Chronic kidney disease in the general population

End-stage kidney disease (ESKD), defined as the need for dialysis, receipt of a transplant, or death from chronic kidney failure, generally affects fewer than 1% of the population. However ESKD is the end result of chronic kidney disease (CKD), a widely prevalent but often silent condition with elevated risks of cardiovascular morbidity and mortality and a range of metabolic complications. A recently devised classification of CKD has facilitated prevalence estimates that reveal an "iceberg" of CKD in the community, of which dialysis and transplant patients are the tip. Hypertension, smoking, hypercholesterolemia, and obesity, currently among the World Health Organization's (WHO's) top 10 global health risks, are strongly associated with CKD. The factors, together with increasing diabetes prevalence and an aging population, will result in significant global increases in CKD and ESKD patients. Treatments now available effectively reduce the rate of progression of CKD and the extent of comorbid conditions and complications. The challenges are (1) to intervene effectively to reduce the excess burden of cardiovascular morbidity and mortality associated with CKD, (2) to identify those at greatest risk for ESKD and intervene effectively to prevent progression of early CKD, and (3) to ultimately introduce cost-effective primary prevention to reduce the overall burden of CKD. The vast majority of the global CKD burden will be in developing countries, and policy responses must be both practical and sustainable in these settings.     

CKD-MBD: impact on management of kidney disease

Chronic kidney disease (CKD) causes various bone mineral disorders, which have recently been named CKD mineral and bone disorder (CKD-MBD). CKD-MBD is associated with extremely high cardiovascular disease (CVD) morbidity and mortality in the endstage kidney disease (ESKD) population. Thus, optimal management of CKD-MBD would lead to a reduction in cardiovascular morbidity and mortality in uremic patients. In addition, it has been suggested that the treatment of CKD-MBD has some favorable effects on the progression of CKD. Recently, novel therapeutic agents, including active vitamin D analogues, noncalcium-containing phosphate binders, and cinacalcet, have become clinically available. In this article, we review novel therapeutic strategies for CKD-MBD.     

Cardiovascular complications of pediatric chronic kidney disease

Cardiovascular disease (CVD) mortality is a leading cause of death in adult chronic kidney disease (CKD), with exceptionally high rates in young adults, according to the Task Force on Cardiovascular Disease. Recent data indicate that cardiovascular complications are already present in children with CKD. This review summarizes the current literature on cardiac risk factors, mortality and morbidity in children with CKD.     

Adenine‐induced chronic kidney disease in rats

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

Chronic kidney disease: a new look at pathogenetic mechanisms and treatment options

The concept of renoprotection has evolved significantly, driven by improved understanding of the pathophysiology of chronic kidney disease (CKD) and the advent of novel treatment options. Glomerular hyperfiltration, hypertension and proteinuria represent key mediators of CKD progression. It is increasingly recognized that proteinuria may actually be pathological and etiological in CKD progression and not just symptomatic. It initiates a sequence of events involving activation of proinflammatory and profibrotic signaling pathways in proximal tubular epithelial cells with transmission of the disease to the tubulointerstitium and progression to end-stage kidney disease (ESKD). Although the etiology and epidemiology of pediatric CKD differs to that in adults, studies in the various animal models of kidney disease, from obstructive uropathy to glomerulonephritis, have revealed that many common proinflammatory and profibrotic pathways are induced in progressive proteinuric CKD, irrespective of the primary disease. This pathomechanistic overlap therefore translates into the potential for common treatment targets for a wide spectrum of kidney diseases. In this review we therefore discuss the experimental and clinical evidence for an array of prospective future drug treatments of CKD progression. While conceptually promising, clear definitive evidence beyond preclinical data does not exist for many of these treatments, and others are limited by serious adverse effects. More studies are needed before general recommendations can be given.     

Inflammation and cachexia in chronic kidney disease

Chronic inflammation is associated with cachexia and increased mortality risk in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Inflammation suppresses appetite and causes the loss of protein stores. In CKD patients, increased serum levels of pro-inflammatory cytokines may be caused by reduced renal function, volume overload, oxidative or carbonyl stress, decreased levels of antioxidants, increased susceptibility to infection in uremia, and the presence of comorbid conditions. Cachexia is brought about by the synergistic combination of a dramatic decrease in appetite and an increase in the catabolism of fat and lean body mass. Pro-inflammatory cytokines act on the central nervous system to alter appetite and energy metabolism and to provide a signal—through the nuclear factor-κB and ATP-ubiquitin-dependent proteolytic pathways—that causes muscle wasting. Further research into the molecular pathways leading to inflammation and cachexia may lead to novel therapeutic therapies for this devastating and potentially fatal complication of chronic disease.     

Chronic kidney disease and bone fracture: a growing concern

Susceptibility to fracture is increased across the spectrum of chronic kidney disease (CKD). Moreover, fracture in patients with end-stage kidney disease (ESKD) results in significant excess mortality. The incidence and prevalence of CKD and ESKD are predicted to increase markedly over the coming decades in conjunction with the aging of the population. Given the high prevalence of both osteoporosis and CKD in older adults, it is of the utmost public health relevance to be able to assess fracture risk in this population. Dual-energy X-ray absorptiometry (DXA), which provides an areal measurement of bone mineral density (aBMD), is the clinical standard to predict fracture in individuals with postmenopausal or age-related osteoporosis. Unfortunately, DXA does not discriminate fracture status in patients with ESKD. This may be, in part, because excess parathyroid hormone (PTH) secretion may accompany declining kidney function. Chronic exposure to high PTH levels preferentially causes cortical bone loss, which may be partially offset by periosteal expansion. DXA can neither reliably detect changes in bone volume nor distinguish between trabecular and cortical bone. In addition, DXA measurements may be low, normal, or high in each of the major forms of renal osteodystrophy (ROD). Moreover, postmenopausal or age-related osteoporosis may also affect patients with CKD and ESKD. Currently, transiliac crest bone biopsy is the gold standard to diagnose ROD and osteoporosis in patients with significant kidney dysfunction. However, bone biopsy is an invasive procedure that requires time-consuming analyses. Therefore, there is great interest in developing non-invasive high-resolution imaging techniques that can improve fracture risk prediction for patients with CKD. In this paper, we review studies of fracture risk in the setting of ESKD and CKD, the pathophysiology of increased fracture risk in patients with kidney dysfunction, the utility of various imaging modalities in predicting fracture across the spectrum of CKD, and studies evaluating the use of bisphosphonates in patients with CKD.     

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.     

Impact of inflammation and oxidative stress on vascular calcifications in chronic kidney disease

Vascular and/or valvular calcifications in patients with chronic kidney disease (CKD) appear to indicate a poor prognosis in terms of overall survival and cardiovascular morbidity and mortality. Inflammation and oxidative stress represent new features of the arterial and/or valvular calcification process. However, only limited observational and epidemiological data are available in these areas. Therefore, the link between inflammation, oxidation and vascular and/or valvular calcifications deserves careful consideration in CKD patients, since they may become targets for the development of new therapeutic strategies.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Effect of anaemia on mortality, cardiovascular hospitalizations and end-stage renal disease among patients with chronic kidney disease

Objective:   To determine whether an independent association exists between anaemia and chronic kidney disease (CKD) outcomes in a quasi-incidence cohort when patients' most recent laboratory values are considered.
Methods:   We conducted a dynamic, retrospective cohort study among patients with incident CKD in a large health maintenance organization administrative data set. CKD was defined by two estimated glomerular filtration rates (eGFR). We measured the absolute rates for all-cause mortality, cardiovascular hospitalizations and end-stage renal disease.
Results:   Our completed cases Cox regression model followed 5885 patients with both CKD and haemoglobin measures. For patients with the most severe anaemia (haemoglobin <10.5 g/dL), we estimated an increased rate of mortality (hazard ratio (HR) = 5.27, CI 4.37–6.35), cardiovascular hospitalizations (HR = 2.18, CI 1.76–2.70) and end-stage renal disease (HR = 5.46, CI 3.38–8.82) when compared with patients who were not anaemic; the HR reflect time-varying haemoglobins and eGFR.
Conclusion:   Anaemia is a predictor of excess mortality, excess cardiovascular hospitalizations and excess end-stage renal disease even when the progression of CKD is considered by controlling for time-varying eGFR values.     

慢性肾脏病患者降压药物的合理选用

高血压作为心血管疾病传统的危险因素,在慢性肾脏病(CKD)的发展中起到了重要作用。它既是导致CKD的主要病因,也是CKD最常见的并发症。控制CKD患者血压达标不仅有利于延缓CKD进展,还可降低心血管事件发生。但CKD患者病因复杂、疾病阶段不一,降压药物的合理选用极为重要。     

Epidemiology and prevention of cardiovascular complication in chronic kidney disease patients

The risk for cardiovascular disease is significantly higher among patients with chronic kidney disease (CKD) than among the general population, considering that cardiovascular disease is the prominent cause of both morbidity and mortality in dialysis patients. This is explained mainly by the considerable prevalence of cardiovascular risk factors among CKD patients since the earliest stages of renal impairment, which include not only the so-called traditional risk factors, but also a number of additional risk factors that are specific to CKD and to the dialytic treatment itself. Considering the multiplicity of cardiovascular risk factors operating in CKD patients, as well as the crucial impact of their cardiovascular condition on long-term outcome, it is mandatory that all the available interventions aimed at the correction of all the modifiable risk factors for cardiovascular disease are performed as early as possible in the progression of the disease. In particular, the results of several controlled clinical trials have shown that a timely correction of anemia and of calcium-phosphate disorders leads to a significant improvement in the cardiovascular conditions of CKD patients. Evidence also is growing regarding the benefits of intervention of newly recognized risk factors for cardiovascular disease such as inflammation and oxidant stress.     

Energy homeostasis and cachexia in chronic kidney disease

Loss of protein stores, presenting as clinical wasting, is reported to have a prevalence of 30–60% and is an important risk factor for mortality in chronic kidney disease (CKD) patients. There is debate as to whether the clinical wasting in CKD patients represents malnutrition or cachexia. Malnutrition results from inadequate intake of nutrients, despite a good appetite, and manifests as weight loss associated with adaptive metabolic responses such as decreased basic metabolic rate and preservation of lean body mass at the expense of fat mass. Furthermore, the abnormalities in malnutrition can usually be overcome simply by supplying more food or altering the composition of the diet. In contrast, cachexia is characterized by maladaptive responses such as anorexia, elevated basic metabolic rate, wasting of lean body tissue, and underutilization of fat tissue for energy. Diet supplementation and intradialytic parenteral nutrition have not been successful in reversing cachexia in CKD. The etiology of cachexia in CKD is complex and multifactorial. Two major factors causing muscle wasting in uremia are acidosis and decreased insulin responses. Inflammation secondary to cytokines may also play a significant role. The hypoalbuminemia of CKD patients is principally associated with inflammation and not changes in food intake. There is also recent evidence that hypothalamic neuropeptides may be important in the downstream signaling of cytokines in the pathogenesis of cachexia in CKD. Elevated circulating levels of cytokines, such as leptin, may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system. Further research into the molecular pathways leading to cachexia may lead to novel therapeutic therapy for this devastating and potentially fatal complication of CKD.Supported by grants from the National Institute of Health R01 DK 50780 and K24 DK59574 to RHM.     

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.     

Diabetic patients with chronic kidney disease: Non-invasive assessment of cardiovascular risk

The prevalence and burden of diabetes mellitus and chronic kidney disease on global health and socioeconomic development is already heavy and still rising. Diabetes mellitus by itself is linked to adverse cardiovascular events, and the presence of concomitant chronic kidney disease further amplifies cardiovascular risk. The culmination of traditional (male gender, smoking, advanced age, obesity, arterial hypertension and dyslipidemia) and non-traditional risk factors (anemia, inflammation, proteinuria, volume overload, mineral metabolism abnormalities, oxidative stress, etc.) contributes to advanced atherosclerosis and increased cardiovascular risk. To decrease the morbidity and mortality of these patients due to cardiovascular causes, timely and efficient cardiovascular risk assessment is of huge importance. Cardiovascular risk assessment can be based on laboratory parameters, imaging techniques, arterial stiffness parameters, ankle-brachial index and 24 h blood pressure measurements. Newer methods include epigenetic markers, soluble adhesion molecules, cytokines and markers of oxidative stress. In this review, the authors present several non-invasive methods of cardiovascular risk assessment in patients with diabetes mellitus and chronic kidney disease.     

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

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

慢性肾脏病继发性甲状旁腺功能亢进的治疗进展

继发性甲状旁腺功能亢进症(SHPT)是慢性肾脏病（CKD）患者最常见的并发症之一,是肾性骨病的重要原因,也是加速CKD病程进展和增加病死率的重要合并症。严重的SHPT是临床医生面临的难题,也是近年来研究的热点。本文综述了CKD导致SHPT的治疗新进展。     

Diabetic nephropathy and inflammation

Diabetic nephropathy(DN) is the leading cause of end-stage renal failure worldwide. Besides, diabetic nephropathy is associated with cardiovascular disease, and increases mortality of diabetic patients. Several factors are involved in the pathophysiology of DN, including metabolic and hemodynamic alterations, oxidative stress, and activation of the renin-angiotensin system. In recent years, new pathways involved in the development and progression of diabetic kidney disease have been elucidated; accumulated data have emphasized the critical role of inflammation in the pathogenesis of diabetic nephropathy. Expression of cell adhesion molecules, growth factors, chemokines and pro-inflammatory cytokines are increased in the renal tissues of diabetic patients, and serum and urinary levels of cytokines and cell adhesion molecules, correlated with albuminuria. In this paper we review the role of inflammation in the development of diabetic nephropathy, discussing some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines, and take part in other mediators of inflammation, as adhesion molecules.     

Bariatric surgery for morbid obesity: risks and benefits in chronic kidney disease patients

Obesity is one of the most preventable causes of morbidity and mortality of the 21st century. Chronic kidney disease (CKD) has been a largely overlooked consequence of obesity; however, accumulating evidence elucidates the association. Obesity is at the core, promoting a cascade of secondary pathologies including diabetes, dyslipidemia, inflammation, hypertension, and the metabolic syndrome; these comorbidities constitute great risk for CKD. With the diagnosis of CKD, there is an increased threat of cardiovascular disease and the attendant increase in morbidity and mortality rates. Substantial weight loss in the obese population can be effectively achieved and maintained through bariatric surgery, which confers major health benefits by producing resolution or improvement of obesity-related comorbidities. This surgical procedure presents an early hazard of acute on chronic kidney failure, which is offset by a potential improvement in the risk of CKD progression with anticipated improvement in hypertension, diabetes, and CKD risk factors. Future research is needed to describe the clinical course and risks and benefits of bariatric surgery in the CKD population.