Kinetic Factors Influencing the Dissolution Behavior of Calcium Oxalate Renal Stones: A Constant Composition Study

Transcription

1 Calcif Tissue Int (1988) 43: Calcified Tissue International Springer-Verlag New York Inc. Kinetic Factors Influencing the Dissolution Behavior of Calcium Oxalate Renal Stones: A Constant Composition Study Donald J. White,* Margaret Coyle-Rees, and George H. Nancollas Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, USA Summary. A constant composition method has been used to examine the dissolution kinetics of calcium oxalate renal stones over a wide range of undersaturation in vitro. Demineralization experiments have been carried out with the concentrations of calcium and oxalate ions and ionic strength (hence the solution undersaturation) held constant by the potentiometrically controlled addition of medium electrolyte solution as diluent, triggered by a calcium ion electrode. Kinetic data for renal stones have been compared with results obtained for synthetic calcium oxalate. In addition, constant composition results have been directly compared with results obtained using conventional dissolution methods for both calculi and synthetic calcium oxalate. Overall, calcium oxalate renal stones exhibited markedly different kinetic dissolution behavior as compared with synthetic controls. The renal stone samples dissolved more slowly at all undersaturations, exhibited increased kinetic orders of reaction, and showed reduced sensitivity to solution hydrodynamics. Stones composed of mixed hydrates of calcium oxalate (mono- and di-) came to dihydrate equilibrium in conventional experiments and underwent net dissolution in solutions supersaturated to monohydrate under constant composition conditions. No conversion of di- to monohydrate was observed under these experimental conditions. These results indicate that stone dissolution is strongly influenced by adsorbed inhibitors, presumably including matrix components, which may complicate efforts to develop systemic *Present address: The Procter and Gamble Company, Sharon Woods Technical Center, Cincinnati, OH 45241, USA. Send reprint requests to Donald J. White at his present address. and/or irrigation measures effective for in situ solubilization. Key words: Calcium oxalate -- Constant composition -- Chemolysis -- Dissolution -- Kinetics -- Renal stones. Historically, there has been much interest in the development of methods capable of dissolving renal calculi in situ. Recent technical advances, however, such as shockwave therapy, have advanced methods of renal stone treatment considerably. Nevertheless, there would still be widespread interest in the development of effective techniques for stone chemolysis, because the solubilization of stone fragments following surgery or disintegration would provide useful ancillary treatments to limit the recurrence of calculus formation [1-2]. The advantages of in situ chemolysis of renal stones are obvious, but a number of factors have limited the development of effective methods to achieve this goal. Overall, there are two approaches to renal stone chemolysis. The first approach (and the ultimate goal of research) is to develop a nontoxic, orally administered compound that would show specificity for being safely excreted into the urine and solubilizing stone mineral deposits. This "systemic" dissolution of calculi, if free of side effects, would be greatly beneficial for stone sufferers. The second approach, more practical in many instances, is the development of methods for flushing the renal system with stone mineral-dissolving solutions using either retrograde irrigation [3] or percutaneous nephrostomy [4-5].

2 320 D.J. White et al.: Dissolution of Renal Stones In general, both systemic and irrigation methods have had varied success in the treatment of renal stone minerals sensitive to ph fluctuations in the urine. Thus, uric acid calculi can be solubilized both systemically [6-8] and by irrigation procedures [9-11], due to the sensitivity of uric acid to increases in ph. Similarly, struvite stones (i.e., magnesium ammonium phosphate), and other phosphatic calculi, have been systemically solubilized [12] and dissolved by irrigation procedures [12, 13] that lower urinary ph. Stones composed of calcium oxalate, in contrast, have proven resistant to dissolution through the alteration of urine ph. Thus, to date, no successful oral or parenteral therapy has been applied for direct solubilization of calcium oxalate calculi. External irrigation, though partially successful, has proved difficult to administer safely due to the high concentration of chelating species, like EDTA or citrate, needed to evoke reasonable rates of stone dissolution [3, 14-16]. The limited success in the development of safe and effective measures towards the in situ solubilization of calcium oxalate calculi is unfortunate, because both the di- (COD) and monohydrate (COM) forms of calcium oxalate (alone, or admixed with other minerals) make up over 80% of all stone mineral deposits [17]. Obviously, it would be most desirable to have effective methods at our disposal for the in situ solubilization of calcium oxalate renal stones. In order to develop these, a more complete understanding of the factors influencing calcium oxalate stone dissolution is necessary. Numerous previous studies of calcium oxalate stone dissolution have focused on the effects of various calcium chelants in an effort to simulate the efficacy of irrigation measures. Thus, Pawelchak et al. [18-21], Wong [22], Verplaetse et al. [15-16], Ziolkowski and Perrin [23], Burns et al. [24] and Butkevitch et al. [25-27] have assessed the effects of factors such as ph, chelant concentration, flow dynamics, and the nature of the metal ion chelating species on the in vitro chemolysis of both synthetic and actual renal stone concretions. In all of these studies, and in model in vitro studies of struvite [28] and uric acid calculi [29], relatively high undersaturations have been used. Studies of calcium oxalate stone dissolution at more moderate undersaturations would provide valuable insight into factors influencing oxalate stone reactivity under conditions more closely simulating possible systemic dissolution, while avoiding tissue damage. In addition, studies of calcium oxalate stone dissolution over a wider range of undersaturation may provide insight into the processes controlling the equilibria and distribution of the metastable hydrate phases of calcium oxalate present in the majority of calculi. Both the di- and trihydrate forms of calcium oxalate have been implicated as precursors to stone initiation and growth [30-32]. In a preliminary study, Tomazic and Nancollas [33] used conventional dissolution methods to compare the demineralization of several calcium oxalate renal stones with synthetic COM and COD. In the present study, both conventional and highly accurate constant composition demineralization methods [34] have been applied to quantitatively compare the dissolution kinetics of calcium oxalate renal calculi with synthetic calcium oxalate minerals. In the constant composition (CC) method, the solution undersaturation is maintained by the potentiometrically controlled addition of background electrolyte (diluent) solution triggered by a calcium electrode within the working solution [34]. The precise control of solution undersaturation enables demineralization experiments to be accurately performed over a wide range of undersaturations and with significant extents (%) of dissolution not possible with conventional techniques. A further benefit of the CC technique is that it allows experiments to be performed in solutions transiently supersaturated with respect to calcium oxalate monohydrate (COM), while undersaturated with respect to calcium oxalate dihydrate (COD), thereby providing information on the processes influencing the phase stability of mineral phases within renal calculi. Methods and Materials Solution Preparation Stock potassium oxalate, calcium chloride, and sodium chloride solutions were prepared from reagent grade chemicals (Fischer Scientific) using doubly distilled deionized water and Grade A glassware. Solutions were filtered (0.22 Ixm, prewashed Millipore) and standardized (_+ 0.10%) by ion exchange (Dowex 50) prior to use. Seed Material Preparation Seed materials for dissolution experiments included synthetic calcium oxalate monohydrate (COM) prepared using methods described previously [35] and characterized by X-ray powder diffraction (Cu Ka radiation, Phillips XRG 3000 Diffractometer). The synthetic seed crystals showed no evidence for the presence of either the di-(cod) or tri-(cot) hydrates. The COM seed, with a specific surface area of 2.47 m2g- 1, (N2, Single Point BET Adsorption, Quantasorb Instrument, Quantachrome Corp.) was

3 D. J. White et al.: Dissolution of Renal Stones 321 Table 1. Composition of dissolution seed materials X-ray phase Material analysis SSA (m2/g) Ca% ~ Mg% P04% Synthetic COM Stone JS COM/COD tr b 0 Stone HS COM/COD Stone DS COM/COD tr 0.5 Stone ES COM tr 0 a Wet wt. % of material in sample b Trace of material seen by atomic absorption--close to detection limit aged for 6 months at 37~ in an aqueous suspension containing 10 mg COM cc -~ of slurry. Samples of renal stones, kindly provided by Dr. Lynwood Smith of the Mayo Clinic, were stored frozen until used. Fractions of each renal stone were removed and ground into fine powders using a mortar and pestle. Weighed portions of the powdered stones were solubilized in hot 0.5 mol L-~ HC1 for analysis of calcium, magnesium, and phosphate ions using a combination method in which the metal ions were determined by atomic absorption and the phosphate was measured spectrophotometrically as a vanadomolybdate complex [36]. X-ray powder diffraction analysis was used to characterize mineral phases present within the powdered calculi, which were composed primarily of COM and COD. The relative proportions of COM/ COD were determined using the X-ray method previously described by Tomazic and Nancollas [30]. The specific surface area of each of the stone samples was measured using the single point BET method described above. Stone analyses are shown in Table 1 in which the wt% calcium contents are reduced relative to the synthetic COM sample due to the presence of organic matrix as well as some adsorbed water. No effort was made to measure either of these quantities. Powdered stone samples were stored at 5~ in polyethylene vials prior to use. Dissolution Experiments Conventional dissolution experiments were carried out in a water thermostated 250 ml double-walled reaction vessel maintained at I~ The reaction solution was stirred magnetically using a 2 inch teflon coated stir bar. Stirring speeds were adjusted stroboscopically. Throughout the experiments, presaturated N2 gas was bubbled continuously through the solution in order to purge CO2. Experiments were initiated by adding 150 ml of 0.15 mol L -~ NaC1 background electrolyte into the reaction vessel and allowing it to come to thermal equilibrium. Following stirring speed adjustment, seed crystals were introduced (by pipette for synthetic COM slurry; as powder for ground stones). The dissolution rate was monitored by filtering aliquots through 0.22 ~m Millipore filters and analyzing the supernatant for calcium using atomic absorption. Solid phases collected during sampling were washed with 5 ml of water, dried under vacuum at room temperature, and examined by scanning electron microscopy (ISI Model Super II) and X-ray powder diffraction. Constant composition dissolution experiments were similarly carried out in the thermostated reaction vessel. During experiments, the calcium ion activity was measured using a Radiom- eter Ca electrode (Model F2112, Radiometer Inst. Co.) coupled with a thermal electrolytic Ag/AgCI reference electrode. The latter was immersed in 4.0 mol L-~ KC1, saturated with respect to AgCI in the thermostated limb of the electrode assembly and was separated from the working solution by an intermediate liquid junction containing the medium electrolyte. Variations in working solution ionic strength, due to salt bridge leakage, were thereby effectively eliminated. To initiate CC experiments, solutions of desired undersaturation were prepared by the addition of stock calcium chloride and potassium oxalate to the reaction vessel containing 0.15 mol L-~ NaC1 medium electrolyte. During calcium addition, the calcium ion electrode was calibrated by monitoring the electromotive force (em0. Following the preparation of the undersaturated solution, the potentiostat (Metrohm- Herisau, Switzerland) was preset at the recorded emf ( mv) to maintain the desired calcium ion activity during demineralization. Experiments were initiated by the addition of seed slurry or powdered renal stone samples into the reaction vessel as described earlier. During dissolution, the reaction solution composition was maintained constant by the pca-stat-controlled addition of 0.15 mol liter -1 NaC1 diluent solution from a single 50 ml piston-driven burette (Dosimat Model E415). In addition, aliquots were periodically withdrawn and analyzed for calcium by atomic absorption in order to verify the constancy of solution composition ( 2.0%). Solid samples were collected and analyzed by X-ray powder diffraction and scanning electron microscopy. Results Conventional Dissolution The results of conventional experiments are shown in Figure 1, in which the dissolution profiles for two renal stones are compared with results for synthetic COM seed. One renal stone, ES, in Figure 1, was comprised of only COM, whereas another stone, labeled HS, consisted of a mixture of COM and COD. During the early stages of dissolution, the synthetic COM was observed to undergo more rapid dissolution than either of the stone samples. Later, both the synthetic COM and the renal stones appeared to approach solubility equilibrium, which differed for the two stone samples. The COM stone

4 " 322 D.J. White et al.: Dissolution of Renal Stones 3 " ' ' " " ' " I ' ~ r r r r t COD I I I I ~o ~t x < 2 / CON i g 1 z ~ U ~ _~1"-~ -a----a--(. i e TINE (Nin) Fig. 1. Conventional dissolution of synthetic COM (A) and renal stone samples ES (0) and HS (B). In each experiment, 10 mg of seed crystals were added. The molar concentration of dissolved CaOx is plotted against time. The equilibrium solubilities of calcium oxalate mono- (COM) and di- (COD) hydrate are shown for reference. came to an equilibrium similar to that for pure COM. Dissolution of the mixed COM/COD stone, however, showed more complex kinetic behavior. Initially, the mixed hydrate stone (HS) dissolved more slowly than synthetic COM, but subsequently the amount dissolved increased above the COM solubility value and approached the solubility expected for COD [30]. Surprisingly, X-ray analysis revealed no apparent conversion of COD --~ COM for the HS stone sample, despite the fact that the saturated solution was supersaturated with respect to COM and that COM was a partial constituent of the stone. The observed equilibrium concentration remained constant for several hours following the plateau shown in Figure 1. Constant Composition Dissolution The constant composition experiments verified the general results of the conventional dissolution, as shown in Figures 2 and 3. In Figure 2, the dissolution rates of four stone samples are compared directly with that for synthetic COM at a single undersaturation. The rate is normalized for the (BET) specific surface area of the various seed materials. In this case, the demineralization solution was undersaturated with respect to both COM and COD. As shown, the dissolution rate of all stone samples was less than that of the synthetic COM control. [//~, I, I, I, 2 4 F; 8 10 TINE (Nin) Fig. 2. Constant composition dissolution of synthetic COM (&) and renal stone samples DS (~), JS (B), ES (&), and HS (~). In each experiment, equal masses of seed crystals (10 mg) were added. The amount of calcium oxalate dissolved, shown in the figure, is normalized for surface area of seed materials. The solution undersaturation was held constant at ~ = 0.63 (w/respect to COM), in all experiments. In Figure 3, the dissolution rates for a mixed hydrate stone (JS) are compared with rates of synthetic COM over a range of undersaturations. The dissolution rate for the stone material was decreased relative to the synthetic COM at high undersaturations. As the undersaturation decreased, however, the rate of stone dissolution was observed to be increased relative to the synthetic COM. In two experiments carried out at an undersaturation with respect to COD but supersaturated with respect to COM, the mixed hydrate stone was observed to undergo net dissolution. Again, X-ray analysis revealed no apparent conversion of COD -~ COM within this experimental period (2 hours). This behavior agrees with the results found for conventional dissolution experiments near the saturation limit of COM, as shown in Figure 1. Quantitative Comparison of Dissolution Kinetics For quantitative comparison of the demineralization kinetics for the stone and synthetic samples it was necessary to monitor the demineralization reactions as a function of the thermodynamic driving force for dissolution [31, 33, 34, 37, 38]. In previous studies, the dissolution rate for calcium oxalate has been shown to follow Equation I:

5 D. J. White et al.: Dissolution of Renal Stones I I I I j ' I ' I % x 4.6.~ c~ 3.e O.B 1.0 Undersaturation er Fig. 3. Constant composition dissolution of synthetic COM (&) and renal stone JS (11) over a range of COM undersaturations. Each data point represents an individual experiment. Dissolution rates are normalized for specific surface area and are in units of mol min- l m 2. Rate = dtcjdt = dtox/dt = kos[kso w -- ([Ca2+][Ox2-])g2] n = kds A n (1) where the rate is expressed as moles of calcium, oxalate, or calcium oxalate per unit time, kd is the specific rate constant, Kso is the solubility product for calcium oxalate hydrate, s is the crystal surface area, the braces enclose the activities of the lattice ions in solution, and n represents the effective order of the reaction. The driving force for dissolution may also be expressed in terms of the relative degree of undersaturation, ~r, normalized for the solubility of the mineral phase: Rate = kdso-" = kds[kso -v2 A] n (2) In the present study, the dissolution rates from both conventional and CC experiments have been normalized for the BET surface areas of the seeds and are expressed as mol min -1 m -2. (For synthetic crystals, the SSA normalization allows direct quantitative comparisons, but for stone materials this normalization can only be considered an estimate, since the matrix occupies an unknown portion of the surface area.) The driving forces for dissolution have been calculated from mass balance and electroneutrality relations, taking into account the formation of ion pairs in the solutions [35, 39]. Activity coefficients were calculated from the extended form of the Debye-Huckel equation proposed by Davies [40]. The thermodynamic solubility products of COM and COD (at 37~ were i 3.0 b'~, I, I ~ 1, fi log z~ Fig. 4. Dissolution kinetic analyses for synthetic COM (B, ~) and renal stone samples JS (&), DS (r HS (A), and ES (D), expressed as a logarithmic plot of equation 1. Filled symbols represent constant composition experiments; open symbols represent conventional dissolution studies. The dissolution rates are all normalized with respect to (BET) surface area. Conventional experiments were carried out at a stirring speed of 200 rpm, and constant composition experiments were made at 100 rpm. The partially filled points (~1) represent conventional experiments carried out at the lower stirring speed. The slope of the best fit lines yields the effective kinetic "order" of the reaction. taken as mol 2 liter -2 and mop liter -2 as described by Tomazic and Nancollas [301. In Figure 4, a logarithmic plot of Equation 1 is used to compare renal stone and synthetic COM demineralization for the conventional and CC experiments. The dissolution rates at the various undersaturations in the conventional experiments were determined by analysis of tangents to the dissolution curve (Gardner and Nancollas [37] and Tomazic and NancoUas [30]). The solid data points reflect data from the conventional experiments, and the open points represent results from CC experiments. The linear plots of unit slope shown in Figure 4 indicate that the dissolution of synthetic COM seed material is described by equation (1) with n = 1 over the undersaturation range from -log A = In addition, a change in stirring speed from 100 to 200 rpm, resulted in a 31% increase in the rate constant for COM dissolution. Both of these observations indicate diffusion-controlled demineralization for synthetic COM, in agreement with previous reports [34, 37, 42]. Importantly, the constant composition and conventional experiments were in excellent agreement

6 324 D.J. White et al.: Dissolution of Renal Stones 16.0 * v, w Discussion Ol o g t TI~ [Min) Fig. 5. Constant composition experiments examining the effect of stirring speed on the dissolution of synthetic COM and renal stone JS; (.), COM, 100 rpm; (ll) COM, 200 rpm; (A) JS, 100 rpm; ([]) JS, 200 rpm. Stone experiments were carried out at an undersaturation of cr = 0.63 (w/respect to COM) and synthetic COM at cr = 0.58 (w/respect to COM), respectively. All rates are normalized for seed specific surface area. under identical conditions of undersaturation and hydrodynamics (the partially filled data points in Fig. 4). Overall, the CC technique provided a more accurate (+ 5%) measure of dissolution rates [34]. In terms of renal stone dissolution, the results of the kinetic analysis in Figure 4 show much more complexity than in the case of synthetic COM. Overall, the results show that the rate of renal stone dissolution is much slower than synthetic mineral over a wide range of undersaturation. The decreased rate averaged about one order of magnitude, following normalization for specific surface area. In addition to slower rates, the renal stone samples exhibited more complex patterns of behavior as a function of undersaturation. The value of n, determined from the slopes of the lines in Figure 4, varied from stone to stone, ranging from 0.5 to 3.5. In addition, the value ofn changed markedly as a function of undersaturation for several renal stones (HS-DS in Fig. 4). The effect of hydrodynamics on stone mineral dissolution are illustrated in Figure 5, where constant composition results for stone and synthetic samples are directly compared. As shown, stone dissolution was insensitive to solution hydrodynamics, whereas synthetic COM dissolution showed large increases with increased stirring speeds. A * The results of this study demonstrate significant differences in dissolution behavior for calcium oxalate renal stones compared with synthetic stone minerals. Primary differences include (1) the absolute rate of dissolution; (2) the variation in dissolution rate as a function of thermodynamic undersaturation; (3) the change in dissolution rate as a function of solution hydrodynamics; and (4) the effect of mixed hydrate composition on the overall dissolution kinetics. In terms of dissolution rates, renal stone materials exhibited significantly decreased rates of demineralization (normalized for approximate mineral surface area) compared with synthetic calcium oxalate. On average, the dissolution rates of renal stones were an order of magnitude less than that observed for synthetic COM over the entire range of solution undersaturation. This difference could not be attributed to variation in crystallinity or mineral content between the stone and synthetic samples, as the mineral content of the stone samples was more than 80% by weight. Analysis of dissolution kinetics as a function of undersaturation (see Fig. 4) indicated more complex behavior for stone samples in contrast to the simple first order kinetics observed for COM. The order of reaction for stone materials (equations! and 2) varied considerably among samples, ranging from 0.5 (mechanistic interpretation unclear) to over 3.5 (probable polynuclear mechanism [38]). In addition, in several cases, the apparent order of reaction changed, within a given sample, as a function of undersaturation, decreasing as the undersaturation increased. This "order of reaction" is partially indicative of the rate-controlling processes governing the kinetics, with n = 1 characterizing simple diffusion control, and n > 1 suggesting more complex surface diffusion or polynucleation processes [38]. The results of these experiments, therefore, suggest that surface-dominated processes may predominate for the dissolution of renal stone minerals over a very wide range of solution undersaturations, and furthermore, that the ratecontrolling processes for stone demineralization may change over a range of undersaturation. (Similar behavior has been observed for synthetic calcium oxalate, but at very low undersaturations, near the solubility equilibrium of COM [34]). These observations are further supported by studies of renal stone demineralization as a function of hydrodynamics, as illustrated in Figure 5. Typically, the combination of (1) decreased rate of dissolution, (2) increased order of reaction, and (3) insensitivity to

7 D. J. White et al.: Dissolution of Renal Stones 325 solution hydrodynamics strongly suggest a surfacecontrolled mechanism for mineral dissolution. These findings are in general agreement with earlier results of Tomazic and Nancollas [33, 42] who, using conventional dissolution methods, observed slower rates and more complex kinetics for powdered calcium oxalate renal stones. The results may be attributed to the influence of adsorbed inhibitors, possibly from the stone matrix, on the calculus mineral surfaces. The nature of these inhibitors cannot be elucidated from the present study, although known inhibitors of calcium oxalate deposition in urine would presumably be involved. Both magnesium and phosphate, components of the stones shown in Table 1, could act as inhibitors when released into solution during demineralization [33]. Recent studies of extracted stone matrix components show these to be effective inhibitors of mineralization as well (Lanzalaco et al, unpublished data, 1987). If we assume that adsorbed inhibitors are responsible for the observed stone dissolution kinetics, the results can be compared with those for calcium oxalate dissolution in the presence of powerful synthetic inhibitors, such as ENTMP (ethylene diamine tetramethylene phosphonic acid), where a first order diffusion reaction becomes surface controlled over a wide range of solution undersaturation [41]. The reason for the variability of the reaction order n for the renal stones is unknown, but may be related to more complex "mixed" inhibition by stone regulators compared with simple synthetic inhibitors. One aspect of these results of particular interest concerned calcium oxalate dihydrate dissolution under conditions supersaturated with respect to the monohydrate phase. In the conventional experiments, mixed hydrate stones were observed to come to COD equilibrium. CC studies further verified substantial rates of mixed hydrate stone dissolution under conditions supersaturated with respect to COM. These results are somewhat surprising, since autocatalytic transformation of COD ~ COM would be expected to occur under these conditions, as previously documented by Tomazic and Nancollas [30, 32, 33] for both synthetic COD and COD stone minerals. It is likely that the inhibitors responsible for the reduced rates of stone dissolution can also interfere with the dissolution/reprecipitation mechanism necessary for the transformation reaction [30, 33]. These species could be released from the stone matrix during dissolution experiments, and would be expected to particularly influence CC results at large extents of sample demineralization. Though phase specificity of inhibitors (i.e., inhibitors working more effectively on COD than COM) cannot be ruled out, the observed reactivity may be speculated as the result of different overall energetics required for crystal growth and dissolution under these conditions, coupled with the effects of inhibitors. In their previous study, Tomazic and Nancoilas [33] similarly observed a short-term COD equilibrium during (COD) stone dissolution, but after extended periods which varied widely between stone samples, the samples did convert to COM. We saw no conversion within the time frame of these experiments, which were of shorter duration. It is possible that different stones contain different amounts of adsorbed inhibitors, and therefore the dissolution and phase transformation reactions may be quite variable. A more extensive analysis would provide further understanding of this phenomenon. It is important to note that the results of the present study and the conventional dissolution studies of Nancollas and Tomazic [33, 42] do differ substantially from results of dissolution experiments on synthetic and natural calculi reported previously [15-27]. In the latter, blocks of renal stones were found to undergo diffusion-controlled dissolution initially, similar to that observed for synthetic calcium oxalate under a variety of conditions [34, 37]. The likely reason for these differences are that previous investigations were carried out only under sink conditions where diffusion control is favored. In contrast, this investigation was carried out at several undersaturations, ranging up to mineral saturation with respect to both COM and COD. Interestingly, the results of the present study show decreased orders of reaction and dissolution rates more closely matching synthetic calcium oxalate as the undersaturation is progressively increased. This behavior, collectively representing a conversion to more diffusion control, would be in direct agreement with prior demineralization investigations at similar driving forces. In any case, it must be pointed out that even under the sink conditions of earlier investigations, the inhibitory effect of the organic matrix was considerable, changing the observed initial bulk diffusion-controlled rates to biphasic dissolution, and significantly slowing chemolysis [18-21]. The results of this study may have significant mechanistic and clinical implications. From a stone mechanism standpoint, the results suggest that the COD ~ COM relationship is extremely complex, with in vivo conversion/growth/dissolution reactivity variably influenced by adsorbed inhibitors and matrix material. Studies of mineral growth/dissolution in the absence of urinary inhibitor species

8 326 D.J. White et al.: Dissolution of Renal Stones may not be representative of natural processes occurring in situ. Alternative in vitro procedures, including the controlled crystallization and/or dissolution in whole urines would possibly represent superior methodologies [43]. From a clinical standpoint, the results of this study clearly confirm the difficulties involved in developing systemic conditions favoring the solubilization of calcium oxalate calculi. Under all but sink conditions, the dissolution of the oxalate renal stone minerals is considerably slower than synthetic minerals. It is well known that calcium oxalate mineral solubility is insensitive to ph fluctuations in the urine [24]. The only alternative to increasing the undersaturation to favor stone dissolution is the reduction in free calcium or oxalate species in the urine. Again, this could only be accomplished by specific chelation of the ions or by dilution, neither of which appears practical at the present time. In terms of irrigation procedures, these results confirm that matrix substances may act not only as a physical barrier towards the effective solubilization of renal stones, but also by specifically inhibiting mineral dissolution. Further studies on the effects of chelators over a range of undersaturation are in progress. Acknowledgment. We thank the National Institutes of Health for a grant (DK 19048) in support of this work, and acknowledge the aid of Dr. A. C. Lanzalaco in initiating these studies. References 1. Miller RA, Payne SR, Wickham JEA (1984) Electrohydraulic nephrolithotripsy: a preferable alternative to ultrasound. Br J Urol 56: Oosterlink W, De Sy WA (1983) A new percutaneous nephrostomy set. J Urol 129: Kallistratos G (1975) Litholytic agents with bacteriostatic properties in the conservative treatment of urolithiasis. 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