Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia/malnutrition, atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the thiobarbituric acid reactive system, asymmetric dimethyl arginine, iron, fetuin-A, and cytokines. Inflammation contributes to the progression of CKD by inducing the release of cytokines and the increased production and activity of adhesion molecules, which together contribute to T cell adhesion and migration into the interstitium, subsequently attracting pro-fibrotic factors. Inflammation in CKD also causes mortality from cardiovascular disease by contributing to the development of vascular calcifications and endothelial dysfunction. Similar to the situation in adults, cardiovascular disease in pediatric CKD is linked to inflammation: abnormal left ventricular wall geometry is positively associated with markers of inflammation. This review focuses on traditional and novel mediators of inflammation in CKD and ESKD, and the deleterious effect inflammation has on the progression of renal and cardiovascular disease.     

Dyslipidemia in children with CKD: should we treat with statins?

Dyslipidemia has been shown to be a risk factor for increased cardiovascular morbidity and mortality in adult patients with chronic kidney disease (CKD) stages 2–4. In patients on dialysis, a paradoxical correlation has been found between low cholesterol values and increased mortality rates. No data exist in children. Treatment with statins has been convincingly shown to both reduce blood lipid levels and mortality rates from cardiovascular disease in adult patients in CKD stages 2–4. There is no strong literature support for treating patients on dialysis or after having had a transplant. Data on benefits of statin therapy do not exist in children with CKD. There are many differences between adult and paediatric kidney patients, and I caution on extrapolating the findings in adult patients to children. Studies are thus needed to evaluate the benefits and potential problems of statin treatment in children with CKD.     

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.     

Can the renal transplant patient be really considered as a patient with chronic renal insufficiency?

To assess if the renal transplant patient can really be considered as a patient with chronic renal insufficiency, disease progression and outcomes were compared in both groups. At the same stage of chronic kidney disease (CKD), the deterioration of renal function was slower and graft survival was longer in renal transplant patients. Despite slower rates of kidney function decline, overall patient survival was similar between the two groups. Interestingly, stage 3 adjusted mortality rates were greater in kidney transplant recipients, most likely because of the disease burden (history of end-stage renal disease in renal transplant recipients) and immunosuppression. The three major causes of mortality in transplant patients (cardiovascular, infectious and malignant) may present with specific characteristics in transplant patients. Renal transplantation is thus a specific form of CKD, controlled by 3 factors, a single kidney, immunosuppression and the burden of the disease. The general application of the KDOQI and KDIGO guidelines to kidney transplant recipients requires therefore further evaluation.     

Should we quantify insulin resistance in patients with renal disease? (Review Article)

Cardiovascular disease is a major cause of morbidity and mortality in dialysis patients. Vascular disease develops before the initiation of dialysis, and it is now recognized that chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Death from cardiovascular disease is a more common endpoint of CKD than progression to dialysis. There are multiple mechanisms that contribute to the increased vascular risk of CKD, one of which is the presence of insulin resistance (IR). CKD is characterised by many features of the metabolic syndrome, and features of IR are also observed in dialysis and transplant patients. IR may be quantified by several different methods. One such method is homeostatic model assessment (HOMA) technique, which derives a measurement of IR from fasting plasma glucose and insulin concentrations. The HOMA index has been demonstrated to be an independent predictor of survival in dialysis patients. CKD is characterised by a chronic inflammatory response and abnormalities in the production and regulation of adipose tissue derived proteins, which may contribute to the development of IR. There are a range of interventions including diet and exercise programmes or medications that may influence IR; however, the impact of these interventions in the context of CKD has not been systematically evaluated.     

The contribution of chronic kidney disease to the global burden of major noncommunicable diseases

Noncommunicable diseases (NCDs) are the most common causes of premature death and morbidity and have a major impact on health-care costs, productivity, and growth. Cardiovascular disease, cancer, diabetes, and chronic respiratory disease have been prioritized in the Global NCD Action Plan endorsed by the World Health Assembly, because they share behavioral risk factors amenable to public-health action and represent a major portion of the global NCD burden. Chronic kidney disease (CKD) is a key determinant of the poor health outcomes of major NCDs. CKD is associated with an eight- to tenfold increase in cardiovascular mortality and is a risk multiplier in patients with diabetes and hypertension. Milder CKD (often due to diabetes and hypertension) affects 5-7% of the world population and is more common in developing countries and disadvantaged and minority populations. Early detection and treatment of CKD using readily available, inexpensive therapies can slow or prevent progression to end-stage renal disease (ESRD). Interventions targeting CKD, particularly to reduce urine protein excretion, are efficacious, cost-effective methods of improving cardiovascular and renal outcomes, especially when applied to high-risk groups. Integration of these approaches within NCD programs could minimize the need for renal replacement therapy. Early detection and treatment of CKD can be implemented at minimal cost and will reduce the burden of ESRD, improve outcomes of diabetes and cardiovascular disease (including hypertension), and substantially reduce morbidity and mortality from NCDs. Prevention of CKD should be considered in planning and implementation of national NCD policy in the developed and developing world.     

Vitamin D treatment in chronic kidney disease

Activated vitamin D continues to be the major treatment for suppressing parathyroid hormone (PTH) levels in dialysis patients who have secondary hyperparathyroidism. Active vitamin D compounds are distinguished by their ability to bind with high affinity to vitamin D receptors (VDRs) not only in the parathyroid glands, but in cells throughout the body. Because of recent data showing that pulsatile, intravenous vitamin D treatment (calcitriol or paricalcitol) confers a survival advantage in the dialysis population, there is new interest in understanding the systemic effects of VDR activation, particularly in the predialysis stages of chronic kidney disease (CKD), where high mortality rates from cardiovascular disease have recently been documented. Previous underutilization of calcitriol treatment to control PTH levels in stages 3 and 4 CKD was often due to concerns about its potential for accelerating the progression of CKD as a consequence of hypercalcemia, hypercalciuria, or hyperphosphatemia. Vitamin D analogs with selective VDR activity (such as paricalcitol) have great potential for preventing parathyroid hyperplasia and bone loss in early CKD without adversely affecting kidney function. Whether they also reduce cardiovascular morbidity and mortality in early CKD, as they appear to do in dialysis patients, remains to be determined.     

Chronic kidney disease progression in kidney transplant recipients: A focus on traditional risk factors

Kidney transplant recipients are a subset of patients with chronic kidney disease (CKD) that remain at high risk for progression to dialysis and mortality. Recent advances in immunosuppression have only partially improved long‐term graft and patient survival. Discovery of new immunosuppressive regimens is a slow and resource‐intensive process. Hence, recognition and management of modifiable allogeneic and non‐allogeneic risk factors for progression to CKD among kidney transplant recipients is of major interest for improving long‐term outcomes. Graft survival is mainly determined by the quality of the allograft and by the patient’s alloimmune response, which is influenced by human leukocyte antigen matching and the presence of donor‐specific antibodies. Alloimmune responses manifest as acute and chronic forms of cell‐ and antibody‐mediated rejection, which can be worsened by patient non‐adherence or under‐immunosuppression. However, donor and patient ages, glomerular disease recurrence, time on dialysis, pre‐existing cardiovascular burden, medication side‐effects and traditional risk factors, such as hypertension, proteinuria, anaemia, dyslipidaemia, diabetes and bone mineral disorder, which can ultimately lead to severe endothelial derangement, also contribute to graft loss and mortality. These traditional risk factors, common to pre‐dialysis patients, often are considered of secondary importance when compared to alloimmunity and immunosuppression concerns. In this review article, we focus on the epidemiological, pathophysiological and therapeutic features of non‐allogeneic traditional risk factors for CKD. We also discuss the benefit of adopting a multidisciplinary approach to pursue the same therapeutic targets recommended for pre‐dialysis patients.     

Cigarette Use and Cardiovascular Risk in Chronic Kidney Disease: An Unappreciated Modifiable Lifestyle Risk Factor

Tobacco use is a major modifiable cardiovascular risk factor in the general population and contributes to excess cardiovascular risk. Emerging evidence from large‐scale observational studies suggests that continued tobacco use is also an independent cardiovascular risk factor among patients with chronic kidney disease (CKD). The benefits of smoking cessation programs on improving the heath status of patients and reducing mortality are unequivocal in the general population. Despite this, there has been little effort in pursuing tobacco cessation programs in dialysis cohorts or those with lesser degrees of kidney impairment. Most of our attention to date has focused on the development of “kidney‐specific” interventions that reduce rates of renal disease progression and improve dialysis outcomes. The purpose of this current review is to describe the epidemiology of tobacco use among patients with CKD, draw attention to its negative impact on cardiovascular morbidity and mortality, and finally highlight potential strategies for successful intervention. We hope that this study heightens the importance of tobacco use in CKD, stimulates renewed interest in the barriers and challenges that exist in achieving smoking cessation, and endorses the efficacy of intervention strategies and the immeasurable benefits of quitting on cardiovascular and noncardiovascular outcomes.     

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.     

A Rational Guide to Reducing Fracture Risk in Dialysis Patients

Extrapolation of evidence-based management of disorders in the general population to patients with chronic kidney disease (CKD) is not always appropriate, and the prevention of bone fracture and reduction of fracture risk in CKD stages 3–5 is one example. Compared to the general population, fracture risk is greater in CKD patients, especially those on dialysis (CKD-5D). Fractures in CKD-5D are associated with a marked increase in morbidity and mortality and with an aging dialysis population the burden of disease caused by fracture is likely to increase. Patients with CKD-5D have distinct risks for fracture, as well as sharing risks identified in the general population. The development of the CKD mineral and bone disorder constitutes a significant cause for these differences. Literature addressing the determination of fracture risk and the efficacy of treatments to reduce fracture in patients on dialysis is limited. While some tools used for the diagnosis and monitoring of osteoporosis are applicable to patients on dialysis, bone mineral density measurement by dual-energy X-ray absorptiometry is generally not helpful and therapeutic interventions that reduce fracture risk in the nonuremic population cannot be generalized to patients on dialysis. This review outlines available evidence on the incidence, risk factors, and management of fractures in CKD-5D with recommendations for strategies to reduce fracture risk.     

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.     

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.     

Outcome of dialysis in children with human immunodeficiency virus infection

Human immunodeficiency virus (HIV) infection accounts for an unknown percentage of children with end-stage kidney disease (ESKD). Our objective was to compare the outcome of renal replacement therapy (RRT) in subjects with ESKD due to HIV and other diagnoses and to examine the prevalence of ESKD due to HIV. We analyzed Kt/V, morbidity, mortality, echocardiography, nutritional, and transplant status in 12 dialysis patients with HIV and 32 without HIV followed at our center between February 2002 and February 2007. Body mass index (BMI) was lower and Kt/V higher in HIV than in non-HIV patients. Shortening fraction was significantly lower in HIV patients. There were six deaths in the HIV group and one in the non-HIV group over the study period. Hemodialysis (HD) is the prevalent mode of RRT in HIV in urban settings, and its adequacy as measured by Kt/V was higher in HIV patients than in non-HIV patients. Decreased BMI and cardiovascular disease may be associated with increased mortality in children with HIV on RRT.     

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.     

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.     

Renal anaemia: recent developments, innovative approaches and future directions for improved management

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers.     

Chronic kidney disease after liver,cardiac, lung,heart–lung,and hematopoietic stem cell transplant

Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease.     

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

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