Inhibitors and Promoters of Stone Formation

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 13 (1978), pp. 361—3 71 Inhibitors and promoters of stone formation HERBERT FLEISCH Department of Pathophysiology, University of Berne, Berne, Switzerland Currently, three main mechanisms are thought to Crystal growth and crystal aggregation be important in the formation of urinary stones: 1) In the past, attention was devoted mostly to the the relationship between the concentration of the formation and growth of crystals. Recently, interest precipitating substances in urine and the solubility of has been directed to an area which, until now, had the mineral phase formed, 2) the role of promoters of been neglected: the crystal aggregation. This term crystallization and aggregation, and 3) the part describes the process of crystals binding one to an- played by inhibitors of crystal formation and aggre- other, resulting in the formation of larger clusters. In gation (Fig. 1). vitro, aggregation of both calcium oxalate [16, 17] Saturation of urine and calcium phosphate crystals [18] occurs readily when the solution is supersaturated. Aggregation It is now widely accepted that even in normal could be the mechanism which distinguishes simple people, urine is ordinarily supersaturated with re- crystalluria, which occurs in most normal people, spect to calcium oxalate [1—6], octocalcium phos- from stone formation. This line of thought is phate [2, 3], hydroxyapatite [1, 2], and sometimes strengthened by the finding that while usually only with respect to brushite [1, 7, 8]. The degree of individual calcium oxalate crystals are found in nor- supersaturation is usually higher in patients with mal people, stone-formers often excrete large aggre- urinary stones [2—4, 7—10]. This is due mainly be- gates of this salt [16, 19]. cause these patients tend to excrete more calcium [10—12], but also because urinary oxalate can be Promoters of crystallization increased [10, 13]. Urine is also often supersaturated A few years ago, great emphasis was placed on the with respect to sodium urate and ammonium urate supposed activating role of organic compounds in [14, 15]. Supersaturation with regard to magnesium urine [20]. This was based on the finding that urinary ammonium phosphate is restricted to the cases proteins bind calcium [21] and can induce calcifica- where the urine becomes alkaline because of ammo- tion in vitro [22] under certain conditions. Further- nium production by bacteria [2] (GRIFFITH, this more, proteins are increased in amount [22, 23] and issue). are qualitatively different [24, 25] in urine samples Supersaturation can vary in degree. It can be in the from stone-formers than in that from normal people. metastable range where precipitation may occur only Such an activating theory was invoked to account for when induced by epitaxy or heterogenous nuclea- the close morphological relation existing between the tion, or it can be in the unstable region where rapid matrix and the mineral in the stones [26, 27]. All spontaneous precipitation does occur. The limit be- these results, however, give no evidence that the tween the two ranges, which can be called the spon- change in the urinary proteins is the primary event in taneous formation product, is not a fixed number but stone formation. Indeed, they just as well might be will depend upon the duration of incubation. secondary to the irritation from the stone and to These theoretical considerations are relevant to infection. The morphological relation between ma- what occurs in vivo. It was found that when the trix and mineral could be due to a co-precipitation of urinary saturation measured chemically is above the the proteins with the mineral or their secondary spontaneous formation product required for a rapid binding onto the crystals [28]. Lately, the theory of induction of precipitation in inorganic solutions, crystals can usually be detected in the voided urine specimen [3]. On the other hand, when the ion prod- 0085—2538/78/0013—0361 $02.20 uct is below this product, crystals are absent. © 1978, by the International Society of Nephrology. 361 362 Fleisch cretion of urate, reduces the formation of calcium I SUPERSATURATED SOLUTION stones [34, 35] (seeCOE,this issue). 4 Homogenous/heterogenous nucleation Inhibitors of crystallization and crystal growth Since urine usually is supersaturated with respect to the various stone-forming salts and contains crys- SMALL CRYSTALS tals, the conditions for crystal formation, aggrega- 9'- tion, and thus stone formation are satisfied. Thus, Crystal growth Crystal aggregation the main question is not why stones can form but 4 1 why stones do not form more generally. One explanation might be the presence in urine of very effec- I LARGECRYSTALS -.0.1 CRYSTALAGGREGATES I tive inhibitors for both these processes, crystal for- t mation and aggregation. Fig.1. Mechanisms of mineral formation. Inhibition of crystal growthis denoted by open arrows; inhibition of crystal aggrega- Inhibitors of ihe formation of calcium phosphate tion is denoted by the large closed arrows. Chemical estimation of inhibitory activity. One of the first techniques testing urine's inhibitory capacity the activating role of urinary proteins has been aban- [36, 37] made use of a system, described in the doned by most investigators. As such a role, how- 1930's, for studying the calcification of cartilage [38]. ever, could not be proven, it also has not been Epiphyseal cartilage from rachitic rats was incubated disproven. in vitro in a supersaturated salt solution, and the In recent years, emphasis has been shifted towards precipitation of calcium phosphate was studied. Ur- the role of crystals of one salt inducing the crystalli- ine or the substances to be tested are added to the zation of a salt of another nature. Such an epitactic incubation fluid. The results, however, are difficult induction between crystals having similarities in lat- to interpret. Since the cartilage is enzymatically very tice dimensions is a well known phenomenon in active, it is likely to destroy certain inhibitors. Fur- crystallography. Relevant lattice similarities are thermore, the test substance or urine may influence present between uric acid, calcium oxalate, and cal- the enzyme activity as well as the metabolic ma- cium phosphate crystals [29], and epitactic induction chinery of the incubating cartilage, thereby altering does occur among them. Thus, the precipitation of the precipitation by a mechanism unrelated to crystal sodium urate is favored by both hydroxyapatite and growth inhibitors [39]. Obviously, the results ob- calcium oxalate [30]. The precipitation of calcium tained can be totally unrelated to stone formation, oxalate can be induced from a metastable solution by and the technique, while possibly useful for cartilage hydroxyapatite [30, 31], brushite [30], and urate [30, calcification, should be abandoned for the study of 32, 33] but not consistently by uric acid [30, 33] (see stone formation. Dr.Coe's article, this issue). Conversely, calcium A theoretically correct approach of practical im- phosphate precipitation is stimulated by both cal- portance is the determination in vitro of the mini- cium oxalate and monosodium urate crystals [30, mum product of calcium x phosphate (formation 33], while uric acid is not effective [30, 33]. Interest- product) necessary for the formation of a solid phase ingly, this effect of calcium oxalate on calcium phos- within a preset time period under defined conditions. phate precipitation is not as efficient as the reverse The experimental conditions of this technique, which [31]. This might be because hydroxyapatite is not the measures mainly heterogenous nucleation (see FIN- first salt to form when calcium phosphate precipi- LAY5ON, this issue), are critical and need to be care- tates, but is preceded by other phases, the nature of fully controlled. For example, the time of incubation which is still disputed. These initially formed phases has an inverse effect: the shorter the time of incuba- spontaneously transform into the more stable tion the greater the formation product [40]. Inhibi- hydroxyapatite. tors will increase this product. It has been reported This epitactic mechanism of precipitation could that inhibitors are not active at very short incubation give an explanation for the well known fact that most times, and that they increase the formation product stones are formed not just by one salt but by a value only up to that obtained at short incubation mixture of different kinds of salts. It could also times [40]. It has been suggested that this occurs explain the clinical findings that patients with cal- because homogenous nucleation is predominant ini- cium stones are often hyperuricosuric [34] and that tially, and is later replaced by heterogenous nuclea- treatment with allopurinol, which decreases the ex- tion. However, as discussed in Finlayson's article Inhibitors and promoters of stones 363 (this issue), it is unlikely that homogenous nucleation measurement of inhibitory activity in diluted urine could proceed in complex solution such as urine. may not be representative of whole urine. Since Moreover, the report showing the independence of inhibitory activity is generally not related linearly formation product from inhibitor activity has not with its concentration, and since the concentration- been confirmed [411. effect relation is different for the various inhibitors, It must

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