DIFFERENTIAL EXPRESSION OF URINARY INTER-alpha-TRYPSIN INHIBITOR TRIMERS AND DIMERS IN NORMAL COMPARED TO ACTIVE CALCIUM OXALATE STONE FORMING MEN

Abstract

Immunoreactive profiles of urinary proteins may be able to be developed into a useful diagnostic tool to identify active stone formation, although a separate panel may be required for men and women. It is possible that these differences may provide clues as to why the incidence of stone disease is higher in men than women.

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

“…By contrast, Suzuki et al (43) found higher urinary concentrations of BK in male SF compared with healthy male controls and that a greater proportion of SF than normal patients had an aberrant BK 25-kDa species, which is identified to be deglycosylated BK, a form with reduced effectiveness in inhibiting CaOx crystal growth. Marengo et al (14,26) found increased HMM forms (P␣I and ITI), but not BK, in SF (14,26), and these differences were constant over several months (26).…”

“…The ITI family of proteins consists of three heavy chains (H1, H2, H3) of 75-to 85-kDa molecular mass, and one light chain, BK, with a molecular mass of 35-40 kDa (17,39). BK can be linked covalently through its chondroitin-4-sulfate side chain to one or two heavy chains, forming the pre-␣-inhibitor (P␣I; H3ϩBK, 125 kDa) or ITI (H1ϩH2ϩBK, 180 -220 kDa) (8,11,36), also known as ITI-trimer (26). The Ͼ50-kDa bands we detected here most likely correspond to heavy chain components, P␣I or ITI.…”

“…Calgranulin is a strong inhibitor of CaOx crystal growth and consists of two monomeric subunits, A and B (also known as MRP8 and MRP14, or S100A8 and S100A9), which are small (11 and 14 kDa, respectively) acidic proteins that can combine to form homo-and heterodimers (24)(25)(26)(27)(28), as well as tetramers and other higher-order multimers (35-48 kDa) (16,31,34,44). In fact, it is the calA/calB heterodimer for which crystal growth inhibition has been documented (34).…”

“…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.…”

Kidney stone disease

“…Osteopontin (14), prothrombin F1 fragment (15), the inter-α-trypsin inhibitor molecule (16), calgranulin (17), Tamm Horsfall glycoprotein (18), as well as albumin, RNA and DNA fragments, and glycosaminoglycans have all been identified as urine inhibitors of CaOx and CaP crystallization (12). They have in common long stretches of polyanion chains that can bond with surface calcium atoms and prevent crystal growth.…”