Epidemiology of vascular disease in renal failure.

Cardiovascular disease (CVD) is the leading cause of death in the general population and a major cause of morbidity and mortality chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. The high prevalence of CVD in incident dialysis populations suggests that CVD begins during or before the stage of chronic renal insufficiency. While traditional risk factors observed in the general population may play a role in the progression of CVD in CKD and ESRD patients, the presence of several nontraditional factors related to the extent of uremia seems to be the more significant feature of CVD in this patient population. Recently, there have been significant advances in our understanding of how inflammation contributes to the pathogenesis of atherosclerosis and myocardial infarction. The fact that chronic inflammation and CVD are highly prevalent in ESRD patients, it is probable that chronic inflammation may be a causative factor for accelerated atherosclerosis observed in CKD and ESRD patients. Given the extent of the problem, efforts to lower the mortality rate among ESRD patients will require new approaches to reduce and/or prevent cardiovascular morbidity and mortality.     

Chronic Kidney Disease as a Coronary Artery Disease Risk Equivalent

Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease (CVD) risk and a higher CVD event rate. Substantial data from prospective cohort studies support the concept that dialysis patients as well as those with advanced stage (stages 3–5) CKD are associated with an increased risk for all-cause and cardiovascular mortality. The risk for coronary artery disease (CAD) increases exponentially with declining kidney function, i.e., stage 3 or higher CKD. Indeed, CVD accounts for more than 50 % of deaths in patients with CKD. CKD patients are more likely to die of CVD than to progress to end stage kidney disease. This increase in CV risk is commonly attributed to co-existence of numerous traditional and nontraditional risk factors for the development of CVD that frequently accompany reduced kidney function. Therefore, CKD itself is now considered an independent CVD risk factor and a coronary artery disease (CAD) equivalent for all-cause mortality. All patients at risk for CAD should be evaluated for kidney disease. Treatments used for management of established CAD might have similar benefits for patients with concomitant CKD.     

Chronic Kidney Disease Japan Cohort (CKD-JAC) study: design and methods

The prevalence and incidence of end-stage renal disease (ESRD) in Japan are the highest and the third highest, respectively, in the world, while the incidence of cardiac death in Japan is the lowest among developed countries. A recent study showed that the prevalence of chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m(2), is extremely high in Japan, about 20% of the adult population. However, the risk of ESRD and cardiovascular disease (CVD) in the CKD population has not been determined nationwide. For this observational study, we will establish a Chronic Kidney Disease Japan Cohort (CKD-JAC) by enrolling 3,000 patients with CKD in 17 clinical centers around Japan, which will be used to determine the incidence of ESRD and CVD in Japanese CKD patients. Risk factors associated with the development of CVD will also be examined. Comorbidity of diabetes in CKD patients will be analyzed to determine whether it is a risk for rapid progression of CKD and high incidence of CVD. In addition, we will study whether the burden of CKD decreases the QOL of patients, and increases hospitalization or health resource utilization. Insights from the CKD-JAC study will provide a basis for future interventional trials focused on reducing the burden of ESRD and CVD in patients with CKD in Japan.     

Cardiovascular disease in children with chronic renal failure

Cardiovascular disease (CVD), including atherosclerosis, hypertension, myocardial infarction, and cerebrovascular accidents, constitutes an important cause of morbidity and mortality in adults with chronic kidney disease (CKD). However, evidence has been accumulating over the past several years that children and young adults with CKD also experience significant cardiovascular complications. Studies in the United States and Europe have shown that CVD is a leading cause of death in young adults diagnosed with CKD in childhood. Risk factors include hypertension, dyslipidemia, anemia, and abnormal calcium–phosphorus metabolism, all of which are present in many children with CKD. Although improved control of uremia and treatment of traditional and nontraditional cardiovascular risk factors have proved to be beneficial in adults with CKD, no such data exist for children. The NIH is currently conducting a large-scale, prospective observational study of children with CKD that should help to elucidate the role of CVD in the progression of CKD in children and what interventions might reduce the risk of cardiovascular complications in these young patients.     

Chronic kidney disease in postmenopausal women

Menopause is derived from the Greek words men (month) and pauses (cessation) and means permanent cessation of menstruation after the loss of ovarian activity. Chronic kidney disease (CKD) has recently been associated with cardiovascular events in several studies. CKD patients have a heavy burden of traditional cardiovascular risk factors in addition to a range of nontraditional risk factors such as inflammation and abnormal metabolism of calcium and phosphate. In this review, the association of CKD and cardiovascular disease (CVD), as well as of osteoporosis in postmenopausal women is discussed. CKD mineral and bone disorder, characterized by disturbances of calcium/phosphate/parathyroid hormone, bone abnormalities and vascular and soft tissue calcification, is highly prevalent in CKD and is a strong, independent predictor of bone fracture, CVD and death. Estrogen has been shown to: (a) decrease the expression of angiotensin type 1 receptors in vasculature and kidneys; (b) reduce the expression and activity of angiotensin-converting enzyme, and (c) cause the release of angiotensinogen substrate from the liver. However, the degree of activation or suppression of the renin-angiotensin-aldosterone system by estrogen has not been clearly established. Clinical data on the effects of estrogen therapy on bone mineral densities are extremely limited in the ESRD population. CVD is the most common cause of death in postmenopausal women with CKD and many contributing factors have been explored. Future research for prevention of CVD in postmenopausal women with CKD would focus on the biology of vascular calcification as well as bone loss.     

Coronary Artery Disease in Patients with Chronic Kidney Disease: A Clinical Update

Chronic kidney disease (CKD) is an independent risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of morbidity and mortality in patients with CKD. The outcomes of CAD are poorer in patients with CKD. In addition to traditional risk factors, several uremia-related risk factors such as inflammation, oxidative stress, endothelial dysfunction, coronary artery calcification, hyperhomocysteinemia, and immunosuppressants have been associated with accelerated atherosclerosis. A number of uremia-related biomarkers are identified as predictors of cardiac outcomes in CKD patients. The symptoms of CAD may not be typical in patients with CKD. Both dobutamine stress echocardiography and radionuclide myocardial perfusion imaging have moderate sensitivity and specificity in detecting obstructive CAD in CKD patients. Invasive coronary angiography carries a risk of contrast nephropathy in patients with advanced CKD. It should be reserved for those patients with a high risk for CAD and those who would benefit from revascularization. Guideline-recommended therapies are, in general, underutilized in renal patients. Medical therapy should be considered the initial strategy for clinically stable CAD. The effects of statins in patients with advanced CKD have been neutral despite a lipid-lowering effect. Compared to non-CKD population, percutaneous coronary intervention (PCI) is associated with higher procedure complications, restenosis, and future cardiac events even in the drug-eluting stent era in patients with CKD. Compared with PCI, coronary artery bypass grafting (CABG) reduces repeat revascularizations but is associated with significant perioperative morbidity and mortality. Screening for CAD is an important part of preoperative evaluation for kidney transplant candidates.     

Pharmacologic Management of Chronic Reno-Cardiac Syndrome

Chronic kidney disease (CKD) significantly increases cardiovascular morbidity and mortality. CKD remains an under-represented population in cardiovascular clinical trials, and cardiovascular disease is an under-treated entity in CKD. Traditional cardiovascular risk factors in conjunction with uremia-related complications often progress to myocardial dysfunction. Such uremic cardiomyopathy leads to over-activation of neurohormonal pathways with detrimental effects. Management of the reno-cardiac syndrome (RCS) requires the targeting of these multiple facets. In this article we discuss the relevant pathophysiology of RCS, and present the clinical data related to its management.     

Serum uric acid levels and long-term outcomes in chronic kidney disease

Hyperuricemia is common in chronic kidney disease (CKD), but data regarding the relationship between serum uric acid levels and the long-term outcomes of CKD patients have been limited. The present study evaluated the associations between baseline serum uric acid levels with mortality and end-stage renal disease (ESRD). The subjects of this study were 551 stage 2–4 CKD patients. Cox proportional hazards models were used to evaluate the relationship between serum uric acid tertiles and all-cause mortality, cardiovascular disease (CVD) mortality, 50 % reduction in estimated glomerular filtration rate (eGFR), and development of ESRD, initially without adjustment, and then after adjusting for several groups of covariates. The mean age of the study subjects was 58.5 years, 59.3 % were men, and 10.0 % had diabetes. The mean eGFR was 42.02 ± 18.52 ml/min/1.73 m². In all subjects, the mean serum uric acid level was 6.57 ± 1.35 mg/dl, and 52.2 % of study subjects were on hypouricemic therapy (allopurinol; 48.3 %) at baseline. Thirty-one patients (6.1 %) died during a follow-up period of approximately 6 years. There was no significant association between serum uric acid level and all-cause mortality, CVD mortality, development of ESRD and 50 % reduction in eGFR in the unadjusted Cox models. In the adjusted models, hyperuricemia was found to be associated with all-cause mortality and CVD mortality after adjustment with CVD risk factors, kidney disease factors, and allopurinol, but not associated with development of ESRD and 50 % reduction in eGFR. The results of this study showed that hyperuricemia but not serum uric acid levels were associated with all-cause mortality, CVD mortality after adjustments with CVD risk factors, kidney disease factors, and allopurinol in stage 2–4 CKD patients.     

The cardiometabolic syndrome as a cardiovascular risk factor

The cardiometabolic syndrome (CMS) is associated with cardiovascular disease (CVD) and includes a constellation of risk factors such as central obesity, hypertension, insulin resistance, dyslipidemia, microalbuminuria, and hypercoagulability. Collectively, these risk factors increase CVD endpoints such as stroke, congestive heart failure, chronic kidney disease (CKD), and overall mortality. The CMS is associated with endothelial dysfunction, inflammation, abnormal thrombolysis, and increased oxidative stress that accentuate progression of CVD. We will review how the varying components of the CMS relate to an increased CVD and renal disease risk.     

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??Abstract??The global population is progressively aging??to the extent that over 1.5 billion people worldwide will be aged 65 years or more by 2050.Chronic kidney disease (CKD) in the elderly has become a major public health problem in China with approximately one third to one half of the individuals older than 70 years have CKD.Rates of treated end-stage renal disease (ESRD) among the elderly have been rising dramatically over the last decade.Most of older individuals with CKD die from cardiovascular diseases??infections and cerebrovascular diseases before reaching ESRD.Proteinuria??hypertension??diabetes??hyperlipidemia??and diet are strong risk factors for progression from CKD to ESRD.In this review??we will discuss comprehensive treatment strategy in preventing and slowing progression of CKD in elderly patients concerning the above risk factors.     

Nontraditional risk factors for cardiovascular disease in diabetes

People with type 2 diabetes are disproportionately affected by cardiovascular disease (CVD), compared with those without diabetes. Traditional risk factors do not fully explain this excess risk, and other "nontraditional" risk factors may be important. This review will highlight the importance of nontraditional risk factors for CVD in the setting of type 2 diabetes and discuss their role in the pathogenesis of the excess CVD morbidity and mortality in these patients. We will also discuss the impact of various therapies used in patients with diabetes on nontraditional risk factors.     

Cardiovascular complications in children with chronic kidney disease

The lifespan of children with advanced chronic kidney disease (CKD) remains low compared with the general pediatric population. As in adults with CKD, cardiovascular disease accounts for the majority of deaths in children with CKD, as these patients have a high prevalence of traditional and uremia-related risk factors for cardiovascular disease. The cardiovascular adaptations that precipitate these terminal events begin in predialysis CKD. Initially, these alterations increase left ventricular performance and vascular function to maintain hemodynamic homeostasis. However, these modifications are unable to sustain cardiovascular function in the long term and ultimately lead to left ventricular failure, impaired cardiorespiratory fitness and even sudden death. In this Review, we provide an update on the prevalence of the risk factors associated with cardiovascular disease in pediatric patients with CKD, the cardiac and vascular adaptations that occur in these patients and the management of cardiovascular risk in this population.     

Increased risk of cardiovascular disease and chronic kidney disease in NAFLD

NAFLD is very common in the general population and its prevalence is increasing worldwide in parallel with the increasing incidences of obesity and metabolic diseases, mainly type 2 diabetes. In some cases, however, the diagnosis of NAFLD remains uncertain because other causes of liver disease are not easy to exclude in patients who are diagnosed with NAFLD after a biochemical or ultrasonographic analysis. Several studies have documented a strong association between NAFLD and traditional and nontraditional risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Accordingly, patients with NAFLD have an increased prevalence and incidence of both CVD and CKD. It is reasonable to believe that NAFLD, CVD and CKD share common risk factors (such as visceral obesity, insulin resistance, dysglycaemia, dyslipidaemia and hypertension) and therefore that NAFLD might simply be a marker rather than a causal risk factor of CVD and CKD. In this context, the identification of NAFLD might be an additional clinical feature to improve the stratification of patients for their risk of CVD and CKD. Growing evidence suggests that in patients with NAFLD, especially if NASH is present, several molecules released from the steatotic and inflamed liver might have pathogenic roles in the development of atherosclerosis and kidney damage. If these findings are confirmed by further studies, NAFLD could become a target for the prevention and treatment of CVD and CKD. NAFLD, whatever its role (marker or causal risk factor), is therefore a clinical condition that deserves greater attention from gastroenterologists, endocrinologists, cardiologists and nephrologists, as well as internists and general practitioners.     

Nontraditional Risk Factors for Progression Through Chronic Kidney Disease Risk Categories: The Coronary Artery Risk Development in Young Adults Study

BackgroundThere may be nontraditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine nontraditional risk factors for incident CKD and its progression.MethodsWe used the generally healthy population (n = 4382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which is an observational longitudinal study. Nontraditional risk factors included forced vital capacity, inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-1996 and repeated every 5 years for 20 years: No CKD, low risk, moderate risk, high risk, and very high risk.ResultsAt baseline, 84.8% had no CKD (eGFR ≥60 mL/min/1.73 m² and UACR <10 mg/g), 10.3% were in the low risk (eGFR ≥60 and UACR 10-29), and 4.9% had CKD (eGFR <60 and/or UACR ≥ 30). Nontraditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and low and moderate risk into CKD were inverse for forced vital capacity and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors.ConclusionSeveral nontraditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.     

Epidemiology, Diagnosis, and Management of Cardiac Disease in Chronic Renal Disease

There is an extremely high burden of cardiovascular disease (CVD) in patients with renal disease. Both traditional as well as uremia-related factors are contributory. Diagnosis of CVD has limitations in patients with renal disease, and suspicion for the presence of CVD needs to be high even in the absence of classic symptoms. Prevention and management of CVD is similar to the general population but important differences need to be noted.     

End-stage renal disease--not an equal opportunity disease: the role of genetic polymorphisms

Despite several decades of development in renal replacement therapy, end-stage renal disease (ESRD) patients continue to have markedly increased morbidity and mortality especially caused by cardiovascular disease (CVD). This shows that current strategies, e.g. the focus on dialysis adequacy, to improve the clinical outcome in ESRD patients have to be complemented by novel approaches. Although traditional risk factors are common in dialysis patients they cannot alone explain the unacceptably high prevalence of CVD in this patient group. Much recent interest has therefore focused on the role of various nontraditional cardiovascular risk factors, such as inflammation, vascular calcification and oxidative stress. Recent studies show that genetic factors, such as DNA single nucleotide polymorphisms, may significantly influence the immune response, the levels of inflammatory markers, as well as the prevalence of atherosclerosis in this patient group. To elucidate the respective roles of DNA polymorphisms in genes that encode inflammatory markers (such as IL-10, IL-6 and TNF-alpha) and other factors that may affect the development of atherosclerosis (such as apolipoprotein E, transforming growth factor and fetuin-A), sufficiently powered studies are needed in which genotype, the protein product and the specific phenotype all are analysed in relation to outcome. The recent developments in the field of genetics have opened up entirely new possibilities to understand the impact of genotype on disease development and progress and thus offer new options and strategies for treatment. It seems conceivable that in the near future, prognostic or predictive multigene DNA assays will provide the nephrological community with a more precise approach for the identification of "high-risk" ESRD patients and the development of accurate individual treatment strategies. For this purpose, integrative studies on genotype-phenotype associations and impact on clinical outcome are needed.     

Association of pulse pressure,pulse pressure index,and ambulatory arterial stiffness index with kidney function in a cross‐sectional pediatric chronic kidney disease cohort from the CKiD study

The morbidity and mortality of adult and pediatric chronic kidney disease (CKD) and end‐stage renal disease (ESRD) populations are mainly driven by cardiovascular disease (CVD). Improving CVD outcomes focuses on risk assessment of factors including diastolic blood pressure (DBP), systolic blood pressure (SBP), left ventricular mass index (LVMI), pulse pressure (PP), and pulse pressure index (PPi), which is calculated as PP/SBP. These markers are also proven predictors of CKD progression; however, their role in children has not been established. This study aims to evaluate the relationship between PP, PPi, ambulatory arterial stiffness index (AASI), and proteinuria with kidney function in pediatric CKD patients; it is a retrospective analysis of 620 patients (1‐16 years) from the NIDDK Chronic Kidney Disease in Children (CKiD) registry. The authors analyzed data for three separate cohorts: an overall CKD as well as immunological versus non‐immunological cause for CKD groups. An inverse relationship was found between SBP, DBP, and PP with iGFR and LVMI in the overall CKD group. Our immunological CKD subgroup showed significantly higher serum creatinine, SBP, DBP, and PP values with significantly lower serum albumin levels compared to the non‐immunological group. There were no significant differences with iohexol‐based glomerular filtration rate (iGFR), LVMI, PPi, or high‐sensitivity C‐reactive protein (hs‐CRP) between the two groups. A subgroup analysis demonstrated that SBP, DBP, and PP all correlated significantly with LVMI in the immunological CKD patients but not the non‐immunological subgroup. Additionally, AASI data in the overall CKD population were significantly correlated with PP, PPi, and DBP. This study is one of the first to correlate noninvasive measurements of vascular compliance including PP, PPi, and AASI with iGFR and LVMI in a pediatric CKD cohort. Improving our understanding of surrogate markers for early CVD is integral to improving the care of pediatric CKD population as these patients have yet to develop the hard end points of ESRD, heart failure, myocardial infarction, or stroke.     

Aspects of Immune Dysfunction in End-stage Renal Disease

End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.Reduced renal function is a significant risk factor for cardiovascular events and death in chronic kidney disease (CKD) patients, and this risk is further increased when CKD has progressed to end-stage renal disease (ESRD) requiring dialysis initiation or kidney transplantation. Despite significant technical improvements in both hemodialysis (HD) and peritoneal dialysis (PD), the mortality rate in ESRD patients is still as high as 20% per yr in patients undergoing renal replacement therapy (1). The major causes of death in ESRD patients are cardiovascular disease (CVD) and infections, together accounting for up to 70% of all deaths in this patient population (Figure 1) (2,3). Although it is well established that a dysfunction of the immune system is induced by the uremic milieu, this ominous disturbance has not been systematically studied as a potential contributing cause of premature deaths resulting from CVD and infections in ESRD. This brief review describes disorders of the innate and adaptive immune systems in ESRD and aims at exploring the possibility that a state of acquired immune dysfunction in uremia could be an important contributing factor for both CVD and infectious complications.     

Statins and kidney disease

The prevalence of chronic kidney disease (CKD) is increasing worldwide. This clinical and social problem is mainly related to the ongoing epidemic of obesity and metabolic syndrome resulting in hypertension and diabetes mellitus. CKD is a well-recognized risk multiplier for the development of cardiovascular disease (CVD), and it is widely known that CVD is the leading cause of morbidity and mortality in patients with CKD. Lipid metabolism abnormalities are commonly associated with CKD. These consist of increased levels of low-density lipoproteins (LDL), triglycerides, very-low-density lipoproteins (VLDL) and lipoprotein(a), and reduced levels of HDL cholesterol. Lipid abnormalities contribute to cardiovascular morbidity and mortality in CKD patients. Some evidence also suggests that dyslipidemia may contribute to the progression of renal disease associated with type 1 and type 2 diabetic as well as non-diabetic renal disease. In the general population, HMG-CoA reductase inhibitors (statins) reduce the cardiovascular risk and prevent CVD. Similar data from secondary analyses of CKD subgroups of larger prospective trials using statins suggest a beneficial effect on cardiovascular outcomes and - albeit with more conflicting evidence - the progression of renal disease. Statins reduce blood levels of LDL cholesterol but also have multiple effects above and beyond cholesterol lowering, including direct effects on vascular tissue, kidney, bone, and glucose metabolism. The evidence linking dyslipidemia management with statins to cardiovascular disease and the decline in renal function in CKD patients will be presented in this review.     

Association between retinopathy and cardiovascular disease in patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study)

Patients with chronic kidney disease experience co-morbid illnesses, including cardiovascular disease (CVD) and retinopathy. The purpose of the present study was to assess the association between retinopathy and self-reported CVD in a subgroup of the participants in the Chronic Renal Insufficiency Cohort study. For this observational, ancillary investigation, 2,605 Chronic Renal Insufficiency Cohort participants were invited to participate in the present study, and nonmydriatic fundus photographs in both eyes were obtained for 1,936 subjects. The photographs were reviewed in a masked fashion at a central photograph reading center. The presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed using standard protocols by trained graders who were masked to the information about the study participants. A history of self-reported CVD was obtained using a medical history questionnaire. Kidney function measurements and traditional and nontraditional risk factors for CVD were obtained from the Chronic Renal Insufficiency Cohort study. A greater severity of retinopathy was associated with a greater prevalence of any CVD, and this association persisted after adjustment for the traditional risk factors for CVD. The presence of vascular abnormalities usually associated with hypertension was also associated with increased prevalence of CVD. We found a direct relation between CVD prevalence and mean venular caliber. In conclusion, the presence of retinopathy was associated with CVD, suggesting that retinovascular pathology might indicate macrovascular disease, even after adjustment for renal dysfunction and traditional CVD risk factors. This would make the assessment of retinal morphology a valuable tool in CKD studies of CVD outcomes.