Oral Magnesium Intake and its Effect on Various Urinary Constituents in the Prophylaxis of Urolithiasis

Vol. 96, Nov.

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright © 1966 by The Williams & Wilkins Co.

ORAL MAGNESIUM INTAKE AND ITS EFFECT ON VARIOUS URINARY CONSTITUENTS IN THE PROPHYLAXIS OF UROLITHIASIS F. PETER KOHLER and CHARLES A. W. UHLE From the Departments of Urology ancl Research, Lankenau Hospital, Philadelphia, Pennsylvania

Mammals are the only animals which concentrate urine at the kidney level and suffer from true stone formation in the upper urinary tract. Calculus formation is one of the inconveniences following the necessity of water conservation in the body. According to Boyce, 80 per cent of patients with urinary calculi exhibit only one episode of stone fonnation in their entire lifetime. Of the remaining group, 80 per cent have hypercalcuria over 325 mg. per 24 hours and in the majority of these patients the etiology of the hypercalcuria is unexplained. 1 Recently there has been renewed interest in the relationship between calcium and magnesium metabolism in the possible prevention of formation of calcium deposits in the upper urinary tract. In 1932 Cramer noticed that omission of magnesium from the diet fed to laboratory rats produced extensive degenerative lesions in glomeruli and renal tubules accompanied by calcareous deposits within the tubular lumen, concomitantly there was a significant decrease in the excretion of fecal and urinary calcium. 2 These changes were accompanied by an increase in the plasma calcium concentration and a decrease in the plasma magnesium concentration. If the magnesium was replenished in the diet the fecal and urinary calcium excretion increased. This observation was also confirmed by Alcock. 3 Hammarsten in 1929 was able to produce urinary calcium oxalate calculi in rats with a magnesium deficient diet. 4 She noticed that addition of Accepted for publication January 26, 1966. Read at annual meeting of Mid-Atlantic Section, American Urological Association, Inc., Washington, D. C., November 3-6, 1965. 1 Boyce, W. H. and King, J. S., Jr.: Effects of high calcium intakes on urine in human beings. Fed. Proc., 18: 1102, 1959. 2 Cramer, W.: Experimental production of kidney lesions by diet. Lancet, 2: 174, 1932. 3 Alcock, N. and MacIntyre, I.: Some effects of magnesium repletion on calcium metabolism in the rat. Clin. Sci., 26: 219, 1964. 4 Hammarsten, G.: On calcium oxalate and its solubility in presence of inorganic salts with special reference to occurrence of crystalluria. Compt. Rend. Trav. Lab., Carlsberg, 17: 83, 1929.

magnesium to the diet protected against stone formation. Feeding of diets high in magnesium markedly reduced the deposition of oxalate in rats deficient in vitamin B6 although they remained hyperoxaluric. She thought that the protective effect of the higher magnesium diets ,vas at least in part related to the effect on urinary citrate levels. Similarly Barat noticed that an extra magnesium load in the diet produced less tendency of stone formation on an artificially implanted nidus in the rat bladder, even though the serum magnesium was not changed as a result of the extra magnesium dietary intake. 5 Diets high in magnesium in rats increase the excretion of inorganic sulfates and phosphates in the urine. High levels of dietary phosphorus interfere with the action of high levels of dietary magnesium in preventing oxalate stones. 6 A variety of dietary factors can affect the deposition of calcium oxalate and calcium phosphate in the urinary tract of rats. Mechanisms of formation are complex and not solely dependent upon urinary concentration of calcium oxalate and phosphate. Johnson noticed that by using the method of Vermeulen by implanting a foreign body in the rat bladder that additional dietary iron will not decrease calcium oxalate vesical calculi formation in rats. 7 He thought that the observation may be due to a diminished absorption of magnesium from the intestinal tract. Vermeulen himself noticed that a low magnesium intake resulted in a low magnesium urinary excretion and therefore reduced magnesium ammonium phosphate formation on the nidus in the rat bladder. If the magnesium 5 Barat, A. K.: Effects of extra magnesium intake in experimental production of urinary calculi. J. Indian Med. Ass., 40: 365, 1963. 6 Faragalla, F. F. and Gershoff, S. N.: Interrelations among magnesium, vitamin B 6 , sulfur and phosphorus in the formation of kidney stones in the rat. J. Nutr., 81: 60, 1963. 7 Johnson, R. G. and Stiefbold, B. L.: The effect of urea, magnesium chloride, ind a low protein diet on the production of calcium oxalate vesical calculi in the rat. J. Urol., 81: 691, 1959.

812

PROPHYLAXIS OF UROLJTHIA.SIS

concentration in the diet was normal stones formed readily around the nidus. 8 l\fagnesium has the same excretion mechanism as has calcium since patients with kidney disease display an increase in ma.gnesium excretion as well as calcium excretion after intravenous calcium injection. 9 After ethanol intake urinary excretion of magnesium increased 167 per cent over the control values. 10 The urinary calcium excretion was also increased but less strikingly so. This increase was not related to change in glomerular filtration or renal blood fl.ow. Ethanol intake results in increased blood lactate, and Barker noticed that the rate of n1agnesium excretion was 2/27 per cent over the control level during intravenous lactate infusion. He also noticed that the calcium excretion in his study was over 800 per cent increased. There was less response to bicarbonate intravenous infusion.11 Indifferent ions in the urine influence solubility of urinary constituents significantly so that sodium in normal concentration in the urine increases solubility of urinary constituents at least three times. 4 It was noticed by Hammarsten that magnesium had a solubilizing pmYer greater than could be explained by a non-specific "salting in" action. magnesium and urinary citrate, thus in a way not understood, favor a state of temporary supersaturation of calcium and phosphate if in sufficient concentration.12 :VIiller performed an experiment by imitating urine by adding the various ions usually contained in urine to distilled water and found that calcium and oxalate may be present in urine in nrnch higher concentrations than in a completely saturated solution of calcium oxalate 3 Vermeulen, C. W., Goeti, H., Ragins, H. D. and Grove, W. J.: Experimental urolithiasis rv: Prevention of magnesium ammonium phosphate calculi by reducing the magnesium intake or by feeding au aluminum gel. J. 1.]rol., 66: 6, 1951. 9 Nanto, V., Kasanen, A. and Forsstrom, J.: Urinary excretion of calcium, magnesium, and phosphorus in renal patients. Ann. JVIed. Exp., Fenn., 41: 539, 1963. 10 Kalbfleisch, J. M., Lindeman, R. D. and Ginn, H. E.: Effects of ethanol administration on urinary excretion of magnesium and other elec·· trolytes in alcoholic and normal subjects. J. Clin. Invest., 42: 1471, 1963. 11 Barker, E. S.,Elkinton, J. R. and Clark, J. K.: Studies the renal excretion of magnesium in man. J. Invest., 38: 1733, 1959. 12 Vermeulen, C. ·w., Lyon, E. S. and :Miller, C . H.: Calcium phosphate solubility in urine as measured by a precipitation test: experimental urolithiasis XIII. J. Urol., 79: 596, 1958.

and water. 13 The pH was not important, bw, Miller noticed a special complexing action nf citrate and magnesi.1.un, the former with calcium, the latter complexing with oxa.latf'. No protective colloid mechanism could bto 11.i, play since no colloid constituents were added to the artificial urine. It would seem that mi nan citrate and magnesium levels a role in a protective effect a.gainst, calcareou~ deposits in the urinary tract. John Eager Howard and his associ:ites have an experimental method which rnchitie ra,; cartilage is placed in urine and it has been found that in general the urine of pa· tients will calcify the rat cartilage, whern,1s the urine of non-stone-forming patients will not. The former urine has been labeled "evil'' wheretci< the latter urine has been labeled " If magnesium is added to "evil" nri11e the i cartilage will not be calcified. KP,vPr~,,1v removal of magnesium from "good" urine will result, in calcification of the rat cartilage. In "evil" mine the requirement for magnesium for oi calcification is much higher than needed to prevent calcification by "good'' urine. there seems to be some substance contained in the urine which prevents some of the from exhibiting its blocking action. 14 The afore mentioned observations have resulted in ,,eveml studies on the value of magnesium for prevention of calculi in the urinary tract of humans and the results as reported have been both tive and negative. Boyce in 1955 wa~ unable t.o demonstrate the beneficial effect of l to gm. magnesium citrate by mouth in patients wilh chronic urolithiasis. 15 Alberquerque. on the other hand, reports a significantly reduced oxalate excretion in patients after administration of 150 mg. magnesium oxide by mouth_16 :VIoore reports on significant decrease in c2.lcium and phosphorus excretion in with. chronic urolithiasis after administration of 420 "JWiller, G. II., Vermeulen, C. W. and Moore, J. D.: Calcium oxalate solubility in urine· mental urolithiasis, XIV. ,J. Urol., 79: 14 Mukai, T. and Howard, J.E.: Some tions 011 the calcification of rachitie urine. Bull. John Hopkins Hosp., 112: 15 Boyce, W. H. · Urol. Survey, 5: (Abstracter's comment on Vermeulen's Basic Mechanisms in lirolithiasis. A.MA. Arch. Surg. 69: 759-761, 1954.) 16 Albuquerque, P. F., and Tuma, JVI.: Tnve,%igations on urolithiasis II: Studies on oxalate.,] Urol., 87: 504, 1962.

814

KOHLER AND UHLE TABLE

Serum mg/100 ml.

Dose

Urine mg/100 ml.

Ca

Ca p

p

Mg oxalic acid

I Mg

I citric I creatiacid nine

Total 24-hour urine Volume liters Ca

Mg

I

p

I

I

oxalate

J. L., 41-year-old man

0 0 500 1000 1500

9.8 9.1 9.3 9.6 9.6

3.9 3.3 3.1 3.2 3.1

1.4 1.9 1. 7 1. 7 1.6

60 36.2 59.1 57.8 62.9

6 5.7 6.8 6.5 6.1

22.2 9.6 35.7 31.0 20.2

32 30.8 25.0 11.4 9.4

122 70 129 139.4 120.0

1.08 0.8 1.12 1.20 1.10

109 100.8 119.8 56.9 39.6

60 45 76 78 67

8.3 8.9 12.2 13.2 13.7

43.4 53.6 57.1 60 46.7

1.0 0.8 9.4 14.8 13.4

31 28.3 37.7 35.1 263

10 9.4 13 12.4 10.7

72 76.6 74.1 82.9 68.5

0.8 1.6 1.5 1.4 1.2

66.4 142.4 183 184 164

8 12.8 141 207 160.8

10.5 12.8 15.8 10.9 12.3

60 52 71 52.9 80.4

4.9 5.3 8.2 4.3 13.1

27 24.5 33.4 23.8 27.5

10 8 10.5 7.2 11.6

120 100 127 78.4 116

1.8 1.8 1. 7 1.8 1.5

189 230.4 268.6 196.2 184.5

10.1 13.9 9.9 22.8 8.4

59.2 34.3 25.2 25.4 33.0

2.5 4.2 1.9 5.2 10.0

7.8 8.8 12.5 13 22.6

5 15.5 10.2 5.3 8.2

61 124 46 45 70.8

1.8 2.2 3.3 3.7 2.4

181.8 305.8 326.7 843.6 201.6

45.0 1065.6 92.4 754.6 62.7 831.6 192.4 939.8 240 792

140.4 193.6 412.5 481 542.4

64.7 59.8 69.5 56.0 51.1

8.9 10.0 14.7 15.2 16.1

23.0 18.6 14.8 10.4 6.4

10 7.4 7.2 8.3 5

90 100 82 90 71

1.3 1.2 1.2 1.3 1.4

150.8 153.6 160.8 182.0 205.8

115.7 120 176.4 197.6 225.4

299 223 177. 6 135.2 71.6

10.1 12.6 10.7 4.7 3.6

600 289 660 693 691

222 76 399 372 222

347.2 857.6 856.5 840.0 560.4

248 452.8 565.5 491.4 315.6

T. R., 42-year-old woman 0 0 500 1000 1500

9.8 9.1 10.2 9.7 9.5

3.0 3.7 2.5 2.6 2.4

2.2 2.4 2.2 2.4 2.2

A. B., 42-year-old man 0 0 500 1000 1500

9.0 8.6 9.7 9.6 9.1

3.0 2.4 3.2 3.0 3.3

1.9 1.9 1.9 1.6 1.9

88.2 1080 95.4 936 139.4 1207 77.4 954 1206.0 1206

486 441 567.8 428.4 402.5

M. M., 36-year-old man 0 0 500 1000 1500

8.8 9.1 9.0 10.2 8.2

3.7 4.0 3.1 3.1 2.8

1.7 1.6 1.6 1.5 2.3

S. Mc, 33-year-old woman 0 0 500 1000 1500

9.1 9.8 9.0 9.3 9.0

3.1 3.2 3.8 3.5 3.7

1.1 1.3 1.2 1.3 1.2

11.6 12.8 13.4 14.0 14.7

mg. magnesium oxide a day. 17 Because of the favorable reports on oral magnesium administration in patients with urolithiasis we have administered oral magnesium to a group of patients with recurrent urolithiasis and have 17 Moore, C. A. and Bunce, G. E.: Reduction in frequency of renal calculus formation by oral magnesium administration. Invest. Urol., 2: 7, 1964.

841.1 717.6 834.0 728.0 715.4

determined various serum and urinary constituents while administering variable doses of magnesium oxide. METHOD

Five patients, 3 men and 2 women, all of whom were chronic stone formers in the urinary tract were selected for the study (see table). None

8L'i

PROPHYLAXIS OF UROLITHIASIS

of the patients were ho~pitalized for the study but were instructed to perform their usually daily routine regarding dietary habits and exercise activities dming the study period. All urine specimens were collected over a 24-hour period and all serum specimens were collected without restricting the venous blood flow during the collection. Two control levels of urine and serum were obtained in each individual and the following serum constituents were determined: calcium, pho,sphorus, and magnesium. The following 24-hour urinary constituents were determined: calcium, phosphorus, magnesium, oxalate, citrate. and creatinine. After the control levels had been obtained each patient was given 500 mg. magnesium oxide orally a day for 14 days and the serum and urine studies were repeated. Each patient was then given 1,000 mg. magnesium oxide by mouth for 14 days and the serum and urinary studie~ once again repeated. Thereafter each patient was given 1,500 mg. magnesium oxide by mouth for 2 weeks and the urine and serum studies were repeated. The table shows the results of the various determinations throughout the study. DISCUSSION

We thought it advisable not to restrict the patients' dietary or activity patterns; although they can be controlled in a hospital environment we hoped to gain a better picture of the true serum and urinary leye]s of the various constituents studied while the patients ,vere performing their daily routine. The data obtained show that there is no uniform response of the group of patients to the administration of oral magnesium. There was no essential change in the measmed serum constituents during this study. In general an increased oral intake of mag11e,sium oxide resulted in increased urinary output. However, doses beyond 1,000 mg. a day caused gastrointestinal upset and decreased absorption. A. D. has medullary sponge kidneys and response to the magnesium intake is quite variable. The 24-hour urinary calcium excretion is not significantly affected. T. R. has nmltiple bilateral renal calculi and although the urinary magnesium

excretion is elevated during this there is rJO change in the urinary calcium excre · tion. Neither is the urinary oxalate nor phosphatP excretion affected. M M. has passed sev<'rnl calcium oxalate calculi from the left kidney and exhibits a quite variable excretion. pattern in the minary constituents. J. L. has multiple bilateral calculi and ureteral-pelvic junction obstructions which have been surgically cornccted. Although there is no definite increase in urinary magnesiun1 excretion there is some decrease in urin~ry calcium excretion during the study period. S. M. had had several previous pregnancies chu-ing each of which she pas~ed at least 8 to 12 calcium oxalate calculi. During the present pregnanc3 while the study was performed no calcium oxalate calculi were passed. She demonstrated a regulai increase of magnesium in the urine as the dosage was increased but also demonstrated an increase of urinary calcium excretion. There was some decrease in the urinary oxalate excretion and no change in the urinary phosphate excretion during the study. Calcium absorption from the gut is nrnre closely related to body need rather than calcium availability. Magnesium absorption may be regulated by the same mechanism. If there is no need for increased magnesium absorption there may be no beneficial effect obtain eel by increased oral magnesium administration. During pregnancy there is an increased need for body calcium and it may be that increase
'\Ve have performed analyses of serun1 and urinary constituents after administration of variable doses of 1nagnesium oxide in 5 patient.-; with chronic urinary tract lithiasis. The data indicate that there is no definite pattern ol' ab sorption or excretion of magnesium oxide and it ,vould seem that the potential beneficial effpc:(; of oral administration of magneRinm prcparnt,ion~ would have to be determined by assessment of their effect on urinary constituents in each individual patient.