Doppler assessment of brachial artery flow as a measure of endothelial dysfunction in pediatric chronic renal failure

Cardiovascular morbidity and mortality are highly prevalent among patients with chronic renal failure (CRF). Endothelial dysfunction is regarded as the initial reversible step in the development of atherosclerosis and has been demonstrated in all stages of renal failure. Non-invasive techniques to assess endothelial function have been recently developed and have been proven to predict future mortality in adults. We aimed to assess endothelial function in children with stage 4 chronic kidney disease (CKD 4) on conservative treatment, using a-non invasive, high-resolution, ultrasound Doppler study of the brachial artery flow, correlating it with other clinical and laboratory parameters. This study included 34 children with CKD 4 on conservative treatment who were compared with 30 healthy controls. Flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NTG-MD) and FMD/NTG-MD ratio were estimated. FMD was abnormal (< 5%) in 24 patients (71%). FMD and FMD/NTG-MD ratio were significantly lower in patients than in controls (P = 0.001 and P = 0.01, respectively). FMD correlated positively with serum calcium and negatively with alkaline phosphatase. We concluded that endothelial dysfunction is present in children with CKD 4 on conservative treatment and may reflect increased atherogenic and thrombogenic properties of the endothelium, contributing to subsequent adverse cardiovascular outcome.     

Chronic kidney disease in children: the global perspective

In contrast to the increasing availability of information pertaining to the care of children with chronic kidney disease (CKD) from large-scale observational and interventional studies, epidemiological information on the incidence and prevalence of pediatric CKD is currently limited, imprecise, and flawed by methodological differences between the various data sources. There are distinct geographic differences in the reported causes of CKD in children, in part due to environmental, racial, genetic, and cultural (consanguinity) differences. However, a substantial percentage of children develop CKD early in life, with congenital renal disorders such as obstructive uropathy and aplasia/hypoplasia/dysplasia being responsible for almost one half of all cases. The most favored end-stage renal disease (ESRD) treatment modality in children is renal transplantation, but a lack of health care resources and high patient mortality in the developing world limits the global provision of renal replacement therapy (RRT) and influences patient prevalence. Additional efforts to define the epidemiology of pediatric CKD worldwide are necessary if a better understanding of the full extent of the problem, areas for study, and the potential impact of intervention is desired.     

Should we quantify insulin resistance in patients with renal disease? (Review Article)

Cardiovascular disease is a major cause of morbidity and mortality in dialysis patients. Vascular disease develops before the initiation of dialysis, and it is now recognized that chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Death from cardiovascular disease is a more common endpoint of CKD than progression to dialysis. There are multiple mechanisms that contribute to the increased vascular risk of CKD, one of which is the presence of insulin resistance (IR). CKD is characterised by many features of the metabolic syndrome, and features of IR are also observed in dialysis and transplant patients. IR may be quantified by several different methods. One such method is homeostatic model assessment (HOMA) technique, which derives a measurement of IR from fasting plasma glucose and insulin concentrations. The HOMA index has been demonstrated to be an independent predictor of survival in dialysis patients. CKD is characterised by a chronic inflammatory response and abnormalities in the production and regulation of adipose tissue derived proteins, which may contribute to the development of IR. There are a range of interventions including diet and exercise programmes or medications that may influence IR; however, the impact of these interventions in the context of CKD has not been systematically evaluated.     

Vascular calcification and arterial stiffness in chronic kidney disease: implications and management

Cardiovascular (CV) disease is the commonest cause of mortality in patients with chronic kidney disease (CKD). Vascular calcification (VC), induced by calcium and phosphate excess and uraemia, is a major risk factor and is independently associated with CV events and death. Local and systemic calcium-regulatory proteins as well as inhibitory extracellular factors are involved in the pathogenesis of VC. In CKD the balance becomes dysregulated leading to differentiation of vascular smooth muscle cells into phenotypically distinct osteoblast-like cells with subsequent ossification of the arterial wall. Associated with imbalances in mineral metabolism, VC has intimate interactions with bone mineralization and enhanced bone resorption. Arterial stiffness represents the functional disturbance of VC, with reduced compliance of large arteries, and predominantly results from greater medial calcification. As with VC, arterial stiffness is an independent predictor of CV mortality and patients with CKD have greater arterial stiffness than the general population resulting in the principal consequences of left ventricular hypertrophy and altered coronary perfusion. Both VC and arterial stiffness can be measured through non-invasive techniques involving computed tomography, ultrasound, echocardiography, and pulse wave velocity. Management in CKD is difficult but detection, prevention and treatment is crucial to reduce CV mortality. The optimal control of mineral metabolism, especially hyperphosphatemia with non-calcium based phosphate binders, has been shown to be effective to reduce VC, and attenuation of arterial stiffness, especially with good blood pressure control, can have a favourable effect with regression of left ventricular hypertrophy. The use of bisphosphonates, calcimimetics, vitamin D therapy and newer experimental treatments, as well as nocturnal dialysis, may have potential benefit.     

Chronic kidney disease and inflammation in pediatric patients: from bench to playground

Signs of an activated immune system can be observed already in the early stages of chronic kidney disease (CKD). Markers of a chronically activated immune system are closely linked to several complications of CKD, such as accelerated atherosclerosis, vascular calcification, insulin resistance, increased muscle catabolism, loss of appetite, bone remodeling, and increased peritoneal permeability. Interestingly, all the aforementioned pathological states resemble a state of accelerated ageing and are strongly associated with increased morbidity and mortality in CKD patients. In recent studies, signs of inflammation have been shown as predictors for mortality in dialysis patients, and the role of inflammation as a risk factor for complications of CKD in children has emerged. Although preliminary findings suggest that inflammation is highly prevalent in the pediatric population with CKD, information related pathogenic links and to clinical outcomes is lacking. For the future, it is crucial for investigations to address the mechanisms and complications of inflammation that are manifested in pediatric patients with CKD in all stages. Since early identification and intervention may generate the most efficient strategies for prevention and treatment of cardiovascular disease in CKD patients, the pediatric population deserves special attention in future studies. In this review, we discuss the mechanisms involved in the inflammatory activation and the main causes and consequences of the inflammatory state observed in the CKD patient, with special emphasis on the pediatric population.     

Cause-Specific Deaths in Non–Dialysis-Dependent CKD

CKD is associated with higher risk of death, but details regarding differences in cause-specific death in CKD are unclear. We examined the leading causes of death among a non–dialysis-dependent CKD population using an electronic medical record-based CKD registry in a large healthcare system and the Ohio Department of Health mortality files. We included 33,478 white and 5042 black patients with CKD who resided in Ohio between January 2005 and September 2009 and had two measurements of eGFR<60 ml/min per 1.73 m² obtained 90 days apart. Causes of death (before ESRD) were classified into cardiovascular, malignancy, and non-cardiovascular/non-malignancy diseases and non–disease-related causes. During a median follow-up of 2.3 years, 6661 of 38,520 patients (17%) with CKD died. Cardiovascular diseases (34.7%) and malignant neoplasms (31.8%) were the leading causes of death, with malignancy-related deaths more common among those with earlier stages of kidney disease. After adjusting for covariates, each 5 ml/min per 1.73 m² decline in eGFR was associated with higher risk of death due to cardiovascular disease (hazard ratio [HR], 1.10; 95% confidence interval [95% CI], 1.08 to 1.12) and non-cardiovascular/non-malignancy diseases (HR, 1.12; 95% CI, 1.09 to 1.14) but not to malignancy. In the adjusted models, blacks had overall-mortality hazard ratios similar to those of whites but higher hazard ratios for cardiovascular deaths. Further studies to confirm these findings and explain the mechanisms for differences are warranted. In addition to lowering cardiovascular burden in CKD, efforts to target known risk factors for cancer at the population level are needed.     

Cardio-renal syndrome type 4: epidemiology, pathophysiology and treatment

Cardiovascular diseases such as coronary artery disease, congestive heart failure, arrhythmia, and sudden cardiac death represent the leading causes of morbidity and mortality in patients with CKD, increasing sharply as patients approach end-stage renal disease. The pathogenesis includes a complex, bidirectional interaction between the heart and kidneys that encompasses traditional and nontraditional risk factors, and has been termed cardio-renal syndrome type 4. In this review, an overview of the epidemiology and scope of this problem is provided, some suggested mechanisms for the pathophysiology of this disorder are discussed, and some of the key treatment strategies are described, with particular focus on recent clinical trials, both negative and positive.     

Dyslipidemia in children with CKD: should we treat with statins?

Dyslipidemia has been shown to be a risk factor for increased cardiovascular morbidity and mortality in adult patients with chronic kidney disease (CKD) stages 2–4. In patients on dialysis, a paradoxical correlation has been found between low cholesterol values and increased mortality rates. No data exist in children. Treatment with statins has been convincingly shown to both reduce blood lipid levels and mortality rates from cardiovascular disease in adult patients in CKD stages 2–4. There is no strong literature support for treating patients on dialysis or after having had a transplant. Data on benefits of statin therapy do not exist in children with CKD. There are many differences between adult and paediatric kidney patients, and I caution on extrapolating the findings in adult patients to children. Studies are thus needed to evaluate the benefits and potential problems of statin treatment in children with CKD.     

Anemia and the heart in chronic kidney disease

Cardiovascular disease is highly prevalent at all stages of chronic kidney disease (CKD) and is the leading cause of morbidity and mortality. Individuals with CKD commonly have multiple risk factors for the development of cardiovascular disease, including both traditional and nontraditional risk factors. Anemia is a nontraditional cardiovascular risk factor found in CKD that contributes to the development and progression of structural abnormalities of the heart, namely left ventricular hypertrophy and dilation. In addition, a deficiency of erythropoietin per se also may have important pathophysiologic consequences. In this review we summarize the evidence from observational studies showing an association between anemia and adverse cardiac outcomes at all stages of CKD. In addition, we provide an overview of the evidence accumulating from randomized controlled trials conducted in both nondialysis and dialysis CKD populations evaluating the effect of anemia correction on cardiac outcomes such as changes in left ventricular hypertrophy.     

Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is high, and the presence of CKD worsens outcomes of cardiovascular disease (CVD). CKD is associated with specific risk factors. Emerging evidence indicates that the pathology and manifestation of CVD differ in the presence of CKD. During a clinical update conference convened by the Kidney Disease: Improving Global Outcomes (KDIGO), an international group of experts defined the current state of knowledge and the implications for patient care in important topic areas, including coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, atrial fibrillation, peripheral arterial disease, and sudden cardiac death. Although optimal strategies for prevention, diagnosis, and management of these complications likely should be modified in the presence of CKD, the evidence base for decision making is limited. Trials targeting CVD in patients with CKD have a large potential to improve outcomes.     

The lipid story in chronic kidney disease: a long story with a happy end?

Cardiovascular (CV) morbidity and mortality increase with the severity of kidney disease, reaching 30 times higher mortality rates in dialysis patients compared with the general population. Although dyslipidemia is a well-established CV risk factor in the general population, the relationship between lipid disorders and CV risk in patients with chronic kidney disease (CKD) is less clear. Despite the clear evidence that statins reduce the risk of atherosclerotic events and death from cardiac causes in individuals without CKD, the use of statins in patients with kidney disease is significantly less frequent. For a long time, one of the explanations was the lack of a prospective, randomized, controlled study designed specifically to CKD patients. After recent publication of the data from Study of Heart and Renal Protection trial, given the safety and potential efficacy of statins, this lipid-lowering treatment should be administered more frequently to individuals with CKD stage 1–4, as well as those undergoing dialysis.     

Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia/malnutrition, atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the thiobarbituric acid reactive system, asymmetric dimethyl arginine, iron, fetuin-A, and cytokines. Inflammation contributes to the progression of CKD by inducing the release of cytokines and the increased production and activity of adhesion molecules, which together contribute to T cell adhesion and migration into the interstitium, subsequently attracting pro-fibrotic factors. Inflammation in CKD also causes mortality from cardiovascular disease by contributing to the development of vascular calcifications and endothelial dysfunction. Similar to the situation in adults, cardiovascular disease in pediatric CKD is linked to inflammation: abnormal left ventricular wall geometry is positively associated with markers of inflammation. This review focuses on traditional and novel mediators of inflammation in CKD and ESKD, and the deleterious effect inflammation has on the progression of renal and cardiovascular disease.     

Chronic kidney disease,mortality, and treatment strategies among patients with clinically significant coronary artery disease

Cardiovascular disease is an important cause of mortality among patients with chronic kidney disease (CKD). This study describes associations between CKD, cardiac revascularization strategies, and mortality among patients with CKD and cardiovascular disease. All patients undergoing cardiac catheterization at Duke University Medical Center (1995 to 2000) with documented stenosis > or =75% of at least one coronary artery and available creatinine data were included. CKD was staged using creatinine clearance (CrCl) derived from the Cockcroft-Gault formula (normal, > or = 90 ml/min; mild, 60 to 89 ml/min; moderate, 30 to 59 ml/min; severe, 15 to 29 ml/min). Cox proportional-hazard regression estimated the relationship between clinical variables, including CrCl and percutaneous coronary artery intervention (PCI), coronary artery bypass grafting (CABG), medical management, and patient survival. There were 4584 patients included, and 24% had CrCl <60 ml/min. Each 10-ml/min decrement in CrCl was associated with an increase in mortality (hazard ratio, 1.14; P < 0.0001). CABG was associated with a survival benefit among patients with both normal renal function and patients with CKD compared with medical management. In patients with normal renal function, CABG was not associated with survival benefit over PCI. However, in patients with CKD, CABG was associated with improved survival. PCI was associated with a survival benefit compared with medical management among patients with normal, mildly, and moderately impaired renal function. Among patients with severe CKD, PCI was not associated with improved survival. CABG is associated with greater mortality reduction than PCI in severe CKD.     

Adiponectin and chronic kidney disease.

Enhanced chronic inflammation and reduced insulin sensitivity are often present in chronic kidney disease (CKD). Cardiovascular disease remains a major cause of morbidity and mortality in end-stage renal patients. Adiponectin (ADP) is a hormone exclusively produced by adipocytes and possesses anti-inflammatory and cardioprotective properties. Despite the high prevalence of insulin resistance and cardiovascular disease, levels of ADP are increased among end-stage renal disease patients on hemo or peritoneal dialysis but also among patients with moderate renal failure or with the nephrotic syndrome. Furthermore, lower ADP levels are associated with poor cardiovascular outcome. In this review, we examine ADP modifications in CKD and discuss the different factors that may have an impact on this adipokine metabolism in renal failure.     

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.     

Adenine‐induced chronic kidney disease in rats

Many animal models have been developed to study the causes and treatments of chronic kidney disease (CKD) in humans, an insidious disease resulting from kidney injury and characterized by persistent functional decline for more than 3 months, with or without evidence of structural deficit. The eventual outcome of CKD may be end‐stage kidney disease (ESKD), where patients need dialysis or transplantation to survive. Cardiovascular disease is accelerated in patients with CKD and contributes to increased mortality, with the relationship between CKD and cardiovascular disease being bi‐directional. Most animal models do not mimic the complexity of the human disease as many do not develop CKD‐associated cardiovascular disease. The adenine diet model of CKD in rodents is an exception. The original adenine diet model produced rapid‐onset kidney disease with extensive tubulointerstitial fibrosis, tubular atrophy, crystal formation and marked vessel calcification. Since then, lower adenine intake in rats has been found to induce slowly progressive kidney damage and cardiovascular disease. These chronic adenine diet models allow the characterization of relatively stable kidney and cardiovascular disease, similar to CKD in humans. In addition, interventions for reversal can be tested. Here the key features of the adenine diet model of CKD are noted, along with some limitations of other available models. In summary, the data presented here support the use of chronic low‐dose adenine diet in rats as an easy and effective model for understanding human CKD, especially the links with cardiovascular disease, and developing potential therapeutic interventions.     

Cardiac surgery for renal failure patients;operative and postoperative management

Chronic kidney disease( CKD) is defined as one of the major risk factors affecting postoperative morbidity and mortality after cardiovascular surgery, and CKD accounts for approximately 9.2~13.7% of the patients undergoing cardiovascular surgery in Japan according to the reports from Japan Adult Cardiovascular Surgery Database (JACVSD). The recent concept on renal dysfunction, recent discussions on the choice of operative procedures[ off-pump coronary artery bypass grafting( CABG)[OPCAB] vs on-pump CABG, bioprosthesis vs mechanical valve prosthesis] and peri-operative managements( electrolyte control, pharmacological management) are also introduced in the text.     

New insights on inflammation in chronic kidney disease-genetic and non-genetic factors

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in chronic kidney disease (CKD). As traditional risk factors cannot alone explain the unacceptable high prevalence and incidence of CVD in this population, inflammation (which is interrelated to insulin resistance, oxidative stress, wasting and endothelial dysfunction) has been suggested to be a significant contributor. Indeed, several different inflammatory biomarkers, such as high sensitivity C-reactive protein (CRP) has been shown to independently predict mortality in CKD patients. The causes of the highly prevalent state of inflammation in CKD are multiple and include factors such as volume overload, co-morbidity, intercurrent clinical events, the dialysis procedure per se as well as genetic factors. Indeed, multiple cytokine DNA polymorphisms may affect the inflammatory state, the clinical phenotype as well as outcome in this patient population.     

The contribution of chronic kidney disease to the global burden of major noncommunicable diseases

Noncommunicable diseases (NCDs) are the most common causes of premature death and morbidity and have a major impact on health-care costs, productivity, and growth. Cardiovascular disease, cancer, diabetes, and chronic respiratory disease have been prioritized in the Global NCD Action Plan endorsed by the World Health Assembly, because they share behavioral risk factors amenable to public-health action and represent a major portion of the global NCD burden. Chronic kidney disease (CKD) is a key determinant of the poor health outcomes of major NCDs. CKD is associated with an eight- to tenfold increase in cardiovascular mortality and is a risk multiplier in patients with diabetes and hypertension. Milder CKD (often due to diabetes and hypertension) affects 5-7% of the world population and is more common in developing countries and disadvantaged and minority populations. Early detection and treatment of CKD using readily available, inexpensive therapies can slow or prevent progression to end-stage renal disease (ESRD). Interventions targeting CKD, particularly to reduce urine protein excretion, are efficacious, cost-effective methods of improving cardiovascular and renal outcomes, especially when applied to high-risk groups. Integration of these approaches within NCD programs could minimize the need for renal replacement therapy. Early detection and treatment of CKD can be implemented at minimal cost and will reduce the burden of ESRD, improve outcomes of diabetes and cardiovascular disease (including hypertension), and substantially reduce morbidity and mortality from NCDs. Prevention of CKD should be considered in planning and implementation of national NCD policy in the developed and developing world.