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.     

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.     

The consequences of uncontrolled secondary hyperparathyroidism and its treatment in chronic kidney disease

Secondary hyperparathyroidism (HPT) is a common complication of chronic kidney disease (CKD) and a frequent cause of clinically significant bone disease. Soft-tissue and vascular calcification, cardiovascular disease, and calcific uremic arteriolopathy (CUA) are additional serious consequences of the disorder that may contribute directly to cardiovascular morbidity and mortality in patients with CKD. Less widely appreciated manifestations include neurological disturbances, hematological abnormalities, and endocrine dysfunction. Secondary HPT arises from alterations in calcium, phosphorus, and vitamin D metabolism that develop early in the course of CKD and become more pronounced as kidney function declines. Treatment is often delayed, however, until the disease is well established. Current therapeutic strategies rely largely on the use of vitamin D sterols to diminish excess parathyroid hormone (PTH) synthesis and to lower serum or plasma PTH levels, but their use is often confounded by increases in serum calcium and phosphorus concentrations, changes that can aggravate soft-tissue and vascular calcification. As such, there is a need for new therapeutic interventions that can effectively lower serum or plasma PTH levels without producing untoward side effects. The current review summarizes the diverse manifestations of secondary HPT in patients with CKD. The consequences of inadequately controlled secondary HPT and the adverse effects of selected therapeutic interventions for the disorder on vascular calcification and cardiovascular disease in those with CKD are discussed.     

Disturbances in Bone Largely Predict Aortic Calcification in an Alternative Rat Model Developed to Study Both Vascular and Bone Pathology in Chronic Kidney Disease

Because current rat models used to study chronic kidney disease (CKD)‐related vascular calcification show consistent but excessive vascular calcification and chaotic, immeasurable, bone mineralization due to excessive bone turnover, they are not suited to study the bone‐vascular axis in one and the same animal. Because vascular calcification and bone mineralization are closely related to each other, an animal model in which both pathologies can be studied concomitantly is highly needed. CKD‐related vascular calcification in rats was induced by a 0.25% adenine/low vitamin K diet. To follow vascular calcification and bone pathology over time, rats were killed at weeks 4, 8, 10, 11, and 12. Both static and dynamic bone parameters were measured. Vascular calcification was quantified by histomorphometry and measurement of the arterial calcium content. Stable, severe CKD was induced along with hyperphosphatemia, hypocalcemia as well as increased serum PTH and FGF23. Calcification in the aorta and peripheral arteries was present from week 8 of CKD onward. Four and 8 weeks after CKD, static and dynamic bone parameters were measurable in all animals, thereby presenting typical features of hyperparathyroid bone disease. Multiple regression analysis showed that the eroded perimeter and mineral apposition rate in the bone were strong predictors for aortic calcification. This rat model presents a stable CKD, moderate vascular calcification, and quantifiable bone pathology after 8 weeks of CKD and is the first model that lends itself to study these main complications simultaneously in CKD in mechanistic and intervention studies. © 2015 American Society for Bone and Mineral Research.     

Disordered mineral metabolism and vascular calcification in nondialyzed chronic kidney disease patients.

It is well established that abnormalities in mineral metabolism are apparent early in the course of chronic kidney disease (CKD) and result in clinically relevant consequences such as renal osteodystrophy. Furthermore, there is emerging evidence linking some of these abnormalities (hyperphosphatemia) to the high cardiovascular morbidity and mortality experienced by nondialyzed patients with CKD. Most studies have evaluated vascular calcification in patients with stage 5 CKD. Reports published over the last 2 years show that the process begins rather early in CKD and is particularly severe among elderly and type 2 diabetic patients. Furthermore, "calcium begets calcium", such that the calcification burden in early CKD is an important predictor of subsequent progression, including the rapid increase seen in stage 5 CKD. There is an increasing body of evidence that supports the thesis that elevated serum levels of phosphorus and calcium and deficiency of inhibitors of calcification (for example, fetuin-A) are important in the progression of vascular calcification in patients with end-stage renal disease. However, the concentrations of calcium and phosphorus shown to induce mineralization in cell culture studies are not observed in most patients until late in stage 4 or stage 5 CKD. Cross-sectional and longitudinal studies have also been unable to show a correlation between serum levels of markers of disordered mineral metabolism and severity of vascular calcification. Future studies should evaluate the pathogenetic role of phosphorus retention, which occurs early in the course of CKD, in the induction and/or progression of vascular calcification. Finally, there is a need to identify alternative pathogenetic mechanisms that may be important causes of the high calcification burden observed early in CKD.     

Vitamin D and Stage 5 Chronic Kidney Disease: A New Paradigm?

Vitamin D receptor agonists (VDRA) are currently recommended for the treatment of secondary hyperparathyroidism in stage 5 CKD. They are considered to be contraindicated in the presence of low or normal (for a dialysis patient) levels of PTH due to the risk of developing adynamic bone disease, with consequent vascular calcification. However, these recommendations are increasingly at odds with the epidemiological evidence, which consistently shows a large survival advantage for patients treated with low-dose VDRAs, regardless of plasma calcium, phosphate, or PTH. A large number of pleiotropic effects of vitamin D have been described, including inhibition of renin activity, anti-inflammation, and suppression of vascular calcification stimulators and stimulation of vascular calcification inhibitors present in the uremic milieu. Laboratory studies suggest that a normal cellular vitamin D level is necessary for normal cardiomyocyte and vascular smooth muscle function. While pharmacological doses of VDRA can be harmful, the present evidence suggests that the level of 1,25-dihydroxycholecalciferol should also be more physiological in stage 5 CKD, and that widespread use of low-dose VDRA would be beneficial. A randomized controlled trial to test this hypothesis is warranted.     

Phosphate is a vascular toxin

Elevated phosphate (P) levels are seen in advanced renal failure and, together with dysregulated calcium, parathyroid hormone and vitamin D levels, contribute to the complex of chronic kidney disease–mineral and bone disease (CKD-MBD). Converging evidence from in vitro, clinical and epidemiological studies suggest that increased P is associated with vascular calcification and mortality. When vessels are exposed to high P conditions in vitro, they develop apoptosis, convert to bone-like cells and develop extensive calcification. Clinical studies in children on dialysis show that high P is associated with increased vessel wall thickness, arterial stiffness and coronary calcification. Epidemiological studies in adult dialysis patients demonstrate a significant and independent association between raised P and mortality. Importantly, raised P is associated with cardiovascular changes even in pre-dialysis CKD, and also in subjects with normal renal function but high P. All P binders can effectively reduce serum P, and this decrease is linked to improved survival. Raised serum P triggers the release of fibroblast growth factor 23 (FGF-23), which has the beneficial effect of increasing P excretion in early CKD, but is increased several 1,000-fold in dialysis, and may be an independent cardiovascular risk factor. Both FGF-23 and its co-receptor Klotho may have direct effects on the vasculature leading to calcification. Fascinatingly, disturbances in FGF-23–Klotho and raised P have also been associated with premature aging. These data suggest that high P levels have adverse vascular effects and that maintaining the serum P levels in the normal range reduces cardiovascular risk and mortality.     

Amplification of atherosclerotic calcification and Mönckeberg's sclerosis: a spectrum of the same disease process

Autopsy studies have shown the near universal presence of fatty streaks and fibroatheromas in the general population from which chronic kidney disease (CKD) patients arise. The vast majority of CKD patients have multiple conventional cardiovascular risk factors. Atherosclerosis, once present, can predominantly manifest as medial calcification, which has been previously termed M?nckeberg's sclerosis. This term has also been used in rare cases to describe vascular calcinosis not related to CKD. This clarification is critical to advance the field in terms of pathological diagnosis and treatment of CKD bone and mineral disorder. Factors that appear to promote the osteoblastic transformation of vascular smooth muscle cells and enhance deposition of calcium hydroxyapatite crystals include phosphorus activation of the Pit-1 receptor, bone morphogenic proteins 2 and 4, leptin, endogenous 1,25 dihydroxy vitamin D, vascular calcification activating factor, and measures of oxidative stress. These entities work to accelerate the atherosclerotic process in CKD patients and may be future targets for diagnosis and treatment. Although conventional atherosclerotic risk factors should be optimally managed, it should be noted that trials of hydroxymethylglutaryl-CoA reductase inhibitors have failed to attenuate the rate of progressive vascular calcification as measured by computed tomography scans.     

An update on vitamin D as related to nephrology practice: 2003

In this article, an up-to-date consideration of vitamin D therapeutics in nephrology is reviewed. The condition of vitamin D insufficiency is defined as the level of serum 25(OH)vitamin D at which vitamin D2 or D3 supplementation leads to a reduction of levels of parathyroid hormone (PTH). The risks of such vitamin D insufficiency in the normal population and likely risks in individuals with chronic kidney disease (CKD) stages 3 and 4 are reviewed. The potential for its safe treatment and prevention using moderate supplements of vitamin D2 or vitamin D3 are outlined. The role of altered "vitamin D nutrition" in leading to the observed greater incidence of secondary hyperparathyroidism in African Americans with ESRD compared to other racial groups is considered. The actions of active vitamin D sterols to augment intestinal absorption of both calcium and phosphorus, the effect to reduce levels of PTH, and to be a factor contributing to the rising incidence of low bone turnover (adynamic bone) are discussed. Growing evidence for contributions of elevated levels of serum calcium, serum phosphorus, and the calcium x phosphorus product as factors contributing to vascular and cardiac calcification in ESRD patients are cited. Questions are raised about whether the current practice of vitamin D usage in ESRD patients might be a contributing factor to such vascular abnormalities. The economic factors that likely affect the usage of intravenous vitamin D sterols in the United States are reviewed. It is recommended that potential adverse vascular effects of vitamin D sterols related to the increments of serum Ca and P be carefully evaluated.     

Risk factors of bone density disorder and vascular calcification in non-dialysis chronic kidney disease patients

Objective To explore the risk factors of bone density disorder and vascular calcification in non-dialysis chronic kidney disease (CKD) patients. Methods Clinical data of non-dialysis CKD patients who were admitted to the First Affiliated Hospital of Fujian Medical University between January 2013 and June 2014 were retrospectively analyzed. Using dual energy X-ray absorptiometry to evaluate their bone mineral density (BMD) and T value. Patients were divided into normal BMD group (T≥-1), osteopenia group (-2.5＜T＜-1) and osteoporosis group (T≤-2.5). The vascular calcification was evaluated by pectoral computed tomography. Multi-factor stepwise logistic regression analysis was used to assess the risk factors for low bone density and vascular calcification in non-dialysis CKD patients. Results A total of 337 non-dialysis CKD patients were enrolled. There were 110 (32.6%) patients with normal BMD, and 146(43.3%) patients with osteopenia, and 81(24.0%) patients with osteoporosis. Gender, history of hypertension, 25-hydroxy vitamin D and N-terminal osteocalcin shown statistical differences among three groups (all P＜0.05). The incidence rate of 25-hydroxy vitamin D deficiency shown statistical difference among three groups (P=0.012). Further, the rates were increased with the decreased bone mass (χ2=7.100, P=0.008). The other mineral bone disorders, such as hypocalcemia, hyperphosphatemia, low intact parathyroid hormone (iPTH) and high iPTH had no statistical difference among three groups (all P＞0.05). Multi-factor stepwise logistic regression analysis revealed that increased iPTH (OR=1.938), and low bone density (OR=1.724) were independent risk factors for CKD patients with vascular calcification (all P＜0.05), while women (OR=3.312) and vascular calcification (OR=1.742) were independent risk factors for CKD patients with low bone density (all P＜0.05). Conclusion Increased iPTH and low bone density are independent risk factors for non-dialysis CKD patients with vascular calcification, while women and vascular calcification are independent risk factors for non-dialysis CKD patients with low bone density.     

Shining D' light on chronic kidney disease: mechanisms that may underpin the cardiovascular benefit of vitamin D

Hypovitaminosis D is a significant health-care burden worldwide, particularly in susceptible populations such as those with chronic kidney disease (CKD). Recent epidemiological studies have identified that both higher serum vitamin D concentrations and use of vitamin D supplements may confer a survival benefit both in terms of all-cause and cardiovascular mortality. There is potential to investigate this inexpensive therapy for the CKD population, which suffers excessive cardiovascular events, although the mechanisms explaining this link have yet to be fully elucidated. This review discusses potential mechanisms identified in the basic science literature that may provide important insights into how vitamin D may orchestrate a change in cardiovascular risk profile through such diverse mechanisms as inflammation, atherogenesis, glucose homeostasis, vascular calcification, renin-angiotensin regulation and alterations in cardiac physiology. Where available, the clinical translation of these concepts to intervention trials in the CKD population will be reviewed.     

慢性肾脏病患者心血管钙化的影响因素分析

慢性肾脏病(chronic kidney disease,CKD)患者因高龄、高血压、高血脂、糖尿病、吸烟、男性等传统心血管钙化危险因素,加上CKD特有因素:矿物质代谢紊乱、含钙磷结合剂及活性维生素D的不合理使用、微炎症状态、氧化应激等常引起严重的心血管钙化,病情进一步发展会加速心血管事件的发生,影响CKD患者的预后。使用磷结合剂、活性维生素D及其类似物、西那卡塞等药物控制高钙、高磷、高PTH对预防心血管钙化至关重要。药物治疗无效或在治疗过程中出现不能控制的矿物质代谢异常,则要考虑手术切除甲状旁腺。甲状旁腺切除术(parathyroidectomy,PTX)作为难治性继发性甲状旁腺功能亢进患者的有效治疗之一,可迅速降低甲状旁腺素(parathyroid hormone,PTH)和血清钙磷水平,减少活性维生素D等药物的使用,缓解骨痛、瘙痒、肌无力等症状,但PTX后是否可以减轻心血管钙化?术后长期的低PTH状态与心血管钙化的关系如何?目前还没有明确的结论,本文就CKD患者心血管钙化的影响因素,尤其是PTX对CKD患者心血管钙化的影响作一综述。     

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.     

Vitamin D receptor activators can protect against vascular calcification

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.     

Renal osteodystrophy: present and future

Evidence is accumulating to indicate that certain abnormalities in mineral metabolism and/or their clinical management can lead to the development of vascular and soft tissue calcifications in patients with end-stage renal disease. Although the long-term consequences of vascular calcification in chronic renal failure have yet to be fully defined, the disorder may contribute to the high mortality rate from cardiovascular causes in patients undergoing long-term dialysis. The relationship between vascular calcification and cardiovascular disease in those with end-stage renal disease needs to be thoroughly evaluated, and substantial changes in the clinical management of patients undergoing dialysis may be appropriate. Phosphate retention and hyperphosphatemia have long been recognized as contributors to vascular and soft tissue calcification in chronic renal failure. Several recent reports indicate, however, that the use of large oral doses of calcium as phosphate-binding agents particularly in patients with persistently elevated serum phosphorus levels, may increase the risk of vascular calcification. Concurrent therapy with supra-physiological doses of calcitriol and other vitamin D sterols to manage secondary hyperparathyroidism leads to episodes of hyperphosphatemia and hypercalcemia, which can further aggravate soft tissue and vascular calcification. The phosphate-binding ion exchange resin sevelamer is now available for clinical use in the United States. It does not contain either calcium or aluminum, and other calcium- and aluminum-free phosphate-binding agents are being developed. These compounds make it possible to manage phosphate retention in patients with chronic renal failure without the risks associated with the sustained ingestion of large daily doses of calcium or aluminum. Several new vitamin D analogs are now available to treat secondary hyperparathyroidism due to chronic renal failure. These compounds may be less likely than calcitriol to enhance intestinal calcium and phosphorus absorption and to promote calcium and phosphorus release from bone. The therapeutic use of new vitamin D sterols as alternatives to calcitriol may permit clinicians to effectively manage secondary hyperparathyroidism while reducing the risks of soft tissue calcification in patients who require vitamin D therapy. Received: July 27, 2000 / Accepted: July 27, 2000     

Uraemic vasculopathy in children with chronic kidney disease: prevention or damage limitation?

Since the inception of pediatric dialysis programmes nearly 50 years ago, there have been vast improvements in both the technology and expertise in the care of children with chronic kidney disease (CKD). Nevertheless, children on dialysis continue to have a significantly higher mortality than their healthy peers and cardiovascular disease (CVD) is the most common cause of death in this group. Chronic kidney disease is described as the “perfect storm” of risk factors for CVD development, and vascular calcification is a highly regulated cell-mediated process with several promoters and inhibitors of calcification. CVD begins early in the course of CKD and there is an independent and graded association between cardiovascular morbidity and renal decline. Also, it is shown that once vascular damage and calcification begin, they progress inexorably in the uraemic milieu and may only be partially reversed after successful transplantation. Thus, preventing the development of CVD is key, and early identification and management of specific CVD-related risk factors should begin from the early stages of CKD. While the vasculopathy of childhood CKD is clearly multifactorial, clinical, epidemiological and cell biology studies provide converging evidence pointing to the role of dysregulated mineral metabolism as an important modifiable risk factor in the development of vascular calcification. In this review we focus on the role of calcium, phosphate, parathyroid hormone and vitamin D in ectopic vascular calcification, and discuss the role of screening, early intervention and management of established vascular calcification.     

Vascular calcification in uremic conditions: new insights into pathogenesis

Chronic kidney disease (CKD) patients have an higher incidence of cardiovascular morbidity and mortality compared with the general population. In the past 10 years, several studies pointed out that vascular calcification is a major cause of cardiovascular disease in the dialysis population. In CKD patients, high levels of serum phosphate and parathyroid hormone play a critical role in the pathogenesis of cardiovascular events. Calcium- and aluminum-free phosphate binders provide a new and effective therapeutic tool in preventing cardiovascular calcifications in CKD in animal models and in hemodialysis patients. Moreover, the pathogenesis of vascular and soft-tissue calcification, which traditionally has been associated with a passive calcium-phosphate deposition, certainly also is related to an active, cell-mediated process. In fact, some bone regulatory proteins seem to be able to induce or inhibit mineral deposition in the vasculature. In particular, bone matrix protein 7, alpha2-HS glycoprotein, and matrix GLA protein may be regulatory keys in preventing extraskeletal calcification in uremic conditions. This review presents the current understanding of the pathogenesis of vascular calcification in CKD patients, focusing on these 3 proteins and their protective action on extraskeletal calcification.     

Fetuin-mineral complex reflects extraosseous calcification stress in CKD

Fetuin-A is an important inhibitor of extraosseous calcification, but some of the studies that used ELISAs did not identify a significant relationship between serum fetuin-A levels and vascular calcification in patients with chronic kidney disease (CKD). Here, we used centrifugation to separate a fetuin-mineral complex (FMC) composed of fetuin-A, fibrinogen, fibronectin-1, and calcium from the serum of hemodialysis patients. In addition, we analyzed serum fetuin-A levels of 73 patients with diabetes and CKD (predialysis) after centrifugation. Fetuin-A concentrations were significantly lower in supernatants than in serum from patients at any stage of CKD, indicating systemic circulation of FMC in these patients. With greater severity of CKD, the contribution of FMC to total fetuin-A increased. Despite the absence of a correlation between serum fetuin-A and coronary artery calcification scores (CACS), supernatant fetuin-A negatively correlated with CACS and the extent to which centrifugation reduced fetuin-A (reduction ratio [RR]) positively correlated with CACS. In a longitudinal study of 12 hemodialysis patients with secondary hyperparathyroidism, parathyroidectomy and cinacalcet therapy each significantly reduced the RR without changing supernatant fetuin-A levels after 1 month, suggesting a reduction in FMC. Moreover, the magnitude of cinacalcet-induced reduction in parathyroid hormone correlated with the decrease in RR but not with changes in serum or supernatant fetuin-A. These data suggest that a quantitative measure of FMC, not supernatant or serum fetuin-A as measured in previous studies, reflects extraosseous calcification stress.     

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3–4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.     

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。