Crystallization Inhibitors in the Pathophysiology and Treatment of Nephrolithiasis

Abstract

It is currently agreed that stone formation in the urinary tract requires supersaturation with respect to a given solid phase. However, this principle fully applies only to stones other than calcium-containing stones, in which case compounds acting as inhibitors are postulated to naturally occur in urine. Stone formation would therefore ensue from an imbalance between promoters and inhibitors. The saturation state can be estimated by means of computer model systems based on ab initio calculations, which account for the main soluble complexes formed in urine between relevant cations and anions. This estimates the overall promoting potential of urine. However, in the case of calcium nephrolithiasis, supersaturation does not make a clear-cut separation between normal subjects and patients. Several studies in the last two decades have identified many inhibitors of calcium oxalate and calcium phosphate crystallization, which are classified into the ionic and macromolecular. They have been shown to act on kinetics by interfering with nucleation, growth and aggregation of crystals. Unfortunately, except for citrate, none of the newly discovered substances has been definitely characterized in its molecular composition and structure, type and potency of inhibition, differences in concentration and structure between stone-forming and non stone-forming subjects. Citrate exhibits a dual action in urine, opposing crystal formation by both thermodynamic and kinetic mechanisms. At present it is the only natural inhibitor which can be measured in urine, quantitated as to inhibitory activity and used in medical treatment.

Protein intake, calcium balance and health consequences

“…In a cohort study of B650 premenopausal and postmenopausal women, an inverse relation between dietary potassium and urinary calcium was found without any effect on calcium balance as reduced calciuria was offset by a reduction in intestinal calcium absorption (Rafferty et al, 2005). In addition, potassium was identified as a major stimulator of urinary excretion of citrate, which is an inhibitor of calcium stone formation (Demigne et al, 2004;Marangella et al, 2004) (Crystallization y). Ingestion of alkali as potassium and magnesium citrate reduced the risk of renal stone formation during a 3-year period in a randomized controlled trial (Ettinger et al, 1997) or during a 5-week bed rest at risk period (Zerwekh et al, 2007).…”

Oxalate Biominerals

“…Interestingly, it is considered that the normal urinary environment is inhibitory to crystal nucleation and aggregation. As a consequence, stone pathogenesis might only develop under conditions permissible for calculogenesis, like those arising from an imbalance between promoters and inhibitors of crystallization [190].…”

Association between IL-1RN VNTR, IL-1β -511 and IL-6 (-174, -572, -597) Gene Polymorphisms and Urolithiasis

“…Environmental factors such as diet, climate, water quality and also genetic factors have been suspected to be risk factors for kidney stone formation [22,23]. Various organic and inorganic molecules have been suspected to be involved in stone formation and disease progression [24,25]. Imbalance between oversaturation factors that might promote the crystallization or inhibit the crystal formation triggers the enlargement of crystals in urine [26].…”