蛋白结合毒素与心血管疾病

慢性肾脏病(CKD)患者肾脏清除体内尿毒症毒素能力明显减退,高浓度的尿毒症毒素尤其是蛋白结合毒素(PBUTs)是心血管疾病(CVD)发生及发展的重要因素。充分认识PBUTs的合成代谢、生物毒性、清除方式对研究其影响CVD的发生机制具有重要的临床指导意义。本文就CKD患者PBUTs特性及其心血管疾病机制研究进展做一综述。     

慢性肾脏病患者血浆成纤维细胞生长因子23与心血管疾病的关系

慢性肾脏病(CKD)患者心血管并发症发生率较普通人群增高,心血管疾病(CVD)是CKD进展的重要危险因子。CKD患者的矿物质与骨代谢异常(MBD)包括血清全段甲状旁腺激素(i PTH)升高、维生素D缺乏及高磷血症等,均为CVD的独立影响因素。成纤维细胞生长因子23(FGF23)能调节体内磷和维生素D代谢水平。血浆FGF23水平在CKD患者早期即进行性升高,一方面是机体对尿毒症状态的适应性变化,另一方面也是骨病与心血管并发症等病理过程的起始因素。血浆FGF23水平与CKD患者的左心室肥厚(LVH)、血管钙化、心血管功能异常及死亡率增加相关。现将FGF23的生理特点及其与CVD的关系、介导CVD的机制等作一综述。     

硫酸吲哚酚对心血管毒性作用的研究进展

慢性肾脏病(chronic kidney disease,CKD)患者心血管疾病(cardiovascular disease,CVD)的发生率高且预后极差,了解CKD患者中CVD发生发展的病理生理变化有助于制定相关治疗策略以降低其发病率和死亡率。一般人群的传统心血管危险因素,如糖尿病、高血压和血脂异常等,在CKD患者中更为常见,但这仍然不足以完全解释其心血管事件高风险的特点。随着肾功能下降,积聚在体内的尿毒症毒素被认为在CKD患者CVD的发生与发展过程中起关键的促进作用,而硫酸吲哚酚(indoxyl sulfate,IS)是当前研究最多的肠源性尿毒素之一。该文就IS对心血管毒性作用的相关研究进展作一综述。     

慢性肾脏病对心血管系统的影响

慢性肾脏病(CKD)患者是心血管疾病(CVD)的高危人群,CVD已成为CKD患者死亡的主要病因,有效干预CKD多重CVD的危险因素,有助于控制CKD患者CVD的发生和发展。     

血液透析患者颈动脉中层厚度与血清磷浓度的交叉--断面关系

近年强调慢性肾脏疾病(CKD)是心血管疾病(CVD)的明显预测因素,CVD和卒中是终末期需透析肾病患者的主要致死原因,其死亡危险是年龄和性别匹配一般人群的10-20倍。高龄、高血压、吸烟和高脂血症是动脉硬化最主要的危险因素, 进行性动脉硬化是非尿毒症糖尿病患者的特征,但目前尚不明确尿毒症患者是否也存在类似特点?血清磷浓度是血管钙化     

慢性肾脏病与心脑血管疾病

慢性肾脏病(CKD)是心血管疾病(CVD)发生、发展的独立危险因素.对于普通人群,CKD可明显增加CVD发生的风险;对于已有CVD或存在CVD危险因素的人群,CKD则可明显增加心血管事件如卒中、急性心肌梗死、心功能不全等的发生.另一方面,CVD又是促进CKD进展、影响CKD预后的重要因素,也是导致CKD患者致残、致死的第一位常见原因.     

重视高同型半胱氨酸血症在慢性肾脏病患者心血管并发症中的作用

流行病学调查显示全世界人口中有近10%慢性肾脏病(CKD)患者。心血管疾病(CVD)则是发病率最高的慢性非传染性疾病,2005年全球近1700万人死于CVD。CKD患者是CVD的高危人群,美国肾脏病数据系统(USRDS)统计显示CKD患者中CVD的发生率为普通人群的10～30倍。CKD早期CVD发生率已增高,终末期肾脏病(ESRD)     

超声心动图在慢性肾脏病患者心血管疾病筛查中的应用

目的探讨超声心动图在慢性肾脏病(CKD)患者心血管疾病(CVD)筛查中的临床应用价值。方法选择CKD患者712例,研究患者基线资料、实验室指标及辅助检查(心电图、胸部X线摄片、超声心动图)结果,分析超声心动图在CKD患者CVD筛查中的临床应用价值。结果712例CKD患者中CKD 1~5期的占比分别为14.19%(101/712)、16.71%(119/712)、22.19%(158/712)、14.47%(103/712)与32.44%(231/712);随患者病情进展,其年龄、血肌酐水平显著升高,肾小球滤过率估计值(e GFR)显著下降(P0.05);CKD 1~5期患者CVD的发生率分别为5.94%(6/101)、17.65%(21/119)、26.58%(42/158)、32.04%(33/103)与9.78%(115/231);CKD患者CVD中冠状动脉疾病(CAD)、左心室肥厚(LVH)和充血性心力衰竭(CHF)的总发生率分别为8.15%、23.31%、11.24%;随CKD患者病情进展,胸部X线片、心电图、超声心动图检出CKD、CVD、CAD、LVH、CHF的阳性率均显著升高(P0.05),且不同分期患者超声心动图检查率均显著高于心电图和胸部X线片(P0.05)。结论 CVD在CKD1期出现,随着病情进展其发生率逐渐上升,超声心动图检查作为CKD与CVD的筛查指标可用于各期CKD及CKD患者CVD的早期筛查。     

脂质代谢异常与慢性肾脏病合并心血管疾病的研究进展

慢性肾脏病(CKD)的患病率逐年上升,而心血管疾病(CVD)是导致其死亡的主要原因。CKD患者往往同时合并脂质代谢异常,这是促进CVD发生发展的重要因素,但CKD患者的脂质代谢异常与CVD发病率和死亡率之间的关系有其特殊性,各类降脂治疗能否有效改善CKD患者的CVD也存在争议。因此,文章就脂质代谢异常与CKD患者合并CVD发生的病理生理机制及相关性作一综述,这对降低CKD患者CVD发生率及改善患者预后具有十分重要的意义。     

哪些慢性肾脏病患者需调脂治疗

慢性肾脏病(CKD)已逐渐成为全球范围内影响健康的重要问题之一,近年来的流行病学调查显示,估算的肾小球滤过率(eGFR)是除高血压、糖尿病、白蛋白尿外,导致心血管疾病(CVD)的重要独立危险因素,轻度肾功能减退患者即使无传统的CVD危险因素,其CVD的发生率和死亡率也明显增加.随着肾脏疾病治疗及透析技术的不断改进及普及,尿毒症患者生存率明显提高,然而心血管并发症仍是导致死亡的重要原因.     

Role of oxidative stress and indoxyl sulfate in progression of cardiovascular disease in chronic kidney disease

Several abnormalities of the cardiovascular system are observed in most cases of chronic kidney disease (CKD). Mechanisms underlying these abnormalities are complicated, and several factors contribute to their pathogenesis. Of these factors, oxidative stress and uremic toxins are considered to play key roles in the progression of cardiovascular disease (CVD) in CKD. Oxidative stress increases significantly in CKD and accelerates proteinuria and renal dysfunction. In addition, oxidative stress has been reported to induce cardiac hypertrophy and fibrosis. Indoxyl sulfate, a uremic toxin, has recently been suggested to play a crucial role in the development of CVD. Recent in vitro data suggest that indoxyl sulfate increases oxidative stress. Some reports have shown that AST-120, which is an oral charcoal adsorbent, can reduce oxidative stress by lowering serum indoxyl sulfate levels. Recently, we have also demonstrated that indoxyl sulfate is associated with the production of oxidative stress, and that increased oxidative stress is significantly correlated with cardiac hypertrophy and fibrosis. Furthermore, results of our basic and clinical studies suggested that AST-120 can prevent progression of cardiac hypertrophy by reducing oxidative stress in CKD. Thus, one of the main targets of the management of CKD and CVD is the control of oxidative stress and uremic toxins, such as indoxyl sulfate.     

Role of indoxyl sulfate in the progression of chronic kidney disease and cardiovascular disease: experimental and clinical effects of oral sorbent AST-120

Indoxyl sulfate, a nephrovascular uremic toxin, is markedly accumulated in the serum of chronic kidney disease (CKD) patients. Because of its protein binding ability, its removal by hemodialysis is not as efficient as that of non-protein bound uremic toxins. AST-120 delays the progression of CKD by adsorbing indole, a precursor of indoxyl sulfate, in the intestines, and consequently reduces the serum levels of indoxyl sulfate. Indoxyl sulfate exhibits cellular toxicity in renal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiac myocytes, and osteoblasts by inducing oxidative stress. Indoxyl sulfate stimulates the progression of CKD by increasing the expression of fibrogenic genes such as transforming growth factor-β1 in CKD rats. Indoxyl sulfate stimulates aortic calcification in hypertensive rats; thus, indoxyl sulfate is involved in the progression of CKD and cardiovascular disease. Experimental and clinical data demonstrate that AST-120 delays the progression not only of chronic kidney disease, but also of cardiovascular disease.     

Effects of Uremic Toxins from the Gut Microbiota on Bone: A Brief Look at Chronic Kidney Disease

Patients with chronic kidney disease (CKD) frequently have mineral and bone disorders (CKD‐MBD) that are caused by several mechanisms. Recent research has suggested that uremic toxins from the gut such as p‐cresyl sulfate (PCS) and indoxyl sulfate (IS) could also be involved in the development of bone disease in patients with CKD. IS and PCS are produced by microbiota in the gut, carried into the plasma bound to serum albumin, and are normally excreted into the urine. However, in patients with CKD, there is an accumulation of high levels of these uremic toxins. The exact mechanisms of action of uremic toxins in bone disease remain unclear. The purpose of this brief review is to discuss the link between uremic toxins (IS and PCS) and bone mineral disease in chronic kidney disease.     

Vascular calcification in patients with chronic kidney disease

Chronic kidney disease (CKD) represents an extremely common condition, and cardiovascular diseases are frequently reported in this patient population. Traditional risk factors are not accurate prognostic predictors in CKD patients, and new potential markers to predict the cardiovascular involvement in uremic patients need to be identified. Vascular calcification (VC) represents a hallmark of the atherosclerotic process in CKD. This review summarizes the processes responsible for VC (particularly focusing on the mechanisms operative in the presence of renal dysfunction), discusses the utility of computer tomography modalities in the detection of VC in patients with CKD, and reports the potential role of VC as pathophysiological link between kidney disease and cardiovascular events.     

Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC‐dependent enhancement of the mitochondrial function

Although mesenchymal stem cell (MSC)‐based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H₂O₂ to induce oxidative stress. CKD‐derived MSCs exhibited greater oxidative stress‐induced senescence than normal‐mMSCs, while melatonin protected CKD‐mMSCs from H₂O₂ and associated excessive senescence. The latter was mediated by PrP^C‐dependent mitochondrial functional enhancement; melatonin upregulated PrP^C, which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin‐treated CKD‐mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD‐mMSCs are more susceptible to H₂O₂‐induced senescence than normal‐mMSCs, and melatonin administration protects CKD‐mMSCs from excessive senescence by upregulating PrP^C and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD‐mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell‐based therapies using mouse‐derived CKD‐mMSCs.     

Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease

Abstract. Stenvinkel P (Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden). Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease (Review). J Intern Med 2010; 268 : 456–467. The epidemics of cardiovascular disease, obesity, diabetes, HIV and cancer have all received much attention from the public, media and policymakers. By contrast, chronic kidney disease (CKD) has remained largely a ‘silent’ epidemic. This is unfortunate because early diagnosis of renal disease based on proteinuria and/or reduced estimated glomerular filtration rate could enable early intervention to reduce the high risks of cardiovascular events, end‐stage renal disease (ESRD) and death that are associated with CKD. Given the global increase in the incidence of the leading causes of CKD – hypertension, obesity and diabetes mellitus – better disease management and prevention planning are needed, as effective strategies are available to slow the progression of CKD and reduce cardiovascular risk. CKD may be regarded as a clinical model of accelerated vascular disease and premature ageing, and the risk‐factor profile changes during the progression from mild/moderate CKD to ESRD. Although many randomized controlled trials in patients with mild to moderate CKD have shown beneficial effects of interventions aimed at preventing the progression of CKD, most trials have been unable to demonstrate a beneficial effect of interventions aimed at improving outcome in ESRD. Thus, novel treatment strategies are needed in this high‐risk patient group.     

Impact of hemodialysis therapy on anemia of chronic kidney disease: the potential mechanisms

A significant and increasing number of chronic kidney disease (CKD) patients are treated with online hemodiafiltration (OL-HDF), even in the absence of more conclusive survival data. OL-HDF affords several clinical benefits including control of anemia of CKD, a common affliction in dialysis patients. In efforts to understand the underlying mechanisms that contribute to the purported benefits of OL-HDF, we examined the potential role and impact of OL-HDF on key stages of anemia and its correction: erythropoiesis of bone marrow, circulating erythrocytes and on anemia therapy. We review evidence that indicates OL-HDF may modulate key processes of anemia and its therapy, including underlying conditions and responses of uremic toxicity and inflammation that aggravate anemia. Our assessment indicates that OL-HDF favorably impacts anemia by not only eliminating putative uremic inhibitors that suppress erythropoiesis, reducing red cell destruction and increasing iron availability, but also by mechanisms restricting underlying inflammation and endothelial dysfunction that are crucial to both CKD and anemia.     

The epidemic of chronic kidney disease: looking at ageing and cardiovascular disease through kidney-shaped lenses

In recent years, a 'silent' chronic kidney disease (CKD) epidemic has been proposed by many authors. The 'outbreak' is because of the inclusion of a large proportion of the elderly population within stage 3 CKD according to the Kidney Disease Outcomes Quality Initiative staging system. Unfortunately, this does not take into account the fact that renal function normally declines with age; in addition, the Modification of Diet in Renal Disease formula used to calculate glomerular filtration rate underestimates renal function in the elderly. Because population preventive strategies need a precise definition of the target for screening, a more accurate tool to detect CKD in the general population is required. Considerable interest in CKD has been generated by the evidence that predialysis CKD is associated with increased risk of cardiovascular disease (CVD). Such an association per se does not imply that CKD is a causal determinant of CVD. As CKD has been detected particularly in elderly individuals, it is tempting to speculate that an association may exist between age and cardiovascular outcomes in patients with CKD. Furthermore, the definition of CKD is a nosographic simplification that includes diseases with different causes and pathogenetic mechanisms. The aetiologies of renal diseases can affect cardiovascular outcomes, and the two major causes of end-stage renal disease, diabetes mellitus and hypertension, indeed do so. These findings point to a need for a better definition of CKD to optimize the allocation of healthcare resources and to clarify the nature of the association between CKD and CVD.     

Cognitive impairment in chronic kidney disease

Objectives: To assess the prevalence of cognitive impairment in persons with chronic kidney disease (CKD) and its relation to the severity of CKD.
Design: Cross-sectional study.
Setting: University-affiliated ambulatory nephrology and dialysis practices.
Participants: Eighty subjects with CKD Stages III and IV not requiring dialysis (CKD) and 80 subjects with CKD Stage V on hemodialysis (end-stage renal disease (ESRD)) with a mean age±standard deviation of 62.5±14.3.
Measurements: Three standardized cognitive tests, the Modified Mini-Mental State Examination (3MS), Trailmaking Test B (Trails B), and California Verbal Learning Trial (CVLT). Glomerular filtration rate was estimated in subjects with CKD using the six-variable Modification of Diet in Renal Disease equation.
Results: There was a graded relation between cognitive function and severity of CKD. Mean scores on the 3MS, Trails B, and CVLT immediate and delayed recall were significantly worse for subjects with ESRD than for subjects with CKD or published norms ( P<. 001 for all comparisons). Scores on the Trails B ( P<. 001) and CVLT immediate ( P=. 01) and delayed ( P<. 001) recall were significantly worse for subjects with CKD not requiring dialysis than for published norms. In addition, the fraction of subjects with impairment on the 3MS and Trails B increased with decreasing kidney function.
Conclusion: Cognitive impairment is associated with the severity of kidney disease. Further studies are needed to determine the reasons for cognitive impairment in subjects with CKD and ESRD.