Fluorine in Urinary Tract Calculi

THE JOURNAL OF UROLOGY

Vol. 80, No. 4, October 1958 Printed in U.S.A.

FLUORINE IN URINARY TRACT CALCULI JOHN R. HERMAN, BRIAN MASON, PH.D.

AND

IGO LIGHT, M.S.

From the Bronx Hospital (J.R.H. and I.L.), the Department of Surgery (Urology), Albert Einstein College of Medicine and the Bronx Municipal Hospital Center, (J.R.H.) and the Museum of Natural History (B.M.), New York, N. Y.

_I I

Urolithiasis kills thousands every year and 9.47 of every 10,000 patients admitted to general hospitals have the diagnosis of urolithiasis. 1 The factors associated with stone formation are numerous (fig. 1) and we are unable to prove the etiology of stone in about 70 per cent of cases. 2 Recent advances in chemistry, physiology, histology and microbiology have not made it possible to reduce the incidence of stone, or lowered the recurrence rate in those 9-15 per cent of patients who are known as "stone formers." 3 • 4 Pyrah 5 and Stout 6 reported that calcification could be found in 20 per cent of so-called norma 1 kidneys and in 54 per cent of kidneys at necropsy. This would seem to indicate that some degree of local or diffuse nephrocalcinosis is widespread. It is possible that these calcific deposits in and around the tubules lead in turn to Accepted for publication May 5, 1958. This investigation was supported by a Research Grant, A-1224 (C), from the National Advisory Council of Arthritis and Metabolic Diseases, Public Health Service. We should like to thank Dr. M. L. Gottlieb, chief of the urological service of the Bronx Hospital, and Dr. A. J. Weil for encouragement and assistance. We should also like to thank Dr. A. S. Goldberg and Mr. M. Weissman for their technical advice on problems in chemistry; Miss Constance Holland for her work in photography and Miss Sylvia Goldstein for secretarial help. 1 Boyce, W. H., Garvey, F. K. and Strawcutter, H. E.: Incidence of urinary calculi among patients in general hospitals, 1948-1952. J. A. M. A., 161: 1437-1442, 1956. 2 Vermeulen, C. W., Miller, G. H. and Sawyer, J. B.: Some non-surgical aspects of urolithiasis. Med. Olin. No. Amer., 39: 281-295, 1955. 3 Baker, R. and Connoly, J. P.: Bilateral and recurrent renal calculi. J. A. M. A., 160: 11061110, 1956. 4 Burkland, C. E. and Rosenberg, M.: Survey of urolithiasis in United States. J. Urol., 73: 198207, 1955. 5 Pyrah, L. N. and Raper, F. P.: Renal calcification and calculus formation. Brit. J. Urol., 27: 333-351, 1955. 6 Stout, H. A., Akin, R. H. and Morton, E.: N ephrocalcinosis in routine necropsies: its relationship to stone formation. J. Urol., 74: 8-22, 1955. 263

Randall's plaques7 and so to stone formation. This may indicate that some of the basic factors for lithogenesis are present more often than is generally considered. Prien and Frondel8 analyzed 700 calculi by x-ray diffraction in the hope that knowledge of stone chemistry could make it possible to trace their natural history. They failed to note the presence of fluorine and, indeed, commented that fluorapatite is not a urinary apatite. In 1954, Dillon9 described the presence of fluorine in a renal calculus and it was further established10 that a large percentage of uroliths contain fluorine in varying quantities. It seemed worthwhile to investigate further the relationship of fluorine to urinary tract calculi. MATERIALS

Materials from 100 consecutive, unselected cases of urolithiasis representing 38 renal, 28 ureteral and 34 vesical calculi were obtained. Too many urologists furnished specimens to acknowledge individually their assistance. We are most grateful for their help and wish to take this opportunity to thank them. All of the patients lived at least part of their lives in New York City, and were operated upon in New York. The patients represented all races, and many originated in other countries or different parts of the United States. There were 81 males and 19 females ranging from 3 H to 84 years old. When several calculi were removed at one time from one patient, they were considered to be one specimen. Later calculi from the same patient were recorded separately. When possible 7 Randall, A.: The etiology of primary renal calculus. Trans. VII Congress of Int. Society of Urol., pt. 1, pp. 186-261, 1939. 8 Prien, E. L. and Frondel, C.: Studies in urolithiasis: I. The composition of urinary calculi. J. Urol., 57: 949-991, 1947. 9 Dillon, C.: Fluorine content of a renal calculus. Dental Pract., 4: 181, 1954. 10 Herman, J. R.: Fluorine in urinary tract calculi. Proc. Soc. Exp. Biol. Med., 91: 189-191, 1956.

264

JOHN R. REBMAN, BRIAN MASON AND IGO LIGHT ------t

Low Fluid Intake

Products of Inflammation

Change in Urinary pH

Decreased Urine Volume

I

MATRIX

I

l~fection

+

+

I

Foreign Surface

RETENTION OF INCIPIENT STONE.,

~

I c!lloids I

=

Alterations in Tubular Ground Substances

Porothormone Oxomide etc.

'?

High Dietary Intake

Fm. 1. Factors responsible for stone formation. Modified with kind permission from Vermeulen, Miller and Sawyer. 2 TABLE

1. Composition of 100 urinary tract calwli

Calcium oxalate Calcium oxalate plus apatite (calcium ortho phosphate) Magnesium ammonium phosphate hexahydrate Apatite (calcium orthophosphate) Magnesium ammonium phosphate hexahydrate plus apatite Magnesium ammonium phosphate hexahydrate plus calcium oxalate Calcium hydrogen phosphate dihydrate Uric acid Cystine Sodium acid urates

13% 38%

TABLE

2. Relationship of fluorine content of calculi to age of patient in 87 cases Parts Per Million of Fluorine

Patient's Age 0-500

34%

15%

in patients operated on for surgical removal of calculi, tissue samples were removed for determination of fluorine content. One hundred and two samples of tissue were obtained including skin, fat, muscle, bladder, kidney, hair and nails. METHODS

The calculi were first washed in distilled water and all superficial blood and tissue !emoved. Some stones were dissected, and inner and outer layers were separately processed. Besides the determination of calcium, fluorine and phosphorus, a portion of the finely ground

0-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 80 plus

501-1000

10011500 1500 plus --- ---

x* X X

X

X

XXX

xx

xx

X

xxxxx xxxx xxxxxx xxxxxxxxx xxxxxxxxx xxxxxxxx xxxxx xxxx

X

X

xx

X

XXX X

X

xxxxx

XXX

X

xx

XXX

*x = 1 specimen calculi was qualitatively analyzed for ammonium, calcium, magnesium, oxalates, phosphates, carbonates and urates, according to the methods outlined in the fifth edition of the Laboratory Methods of the U. S. Army. For the quantitative determination of calcium, a portion of stone was ignited at 650° with sodium carbonate. The material was dissolved in HCl, brought to pH 5.5, precipitated with ammoniumoxalate, and the washed precipitate titrated (in

265-

FLUORINE IN URINARY TRACT CALCULI

•• •

•• •

•

•••

--- -

FIG. 2. A, relationship of fluorine in parts per million to calcium content of calculi. B, relationshipof fluorine in parts per million to phosphate content of calculi.

the usual way) with 0.1 N potassium permanganate solution. The phosphorus in the renal calculi was determined by the colorimetric method of Rockstein and Herron11 using ferrous sulfate as a reducing agent. Fluorine was determined quantitatively by the method of Willard and Winter12 as modified by Adams and Koppe. 13 This involves fusion of the calculus with sodium carbonate, steam distillaRockstein, M. and Herron, P. W.: Colorimetric determination of inorganic phosphate in microorganic quantities. Anal. Chem., 23: 150011

1507, 1951.

12 Willard, H. H. and Winter, 0. B.: Volumetric method for determination of fluorine. Ind. & Eng. Chem. (Anal. Ed.) 5: 7-10, 1933. 13 Adams, D. F. and Koppe, R. K.: Effect of pH on high salt-thorium fluoridititration. Anal. Chem., 28: 116-117, 1956.

tion of the fluorine as hydrosilicofluoric acid, and titration with thorium nitrate. Control studies showed about 92 per cent of fluorine was recovered by this method and therefore the calculated limits of error of this determination are plus or minus 10 per cent. A fluorine content is reported as nil if it is under five parts per million (hereafter referred to as p. p .m.). RESULTS

These calculi are considered to be quite representative as compared with the results of Prien and Frondel8 and the compilation of their qualitative analysis is shown in table 1. The fluorine contents vary from nil to 1800 p.p.m. and are not correlated with the patient's sex, age or race (table 2). There is no significant difference in the fluorine content of the calculi

266

JOHN R. HERMAN, BRIAN MASON AND IGO LIGHT

3. Fluorine content of tissues in relation to fluorine content of stone in 38 surgical cases of urolithiasis

TABLE

Parts Per Million of Fluorine Stone ---

5

19 24 78 85 89 101 114 142 143 164 172 177 188 197 204 210 213 237 239 240 241 264 276 308 350 380 412 557 563 707 790 850 1119 1127 1357 1575

Hair

Nails

15 24 171

14 31

Fat

Skin

Other tissues

--- --- --- --- ------132 Prostate 28 13 13 Bladder 185 36 Prostate nil 4 Bladder 15 18 44 2 25 121 195 Kidney 181 77 Bladder 56 29 53 47 23 19

nil

27 105 31 28 54 25

47

33 26 23 29 124 162 65 143

63 30

Prostate nil

63

54 290 41 46

58 101 58

43 69 68

20 67

34

15 69 97

43

104

10

82

Prostate 50 Prostate 5

75

ANALYSIS BY X-RAY DIFFRACTION

26

10

145 62 12

Prostate 86 Bladder 60 Bladder 116 Kidney nil

34 186 5

100 10

80

24

2

100 p.p.m. As depicted in figure 2, A there is no other direct correlation between these components. The fluorine present in the calculi bears roughly the same relationship to the phosphatic content as it does to the calcium content (fig. 2, B). Where there is less than 4 per cent of phosphates, the fluorine is usually low; above 4 per cent phosphates, the fluorine is generally elevated above 100 p.p.m. In 38 surgical cases of calculous disease, tissue samples were taken for determination of fluorine content as follows: Hair and nails 32, subcutaneous fat 27 and skin 27, prostate 9, bladder 5 and kidney 2. No relationship is found between the fluorine content of the calculi and the fluorine in the tissues (table 3). None of the tissues revealed fluorine contents elevated significantly above the normals established in the literature14-rn Thus, it is seen that in our cases, the fluorine content of the stone is not related to systemic fluorosis as determined by the fluorine content of the tissues.

Prostate 15

77

found in different anatomical portions of the urinary tract. Uric acid calculi, containing little or no calcium, contain only relatively small amounts of fluorine. Roughly, if the calcium content of the calculus is 5 per cent or less, the fluorine is less than 100 p.p.m. When the calculus is composed of larger percentiles of calcium and calcium compounds, the fluorine content is generally found to be over

X-ray diffraction analysis of 12 calculi including two of very low fluorine content showed that calculi with high fluorine content (241 p.p.m. or over), all contain ortho phosphates of calcium compounds known to mineralogists as apatites. These are materials of analogous chemical composition, essentially the ortho phosphates of calcium with fluorine, chlorine, carbonate or hydroxyl ions in varying percentiles. All of these ions may be present in the same specimen, or they may be present individually. Other compounds found to be present in these calculi are whewellite or calcium oxalate monohydrate, weddellite or calcium oxalate dihydrate, struvite or magnesium phosphate hexahydrate and uric acid (table 4). Apatite is the only compound that is a constant finding m all these"high-fluorine" calculi. As apatite is known to adsorb fluorine readily, we may suppose that the fluorine present in these calculi is related to the apatite. Apatite saturated with fluorine contains 3.77 per cent of fluorine 16 14 Gautier, A. and Clausmann, P: Fluorine in animal organs ( "Le fluor dans l'organisme animal"). Compt. rend., 157: 94-lCO, 1913. 15 Gettler, A. 0. and Ellerbrook, L.: Toxicology of fluorides. Am. J. Med. Sc., 197: 625,

1939. 16

Roholm, K.: Fluorine Intoxication. London:

H. K. Lewis & Co. Ltd., 1937.

267

FLUORINE IN URINARY TRACT CALCULI TABLE

Fluorine (p.p.m.)

4. Fluorine content of calculi as related to their composition (determined by qualitative chemistry and x-ray diffraction) X-Ray Diffraction Qualitative Chemical Analysis Apatite

1575

1049

1357 1540

1414

1119 442 1156

241

826 12 1

Calcium Oxalate Trace of phosphates Ammonium, calcium, oxalate phosphates, carbonates uric acid Calcium, oxalates phosphates Ammonium, calcium, magnesium oxalate, phosphates, carbonates and uric acid Ammonium, calcium, magnesium oxalate, phosphates, carbonates and uric acid Calcium, magnesium, phosphates Calcium, ammonium, oxalates, phosphates Calcium, oxalates, phosphates, carbonates, and uric acid Calcium, oxalates, phosphates and uric acid Calcium, oxalate, phosphates and uric acid Uric acid Uric acid

and is known as pure fluoroapatite usually represented as 3Ca3(P0 4)2 • CaF2. This is rarely found in nature, but apatites with lesser concentrations of fluorine are very frequently found.* To calculate the per cent of fluorine saturation of the apatite in these calculi, it was necessary to estimate the total apatite content. Premised on the probability that all the phosphorus in the calculus is present in the apatite, by determining the phosphorus content, it was then possible by stoicheiometrical calculations based on the accepted formula to determine the amount of apatite present. This proved the fluorine content of the apatite in the calculi to be generally below 0.3 per cent. We have not found chlorine in these calculi.

* Apatites containing fluorine have been called variously fluorapatites, fluorine bearing apatites and apatites with fluorine. The different nomenclature is only of academic interest here, and we shall call all of these apatites with varying fluorine content, fluorapatites.

Whewellite

Weddellite

Struvite

Uric Acid

X

X

X

X

(trace) X

(trace)

X

X

X

X

X

X

X

X

X

X

X

X

X X X

DISCUSSION

Mineralogists and archeologists have long known that the fluorine content of different bones excavated in the same geographical areas can be utilized to estimate the age of the bone.17 This conclusion is based on the accepted fact that bone exposed to ground water containing small percentages of fluorine will adsorb this fluorine in quantities increasing as the age and, therefore, exposure of the bones to fluorine increases. Hendricks and associates18 postulated that not only bone, but carbonate-apatite, hydroxylapa17 Jaffe, E. B. and Sherwood A. M.: Trace elements memorandum report 149. Physical and chemical comparison of modern and fossil tooth and bone material, 1951. 18 Hendricks, S. B., Hill, W. L., Jacob, K. D. and Jefferson, M. E.: Structural characteristics of apatite-like substances and composition of phosphate rock and bone as determined from microscopical and x-ray diffraction examination. Ind. and Eng. Chem., 23: 1413-1418, 1931.

268

JOHN R. HERMAN, BRIAN MASON AND IGO LIGHT

tite and tricalcium phosphates change to fluorapatite as they age. The analogy to this situation in urolithiasis would seem to be as follows: The fluorine content of an apatite calculus will vary in relation to the amount of fluorine in the urine, the length of exposure to the fluorine, the percentage of apatite in the calculus and the surface area exposed. We have no reason to suppose that the fluorine will increase the rate of growth of a calculus, but investigation of this remote possibility is in progress. No evidence has been found to show that

fluorine in the amounts ingested by the average population in the vicinity of New York has been toxic to the kidneys. SUMMARY

The data presented establish that fluorine is present in apatite containing urinary calculi and is not related to systemic fluorosis. That fluorapatite is the actual compound formed is not proven, but may be accepted as a good working hypothesis.

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