Cardiovascular changes during chronic hypertensive states

It is well established that elevated blood pressure constitutes a major risk factor for coronary heart disease, arrythmias, heart failure, cerebrovascular disease, peripheral artery disease and renal failure. Blood pressure level and the duration of arterial hypertension (HTN) impact target organ damage. Many studies in adults have demonstrated the role of antihypertensive therapy in preventing cardiovascular (CV) events. The so-called hard end-points, such as death, myocardial infarction (MI) or stroke, are rarely seen in children, but intermediate target organ damage, including left ventricular hypertrophy, increased intima-media thickness and microalbuminuria, is already detectable during childhood. The goal of antihypertensive treatment is to reduce the global risk of CV events. In the adult population stratification of CV risk is based on blood pressure level, risk factors, subclinical target organ damage and established CV and kidney disease. Increased CV risk begins early in the course of kidney disease, and CV diseases are the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD). Children with CKD are especially prone to the long-term effects of CV risk factors, which result in high morbidity and mortality in young adults. To improve the outcome, pediatric and adult CKD patients require nephro- and cardioprotection.     

Chronic kidney disease epidemics--a gap in effectiveness: the distance between potential and actual treatment benefits

Metabolic syndrome is a cluster of traditional risk factors including hypertension, abdominal obesity, hypertriglyceridemia, low HDL cholesterol and fasting hyperglycemia. This syndrome is a noxious condition not only for the cardiovascular (CV) system but also for the kidney. In a recent analysis of the NHANES III study the prevalence rate of chronic kidney disease (CKD) was very low in patients without risk factors, but reached 9% in those with five risk factors. Furthermore, in the NHANES III survey it was also found that mild renal insufficiency is frequent in the US population affecting about one-third of individuals. Recent estimates in Europe indicate that mild renal insufficiency is at least as frequent as it is in the US. While research on emerging risk factors in CKD is flourishing, clinical outcomes in these patients remain poor. This could depend on the fact that pathophysiological knowledge of the high renal and CV risk associated with CKD is still largely incomplete. Yet recent surveys have shown that treatment targets in these patients are largely unmet. Therefore, there is ample room for improving clinical outcomes in CKD by the systematic application of available treatments according to the recommendations of current clinical guidelines.     

How Do Living Kidney Donors Develop End‐Stage Renal Disease?

The clinical course and risk factors for developing end-stage renal disease (ESRD) after heminephrectomy in living kidney donors have scarcely been investigated. We reviewed medical records and identified eight case donors who developed chronic kidney disease (CKD) stage 5 or ESRD, and subsequently investigated the association between postoperative clinical courses and changes in renal function. To conduct a case-control study, we also selected a control group comprising 24 donors who had maintained stable renal function and were matched for age, sex and follow-up time since donation. Except for one donor who developed ESRD caused by a traffic accident, none of the donors developed progressive renal dysfunction immediately after donation. Their renal functions remained stable for a long period of time, but started to decline after developing new comorbidities, especially risk factors known as progression factors (proteinuria or hypertension) or accelerating factors (cardiovascular [CV] event or infection) of CKD. As compared with the control donors, incidence of postoperative persistent proteinuria, acute CV event, severe infection and hospitalization due to accelerating factors of CKD were significantly higher in the case donors. These results suggest the importance of long-term (more than 10 years) follow-up of donors with special attention on the risk factors of CKD.     

Cardiovascular Complications in Diabetic Kidney Disease

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). Due to an explosion in the incidence and the prevalence of Type 2 DM, the burden of CKD is expected to increase proportionately. Both DM and CKD are associated with a high incidence of cardiovascular (CV) morbidity and mortality, and it is important to understand the unique nature of CV disease in patients with the combination of these two conditions. In this report, we review the traditional and nontraditional risk factors that underlie the high risk of CV disease in this population, with a particular focus on vascular calcification, mineral metabolism, and therapeutic paradigms for the treatment of cardiovascular disease in this unique and high‐risk population.     

Chronic kidney disease in the United States: an underrecognized problem

The continued growth of the population with end-stage renal disease (ESRD) is partially related to the underrecognition of earlier stages of chronic kidney disease (CKD) and risk factors for the development of CKD. There are several published estimates of the prevalence of CKD in the United States. From Third National Health and Nutrition Examination Survey data it has been estimated that there are 6.2 million individuals with serum creatinine levels at or above 1.5 mg/dL, or 8.3 million individuals with decreased glomerular filtration rate (<60 mL/min/1.73 m (2)). Estimates of prevalence from a health maintenance organization study suggest that there are 4.2 million Americans with persistently elevated serum creatinine levels. In addition to the high prevalence, several studies have shown that CKD is associated with increased risk for cardiovascular disease, hospitalizations, and mortality. To promote earlier detection of CKD, The National Kidney Foundation Guidelines for CKD: Evaluation, Classification and Stratification, recommended screening individuals at increased risk for CKD, such as patients with diabetes, high blood pressure, and family history of kidney disease. Therapeutic interventions to delay progression and reduce comorbidity, such as cardiovascular disease, are more likely to be effective if they are implemented early in the course of CKD.     

Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease

Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population.     

Endothelial dysfunction in chronic kidney disease: determinant of susceptibility to end-organ damage and therapeutic response

Endothelial dysfunction (ED) seems to be a crucial mediator of increased cardiovascular risk observed among patients with chronic kidney disease (CKD). Importantly, systemic ED does not only occur in patients with severe renal failure, but also in individuals with earlier stages of CKD. Close association between microalbuminuria and systemic ED renders renal vascular function an important marker for the severity of cardiovascular damage. Furthermore, changes in renal endothelium might be actively involved in the progression of renal end-organ damage. Recently, experimental evidence showed that interindividual variability in endothelial function of healthy rats predicts susceptibility to renal damage and the efficacy of renoprotective treatment. Therefore, a specific manipulation of renal and systemic ED might provide benefits in various stages of CKD. ED thus may represent an ideal therapeutic target not only for treatment, but also for primary prevention of renal disease.     

Racial differences in mortality among those with CKD

Compared with white individuals, black individuals have a significantly higher risk for death in the general population but seem to have a survival advantage in the ESRD population. Data on the relationship of race to survival in early stages of chronic kidney disease (CKD) are inconsistent. This study evaluated racial differences in mortality among the adult participants of the Third National Health and Nutrition Examination Survey, a population-based survey of community-dwelling individuals. CKD was defined either by an estimated GFR < 60 ml/min per 1.73 m2 or by the presence of albuminuria, and this status was determined for 14,611 individuals, 2892 of whom were found to have CKD. Adjusting for age,gender, and race, risk for all-cause mortality among individuals with CKD was more than double that of individuals with normal renal function. In the subgroup with CKD, adjusting for age and gender,black individuals had a significantly higher risk for death, and this risk was modified by age;specifically, black individuals who were younger than 65 yr were 78% more likely to die than white individuals, whereas no significant differences in mortality were observed among individuals who were > or = 65 yr of age. Further adjustment for cardiovascular risk factors and CKD stage did not materially change the results, but the hazard ratios were significantly attenuated after adjustment for socioeconomic factors. In conclusion, these data demonstrate racial/ethnic disparities in mortality among individuals with CKD. This higher risk for death in early stages of CKD may explain the apparent survival advantage observed among black individuals who live long enough to reach stage 5 CKD.     

Applying multiple interventions in chronic kidney disease

The medical, social, and financial burdens posed by end-stage renal disease (ESRD) are many and growing rapidly. People generally reach ESRD as a result of chronic progressive kidney disease. Advancing kidney disease is associated with several treatable complications, which if poorly managed reduce the length and quality of life. In addition, there are strong links between chronic kidney disease (CKD) and cardiovascular disease (CVD). Many people with less advanced CKD will die or suffer complications of CVD before reaching ESRD. Efficacious interventions, such as lowering blood pressure and treating dyslipidemia, can substantially reduce the progression of both kidney and cardiovascular disease. Careful management of these complex and interrelated diseases and risk factors requires detailed longitudinal and focused care which does not seem to be optimally delivered by health service practitioners organized in traditional ways. A disease management approach offers promise in this setting, but requires further study of clinical and economic impact.     

Cardiorenal connection in chronic kidney disease

Chronic kidney disease (CKD), as defined by reduced glomerular filtration rate (<60 ml/min/1.73 m²) and/or the presence of renal damage for >3 months, is a significant threat for public health in modern societies. Recent epidemiological studies have demonstrated that CKD is a significant risk for cardiovascular events independently of classical risk factors such as hypertension, dyslipidemia and diabetes. The mechanisms by which CKD increases the risk of cardiovascular events are currently under intensive investigation. Among various components of CKD, microalbuminuria is of particular interest, because it is a significant risk factor not only in diabetic and hypertensive subjects but also in the general population. Microalbuminuria is also closely associated with salt sensitivity of blood pressure, and the salt sensitivity is an independent risk factor for cardiovascular disease even in normotensive subjects. Several factors are likely to be involved in such associations, including the renin–angiotensin system (RAS), oxidative stress and inflammation. In addition, there may be more specific hemodynamic mechanisms in the kidney and other vital organs underlying these associations. This review describes ‘the strain vessel hypothesis’ as a possible mechanism for cerebrocardiorenal connections. In addition we discuss the significance of underlying diseases as cardiovascular risks of CKD as well as the role of RAS inhibition in the management of CKD patients.     

Traditional and emerging cardiovascular and renal risk factors: an epidemiologic perspective

Patients with chronic kidney disease (CKD) represent an important segment of the population (7-10%) and, mostly because of the high risk of cardiovascular complications associated with renal insufficiency, detection and treatment of CKD is now a public health priority. Traditional risk factors can incite renal dysfunction and cardiovascular damage as well. As renal function deteriorates, non-traditional risk factors play an increasing role both in glomerular filtration rate (GFR) loss and cardiovascular damage. Secondary analyses of controlled clinical trials suggest that inflammation may be a modifiable risk factor both for cardiac ischemia and renal disease progression in patients with or at risk of coronary heart disease. Homocysteine predicts renal function loss in the general population and cardiovascular events in end-stage renal disease (ESRD), but evidence that this sulfur amino acid is directly implicated in the progression of renal disease and in the high cardiovascular mortality of uremic patients is still lacking. High sympathetic activity and raised plasma concentration of asymmetric dimethylarginine (ADMA) have been associated to reduced GFR in patients with CKD and to cardiovascular complications in those with ESRD but again we still lack clinical trials targeting these risk factors. Presently, the clinical management of CKD patients remains largely unsatisfactory because only a minority of these attain the treatment goals recommended by current guidelines. Thus, in addition to research into new and established risk factors, it is important that nephrologists make the best use of knowledge already available to optimize the follow-up of these patients.     

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.     

Chronic kidney disease and mortality risk: a systematic review

Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.     

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.     

Cardiovascular risk assessment in children with chronic kidney disease

Chronic kidney disease (CKD) is a major factor contributing to cardiovascular (CV) morbidity and mortality with the highest risk in patients on dialysis. An estimation of CV risk is important not only to identify potential modifiable risk factors but also to evaluate the effect of treatments aimed to reduce the risk. Non-invasive methods of measuring vascular changes and circulating biomarkers are available to assess the presence and severity of cardiovascular damage. These include measures of structural (carotid intima-media thickness and coronary artery calcification score) and functional (aortic pulse wave velocity, 24-h ambulatory blood pressure monitoring, ambulatory arterial stiffness index, heart rate variability and flow-mediated dilatation) changes in the vessel wall. In addition, a number of circulating biomarkers of vascular damage and its progression have been studied. Many of these tests are well validated as surrogate markers of future cardiovascular events and death in adult CKD patients, but need technical adaptation, standardization and validation for use in children. With our current state of knowledge, these are best reserved for research studies and scarce clinical resources may be better utilized for preventative strategies to reduce the modifiable risk factors for calcification from early CKD stages.     

Prevention of chronic kidney and vascular disease: toward global health equity--the Bellagio 2004 Declaration

Chronic kidney disease (CKD) not only reflects target organ injury in systemic vascular disease in the general population and in association with diabetes, hypertension, and smoking, but it is recognized as one of the major risk factors in the pathogenesis and outcome of cardiovascular disease. Recent surveys have revealed that the prevalence of CKD, particularly the hidden mild form (mildly elevated levels of serum creatinine or urinary albumin excretion), is surprisingly high in the general population. In recent years, the global epidemic of type 2 diabetes has led to an alarming increase in the number of patients with CKD. Most patients with CKD (over 50 million individuals worldwide) succumb to cardiovascular events, while each year over 1 million develop end-stage renal failure, which requires costly treatment and in many countries of the world, unaffordable renal replacement therapy by chronic dialysis or renal transplantation. Alarmed by the immense challenge to human morbidity and the economic burden of CKD and ensuing systemic cardiovascular disease, the International Society of Nephrology convened a multidisciplinary group of expert physicians and public health leaders from around the world to develop strategies to delay and avert this bleak future by effective prevention of CKD based on awareness, early detection, and effective treatment.     

Hypertension and the kidney

Hypertension is an important and widely prevalent risk factor for the development of chronic kidney disease (CKD), which unfortunately may progress to end-stage renal disease. CKD is a progressive condition that causes significant morbidity and mortality. Diabetes is the leading cause of end-stage renal disease in the Western world. Both hypertension and diabetes are the causative factors for the occurrence of CKD and its consequences. Aggressive control of hypertension and diabetes is indicated to reduce the risk for kidney disease in the community. Certainly, effective control of hypertension is a proven modality to prevent renal disease. The concept of decreasing the systemic blood pressure as well as the intraglomerular pressure has led to the application of rational therapeutic options in patients with renal insufficiency. Although treatment of hypertension alone is critical, drugs that block the renin-angiotensin system have been shown to have special renal (and cardiovascular) benefits. Early detection and treatment of microalbuminuria is an integral part of disease management. This article reviews the pathophysiologic and therapeutic implications of the link between hypertension and the kidney.     

Outcomes of stage 1–5 chronic kidney disease in Mainland China

Objective: This study aims to quantify and compare the risks of death and end stage renal disease (ESRD) in a prospective cohort of patients with chronic kidney disease (CKD) stages 1–5 under renal management clinic at Peking University Third Hospital and to evaluate the risk factors associated with these two outcomes. Method: This was a prospective cohort study. Finally, 1076 patients at CKD stage 1–5 short of dialysis were recruited from renal management clinic. Patients were monitored for up to Dec, 2011 or until ESRD and death. Glomerular filtration rate was estimated (eGFR) according to the using the CKD Epidemiology Collaboration (CKD-EPI) formula. Results: At the end of follow-up, 111 patients (10.1%) developed ESRD (initiated dialysis or kidney transplantation (ESRD)) and 24 patients (2.2%) had died. There were more ESRD occurrence rate in patients with baseline diabetic nephropathy, lower eGFR, hemoglobin <100?g/L and 24?h urinary protein excretion ≥3.0?g. By multivariate Cox regression model, having heavy proteinuria and CKD stage were the risk factors of ESRD. For all-cause mortality, the most common cause was cardiovascular disease, followed by infectious disease and cancer. But we failed to conclude any significant variable as risk factors for mortality in multivariate analysis. Conclusions: Our study indicated that baseline diabetic nephropathy, lower hemoglobin level, lower baseline GFR and heavy proteinuria were the risk factors of ESRD. In this CKD cohort, patients were more likely to develop ESRD than mortality, and cardiovascular mortality was the leading cause of death, and then followed by infectious diseases and cancer in this population.     

Traditional cardiac risk factors in individuals with chronic kidney disease

Individuals with chronic kidney disease (CKD) are at increased risk for the development and progression of cardiovascular disease (CVD). The increased risk is due to a higher prevalence of both traditional risk factors as well as nontraditional risk factors. In this review we focus on individuals at all stages of CKD and discuss modifiable traditional risk factors, namely hypertension, dyslipidemia, diabetes mellitus and poor glycemic control, smoking, and physical inactivity. The prevalence of each risk factor and its relationship with CVD is described. Treatment recommendations are provided using evidence available from populations with CKD or evidence extrapolated from the general population when there are insufficient data on individuals with CKD.     

Familial clustering of chronic kidney disease

The incidence and prevalence rates of most forms of chronic kidney disease (CKD) had steadily been increasing for the past 30 years, although these rates now appear to have reached a plateau. It is clear that an individual's likelihood of developing progressive CKD results from complex interactions between multiple genetic and environmental factors. Familial clustering of CKD and end-stage renal disease (ESRD) is observed among all the common etiologies of nephropathy. This article reviews the epidemiology of the familial clustering of kidney disease, as well as potential environmental and genetic contributors. The related impact of familial clustering of cardiovascular disease (CVD) and the impact of CVD on the current epidemic of ESRD is also discussed. It is imperative that nephrologists and primary care physicians recognize that individuals who have relatives with advanced nephropathy are themselves at high risk for subsequent kidney disease, proteinuria, and atherosclerotic cardiovascular complications. Until kidney failure genes are identified, it is reasonable to use "family history" (FH) as a surrogate marker for risk of future nephropathy. The detection of kidney disease genes holds great promise for detecting novel pathways that initiate renal fibrosis and lead to progressive loss of renal function. These pathways are likely to offer new therapies that may slow or halt development of chronic kidney failure.