The future of stone research: rummagings in the attic, Randall's plaque, nanobacteria, and lessons from phylogeny.

The prevention or cure of stone disease will be achieved only by identifying biochemical, physiological and molecular mechanisms operating before the formation of a calculus. Yet, the gradual increase in the total number of papers devoted to the study of kidney stones that has occurred since the beginning of the 21st century can be attributed almost entirely to papers concerned with the investigation of factors associated with urolithiasis after stones have already formed. The need to prevent stones by discovering how the human body routinely stops their formation in those of us who do not suffer from them is therefore as exigent as ever and a new approach to investigating the causes of stones is urgently needed. In this paper, I develop the view that stone research will best progress by examining and understanding how healthy plants and animals control the formation of biominerals. In addition to structures like bones, teeth, shells and spines, many organisms spanning the entire phylogenetic tree form intra- and extracellular granules which are use as storage depots for calcium and other important ions, which they can reclaim to maintain homeostasis or to satisfy specific needs during periods of high demand, such as shell formation, moulting or skeletal development. These electron-dense granules, which also bear an uncanny resemblance to calcified nanobacteria, are remarkably similar in general structure, size and composition to particles observed in healthy human kidneys and in Randall's plaque. Therefore, it is likely that the granules in human kidneys fulfil analogous functions to those in other organisms-particularly in calcium homeostasis. Their study in a large range of creatures has already provided a deep well of information about their structure, movement, composition, macromolecular content, synthesis and resorption, from which we can draw to quench our thirst for knowledge of basic mechanisms and events involved in the formation of human kidney stones.