The Role of Novel Biomarkers of Cardiovascular Disease in Chronic Kidney Disease: Focus on Adiponectin and Leptin

Cardiovascular disease (CVD) remains a major cause of premature death in patients with chronic kidney disease (CKD), including renal transplant recipients. Both interplay of traditional cardiovascular and renal specific risk factors have been shown to be associated with an increased risk of cardiovascular death in patients with CKD. Recently, there has been great interest in the role of novel biomarkers, in particular adiponectin and leptin, and its association with CVD in the CKD population. Adiponectin is a multifunctional adipocyte-derived protein with anti-inflammatory, antiatherogenic and insulin sensitizing activity. Recent observational studies have shown adiponectin to be a novel risk marker of CVD in patients with stages 1 to 5 CKD. Leptin is an adipocyte-derived hormone that promotes weight loss by decreasing food intake. Similarly, there are observational studies to support an association between leptin and CVD, including patients with CKD. In the CKD population, leptin may be associated with uremic cachexia and subsequent increased mortality. This review aims to summarize the pathophysiological and potential clinical roles of these cardiovascular biomarkers in patients with CKD.Key Words: Biomarker, cardiovascular disease, adiponectin, leptin, kidney disease.     

Stroke and renal dysfunction: are we always conscious of this relationship?

Cerebrovascular disease may represent an important clinical presentation of atherosclerosis in chronic kidney disease (CKD), and atherosclerosis is frequently encountered in CKD. In fact, kidney disease is now considered a risk factor for development of cardiovascular disease. Although guidelines for primary prevention of stroke have been recently published, CKD is hardly mentioned. Based on a series of available studies, we analyzed the relationship between reduced renal function, end-stage renal disease (ESRD), and stroke. Reduced renal function and risk of stroke appear to be related to the highest risk of patients on dialysis treatment. Primary and secondary prevention of stroke should be encouraged in participants with renal dysfunction.     

Cardiovascular disease and chronic kidney disease: insights and an update

Despite the high prevalence and significant morbidity and mortality rates of chronic kidney disease (CKD) related to cardiovascular disease, it remains vastly understudied. Most of the current practice recommendations come from small under-powered prospective studies, retrospective reviews, and assuming patients with CKD will similarly benefit from medications and treatments as patients with normal renal function. In addition, because of the previous lack of a consistent definition of CKD and how to measure renal function, definitions of the degree of renal dysfunction have varied widely and compounded the confusion of these data. Remarkably, despite patients with CKD representing the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus, there has been a systematic exclusion of patients with CKD from therapeutic trials. This review outlines our current understanding of CKD as a cardiovascular risk factor, treatment options, and the future directions that are needed to treat cardiovascular disease in patients with CKD.     

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.     

Chronic kidney disease epidemic: myth and reality

In recent years, an epidemic of chronic kidney disease (CKD) has emerged as one of the major public health problem. The prevalence of CKD is largely sustained by the inclusion of a substantial proportion of the elderly population within stage 3 CKD, according to the Kidney Disease Outcomes Quality Initiative staging system. However, some clarifications are necessary when interpreting these data. In fact, renal function "normally" declines with age, without bearing any unfavourable outcome; in addition, the Modification of Diet in Renal Disease formula used to calculate glomerular filtration rate (GFR) underestimates kidney function in the elderly and in women. Considerable interest in CKD has been generated by the evidence that predialysis CKD is associated with the increased risk of cardiovascular disease (CVD). Again, potential confounding factors must be ruled out. Age is thought to play a major role in this context. The most common causes of CKD, hypertension and diabetes mellitus, are also known to affect cardiovascular outcomes directly, thus preventing the recognition of an independent effect of kidney dysfunction on mortality by CVD. Taken together, these considerations point for a better definition of CKD. Early identification of patients at risk for accelerated decline in renal function is mandatory to plan strategies for screening and preventing CKD and its complications. At present, detection of CKD in the general population requires a multi-dimensional approach that should include the evaluation of clinical risk conditions, evaluation of albuminuria and sequential monitoring of GFR.     

Hypertension management: Special considerations in chronic kidney disease patients

It has been estimated that approximately 11% of the US adult population has chronic kidney disease (CKD), and it has been demonstrated that the prevalence of hypertension rises significantly as renal function declines. Even mild CKD significantly increases mortality risk, and cardiovascular disease remains the main cause of death among these patients. Although CKD patients have generally been excluded from trials testing the effect of lowering blood pressure on cardiovascular outcomes, guidelines suggest lowering blood pressure in hopes of reducing cardiovascular mortality and slowing the progression of renal disease. The preferred antihypertensive agents among these patients are drugs that block the renin-angiotensin system. In most hypertensive CKD patients, however, multiple agents are necessary to reach blood pressure targets. In general, diuretics and calcium channel blockers are added subsequently as adjunctive therapy. Hopefully, with increased recognition of the unique aspects of treating hypertension in this population, end-stage renal disease and cardiovascular morbidity and mortality will be delayed or avoided in the millions of patients with CKD.     

Atherosclerosis in CKD: differences from the general population

The prevalence of cardiovascular morbidity and mortality is higher in patients with chronic kidney disease (CKD)-especially those with end-stage renal disease-than in the general population. The contribution of atherosclerosis to cardiovascular disease in patients with CKD remains unclear. Researchers in the 1970s proposed that atherosclerosis was the main cause of cardiovascular disease in patients with CKD and that its progression, based on observations of patients on long-term dialysis, was accelerated by the uremic state. Subsequent reports, however, favor the involvement of other mechanisms, such as arteriosclerosis (characterized by vascular stiffening), vascular calcification, 'myocyte/capillary mismatch', congestive cardiomyopathy, and sudden cardiac death. Imaging and morphological studies have contributed to our understanding of the pathogenesis and progression of cardiovascular disease associated with CKD. Based on clinical and experimental findings, we hypothesize the following: the initial cardiovascular abnormalities in the CKD setting include arteriosclerosis, left ventricular diastolic dysfunction, and left ventricular hypertrophy, abnormalities which, in adult patients, are often accompanied by atherosclerosis. The prevalence of atherosclerosis increases with age and is aggravated, but not specifically induced, by CKD. The cardiovascular events associated with atherosclerosis are more often fatal in patients with CKD than in individuals without CKD.     

Cardiac Imaging for Coronary Heart Disease Risk Stratification in Chronic Kidney Disease

Chronic kidney disease (CKD), defined as dysfunction of the glomerular filtration apparatus, is an independent risk factor for the development of coronary artery disease (CAD). Patients with CKD are at a substantially higher risk of cardiovascular mortality compared with the age- and sex-adjusted general population with normal kidney function. The risk of CAD and mortality in patients with CKD is correlated with the degree of renal dysfunction including presence of microalbuminuria. A greater cardiovascular risk, albeit lower than for patients receiving dialysis, persists even after kidney transplantation. Congestive heart failure, commonly caused by CAD, also accounts for a significant portion of the cardiovascular-related events observed in CKD. The optimal strategy for the evaluation of CAD in patients with CKD, particularly before renal transplantation, remains a topic of contention spanning over several decades. Although the evaluation of coexisting cardiac disease in patients with CKD is desirable, severe renal dysfunction limits the use of radiographic and magnetic resonance contrast agents due to concerns regarding contrast-induced nephropathy and nephrogenic systemic sclerosis, respectively. In addition, many patients with CKD have extensive and premature (often medial) calcification disproportionate to the severity of obstructive CAD, thereby limiting the diagnostic value of computed tomography angiography. As such, echocardiography, non–contrast-enhanced magnetic resonance, nuclear myocardial perfusion, and metabolic imaging offer a variety of approaches to assess obstructive CAD and cardiomyopathy of advanced CKD without the need for nephrotoxic contrast agents.     

Outcomes after percutaneous coronary interventions in patients with chronic kidney disease

Introduction Chronic kidney disease (CKD) is a significant contributor to cardiovascular morbidity and mortality. Patients with CKD are known to have a greater prevalence of cardiovascular disease than the general population, and patients with concurrent CKD and coronary artery disease (CAD) have greater mortality than patients without CKD.The rate of cardiovascular mortality is approximately 50%, five to 10 times higher than the general population.     

Renal osteodystrophy in children: A systemic disease associated with cardiovascular manifestations

The increasing prevalence of chronic kidney disease (CKD) in the United States demands a closer evaluation of and attention to associated morbidities, and, particularly, the rising mortality related to cardiovascular disease in all age groups. Patients with CKD demonstrate an increased risk of coronary artery disease due to calcium deposition and subsequent arterial stiffening, in addition to left ventricular dysfunction with associated heart failure and arrhythmias. While clearly impacted by the traditional risk factors for development of cardiovascular disease (CVD), patients with CKD are also affected by non-traditional risk factors, including calcium overloading related to aggressive management of secondary hyperparathyroidism.Recent data have shown that a substantial number of patients with CKD are deficient in vitamin D on a nutritional basis, in addition to the known decrease in the kidney-produced active metabolite during progressive CKD. Historically, vitamin D has been described as an endocrine hormone that regulates blood calcium and parathyroid hormone levels. It has become increasingly clear, through the recognition of a vitamin D receptor in most tissues, that vitamin D possesses functions well beyond calcium homeostasis, such that a deficiency may contribute to the development of CVD. In this brief review, the role of vitamin D activation through its vitamin D receptor will serve as an introduction to the magnitude of the nutritional deficits in children, adults, and those with CKD. As therapeutic entities in the management of renal osteodystrophy, vitamin D analogues play an important role in cardiovascular health that continues to evolve. Preliminary studies indicate that vitamin D therapy for control of secondary hyperparathyroidism may confer cardioprotection and reduce mortality. Attention to care of osteodystrophy in CKD must take into account heart health as well.     

Risk factors for coronary artery disease in patients with renal failure

Cardiovascular mortality is markedly increased in patients with end-stage renal disease (ESRD), particularly those receiving dialysis. Coronary artery disease is the most important cause of death in these patients. As in the general population, older age, male gender, and the postmenopausal state in women are cardiovascular risk factors in patients with ESRD. However, hypertension, diabetes mellitus, and dyslipidemia, known to promote cardiovascular disease in the general population, are particularly likely to do so in patients with ESRD because of their high prevalence in this population. In addition, nontraditional cardiovascular risk factors, such as hyperhomocystinemia, inflammation, elevated calcium x phosphate product, endothelial dysfunction, and oxidant stress, occur frequently in patients with ESRD. Vigorous treatment of modifiable cardiovascular risk factors has reduced cardiovascular risk in patients without ESRD. The extent to which such risk factor modification would alter cardiovascular risk in ESRD remains uncertain.     

Echocardiographic assessment in patients with chronic kidney disease: Current update

Patients with chronic kidney disease (CKD) carry a high cardiovascular risk. An abundance of evidence has emerged in recent years establishing minor reductions in estimated glomerular filtration rate as an independent risk factor for cardiovascular mortality. Additionally, cardiac changes, such as left ventricular hypertrophy and impaired left ventricular systolic function, have been associated with an unfavorable prognosis. Despite the significant prevalence of underlying cardiac abnormalities, symptoms may not manifest in many patients with CKD. A range of available and emerging echocardiographic modalities may assist with diagnosing heart disease in CKD. Furthermore, some of these emerging techniques can give an important insight into the pathophysiology of subclinical dysfunction in CKD. This review discusses how current and emerging echocardiographic modalities such as speckle tracking echocardiography and 3D echocardiography might help cardiologists in providing important information to help with diagnosis and risk stratification of cardiac‐related morbidity and mortality in patients with renal disease, as well applicability of these tools to current clinical practice.     

Renal Failure in Sickle Cell Disease: Prevalence,Predictors of Disease,Mortality and Effect on Length of Hospital Stay

Renal dysfunction in sickle cell disease is not only a chronic comorbidity but also a mortality risk factor. Though renal dysfunction starts early in life in sickle cell patients, the predictors that can identify sickle cell disease patients at risk of developing renal dysfunction is not known. We used the Truven Health MarketScan^® Medicaid Databases from 2007 to 2012. Incidence of new acute renal failure (ARF) and chronic kidney disease (CKD) was calculated in this cohort. There were 9481 patients with a diagnosis of sickle cell disease accounting for 64,201 hospital admissions, during the study period. Both ARF and CKD were associated with higher risk of inpatient mortality, longer duration of the hospital stay and expensive hospitalizations. The yearly incidence of new ARF in sickle cell disease patients was 1.4% and annual CKD incidence was 1.3%. The annual rate of new ARF and CKD in the control group was 0.4 and 0.6%, respectively. The most important predictors of new CKD were proteinuria, ARF and hypertension. Chronic kidney disease, hypertension and sickle cell crisis were the most important predictors of new ARF. The annual rate of incidences of ARF and CKD were 2- to 3-fold higher in sickle cell disease compared to the non sickle cell disease group. Besides the common risk factors for renal disease in the general population, it is imperative to monitor the sickle cell disease patients with more severe disease to prevent them from developing renal dysfunction.     

Progression of Renal Dysfunction in Patients with Cardiovascular Disease

It has been established that patients with chronic kidney disease (CKD) suffer from frequent cardiovascular events. On the other hand, recent studies suggest that renal damage tends to worsen in patients with cardiovascular diseases (CVD). Although the mechanisms for the cardiorenal association are unclear, the presence of arteriosclerotic risk factors common to both CVD and CKD is important. In arteriosclerosis, vascular derangement progresses not only in the heart but also in the kidney. In addition, heart failure, cardiac catheterization and hesitation of medical treatments due to renal dysfunction may explain the progression of renal damage. Therefore, the goal of treatments is a total control of arteriosclerotic risk factors. Medication should be selected among agents with protective effects on both heart and kidney. It is important to always consider the presence of CKD for the treatment of the cardiovascular disease and strictly control the risk factors.Key Words: CKD, angiotensin II, aldosterone, ARB, hypertension.     

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.     

Different impact of aspirin on renal progression in patients with predialysis advanced chronic kidney disease with or without previous stroke

BackgroundThe benefit of reducing the risk of stroke against increasing the risk of renal progression associated with antiplatelet therapy in patients with advanced chronic kidney disease (CKD) is controversial.MethodsWe enrolled 1301 adult patients with advanced CKD treated with erythropoiesis stimulating agents from January 1, 2002 to June 30, 2009 from the 2005 Longitudinal Health Insurance Database in Taiwan. All of the patients were followed until the development of the primary or secondary endpoints, or the end of the study (December 31, 2011). The primary endpoint was the development of ischemic stroke, and the secondary endpoints included hospitalization for bleeding events, cardiovascular mortality, all-cause mortality, and renal failure. The adjusted cumulative probability of events was calculated using multivariate Cox proportional regression analysis.ResultsAdjusted survival curves showed that the usage of aspirin was not associated with ischemic stroke, hospitalization for bleeding events, cardiovascular mortality or all-cause mortality, however, it was significantly associated with renal failure. In subgroup analysis, aspirin use was associated with renal failure in the patients with no history of stroke (HR, 1.41; 95% CI, 1.14–1.73), and there was a borderline interaction between previous stroke and the use of aspirin on renal failure (interaction p = 0.0565).ConclusionsThere was no significant benefit in preventing ischemic stroke in the patients with advanced CKD who received aspirin therapy. Furthermore, the use of aspirin was associated with the risk of renal failure in the patients with advanced CKD without previous stroke.     

Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney disease: Cause or association?

Chronic kidney disease (CKD) is strongly associated with cardiovascular disease (CVD); a graded inverse relationship between estimated glomerular filtration rate (eGFR) and cardiovascular event rates has emerged from large-scale observational studies. Chronic kidney disease is also associated with endothelial dysfunction (ED) although the precise relationship with GFR and the "threshold" at which ED begins are contentious. Abnormal endothelial function is certainly present in late-stage CKD but data in early-stage CKD appear confounded by disease states such as diabetes and hypertension which themselves promote ED. Thus, the direct effect of a reduction in GFR on endothelial function and, therefore, cardiovascular (CV) risk is far from completely established. In human studies, the precise duration of kidney impairment is seldom known and the onset of CVD often insidious, making it difficult to determine exactly when CVD first appears in the context of CKD. Kidney donors provide a near-ideal experimental model of CKD; subjects undergo an acute change from normal to modestly impaired renal function at the time of nephrectomy and lack the confounding co-morbidity that has made observational studies of CKD patients so challenging to interpret. By examining changes in endothelial function in living kidney donors before and after nephrectomy, useful insight might be gained into the pathophysiology of CVD in CKD and help determine whether targeting ED or the renal disease itself has the potential to reduce CV risk.     

The epidemic of chronic kidney disease: looking at ageing and cardiovascular disease through kidney-shaped lenses

In recent years, a 'silent' chronic kidney disease (CKD) epidemic has been proposed by many authors. The 'outbreak' is because of the inclusion of a large proportion of the elderly population within stage 3 CKD according to the Kidney Disease Outcomes Quality Initiative staging system. Unfortunately, this does not take into account the fact that renal function normally declines with age; in addition, the Modification of Diet in Renal Disease formula used to calculate glomerular filtration rate underestimates renal function in the elderly. Because population preventive strategies need a precise definition of the target for screening, a more accurate tool to detect CKD in the general population is required. Considerable interest in CKD has been generated by the evidence that predialysis CKD is associated with increased risk of cardiovascular disease (CVD). Such an association per se does not imply that CKD is a causal determinant of CVD. As CKD has been detected particularly in elderly individuals, it is tempting to speculate that an association may exist between age and cardiovascular outcomes in patients with CKD. Furthermore, the definition of CKD is a nosographic simplification that includes diseases with different causes and pathogenetic mechanisms. The aetiologies of renal diseases can affect cardiovascular outcomes, and the two major causes of end-stage renal disease, diabetes mellitus and hypertension, indeed do so. These findings point to a need for a better definition of CKD to optimize the allocation of healthcare resources and to clarify the nature of the association between CKD and CVD.     

Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the Prospective Longitudinal RRI-CKD Study)

Although the determinants of cardiovascular calcium have been well described in dialysis patients, the prevalence and predictors in predialysis chronic kidney disease (CKD) are less known. One hundred six patients with CKD from the Renal Research Institute-CKD Study underwent multidetector computed tomography for the assessment of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve. Cardiovascular risk factors and renal function-related parameters (glomerular filtration rate, glomerular filtration rate slope, serum creatinine, serum urea nitrogen, hemoglobin, albumin, calcium, phosphate, and parathyroid hormone) were included in multivariate regression models to predict cardiovascular calcium. Prevalences of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve were 69%, 46%, 39%, and 16%, respectively. On multivariate analysis, coronary artery calcium score was predicted by age (p < 0.0001), gender (p = 0.0001), diabetes (p = 0.024), and history of coronary artery disease (p = 0.016), but not by renal function related parameters. Similarly, renal function related parameters were not predictive of aortic or valvular calcium. In conclusion, predialysis CKD is associated with a high prevalence of cardiovascular calcium. The extent of cardiovascular calcium in patients with predialysis CKD is related to some of the traditional risk factors for atherosclerosis but not to indexes of abnormal renal function or progression in renal dysfunction.     

Anticoagulación oral en la enfermedad renal crónica con fibrilación auricular

Chronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist, amplifying the risk of cardiovascular events and mortality. In patients with CKD stage 3 and non-valvular AF, direct oral anticoagulants (DOACs) have shown, compared to vitamin K antagonists (VKA), equal or greater efficacy in the prevention of stroke and systemic embolism, and greater safety. There are no randomized trials of the efficacy and safety of DOACs and VKA in advanced CKD. On the other hand, observational studies suggest that DOACs, compared to warfarin, are associated with a lower risk of acute kidney damage and generation/progression of CKD. This paper reviews the epidemiological and pathophysiological aspects of the CKD and AF association, the evidence of the efficacy and safety of warfarin and ACODs in various stages of CKD with AF as well as the comparison between warfarin and ACODs in efficacy and anticoagulant safety, and in its renal effects.