets per meal (one before and one after the meal). Each tablet contained 4.22 mmol (667 mg) of calcium acetate (equivalent to 4.22 mmol [169 mg] elemental calcium). The dose was subsequenty adjusted every 2 weeks, attempting to maintain the predialysis serum phosphorus concentration between 1.45 mmollL (4.5 mg/l00 mL) and 1.78 mmollL (5.5 mg/dL).
Predialysis blood samples were collected following the 2week qualification period (off all phosphorus binders) and then
every 2 weeks during part A. Samples were analyzed for sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, uric acid, albumin, calcium, and phosphorus by local laboratories at each study site. At 4-week intervals, aluminum, and C-terminal and N-terminal PTH levels were measured (Nichols Institute, San Juan Capistrano, CA). Patients remained in study part A for 3 months unless forced to drop out (hospitalization, kidney transplant, severe intercurrent illness, or death).
Part B Each patient completing part A was requalified by discontinuing calcium acetate for 1 to 2 weeks and demonstrating that the serum phosphorus concentration increased to at least 1. 81 mmol/L (5.6 mg/l00 mL). Qualified patients were randomized with a computer-generated random number table. They received either calcium acetate or placebo (lactose) using a double-blind crossover protocol. Each patient's drug dose was identical to the dose of calcium acetate received by that patient at the conclusion of study part A. After 2 weeks of therapy, patients were crossed over to the alternative treatment (placebo or calcium acetate). Weekly predialysis blood samples were collected for measurement of sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, uric acid, albumin, calcium, and phosphorus. Aluminum and C-terminal and N-terminal PTH levels were measured on entry and every 2 weeks (Nichols Institute). Part B duration was 4 weeks (2 weeks of placebo and 2 weeks of calcium acetate).
Data Analysis Patients entered in part A were included for data analysis if they completed at least 50% (6 weeks) of the study. Patients entered in part B were included for analysis only if they completed the entire 4-week protocol. Site comparisons, treatment order effects, and changes in laboratory values over time were analyzed by repeated measures analysis of variance. 9 In the event of a significant difference, means were compared by Fisher's least significant difference. \0 Differences with P values less than or equal to 0.05 were considered significant. All computers and programs used were validated with a standard data set. All data are reported as mean ± SEM unless otherwise stated.
RESULTS
Part A One hundred three patients entered study part A. Ninety-one completed at least 6 weeks of the study and 85 completed the entire 12-week protocol. Reasons for drop out included intercurrent illness, renal transplantation, etc. Nine serious and/or fatal events that occurred are listed in Table 1. Calcium acetate therapy was not thought to have contributed to any of these events. The calcium and phosphorus concentrations measured before each event is shown in Table 1.
546
EMMETT ET AL Table 1.
Serious or Unexpected Adverse Events: Part A Calcium-
Age/Sex
68/M
Reaction
59/M
Diagnosed terminal cancer, initiated after study Death due to eVA Death due to eVA Death due to MI Death due to surgical complications Foot infection
59/F
ehest pains
61/M
Foot ulcer, nausea, vomiting Atrial flutter
39/F 48/F 71/M 28/F
411F
Conclusions and Outcome
mmol/L
Phosphorus mmollL
(mg/l00 mL)
Unrelated to study: completed study
2.42
(9.7)
2.39
(7.4)
Unrelated Unrelated Unrelated Unrelated
2.12 2.27 2.15 2.15
(8.5) (9.1) (8.6) (8.6)
1.71 1.91 2.32 1.94
(5.3) (5.9) (7.2) (6.0)
2.52
(10.1)
1.45
(4.5)
2.47
(9.9)
1.84
(5.7)
2.35
(9.4)
2.61
(8.1)
2.52
(10.1)
1.87
(5.8)
to to to to
study study study study
Unrelated to study: medication discontinued Unrelated to study: resolved, completed study Unrelated to study: resolved Unrelated to study: resolved
(mg/l00 mL)
Abbreviations: eVA, cerebrovascular accident; MI, myocardial infarction. * Last measurement before the event.
The 91 patients completing at least 6 weeks of study part A included 48 men and 43 women. Their average age was 54 ± 5 years. Seventy-five percent of these patients had been using aluminum salts (alone or together with calcium salts) before the study, while 25 % had used calcium salts without aluminum. Ten patients were using vitamin D preparations (eight by mouth, two parenteral) and they were continued. During the 3-month study period, the average calcium acetate dose increased from the initial two tablets (8.43 mmol [338 mg]) elemental calcium per meal, to 3.5 tablets (14.8 mmol [592 mg]) elemental calcium per meal, as shown in Table 2. Dose titration had largely been accomplished by the end of the second month. The effect of calcium acetate treatment on biochemical parameters is shown in Table 3. Mean serum phosphorus concentration decreased from 2.39 mmollL (7.4 mg/loo mL) to 1.68 mmollL (5.2 mg/loo mL). The greatest decrease in phosphorus concentration occurred during the first month of therapy. Mean serum calcium concentration increased from 2.22 mmollL (8.9 mg/too Table 2. Time (wk) Tablets Elemental calcium, mmol (mg)
mL) to 2.42 mmollL (9.7 mg/too mL). Again, the increase in calcium concentration was greatest during the first month of therapy. Phosphorus and calcium concentrations did not change significantly during the final month of therapy. Throughout the study, the decrease in phosphorus exceeded the increase in calcium. Therefore, the calcium X phosphorus product, which was initially 66.1, decreased to 50.6 after 12 weeks of calcium acetate therapy. Aluminum levels decreased significantly from an initial level of2.99 jtmollL (80.7 jtg/L) to 2.54 jtmollL (68.4 jtg/L) after 12 weeks of therapy. Although N-terminal and C-terminal PTH levels both decreased, only the decrease in C-PTH was statistically significant (P
Prescribed Dose of Calcium Acetate per Meal: Part A
o 2 8.43 (338)
4 2.4 ± 0.1 10.2 ± 2.50 (406 ± 10)
8
3.2 ± 0.1 13.5 ± 5.00 (541 ± 20)
12 3.5 ± 0.1 14.8 ± 5.94 (592 ± 22)
547
CALCIUM ACETATE PHOSPHORUS BINDING Table 3.
Laboratory Measurements: Part A Time (wk)
Normal Range No. of patients Phosphorus, mmol/L (mg/100 mL) Calcium, mmol/L (mg/100 mL) Ca x P Aluminum, J.lmol/L (J.lg/L) N-PTH, pg/mL C-PTH, ng/mL Sodium, mmol/L Potassium, mmol/L Chloride, mmol/L Bicarbonate, mmol/L BUN, mmollL (mg/100 mL) Creatinine, mmol/L (mg/100 mL) Uric acid, mmol/L (mg/100 mL) Albumin (g/100mL)
0
103 .81-1.36 (2.5-4.2) 2.12-2.62 (8.5-10.5) <1.48 «40) 8-24 .05-.33 136-145 3.5-5.0 96-106 24-30 3.6-10.0 (10-28) 88-132 (1-1.5) 130-458 (2.2-7.7) 3.0-5.5
2.30 (7.4 2.22 (8.9 66.1 2.99 (80.7 80.1 14.6 138.0 4.6 99.4 21.7 26.0 (72.7 1,308 (14.8 470 (7.9 3.7
± .06 ± .17) ± .02 ± .09) ± 1.7 ± .21 ± 5.6) ± 6.6 ± 1.6 ± .04 ± .07 ± .06 ± 0.5 ± 0.7 ± 1.9) ± 35 ± 0.4) ±6 ± 0.1) ± .04
3.17 mmollL [12.7 mg/loo mLl), hypercalcemia was mild and did not exceed 3.0 mmollL (12 mg/ 100 mL). The hypercalcemic episodes resolved either spontaneously (7/16), or following a calcium acetate dose reduction (9/16). The 16 patients who became hypercalcemic had a calcium concentration at entry into part A of 2.32 ± 0.07 mmollL (9.3 ± 0.3 mg/loo mL). This was not statistically different from the initial calcium concentration of the entire study group, 2.22 ± 0.02 mmol/L (8.9 ± 0.1 mg/loo mL). The hypercalcemic group included two of the 10 patients using vitamin D preparations. Seven patients complained of nausea and/or vomiting. Patients did not complain of new onset, or worse, constipation. Indeed, many patients spontaneously expressed their preference for calcium acetate compared with aluminum salts because the former was not constipating. Analysis showed only minor differences between study centers with respect to prestudy chemical parameters or response to therapy. Part B
Sixty-nine patients who completed part A discontinued phosphorus binders for 1 to 2 weeks and then entered study part B. Thirty-eight were men and 31 were women, with an average age of 55.5
95 1.91 (5.9 2.37 (9.5 55.9
70.9 11.9 138.0 4.9 100.5 21.3 26.7 (74.9 1,343 (15.2 487 (8.2 3.8
± ± ± ± ±
p
12
8
4
.05 .16) .02 .10) 1.5
± 6.5 ± 1.3 ± 0.4 ± .09 ± 0.5 ± 0.5 ± 0.8 ± 2.2) ± 35 ± 0.4) ± 12 ± 0.2) ± .04
89 1.81 ± (5.6 ± 2.42 ± (9.7 ± 53.2 ± 69.3 12.6 138.0 4.8 99.9 21.6 26.9 (75.4 1,326 (15.0 476 (8.0 3.8
.06 .17) .02 .10) 1.6
± 6.6 ± 1.6 ± 0.4 ± .08 ± 0.5 ± 0.5 ± 0.9 ± 2.4) ± 35 ± 0.4) ± 12 ± 0.2) ± .04
85 1.68 ± .06 (5.2 ± .17) 2.42 ± .02 (9.7 ± .10) 50.6 ± 1.4 2.54 ± 1.8 (68.4 ± 4.8) 65.8 ± 6.3 13.2 ± 1.8 139.0 ± 0.4 4.8 ± .09 101.7 ± 0.5 20.0 ± 0.5 27.1 ± 0.9 (75.9 ± 2.5) 1,317 ± 35 (14.9 ± 0.4) 476 ± 12 (8.0 ± 0.2) 3.8 ± .04
Value
<0.01 <0.01 <0.001 <0.01 NS
<0.01 NS
<0.01 <0.01 NS NS NS NS NS
years. There were no important differences between study centers with respect to prestudy chemical parameters or response to therapy. Patients were randomly assigned to treatment with either calcium acetate or placebo. The drug (or placebo) dose used in each subject was based on the calcium acetate dose required by each patient during study part A. After 2 weeks, subjects were crossed over to the alterative treatment (placebo or calcium acetate). Table 4 shows the part B results. Patients initially receiving calcium acetate (group I) had a reduction in serum phosphorus from 2.42 mmollL (7.5 mg/loo mL) to 1.90 mmollL (5.9 mg/lOO mL), while serum calcium increased from 2.20 mmollL (8.8 mg/loo mL) to 2.35 mmol/L (9.4 mg/loo mL). When placebo replaced calcium acetate, serum phosphorus and calcium concentrations returned to baseline levels. The group initially receiving placebo (group II) showed a similar response when switched to calcium acetate. Treatment order effects were not detected. Therefore, group I and group II results were pooled as shown in Fig 1. The changes in serum phosphorus, calcium, and calcium X phosphorus product were all significant. Five episodes of transient mild hypercalcemia occurred during calcium acetate treatment (range, 2.79 mmollL [11.2 mg/loo mL] to 2.89 mmollL
548
EMMETI ET AL
Table 4.
Calcium and Phosphorus Measurements: Part B Baseline
Group I (n = 36) Phosphorus, mmollL (mg/100 mL) Calcium, mmol/L (mg/100 mL)
2.42 (7.5 2.20 (8.8
± .09 ± .27) ± .03 ± .14)
Baseline
Group II (n = 32) Phosphorus, mmol/L (mg/100 mL) Calcium, mmol/L (mg/100 mL)
2.29 (7.1 2.25 (9.0
± ± ± ±
.08 .24) .04 .16)
2 Weeks Calcium Acetate
1.90 (5.9 2.35 (9.4
± ± ± ±
.09* .29)* .04* .17)*
2 Weeks Placebo
2.52 (7.8 2.20 (8.8
± ± ± ±
.11 .34) .03 .14)
2 Weeks Placebo
2.55 (7.9 2.17 (8.7
± ± ± ±
.12 .38) .04 .18)
2 Weeks Calcium Acetate
1.90 (5.9 2.35 (9.4
± ± ± ±
.08* .25)* .05* .19)*
NOTE. Group I received calcium acetate first; group II received placebo first. *P<0.01 compared with baseline.
[11.6 mg/100 mL]). None of these patients had developed hypercalcemia during part A. Each hypercalcemic episode quickly resolved after calcium acetate was discontinued (as planned after 2 weeks) . No other adverse reactions were asso-
10
Baseline
Placebo
Calcium Acetate
9 Ul
:l
eo
-a Ul
8
o .c
a..
o
E
7
:l
'0
~ 6 E o
o ~ E
5 4
3L--U~
Cax P
__~__-J~~-L____~aL~L
65.0
68.6
56.0
Fig 1. Combined data-part B (n 69 patients). Following 2 weeks of calcium acetate, the reduction in serum phosphorus, increase in serum calcium, and reduction in Ca x P product are significantly different from the effect of placebo (P
ciated with calcium acetate therapy during study part B. DISCUSSION
The use of calcium salts to bind dietary phosphorus may be limited by excessive calcium absorption and hypercalcemia. High calcium concentrations in the gastrointestinal tract drive passive calcium absorption. II Therefore, patients with chronic renal failure absorb 20% to 30% of large oral calcium loads, even if they are vitamin D-deficient. II Vitamin D supplementation further increases calcium absorption. (1\\'0 of the 10 patients who were receiving vitamin D supplementation developed transient hypercalcemia.) Ingested calcium salts can reduce serum phosphorus via several mechanisms. First, calcium will bind ingested phosphorus within the gastrointestinal tract and reduce its absorption. Second, absorbed calcium can increase systemic calcium concentrations and precipitate phosphorus in the skeleton, as well as soft tissues.2.12-15 Third, increased calcium concentrations decrease PTH levels. This may decrease skeletal phosphorus release. 16 Therefore, a reduction in serum phosphorus concentration following calcium salt ingestion does not prove that intestinal phosphorus binding has occurred. Gastrointestinal balance studies are needed to prove that ingested compounds bind and decrease the absorption of dietary phosphorus. Balance studies have shown that calcium acetate binds about twice as much dietary
CALCIUM ACETATE PHOSPHORUS BINDING
phosphorus as equivalent quantities of calcium carbonate. 7.8 An average calcium acetate dose of 3.5 tablets (14.8 mmol [592 mg]) elemental Ca2 + per meal decreased the mean predialysis serum phosphorus concentration from 2.39 mmollL (7.4 mg/IOO mL) to 1.68 mmollL (5 .2 mg/IOO mL) over the 3month treatment period. The reduction in phosphorus was largely achieved during the first month of treatment, although there was a trend toward further reduction over the next 2 months. The decrease in phosphorus was accompanied by an increase in serum calcium from 2.22 mmollL (8.9 mg/lOO mL) to 2.42 mmollL (9.7 mg/l00 mL). However, the reduction in phosphorus exceeded the increase in calcium so that the calcium X phosphorus product decreased. Hypercalcemia developed in 17 % of the patients, but was mild and readily reversed. The crossover trial (part B) showed that calcium acetate significantly reduced phosphorus and increased calcium concentrations within 2 weeks of initiation of therapy. Again, the calcium x phosphorus product decreased during calcium acetate therapy. Phosphorus and calcium concentrations returned to baseline within 2 weeks of substituting placebo for calcium acetate. Recently, Slatopolsky et al reported that calcium carbonate, at an average dose of 84.8 mmol (3,400 mg) elemental calcium per day, controlled phosphorus concentrations in most dialysis patients. 5 However, despite this relatively high calcium dose, 30% of the patients required supplemental aluminum salts to achieve acceptable phosphorus control. Calcium carbonate therapy produced hypercalcemia in 35 % of the patients over the 2month study period. A 1.625-mmollL (3 .25-mEq/ L) calcium dialysis bath was used. Although the dialysate calcium concentration can be reduced to permit the use of even larger doses of calcium carbonate,17.18 this may exacerbate secondary hyperparathyroidism in some patients. 19 Assuming three meals per day (most likely an overestimation), our patients ingested 41.92 mmol (1,680 mg) elemental calcium as calcium acetate per day to control serum phosphorus. This is about one half the calcium carbonate dose reported by Slatopolsky et al. 5 During the 3-month study, 17% of our patients developed hypercalcemia. This
549
compares favorably with the reported hypercalcemic frequency of 35 % produced by calcium carbonate over a shorter study period. 4.5 Patients with chronic renal failure may be hypochlorhydric or achlorhydric . 20.21 They frequently receive antacids and inhibitors of gastric acid secretion. Impaired gastric acidification will slow calcium carbonate dissolution and may decrease its phosphorus-binding efficacy; by contrast, calcium acetate is an excellent phosphorus binder at relatively high pH. 7 Plasma aluminum levels decreased from 2.99 /LmollL (80.7 /Lg/L) to 2.54 /LmollL (68.4 /Lg/L) after 3 months of calcium acetate therapy (P < 0.01). Although unstimulated plasma aluminum levels may not accurately reflect the total aluminum burden, the observed decrease suggests aluminum intoxication will be ameliorated, or prevented, by conversion to calcium acetate. The 15 % decrease in serum aluminum levels was less dramatic than the reductions reported in prior studies of calcium salt substitution. However, 25 % of our patients were not using any aluminum salts before entry in the study, and most had used both aluminum and calcium salts . Therefore, their basal exogenous aluminum load was smaller. PTH levels decreased slightly over the 3-month study period in response to increased blood calcium concentrations. However, the reduction in PTH levels was probably blunted by declining aluminum levels. Aluminum suppresses PTH secretion and lower aluminum levels will produce less suppression. The acetate load ingested by our patients was relatively small, averaging less than 30 mmol per meal. Although the fraction absorbed is unknown, there was no detectable increase in serum bicarbonate concentrations. Large, rapidly infused loads of acetate may have adverse hemodynamic and lipid effects, but it is unlikely that the relatively small amounts of acetate ingested by our patients would have such effects. Calcium citrate is known to markedly increase gastrointestinal aluminum absorption.22 In contrast, calcium acetate has no such effect.23 Therefore, if serum phosphorus cannot be controlled with calcium acetate alone, aluminum binders can be added without additional stimulation of aluminum absorption.
EMMETT ET AL
550
This study shows that calcium acetate can be used to control serum phosphorus in hemodialysis outpatients on a long-term basis. Calcium acetate is well tolerated and accepted by patients. The lower dose requirements and low frequency of hypercalcemia are consistent with one-meal/onedose balance data, which showed that calcium acetate bound phosphorus more efficiently, and was
associated with less calcium absorption than calcium carbonate. ACKNOWLEDGMENT The authors wish to thank Karen McGregor, PA-C, and Lezlie Miller, PA-C, for their valuable assistance in the completion of this study, and Ann Drew for the excellent preparation of the manuscript.
REFERENCES 1. Ramirez lA, Emmett M, White MG, et al: The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 30:753-759, 1986 2. Meyrier A, Marsac 1, Richet G: The influence of a high calcium carbonate intake on bone disease in patients undergoing hemodialysis. Kidney Int 4:146-153, 1973 3. Fournier A, Moriniere P, Sebert lL, et al: Calcium carbonate, an aluminum-free agent for control of hyperphosphatemia, hypocalcemia, and hyperparathyroidism in uremia. Kidney Int 29:S114-S119, 1986 (suppl) 4. Gonella M, Calabrese G, Vagelli G, et al: Effects of high CaC0 3 supplements on serum calcium and phosphorus in patients on regular hemodialysis treatment. Clin Nephrol24: 147150, 1985 5. Slatopolsky E, Weerts C, Lopez-Hilker S, et al: Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing hemodialysis. N Engl 1 Med 315:157-161, 1986 6. Hercz G, Kraut lA, Andress DA, et al: Use of calcium carbonate as a phosphate binder in dialysis patients. Miner Electrolyte Metab 12:314-319, 1986 7. Sheikh MS, Maguire lA, Emmett M, et al: Reduction of dietary phosphorus absorption by phosphorus binders: A theoretical, in vitro, and in vivo study. 1 Clin Invest 83:66-73, 1989 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. Winer BI: Statistical Principles in Experimental Design (ed 2). New York, NY, McGraw-Hill, 1971 10. Millikin GA, lohnson DE: Analysis of Messy Data, vol I, Designed Experiments. Belmont, CA, Lifetime Learning, 1984 II. Sheikh MS, Ramirez A, Emmett M, et al: Role of vitamin D-dependent and vitamin D-independent mechanisms in absorption of food calcium. 1 Clin Invest 81: 126-132, 1988
12. Clarkson EM, McDonald Sl, de Wardener HE: The effect of a high intake of calcium carbonate in normal subjects
and patients with chronic renal failure. Clin Sci 30:425-438, 1966 13. Gipson RM, Coburn lW, Adams AA, et al: Calciphylaxis in man: A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 136: 1273-1280, 1976 14. Renaud H, Atik A, Herve M, et al: Evaluation of vascular calcinosis risk factors in patients on chronic hemodialysis: Lack of influence of calcium carbonate. Nephron 48:28-32, 1988 15. Campistol 1M, Almirall 1, Martin E, et al: Calcium carbonate-induced calciphylaxis. Nephron 51:549-550, 1989 16. Massry SG, Cobern lW, Popovtzer MM, et al: Secondary hyperparathyroidism in chronic renal failure. Arch Intern Med 124:431-441, 1969 17. Slatopolsky E, Weerts C, Norwood K, et al: Long-term effects of calcium carbonate and 2.5 mEq/liter calcium dialysate on mineral metabolism. Kidney Int 36:897-903, 1989 18. Mactier RA, Van Stone 1, Cox A, et al: Calcium carbonate is an effective phosphate binder when dialysate calcium concentration is adjusted to control hypercalcemia. Clin Nephrol 28:222-226, 1987 19. Wens R, Bergmann P, Dratwa M, et al: Variations of intact PTH levels during hemodialysis: Effects of dialysate calcium. Kidney Int 37:324, 1990 (abstr) 20. Milito G, Taccone-Gallucci M, Brancaleone C, et al: Assessment of the upper gastrointestinal tract in hemodialysis patients awaiting renal transplantation. Am 1 Gastroenterol 78:328-331, 1983 21. Gold CH, Morley IE, Viljoen M, et al: Gastric acid secretion and serum gastrin levels in patients with chronic renal failure on regular hemodialysis. Nephron 25:92-95, 1985 22. Molitoris BA, Froment DH, MacKenzie TA, et al: Citrate: A major factor in the toxicity of orally administered aluminum compounds. Kidney Int 36:949-953, 1989 23. Nolan CR, Califano lR, Butzin CA: Influence of calcium acetate or calcium citrate on intestinal aluminum absorption. Kidney Int 38:937-941, 1990