Experimental determination of multiple thermodynamic and kinetic risk factors for nephrolithiasis in the urine of healthy controls and calcium oxalate stone formers: does a universal discriminator exist?

Abstract

Nephrolithiasis is thought to be governed by urinary thermodynamic and kinetic risk factors. However, identification of one or more of these factors which consistently and unambiguously differentiates between healthy subjects (N) and calcium oxalate (CaOx) renal stone patients (SF) remains elusive. The present study addresses this challenge. 24 h urines were collected from 15 N and 10 SF. Urine compositions were used to compute thermodynamic risk indices including urinary ratios, quotients and supersaturation (SS) values, while CaOx metastable limits (MSL) were determined experimentally. Crystallisation kinetics was determined by measuring rates of particle formation (number, volume, size) using a Coulter counter multisizer (CC) and a Coulter flow cytometer (FC). Particle shapes were qualitatively differentiated by FC and were viewed directly by scanning electron microscopy. Several urinary composition ratios and risk quotients were significantly different between the groups. However, there were no significant differences between CaOx MSL or SS values. Using transformed FC data, the rate of CaOx crystallisation in SF was significantly greater than in N. This was not supported by CC measurements. There were no significant differences between the groups with respect to particle size or CaOx crystal growth rates. Single and aggregated CaOx dihydrate crystals were observed in both groups with equal frequency and there were no differences in the kinetic properties of these deposits. A few CaOx monohydrate crystals were observed in SF. Although several risk factors were found to be significantly different between the groups, none of them were consistently robust when compared to other cognate factors. Arguments were readily invoked which demonstrated inter-factor inconsistencies and conflicts. We suspect that a unique discriminatory factor, such as any of those which we investigated in the present study, may not exist.

Kinetics of calcium oxalate crystal formation in urine

“…The remaining supersaturation after initial nucleation drives further crystal growth. This may be one possible explanation for the drop in mean crystallization speed from BRI classes 7 to 8, as the rapid drop in supersaturation due to extensive mass crystallization in BRI class 8 can lower the remaining supersaturation to a level sufficient "only" for growth rates similar to those of BRI class 5 and 6 [44,45]. A second cause of that phenomenon might be the fact that the very small crystal nuclei formed under the triggered conditions of mass crystallization cannot be clearly detected by turbidity measurement at λ = 625 nm.…”

“…This might, inter alia, explain why each of the existing risk indices shows a certain lack in discriminatory power between healthy subjects and stone formers [45]; therefore, the clinical validation of risk indices for recurrence prediction or therapy improvement is still ongoing [46].…”

Physicochemical mechanisms of stone formation

“…These are thermodynamic properties [8,9,21]. On the other hand, although crystallization is determined by supersaturation laws, it is also governed by kinetic factors which determine the rate at which these processes occur [8,9,21]. In stone research, this is extremely important.…”

“…Supersaturation (SS) requires an understanding of chemical speciation, which in turn is determined by chemical equilibria and their associated formation constants [1,16]. These are thermodynamic properties [8,9,21]. On the other hand, although crystallization is determined by supersaturation laws, it is also governed by kinetic factors which determine the rate at which these processes occur [8,9,21].…”

Timelines of the “free-particle” and “fixed-particle” models of stone-formation: theoretical and experimental investigations

“…For hereditary hyperoxaluria, correction of the risk factor unfortunately is a problem, but primary hyperparathyroidism can be treated and this does normalize the risk factors (hypercalcemia and hypercalciuria) and does prevent new stone formation. For most stoneformers, however, there is a large overlap in risk factor values with people who do not form stones, and urine supersaturation often is not an obvious cause for stone formation [4, 5]. Prime examples are the so-called “idiopathic” stoneformers in risk factor analysis shows a normal situation.…”