Uremia-related Risk Factors Research Articles

Traditional and Non-traditional Risk Factors for Osteoporosis in CKD.

Osteoporosis is a state of bone fragility with reduced skeletal resistance to trauma, and consequently increased risk of fracture. A wide range of conditions, including traditional risk factors, lifestyle choices, diseases and their treatments may contribute to bone fragility. It is therefore not surprising that the multi-morbid patient with chronic kidney disease (CKD) is at a particularly high risk. CKD is associated with reduced bone quantity, as well as impaired bone quality. Bone fragility in CKD is a composite of primary osteoporosis, accumulation of traditional and uremia-related risk factors, assaults brought on by systemic disease, and detrimental effects of drugs. Some risk factors are modifiable and represent potential targets for intervention. This review provides an overview of the heterogeneity of bone fragility in CKD.

Calcification of the cavernosal bodies may be responsible for development of erectile dysfunction in uremic apolipoprotein E deficient (apoE−/−) mice

Introduction and objectiveErectile dysfunction's physiopathology in uremia is complex and multifactorial, involving a combination of classical risk factors and specific uremia-related risk factors such as increased oxidative stress, endothelial dysfunction and inflammation. The aim of the study is to investigate the effect of chronic kidney disease (CKD) on vascular calcification and endothelial function of cavernosal bodies in apolipoprotein E deficient (apoE−/−) mice, a well known model of erectile dysfunction. Materials and methodsEight-week-old male apoE−/− mice were randomly assigned to the following 3 groups: (i) subtotally nephrectomised (SNX apoE−/−, 12 mice), (ii) uninephrectomised (UNX apoE−/−, 11 mice) or (iii) sham operated (sham-op apoE−/−, 15 mice). At 16 weeks after surgery, aortas and penile erectile tissues were harvested for histological studies to assess atherosclerosis, vascular calcification, nitrotyrosine staining, total collagen content and macrophage staining. ResultsAt sacrifice, SNX and UNX mice had significantly higher serum urea, total cholesterol, and triglyceride concentrations than sham-op controls. Atherosclerotic lesions in thoracic aorta were significantly larger in uremic apoE−/− mice than in controls. There were no atheromatous lesions in cavernosal bodies or penile artery observed in any group. However, SNX and UNX animals showed a significant increase in calcification score, collagen content and nitrotyrosine staining in cavernosal bodies when compared with controls. The degree of macrophage infiltration was comparable between the 3 groups. ConclusionIn conclusion, even mild renal dysfunction, i.e., after uninephrectomy increases calcification score and aggravates endothelial function of cavernosal bodies in apoE−/− mice and this effect might be linked to increased oxidative stress in penile endothelium.

Risk factors for cardiovascular disease in children on chronic hemodialysis - Uremia related (non-traditional) risk factors, part II.

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Endothelial Progenitor Cells in Kidney Transplant Patients.

Background: Circulating bone-marrow derived endothelial progenitor cells (EPCs) promote vascular repair. Lower concentrations of EPCs correlate with cardiovascular risk. In uremic patients, the number of functionally active EPCs is reduced. Kidney transplantation (KTx) improves both survival and endothelial function in patients with advanced renal failure. The aim of this study was to determine the impact of KTx and immunosuppressive therapy on the number of EPCs. Methods: EPCs were measured by flow cytometry analysis in 51 renal transplant patients (52±13,92 years; mean eGFR 52,61±19,90 ml/min) and 25 healthy subjects (49±15 years; mean eGFR 94±23 ml/min). We examined the associations between counts of EPCs and traditional cardiovascular risk factors, uremia related risk factors, kidney function and immunosuppressive agents. Results: EPCs numbers were similar in Kidney transplant recipients and controls. We found significant (p<0.05) independent inverse associations between counts of EPCs and age, sistolic and diastolic blood pressure and C-Reactive Protein (CRP). Renal transplant recipients with reduced graft function (mean eGFR <30 ml/min) had lower EPCs counts compared with healthy volunteers(1,05-05 ± 1,17-05 vs.3,95-04 ± 8,35-04 as % on 5x106 PBMc; p=0,0105). Patients receiving regimen therapy including corticosteroids showed significantly lower EPCs number (1,77-02± 1,24-02 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p<0,0001). The use of Cyclosporine and Everolimus induced a further decrease in EPCs number compared to Cyclosporine and Mycophenolate (7,70-05 ± 1,65-04 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p=0,0044). Conclusions: EPCs numbers in KTx are comparable to those found in healthy subjects. In addition, this study suggests negative associations in KTx between EPC counts and age, blood pressure, CRP, graft function and use of some immunosuppressive drugs combination. These findings indicate an improved potential for endothelial repair after KTx, suggest a different effect from different anti-rejection drugs and emphasize the role of EPCs as marker of endothelial health and predictors of cardiovascular outcomes.

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.

Common echocardiography findings in pretransplant dialysis patients and their associations

Abnormality in cardiac structure and function is common in chronic kidney disease (CKD) patients. We aimed to evaluate the prevalence of different abnormal echocardiographic findings in CKD patients and find their associated factors. This retrospective cross-sectional study was conducted in the Nephrology and Dialysis Department of the Shiraz University of Medical Sciences. A total number of 1354 kidney transplant candidates between the years 2000 and 2010 were included. Association between variables was assessed by Chi-square test and Student t test. We analyzed our data using multivariate logistic and linear regression when appropriate. Left ventricular hypertrophy (LVH; 47.5%) was the most common finding in this study, followed by left atrial enlargement (43.7%), diastolic dysfunction (25.4%), left ventricular end diastolic dilation (23.1%), and systolic dysfunction (18.5%), in order of frequency. Older age was associated with abnormality in all echocardiographic indexes. Male gender was associated with LVH and systolic dysfunction. We found an association between a longer duration since CKD diagnosis and LVH. Left ventricular end diastolic dilation, left atrial enlargement, and diastolic dysfunction were associated with a longer duration of dialysis. Anemia was associated with all echocardiographic abnormalities except diastolic dysfunction. Hypoalbuminemia and hypocalcemia were associated with only left atrial enlargement and left ventricular end diastolic dilation, respectively. Patients on peritoneal dialysis had a lower prevalence of left atrial enlargement and left ventricular end diastolic dilation. Different echocardiographic abnormalities, especially LVH, are prevalent among CKD patients. Traditional risk factors, such as age, diabetes mellitus, and hypertension, and uremia-related risk factors, such as anemia and hypoalbuminemia, are associated with an increase in the prevalence of these abnormalities. 背景：心臟結構及功能異常在慢性腎病患者 (CKD) 間相當常見，本研究旨在調查 CKD 患者間心臟超音波異常表現的盛行狀況及其中的相關因子。 方法：這是伊朗設拉子醫學大學腎臟醫學與透析部的一項回溯性橫斷研究，納入 2000 至 2010 年間共 1354 位移植候選者，並採用卡方檢定及 Student's t test 以檢定各變項間的關聯性。 結果：最常見的發現依序有：左心室肥大 (LVH) (47.5%)、左心房擴大 (43.7%)、舒張功能障礙 (25.4%)、左心室舒張末擴張 (23.1%)、及收縮功能障礙 (18.5%)。所有心臟超音波指標的異常均與年老有關，其中 LVH 及收縮功能障礙與男性性別有關。我們亦發現 LVH 與 CKD 診斷後的較長時間有關；左心室舒張末擴張、左心房擴大、及舒張功能障礙則與較長的透析時間有關。除了舒張功能障礙之外，貧血與所有的心臟超音波異常均有關。低白蛋白血症及低鈣血症，則分別僅與左心房擴大及左心室舒張末擴張有關。在正接受腹膜透析的病人間，左心房擴大及左心室舒張末擴張的盛行率均較低。 結論：心臟超音波指標異常特別是 LVH 在 CKD 患者間相當常見，它們的出現與傳統的危險因子有關，例如年齡、糖尿病、及高血壓；及尿毒症的相關危險因子如貧血及低白蛋白血症。

Epidemiology of Peripheral Artery Disease in CKD Patients

Peripheral artery disease (PAD) is underdiagnosed, undertreated, and poorly understood by the medical community. Yet, PAD is a strong predictor of coronary artery disease and a risk factor for mortality in the general population. This is of particular interest to nephrologists because the prevalence of PAD appears to be much higher among patients with end stage renal disease (ESRD) than in the general population. This is explained by the association between traditional and uremia-related risk factors. In fact, kidney disease is an independent risk factor for the development of PAD, with risk increasing with worsening kidney function. The current epidemiology in ESRD patients is here reviewed.

Interrelationship between Chronic Kidney Disease and Risk of Cardiovascular Diseases

An estimated 11% of the U.S. population has chronic kidney disease (CKD). Cardiovascular morbidity and mortality remain high among individuals with CKD and the higher mortality from cardiovascular disease persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of cardiovascular disease in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. Given the high cardiovascular morbidity and mortality, patients with CKD should be a target for aggressive cardiovascular risk reduction.

Avaliação cardiológica de pacientes portadores de doença renal crônica: quais as lições?

Patients with chronic kidney disease (CKD) experiment a synergistic effect of the traditional and the emerging uremia-related risk factors for atherosclerosis. Draw the epidemiologic profile of a group of CKD patients who underwent cardiac evaluation. Symptomatic patients, patients with ischemia on myocardial scintigraphy and/or systolic dysfunction on echocardiography, patients older than 50 years and diabetes mellitus (DM) as a cause of CKD, and those with two or more risk factors underwent coronary angiography. Asymptomatic, non-diabetic patients and patients with no risk factors were investigated with echocardiography. Those with a single risk factor were investigated with echocardiography and scintigraphy. 46 patients (58.7% men) were enrolled. Their mean age was 50.7 ± 11.7 years. 91.3% were on dialysis, for 61.96 ± 55.1 months. Hypertension was the cause of CKD in 56.5%. Of the 28 patients (60.9%) who underwent angiography, 53.6% had coronary artery disease (CAD). The patients were divided into three groups: those with CAD (A), those without CAD (B) and those who didn't undergo coronary angiography (C). A significant difference occurred only between groups B and C, as regards an abnormal ABI (p = 0.026), with no ABI abnormality in group C, and as regards the mean age, which was higher in group B (p = 0.045). In group A, 53.3% of the patients were in the preoperative stage of parathyroidectomy. This study confirmed the high rate of cardiovascular disorders, including CAD, in patients with CKD, especially those on dialysis.

Treatment of dyslipidemia in chronic kidney disease: Effectiveness and safety of statins

Several cardiovascular (CV) risk factors may explain the high rate of CV death among patients with chronic kidney disease (CKD). Among them both traditional and uremia-related risk factors are implicated and, moreover, the presence of kidney disease represents "per se" a multiplier of CV risk. Plasma lipid and lipoprotein profiles are changed in quantitative, but above all in qualitative, structural, and functional ways, and lipoprotein metabolism is influenced by the progressive loss of renal function. Statin therapy significantly reduces cholesterol synthesis and both CV morbidity and mortality either directly, by reducing the lipid profile, or via pleiotropic effects; it is supposed to be able to reduce both the progression of CKD and also proteinuria. These observations derive from a post-hoc analysis of large trials conducted in the general population, but not in CKD patients. However, the recently published SHARP trial, including over 9200 patients, either on dialysis or pre-dialysis, showed that simvastatin plus ezetimibe, compared with placebo, was associated with a significant low-density lipoprotein cholesterol reduction and a 17% reduction in major atherosclerotic events. However, no benefit was observed in overall survival nor in preserving renal function in patients treated. These recent data reinforce the conviction among nephrologists to consider their patients at high CV risk and that lipid lowering drugs such as statins may represent an important tool in reducing atheromatous coronary disease which, however, represents only a third of CV deaths in patients with CKD. Therefore, statins have no protective effect among the remaining two-thirds of patients who suffer from sudden cardiac death due to arrhythmia or heart failure, prevalent among CKD patients. The safety of statins is demonstrated in CKD by several trials and recently confirmed by the largest SHARP trial, in terms of no increase in cancer incidence, muscle pain, creatine kinase levels, severe rhabdomyolysis, hepatitis, gallstones and pancreatitis; thus confirming the handiness of statins in CKD patients. Here we will review the latest data available concerning the effectiveness and safety of statin therapy in CKD patients.

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.

Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients--a prospective cohort study

The mortality rate of elderly hemodialysis (HD) patients is high. Serum p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are associated with cardiovascular (CV) disease and mortality in renal patients. The association between such biomarkers and mortality in elderly HD patients has a high clinical value but remains unclear. This prospective cohort study investigated the association of serum IS and PCS with all-cause and CV mortality in elderly HD patients. Multivariate Cox regression analysis was used to estimate the risk of all-cause and CV mortality in this prospective cohort. Of 112 patients, 45 deaths (18 CV deaths) were identified after a mean follow-up of 33.2 months. The cumulative and CV survival of patients with lower free PCS was significantly better than high free PCS patients. In multivariate Cox regression analysis, serum free PCS was associated with all-cause and CV mortality after various adjustments, including age, gender and diabetes status (Model 1), albumin (Model 2), Ca × P product and intact parathyroid hormone (Model 3), hemoglobin and high-sensitivity C-reactive protein (Model 4) and hierarchically selected covariates (age, diabetes status and albumin, Model 5). Serum free PCS levels may help in predicting risk of all-cause and CV mortality in elderly HD patients beyond traditional and uremia related risk factors.

Noninvasive imaging for assessment of calcification in chronic kidney disease

Vascular calcification is highly prevalent in patients with chronic kidney disease and has a progressive course. Several cardiovascular and uremia-related risk factors, such as abnormalities in mineral metabolism, contribute to the development of vascular calcification, although the pathophysiological mechanisms are still unclear. The presence and extent of vascular calcification is associated with an increased risk of cardiovascular events and mortality. By contrast, patients who do not have calcification seem to have a good prognosis, with minimal or no calcification progression over an extended period of time. A number of noninvasive imaging methods are available to detect vascular calcification and may help clinicians to make therapeutic decisions. Cardiac CT remains the reference standard to detect and quantify coronary artery, aortic and cardiac valve calcification. However, the high cost of equipment, the inability to perform in-office testing and the expertise required limit its use on a routine basis. Other imaging methods, such as planar X-ray, ultrasound and echocardiography, are appropriate alternatives to evaluate vascular and valvular calcification. In this review, we discuss the noninvasive imaging methods most frequently used to assess vascular and valvular calcification, with their advantages and limitations.

Inflammation and cardiovascular complications in chronic kidney disease

Cardiovascular disease is a leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), accounting for 50% of deaths of patients on dialysis, even young adults. The etiology of accelerated cardiovascular disease in these patients is likely multifactorial. Although patients with CKD demonstrate a high prevalence of traditional risk factors for cardiovascular disease, these risk factors alone cannot explain the high burden of cardiovascular disease in this patient population. One of several uremia-related risk factors thought to contribute to disease progression is low-grade systemic inflammation. This review summarizes the current literature on the role of inflammation in promoting cardiovascular disease in this patient population as well as potential therapies to address this non-traditional risk factor.

Vascular Calcification in Chronic Kidney Disease: Pathogenesis and Clinical Implications

Cardiovascular disease is the primary cause of morbidity and mortality in chronic kidney disease (CKD). Nontraditional uremia-related risk factors as well as traditional risk factors may contribute to the unique features of cardiovascular disease in patients with CKD. Vascular calcification is a prominent feature of arterial disease in CKD and may have an impact on cardiovascular mortality through modulating both arteriosclerosis (arterial stiffening) and atherosclerosis. There are two pathophysiological processes involved in the development of vascular calcification: apoptosis and phenotypic transition to chondrocytes or osteoblasts (chodro/osteogenic differentiation). In CKD, abnormal mineral metabolism, predominantly hyperphosphatemia and hypercalcemia, facilitates progression of vascular calcification in association with functional disturbances of its inhibitory molecules (inhibitors of vascular calcification) such as pyrophosphate, matrix Gla protein, fetuin-A, and osteoprotegerin.

Vascular Calcifications in Uremia: Old Concepts and New Insights

The annual mortality rate in uremic patients, corrected for age, sex, and race, is significantly higher than in the general population. This is primarily due to cardiovascular events. Vascular calcifications play a vital role in the development of cardiovascular morbidity and subsequent increased mortality. Vascular calcification affects both vascular intima and media layers and its mechanism remains poorly understood. Over the last few years it has been shown that, in addition to traditional cardiovascular risk factors, disturbances in mineral metabolism in the uremic milieu, calcium-containing phosphate binders, and vitamin D treatment of secondary hyperparathyroidism may contribute to the pathogenesis of vascular calcifications. Other uremia-related risk factors (e.g.increased oxidized low-density lipoprotein cholesterol, uremic toxins, increased oxidative stress, dialysis and dialysate-related factors, hemodynamic overload, hyperhomocysteinemia) may also play a role. In uremic patients, apart from these facilitating factors, decreased levels of endogenous calcification inhibitors such as fetuin-Amatrix Gla protein, osteoprotegerin, and osteopontin have also been associated with increased calcium-phosphate precipitation in extraskeletal tissues. Finally, vascular calcification is the outcome of the active and dynamic balance of procalcifying and anticalcifying influences. For the prevention and treatment of vascular calcifications, it is essential to avoid treatment modalities that lead to calcium overload, achieve good metabolic control, and optimize dialysis.

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.

Coronary calcification in hemodialysis patients: The contribution of traditional and uremia-related risk factors

Coronary artery calcification is a common feature of atherosclerosis, occurring in 90% of angiographically significant lesions. There is recent evidence that coronary artery calcification is frequent in hemodialysis patients and it has been suggested that this increased incidence may be associated to uremia-related factors. The development and progression of coronary artery calcification is similar to osteogenesis. The aim of this study was to evaluate the relationship between coronary artery calcification, uremia-related factors, and bone histomorphometry in hemodialysis patients. A total of 101 hemodialysis patients were assessed for biochemical markers of inflammation, oxidative stress, and bone metabolism. Subsequently, they were submitted to multislice coronary tomography (MSCT) and transiliac bone biopsy. The median calcium score was 116.2 (range 0 to 5547). Fifty-two percent of the patients showed moderate and severe coronary artery calcification, 20% had calcium scores greater than 1000. In univariate analysis, age (r= 0.57, P < 0.000001), osteoprotegerin (OPG) (r= 0.44, P= 0.00002), and body mass index (BMI) (r= 0.24, P= 0.01) correlated positively with calcium score. Bone trabecular volume and trabecular thickness correlated negatively with calcium score (r=-0.24, P= 0.02; r=-0.22, P= 0.03). There was a correlation of borderline significance between calcium score and C-reactive protein (CRP) (r= 0.18, P= 0.062). The multiple linear regression analysis identified OPG as the only variable independently associated with coronary artery calcification. Coronary artery calcification is highly prevalent in the hemodialysis population and is associated with older age, higher BMI, inflammation and reduced trabecular bone volume. Higher OPG is independently associated with coronary artery calcification and may represent an incomplete self-defensive response to the progression of atherosclerosis in hemodialysis patients.

Facteurs de risque vasculaire et insuffisance rénale

Patients with chronic kidney disease (CKD) have a substantially increased risk of cardiovascular disease (CVD) compared with the general population. The high prevalence of established traditional risk factors for atherosclerosis (diabetes, hypertension, dyslipidemia) in these patients undoubtedly contributes to the accelerated rate of vascular disease. In addition, several hypotheses have emerged to explain the high prevalence of CVD in patients with chronic renal failure. Growing evidence has been gathered over the last 15 years regarding the role of uremia-related risk factors such as inflammation and oxidant stress in the pathogenesis of atherosclerosis in subjects with renal failure. This paper will review current knowledge regarding the potential role of these non-traditional or uremia-related risk factors for atherosclerosis with special emphasis on prevalence, cardiac risk, and management in patients with CKD.

Impact of kidney transplantation on the progression of cardiovascular disease

Kidney transplantation, of all the treatment modalities for end-stage renal disease, affords the greatest potential for prolonged survival and improved quality of life. Great strides in immunosuppressant therapy have improved graft survival and forced clinicians to consider other health-care needs of kidney transplant recipients. Chief among these needs is the prevention and treatment of cardiovascular disease. Cardiovascular disease is the most common cause of death among patients with a working renal allograft. Because therapies for primary and secondary prevention are successful in the general population, transplant clinicians are increasingly focused on preventing or limiting the progression of cardiovascular disease. Initiation of aggressive management of conventional atherosclerotic risk factors and uremia-related risk factors, ideally during the early stages of chronic kidney disease (CKD) or after kidney transplantation, and efforts to delay the progression of kidney disease will hopefully reduce the cardiovascular burden in transplant recipients.