Formation mechanisms of calcium phosphate plaques and attached calcium oxalate kidney stones

磷酸钙斑块及附着草酸钙肾结石的形成机制

• 批准号: 415094771
• 负责人: Professor Dr. Hans-Joachim Kleebe
• 金额: --
• 依托单位: Institut für Angewandte Geowissenschaften (IAG)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/415094771?language=en
• 关键词: Formation; mechanisms; calcium; phosphate; plaques

Calcium oxalate (CaOx) kidney stones are a major health problem, the causes and pathogenesis of which are not entirely clear, but are often related to metabolic disorders. After successful stone treatment, there is a high risk of recurrent CaOx stones. For most CaOx stones, a precondition appears to be the formation of calcium phosphate (CaP) precipitates in extracellular tissue of the kidney. These calcifications called Randall’s plaque (RP) form presumably during urine production in the tubular system of the kidney, when ions become reabsorbed and diffuse into the surrounding tissue. A local increase in pH and the concentrations of calcium and phosphate ions induce an increasing CaP supersaturation of the body fluid in the tissue. Inside the porous tissue various CaP minerals can form which may lead to lesions in the epithelium of the renal pelvis, where they come in contact with urine. Subsequently, CaOx stones form from urine by crystal growth at these RP surfaces. Certain naturally produced proteins, such as osteopontin (OPN), appear to inhibit the precipitation of CaP and CaOx in body fluid and in urine.However, the conditions of RP formation are not well known and the role of RP in the formation of CaOx stones is not entirely clear. Therefore, CaOx kidney stones and especially adherent RP will be investigated for their microstructures and local chemical and mineralogical composition with the aim of drawing conclusions about mechanisms of their formation. An attempt will be made to correlate characteristic signatures to specific metabolic disorders. In complementary model experiments based on ion diffusion in collagen, gelatin and agarose hydrogels, the formation of CaP plaques will be simulated. Additionally, the effect of OPN on CaP precipitation in these systems will be studied. Throughout the experiments, the formation of plaques will be monitored in situ using confocal Raman spectroscopy. Furthermore, samples will be characterized using scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffractometry, atomic force microscopy, atomic absorption spectroscopy and ion chromatography. Structural approximation of experimental CaP plaques to pathological RP is proposed to be achieved by iterative adjustment of the precipitation conditions in order to obtain clues about the conditions of RP formation. Finally, the proposed hypothesis, according to which calcium ions diffuse through RP and induce CaOx precipitation at the RP/urine interface, will be tested experimentally. These CaOx precipitates may serve as nuclei for the growth of larger stones from urine. Such an initiating mechanism would be particularly relevant for the formation of kidney stones and would promote their recurrence as well. It is expected that the results of this project enhance the understanding of the formation of RP and CaOx kidney stones and support the development of preventive medical treatments.

草酸钙（CAOX）肾结石是一个主要的健康问题，其原因和发病机理并不完全清楚，但通常与代谢性疾病有关。成功的石材处理后，经常性的Caox石头风险很高。对于大多数Caox结石，前提似乎是肾脏外组织中磷酸钙（CAP）沉淀的形成。这些钙化称为肾脏在肾脏系统中的尿液产生过程中，当离子被重新吸收并扩散到周围组织中时，这些钙化称为Randall的斑块（RP）。 pH的局部增加，钙和磷酸盐离子的浓度诱导组织中体液的帽过饱和度增加。在多孔组织内部，各种瓶盖的矿物质可能形成，可能导致肾脏骨盆上皮的病变，在那里它们与尿液接触。随后，通过在这些RP表面的晶体生长形成了Caox石头。某些天然产生的蛋白质，例如骨桥蛋白（OPN），似乎抑制了体液和尿液中帽和Caox的沉淀。但是，RP形成的条件尚不清楚，RP在Caox Stones的形成中的作用尚不完全清楚。因此，将研究CAOX肾结石，尤其是依从型RP的微观结构以及局部化学和矿物学成分，目的是得出有关其形成机制的结论。将尝试将特征签名与特定的代谢疾病相关联。在基于胶原蛋白，明胶和琼脂糖水凝胶中离子扩散的互补模型实验中，将模拟盖块的形成。此外，将研究OPN对这些系统中盖沉淀的影响。在整个实验中，将使用共聚焦拉曼光谱法原位监测斑块的形成。此外，将使用扫描电子显微镜，能量分散性X射线光谱，X射线衍射测量法，原子力显微镜，原子吸收光谱和离子色谱法对样品进行表征。提议通过迭代调整降水条件来实现实验盖斑块与病理RP的结构近似，以获取有关RP形成条件的线索。最后，根据该假设，将根据该假说通过该假设通过RP/尿液界面在RP/尿液界面诱导CAOX降水。这些CAOX沉淀物可以用作尿液中较大石头的生长的核。这种启动机制将与肾结石的形成特别相关，并且也会促进其复发。预计该项目的结果会增强对RP和Caox肾结石形成的理解，并支持预防药物治疗的发展。