Cachexia In Chronic Kidney Disease Research Articles

Body mass index and weight loss for diagnosing Asian cachexia in chronic kidney disease

Body mass index and weight loss for diagnosing Asian cachexia in chronic kidney disease

Kidney function in cachexia and sarcopenia: Facts and numbers.

Cachexia, in the form of unintentional weight loss >5% in 12months or less, and secondary sarcopenia in the form of muscle wasting are serious conditions that affect clinical outcomes. A chronic disease state such as chronic kidney disease (CKD) often contributes to these wasting disorders. The purpose of this review is to summarize the prevalence of cachexia and sarcopenia, their relationship with kidney function, and indicators for evaluating kidney function in patients with CKD. It is estimated that approximately half of all persons with CKD will develop cachexia with an estimated annual mortality rate of 20%, but few studies have been conducted on cachexia in CKD. Hence, the true prevalence of cachexia in CKD and its effects on kidney function and patient outcomes remain unclear. Some studies have highlighted the concept of protein-energy wasting (PEW) which usually include sarcopenia and cachexia. Several studies have examined kidney function and CKD progression in patients with sarcopenia. Most studies use serum creatinine levels to estimate kidney function. However, creatinine may be influenced by muscle mass, and creatinine-based glomerular filtration rate may overestimate kidney function in patients with reduced muscle mass or muscle wasting. Cystatin C, which is least affected by muscle mass, has been used in some studies, and creatinine-to-cystatin-C ratio has emerged as an important prognostic marker. A previous study incorporating 428320 participants reported that participants with CKD and sarcopenia had a 33% higher hazard of mortality compared with those without (7% to 66%, P=0.011), and that those with sarcopenia were twice as likely to develop end-stage kidney disease (hazard ratio: 1.98; 1.45 to 2.70, P<0.001). Future studies on cachexia and sarcopenia in patients with CKD are needed to report rigorously defined cachexia concerning kidney function. Moreover, in studies on sarcopenia with CKD, it is desirable to accumulate studies using cystatin C to accurately estimate kidney function.

Using a generic definition of cachexia in patients with kidney disease receiving haemodialysis: a longitudinal (pilot) study.

Research indicates that cachexia is common among persons with chronic illnesses and is associated with increased morbidity and mortality. However, there continues to be an absence of a uniformed disease-specific definition for cachexia in chronic kidney disease (CKD) patient populations. The primary objective was to identify cachexia in patients receiving haemodialysis (HD) using a generic definition and then follow up on these patients for 12 months. This was a longitudinal study of adult chronic HD patients attending two hospital HD units in the UK. Multiple measures relevant to cachexia, including body mass index (BMI), muscle mass [mid-upper arm muscle circumference (MUAMC)], handgrip strength (HGS), fatigue [Functional Assessment of Chronic Illness Therapy (FACIT)], appetite [Functional Assessment of Anorexia/Cachexia Therapy (FAACT)] and biomarkers [C-reactive protein (CRP), serum albumin, haemoglobin and erythropoietin resistance index (ERI)] were recorded. Baseline analysis included group differences analysed using an independent t-test, dichotomized values using the χ2 test and prevalence were reported using the Statistical Package for the Social Sciences 24 (IBM, Armonk, NY, USA). Longitudinal analysis was conducted using repeated measures analysis. A total of 106 patients (30 females and 76 males) were recruited with a mean age of 67.6 years [standard deviation (SD) 13.18] and dialysis vintage of 4.92 years (SD 6.12). At baseline, 17 patients were identified as cachectic, having had reported weight loss (e.g. >5% for >6 months) or BMI <20 kg/m2 and three or more clinical characteristics of cachexia. Seventy patients were available for analysis at 12 months (11 cachectic versus 59 not cachectic). FAACT and urea reduction ratio statistically distinguished cachectic patients (P = 0.001). However, measures of weight, BMI, MUAMC, HGS, CRP, ERI and FACIT tended to worsen in cachectic patients. Globally, cachexia is a severe but frequently underrecognized problem. This is the first study to apply the defined characteristics of cachexia to a representative sample of patients receiving HD. Further, more extensive studies are required to establish a phenotype of cachexia in advanced CKD.

Vitamin D ameliorates adipose browning in chronic kidney disease cachexia

Patients with chronic kidney disease (CKD) are often 25(OH)D3 and 1,25(OH)2D3 insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D3 and 1,25(OH)2D3 (75 μg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D3 and 1,25(OH)2D3 in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.

P0915PROTEIN ENERGY WASTING IS ASSOCIATED WITH A DECLINE IN MUSCLE PROTEIN SYNTHESIS IN CKD PATIENTS

Abstract Background and Aims Skeletal muscle is a highly adaptive tissue, however even small imbalances between protein synthesis and degradation can lead to substantial protein loss. Althought proteolysis plays a major role in the development of cachexia in CKD (chronic kidney disease), the responses of muscle protein metabolism to malnutrition had not been completely elucidated. We evaluated retrospectively the results of kinetic studies of protein turnover estimated by the forearm perfusion method associated with H2phenylalanine kinetic, obtained in CKD patients and controls in the last 25 years. Method We analyzed 59 forearm H2phenylalanine kinetic studies obtained in 14 controls (C) (M 11, F 3) and 45 patients with CKD, of whom 15 (M 10, F 5) were on conservative treatment (CKD stage IV-V), 16 (M 14, F 2) under maintenance hemodialysis (HD), 14 (M 12, F 2) in peritoneal dialysis (DP); all subjects were on non-restricted protein/calorie (0.8-1.1 g/kg and 28-32 kcal/kg, respectively) diets. Ten (M 9, F 1) HD patients had Protein Energy Wasting. Acidosis was corrected in all patients (HCO3 24.2±1.9 mmol/L) and studies were performed in the post-absorptive overnight fasted state at rest. Results Overall, Muscle protein synthesis and degradation were similar (p=NS) in patients and controls. Protein net balance was reduced in patients with PD and those with CKD Stage IV-V (p &amp;lt;0.003 - p &amp;lt;0.014) indicating a reduced catabolic state and nitrogen conservation. However PEW HD patients showed reduced rates of protein synthesis and degradation (p &amp;lt;0.048 and p &amp;lt;0.04 respectively). In addition the efficiency of muscle protein turnover, a parameter expressing muscle's ability to reuse amino acids derived from degradation into protein synthesis, was significantly reduced in HD PEW patients vs. controls (55.5 vs. 61.2 %, p &amp;lt;0.018, respectively) and vs. not malnourished patients in conservative treatment (70.1 % p &amp;lt;0.0025) or in PD (74.6 % p &amp;lt;0.005). Conclusion In CKD patients, in absence of acidosis, muscle is able to increase the efficiency of protein metabolism for the maintenance of nitrogen balance. However, in PEW patients, combined alterations of protein synthesis and degradation proceed together to a reduced efficiency of amino acids recycled into protein synthesis and contribute to maintaining wasting. These data also suggest that calorie/protein requirements of CKD patients with PEW may be higher than currently theorized.

Cachexia in children with chronic kidney disease: challenges in diagnosis and treatment.

Although cachexia is highly prevalent in adult patients with chronic kidney disease (CKD), it is understudied and less well characterized in children. Recent evidence suggests that cachexia is also prevalent in children with CKD but presents challenges in diagnosis and treatment. A study from the CKD in children cohort showed that CKD cachexia or protein-energy wasting, using modified pediatric diagnostic criteria, such as lack of expected weight gain instead of weight loss and BMI for height age, had a prevalence of 7-20%. When growth indices such as height SD score (SDS)/height velocity SDS was included in the criteria, cachexia or PEW correlated with the morbidity outcome of increased hospitalization risk in children with CKD. Conversely, aggressive nutritional supplementation in children with advanced CKD, with nasogastric or gastric tube feeding, led to prevalence of obesity over that of cachexia. Body habitus of underweight and obesity have been shown to be associated with the worst clinical outcomes in both adults and children with CKD. Optimal nutritional therapy remains the mainstay of treatment of cachexia in CKD children with therapeutic goals of maintaining BMI as well as linear growth within the normal range.

Exploiting the therapeutic potential of leptin signaling in cachexia.

The anorexia-cachexia syndrome is a complication of many chronic conditions including cancer, chronic obstructive pulmonary disease, congestive heart failure, and chronic kidney disease (CKD). Leptin levels are significantly elevated in CKD patients and are associated with markers of poor nutritional status as well as mortality and morbidity. This review will focus on the mechanism and exploit the therapeutic potential of leptin signaling in CKD-associated cachexia. Studies in db/db mice show that the lack of leptin receptor is protective against CKD-induced cachexia. Blockade of leptin's downstream mediators, such as melanocortin-4 receptor, attenuated CKD-associated cachexia. Pegylation of leptin antagonists resulted in a potent and effective long-acting reagents suitable for in-vivo studies or therapies. Pegylated leptin antagonist treatment ameliorates CKD-associated cachexia in mice. Leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.

Ghrelin and cachexia in chronic kidney disease

Ghrelin is a growth hormone (GH) secretagogue and a potent orexigenic factor that stimulates feeding by interacting with hypothalamic feeding-regulatory nuclei. Its multifaceted effects are potentially beneficial as a treatment in human disease states. In both adult and pediatric chronic kidney disease (CKD) patients, decreased appetite plays a major role in wasting, which in turn is linked to morbidity and mortality; wasting has also been linked to high levels of leptin and proinflammatory cytokines. The beneficial effects of ghrelin treatment in CKD are potentially mediated by multiple concurrent actions, including the stimulation of appetite-regulating centers, anti-inflammatory effects, and direct kidney effects. Further evaluation of this appetite-regulating hormone in CKD is needed to confirm previous findings and to determine the underlying mechanisms.

Cachexia as a major underestimated and unmet medical need: facts and numbers

Cachexia is a serious, however underestimated and underrecognised medical consequence of malignant cancer, chronic heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, rheumatoid arthritis, Alzheimer's disease, infectious diseases, and many other chronic illnesses. The prevalence of cachexia is high, ranging from 5% to 15% in CHF or COPD to 60% to 80% in advanced cancer. By population prevalence, the most frequent cachexia subtypes are in order: COPD cachexia, cardiac cachexia (in CHF), cancer cachexia, and CKD cachexia. In industrialized countries (North America, Europe, Japan), the overall prevalence of cachexia (due to any disease) is growing and currently about 1%, i.e., about nine million patients. The relative prevalence of cachexia is somewhat less in Asia, but is a growing problem there as well. In absolute terms, cachexia is, in Asia (due to the larger population), as least as big a problem as in the Western world. Cachexia is also a big medical problem in South America and Africa, but data are scarce. A consensus statement recently proposed to diagnose cachexia in chronic diseases when there is weight loss exceeding 5% within the previous 3–12 months combined with symptoms characteristic for cachexia (e.g., fatigue), loss of skeletal muscle and biochemical abnormalities (e.g., anemia or inflammation). Treatment approaches using anabolics, anti-catabolic therapies, appetite stimulants, and nutritional interventions are under development. A more thorough understanding of the pathophysiology of cachexia development and progression is needed that likely will lead to combination therapies being developed. These efforts are greatly needed as presence of cachexia is always associated with high-mortality and poor-symptom status and dismal quality of life. It is thought that in cancer, more than 30% of patients die due to cachexia and more than 50% of patients with cancer die with cachexia being present. In other chronic illnesses, one can estimate that up to 30% of patients die with some degree of cachexia being present. Mortality rates of patients with cachexia range from 10% to 15% per year (COPD), to 20% to 30% per year (CHF, CKD) to 80% in cancer.

Nutritional Considerations in Kidney Disease: Core Curriculum 2010

Nutritional Considerations in Kidney Disease: Core Curriculum 2010

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-kappaB 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.

Therapeutic strategy for cachexia in chronic kidney disease

This review will provide an update on advances in the understanding of the pathophysiology and novel therapeutic approach to cachexia in chronic kidney disease. Recent studies examine the metabolic effects of nutritional supplementation and show short-term salutary effects. Studies on peripheral hormones involved in energy homeostasis and their hypothalamic signaling in the pathophysiology of uremic cachexia have led to potential novel therapeutic strategies. Most of the information on therapeutic strategy for cachexia of chronic kidney disease is currently at the experimental level and awaits confirmation by clinical trials. The few available clinical studies are preliminary and have the limitation of not having a randomized placebo-controlled group. Further long-term well designed studies to assess the clinical applicability as well as side-effects are needed before these therapeutic strategies can be recommended for treatment of cachexia in chronic kidney disease.

Nutrition Assessment and Hormonal Influences on Body Composition in Children with Chronic Kidney Disease

Malnutrition is a serious complication of chronic kidney disease (CKD) in the pediatric population. Management of the nutritional status of children presents the challenge of ensuring sufficient energy to promote linear growth, development of brain and organs, and maintenance of appropriate fat and muscle stores, while preventing excess protein intake and controlling electrolytes. Aggressive nutrition intervention in the early stages of CKD may be critical in the prevention of more serious complications further in the disease process. Nutrition assessment involves analysis of dietary intake, anthropometric parameters, and laboratory data. Currently, no guidelines are available for nutritional management of pediatric patients with CKD before the onset of dialysis. The content and algorithms in this article are intended to serve as a guide in the management of the nutritional status of children with CKD. Although adequate calorie and protein intake is critical in prevention of malnutrition, it is only part of a complex mechanism in the development of cachexia in CKD. Research suggests that the effects of inflammatory cytokines and hormones such as leptin and ghrelin play a role in the development of malnutrition in CKD. As a more thorough understanding of this mechanism emerges, new treatments aimed at inhibiting cachexia can be developed.

Cachexia in chronic kidney disease: role of inflammation and neuropeptide signaling

This review will update clinicians and basic scientists who are interested in the clinical relevance and molecular mechanism of uremic cachexia. Recent studies that examine the role of cytokines and hypothalamic neuropeptides are emphasized. A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate. Proinflammatory cytokines also activate the transcription factor nuclear factor-kappaB, resulting in decreased protein synthesis, and activate the ubiquitin-mediated proteolytic system, which is the major system involved in increased protein degradation. This review highlights the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and the potential of peripheral administration of melanocortin-4 receptor antagonists as a novel therapeutic approach.

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.

Leptin and inflammation-associated cachexia in chronic kidney disease

Leptin is an adipocyte-derived hormone that acts as a major regulator of food intake and energy homeostasis. It circulates both as a free and as a protein-bound entity. Leptin is released into the blood in proportion to the amount of body fat and exerts sustained inhibitory effects on food intake while increasing energy expenditure. The leptin receptor belongs to the class I cytokine receptor superfamily and possesses strong homology to the signal-transducing subunits of the IL-6 receptor. The hypothalamic melanocortin system, and specifically the melanocortin-4 receptor (MC-4R), is critical in mediating leptin's effect on appetite and metabolism. Serum leptin concentrations are elevated in patients with chronic kidney disease (CKD) and correlate with C-reactive protein levels suggesting that inflammation is an important factor that contributes to hyperleptinemia in CKD. Hyperleptinemia may be important in the pathogenesis of inflammation-associated cachexia in CKD. We showed that experimental uremic cachexia was attenuated in db/db mice, a model of leptin receptor deficiency. Nephrectomy in these animals did not result in any change in weight gain, body composition, resting metabolic rate, and efficiency of food consumption. Furthermore, experimental uremic cachexia could be ameliorated by blocking leptin signaling through the hypothalamic MC-4R. MC-4R knockout mice or mice administered the MC-4R and MC-3R antagonist, agouti-related peptide, resisted uremia-induced loss of lean body mass and maintained normal basal metabolic rates. Thus, melanocortin receptor antagonism may provide a novel therapeutic strategy for inflammation-associated cachexia in CKD.

Cachexia in chronic kidney disease: a link to defective central nervous system control of appetite

Anorexia is one of several abnormalities characterizing chronic kidney disease (CKD) that cause cachexia, the loss of muscle and adipose stores. It has been attributed to mechanisms ranging from accumulation of toxic "middle molecules" to psychological problems. In this issue of the JCI, Cheung and coworkers used elegant techniques to demonstrate that CKD-associated anorexia is caused by defective hypothalamic regulation of appetite. They attributed the defect to an alteration in the hypothalamus's response to leptin and inflammation. Since similar hypothalamic defects suppress appetite in inflammatory states and in cancer, it is possible that anorexia in several cachexia-inducing conditions results from a common set of hypothalamic abnormalities. The development of small molecules capable of preventing these regulatory abnormalities holds the promise of eliminating the contribution of anorexia to the development of cachexia.

Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease

Malnutrition is defined as abnormalities caused by an inadequate diet, but this term is often used inappropriately to describe the syndrome of loss of body weight with muscle mass being replaced by fatty tissue and declining serum proteins present in adults and children with chronic kidney disease (CKD). This syndrome is more accurately described as cachexia, and manifests as growth failure in children with CKD. Cachexia is common and is an important risk factor for poor quality of life and increased mortality and morbidity in both adults and children with CKD. Anorexia, acidosis and inflammation are important causes of cachexia, but the underlying molecular mechanism is not well understood. Dietary intake is often poor and resting metabolic rate is increased in CKD. The energy cost of growth is increased in experimental CKD. Circulating concentrations of cytokines, such as leptin, tumor necrosis factor-alpha and interleukins 1 and 6 are increased in patients with CKD and correlate with the degree of cachexia in these individuals. We hypothesize that cytokines signal through orexigenic neuropetides such as agouti-related peptide and neuropeptide Y (NPY), and anorexigenic neuropetides such as proopiomelanocortin and alpha-melanocyte-stimulating hormone in the arcuate nucleus in the hypothalamus. This signaling system also involves the NPY receptor and the melanocortin receptors and controls appetite and metabolic rate in health and disease. Furthermore, the first order neurons of this system are located outside the blood-brain barrier and can therefore sense the circulating levels of cytokines, as well as long-term satiety hormones such as leptin and insulin and short-term satiety hormones such as ghrelin and peptide (P) YY. There is experimental evidence that this hypothalamic neuropeptide signaling system may have an important role in the pathogenesis of cachexia in CKD. Understanding the molecular mechanism of cachexia in CKD may lead to novel therapeutic strategies.