慢性肾脏病患者磷代谢调节因果网络的研究

高磷血症是慢性肾脏病（CKD）患者死亡的主要危险因素之一，然而针对终末期肾病患者高磷血症的治疗面临严峻挑战，临床对肾病早期高磷血症的防治提出需求。人体内的磷稳态依赖于复杂的调节网络。网络内的调磷激素在肾病进展时发生改变，早期可代偿性的促进肾脏排磷维持血磷正常，终末期因肾功能丧失演变为病理效应加重高磷血症。故申请人推测若能明确慢性肾病磷调节网络中各因子改变的意义，通过早期临床干预，可能延缓或减轻磷调节网络失代偿，达到早期防控磷代谢紊乱的目的。课题组前期利用结构方程模型建立了血透患者磷代谢调节网络模型，验证了调节网络在血透期失代偿的表现。因此，本项目拟（1）通过结构方程模型建立并验证CKD各阶段的磷代谢调节因果网络，探讨磷代谢调节因果关系的全貌及早期磷代谢的干预环节；（2）根据模型信息建立维生素D早期治疗方案，通过前瞻性干预研究，评估模型的临床指导价值，为临床维生素D治疗提供借鉴。

Hyperphosphatemia is an important risk factor of mortality in patients with chronic kidney disease (CKD). However, the treatment on hyperphosphatemia in patients with End Stage Renal Disease (ESRD) is far from satisfactory and facing more and more challenges. Basic and clinical studies reveal that the homeostasis of phosphate is maintained by a regulatory network. The factors in the network change as the renal function decreases. At the early stage of CKD, the network causes an increase in the phosphate excretion and maintains serum phosphate in a normal range. As CKD progresses, total phosphate excretion becomes so limited, in turn, the network induce a series of pathological effects which aggravate hyperphosphatemia. Therefore, we hypothesize that treatment should be taken at early stage of CKD to intervene the potential mechanisms in the regulatory network that may aggravate hyperphosphatemia in ESRD and delay the collapse of the network. We have established the regulatory network in hemodialysis patients by causal inference and proved that it did aggravate hyperphosphatemia in those patients. So, this project aims to, first, establish the regulatory network of phosphate metabolism at every CKD stage by causal inference and identify the pathological mechanisms in the network, second, evaluate the clinical value of the network by a randomized controlled trial using supplement of active vitamin D at early stage of CKD as the experimental group and no supplement of vitamin D as the control group, and finally, provide guidance for early prevention of hyperphosphatemia.