Idiopathic urinary stone disease: possible polygenic aetiological factors.

About 12% of men and 5% of women of Western European descent develop at least one urinary stone during their lifetime. The incidence is somewhat less in individuals of sub-Saharan African or Asian descent, although there is a high incidence in the Middle Eastern countries. Calcium oxalate is a major constituent of about 70% of these stones. They are of multifactorial origin, with both genetic and environmental factors involved. The genetic factors influence different components of a highly complex system whereby calcium oxalate, which has a very low solubility in water, remains in solution. When the system is perturbed, the calcium oxalate crystallizes, the crystals aggregate and stones form. The genetic factors operate through mechanisms that are less obvious than the environmental ones such as the patient’s state of hydration and dietary effects on the concentrations of the relevant ionic species. It is now generally accepted that the crystallization process begins in the distal ducts of the kidney by adhesion of calcium and oxalate to the epithelial surfaces of the tubule cells and their internalization. The calcium oxalate crystal becomes detached, with some incorporated organic materials forming a microlith. This process of microlith formation could arise either because of genetically determined alterations in the surface properties of the cells, or in the composition and/or concentration of substances in the urine that inhibit crystal nucleation and/or aggregation. The microliths pass through the collecting tubules more slowly than calcium oxalate in simple physical solution, aggregating until they reach the pelvicalycial system, where they grow into stones and pass down the ureters. It has been suggested that a shift in the crystal form from the mono-hydrate to the di-hydrate form reduces the likelihood of such adhesion, and that molecular inhibitors of crystallization operate by favouring the dihydrate form. Calcium oxalate urolithiasis had, until relatively recently, been thought of primarily in relation to the calcium content of the urine; patients with unexplained hypercalciuria have been labelled as having ‘idiopathic hypercalciuria’, which accounts for 30–40% of calcium oxalate stone formers, and those without hypercalciuria as having ‘idiopathic stone disease’. However, stone formation is also influenced by oxalate, citrate, phosphate, magnesium and the glycoproteins (Tamm-Horsfal protein, osteopontin and nephrocalcin) in the urine. This paper reviews biochemical sites at which some individually undetectable genetically determined phenotypic changes could act additively to produce calcium oxalate stone disease, which would then appear to be either idiopathic or due to unexplained hypercalciuria. These postulated mutations with individually undetectable effects would also operate against the background of the whole genome, with its potential for the multiple polymorphisms which are the basis of an individual’s uniqueness and therefore predisposition to disease. Single nucleotide polymorphisms