Effects of inter-α-inhibitor and several of its derivatives on calcium oxalate crystallization in vitro

Abstract

The bikunin peptide chain of the protease inhibitor inter-alpha-inhibitor (IalphaI) has been reported to be an inhibitor of calcium oxalate (CaOx) crystallization, and hence has been proposed as having a role in CaOx kidney stone formation. However, further experimental evidence is required to assess if fragments of IalphaI other than bikunin may play a role in the regulation of crystallization events in stone formation. The aim of the present study was to assess the effects of IalphaI and several of its derivatives on CaOx crystallization in a seeded inorganic system and to compare these effects with those of a known inhibitor of crystallization, prothrombin. IalphaI was purified from a preparation of human plasma and fragmented by alkaline hydrolysis, and two of its peptide chains, bikunin and heavy chain 1 (H1), were purified further by HPLC. Their purity was confirmed by SDS/PAGE. Using Coulter counter and [(14)C]oxalate analysis and scanning electron microscopy, IalphaI, its H1 chain and bikunin from urine and from plasma were shown to be relatively weak inhibitors of CaOx crystallization in vitro at expected physiological concentrations. It was concluded that members of the IalphaI family may not be as important in kidney stone formation as has been generally proposed, although further studies are required before a possible role for IalphaI and its fragments in stone formation can be unambiguously discounted.

Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

“…Such proteins include TammHorsfall protein (THP) (20), osteopontin (uropontin) (2), prothrombin fragment 1 (PF1) (38), inter-␣-trypsin inhibitor (ITI) (9), and bikunin (BK), a portion of ITI (3), calgranulin (34), CD59 (7), and albumin (10). Although some reports suggest defects, deficiencies, or variations of these molecules among SF vs. normal subjects (13,14,26,27,43), it remains unclear whether any of these is a cause or a consequence of stones; no research thus far has translated molecular knowledge into clinical practice.…”