Intracellular Phosphate and ATP Depletion Measured by Magnetic Resonance Spectroscopy in Patients Receiving Maintenance Hemodialysis

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Comparative Efficacy and Safety of Phosphate Binders in Hyperphosphatemia Patients With Chronic Kidney Disease

Background: In this study, we coordinated a network meta‐analysis to establish the efficacy and safety of different agents used in the treatment of hyperphosphatemia patients with chronic kidney disease. Methods: PubMed, CNKI, and Embase were systematically searched to retrieve relevant studies. Outcomes were presented by mean differences, odds ratios, and corresponding 95% credible intervals for continuous outcomes and binary outcomes, respectively. Each therapy was ranked according to the value of surface under the cumulative ranking curve. Consistencies between direct and indirect comparisons were assessed with a node‐splitting plot. Results: In terms of efficacy end points (including levels of serum phosphate, serum calcium, serum intact parathyroid hormone, and serum calcium × phosphorus product), all 7 kinds of agents outperformed or performed at least equally to placebo, with iron‐based phosphate‐binding agents being potentially the most effective. As for safety end points (including mortality, adverse events, and all‐cause discontinuation), almost all agents were equivalent in term of mortality and all‐cause discontinuation except in the comparison between iron‐based phosphate‐binding agents and placebo. Meanwhile, iron‐based phosphate‐binding agents colestilan and nicotinic acid performed poorly compared with placebo in terms of adverse events. Furthermore, iron‐based phosphate‐binding agents were potentially the safest agents followed sequentially by calcium‐based phosphate‐binding agents and placebo. Conclusion: Iron‐based phosphate‐binding agents were the preferable agents when considering efficacy and safety simultaneously.     

烟酰胺联合司维拉姆治疗血液透析高磷血症的临床研究

目的 探讨烟酰胺片联合碳酸司维拉姆片治疗血液透析高磷血症的临床疗效。方法 选取2016年3月—2017年3月在云阳县人民医院肾内科维持血液透析的高磷血症患者100例作为研究对象,所有患者随机分为对照组和治疗组,每组各50例。对照组患者餐中口服碳酸司维拉姆片,用量根据具体血磷水平进行调整（当血磷≥2.41 mmol/L,口服剂量为1 600 mg/次;当血磷<2.41 mmol/L,口服剂量为800 mg/次）,3次/d;治疗组患者在对照组治疗的基础上口服烟酰胺片,500 mg/次,1次/d。两组患者均连续治疗2个月。观察两组患者的临床疗效,比较治疗前后的血清学指标、冠状动脉钙化积分（CACS）、白细胞介素-6（IL-6）和甲状旁腺激素（PTH）水平。结果 治疗后,对照组和治疗组的临床总有效率分别为78.00%、94.00%,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者的血磷、钙磷乘积水平均显著降低,血钙水平显著升高,同组治疗前后比较差异具有统计学意义（P<0.05）;且治疗后治疗组血清学指标显著优于对照组,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者的CACS、IL-6、PTH水平均显著降低,同组治疗前后比较差异具有统计学意义（P<0.05）;且治疗后治疗组患者CACS、IL-6、PTH水平显著低于对照组,两组比较差异具有统计学意义（P<0.05）。结论 烟酰胺片联合碳酸司维拉姆片治疗血液透析高磷血症患者疗效显著,可显著降低血磷水平,减轻炎性反应,安全性较高,具有一定的临床推广应用价值。     

Hyperphosphatemia,Phosphoprotein Phosphatases,and Microparticle Release in Vascular Endothelial Cells

Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.     

马尔可夫模型评价三种磷结合剂治疗高磷血症的研究

目的：评价碳酸钙、碳酸镧和盐酸司维拉姆三者在治疗高磷血症方面的经济性。方法：通过构建马尔可夫模型进行成本效果评价。结果：碳酸镧降磷效果最好,盐酸司维拉姆次之,碳酸钙最差,但考虑成本之后碳酸钙为最优方案。结论：在3倍人均GDP为支付阈值的条件下碳酸钙是最具有成本效果优势的方案。     

Advances in pharmacotherapy for hyperphosphatemia in renal disease

Introduction: Hyperphosphatemia in chronic kidney disease (CKD) is considered as an independent risk factor for surrogate clinical end points like vascular calcification (VC) and bone disease, or hard clinical outcomes like cardiovascular events. Various treatment options are available for phosphate removal or reduction. Calcium-based phosphate binders (CBB) with their possible positive calcium balance became culprits for progressive VC and increased mortality risk. Non-calcium-based binders (NCBB) treatment allowed a comparable control of hyperphosphatemia with a lower risk of hypercalcemia and a slower progression of VC. Recent data have shown a 22% risk reduction in all-cause mortality with NCBB compared to CBB treatment. The appropriate timing of phosphate binder initiation in CKD patients is still unclear. Recent reports in patients with CKD stages 3b-4 showed increased VC progression when actively treated compared to placebo and a positive calcium, but no negative phosphate balance.

Areas covered: This review discusses the advantages and disadvantages of the pharmacological options to treat hyperphosphatemia.

Expert opinion: The use of phosphate binders is essential in preventing morbidity and mortality in dialysis patients. The choice of phosphate binder takes into account CKD stage, the presence of other components of CKD-mineral and bone disorders, concomitant therapies and drug side-effect profile.     

碳酸镧咀嚼片引起便秘及腹部影像学异常的病例分析

目的 为临床合理使用碳酸镧咀嚼片出现影像学异常提供分析参考。方法 通过对1例CKD5期高磷血症患者使用碳酸镧咀嚼片引起便秘和影像学异常的病例进行分析,药师协助临床查找原因,并对患者进行用药指导和监护随访。结果 经过分析,影像学异常为患者错误服用碳酸镧引起的影像学表现,经过通便处理,影像学恢复正常,临床药师由此制定了碳酸镧咀嚼片的使用监护流程,保证了患者的安全正确用药。结论 临床药师对使用碳酸镧咀嚼片的患者进行详细的用药指导和持续随访,可促进患者正确用药。