The endothelin system and its antagonism in chronic kidney disease

The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease (CVD) is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Treatments that slow the progression of CKD and improve the cardiovascular risk profile of patients with CKD are needed. The endothelins (ET) are a family of related peptides, of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both CVD and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness and more novel cardiovascular risk factors such as oxidative stress and inflammation. Through these, ET also contributes to endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In particular relation to the kidney, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET likely also is involved in progression of renal disease, and data are emerging to suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.     

Clinical assessment and management of dyslipidemia in patients with chronic kidney disease

Chronic kidney disease (CKD) is a common cause of cardiovascular disease (CVD). Several factors contribute to the onset and progression of atherosclerosis and CVD in CKD patients. Most of the cases of coronary heart disease in the general population can be explained by traditional risk factors, whereas non-traditional risk factors, including oxidative stress, anemia, inflammation, malnutrition, vascular calcification, and endothelial dysfunction, have been proposed to play a central role in the pathogenesis of CVD in CKD patients. However, the precise mechanism of CVD initiation in CKD patients remains unclear. Lipid-lowering therapies may decrease proteinuria, and increase or maintain renal function. Because the serum levels of triglyceride-rich lipoproteins are increased in CKD patients, particularly in advanced stages, the serum non-HDL cholesterol level may be a better biomarker of dyslipidemia than the serum LDL cholesterol level in this population. A meta-analysis showed that statin therapy was associated with decreased albuminuria in comparison with a placebo. Moreover, lipid-lowering therapy with statins is effective in reducing the risk of CVD in the early stages of CKD, whereas the benefit of statins in patients with end-stage renal disease may be limited.     

慢性肾脏病患者心血管疾病危险因素探讨

目的探讨慢性肾脏病（CKD）患者心血管疾病的危险因素。方法收集我院542例住院CKD患者的病史、实验室检查和辅助检查结果,将患者根据有无心血管疾病分为2组,根据Logistic回归分析结果探讨心血管疾病的危险因素。结果高龄、高血压、高尿酸血症、贫血、蛋白尿是CKD患者心血管疾病的危险因素;CKD1～5期患者心血管疾病的危险因素各不相同。结论CKD进展和CKD患者心血管疾病的发生拥有部分相同的危险因素;在CKD早期以传统危险因素为主,随着肾功能的恶化,非传统危险因素起主导的作用。     

Prevention of chronic kidney disease: a global challenge

In view of the increasing number of patients requiring renal replacement therapy (RRT) every year worldwide, attention has focused over the last two decades on meeting the health care need of patients with end-stage renal failure (ESRF). More recently, increasing awareness of the growing burden of chronic kidney disease (CKD), with a large percentage of the population affected by early stages of CKD, has shifted attention and health care priority to the prevention and early detection of CKD. This article addresses issues related to general population as well as targeted screening, favoring the latter. It also examines some of the screening initiatives undertaken in both the developing and developed worlds. It also highlights the links between albuminuria, CKD, and cardiovascular disease (CVD) as an increasing number of studies identify albuminuria/proteinuria, as well as CKD as major markers of CVD. Finally, a brief review is included of primary and secondary intervention strategies for CKD and issues related to their implementation: manpower and funding.     

血浆不对称二甲基精氨酸与慢性肾脏疾病非透析患者心血管并发症的关系

目的 探讨不对称二甲基精氨酸（ADMA）与慢性肾脏疾病（CKD）非透析患者心血管并发症（CVD）的关系。 方法 高效液相色谱-质谱联用仪检测76例患者的血浆ADMA水平，分析其与颈动脉超声、心脏超声等相关指标及既往CVD病史的关系。 结果 CKD非透析患者的血浆ADMA水平较健康对照组显著升高[(41.56±12.76) 比 (17.12±7.09) mg/L, P < 0.01]。逐步多元回归分析显示ADMA是颈总动脉内-中膜厚度（β = 0.544, P < 0.01）和左室心肌重量指数（β = 2.521, P < 0.01）的独立危险因素。既往有CVD史者其血浆ADMA水平较既往无CVD史者显著升高[(47.60±15.14)比 (36.93±8.10) mg/L，P < 0.01]。Logistic回归分析显示血浆ADMA（β = 1.117，95%CI：1.013~1.232, P < 0.05）是CKD非透析患者CVD的独立危险因素。 结论 CKD患者普遍存在CVD，ADMA可能参与了CKD非透析患者CVD的发生发展。     

Anemia as a risk factor for chronic kidney disease

Chronic kidney disease (CKD) is an important and leading cause of end-stage renal disease (ESRD) and moreover, plays a role in the morbidity and mortality due to cardiovascular disease, infection, and cancer. Anemia develops during the early stages of CKD and is common in patients with ESRD. Anemia is an important cause of left ventricular hypertrophy and congestive heart failure. Correction of anemia by erthyropoiesis-stimulating agent (ESA) has been shown to improve survival in patients with congestive heart failure. Anemia is counted as one of the non-conventional risk factors associated with CKD. Hypoxia is one of the common mechanisms of CKD progression. Treatment by ESA is expected to improve quality of life, survival, and prevent the CKD progression. Several clinical studies have shown the beneficial effects of anemia correction on renal outcomes. However, recent prospective trials both in ESRD and in CKD stages 3 and 4 failed to confirm the beneficial effects of correcting anemia on survival. Similarly, treatment of other risk factors such as hyperlipidemia by statin showed no improvement in the survival of dialysis patients. Given the high prevalence of anemia in ESRD and untoward effects of anemia in CKD stages 3 and 4, appropriate and timely intervention on renal anemia using ESA is required for practicing nephrologists and others involved in the care of high-risk population. Lessons from the recent studies are to correct renal anemia (hemoglobin <10 g/dl not hemoglobin > or =13 g/dl). Early intervention for renal anemia is a part of the treatment option in the prevention clinic. In this study, clinical significance of anemia management in patients with CKD is discussed.     

Cardiovascular disease in chronic kidney disease from a cardiologist's perspective

PURPOSE OF REVIEW: Cardiovascular disease accounts for the majority of morbidity and mortality in patients with chronic kidney disease (CKD). This review therefore concentrates on CKD from the viewpoint of the cardiologist. RECENT FINDINGS: Studies have identified several explanations for this observation, including high rates of risk factors for cardiovascular disease, lesser use of cardioprotective strategies, adverse outcomes with cardiovascular drugs and procedures, and accelerated atherosclerosis and myocardial disease in CKD. Because recent studies have rigorously controlled for confounding factors, there is an emerging recognition that CKD is an independent cardiovascular risk state. Conversely, CKD appears to be the result of systemic atherosclerosis. The relative under-utilization of cardioprotective therapies has been an increasingly reported finding in the literature. It appears that conventional cardiovascular risk factor reduction in both the chronic and acute care settings has a greater relative benefit in those patients with CKD than in those with normal renal function. SUMMARY: CKD is an independent cardiovascular risk state. Hence, there is a strong rationale for research in CKD patients into the pathogenesis of CVD. In addition, there are multiple opportunities for improving cardiovascular outcomes in patients with CKD, including both chronic and acute cardiovascular risk reduction.     

Predicting initiation and progression of chronic kidney disease: Developing renal risk scores

Epidemiological studies have raised awareness of the problem of undiagnosed chronic kidney disease (CKD) and suggest that early identification and treatment will reduce the global burden of patients requiring dialysis. This has highlighted the twin problems of how to identify subjects for screening and target intervention to those with CKD most likely to progress to end-stage renal disease. Prospective studies have identified risk factors for CKD in the general population as well as risk factors for progression in patients with established CKD. Risk factors may thus be divided into initiating factors and perpetuating factors, with some overlap between the groups. In this paper, we review current data regarding CKD risk factors and illustrate how each may impact upon the mechanisms underlying CKD progression to accelerate loss of renal function. We propose that these risk factors should be used as a basis for developing a renal risk score, analogous to the Framingham risk score for ischemic heart disease, which will allow accurate determination of renal risk in the general population and among CKD patients.     

The role of statins in chronic kidney disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality not only amongst the general population, but also in patients with chronic kidney disease (CKD). Persons with CKD are much more likely to die of CVD than to experience kidney failure. Clinical trials have demonstrated that statins are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD. In CKD patients the role of statins in primary prevention of CVD remains to be clarified. The absolute benefit of treatment with a statin seems to be greater among nondialysis-dependent-CKD patients. Studies in end-stage renal disease patients on dialysis did not confirm these results. Recently, however, the Study of Heart and Renal Protection (SHARP) has suggested that statins with ezetimibe may be beneficial even in dialysis patients. Clinical studies with statins on proteinuria reduction and renal disease progression have yielded conflicting results. Some studies have shown a prominent reduction in proteinuria, while other studies have shown that statins had no effect or may cause proteinuria at high doses. This review examines the clinical evidence of the observed benefits of kidney function with the use of this drug category in CKD patients.     

Cardiovascular disease in children with chronic kidney disease

In children with end-stage renal disease (ESRD), cardiovascular disease (CVD) mortality has not changed for the past 3 decades. Cardiac disease remains the second most common cause of death. Recent data demonstrate a high incidence and prevalence of traditional and chronic kidney disease (CKD)-related CVD risk factors in children. Early markers of cardiomyopathy, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction (LV dysfunction), and early markers of atherosclerosis, such as increased carotid artery intima-media thickness (IMT) and carotid arterial wall stiffness, are frequently found in this patient population. Early identification of modifiable risk factors and treatment of asymptomatic CVD might lead to decrease of cardiovascular morbidity and mortality in young adults who developed CKD during childhood.     

Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease

Decreased nitric oxide (NO) production and/or impaired NO bioavailability may occur in patients with chronic kidney disease (CKD), and could contribute to the elevation of blood pressure, cardiovascular disease (CVD) and the progression of renal injury in these patients. However, the underlying molecular mechanisms for reduced NO action in patients with CKD remains to be elucidated. Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue found in plasma and various types of tissues, acting as an endogenous NO synthase inhibitor in vivo. Further, plasma level of ADMA is elevated in patients with CKD and found to be a strong biomarker or predictor for future cardiovascular events. In addition, plasma level of ADMA could predict the progression of renal injury in these patients as well. These findings suggest that elevation of ADMA may be a missing link between CVD and CKD. In this review, we discuss the molecular mechanisms for the elevation of ADMA and its pathophysiological role for CVD in high-risk patients, especially focusing on patients with CKD.     

Cardiovascular disease in early stages of chronic kidney disease in a Chinese population

Cardiovascular disease (CVD) is one of the most serious complications of kidney disease, yet studies of CVD in early stage of chronic kidney disease (CKD) in Asian patients are very limited. Therefore, this study determined the prevalence and the spectrum of CVD in individuals with early-stage CKD and compared them with data of individuals without CKD. Compared with individuals with estimated GFR (eGFR) >90 ml/min per 1.73 m2, the prevalence of myocardial infarction, stroke, and total CVD of individuals with eGFR 60 to 89 ml/min per 1.73 m2 was increased by 91.4, 71.7, and 67.6%, respectively. For individuals with eGFR 30 to 59 ml/min per 1.73 m2, the percentage was 105.2, 289.1, and 200.7%, respectively. For each eGFR category, stroke was more prevalent than myocardial infarction. Compared with individuals with eGFR >90 ml/min per 1.73 m2, participants with eGFR 60 to 89 and 30 to 59 ml/min per 1.73 m2 tended to have more cardiovascular risk factors, and there were strong unadjusted and adjusted associations between CVD with different stages of eGFR (eGFR >90 ml/min per 1.73 m2 as reference). This is the first report on the prevalence and the spectrum of CVD in early stages of CKD in a community-based Chinese population. The spectrum of CVD in this Chinese population is different from reports of Western countries. Individuals with subtle decreased renal function seem much more likely to have multiple cardiovascular risk factors and have higher prevalence of CVD than those without CKD.     

Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Both in dialysis and in transplant patients, CVD remains the leading cause of death. There is accumulating evidence that the increase in CVD burden is present in patients prior to dialysis, due to both conventional risk factors as well as those specific to kidney disease. Of importance is that even in patients with mild kidney disease, the risk of cardiovascular events and death is increased relative to patients without evidence of kidney disease. The new classification system proposed by the National Kidney Foundation as part of the Dialysis Outcomes Quality Initiative (DOQI) process describes the five stages of kidney disease, as well as those complications associated with chronic kidney disease (CKD), in particular cardiovascular risk factors and disease. Patients with kidney disease are deemed to be at highest cardiovascular risk. CVD, defined as the presence of either congestive heart failure (CHF), ischemic heart disease (IHD), or left ventricular hypertrophy (LVH), is prevalent in cohorts with established CKD (8-40%). The prevalence of hypertension, a major risk factor for coronary artery disease (CAD) and LVH is high in patients with CKD (87-90%). At least 35% of patients with CKD have evidence of an ischemic event (myocardial infarction or angina) at the time of presentation to a nephrologist. The prevalence of LVH increases at each stage of CKD, reaching 75% at the time of dialysis initiation, and the modifiable risk factors for LVH include anemia and systolic blood pressure, which are also worse at each stage of kidney disease. Even under the care of nephrologists, a change in cardiac status (worsening of heart failure or anginal symptoms) occurs in 20% of patients. The presence of CVD predicts a faster decline of kidney function and the need for dialysis, after controlling for all other factors including glomerular filtration rate (GFR), age, and the presence of LVH. This article describes the new classification system for staging of CKD, defines and describes CVD in CKD, and reviews the evidence and its limitations with respect to the current understanding of CKD and CVD. Specifically, methodologic issues related to survival and referral bias limit our current understanding of the complex interaction of conventional and nonconventional kidney disease-specific risk factors. We identify the importance of well-conducted studies of patient groups with and without CVD, with and without CKD, in order to better understand the complex physiology so that treatment strategies can be appropriately applied.     

Cardiovascular calcification in nondialyzed patients with chronic kidney disease

Chronic kidney disease (CKD) has become a major health-care problem of global proportions. Progression to end-stage renal disease (ESRD), the need for renal replacement therapy, and the high annual death rate of dialysis patients are the most noticeable outcomes of CKD. Less appreciated, however, is the fact that most patients with CKD actually die mainly from cardiovascular disease, rather than progress to ESRD. Coronary artery calcification (CAC), a surrogate marker of atherosclerosis, is common in dialysis and CKD patients. Coronary artery calcium scores, as measured by ultrafast computed tomography, is an independent predictor of future cardiac events. Using this technique, several studies have documented extensive calcification in dialysis patients, a subject of several exhaustive reviews. Unfortunately, much less attention has been paid to calcification in nondialyzed patients with CKD. In this review, I will emphasize the fact that CVC is common in patients with CKD not yet on dialysis, develops early in the course of CKD, and worsens with the decline in renal function particularly among diabetics who progressed to ESRD. I will also discuss the pathogenesis of CVC in CKD patients and highlight the lack of a major role for abnormalities of mineral metabolism in the pathogenesis of calcification in CKD patients. In addition to the high prevalence of traditional risk factors for CAD, the presence of proteinuria, reduced renal function, diabetic nephropathy, and the rate of progression to ESRD may represent the main uremia-related factors that increase the risk for calcification in CKD. Finally, I will review the protective role of inhibitors of calcification in CKD.     

Biomarkers in chronic kidney disease: a review

Chronic kidney disease (CKD) is a major public health problem. The classification of CKD by KDOQI and KDIGO and the routine eGFR reporting have resulted in increased identification of CKD. It is important to be able to identify those at high risk of CKD progression and its associated cardiovascular disease (CVD). Proteinuria is the most sensitive marker of CKD progression in clinical practice, especially when combined with eGFR, but these have limitations. Hence, early, more sensitive, biomarkers are required. Recently, promising biomarkers have been identified for CKD progression and its associated CVD morbidity and mortality. These may be more sensitive biomarkers of kidney function, the underlying pathophysiological processes, and/or cardiovascular risk. Although there are some common pathways to CKD progression, there are many primary causes, each with its own specific pathophysiological mechanism. Hence, a panel measuring multiple biomarkers including disease-specific biomarkers may be required. Large, longitudinal observational studies are needed to validate candidate biomarkers in a broad range of populations prior to implementation into routine CKD management. Recent renal biomarkers discovered include neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid-binding protein. Although none are ready for use in clinical practice, it is timely to review the role of such biomarkers in predicting CKD progression and/or CVD risk in CKD.     

Mechanism by which chronic kidney disease causes cardiovascular disease and the measures to manage this phenomenon

In Japan, the number of chronic kidney disease (CKD) patients is thought to be 13,300,000, next in size after those with hypertension and diabetes. Although the number of patients with CKD seems large, it does not mean that all these patients require special treatment. Among them, nephrologists should pay special attention to patients with glomerular filtration rate below 50 mL/min/1.73 m² and progressive deterioration of renal function. Treatment of these CKD patients by a limited number of specialists is simply impossible; hence, it is essential to request treatment from physicians who are involved in general internal medicine and primary care. It is well known that not only does CKD cause end-stage renal failure, it also causes the onset of cardiovascular diseases (CVD) such as cardiac infarction and cerebral stroke; however, the question is how much significance does CKD have as a risk factor for CVD. It is understandable that hypertension and CVD are often complications of CKD; however, in addition to what is conventionally mentioned, there are three or four mechanisms that we would like to emphasize, and discuss herein. Among them, we would like to stress the role of klotho genes with special reference to the generation of CVD in CKD patients. When patients develop CKD, it is therefore necessary to remove as far as possible any factors that could represent a risk for CVD. Moreover, by taking appropriate measures against clinical conditions that often complicate CKD, such as hypertension, renal anemia, hyperuricemia, and hyperlipidaemia, the development of CVD can be prevented.     

Relationship between renal function at the time of percutaneous coronary intervention and prognosis in ischemic heart disease patients

BACKGROUND: As hypertension and diabetes mellitus increase, the number of patients developing complications of cardiovascular disease (CVD) associated with conventional risk factors is increasing. In addition to these risk factors for CVD, chronic kidney disease (CKD) has also been reported to play an important role. We investigated the association of representative ischemic heart disease and CKD. METHODS: Between July 1, 2000, and June 30, 2005, a total of 790 patients who underwent percutaneous coronary intervention (PCI) for angina pectoris or myocardial infarction in our division of cardiovascular disease were reviewed. Serum markers at the implementation of PCI were compared in patients classified according to renal function. For prognosis, in-hospital mortality, 1-year survival rate, overall mortality, and CVD death were investigated. Changes in renal function were also monitored during the follow-up period. The glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease Study Group (MDRD) formula. RESULTS: The mean estimated GFR (eGFR) at PCI implementation was 66.2 +/- 21.0 ml/min/1.73 m(2). Stage 2 CKD was shown in 51.5% of all the patients. During the overall follow-up period, 126 patients died. With the progression of CKD stage, all-cause, CVD, and in-hospital mortality increased, and the 1-year survival rate decreased. It was proved that a medical history of hypertension, hyperlipidemia, and diabetes, multiple vessel lesions, hypoalbuminemia, C-reactive protein (CRP), and estimated GFR were independent risk factors for all-cause death. In CVD death, in addition to the above risk factors, anemia and total cholesterol were also an independent risk factor. Renal function deteriorated significantly during the follow-up period. CONCLUSIONS: Patients with ischemic heart disease requiring PCI often develop renal dysfunction, which may considerably affect prognosis.     

Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.     

Epidemiology and prevention of cardiovascular complication in chronic kidney disease patients

The risk for cardiovascular disease is significantly higher among patients with chronic kidney disease (CKD) than among the general population, considering that cardiovascular disease is the prominent cause of both morbidity and mortality in dialysis patients. This is explained mainly by the considerable prevalence of cardiovascular risk factors among CKD patients since the earliest stages of renal impairment, which include not only the so-called traditional risk factors, but also a number of additional risk factors that are specific to CKD and to the dialytic treatment itself. Considering the multiplicity of cardiovascular risk factors operating in CKD patients, as well as the crucial impact of their cardiovascular condition on long-term outcome, it is mandatory that all the available interventions aimed at the correction of all the modifiable risk factors for cardiovascular disease are performed as early as possible in the progression of the disease. In particular, the results of several controlled clinical trials have shown that a timely correction of anemia and of calcium-phosphate disorders leads to a significant improvement in the cardiovascular conditions of CKD patients. Evidence also is growing regarding the benefits of intervention of newly recognized risk factors for cardiovascular disease such as inflammation and oxidant stress.     

Understanding the role of genetic polymorphisms in chronic kidney disease

Although no valid studies clearly indicate increasing or decreasing numbers of incident paediatric patients, the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) is growing worldwide. This is mainly due to improved access to renal replacement therapy (RRT), increased survival after dialysis and kidney transplantation and an increase in diagnosis and referral of these patients. Although the increase in CKD prevalence is mainly caused by environmental factors, genetic factors may also influence the incidence and/or the progression of CKD and its complications. As CKD patients might be more sensitive to genetic effects due to the exposure to a uraemic milieu, this makes studies of genetic factors especially interesting in this population. The goal of identifying genetic factors that contribute to the outcome of CKD is to gain further understanding of the disease pathogenesis and underlying causes and, possibly, to use this knowledge to predict disease or its complications and to identify a risk population. Therefore, genetic screening of paediatric CKD patients may enhance the impact of preventive measures that could have a positive effect on outcome. Furthermore, by identifying patients’ genetic backgrounds, it is possible that a more individualised therapy could be designed.