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Magnesium absorption and metabolism in patients with chronic renal failure and in patients with normal renal function
GASTROENTEROLOGY
7926~34,1999
Magnesium Absorption and Metabolism in Patients with Chronic Renal Failure and in Patients with Normal Renal Function HERTA SPENCER, MARGARET LESNIAK, CAROL A. GATZA, DACE OSIS, AND MENAHEM LENDER Metabolic
Section,
Veterans
Administration
The intestinal absorption of magnesium was determined under strictly controlled dietary conditions in patients with chronic renal disease and in patients with normal renal function. The average net absorption of magnesium of patients with chronic renal failure was significantly lower (1% of magnesium intake) than the absorption of patients with normal renal function (48.5%). The lower absorption of magnesium of patients with chronic renal failure was due to the significantly higher fecal magnesium excretion, averaging 82.5% of the magnesium intake, compared with an average of 51.5% for patients with normal renal function. The fecal/urinary magnesium excretion ratio for patients with normal renal function was close to 1.0, whereas it averaged 1.75 for patients with chronic renal failure, which indicates a shift of the magnesium excretion from the kidney to the intestine. The magnesium balance did not differ signi@antly from that of age-matched patients with normal kidney function receiving a similar or higher magnesium intake. In a long-term study of a patient with chronic renal failure, the net absorption of magnesium was greater during a higher magnesium intake than during the lower magnesium intake; however, the magnesium absorption was only half the value, 24% vs. 48%, for patients with normal renal function receiving the same magnesium intake. Increasing the calcium intake from 200 to 800, 1400, and 2000 mg/day did not change the magnesium balance or the net absorption of magneReceived June 5, 1979. Accepted February 5, 1980. Address requests for reprints to: Herta Spencer, M.D., Chief, Metabolic Section, Box #35, Veterans Administration Hospital, Hines, Illinois 60141. This study was supported by U.S. Public Health Service Grant DE-02486 0 1980by the American Gastroenterological Association 0016-5085/80/070026-09$02.25
Hospital,
Hines, Illinois
sium of patients with chronic renal failure and of patients with normal renal function. Only a few reports have been published on magnesium metabolism of patients with chronic renal disease studied by determining metabolic balances in comparison with the metabolism of persons with normal renal function. In one of these studies, the urinary magnesium excretion was reported to be low, the magnesium balance to be normal, and the intestinal absorption of magnesium to be reduced compared with normals.’ In another study, metabolic balances of magnesium of patients with chronic renal failure were reported, but no data of normals were presented.2 The magnesium excretions of the patients with chronic renal failure as well as the absorption of magnesium were reported to be normal.’ In an intestinal perfusion study the jejunal absorption of magnesium was significantly lower than that of patients with normal renal function.” In a study of the correlation of the serum and urinary magnesium in patients with chronic renal disease the fractional urinary magnesium excretion was higher than in normals. In the present study, magnesium balances were determined under strictly controlled conditions in patients with chronic renal disease and in agematched patients with normal renal function in order to compare the magnesium excretions in urine and stool, the magnesium balances, the net absorption of magnesium, and the effect of different calcium intakes on these parameters.
Materials and Methods Sixteen magnesium balance studies were carried out in 8 male patients with chronic renal failure (Table 1)
July 1990
MAGNESIUM ABSORPTION AND KIDNEY FUNCTION
under strictly controlled dietary conditions in the Metabolic Research Ward. (The studies were carried out in compliance with DHEW guidelines and informed consent has been obtained.) Ten of these studies were carried out during a low magnesium intake averaging 159 mg/day and a low calcium intake averaging 200 mg/day (Table Z), and six were carried out during a similar dietary magnesium intake but during different calcium intakes ranging from 800 to 2000 n&day (Table 3). In one of the studies carried out during the 606 mg calcium intake, the magnesium intake was inadvertently higher, averaging 310 mg/day, owing to the analyzed magnesium content of the calcium gluconate tablets that were used to achieve the 600 mg calcium intake. Thirty-three control studies were carried out in patients with normal renal function, 10 of these during a low calcium intake averaging 200 mg calcium/day (Table 2) and 17 of these during different calcium intakes ranging from 600 to ~000 mg/day (Table 4). In two of the studies carried out during the 600 mg calcium intake, the magnesium intake averaged 311 mg/day (Table 4), similar to the relatively high magnesium intake of a patient with chronic renal failure. Ten of the patients with normal renal function were age matched with the patients with chronic renal failure but had received a normal magnesium intake, averaging 283 mg/day, which was contained in the metabolic diet (Table 2). In 3 patients the dietary magnesium intake was matched to that of patients with chronic renal failure, 159 mg/day (group l), and 3 others (group 2) received a somewhat higher magnesium intake averaging 191 mg/day (Table 2). The patients with chronic renal failure were fully ambulatory, in good physical condition, and had normal gastrointestinal and liver function. These patients were in a steady state during the study; they did not undergo dialysis. They did not receive any medications, except for patient 7 who received propanolol, 60 mg/day, hydralazine, 100 mg/day, and Lasix, 40 mg/day. The age of the patients, ranging’ from 47 to 67 yr and averaging 57 yr, and the serum levels of creatinine, blood urea nitrogen, magnesium, calcium, phosphorus, and alkaline phosphatase are listed in Table 1. The serum levels of creatinine were elevated, ranging from 2.4 to 14.8 mg/lOO ml, as were the levels of the blood urea nitrogen (BUN), which ranged from 26 to 108 mg/ltKl ml. The creatinine clearance ranged from
Table
1.
List of Patients
with Chronic
Age
1 2 3 4
67 63 57 47
5
55
6 7 6
51 50 65
(kg) 69.5 77.5 63.2 75.6 77.4 66.5 70.2 62.7 75.6 62.9
5 to 54 ml/min. The patients with normal renal function were volunteers, they were fully ambulatory adult males who had normal renal, gastrointestinal, and liver functions, and the results of all clinical and laboratory tests performed on these volunteers were normal. The duration of the studies of the patients with chronic renal failure averaged 26 days during the low calcium intake and 72 days during the higher calcium intakes. For patients with normal renal function, the duration of all studies carried out during the low calcium intake averaged 40 days and during the higher calcium intakes the average was 26 days. The patients with chronic renal failure received a constant, analyzed, low-protein diet containing 40-50 g protein/day, depending on the serum creatinine level, an average of 2043 kcal, 310 g carbohydrate, 67 g fat, 172 mg magnesium, 179 mg calcium, 520 mg phosphorus, 45 meq sodium, and 50 meq potassium. The food items contained in the.metabolic diet of this Research Unit5 were used in this low-protein diet. The patients with normal renal function received the constant metabolic low-calcium diet that contained 2223 kcal, an average of 71 g protein, 325 g carbohydrate, 71 g fat, 230 mg magnesium, 220 mg calcium, and 800 mg phosphorus per day.’ Both groups of patients received the constant, analyzed diet in the Metabolic Research Ward for several weeks before the start of the study and throughout the time period of the magnesium balance studies. This diet was analyzed for magnesium, calcium, phosphorus, and nitrogen in each 6-day metabolic study period. The daily fluid intake of all patients was kept constant throughout the studies. The drinking water was demineralized, and all beverages were prepared with this water. The low calcium intake of 200 mg/day was that contained in the metabolic diet, all higher calcium intakes were achieved by adding calcium gluconate tablets to this diet. When higher calcium intakes were given, each patient served as his own control. All urine and stool specimens were collected from the start of the study. The body weight, 24hr urine volume, and urinary excretions of creatinine were determined daily. Metabolic balances of magnesium were determined in each 6day study period on aliquots of the diet and on aliquots of 6-day collection pools of urine and stool. Magnesium and calcium in the diet, urine, stool, and serum were determined by atomic absorption spectroscopy,“*’
Renal Failure
Body Weight Patient
27
Serum Values (mg/109 ml) BUN .43 79 40 49 106 64 78 96 26 26
a International units, normal values 50-90 IU.
Creatinine
Ca
P
4.5 6.5 5.7 6.5 14.0 7.4 13.0 14.8 2.4 2.4
9.5 6.3 9.0 6.9 8.6 6.9 6.3 9.3 9.9 9.6
3.5 5.2 3.8 6.5 8.5 5.1 5.5 5.6 3.6 3.5
w 2.7 1.9 2.5 2.2 2.4 2.2 2.3 2.2 2.3 1.9
Alkaline Phosphatase (IUT 85 129, NH3 69 59 112 120 65 119 96
Creatinine Clearance (mI/min) 16 14 17 12 5 13 5 5 40 54
28
SPENCER
Table
2.
ET AL.
GASTROENTEROLOGY
Average Magnesium Balances and Net Absorption of Magnesium of Patients with Chronic Renal Failure and of Patients with Normal Renal Function During a Low Calcium Intake” Magnesium (mg/day)
Patient
Vol. 79, No. 1
Age
Study days
Intake
Urine
Stool
Mg Excretion (% of intake) Balance
Urine
Stool
Net absorption (%)
Patients with chronic renal failure 1 2 3 4
67 63 57 47
5
55
6 7
51 50
8
65
30 30 42 48 12 36 12 18 30 24
Average SEM
57
28
1 2 3 4 5 6 7 8 9 10 Average SEM
48 36 16 78
67 63 57 58 57 51 50 48 50 65
30 36 66 48 30 18
57
41
140 187 150 159 179 126 124 151 158
101 56 77 96 57 70 56 53 72
147 119 139 110 126 93 113 157 135
-108 +6 -66 -47 -4 -37 -45 -59 -49
72.2 29.9 51.3 60.4 31.8 55.6 45.2 35.1 45.5
213
79
157
-23
159 f8.7
72 f5.3
130 f6.7
-43 f10.2
189 196 220 342 336 228 264 295 304 253 263 f17.4
37.1
105.0 63.6 92.7 69.2 70.4 73.8 91.1 104.0 85.4 73.7
26 8 -4 15 26
46.4 f4.3
82.8 f4.6
17 f4.7
74.1 59.2 53.2 43.0
42.0 56.6 50.2
47.1 50.5 56.8 42.7 65.8 40.4 34.8 58.0 67.8 51.0
52.9 49.5 43.2 57.3 34.2 59.6 65.2 42.0 32.3
55.0 f2.9
51.5 h1.4
48.5 f3.4
61.3 69.7 51.6
61.3 57.4 45.3
39.0 42.5 55.0
-25 f14.9
60.9 f5.2
54.7 f4.8
45.5 f4.8
-19 -40 +a
59.2 74.1 48.9
50.5 47.1 46.8
49.5 52.9 53.2
-17 f13.6
60.7 f7.3
48.1 il.1
51.8 fl.1
Patients with normal renal function Age-matched 89 -40 140 99 -19 116 125 -22 117 146 +49 147 221 -78 193 92 +7 129 92 +19 153 171 0 124 206 -74 172 129 -3 127 137 f15.2
142 f7.9
57.4 56.6
-16 f12.5
Patients with normal renal function Intake-matched Group 1 100 -37 100 89 -42 108 73 +5 83
1 2 3
58 46 62
30 36 32
163 155 161
Average SEM
56
34
159 f2.4
1 2 3
70 49 69
36 48 24
196 189 186
116 140 92
Average SEM
63
36
191 f4.5
116 f13.8
87 f7.8
97 f7.3
Group 2 99 89 86 92 f3.5
-5 36 7 31 30
o Calcium intake = 220 mg/day.
phosphorus in the diet was determined by a modification of the method of Fiske and SubbaRow,8 and nitrogen in the diet was determined by the Kjeldahl method.’ The net absorption of magnesium was determined from the dietary magnesium intake and from the fecal magnesium excretions according to the following formula: -
Net absorption,% = magnesium intake - fecal magnesium
x loo.
magnesium intake Although the dietary items were purchased as one lot for
MAGNESIUM ABSORPTION AND KIDNEY FUNCTION
July 1980
the entire study year, the magnesium analysis in each 6day period revealed some variability in dietary magnesium content. The data for the magnesium balances and of the net absorption of magnesium were analyzed statistically, using Student’s unpaired t-test” when comparing the data of patients with chronic renal failure with those of patients with normal renal function. The paired Student’s t-test was used for studies carried out in the same subject during different
calcium
or magnesium
intakes.
Results Table 2 shows data of magnesium balance studies and of the net absorption of magnesium of patients with chronic renal failure and of patients with normal renal function determined during a low calcium intake averaging 200 mg/day. Patients with Chronic Renal Failure Owing to the low protein intake, the dietary magnesium intake was low, ranging from 124 mg to 187 mg/day, except for patient a who received a higher intake of 213 mg/day, and averaged 159 mg/ day. The urinary magnesium excretions, averaging 72 f 5.3 mg/day, corresponded to 46.4% of the magnesium intake, and the fecal magnesium excretions were high in relation to the magnesium intake, averaging 130 f 6.7 mg/day, and corresponded to 82.8% of the magnesium intake. The net absorption of magnesium was low, ranging from -5% to 36% and averaging 17% f 4.7%. The magnesium balances ranged from slightly positive to negative values and averaged -43 mg/day. This balance differed significantly
Table 3. Magnesium
Balances
of Patients
with Chronic
from zero. In 2 of the patients, magnesium balances were determined at different stages of the renal disease. For patient 4 the net absorption of magnesium was similar at a creatinine clearance of 12 ml/min and of 5 ml/min, 31% and 30%, respectively, while for patient 5, the net absorption was 26% when the creatinine clearance was 13 ml/min and was considerably lower, 8%, when the creatinine clearance had decreased to 5 ml/min. As the renal function deteriorated, the urinary magnesium excretion of both patients decreased.
Patients with Normal Renal Function The data of 10 age-matched patients, who received the same calcium intake as the patients with chronic renal failure but received a normal dietary magnesium intake averaging 263 mg/day (Table 2), show that the urinary magnesium, averaging 142 mg/day, was significantly greater than the excretion of patients with chronic renal disease (P < 0.001). However, expressed as percent of the magnesium intake, the urinary magnesium excretion of both groups did not differ significantly. The fecal magnesium excretions and the magnesium balances of both groups did not differ significantly, but the fecal magnesium excretions expressed as percent of the magnesium intake was significantly lower for patients with normal renal function, averaging 51.5% of the magnesium intake vs. 82.8% for patients with chronic renal failure (P < 0.001). The net absorption of magnesium of the patients with normal renal function was therefore significantly greater, averag-
Renal Failure During Different Calcium
Magnesium (mg/day)
Intakes
Mg Excretion (X intake)
Calcium intake (ma/day)
Study days
Intake
140 *3.9 161 zt5.0 3100 zt1.4 190 fO.OO1 189 f12.0
Urine
200
30
101 f7.0 105 f4.5 103 f1.4 112 f8.9 100 fl.O
800
42
600
308
1400
138
2000
102
200 2000
30 42
150 177
77 62
2cQ 800
36 36
158 176
72 77
29
Stool Patient 1 147 f8.1 170 f6.0 243 f5.4 173 f2.4 184 f2.0 Patient 2 139 173 Patient 7 135 147
Balance
Urine
stool.
Net absorption (%)
-108 f10.9 -114 *3.5 -36 *4.0 -95 f11.2 -95 *9.0
72.1 f4.7 65.1 f4.8 33.2 f0.5 59.1 f4.6 53.0 f2.8
105.0 f5.8 105.6 f0.4 78.4 f1.4 91.2 f1.2 97.6 f5.1
-5.4 f4.4 -6 *0.5 21.4 zt1.3 9 il.4 3 *4.5
-66 -58
51.3 35.0
92.7 97.7
7 2
-49 -48
45.5 43.7
85.4 83.5
15 16
a Higher magnesium intake owing to the inadvertent magnesium content of the specific lot of calcium gluconate tablets used to increase the calcium intake from 200 to 800 mg/day. Values are means k SEM.
30
SPENCER ET AL.
GASTROENTEROLOGY Vol. 79, No. 1
ing 48.5%vs.17%, for patients with chronic renal failure (P C 0.001). The data of patients with normal renal function in whom the magnesium intake was.matched to that of patients with chronic renal failure (Table 2) showed similar results. The urinary magnesium excretion was greater than that of patients with chronic renal failure, 97 vs. 72 mg/day, while the fecal magnesium excretion was significantly lower, a7vs.130mg/day, corresponding to 54.7% vs. 82.8%of the magnesium intake for patients with normal and for those with abnormal renal function, respectively. The net absorption of magnesium of 3 patients with normal renal function in whom the magnesium intake was matched (group 1) was significantly greater, 45.5% vs. l7%, for the patients with chronic renal failure (P < 0.001). Similar results of the magnesium excretions and absorption were also obtained in 3 patients with normal renal function who received a slightly higher magnesium intake averaging 191 mg/day (group 2). Both th e f ecal magnesium excretion and the net absorption of this group also differed significantly from the values obtained in the patients with chronic renal failure (P < O.OOl),the average absorption being 51.6% vs. 17%, respectively. The magnesium balance of both groups of patients with normal renal function was less negative than that of the patients with chronic renal failure, and these balances did not differ significantly from those of patients with chronic renal failure. Table 3 shows data of magnesium balances and of the net absorption of magnesium of 3 patients with chronic renal failure studied during different cal4.
Table
Number of studies
Magnesium Age of patients (yr)
Balances
of Patients
cium intakes. The data of the magnesium balance studies, determined during the low calcium intake of 200 mg/day, are shown for comparison for each patient. In patient 1, multiple high calcium studies were carried out over a 2-yr period. During a relatively low magnesium intake ranging from 161 to 190 mg/day and during calcium intakes of aoo,l4OO, and 2000 mg/day, the urinary magnesium excretion was approximately the same as during the low calcium intake. Expressed as percent of the magnesium intake, the urinary magnesium ranged from 53.0% to 72.1% during the different calcium intakes and was lowest during the 2000 mg calcium intake. The fecal magnesium excretion during the 600 and 1400 mg calcium intake were about the same, while it was slightly greater during the 2000 mg calcium intake, la4 mg/day vs. 170 mg/day during the lower calcium intakes. The fecal magnesium excretions as percent of intake were very high during all calcium intakes, ranging from 97.6% to 105% of the magnesium intake. The magnesium balances during the different calcium intakes were in a similar range as during the low calcium intake. In the long-term study’carried out during a higher magnesium intake averaging 310 mg/day and a calcium intake of 600 mg/day, the urinary magnesium excretion did not differ from the excretion during the lower magnesium intakes, however, expressed as percent of the magnesium intake, this excretion was significantly lower (P c 0.005). The fecal magnesium excretion was markedly increased during the higher magnesium intake, however, expressed as percent of the magnesium intake, the fecal magnesium was dis-
with Normal Renal Function
During Diflerent
Magnesium (mg/day) Study days
Intake
Urine
Stool
Calcium
Intakes
Mg Excretion (%intake) Balance
Urine
Stool
Net absorption (V
Age-matched patients 3
58
24
241 SEM f18.8
3
88
39
197 SEM f19.8
5
82
22
255 SEM f5.0
1 2
53 84
24 72
199 3110 SEM ~~1.5
3
84
24
184 SEM f4.3
800 mg Calcium intake 142 118 f19.8 f10.3 1400 mg Calcium intake 133 89 f17.8 f9.4 2000 mg Calcium intake 115 131 f10.0 rt2.2 Intake-matched patients 800 mg Calcium intake 125 95 184 181 f12.0 fl8.0 1400 mg Calcium intake 98 84 f3.1 f13.2
-19 f8.1
58.3 f4.4
48.8 f2.7
51.1 f2.7
-25 f10.8
87.1 f2.8
45.5 f3.0
54.5 f3.0
+8 f13.2
45.7 f4.7
51.4 f0.8
47.8 zt1.2
-21 -14 zt5.5
72.9 52.8 zt3.8
47.7 51.9 f5.4
52.3 48.1 f5.4
-18 f13.3
59.8 f1.8
50.9 f8.8
49.1 f8.8
QHigher magnesium intake was due to the magnesium content of the calcium gluconate tablets.
July 1980
MAGNESIUM
tinctly less than during the lower magnesium intakes. The magnesium balance was also distinctly less negative during the higher magnesium intake. The magnesium balances and the net absorption of magnesium differed significantly during the two magnesium intakes (P c 0.001). The net absorption of magnesium was very low in all studies during all calcium intakes used during the low magnesium intake, ranging from -6% to 16%,and was greater, averaging 21.4%,during the higher magnesium intake of 310 mg/day. The serum magnesium level did not significantly change during the higher magnesium intake. In patients 2 and 7 (Table 3) during a calcium intake of 2000 mg and 600 mg per day, respectively, the urinary magnesium was the same as during the low calcium intake of 200 mg/day. The fecal magnesium excretion of both patients was slightly greater during the higher calcium intakes. As percent of the magnesium intake, these excretions were very high for both patients during both the low and high calcium intakes, and the net absorption of magnesium was therefore low but similar during the low and higher calcium intakes. The magnesium balances remained unchanged. Table 4 shows data of magnesium balances of two groups of patients with normal renal function studied during calcium intakes ranging from 600 to 2000 mg/day. One group was age-matched with the patients with chronic renal failure, and in one group the magnesium intake was matched. The agematched patients had received a normal diet, and therefore the dietary magnesium intake was greater than that of the patients with chronic renal failure. In both groups of patients with normal renal function receiving the different calcium intakes, the fecal magnesium excretion was either lower than the urinary magnesium excretion or these excretions were
ABSORPTION
AND KIDNEY FUNCTION 31
in a ratio of about 1: 1. The net absorption of magnesium of the patients with normal renal function was high, ranging from 47.6% to 54.5% of the magnesium intake. The fecal magnesium excretion and the net absorption of magnesium of the patients receiving the 600 mg calcium intake differed significantly from those of patients with chronic renal failure P c 0.025). Similarly, during the 1400 and 2CWOmg calcium intake, the fecal magnesium excretions and the net absorption of magnesium also differed significantly from those of patients with chronic renal failure (P c O.OOl),while the urinary magnesium excretion did not differ significantly during any of the calcium intakes. Figure 1 summarizes the data of the magnesium absorption of patients with chronic renal failure compared with that of patients with normal renal function. During all calcium intakes, ranging from 200 to 2000 mg/day, the net absorption of magnesium of the patients with chronic renal failure was significantly lower than that of the patients with normal renal function, irrespective of the magnesium intake of these patients. This figure also shows that the magnesium absorption in chronic renal failure had improved during a relatively high magnesium intake of 310 mg/day, however, this absorption was significantly lower than the magnesium absorption in patients with normal renal function receiving the same magnesium intake.
Discussion The present studies have shown that the net absorption of magnesium of patients with chronic renal failure is significantly lower than that of patients with normal renal function receiving the same or a higher dietary magnesium intake. The significantly lower net absorption of magnesium of 17% for
Chronic Renal Failure Mg
intake F&l LOW
Normal Renal Functian _Mp
Intake _!t!g_!!!!&L Normal H&&l Law
300 Figure 1. Summary of net absorption of magnesium of patients with chronic renal disease and of patients with normal renal function determined during different calcium intakes. Data of magnesium absorption obtained during a relatively high magnesium intake of 310 mg/day in chronic renal failure and in control studies are also shown.
s” ‘200 e i .3 H
loo
Ca Intatmin 100 mg/cdq1 Net AbaorptianY :
2el420
I7 I9 9
2
8
24
2’8
I4 2
49 9249
5!
32 SPENCER ET AL.
patients with chronic renal failure compared with an absorption of 46.6% for patients with normal renal function during a similar magnesium intake and compared with 46.5% during a higher magnesium intake was demonstrated by the very high fecal magnesium excretions as percent of the magnesium intake. The low magnesium absorption of the patients with chronic renal failure was a result of the very high fecal magnesium excretions as percent of the magnesium intake. The magnesium absorption of approximately 50% of patients with normal renal function is in agreement with data reported by others’ and with “Mg absorption studies carried out in this Research Unit.” The magnesium balances of the two groups of patients did not differ significantly owing to the lower urinary magnesium excretion of patients with chronic renal failure in agreement with results reported by others.’ The patients with chronic renal failure in this latter study were in positive magnesium balance,’ in contrast to the negative magnesium balances in the present study. However, in several of their cases the magnesium intake was also greater’ than in the present study. In evaluating the apparently persistent negative magnesium balance of patient 1 (Table Z), this patient may have replenished his magnesium stores whenever he was outside the hospital in the interims between studies performed in the Metabolic Ward. The low absorption of magnesium of patients with chronic renal failure observed in the present study is in agreement with data reported by several investigatorS,"3.12.13 but is in contrast to results reported by others.* In one study the net absorption of magnesium of patients with chronic renal failure was low, ranging from 16% to 34% of the magnesium intake compared with an absorption value of 50% for patients with normal renal function.’ In another study the absorption of magnesium of uremic patients was slightly decreased.” In a “Mg study the intestinal absorption of 4 of 7 patients with chronic renal failure was lower than of patients with normal renal function.13 In vivo intestinal perfusion studies have shown that the rate of jejunal magnesium absorption of patients with chronic renal failure was decreased to less than half that of patients with normal renal function.3 The mechanism which is operative in decreasing the intestinal absorption of magnesium in renal failure is not clear. Vitamin D may play a role, however, contradictory results have been reported. Vitamin D consistently increased the absorption of magnesium in rats.” Large doses of vitamin D markedly decreased the fecal magnesium in the rat and increased the urinary magnesium, indicating that vitamin D increased the intestinal absorption of
GASTROENTEROLOGYVole79,No. 1
magnesium.” In rachitic chicks, vitamin D increased the duodenal absorption of magnesium.le In vitamin D-deficient baby pigs, the low magnesium retention was greatly improved by vitamin D.17In humans, the use of the vitamin D metabolite lcu-hydroxy-D, resulted in hypermagnesemia and magnesium toxicity in a patient with chronic renal failure,“’ presumably on the basis of increased magnesium absorption. However, this vitamin D metabolite did not increase the absorption of magnesium in short-term studies in animals, and these authors report that this vitamin D metabolite also did not affect the absorption of magnesium in patients with chronic renal failure.19 Lack of vitamin D metabolite 1,25dihydroxyI& in the kidney of patients with chronic renal failureU’may contribute to the low absorption of magnesium of these patients. One report states that the slightly reduced magnesium absorption of uremic patients increased after successful renal transplantation.” This observation may indicate that the improvement in magnesium absorption may have been mediated by the availability of the vitamin D metabolite 1,25-dihydroxy-D, after renal transplantation. In patients with chronic renal failure undergoing hemodialysis using a regional perfusion technique, the administration of 1,25-dihydroxy-D, increased the low serum concentration of this vitamin D metabolite and restored the significantly decreased jejunal absorption of magnesium to normal levels (Fordtran JS, et al: Unpublished data). Other possible mechanisms for the lower absorption of magnesium in chronic renal failure have been suggested. The intestinal absorption of magnesium may be related to the ability of the kidney to excrete magnesium, and the decreased renal excretory function in renal failure may therefore play a role in lowering the intestinal absorption of magnesium.‘l Reduced entry of magnesium into the intestinal mucosal cells as a result of increased magnesium levels in the extracellular fluid may also play a role. In “Mg kinetic studies in patients with uremia and hypermagnesemia, the fractional cell influx of magnesium has been reported to be reduced.” Both the ionic and total serum magnesium levels of patients with renal failure are increased, the increase of the total magnesium concentration being greater than that of ionic magnesium.z3 The reported improvement of the absorption of magnesium after chronic hemodialysis” may in part be explained by lowering of the serum and extracellular fluid magnesium levels after this procedure. Of interest is the observation of the increase in magnesium absorption in chronic renal failure during a higher magnesium intake of 310 mg/day (patient 1, Table 3) compared with the magnesium ab-
July 1980
sorption during a lower magnesium intake in the same patient. The increased magnesium absorption was evidenced by the considerably lower fecal magnesium excretion as percent of the intake than during the lower magnesium intake. Despite this increase, the magnesium absorption was still one-half the absorption of patients with normal renal function receiving a similar magnesium intake (Table 4 and Figure 1).The mechanism for the increase in magnesium absorption during the higher magnesium intake in patients with chronic renal failure is not known and may be similar to that for the higher absorption of calcium during a higher calcium intake.“” In patients with normal renal function, a higher magnesium intake can lead to enhanced magnesium absorption. An intestinal perfusion study in which the magnesium content of the solution was increased demonstrated that the absorption of magnesium increased in patients with normal renal function.” The reason for the normal or elevated serum magnesium levels of patients with chronic renal failure in the presence of the low absorption of magnesium is not clear. Other investigators found that the serum magnesium level of patients with chronic renal failure did not differ significantly from those of normals,25 and stated that the remaining normal nephrons in chronic renal failure are able to increase the urinary magnesium excretion. When the renal function deteriorates further, this compensatory increase becomes insufficient and the serum magnesium level increases.25 The present data show, in agreement with previous results reported by others,4 that the fractional urinary magnesium excretion of patients with chronic renal failure was considerably greater than that of the control subjects. The patients with chronic renal failure excreted an average of 46.4% of the magnesium intake and absorbed only l7%, while the urinary magnesium excretion of the control subjects was only somewhat higher, 55%, and the absorption averaged 46.5% of the magnesium intake. The lack of effect of increasing the calcium intake on the magnesium balance of patients with chronic renal failure observed in this study is in agreement with results reported by others.‘-3 Similar results were also obtained in this Research Unit in magnesium balance studies” in patients with normal renal function and in magnesium absorption studies using “Mg as the tracer.” The latter study showed that the intestinal absorption of “Mg averaged 46% of the dose during a low calcium intake of 266 mg/day and remained unchanged when the calcium intake was increased to 2606 mg/day. In contrast, in magnesium depletion in humans, the fecal magnesium excretion increased during a high calcium intake, indicating
MAGNESIUM ABSORPTION AND KIDNEY FUNCTION 33
that calcium decreases the intestinal magnesium under these conditions.*7
absorption
of
References 1. Clarkson EM, McDonald SJ, dewardener HE, et al: Magnesium metabolism in chronic renal failure. Clin Sci 28107-115, 1965 2. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia. II. Calcium, phosphorus, and magnesium. Medicine (Baltimore) 52597607, 1973 3. Brannan PG, Vergne-Marini P, Pak CYC, et al: Magnesium absorption in the human small intestine. J Clin Invest 57:1412-1418, 1976 4. Popovtzer MM, Massry SG, Coburn JW, et al: The interrelationship between sodium, calcium, and magnesium excretion in advanced renal failure. J Lab Clin Med 73:763-771, 1969 5. Spencer H, Friedland JA, Ferguson V: Human balance studies in mineral metabolism. In: Biological Mineralization. Edited by I Zipkin. New York, John Wiley & Sons, Inc., 1973, p 889727 6. Willis JB: Determination of metals in blood serum by atomic absorption spectroscopy. I. Calcium. II. Magnesium. Spectrochim Acta 16259-272, 1960 7. Willis JB: Determination of calcium and magnesium in urine by atomic absorption spectroscopy. Anal Chem 33:558-559. 1961 8. Fiske CH, SubbaRow YT: The calorimetric determination of phosphorus. J Biol Chem 66:375-400, 1925 9. Henry RJ: Protein by Kjeldahl determination of protein-nitrogen. In: Clinical Chemistry-Principles and Technics. New York, Harper & Row, 1964, p 175-179 10.Snedecor GW: Statistical Methods. Fifth edition. Ames, Iowa, Iowa State University Press, 1959 11.Spencer H, Schwartz R, Norris C, et al: Studies of magnesium metabolism in man using “Mg as the tracer. Radiat Res 74:557-558,1978 12.Randall RE Jr: Magnesium metabolism in chronic renal disease. Ann NY Acad Sci 162:831-946, 1969 13.Mountokalakis Th. Singhellakis PN, Alevizaki CC, et al: Absorption intestinale du magnesium chez des malades en insuffisance renale chronique. Rev Fr Endocrinol Clin 17:229232,1976 14.Meintzer RB, Steenbock H: Vitamin D and magnesium absorption J Nutr 56285-294, 1955 15.Hanna S: Influence of large doses of vitamin D on magnesium metabolism in rats. Metabolism 10:735-743, 1961 16.Wasserman RH: Studies on vitamin D3 and the intestinal absorption of calcium and other ions in the rachitic chick. J Nutr 77:69-86, 1962 17.Miller ER, Ullrey DE, Zutaut CL, et al: Mineral balance studies with the baby pig: Effects of dietary vitamin D2 level upon calcium, phosphorus and magnesium balance. J Nutr 85:255259, 1965 J: Iatrogenic 18.Sorensen E, Tougaard L, Brochner-Mortensen magnesium intoxication during I-a-hydroxycholecalciferol treatment. Br Med J 2:215, 1976 19.Kanis JA, Smith R, Walton RJ, et al: Magnesium intoxication during l-a-hydroxycholecalciferol treatment. Br Med J 2:878, 1976 20.Mawer EB, Backhouse J, Taylor CM, et al: Failure of forma-
34
SPENCER ET AL.
GASTROENTEROLOGY
Vol. 79, No. 1
tion of 1,25-dihydroxycholecalciferol in chronic renal inlarge intake of calcium citrate in normal subjects and patients sufficiency. Lancet 1:626-6251973 with chronic renal failure. Clin Sci 26:27-39, 1964 25.Steele TH, Wen SF, Evenson MA, et al: The contribution of 21. Ring RG, Stanbury SW: Magnesium metabolism in primary hyperparathyroidism. Clin Sci 39~281-303, 1970 the chronically diseased kidney to magnesium homeostasis in 22.Wallach S, Rizek JE, Dimich A, et al: Magnesium transport in man. J Lab Clin Med 71:455-463, 1905 normal and uremic patients. J Clin Endocr 26:1089-1060,19l36 26. Spencer H, Lesniak M, Gatza C, et al: Magnesium-calcium inhyterrelationships in man. In: Trace Substances in Rnvironmen23.Walser M: The separate effects of hyperparathyroidism, tal Health-XII. Edited by DD Hemphill. Columbia, Univerpercalcemia of malignancy, renal failure, and acidosis on the state of calcium, phosphate, and other ions in plasma. J Clin sity of Missouri, 1978, p 241-247 27. Dunn MJ, Walser M: Magnesium depletion in normal man. 1962 Invest 41:1454-1471, 24.McDonald SJ, Clarkson EM, dewardener HE: The effect of a Metabolism 15:884-895, 1966
7926~34,1999
Magnesium Absorption and Metabolism in Patients with Chronic Renal Failure and in Patients with Normal Renal Function HERTA SPENCER, MARGARET LESNIAK, CAROL A. GATZA, DACE OSIS, AND MENAHEM LENDER Metabolic
Section,
Veterans
Administration
The intestinal absorption of magnesium was determined under strictly controlled dietary conditions in patients with chronic renal disease and in patients with normal renal function. The average net absorption of magnesium of patients with chronic renal failure was significantly lower (1% of magnesium intake) than the absorption of patients with normal renal function (48.5%). The lower absorption of magnesium of patients with chronic renal failure was due to the significantly higher fecal magnesium excretion, averaging 82.5% of the magnesium intake, compared with an average of 51.5% for patients with normal renal function. The fecal/urinary magnesium excretion ratio for patients with normal renal function was close to 1.0, whereas it averaged 1.75 for patients with chronic renal failure, which indicates a shift of the magnesium excretion from the kidney to the intestine. The magnesium balance did not differ signi@antly from that of age-matched patients with normal kidney function receiving a similar or higher magnesium intake. In a long-term study of a patient with chronic renal failure, the net absorption of magnesium was greater during a higher magnesium intake than during the lower magnesium intake; however, the magnesium absorption was only half the value, 24% vs. 48%, for patients with normal renal function receiving the same magnesium intake. Increasing the calcium intake from 200 to 800, 1400, and 2000 mg/day did not change the magnesium balance or the net absorption of magneReceived June 5, 1979. Accepted February 5, 1980. Address requests for reprints to: Herta Spencer, M.D., Chief, Metabolic Section, Box #35, Veterans Administration Hospital, Hines, Illinois 60141. This study was supported by U.S. Public Health Service Grant DE-02486 0 1980by the American Gastroenterological Association 0016-5085/80/070026-09$02.25
Hospital,
Hines, Illinois
sium of patients with chronic renal failure and of patients with normal renal function. Only a few reports have been published on magnesium metabolism of patients with chronic renal disease studied by determining metabolic balances in comparison with the metabolism of persons with normal renal function. In one of these studies, the urinary magnesium excretion was reported to be low, the magnesium balance to be normal, and the intestinal absorption of magnesium to be reduced compared with normals.’ In another study, metabolic balances of magnesium of patients with chronic renal failure were reported, but no data of normals were presented.2 The magnesium excretions of the patients with chronic renal failure as well as the absorption of magnesium were reported to be normal.’ In an intestinal perfusion study the jejunal absorption of magnesium was significantly lower than that of patients with normal renal function.” In a study of the correlation of the serum and urinary magnesium in patients with chronic renal disease the fractional urinary magnesium excretion was higher than in normals. In the present study, magnesium balances were determined under strictly controlled conditions in patients with chronic renal disease and in agematched patients with normal renal function in order to compare the magnesium excretions in urine and stool, the magnesium balances, the net absorption of magnesium, and the effect of different calcium intakes on these parameters.
Materials and Methods Sixteen magnesium balance studies were carried out in 8 male patients with chronic renal failure (Table 1)
July 1990
MAGNESIUM ABSORPTION AND KIDNEY FUNCTION
under strictly controlled dietary conditions in the Metabolic Research Ward. (The studies were carried out in compliance with DHEW guidelines and informed consent has been obtained.) Ten of these studies were carried out during a low magnesium intake averaging 159 mg/day and a low calcium intake averaging 200 mg/day (Table Z), and six were carried out during a similar dietary magnesium intake but during different calcium intakes ranging from 800 to 2000 n&day (Table 3). In one of the studies carried out during the 606 mg calcium intake, the magnesium intake was inadvertently higher, averaging 310 mg/day, owing to the analyzed magnesium content of the calcium gluconate tablets that were used to achieve the 600 mg calcium intake. Thirty-three control studies were carried out in patients with normal renal function, 10 of these during a low calcium intake averaging 200 mg calcium/day (Table 2) and 17 of these during different calcium intakes ranging from 600 to ~000 mg/day (Table 4). In two of the studies carried out during the 600 mg calcium intake, the magnesium intake averaged 311 mg/day (Table 4), similar to the relatively high magnesium intake of a patient with chronic renal failure. Ten of the patients with normal renal function were age matched with the patients with chronic renal failure but had received a normal magnesium intake, averaging 283 mg/day, which was contained in the metabolic diet (Table 2). In 3 patients the dietary magnesium intake was matched to that of patients with chronic renal failure, 159 mg/day (group l), and 3 others (group 2) received a somewhat higher magnesium intake averaging 191 mg/day (Table 2). The patients with chronic renal failure were fully ambulatory, in good physical condition, and had normal gastrointestinal and liver function. These patients were in a steady state during the study; they did not undergo dialysis. They did not receive any medications, except for patient 7 who received propanolol, 60 mg/day, hydralazine, 100 mg/day, and Lasix, 40 mg/day. The age of the patients, ranging’ from 47 to 67 yr and averaging 57 yr, and the serum levels of creatinine, blood urea nitrogen, magnesium, calcium, phosphorus, and alkaline phosphatase are listed in Table 1. The serum levels of creatinine were elevated, ranging from 2.4 to 14.8 mg/lOO ml, as were the levels of the blood urea nitrogen (BUN), which ranged from 26 to 108 mg/ltKl ml. The creatinine clearance ranged from
Table
1.
List of Patients
with Chronic
Age
1 2 3 4
67 63 57 47
5
55
6 7 6
51 50 65
(kg) 69.5 77.5 63.2 75.6 77.4 66.5 70.2 62.7 75.6 62.9
5 to 54 ml/min. The patients with normal renal function were volunteers, they were fully ambulatory adult males who had normal renal, gastrointestinal, and liver functions, and the results of all clinical and laboratory tests performed on these volunteers were normal. The duration of the studies of the patients with chronic renal failure averaged 26 days during the low calcium intake and 72 days during the higher calcium intakes. For patients with normal renal function, the duration of all studies carried out during the low calcium intake averaged 40 days and during the higher calcium intakes the average was 26 days. The patients with chronic renal failure received a constant, analyzed, low-protein diet containing 40-50 g protein/day, depending on the serum creatinine level, an average of 2043 kcal, 310 g carbohydrate, 67 g fat, 172 mg magnesium, 179 mg calcium, 520 mg phosphorus, 45 meq sodium, and 50 meq potassium. The food items contained in the.metabolic diet of this Research Unit5 were used in this low-protein diet. The patients with normal renal function received the constant metabolic low-calcium diet that contained 2223 kcal, an average of 71 g protein, 325 g carbohydrate, 71 g fat, 230 mg magnesium, 220 mg calcium, and 800 mg phosphorus per day.’ Both groups of patients received the constant, analyzed diet in the Metabolic Research Ward for several weeks before the start of the study and throughout the time period of the magnesium balance studies. This diet was analyzed for magnesium, calcium, phosphorus, and nitrogen in each 6-day metabolic study period. The daily fluid intake of all patients was kept constant throughout the studies. The drinking water was demineralized, and all beverages were prepared with this water. The low calcium intake of 200 mg/day was that contained in the metabolic diet, all higher calcium intakes were achieved by adding calcium gluconate tablets to this diet. When higher calcium intakes were given, each patient served as his own control. All urine and stool specimens were collected from the start of the study. The body weight, 24hr urine volume, and urinary excretions of creatinine were determined daily. Metabolic balances of magnesium were determined in each 6day study period on aliquots of the diet and on aliquots of 6-day collection pools of urine and stool. Magnesium and calcium in the diet, urine, stool, and serum were determined by atomic absorption spectroscopy,“*’
Renal Failure
Body Weight Patient
27
Serum Values (mg/109 ml) BUN .43 79 40 49 106 64 78 96 26 26
a International units, normal values 50-90 IU.
Creatinine
Ca
P
4.5 6.5 5.7 6.5 14.0 7.4 13.0 14.8 2.4 2.4
9.5 6.3 9.0 6.9 8.6 6.9 6.3 9.3 9.9 9.6
3.5 5.2 3.8 6.5 8.5 5.1 5.5 5.6 3.6 3.5
w 2.7 1.9 2.5 2.2 2.4 2.2 2.3 2.2 2.3 1.9
Alkaline Phosphatase (IUT 85 129, NH3 69 59 112 120 65 119 96
Creatinine Clearance (mI/min) 16 14 17 12 5 13 5 5 40 54
28
SPENCER
Table
2.
ET AL.
GASTROENTEROLOGY
Average Magnesium Balances and Net Absorption of Magnesium of Patients with Chronic Renal Failure and of Patients with Normal Renal Function During a Low Calcium Intake” Magnesium (mg/day)
Patient
Vol. 79, No. 1
Age
Study days
Intake
Urine
Stool
Mg Excretion (% of intake) Balance
Urine
Stool
Net absorption (%)
Patients with chronic renal failure 1 2 3 4
67 63 57 47
5
55
6 7
51 50
8
65
30 30 42 48 12 36 12 18 30 24
Average SEM
57
28
1 2 3 4 5 6 7 8 9 10 Average SEM
48 36 16 78
67 63 57 58 57 51 50 48 50 65
30 36 66 48 30 18
57
41
140 187 150 159 179 126 124 151 158
101 56 77 96 57 70 56 53 72
147 119 139 110 126 93 113 157 135
-108 +6 -66 -47 -4 -37 -45 -59 -49
72.2 29.9 51.3 60.4 31.8 55.6 45.2 35.1 45.5
213
79
157
-23
159 f8.7
72 f5.3
130 f6.7
-43 f10.2
189 196 220 342 336 228 264 295 304 253 263 f17.4
37.1
105.0 63.6 92.7 69.2 70.4 73.8 91.1 104.0 85.4 73.7
26 8 -4 15 26
46.4 f4.3
82.8 f4.6
17 f4.7
74.1 59.2 53.2 43.0
42.0 56.6 50.2
47.1 50.5 56.8 42.7 65.8 40.4 34.8 58.0 67.8 51.0
52.9 49.5 43.2 57.3 34.2 59.6 65.2 42.0 32.3
55.0 f2.9
51.5 h1.4
48.5 f3.4
61.3 69.7 51.6
61.3 57.4 45.3
39.0 42.5 55.0
-25 f14.9
60.9 f5.2
54.7 f4.8
45.5 f4.8
-19 -40 +a
59.2 74.1 48.9
50.5 47.1 46.8
49.5 52.9 53.2
-17 f13.6
60.7 f7.3
48.1 il.1
51.8 fl.1
Patients with normal renal function Age-matched 89 -40 140 99 -19 116 125 -22 117 146 +49 147 221 -78 193 92 +7 129 92 +19 153 171 0 124 206 -74 172 129 -3 127 137 f15.2
142 f7.9
57.4 56.6
-16 f12.5
Patients with normal renal function Intake-matched Group 1 100 -37 100 89 -42 108 73 +5 83
1 2 3
58 46 62
30 36 32
163 155 161
Average SEM
56
34
159 f2.4
1 2 3
70 49 69
36 48 24
196 189 186
116 140 92
Average SEM
63
36
191 f4.5
116 f13.8
87 f7.8
97 f7.3
Group 2 99 89 86 92 f3.5
-5 36 7 31 30
o Calcium intake = 220 mg/day.
phosphorus in the diet was determined by a modification of the method of Fiske and SubbaRow,8 and nitrogen in the diet was determined by the Kjeldahl method.’ The net absorption of magnesium was determined from the dietary magnesium intake and from the fecal magnesium excretions according to the following formula: -
Net absorption,% = magnesium intake - fecal magnesium
x loo.
magnesium intake Although the dietary items were purchased as one lot for
MAGNESIUM ABSORPTION AND KIDNEY FUNCTION
July 1980
the entire study year, the magnesium analysis in each 6day period revealed some variability in dietary magnesium content. The data for the magnesium balances and of the net absorption of magnesium were analyzed statistically, using Student’s unpaired t-test” when comparing the data of patients with chronic renal failure with those of patients with normal renal function. The paired Student’s t-test was used for studies carried out in the same subject during different
calcium
or magnesium
intakes.
Results Table 2 shows data of magnesium balance studies and of the net absorption of magnesium of patients with chronic renal failure and of patients with normal renal function determined during a low calcium intake averaging 200 mg/day. Patients with Chronic Renal Failure Owing to the low protein intake, the dietary magnesium intake was low, ranging from 124 mg to 187 mg/day, except for patient a who received a higher intake of 213 mg/day, and averaged 159 mg/ day. The urinary magnesium excretions, averaging 72 f 5.3 mg/day, corresponded to 46.4% of the magnesium intake, and the fecal magnesium excretions were high in relation to the magnesium intake, averaging 130 f 6.7 mg/day, and corresponded to 82.8% of the magnesium intake. The net absorption of magnesium was low, ranging from -5% to 36% and averaging 17% f 4.7%. The magnesium balances ranged from slightly positive to negative values and averaged -43 mg/day. This balance differed significantly
Table 3. Magnesium
Balances
of Patients
with Chronic
from zero. In 2 of the patients, magnesium balances were determined at different stages of the renal disease. For patient 4 the net absorption of magnesium was similar at a creatinine clearance of 12 ml/min and of 5 ml/min, 31% and 30%, respectively, while for patient 5, the net absorption was 26% when the creatinine clearance was 13 ml/min and was considerably lower, 8%, when the creatinine clearance had decreased to 5 ml/min. As the renal function deteriorated, the urinary magnesium excretion of both patients decreased.
Patients with Normal Renal Function The data of 10 age-matched patients, who received the same calcium intake as the patients with chronic renal failure but received a normal dietary magnesium intake averaging 263 mg/day (Table 2), show that the urinary magnesium, averaging 142 mg/day, was significantly greater than the excretion of patients with chronic renal disease (P < 0.001). However, expressed as percent of the magnesium intake, the urinary magnesium excretion of both groups did not differ significantly. The fecal magnesium excretions and the magnesium balances of both groups did not differ significantly, but the fecal magnesium excretions expressed as percent of the magnesium intake was significantly lower for patients with normal renal function, averaging 51.5% of the magnesium intake vs. 82.8% for patients with chronic renal failure (P < 0.001). The net absorption of magnesium of the patients with normal renal function was therefore significantly greater, averag-
Renal Failure During Different Calcium
Magnesium (mg/day)
Intakes
Mg Excretion (X intake)
Calcium intake (ma/day)
Study days
Intake
140 *3.9 161 zt5.0 3100 zt1.4 190 fO.OO1 189 f12.0
Urine
200
30
101 f7.0 105 f4.5 103 f1.4 112 f8.9 100 fl.O
800
42
600
308
1400
138
2000
102
200 2000
30 42
150 177
77 62
2cQ 800
36 36
158 176
72 77
29
Stool Patient 1 147 f8.1 170 f6.0 243 f5.4 173 f2.4 184 f2.0 Patient 2 139 173 Patient 7 135 147
Balance
Urine
stool.
Net absorption (%)
-108 f10.9 -114 *3.5 -36 *4.0 -95 f11.2 -95 *9.0
72.1 f4.7 65.1 f4.8 33.2 f0.5 59.1 f4.6 53.0 f2.8
105.0 f5.8 105.6 f0.4 78.4 f1.4 91.2 f1.2 97.6 f5.1
-5.4 f4.4 -6 *0.5 21.4 zt1.3 9 il.4 3 *4.5
-66 -58
51.3 35.0
92.7 97.7
7 2
-49 -48
45.5 43.7
85.4 83.5
15 16
a Higher magnesium intake owing to the inadvertent magnesium content of the specific lot of calcium gluconate tablets used to increase the calcium intake from 200 to 800 mg/day. Values are means k SEM.
30
SPENCER ET AL.
GASTROENTEROLOGY Vol. 79, No. 1
ing 48.5%vs.17%, for patients with chronic renal failure (P C 0.001). The data of patients with normal renal function in whom the magnesium intake was.matched to that of patients with chronic renal failure (Table 2) showed similar results. The urinary magnesium excretion was greater than that of patients with chronic renal failure, 97 vs. 72 mg/day, while the fecal magnesium excretion was significantly lower, a7vs.130mg/day, corresponding to 54.7% vs. 82.8%of the magnesium intake for patients with normal and for those with abnormal renal function, respectively. The net absorption of magnesium of 3 patients with normal renal function in whom the magnesium intake was matched (group 1) was significantly greater, 45.5% vs. l7%, for the patients with chronic renal failure (P < 0.001). Similar results of the magnesium excretions and absorption were also obtained in 3 patients with normal renal function who received a slightly higher magnesium intake averaging 191 mg/day (group 2). Both th e f ecal magnesium excretion and the net absorption of this group also differed significantly from the values obtained in the patients with chronic renal failure (P < O.OOl),the average absorption being 51.6% vs. 17%, respectively. The magnesium balance of both groups of patients with normal renal function was less negative than that of the patients with chronic renal failure, and these balances did not differ significantly from those of patients with chronic renal failure. Table 3 shows data of magnesium balances and of the net absorption of magnesium of 3 patients with chronic renal failure studied during different cal4.
Table
Number of studies
Magnesium Age of patients (yr)
Balances
of Patients
cium intakes. The data of the magnesium balance studies, determined during the low calcium intake of 200 mg/day, are shown for comparison for each patient. In patient 1, multiple high calcium studies were carried out over a 2-yr period. During a relatively low magnesium intake ranging from 161 to 190 mg/day and during calcium intakes of aoo,l4OO, and 2000 mg/day, the urinary magnesium excretion was approximately the same as during the low calcium intake. Expressed as percent of the magnesium intake, the urinary magnesium ranged from 53.0% to 72.1% during the different calcium intakes and was lowest during the 2000 mg calcium intake. The fecal magnesium excretion during the 600 and 1400 mg calcium intake were about the same, while it was slightly greater during the 2000 mg calcium intake, la4 mg/day vs. 170 mg/day during the lower calcium intakes. The fecal magnesium excretions as percent of intake were very high during all calcium intakes, ranging from 97.6% to 105% of the magnesium intake. The magnesium balances during the different calcium intakes were in a similar range as during the low calcium intake. In the long-term study’carried out during a higher magnesium intake averaging 310 mg/day and a calcium intake of 600 mg/day, the urinary magnesium excretion did not differ from the excretion during the lower magnesium intakes, however, expressed as percent of the magnesium intake, this excretion was significantly lower (P c 0.005). The fecal magnesium excretion was markedly increased during the higher magnesium intake, however, expressed as percent of the magnesium intake, the fecal magnesium was dis-
with Normal Renal Function
During Diflerent
Magnesium (mg/day) Study days
Intake
Urine
Stool
Calcium
Intakes
Mg Excretion (%intake) Balance
Urine
Stool
Net absorption (V
Age-matched patients 3
58
24
241 SEM f18.8
3
88
39
197 SEM f19.8
5
82
22
255 SEM f5.0
1 2
53 84
24 72
199 3110 SEM ~~1.5
3
84
24
184 SEM f4.3
800 mg Calcium intake 142 118 f19.8 f10.3 1400 mg Calcium intake 133 89 f17.8 f9.4 2000 mg Calcium intake 115 131 f10.0 rt2.2 Intake-matched patients 800 mg Calcium intake 125 95 184 181 f12.0 fl8.0 1400 mg Calcium intake 98 84 f3.1 f13.2
-19 f8.1
58.3 f4.4
48.8 f2.7
51.1 f2.7
-25 f10.8
87.1 f2.8
45.5 f3.0
54.5 f3.0
+8 f13.2
45.7 f4.7
51.4 f0.8
47.8 zt1.2
-21 -14 zt5.5
72.9 52.8 zt3.8
47.7 51.9 f5.4
52.3 48.1 f5.4
-18 f13.3
59.8 f1.8
50.9 f8.8
49.1 f8.8
QHigher magnesium intake was due to the magnesium content of the calcium gluconate tablets.
July 1980
MAGNESIUM
tinctly less than during the lower magnesium intakes. The magnesium balance was also distinctly less negative during the higher magnesium intake. The magnesium balances and the net absorption of magnesium differed significantly during the two magnesium intakes (P c 0.001). The net absorption of magnesium was very low in all studies during all calcium intakes used during the low magnesium intake, ranging from -6% to 16%,and was greater, averaging 21.4%,during the higher magnesium intake of 310 mg/day. The serum magnesium level did not significantly change during the higher magnesium intake. In patients 2 and 7 (Table 3) during a calcium intake of 2000 mg and 600 mg per day, respectively, the urinary magnesium was the same as during the low calcium intake of 200 mg/day. The fecal magnesium excretion of both patients was slightly greater during the higher calcium intakes. As percent of the magnesium intake, these excretions were very high for both patients during both the low and high calcium intakes, and the net absorption of magnesium was therefore low but similar during the low and higher calcium intakes. The magnesium balances remained unchanged. Table 4 shows data of magnesium balances of two groups of patients with normal renal function studied during calcium intakes ranging from 600 to 2000 mg/day. One group was age-matched with the patients with chronic renal failure, and in one group the magnesium intake was matched. The agematched patients had received a normal diet, and therefore the dietary magnesium intake was greater than that of the patients with chronic renal failure. In both groups of patients with normal renal function receiving the different calcium intakes, the fecal magnesium excretion was either lower than the urinary magnesium excretion or these excretions were
ABSORPTION
AND KIDNEY FUNCTION 31
in a ratio of about 1: 1. The net absorption of magnesium of the patients with normal renal function was high, ranging from 47.6% to 54.5% of the magnesium intake. The fecal magnesium excretion and the net absorption of magnesium of the patients receiving the 600 mg calcium intake differed significantly from those of patients with chronic renal failure P c 0.025). Similarly, during the 1400 and 2CWOmg calcium intake, the fecal magnesium excretions and the net absorption of magnesium also differed significantly from those of patients with chronic renal failure (P c O.OOl),while the urinary magnesium excretion did not differ significantly during any of the calcium intakes. Figure 1 summarizes the data of the magnesium absorption of patients with chronic renal failure compared with that of patients with normal renal function. During all calcium intakes, ranging from 200 to 2000 mg/day, the net absorption of magnesium of the patients with chronic renal failure was significantly lower than that of the patients with normal renal function, irrespective of the magnesium intake of these patients. This figure also shows that the magnesium absorption in chronic renal failure had improved during a relatively high magnesium intake of 310 mg/day, however, this absorption was significantly lower than the magnesium absorption in patients with normal renal function receiving the same magnesium intake.
Discussion The present studies have shown that the net absorption of magnesium of patients with chronic renal failure is significantly lower than that of patients with normal renal function receiving the same or a higher dietary magnesium intake. The significantly lower net absorption of magnesium of 17% for
Chronic Renal Failure Mg
intake F&l LOW
Normal Renal Functian _Mp
Intake _!t!g_!!!!&L Normal H&&l Law
300 Figure 1. Summary of net absorption of magnesium of patients with chronic renal disease and of patients with normal renal function determined during different calcium intakes. Data of magnesium absorption obtained during a relatively high magnesium intake of 310 mg/day in chronic renal failure and in control studies are also shown.
s” ‘200 e i .3 H
loo
Ca Intatmin 100 mg/cdq1 Net AbaorptianY :
2el420
I7 I9 9
2
8
24
2’8
I4 2
49 9249
5!
32 SPENCER ET AL.
patients with chronic renal failure compared with an absorption of 46.6% for patients with normal renal function during a similar magnesium intake and compared with 46.5% during a higher magnesium intake was demonstrated by the very high fecal magnesium excretions as percent of the magnesium intake. The low magnesium absorption of the patients with chronic renal failure was a result of the very high fecal magnesium excretions as percent of the magnesium intake. The magnesium absorption of approximately 50% of patients with normal renal function is in agreement with data reported by others’ and with “Mg absorption studies carried out in this Research Unit.” The magnesium balances of the two groups of patients did not differ significantly owing to the lower urinary magnesium excretion of patients with chronic renal failure in agreement with results reported by others.’ The patients with chronic renal failure in this latter study were in positive magnesium balance,’ in contrast to the negative magnesium balances in the present study. However, in several of their cases the magnesium intake was also greater’ than in the present study. In evaluating the apparently persistent negative magnesium balance of patient 1 (Table Z), this patient may have replenished his magnesium stores whenever he was outside the hospital in the interims between studies performed in the Metabolic Ward. The low absorption of magnesium of patients with chronic renal failure observed in the present study is in agreement with data reported by several investigatorS,"3.12.13 but is in contrast to results reported by others.* In one study the net absorption of magnesium of patients with chronic renal failure was low, ranging from 16% to 34% of the magnesium intake compared with an absorption value of 50% for patients with normal renal function.’ In another study the absorption of magnesium of uremic patients was slightly decreased.” In a “Mg study the intestinal absorption of 4 of 7 patients with chronic renal failure was lower than of patients with normal renal function.13 In vivo intestinal perfusion studies have shown that the rate of jejunal magnesium absorption of patients with chronic renal failure was decreased to less than half that of patients with normal renal function.3 The mechanism which is operative in decreasing the intestinal absorption of magnesium in renal failure is not clear. Vitamin D may play a role, however, contradictory results have been reported. Vitamin D consistently increased the absorption of magnesium in rats.” Large doses of vitamin D markedly decreased the fecal magnesium in the rat and increased the urinary magnesium, indicating that vitamin D increased the intestinal absorption of
GASTROENTEROLOGYVole79,No. 1
magnesium.” In rachitic chicks, vitamin D increased the duodenal absorption of magnesium.le In vitamin D-deficient baby pigs, the low magnesium retention was greatly improved by vitamin D.17In humans, the use of the vitamin D metabolite lcu-hydroxy-D, resulted in hypermagnesemia and magnesium toxicity in a patient with chronic renal failure,“’ presumably on the basis of increased magnesium absorption. However, this vitamin D metabolite did not increase the absorption of magnesium in short-term studies in animals, and these authors report that this vitamin D metabolite also did not affect the absorption of magnesium in patients with chronic renal failure.19 Lack of vitamin D metabolite 1,25dihydroxyI& in the kidney of patients with chronic renal failureU’may contribute to the low absorption of magnesium of these patients. One report states that the slightly reduced magnesium absorption of uremic patients increased after successful renal transplantation.” This observation may indicate that the improvement in magnesium absorption may have been mediated by the availability of the vitamin D metabolite 1,25-dihydroxy-D, after renal transplantation. In patients with chronic renal failure undergoing hemodialysis using a regional perfusion technique, the administration of 1,25-dihydroxy-D, increased the low serum concentration of this vitamin D metabolite and restored the significantly decreased jejunal absorption of magnesium to normal levels (Fordtran JS, et al: Unpublished data). Other possible mechanisms for the lower absorption of magnesium in chronic renal failure have been suggested. The intestinal absorption of magnesium may be related to the ability of the kidney to excrete magnesium, and the decreased renal excretory function in renal failure may therefore play a role in lowering the intestinal absorption of magnesium.‘l Reduced entry of magnesium into the intestinal mucosal cells as a result of increased magnesium levels in the extracellular fluid may also play a role. In “Mg kinetic studies in patients with uremia and hypermagnesemia, the fractional cell influx of magnesium has been reported to be reduced.” Both the ionic and total serum magnesium levels of patients with renal failure are increased, the increase of the total magnesium concentration being greater than that of ionic magnesium.z3 The reported improvement of the absorption of magnesium after chronic hemodialysis” may in part be explained by lowering of the serum and extracellular fluid magnesium levels after this procedure. Of interest is the observation of the increase in magnesium absorption in chronic renal failure during a higher magnesium intake of 310 mg/day (patient 1, Table 3) compared with the magnesium ab-
July 1980
sorption during a lower magnesium intake in the same patient. The increased magnesium absorption was evidenced by the considerably lower fecal magnesium excretion as percent of the intake than during the lower magnesium intake. Despite this increase, the magnesium absorption was still one-half the absorption of patients with normal renal function receiving a similar magnesium intake (Table 4 and Figure 1).The mechanism for the increase in magnesium absorption during the higher magnesium intake in patients with chronic renal failure is not known and may be similar to that for the higher absorption of calcium during a higher calcium intake.“” In patients with normal renal function, a higher magnesium intake can lead to enhanced magnesium absorption. An intestinal perfusion study in which the magnesium content of the solution was increased demonstrated that the absorption of magnesium increased in patients with normal renal function.” The reason for the normal or elevated serum magnesium levels of patients with chronic renal failure in the presence of the low absorption of magnesium is not clear. Other investigators found that the serum magnesium level of patients with chronic renal failure did not differ significantly from those of normals,25 and stated that the remaining normal nephrons in chronic renal failure are able to increase the urinary magnesium excretion. When the renal function deteriorates further, this compensatory increase becomes insufficient and the serum magnesium level increases.25 The present data show, in agreement with previous results reported by others,4 that the fractional urinary magnesium excretion of patients with chronic renal failure was considerably greater than that of the control subjects. The patients with chronic renal failure excreted an average of 46.4% of the magnesium intake and absorbed only l7%, while the urinary magnesium excretion of the control subjects was only somewhat higher, 55%, and the absorption averaged 46.5% of the magnesium intake. The lack of effect of increasing the calcium intake on the magnesium balance of patients with chronic renal failure observed in this study is in agreement with results reported by others.‘-3 Similar results were also obtained in this Research Unit in magnesium balance studies” in patients with normal renal function and in magnesium absorption studies using “Mg as the tracer.” The latter study showed that the intestinal absorption of “Mg averaged 46% of the dose during a low calcium intake of 266 mg/day and remained unchanged when the calcium intake was increased to 2606 mg/day. In contrast, in magnesium depletion in humans, the fecal magnesium excretion increased during a high calcium intake, indicating
MAGNESIUM ABSORPTION AND KIDNEY FUNCTION 33
that calcium decreases the intestinal magnesium under these conditions.*7
absorption
of
References 1. Clarkson EM, McDonald SJ, dewardener HE, et al: Magnesium metabolism in chronic renal failure. Clin Sci 28107-115, 1965 2. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia. II. Calcium, phosphorus, and magnesium. Medicine (Baltimore) 52597607, 1973 3. Brannan PG, Vergne-Marini P, Pak CYC, et al: Magnesium absorption in the human small intestine. J Clin Invest 57:1412-1418, 1976 4. Popovtzer MM, Massry SG, Coburn JW, et al: The interrelationship between sodium, calcium, and magnesium excretion in advanced renal failure. J Lab Clin Med 73:763-771, 1969 5. Spencer H, Friedland JA, Ferguson V: Human balance studies in mineral metabolism. In: Biological Mineralization. Edited by I Zipkin. New York, John Wiley & Sons, Inc., 1973, p 889727 6. Willis JB: Determination of metals in blood serum by atomic absorption spectroscopy. I. Calcium. II. Magnesium. Spectrochim Acta 16259-272, 1960 7. Willis JB: Determination of calcium and magnesium in urine by atomic absorption spectroscopy. Anal Chem 33:558-559. 1961 8. Fiske CH, SubbaRow YT: The calorimetric determination of phosphorus. J Biol Chem 66:375-400, 1925 9. Henry RJ: Protein by Kjeldahl determination of protein-nitrogen. In: Clinical Chemistry-Principles and Technics. New York, Harper & Row, 1964, p 175-179 10.Snedecor GW: Statistical Methods. Fifth edition. Ames, Iowa, Iowa State University Press, 1959 11.Spencer H, Schwartz R, Norris C, et al: Studies of magnesium metabolism in man using “Mg as the tracer. Radiat Res 74:557-558,1978 12.Randall RE Jr: Magnesium metabolism in chronic renal disease. Ann NY Acad Sci 162:831-946, 1969 13.Mountokalakis Th. Singhellakis PN, Alevizaki CC, et al: Absorption intestinale du magnesium chez des malades en insuffisance renale chronique. Rev Fr Endocrinol Clin 17:229232,1976 14.Meintzer RB, Steenbock H: Vitamin D and magnesium absorption J Nutr 56285-294, 1955 15.Hanna S: Influence of large doses of vitamin D on magnesium metabolism in rats. Metabolism 10:735-743, 1961 16.Wasserman RH: Studies on vitamin D3 and the intestinal absorption of calcium and other ions in the rachitic chick. J Nutr 77:69-86, 1962 17.Miller ER, Ullrey DE, Zutaut CL, et al: Mineral balance studies with the baby pig: Effects of dietary vitamin D2 level upon calcium, phosphorus and magnesium balance. J Nutr 85:255259, 1965 J: Iatrogenic 18.Sorensen E, Tougaard L, Brochner-Mortensen magnesium intoxication during I-a-hydroxycholecalciferol treatment. Br Med J 2:215, 1976 19.Kanis JA, Smith R, Walton RJ, et al: Magnesium intoxication during l-a-hydroxycholecalciferol treatment. Br Med J 2:878, 1976 20.Mawer EB, Backhouse J, Taylor CM, et al: Failure of forma-
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tion of 1,25-dihydroxycholecalciferol in chronic renal inlarge intake of calcium citrate in normal subjects and patients sufficiency. Lancet 1:626-6251973 with chronic renal failure. Clin Sci 26:27-39, 1964 25.Steele TH, Wen SF, Evenson MA, et al: The contribution of 21. Ring RG, Stanbury SW: Magnesium metabolism in primary hyperparathyroidism. Clin Sci 39~281-303, 1970 the chronically diseased kidney to magnesium homeostasis in 22.Wallach S, Rizek JE, Dimich A, et al: Magnesium transport in man. J Lab Clin Med 71:455-463, 1905 normal and uremic patients. J Clin Endocr 26:1089-1060,19l36 26. Spencer H, Lesniak M, Gatza C, et al: Magnesium-calcium inhyterrelationships in man. In: Trace Substances in Rnvironmen23.Walser M: The separate effects of hyperparathyroidism, tal Health-XII. Edited by DD Hemphill. Columbia, Univerpercalcemia of malignancy, renal failure, and acidosis on the state of calcium, phosphate, and other ions in plasma. J Clin sity of Missouri, 1978, p 241-247 27. Dunn MJ, Walser M: Magnesium depletion in normal man. 1962 Invest 41:1454-1471, 24.McDonald SJ, Clarkson EM, dewardener HE: The effect of a Metabolism 15:884-895, 1966