Do "inhibitors of crystallisation" play any role in the prevention of kidney stones? A critique

Abstract

A critical examination of data in the literature and in as yet unpublished laboratory records on the possible role of so-called inhibitors of crystallisation in preventing the formation of calcium-containing kidney stones leads to the following conclusions. So-called inhibitors of spontaneous "self-nucleation" are unlikely to play any role in the initiation of the crystallisation of CaOx or CaP in urine because excessive urinary supersaturation of urine with respect to these salts dominates the onset of "self-nucleation" within the normal time frame of the transit of tubular fluid through the nephron (3-4 min). Inhibitors of the crystal growth of CaOx crystals may or may not play a significant role in the prevention of CaOx stone-formation since once again excessive supersaturation of urine can overwhelm any potential effect of the inhibitors on the growth process. However, they may play a role as inhibitors of crystal growth at lower levels of metastable supersaturation when the balance between supersaturation and inhibitors is more equal. Inhibitors of CaOx crystal aggregation may play a significant role in the prevention of stones, since they do not appear to be strongly affected by excessive supersaturation, either in vitro or in vivo. Inhibitors of CaOx crystal binding to renal tubular epithelium may exist but further studies are necessary to elucidate their importance in reducing the risk of initiating stones in the renal tubules. Inhibitors of CaOx crystal binding to Randall's Plaques and Randall's Plugs may exist but further studies are necessary to elucidate their importance in reducing the risk of initiating stones on renal papillae. There may be an alternative explanation other than a deficiency in the excretion of inhibitors for the observations that there is a difference between CaOx crystal size and degree of aggregation in the fresh, warm urines of normal subjects compared those in urine from patients with recurrent CaOx stones. This difference may depend more on the site of "self-nucleation" of CaOx crystals in the renal tubule rather than on a deficiency in the excretion of so-called inhibitors of crystallisation by patients with CaOx stones. The claim that administration of potassium citrate, potassium magnesium citrate or magnesium hydroxide reduces the rate of stone recurrence may be due to the effect of these forms of medication on the supersaturation of urine with respect to CaOx and CaP rather than to any increase in "inhibitory activity" attributed to these forms of treatment. In summary, there is a competition between supersaturation and so-called inhibitors of crystallisation which ultimately determines the pattern of crystalluria in stone-formers and normals. If the supersaturation of urine with respect to CaOx reaches or exceeds the 3-4 min formation product of that salt, then it dominates the crystallisation process both in terms of "self-nucleation" and crystal growth but appears to have little or no effect on the degree of aggregation of the crystals produced. At supersaturation levels of urine with respect to CaOx well below the 3-4 min formation product of that salt, the influence of inhibitors increases and some may affect not only the degree of aggregation but also the crystal growth of any pre-formed crystals of CaOx at these lower levels of metastability.

Keywords: Calcium oxalate; Calcium phosphate; Crystal aggregation; Crystal growth; Crystal nucleation; Inhibitors of crystallisation.