慢性肾脏病血管钙化机制研究进展-抑制与促进血管钙化两类因子的重要作用

慢性肾脏病患者血管钙化发生率高、进展快,对慢性肾功能不全患者生存率产生重大影响.通过研究血管钙化发生机制,有望找到预防血管钙化发生,阻断血管钙化进展的有效方法.本文扼要阐明慢性肾功能不全血管钙化机制的研究进展,并着重对抑制与促进血管钙化两类因子的重要作用加以介绍.     

慢性肾脏病患者心血管疾病的研究现状

慢性肾脏病（CKD）与心血管疾病（CVD）发生有着密切关系，CKD是心血管事件的高危组，即使在肾功能轻度受累时亦有心血管事件发生，大多CKD患者死于心血管疾病。本文概述了CKD患者与CVD的关系，CKD及其心血管并发症是可以预防的，因此慢性肾脏病的防治应从早期开始。     

慢性肾脏病的心血管并发症

慢性肾脏病的心血管并发症包括左心室肥大、动脉粥样硬化和动脉硬化；在慢性肾脏病的早期往往已出现心血管并发症。随着肾功能的衰退死于心血管并发症者多于发展成终末期肾病者。慢性肾脏病所以心血管病发生率高，除与传统的危险因素如高血脂、糖尿病等有关外，血尿、蛋白尿、贫血、钙磷失调等尿毒症相关因素发挥了重要作用。因此。早期开展对传统和尿毒症相关危险因素的治疗意义重大。     

透明质酸在慢性肾脏病中作用机制研究进展

透明质酸(hyoluronic acid,HA)作为细胞外基质的重要成分,不仅对肾脏固有细胞起支撑作用,也是一种重要的信号分子,参与细胞移行、黏附及信号转导等多种生物学过程,进而影响肾脏纤维化的发生发展.本文就透明质酸在肾脏病中作用机制的研究进展进行综述.     

慢性肾脏病的心血管并发症

慢性肾脏病的心血管并发症包括左心室肥大、动脉粥样硬化和动脉硬化 ;在慢性肾脏病的早期往往已出现心血管并发症 ,随着肾功能的衰退死于心血管并发症者多于发展成终末期肾病者。慢性肾脏病所以心血管病发生率高 ,除与传统的危险因素如高血脂、糖尿病等有关外 ,血尿、蛋白尿、贫血、钙磷失调等尿毒症相关因素发挥了重要作用。因此 ,早期开展对传统和尿毒症相关危险因素的治疗意义重大。     

树突状细胞在慢性肾脏病中的研究进展

树突状细胞在维持机体自身免疫耐受和活化外周T、B淋巴细胞中发挥重要作用,与炎症反应、自身免疫性疾病、移植免疫及肿瘤治疗等密切相关,现在普遍认为CKD可能导致DCs缺陷,同时DCs的数量及功能降低又可以反过来影响CKD的进展.本文就DCs与CKD免疫机制相关研究进展作一综述.     

脂联素与慢性肾脏病

脂联素是脂肪细胞分泌的一种特殊蛋白质,参与多种生理病理过程.随着对脂联素研究的不断深入,发现它与慢性肾脏病的发生、发展、预后等密切相关.我们就脂联素与慢性肾脏病的相关基础及临床研究作一综述.     

脂联素与慢性肾脏病

脂联素是脂肪细胞分泌的一种特殊蛋白质,参与多种生理病理过程。随着对脂联素研究的不断深入,发现它与慢性肾脏病的发生、发展、预后等密切相关。我们就脂联素与慢性肾脏病的相关基础及临床研究作一综述。     

早期慢性肾脏病的流行病学研究现状

慢性肾脏疾病(CKD)已成为21世纪人类面临的公共健康问题。筛查CKD高危人群,发现早期CKD病人,进行适当的干预或治疗,可以延缓CKD的进展,甚至防止终末期肾病(ESRD)的发生。近年来,许多国家已经进行了较大规模的CKD筛查和流行病学研究。本文就早期慢性肾脏病流行病学研究的现状作一综述。     

Pathogenesis of vascular calcification in chronic kidney disease

Pathogenesis of vascular calcification in chronic kidney disease. Background. Hyperphosphatemia and hypercalcemia are independent risk factors for higher incidence of cardiovascular events in patients with chronic kidney disease. In addition to increased calcium-phosphate product, hyperphosphatemia accelerates the progression of secondary hyperparathyroidism with the concomitant bone loss, possibly linked to vascular calcium-phosphate precipitation. Results. The control of serum phosphate levels reduces vascular calcification not only by decreasing the degree of secondary hyperparathyroidism and calcium-phosphate product, but also by reducing the expression of proteins responsible for active bone mineral deposition in cells of the vasculature. The calcium and aluminum-free phosphate-binders provide a new and effective therapeutic tool in preventing vascular calcifications in chronic kidney disease in animal models and in hemodialysis patients. Conclusion. Additional investigations are necessary to examine the benefits of different phosphate-binders in reducing mortality from cardiovascular disease.     

Mechanisms of vascular calcification in chronic kidney disease

Vascular calcification is common in chronic kidney disease and associated with increased morbidity and mortality. Its mechanism is multifactorial and incompletely understood. Patients with chronic kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell; high total body burden of calcium and phosphorus due to abnormal bone metabolism; low levels of circulating and locally produced inhibitors; impaired renal excretion; and current therapies. Together these factors increase risk and complicate the management of vascular calcification.     

Vitamin D and vascular calcification in chronic kidney disease

Vascular calcification is common in patients with chronic kidney disease (CKD) and contributes to the increased rate of cardiovascular morbidity and mortality. The mechanisms regulating vascular calcification are under investigation; it is accepted that vascular calcification is an active and complex process involving many factors that promote or inhibit calcification. Vascular smooth muscle cells undergo transformation into osteogenic cells. This transformation is being stimulated by high phosphate, and more recently the role of the calcium phosphate nanocrystals has gained attention. Experimental models of uremia and in vitro studies have shown that an excess of calcitriol accelerates vascular calcification. However, observational studies suggest that vitamin D provides a survival advantage for patients with CKD. Experimental work shows that for similar serum concentrations of calcium and phosphate paricalcitol produces less vascular calcification than calcitriol suggesting a differential effect at the cellular level. Important issues regarding the role of vitamin D compounds on vascular calcification will be commented in this review.     

Klotho deficiency causes vascular calcification in chronic kidney disease

Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na(+)-dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.     

慢性肾脏病患者血清胎球蛋白A与血管钙化

目的探讨血清胎球蛋白A水平在慢性肾脏病（CKD）发展过程中的变化,以及与血管钙化的关系。方法选择128例CKD患者,予以双侧颈总动脉超声检查,根据CKD标准进行分期,分为2、3、4、5期患者,分别设为B组19例,C组18例,D组24例,E组67例;另设23名门诊健康体检者为对照组（A组）。每组根据颈总动脉钙化分为有钙化和无钙化2个亚组,所有患者均测定血清中胎球蛋白A水平,测定血钙、血磷等常规生化指标。计算各组血清胎球蛋白A的平均水平。结果C组患者中血清胎球蛋白A含量明显高于E组（P〈0．05）,同时C组患者中血清胎球蛋白A含量明显低于A组（P〈O．05）。D、E组中高胎球蛋白A组和低胎球蛋白A组相比较,血管钙化的发生率有显著差异（P〈0．01）。E组直线相关性分析血清胎球蛋白A水平与血磷呈负相关（r=-0．320,P〈0．05）。与血钙不相关。结论血清胎球蛋白A水平随着肾脏病的进展呈进行性下降,终末期肾脏病患者血清胎球蛋白A受血磷影响。     

Bone health and vascular calcification relationships in chronic kidney disease

Abnormal bone in chronic kidney disease (CKD) may adversely affect vascular calcification via disordered calcium and phosphate metabolism. In this context, bone health should be viewed as a prerequisite for the successful prevention/treatment of vascular calcification (VC) along with controlled parathyroid hormone (PTH) secretion, the use of calcium-based phosphate binders and vitamin D therapy. In CKD patients, VC occurs more frequently and progresses more rapidly than in the general population, and is associated with increased cardiovascular disease (CVD) morbidity and mortality. A number of therapies aimed at reducing PTH concentration are associated with an increase of calcaemia and Ca × P product, e.g. calcium-containing phosphate binders or active vitamin D. The introduction of calcium-free phosphate binders has reduced calcium load, attenuating VC and improving trabecular bone content. In addition, a major breakthrough has been achieved through the use of calcimimetics, as first agents which lower PTH without increasing the concentrations of serum calcium and phosphate. Nowadays, it is becoming evident that even early stage CKD is recognised as an independent CVD risk factor. Moreover, the excess of CVD among dialysis patients cannot be explained entirely on the basis of abnormal mineral and bone metabolism. Hence, much controversy has surrounded the cost-effectiveness of treatment with the new phosphate-binding drugs as well as new vitamin D analogs and calcimimetics. Thus, it seems prudent and reasonable that maintaining bone health and mineral homeostasis should rely on some modifications of standard phosphate binding and calcitriol therapy. Hypophosphataemia and hypercalcaemia in adynamic bone disease (ABD) might be treated by reducing the number of calcium carbonate/acetate tablets in order to increase serum phosphate and decrease serum calcium, which, in turn, might positively stimulate PTH secretion. The same rationale is assumed for the use of a low calcium dialysate. On the other hand, secondary hyperparathyroidism with hyperphosphataemia and hypocalcaemia should be treated with a substantial number of calcium carbonate/acetate tablets in combination with calcitriol and low calcium dialysate in order to decrease serum phosphate and maintain the Ca × P product within K/DOQI guidelines (<4.4 mmol l⁻¹). Finally, it becomes apparent that prevention, with judicious use of calcium-based binders, vitamin D and a low calcium dialysate without adverse effects on Ca × P or oversuppression of PTH, provides the best management of VC and mineral and bone disorder in CKD patients.     

The role of vitamin D in vascular calcification in chronic kidney disease

Vascular calcification is a significant cause of morbidity and mortality in patients with chronic kidney disease (CKD). Disorders of mineral metabolism are likely involved in the pathogenesis of vascular calcification. Calcitriol and its analogs are effective in suppressing parathyroid hormone levels in patients with secondary hyperparathyroidism and CKD, but experimental studies demonstrate that these drugs can act directly on vascular smooth muscle cells. In some in vitro studies and in animal models of CKD, calcitriol has induced vascular calcification. Newer analogs of vitamin D appear to be less likely to induce vascular calcification, although published data are scarce. However, there is really no clear evidence in dialysis patients that calcitriol or analog administration is directly responsible for the induction of vascular calcification. However, indirectly, by oversuppression of parathyroid hormone (PTH) and induction of a low-turnover bone disease state, or by increased calcium-phosphorus product, the administration of calcitriol or its analogs may contribute to vascular calcification in patients with CKD. However, prospective randomized trials in CKD patients are necessary to fully understand the impact of calcitriol and analog therapy on vascular calcification.     

Calcimimetics, parathyroid hormone, and vascular calcification in chronic kidney disease

Vascular calcification (VC) occurs frequently in chronic kidney disease, contributing to cardiovascular mortality. Numerous risk factors have been identified, including renal osteodystrophy and bone turnover, with low turnover as a main determinant. Other reports support high turnover as a factor in VC. Calcimimetics, which lower serum parathyroid hormone, and parathyroidectomy each prevented VC induced by five-sixths nephrectomy in rats. These results favor increased bone turnover due to hyperparathyroidism, instead of low turnover, as a factor in VC in uremia.     

Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD)

BACKGROUND: The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. METHODS: In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. RESULTS: There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). CONCLUSION: These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.