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.     

Cardiovascular disease in patients with chronic kidney disease

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with renal failure. Patients with chronic kidney disease have significant CVD, and carry a high cardiovascular burden by the time they commence renal replacement therapy (RRT). The severity of CVD that has been observed in dialysis patients lead to a growing body of research examining the pathogenesis and progression of CVD during the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) (ie, predialysis phase). Multiple factors are involved in the development of CVD in CKD. More importantly, critical and key factors seem to develop early in the course of CKD, and result in preventable worsening of CVD in this patient population. Anemia is common in patients with CKD, and has been shown to have an independent role in the genesis of left ventricular hypertrophy (LVH) and subsequent CVD. Unfortunately, it is underdiagnosed and undertreated in patients with CKD. Early intervention, and better correction of anemia, seems to gain a great momentum in the prevention and management of CVD in CKD. Hypertension is another risk factor that has been targeted by the National Kidney Foundation Task Force on CVD in chronic kidney disease. This article reviews the different factors involved in the pathogenesis of CVD in CKD and the evidence supporting early and aggressive intervention.     

Cardiovascular care in end-stage renal disease

Cardiovascular disease (CVD) accounts for the majority of morbidity and mortality in patients with end-stage renal disease (ESRD). Chronic kidney disease, and ESRD as its most severe form, are now acknowledged to be independent risk factors for CVD. The spectrum of CVD includes accelerated atherosclerosis, myocardial disease and heart failure, cardiac arrhythmias, and valvular heart disease. In addition, CKD and ESRD are independent and powerful factors that complicate cardiovascular procedures and have been directly linked to increased mortality. This issue of Advances in Chronic Kidney Disease will explore the spectrum of risk and the opportunities to improve care in ESRD in outpatient management, during dialysis, after kidney transplantation, and in coronary revascularization.     

A population-based assessment of the familial component of chronic kidney disease mortality

BACKGROUND/AIM: While the familial nature of chronic kidney disease (CKD) has been recognized, it has primarily been defined from studies of first-degree relatives of selected sets of cases. The goal of this study is an evaluation of the familial clustering of end-stage renal disease (ESRD) and CKD mortality using a population-based genealogy of Utah. This is the first population-based analysis of the familial component of ESRD and non-ESRD CKD. METHODS: We have defined two distinct patient groups for this analysis, using individuals with death certificates in the Utah Population Database indicating ESRD (n = 192) and non-ESRD CKD (n = 335) as the cause of death. Two measures of familiality were used: (1) relative risk (RR) of CKD or ESRD death in relatives of cases and (2) an average relatedness statistic, i.e., the Genealogical Index of Familiality. RESULTS: The RR for dying with ESRD among the first-degree relatives of individuals dying with ESRD is estimated to be 10.1 (p = 0.0007, 95% confidence interval CI 2.76-25.95), but is not significantly elevated among second-degree relatives. The RR for dying with non-ESRD CKD among first- and second-degree relatives of individuals dying with non-ESRD CKD was 3.89 (p = 0.0051, 95% CI 1.43-8.46) and 3.11 (p = 0.04, 95% CI 0.85-7.95), respectively. The Genealogical Index of Familiality statistic demonstrated that the individuals dying with ESRD are significantly more related than expected in this population (p = 0.013); significant excess relatedness was also observed for individuals dying with non-ESRD CKD (p = 0.006), suggesting a familial component for both, with evidence for common environmental and genetic effects. CONCLUSION: The results of this analysis of individuals dying with ESRD and non-ESRD CKD supports a significant and independent familial component to both conditions, suggesting a heritable factor playing a role.     

Chronic kidney disease and cardiovascular disease in the Medicare population

BACKGROUND: The extent of diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD) in the Medicare population is relatively unknown. Also unknown is the effect of these diseases on patient survival before end-stage renal disease (ESRD). METHODS: Prevalent cohorts of Medicare enrollees from 1996 to 2000 were assessed for diabetes and CKD, presence of CVD, and probability of death versus ESRD in the follow-up period. Hospitalization rates and, in diabetics, lipid testing and glycemic control monitoring were also assessed. RESULTS: The prevalence of diabetes in the Medicare population increased at 4.4% per year, reaching 18.9% in the 1999-2000 cohort. Approximately 726,000 elderly Medicare enrollees carry a diagnosis code for CKD. Those with CKD are 5 to 10 times more likely to die before reaching ESRD than the non-CKD group. In CKD patients, CVD is twice as common and advances at twice the rate. Cardiovascular disease advances at a similarly higher rate in CKD patients who die and those who survive to ESRD. Heart failure hospitalizations are 5 times greater in CKD patients and only 30% less than those in dialysis patients. Only half of the CKD patients with diabetes who advance to ESRD had a lipid or glycosylated hemoglobin test done in the year before or after dialysis initiation. CONCLUSION: Diabetes, the leading cause of ESRD, is increasing in the general Medicare population at 4.4% per year. Cardiovascular disease is common, progresses at twice the rate, is associated with death before ESRD, and patients receive suboptimal risk factor monitoring. Active identification and treatment of CKD patients is needed.     

Genetic factors in end-stage renal disease

Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness.     

Population-based screening for family history of end-stage renal disease among incident dialysis patients

BACKGROUND: We determined the familial aggregation of end-stage renal disease (ESRD) in a large, population-based sample of incident ESRD cases to assess the feasibility of developing a targeted screening and prevention program directed at members of families at high risk for kidney disease. METHODS: Between January 1, 1995, and December 31, 2003, incident dialysis patients in ESRD Network 6 facilities were asked to complete a voluntary questionnaire on family history (FH) of ESRD. Cases with ESRD attributed to Mendelian diseases or urologic causes were excluded. FH was considered present if first- or second-degree relatives had ESRD. De-identified FH data were collated with demographic data at dialysis initiation. RESULTS: More than 46% of eligible patients (25,883/55,929) provided FH information and 22.8% (5,901/25,883) of these reported having a FH of ESRD. FH of ESRD was positively associated with female gender, earlier age at ESRD onset, and primary cause of ESRD, and negatively associated with white race. FH associations with age, race, gender, and primary cause of renal failure remained statistically significant after simultaneous adjustment in a multivariate logistic regression model. CONCLUSIONS: Approximately 23% of incident dialysis patients have close relatives with ESRD. Far more are likely to have relatives with clinically silent proteinuria or chronic kidney disease (CKD), both risk factors for future cardiovascular events and ESRD. Physicians caring for patients with CKD should be aware of the marked familial aggregation of ESRD and consider focusing screening efforts on high-risk family members in an attempt to slow the exponential growth rate of kidney disease.     

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.     

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.     

Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Both in dialysis and in transplant patients, CVD remains the leading cause of death. There is accumulating evidence that the increase in CVD burden is present in patients prior to dialysis, due to both conventional risk factors as well as those specific to kidney disease. Of importance is that even in patients with mild kidney disease, the risk of cardiovascular events and death is increased relative to patients without evidence of kidney disease. The new classification system proposed by the National Kidney Foundation as part of the Dialysis Outcomes Quality Initiative (DOQI) process describes the five stages of kidney disease, as well as those complications associated with chronic kidney disease (CKD), in particular cardiovascular risk factors and disease. Patients with kidney disease are deemed to be at highest cardiovascular risk. CVD, defined as the presence of either congestive heart failure (CHF), ischemic heart disease (IHD), or left ventricular hypertrophy (LVH), is prevalent in cohorts with established CKD (8-40%). The prevalence of hypertension, a major risk factor for coronary artery disease (CAD) and LVH is high in patients with CKD (87-90%). At least 35% of patients with CKD have evidence of an ischemic event (myocardial infarction or angina) at the time of presentation to a nephrologist. The prevalence of LVH increases at each stage of CKD, reaching 75% at the time of dialysis initiation, and the modifiable risk factors for LVH include anemia and systolic blood pressure, which are also worse at each stage of kidney disease. Even under the care of nephrologists, a change in cardiac status (worsening of heart failure or anginal symptoms) occurs in 20% of patients. The presence of CVD predicts a faster decline of kidney function and the need for dialysis, after controlling for all other factors including glomerular filtration rate (GFR), age, and the presence of LVH. This article describes the new classification system for staging of CKD, defines and describes CVD in CKD, and reviews the evidence and its limitations with respect to the current understanding of CKD and CVD. Specifically, methodologic issues related to survival and referral bias limit our current understanding of the complex interaction of conventional and nonconventional kidney disease-specific risk factors. We identify the importance of well-conducted studies of patient groups with and without CVD, with and without CKD, in order to better understand the complex physiology so that treatment strategies can be appropriately applied.     

The epidemics of cardiovascular disease in elderly patients with chronic kidney disease – Two facets of the same problem

There is increasing evidence that even mild renal dysfunction is a novel potent cardiovascular risk factor in the general elderly population. With more severe renal impairment, cardiovascular risk increases proportionately. This issue deserves attention, as chronic kidney disease (CKD) is predominantly a disease of the elderly, and the mean age of end-stage renal disease patients entering dialysis is growing constantly. In the dialysis population, when clinically significant cardiovascular disease (CVD) (particularly congestive heart failure) is present, survival is worse. Thus, every effort should be made to identify and treat cardiovascular risk factor in the early stages of CKD. However, elderly renal patients receive less proper cardiovascular therapy compared to non-renal subjects of the same age. This review deals briefly with the most significant data published in the last decade on CVD in elderly with CKD.     

The risk of cardiovascular disease in adults who have had childhood nephrotic syndrome

While increased risk of cardiovascular disease (CVD) in patients with hyperlipidemia, chronic kidney disease (CKD), or end-stage renal disease (ESRD) is well documented, transient hyperlipidemia or intermittent renal disease as a consequence of relapsing nephrotic syndrome (NS) has not been studied. To investigate this enigma, 62 patients, between 25 and 53 years of age, who had steroid-responsive/dependent NS during childhood, were identified from the records of the Division of Pediatric Nephrology at Yale School of Medicine. Forty patients were located and contacted to ascertain symptoms or occurrences of CVD via a telephone interview. At the time of follow-up, 23–46 years after cessation of NS, none of these patients had ESRD or CKD. Three patients had experienced a myocardial infarction (MI): a 32-year-old male with a family history of CVD; a 41-year-old male with a history of heavy smoking, hypertension, diabetes mellitus, and elevated cholesterol; a 31-year-old male after a cocaine overdose. The occurrence of events (8%) and mortality from CVD (none) in this cohort of patients is comparable to patients of a similar age in the general population and is lower than that of patients of the same age who are on dialysis. The data suggest that relapsing NS during childhood does not place patients at increased risk for CVD mortality or morbidity compared with the general population. Consequently, it would appear that factors related to persistent proteinuria or renal insufficiency, rather than transient proteinuria and renal disease, contribute to the CVD documented in patients with CKD or ESRD.     

Hypertension and kidney protection in the elderly: what is the evidence in 2007?

Hypertension and diabetes mellitus are the two most widely recognized risk factors for cardiovascular disease (CVD), chronic kidney disease (CKD), and end-stage renal disease (ESRD) requiring dialysis/transplantation; both become increasingly important as one ages. Common pathways and mechanisms are involved in the development of renal vascular lesions in both conditions, and effective treatments for each are now available to reduce morbidity, mortality and progression of organ damage. Although this review will focus primarily on the ability to protect the kidney and vasculature elsewhere by lowering blood pressure in the elderly, other approaches, specifically dietary restriction of protein, strict control of diabetes mellitus, and the management of the different dyslipidemias, must be used in conjunction with the antihypertensive agents to obtain optimum protection.     

Mechanism by which chronic kidney disease causes cardiovascular disease and the measures to manage this phenomenon

In Japan, the number of chronic kidney disease (CKD) patients is thought to be 13,300,000, next in size after those with hypertension and diabetes. Although the number of patients with CKD seems large, it does not mean that all these patients require special treatment. Among them, nephrologists should pay special attention to patients with glomerular filtration rate below 50 mL/min/1.73 m² and progressive deterioration of renal function. Treatment of these CKD patients by a limited number of specialists is simply impossible; hence, it is essential to request treatment from physicians who are involved in general internal medicine and primary care. It is well known that not only does CKD cause end-stage renal failure, it also causes the onset of cardiovascular diseases (CVD) such as cardiac infarction and cerebral stroke; however, the question is how much significance does CKD have as a risk factor for CVD. It is understandable that hypertension and CVD are often complications of CKD; however, in addition to what is conventionally mentioned, there are three or four mechanisms that we would like to emphasize, and discuss herein. Among them, we would like to stress the role of klotho genes with special reference to the generation of CVD in CKD patients. When patients develop CKD, it is therefore necessary to remove as far as possible any factors that could represent a risk for CVD. Moreover, by taking appropriate measures against clinical conditions that often complicate CKD, such as hypertension, renal anemia, hyperuricemia, and hyperlipidaemia, the development of CVD can be prevented.     

The evaluation of underlying cardiovascular disease among patients with end-stage renal disease

Although coronary artery disease (CAD) is highly prevalent among patients with chronic kidney disease (CKD), interventions proven to reduce cardiovascular disease (CVD) mortality are underutilized in this population of patients. Given the burden of CVD in this population, knowledge of specific diagnostic tests for detection and evaluation of CAD in patients with end-stage renal disease (ESRD) and their correlation with outcomes is imperative for the practicing nephrologist. Studies that examine the use of exercise electrocardiography testing, pharmacologic stress imaging, single-photon emission computed tomographic myocardial perfusion imaging, electron beam computed tomography, and dobutamine stress echocardiography among patients with ESRD are detailed with recommendations for the noninvasive evaluation of CAD in this population.     

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.     

Kidney Transplantation Halts Cardiovascular Disease Progression in Patients with End-Stage Renal Disease

Morbidity and mortality from cardiovascular disease have a devastating impact on patients with chronic kidney disease (CKD) and end-stage renal disease. Renal function decline in itself is thought to be a strong risk factor for cardiovascular disease (CVD). In this study, we investigated the hypothesis that the elevated CV mortality in kidney transplant patients is due to the preexisting CVD burden and that restoring renal function by a kidney transplant might over time lower the risk for CVD. We analyzed 60,141 first-kidney-transplant patients registered in the USRDS from 1995 to 2000 for the primary endpoint of cardiac death by transplant vintage and compared these rates to all 66813 adult kidney wait listed patients by wait listing vintage, covering the same time period. The CVD rates peaked during the first 3 months following transplantation and decreased subsequently by transplant vintage when censoring for transplant loss. This trend could be shown in living and deceased donor transplants and even in patients with end-stage renal disease secondary to diabetes. In contrast, the CVD rates on the transplant waiting list increased sharply and progressively by wait listing vintage. Despite the many mechanisms that may be in play, the enduring theme underlying rapid progression of atherosclerosis and cardiovascular disease in renal failure is the loss of renal function. The data presented in this paper thus suggest that the development or progression of these lesions could be ameliorated by restoring renal function with a transplant.     

Understanding the role of genetic polymorphisms in chronic kidney disease

Although no valid studies clearly indicate increasing or decreasing numbers of incident paediatric patients, the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) is growing worldwide. This is mainly due to improved access to renal replacement therapy (RRT), increased survival after dialysis and kidney transplantation and an increase in diagnosis and referral of these patients. Although the increase in CKD prevalence is mainly caused by environmental factors, genetic factors may also influence the incidence and/or the progression of CKD and its complications. As CKD patients might be more sensitive to genetic effects due to the exposure to a uraemic milieu, this makes studies of genetic factors especially interesting in this population. The goal of identifying genetic factors that contribute to the outcome of CKD is to gain further understanding of the disease pathogenesis and underlying causes and, possibly, to use this knowledge to predict disease or its complications and to identify a risk population. Therefore, genetic screening of paediatric CKD patients may enhance the impact of preventive measures that could have a positive effect on outcome. Furthermore, by identifying patients’ genetic backgrounds, it is possible that a more individualised therapy could be designed.     

慢性肾脏病住院患者白蛋白尿与心血管疾病相关性研究

目的：研究慢性肾脏病（CKD）住院患者白蛋白尿与心血管疾病（CVD）的相关性,探讨白蛋白尿对非糖尿病CKD患者CVD的预测价值。方法：回顾性分析1245例非糖尿病CKD患者的一般情况、生化指标、心电图、胸部X线、心超及CVD的危险因素。结果：（1）1245例患者中CKD1、2、3、4、5期分别为304例（24.4%）、281例（22.6%）、372例（29.9%）、157例（12.6%）、131例（10.5%）;CKD1～5各期有蛋白尿者分别为208例（68.8%）、194例（69%）、269例（72.3%）、117例（74.5%）、106例（80.9%）。（2）与CKD1期患者相比,CKD2～5期患者年龄、SBP、DBP、Scr、UA明显升高,eGFR、Hb、Alb明显降低（P〈0.05）;CKD3期患者TG、LDL升高,HDL降低（P〈0.05）;CKD4、5期患者TC、LDL、HDL降低;TG升高（P〈0.05）。（3）与CKD同期非白蛋白尿组相比,白蛋白尿组CKD1～5期患者Scr、UA明显升高,Alb明显降低（P〈0.05）;CKD2～5期患者SBP、DBP明显升高,eGFR、Hb明显降低（P〈0.05）;CKD4、5期患者TC、HDL降低,TG、LDL升高（P〈0.05）。（4）CKD患者CVD发病率从CKD1～CKD5期逐步升高（P〈0.05）,白蛋白尿患者CVD发病率以及胸部X片、心电图、心超异常阳性率升高更加明显（P〈0.05）。（5）Logistic回归分析显示CVD与年龄、SBP、UA、TG、白蛋白尿呈现正相关,与GFR、Hb呈现负相关（P〈0.05）。结论：非糖尿病CKD患者CVD发病率随CKD进展而增高,与白蛋白尿密切相关,白蛋白尿是CVD患者心血管疾病危险标志。