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

Abstract

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.

Evaluation of the interaction between calcifying nanoparticles and human dental pulp cells: a preliminary investigation

“…1,2 The defining characteristics for CNPs are their ability to aggregate calcium and phosphate on their outer envelope at physiologic concentrations and conditions. 3 Therefore it precipitates CNPs as a potential etiological factor involved in various pathological calcification diseases in human beings, such as kidney stones, [4][5][6][7] calcified arteries, [8][9][10] human breast cancer, 11 and gallbladder stones. 12,13 As there is a close relationship between CNPs and pathological calcification diseases in human beings, it is essential to clarify their effect on cultured mammalian cells.…”

Biomimetic Randall’s plaque as an in vitro model system for studying the role of acidic biopolymers in idiopathic stone formation

“…We believe these bright specks are mineral phase because calcium phosphate would be expected to give a higher z-contrast in SEM. These small specks are spherical and similar in size to the ~50 nm spherules in the initial plaque deposits found in the basement membrane seen in Randall’s plaques, but further studies at high magnification with TEM were needed to determine if the spherules have the signatory concentric laminations found in RP [4, 7, 8, 10, 14, 20, 21, 23, 26, 62]. The surface also contained a few external HA crystals, but the amount was significantly less than that of the conventional crystallization.…”

“…For example, the smaller mineral deposits in the basement membrane of RP appear as electron dense, spherical objects, around 50 nm in diameter, while the larger deposits show alternating rings of mineral (apatite) and organic matrix (Figure 2c & d) [4, 6, 8, 9, 14, 20, 23, 26, 62]. We hypothesize that the spherules seen in the basement membrane may be due to phase separation of PILP droplets, which could accumulate and fuse into larger structures due to their fluidic character.…”

Occurrence of Nanobacteria-Like Particles in Renal Stones of a Southern Brazilian Population

“…However, other investigators contested the "nidi" hypothesis for NB/CNP suggesting that these structures are self- propagating mineral compounds. The "nidi" hypothesis was again contested by Ryall's group [19], who demonstrated that CaOx monohydrate crystals precipitated sponment on the bottom of the tubes whereas the control did taneously from sterile human urine, suggesting that some, if not all, "nanobacteria" associated with pathological calcification might be nanoparticles formed spontaneously under conditions of high physiological supersaturation. Recently, Martel and Young [20] reported that calcium carbonate precipitates prepared in vitro were remarkably similar to purported NB in terms of their uniformly size, membrane-delineated vesicular shapes, with cellular division-like formations and aggregations in the form of colonies.…”