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Annu. Rev. Med. 1975.26:173-179. Downloaded from www.annualreviews.org Access provided by University of Texas Southwestern Medical Center on 01/27/15. For personal use only.

Copyright 1975. All rights reserved

CALCIUM OXALATE RENAL

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STONES Edwin L. Prien, Jr., MD. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Modern Western stone disease is composed of four major stone entities. with the majority of patients ( 70%) suffering from what has been loosely defined as "calcium stone disease" (1). For this reason it is especially distressing that the pathogenesis and therapy of this disorder has remained so elusive. There can be little doubt that cystine. uric acid (not urate). and mixed magnesium ammonium phos­ phate/apatite ("infected") stones are a consequence of excessive supersaturation of the urine for the offending species (2). Such clear-cut excessive supersaturation is not always demonstrable in calcium stone disease although it is generally suspected when either marked hypercalciuria or primary hyperoxaluria are present. In this short review I will attempt to deal with this problem and comment on the current status of the older theories of pathogenesis as well as several newer concepts. All theories of stone formation require a certain degree of urine supersaturation if not for spontaneous nucleation at least for continued stone growth. In order to determine the degree of supersaturation. a specific solid phase (crystal) must be anticipated. Calcium oxalate (mono- and dihydrate) and apatite (a complex calcium phosphate similar to bone salt) comprise at least 90% of calcium stones. They are either pure calcium oxalate or calcium oxalate with variable amounts of apatite intermixed. This apatite may be nuclear. or may appear in scattered nests or in layers alternating with calcium oxalate. Approximately 5% are pure apatite and 3% contain brushite (CaHP0402H20) either solely or admixed with other constituents (1). r-v

URINARY CALCIUM

Whatever the variety it is apparent that calcium is common to all these crystalline compounds. This. together with the relative ease of calcium measurement and the observation that stones are sometimes associated with disorders of calcium metabo­ lism has led to the assumption that all calcium stones are the result of abnormalities 173

Annu. Rev. Med. 1975.26:173-179. Downloaded from www.annualreviews.org Access provided by University of Texas Southwestern Medical Center on 01/27/15. For personal use only.

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of calcium metabolism. It can safely be said that many stone formers have an elevation of calcium excretion and presumably of urinary calcium concentration. A chief difficulty in the refinement of this notion has been in defining the normal range. If it is taken as the range of excretion for 90% of the population, then a reasonable upper limit of 300 mg per day for men and 275 mg for women has been suggested. However, more recent data indicate levels as high as 400 mg for men (3). If a different definition of normal is used, namely the absence of stone, then clearly there are individuals with still higher urinary calcium who do not suffer stone disease. Are such people "normal" or should they be considered "stone formers" who lack some other factor necessary for stone production? It would also be important to be sure they are not relatives of stone formers, a simple precaution generally overlooked. A second difficulty in assessing urinary calcium excretion, apart from its intrinsic daily variation, is its relation to dietary calcium. In the majority of normals urine calcium is little affected by dietary calcium. However, in perhaps a majority of stone formers there is a relatively steep rise (slope) of calcium excretion with increasing calcium intake. Thus on low calcium diets most stone formers have normal urinary calcium while on high intakes the majority are elevated (3). No doubt simple dietary restriction accounts for the multitudes of young men who have but one stone per lifetime. The riddle is why stone disease continues to recur in some patients whose urine calcium has been normalized on low calcium diets or in patients who have always had low normal urine calciums (100-200 mg per day) not to mention why some remain stone-free with much higher calciums. This dilemma has led investigators to search for other factors. INHIBITORS OF CRYSTALLIZATION

Normal urine has an abundance of inhibitors of crystal formation including ionic strength, various complexers, and certain "crystal poisons" that function in exceed­ ingly low concentrations (1Q-6 M). Studies utilizing the rachitic rat cartilage assay suggested that a substance, possibly a peptide, was deficient in stone formers and the concept of "evil urine" was born (4). To date no specific deficient inhibitor has been isolated. One inhibitor that has been well characterized is inorganic pyrophos­ phate, but it is not deficient. Recently, the specific aspects of calcium oxalate crystal growth and aggregation (not nucleation) have been studied (5). Again stone-forming urine appears to show a deficiency of inhibition, but whether this effect is due to lack of an inhibitor or whether the more rapid rates of crystal growth observed are a consequence of higher degrees of supersaturation remains to be seen. STONE MATRIX

An alternative theory has evolved from the observation that all urinary calculi have a mucoprotein matrix accounting for'" 3% of stone weight (6). It is possible that matrix might function as a specific template (by epitaxy) for nucleation of crystalline components from normally supersaturated urines, although its occurrence in stones

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Annu. Rev. Med. 1975.26:173-179. Downloaded from www.annualreviews.org Access provided by University of Texas Southwestern Medical Center on 01/27/15. For personal use only.

of all compositions is an argument against specificity. Initially, the major component of matrix, characterized immunologically as matrix substance A, was found only in the urine of stone formers and not normals. It has since been found in other nonstone kidney diseases and appears to be related to renal inflammation or destruction rather than to stone (6). URINE SUPERSATURATION

In studies which can only be described as elegant and comprehensive the Leeds group has made important recent observations. By counting the number and volume of calcium oxalate crystals in fresh warm urine (37°C), only stone formers are found to have large and aggregated crystals, while both they and normals may have much smaller crystals averaging 5 fA. in size (7). They then undertook the complex calcula­ tion (computer-assisted) of the degree of supersaturation (ion products) for calcium oxalate in these urine specimens. The greater crystal volumes in stone formers did correlate with greater peak supersaturation. This result was due simply to greater concentrations of calcium and oxalate and not to differences in other ion species, complexers, or ionic strength (8). URINARY OXALATE

The Leeds group then made what may prove to be a seminal observation. With the computer they compared the effect on supersaturation of either increasing calcium concentration or increasing oxalate concentration. Surprisingly, increases of oxalate were more potent in raising supersaturation while additions of calcium were largely complexed (3). Here may be an eloquent answer to the riddle of why stone disease correlates so incompletely with urinary calcium. It remains only to show that stone formers have higher 24-hr urinary oxalate excretions than do normals. However, this has been conclusively shown only for primary hyperoxaluria and for the newer entity of hyperoxaluria secondary to disease (or resection) of the terminal ileum (9). With one exception, numerous investigators including the Leeds group have found at most only slightly higher mean values in stone formers with a wide range of overlap. However, a group in Paris has performed over 20,000 such determinations using gas-liquid chromatography and claims elevations in the majority of patients (10). This problem is potentially one of great importance and ·subtlety. Not only is oxalate notoriously difficult to measure, but it is present in low concentrations (one tenth that of calcium on a molar basis), and small differences may be significant. Further, the daily variation is considerable even on a constant diet, and perhaps most important it is a function of dietary calcium intake. Urinary oxalate excretion can be shown to rise with calcium restriction (11). This phenomenon would provide a tidy explanation of stone recurrence in a patient whose initial stone was due mainly to hypercalciuria and whose subsequent stone on a low calcium diet might be due to secondary elevations of urinary oxalate. While the potential role of oxalate in

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stone disease is intriguing, there is little current data based on 24-hr urine collections to support it.

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POSSIBLE ROLE OF CALCIUM PHOSPHATE

So far nothing has been said of the calcium phosphate (apatite) that occurs either with calcium oxalate or as pure apatite stones. A feature common to all urinary phosphates is decreasing solubility with increasing pH. The evidence suggests that the stones in distal renal tw>ular acidosis are essentially pure apatite. The persistence of relatively more alkaline urine than normlW (pH> 6.0) is no doubt fundamental, although it is clearly not corrected with alkalinization therapy directed at the systemic acidosis and related hypercalciuria and low citrate excretion. However, since renal tubular acidosis is a rare disorder, file majority of pure or predominantly apatite stones are found in the large group of calcium stone formers. These patients appear to have generally more alkaline urines than do their counter­ parts with pure or predominantly calC+Um oxalate stones (12). It is not clear that gentle measures to acidify their urines would do anything more than change their stone composition to purer calcium oxalate, as the Leeds group finds as high peak urine calcium and oxalate concentrations as in the other stone formers (12). This admixed calcium phosphate may simply represent crystalluria which has been caught up in a calcium oxalate stone during alkaline tides. In this context an alternative theory has been proposed (13). Since at least 50% of calcium oxalate stones contain variable amounts of apatite, occasionally in a "nuclear" location, the suggestion has been made that it may well be this calcium phosphate that nucleates and "governs" the development of calcium oxalate calculi. By a mechanism analogous to one theory of bone formation, it is postulated that brushite (CaHP04) is the antecedant of the apatite in calculi and that supersatura­ tion of the urine for brushite may be the fundamental abnormality in calcium oxalate stone formers. The brushite would nucleate the calcium oxalate and then transform into apatite by hydrolysis. This transformation in urine is generally accepted and would account for the rarity of brushite in stones. It can also be shown that brushite will nucleate calcium oxalate. However, it is the application of this theory to patients and to urine that remains at issue. A potent regulator of brushite supersaturation is the pH of that urine. In the absence of hypercalciuria, urine is excessively supersaturated with brushite only when relatively alkaline. This is true of both stone formers and normals (13). In the Leeds study more alkaline urine is associated with the appearance of apatite in the calcium oxalate stones (12). So while such supersaturation for brushite accounts nicely for the apatite in stones, the dilemma is to show that it has anything at all to do with the calcium oxalate, especially in patients with normally acid urines. Finally, it seems likely that it is not the nucleation of calcium oxalate that is critical, as normal individuals have calcium phosphate crystalluria during alkaline tides as well as the small calcium oxalate crystals noted above. What is important for stone production are factors that promote stone growth of the relevant species, namely, calcium oxalate. These factors must be either calcium, oxalate, or lack of growth inhibitors.

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POSSIBLE ROLE OF URIC ACID

Another theory that represents a unique departure derives from the clinical observa­ tion that hyperuricemia is associated with calcium stone disease (14). In fact, given that calcium stones are about twelve times more common than uric acid stones and that only a minority of patients with uric acid stones have hyperuricemia, the likelihood is that a hyperuricemic stone patient will be a calcium oxalate stone former. This phenomenon has created the uneasy feeling that somehow uric acid may be nucleating calcium oxalate. However, it can be categorically stated that such stones do not have uric acid nuclei. The association of these two components is uncommon. A recent study has shown that some calcium stone formers do have small elevations of uric acid excretion even in the absence of hyperuricemia (15). But whether this is simply a consequence of diet or altered uric acid metabolism or renal handling is unclear, and whether it contributes to calculus production is simply speculation. If the notion is that exceedingly small uric acid crystals are nucleating calcium oxalate, then data concerning the possibility of more acid urines than normal should also be developed. It is interesting to note that both these new theories of stone pathogenesis (brush­ ite theory, uric acid theory) have relegated calcium oxalate to the role of the innocent bystander. In effect this is only possible by placing constraints on urinary pH. A tendency to more alkaline urine in the former and, by implication, more acid urine in the latter, is required. For calcium oxalate stones the dilemma is twofold: on the one hand it will be necessary to show that these phenomena are present without simply resulting in the appearance of significant amounts of apatite or uric acid in calcium oxalate stones, ane! on the other hand it will remain difficult to show that vanishingly small amounts of either apatite or uric acid control the growth of a stone that is greater than 95% calcium oxalate. TREATMENT

In the treatment of recurrent calcium stone disease several facts emerge. There are a host of therapeutic regimens and their theoretical utility depends on widely differing mechanisms. Yet, their proponents all claim effectiveness. In a disorder known for its intermittency and unpredicability, it is unfortunate that none of the therapeutic trials has a control group. The only control has been the patient's stone history prior to therapy. Also it is only human nature that patients will embark on therapy after having just passed one or more stones. One inescapable interpretation is that a control group would do just as well when being followed in a program by enthusiastic clinicians while maintaining dietary restriction and forcing fluids. In fact this possibility would make the detection of a truely effective medicine in a properly controlled setting all the more difficult. The first step in treatment is dietary calcium restriction and promotion of fluid intake. If stones continue to recur in spite of reductions of urinary calcium, then dietary oxalate restriction may be useful. Although such restriction has been shown to curtail secondary urinary oxalate elevations, adherence to such a regimen is difficult on an outpatient basis (11).

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For those patients who fail on dietary therapy, any of the following programs has been recommended. Cellulose phosphate is effective in reducing urinary calcium but has not been released by the FDA (16). It does not prevent secondary oxalate elevations (17). Thiazides are well tolerated and reduce urinary calcium by 50% (18) and do not appear to be associated with rises in oxalate (17). Oral phosphate therapy reduces urine calcium only modestly while greatly augmenting urine phosphate and increasing urine oxalate (19). Any beneficial effect of this drug probably resides in increased urinary pyrophosphate excretion. Magnesium oxide has been advocated by virtue of its ability to prevent calculi in pyridoxine-deficient rats, although the mechanism is uncertain (20), and pyridoxine has been used in conjunction with magnesium in the hope of lowering urinary oxalate excretion, although this effect has been inconstant (21). Allopurinol has been claimed effective although no entirely logical mechanism is evident (22). It might be related to decreases in urinary uric acid. Interestingly, xanthine oxidase is one of the three enzymes involved in the conversion of glyoxalate to oxalate. But this pathway appears to be of minor impor­ tance and the administration of allopurinol does not reduce urinary oxalate (23). Finally, succinimide (not available in the USA) lowers urinary oxalate perhaps by condensing with it and allowing it to be consumed by the Krebs cycle (10). Clearly, there is much work still to be done on the mechanisms underlying recurrence of calcium oxalate stones as well as its proper therapy. The question is of sufficient subtlety that it is unlikely that animal models will be useful as the one animal which most closely resembles the stone former is the normal human non­ stone former. Literature Cited

I.

2.

3. 4. 5.

6. 7.

Prien, E. L., Prien, E. L. Jr. 1968. Com­ position and structure of urinary stone. Am. J. Med. 45:654-72 Smith, L. H. Jr., Williams, H. E. 1971. Kidney stones. In Diseases of the Kid­ ney, ed. M. B. Strauss, L. G. Welt. 973-96. Boston: Little, Brown. 2nd ed. 1456 pp. Nordin, B. E. C. 1973. Metabolic Bone and Stone Disease. Baltimore: Williams and Wilkins. 309 pp. Howard, J. E., Thomas, W. C. Jr. 1968. Control of crystallization in urine. Am. J. Med. 45:693-99 Robertson, W. G., Peacock, M. 1972. Calcium oxalate crystalluria and inhibi­ tors of crystallization in recurrent renal stone formers. Clin. Sci. 43:499-506 Boyce, W. H. 1968. Organic matrix of human urinary concretions. Am. J. Med. 45:673-83 Robertson, W. G., Peacock, M., Nor­ din, B. E. C. 1969. Calcium crystalluria in recurrent renal stone formers. Lancet ii: 21-24

8. Robertson, W. G., Peacock, M., Nor­ din, B. E. C. 1971. Calcium oxalate crystalluria and urine saturation in re­ current renal stone formers. Clin. Sci. 40:365-74 9. Chadwick, V. S., Modha, K., Dowling, R. H. 1973. Mechanism for hyperox­ aluria in patients with ileal dysfunction. N Engl. J. Med. 289: 172-76 10. Thomas, J. et a1 1973. The role of oxalic acid in oxalic nephrolithiasis. In Pro­ ceedings of the International Sym­ posium on Renal Stone Research, ed.

L. Cifuentes Delatte, A. Rapado, A. Hodgkinson. 57-66. Madrid, Spain: S. Karger. 363 pp. II. Marshall, R. W., Cochran, M., Hodg­ kinson, A. 1972. Relationships between calcium and oxalic acid intake in the diet and their excretion in the urine of normal and renal-stone-forming sub­ jects. Clin. Sci. 43:91-99 12. Marshall, R. W. et aI1972. The relation between the concentration of calcium salts in the urine and renal stone com­ position in patients with calcium-con-

CALCIUM OXALATE RENAL STONES

Annu. Rev. Med. 1975.26:173-179. Downloaded from www.annualreviews.org Access provided by University of Texas Southwestern Medical Center on 01/27/15. For personal use only.

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14.

IS.

16.

17.

taining renal stones. Clin. Sci. 43: 433--41 Pak, C. Y. C. 1969. Physiochemical ba­ sis for the formation of renal stones of calcium phosphate origin: Calculation of the degree of saturation of the urine with respect to brushite. J Clin. Invest. 48:1914-22 Smith, M. J. Y., Hunt, L. D., King, J. S. Jr., Boyce, W. H. 1969. Uricemia and urolithiasis. JUral. 101:637--42 Kavalich, A., Moran, E., Coe, F. 1973. Mechanism of hyperuricosuria in cal­ cium stone formers. Proc. Am. Soc. Ne­ phrol. 6:57 (Abstr.) Pak, C. Y. c., Delea, C. S., Bartter, F. C. 1974. Successful treatment of re­ current nephrolithiasis (calcium stones) with cellulose phosphate. N. Engl. J Med. 290:175-80 Marshall, R. W., Barry, H. 1973. Urine saturation and the formation of calci­ um-containing renal calculi: The effects of various forms of therapy. See Ref. 10,

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pp. 164-69 18. Yendt, E. R., Guay, G. F., Garcia, D. A. 1970. The use of thiazides in the pre­ vention of renal calculi. Can. Med. As­ soc. J 102:614-20 19. Smith, L. H., Thomas, W. C. Jr., Ar­ naud, C. D. 1973. Orthophosphate therapy in calcium renal lithiasis. See Ref. 10, pp. 188-97 20. Melnick, I., Landes, R. R., Hoffman, A. A., Burch, J. F. 1971. Magnesium therapy for recurring calcium oxalate urinary calculi. JUral. 105:119-22 21. Prien, E. L., Gershoff, S. F. 1974. Mag­ nesium oxide-pyridoxine therapy for recurrent calcium oxalate calculi. J Ural. 112:509-12 22. Coe, F. L., Raisen, L. 1973. Allopurinol treatment of uric acid disorders in cal­ cium stone formers. Lancet i:129-31 23. Gibbs, D. A., Watts, R. W. E. 1966. An investigation of the possible role of xan­ thine oxidase in the oxidation of glyoxa­ late to oxalate Clin. ScL 31:285-97

Calcium oxalate renal stones.

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