Proteolytic mechanisms, not malnutrition, cause loss of muscle mass in kidney failure.

Hypoalbuminemia and muscle atrophy are frequently found in patients with chronic kidney disease (CKD) and patients being treated by dialysis. These abnormalities are usually attributed to malnutrition, meaning that they are caused by an inadequate diet. However, the evidence indicates that malnutrition is rarely the mechanism causing loss of protein stores. Instead, low values of serum albumin are closely related to the presence of inflammation and loss of muscle mass is attributable to activation of specific proteases. In uremic rodents and patients, the initial step in the loss of muscle protein is an activation of caspase-3. This cleaves the complex structure of muscle, and its action can be detected by the presence of a characteristic 14-kDa actin fragment in the insoluble fraction of muscle. The second step in uremia-induced loss of muscle protein is an activation of the ubiquitin-proteasome system, which rapidly degrades proteins released by caspase-3 cleavage of muscle proteins. Activation of both caspase-3 and the ubiquitin-proteasome system occur when there is suppression of the cellular signaling pathway activated by insulin/insulinlike growth factor 1, the phosphatidylinositol 3-kinase/Akt pathway. A potential therapeutic target for preventing loss of muscle protein is to stimulate activity of this signaling pathway.     

Malnutrition is an unusual cause of decreased muscle mass in chronic kidney disease.

Patients with chronic kidney disease (CKD), including those who are treated with hemodialysis, frequently develop hypoalbuminemia and a decrease in body weight. These abnormalities are usually attributed to malnutrition, but true malnutrition (ie, a disorder due to an abnormal diet) is rarely the mechanism causing decreased protein stores. Hypoalbuminemia is closely related to evidence of inflammation, and a decrease in muscle mass is caused by activation of muscle protein breakdown. In uremic rodents and patients, the initial step in the loss of muscle protein is activation of caspase-3, which cleaves the complex structure of muscle to provide substrates for the ubiquitin-proteasome pathway (UPP). The activity of caspase-3 can be detected by the presence of a characteristic 14-kDa actin fragment in the insoluble fraction of a muscle biopsy specimen. Abnormalities in cell signaling activate caspase-3 and the UPP; a key abnormality is decreased activity in the phosphatidylinositol-3-kinase/Akt pathway, leading to activation of caspase-3 and a specific E3 ubiquitin conjugating enzyme, atrogin-1/MAFbx. Inflammatory cytokines also represent a potential cell signaling abnormality that activates muscle protein breakdown, possibly because cytokines activate the E3 ubiquigin conjugating enzyme, MuRF1. An understanding of these pathways could help the clinician to identify therapeutic targets for preventing loss of muscle protein.     

Role of adipose tissue in determining muscle mass in patients with chronic kidney disease.

OBJECTIVE: Malnutrition is a powerful predictor of mortality in chronic kidney disease (CKD). However, its etiology is unclear. We hypothesized that the adipocyte-derived proteins leptin and adiponectin, inflammation (as measured by C-reactive protein, CRP), and insulin resistance (as measured by homeostasis model assessment, HOMA), implicated in the malnutrition-inflammation complex syndrome commonly seen in maintenance dialysis patients, would be associated with the loss of muscle mass in earlier stages of CKD. Arm muscle area was used as an indicator of muscle mass. PATIENTS AND SETTING: The Modification of Diet in Renal Disease Study cohort of people with CKD stages 3 and 4 was used for analysis (N = 780). MAIN OUTCOME MEASURES: Regression models were carried out to examine the relationships of leptin, adiponectin, CRP, and HOMA with arm muscle area (the main study outcome). RESULTS: Arm muscle area was 39 +/- 15 cm(2) (mean +/- SD), and adiponectin levels were 13 +/- 7 microg/mL. Median and interquartile range (IQR) concentrations were: 9.0 (13.6) ng/mL for leptin, 2.3 (4.9) mg/L for CRP, and 2.4 (2.0) for HOMA. Higher leptin (beta coefficient and 95% confidence interval, -6.9 [-8.7 to -5.1], P < .001) and higher CRP (beta coefficient and 95% confidence interval, -2.7 [-3.9 to -1.4], P < .001) were associated with lower arm muscle area. There was a trend toward lower arm muscle area with higher adiponectin (P = .07), but no association with HOMA (P = .80). CONCLUSION: Leptin and CRP were associated with lower muscle mass in subjects with CKD at stages 3 and 4. Further studies are needed to understand the mechanisms underlying these associations, and to develop targeted interventions for this patient population.     

表观遗传学与糖尿病肾脏病

糖尿病肾脏病(diabetic kidney disease,DKD)是糖尿病患者普遍存在的一种微血管并发症,它也是糖尿病患者死亡的主要病因之一。近年来大量体内和体外实验发现和证实,表观遗传学通过多种机制改变基因表达,造成细胞功能异常,最终导致DKD的发生与进展。本文从DNA甲基化、组蛋白修饰和非编码核糖核酸(ncRNA)参与DKD肾小球足细胞损伤、肾小管上皮细胞损伤和炎性反应等病理生理过程的研究进展做一综述。     

Strategies for suppressing muscle atrophy in chronic kidney disease: mechanisms activating distinct proteolytic systems.

Loss of protein and lean body mass occurs commonly in patients with chronic kidney disease (CKD). CKD or conditions associated with CKD will stimulate muscle loss, but the cellular mechanisms by which these conditions cause muscle atrophy are largely undefined. In animal models of uremia and other catabolic conditions or in peritoneal dialysis patients, there is evidence that the ubiquitin-proteasome proteolytic system is activated to degrade actomyosin and myofibrillar proteins in muscle. Before the ubiquitin system can degrade muscle proteins, however, an initial cleavage of actomyosin and myofibrils must occur. Caspase-3 performs this initial cleavage of actomyosin and leaves a footprint of its activity, accumulation of a 14-kDa actin fragment in muscle. A critical step in stimulating the ubiquitin-proteasome system in muscle was recently discovered, the activation of a specific E3 ubiquitin-conjugating enzyme, atrogin-1. Both caspase-3 and the ubiquitin system, including atrogin-1, are activated when insulin signaling is impaired, and specifically when phosphatidylinositol 3 kinase activity is suppressed. Strategies that prevent a decrease in phosphatidylinositol 3 kinase activity or inhibit caspase-3 activity could lead to treatments that prevent muscle wasting in CKD patients.     

Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease

A substantial body of evidence has accumulated linking an increased incidence of cardiovascular disease in patients with acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD). A multitude of novel risk factors related to decreased kidney function might interact with the renal and systemic immune systems involved in renal injury and repair to participate in accelerated atherogenesis (Immune inflammation-Renal injury-Atherosclerosis--the IRA Paradigm). In this review, we will discuss several of these novel risk factors and present the potential for the role of the immune-inflammatory system in accelerated atherosclerosis of kidney disease.     

Investigating mechanisms of chronic kidney disease in mouse models

Animal models of chronic kidney disease (CKD) are important experimental tools that are used to investigate novel mechanistic pathways and to validate potential new therapeutic interventions prior to pre-clinical testing in humans. Over the past several years, mouse CKD models have been extensively used for these purposes. Despite significant limitations, the model of unilateral ureteral obstruction (UUO) has essentially become the high-throughput in vivo model, as it recapitulates the fundamental pathogenetic mechanisms that typify all forms of CKD in a relatively short time span. In addition, several alternative mouse models are available that can be used to validate new mechanistic paradigms and/or novel therapies. Here, we review several models—both genetic and experimentally induced—that provide investigators with an opportunity to include renal functional study end-points together with quantitative measures of fibrosis severity, something that is not possible with the UUO model.     

Novel mechanisms in accelerated atherosclerosis in kidney disease.

OBJECTIVE: Urea undergoes a spontaneous, nonenzymatic transformation to cyanate, the active part of which is isocyanic acid, which can cause modifications of a variety of proteins in a process called carbamylation. We postulated that, in patients with renal disease, the carbamylation of low-density lipoprotein (LDL) is a nontraditional risk factor for cardiovascular disease, and that elevated urea leads to carbamylated LDL (cLDL), which causes vascular injury and leads to atherosclerosis. RESULTS: We showed that carbamylated LDL manifests all of the biological effects relevant to atherosclerosis, including endothelial-cell injury, the expression of adhesion molecules, and vascular smooth muscle cell proliferation. We also developed an enzyme-linked immunosorbent assay to measure carbamylated LDL in patients, and showed that cLDL is markedly elevated in dialysis patients. CONCLUSIONS: Our data indicate that cLDL may be an important nontraditional risk factor for atherosclerosis in patients with kidney disease.     

Intrinsic form of ureteral endometriosis causing ureteral obstruction and partial loss of kidney function

INTRODUCTION: Urinary tract endometriosis is rare and occurs in about 1% of all endometriotic lesions. About 30% of patients suffer from reduced kidney function at the time of diagnosis. CASE REPORT: A 49-year-old woman presented with a history of abdominal hysterectomy without adnexae because of uterus myomatosus without any signs of endometriosis 6 years before. Now she complained of dysuria and intermittent left loin pain. Sonography and retrograde pyelography demonstrated incomplete ureteric obstruction and scintigraphy revealed a partial loss of kidney function. Intraoperatively frozen section histology and final histologic examination demonstrated a tumor-like intrinsic form of ureteral endometriosis engulfing the left ureter. The patient was treated with uretero-ureterostomy and danazole for preventing recurrence. She is well 28 months postoperatively. CONCLUSIONS: In the extrinsic form (about 75% of all cases), ureteral endometriosis is localised to the adventitia or surrounding connective tissue of the ureter, whereas the intrinsic form of ureteral endometriosis is very rare and more often needs aggressive surgery.     

Cost-effectiveness of chronic kidney disease mass screening test in Japan

Background  

Chronic kidney disease (CKD) is a significant public health problem. Strategy for its early detection is still controversial. This study aims to assess the cost-effectiveness of population strategy, i.e. mass screening, and Japan’s health checkup reform.     

Role of fat mass and adipokines in chronic kidney disease

PURPOSE OF REVIEW: As traditional risk factors cannot alone explain the high prevalence and incidence of cardiovascular disease in chronic kidney disease, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as an important non-traditional risk factor. Recent studies show that the adipose tissue is a complex organ with pleiotropic functions far beyond the mere storage of energy. Fat tissue secretes a number of adipokines including leptin and adiponectin, as well as cytokines, such as resistin, visfatin, tumor-necrosis factor-alpha and interleukin-6. RECENT FINDINGS: Adipokine serum levels are markedly elevated in chronic kidney disease, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and vascular outcome. SUMMARY: Fat tissue is a storage depot for energy and a source of circulating signaling molecules. It plays an important role in the catabolic uremic milieu, and has been linked to systemic inflammation and uremic anorexia. Further research is needed to investigate the complex interactions between adipokine signaling networks and its effects on vascular health and outcome in chronic kidney disease.     

Association of chronic kidney disease with muscle deficits in children

The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.     

Cellular and molecular mediators in common pathway mechanisms of chronic renal disease progression

Injury mechanisms activated by the hemodynamic adaptations to nephron loss are considered to represent a final common pathway that underlies the progressive nature of chronic renal disease. In this article, we review experimental evidence that the induction of cell adhesion molecule, cytokine and profibrotic growth factor gene expression and the resultant renal infiltration by inflammatory cells, especially macrophages, are important components of these common pathway mechanisms. Interventions aimed at inhibiting these mechanisms may offer new treatments for slowing or arresting the progression of chronic renal disease.     

Hypertension of polycystic kidney disease: mechanisms and hemodynamic alterations

32 polycystic kidney disease (PKD) patients, 16 with normal 16 with variably decreased renal function, were studied; 12 were normotensive, 20 were hypertensive. Mean arterial pressure (MAP) was 90 +/- 8 mm Hg in the normotensive group and 117 +/- 17 in hypertensive patients; plasma renin activity (PRA) was similar. The glomerular filtration rate (GFR) was lower, but not significantly, in the hypertensive group and plasma volume (PV) was higher in hypertensive patients (normotensive 40.25 +/- 3.47 ml/kg body weight; hypertensive 46.30 +/- 3.54). No correlation was found between MAP, and PRA or GFR but MAP correlated with PV. Cardiac output was higher in hypertensive patients (normotensive 3.48 +/- 0.70 l/min/m2; hypertensive 3.89 +/- 1.47), also total peripheral resistance was higher in the hypertensive group (normotensive 2,035 +/- 503 dyn/s/cm-5/m2; hypertensive 2,577 +/- 808). Cardiac output and PV showed a high degree of correlation, but no correlation was seen between total peripheral resistance and PV, or PRA. The hypertensive patients were divided into two groups: one with hypertension of less than 2 years duration and one with more than 2 years but with similar GFR, PRA, PV and hemodynamic pattern. Our data indicate that hypertension in PKD is volume-dependent; that the increase in PV was not related to the loss of GFR, and that the role of the renin-angiotensin system in maintaining the hypertensive state is not well defined. Hemodynamically hypertension is characterized by high cardiac output and total peripheral resistance independent of the duration of hypertension.