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）肾结石是一种主要的健康问题，其病因和发病机制尚不完全清楚，但通常与代谢紊乱有关。结石治疗成功后，复发CaOx结石的风险很高。对于大多数CaOx结石，一个先决条件似乎是在肾细胞外组织中形成磷酸钙（CaP）沉淀。这些被称为兰德尔斑块（RP）的钙化可能是在肾小管系统的尿液产生过程中形成的，当时离子被重新吸收并扩散到周围的组织中。局部pH值的升高以及钙和磷酸盐离子浓度的升高会引起组织中体液CaP过饱和的增加。在多孔组织内部可以形成各种CaP矿物质，这些矿物质与尿液接触可能导致肾盂上皮病变。随后，尿液通过这些RP表面的晶体生长形成CaOx结石。某些天然产生的蛋白质，如骨桥蛋白（OPN），似乎可以抑制体液和尿液中CaP和CaOx的沉淀。然而，RP形成的条件尚不清楚，RP在CaOx石形成中的作用也不完全清楚。因此，我们将对CaOx肾结石，特别是附着的RP进行微观结构和局部化学矿物组成的研究，以得出其形成机制的结论。将尝试将特征特征与特定的代谢紊乱联系起来。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CaP斑块的形成。此外，还将研究OPN对这些系统中CaP降水的影响。在整个实验过程中，将使用共聚焦拉曼光谱原位监测斑块的形成。此外，样品将使用扫描电子显微镜、能量色散x射线光谱、x射线衍射、原子力显微镜、原子吸收光谱和离子色谱进行表征。提出通过反复调整沉淀条件来实现实验性CaP斑块与病理性RP的结构近似，从而获得RP形成条件的线索。最后，我们将通过实验验证所提出的假设，即钙离子通过RP扩散并在RP/尿液界面诱导CaOx沉淀。这些CaOx沉淀物可作为尿液中较大结石生长的核。这种启动机制与肾结石的形成特别相关，也会促进肾结石的复发。期望本项目的研究结果能增进对RP和CaOx肾结石形成的认识，并支持预防性医学治疗的发展。