Growth Hormone Improves Adipose Tissue Browning and Muscle Wasting in Mice with Chronic Kidney Disease-Associated Cachexia.

Cachexia associated with chronic kidney disease (CKD) has been linked to GH resistance. In CKD, GH treatment enhances muscular performance. We investigated the impact of GH on cachexia brought on by CKD. CKD was induced by 5/6 nephrectomy in c57BL/6J mice. After receiving GH (10 mg/kg/day) or saline treatment for six weeks, CKD mice were compared to sham-operated controls. GH normalized metabolic rate, increased food intake and weight growth, and improved in vivo muscular function (rotarod and grip strength) in CKD mice. GH decreased uncoupling proteins (UCP)s and increased muscle and adipose tissue ATP content in CKD mice. GH decreased lipolysis of adipose tissue by attenuating expression and protein content of adipose triglyceride lipase and protein content of phosphorylated hormone-sensitive lipase in CKD mice. GH reversed the increased expression of beige adipocyte markers (UCP-1, CD137, Tmem26, Tbx1, Prdm16, Pgc1α, and Cidea) and molecules implicated in adipose tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in CKD mice. Additionally, GH normalized the molecular markers of processes connected to muscle wasting in CKD, such as myogenesis and muscle regeneration. By using RNAseq, we previously determined the top 12 skeletal muscle genes differentially expressed between mice with CKD and control animals. These 12 genes' aberrant expression has been linked to increased muscle thermogenesis, fibrosis, and poor muscle and neuron regeneration. In this study, we demonstrated that GH restored 7 of the top 12 differentially elevated muscle genes in CKD mice. In conclusion, GH might be an effective treatment for muscular atrophy and browning of adipose tissue in CKD-related cachexia.

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia.

Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 µg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

A pegylated leptin antagonist ameliorates CKD-associated cachexia in mice.

Elevated serum leptin levels correlate with inflammation and predict changes in lean body mass in patients with CKD, and activation of the melanocortin system by leptin signaling mediates the pathophysiology of CKD-associated cachexia. We tested whether treatment with a pegylated leptin receptor antagonist (PLA) attenuates cachexia in mice with CKD. CKD and Sham mice received vehicle or PLA (2 or 7 mg/kg per day). At these doses, PLA did not influence serum leptin levels in mice. Treatment with 7 mg/kg per day PLA stimulated appetite and weight gain, improved lean mass and muscle function, reduced energy expenditure, and normalized the levels of hepatic TNF-α and IL-6 mRNA in mice with CKD. Furthermore, treatment with 7 mg/kg per day PLA attenuated the CKD-associated increase in the transcriptional and protein abundance of uncoupling proteins that mediates thermogenesis, and it normalized the molecular signatures of processes associated with muscle wasting in CKD, including proteolysis, myogenesis and muscle regeneration, and expression of proinflammatory muscle cytokines, such as IL-1α, -1ß, and -6 and TNF-α. Our results suggest that leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.

The effect of vitamin D status on risk factors for cardiovascular disease.

Vitamin-D-related pathways are implicated in various endocrine, inflammatory and endothelial functions. An estimated 1 billion people in the world have vitamin D deficiency or insufficiency, and undiagnosed vitamin D deficiency is common. Vitamin D deficiency is associated with substantial increases in the incidence of hypertension, hyperlipidaemia, myocardial infarction and stroke, as well as in diseases such as chronic kidney disease and type 2 diabetes. Low vitamin D levels also upregulate the renin-angiotensin-aldosterone system, increase inflammation and cause endothelial dysfunction. However, the role of vitamin D deficiency in cardiovascular morbidity and mortality is an emerging and hotly debated topic. Epidemiological studies suggest an association between low vitamin D levels and risk factors for cardiovascular disease, but a causal relationship has not been established, and clinical trials and meta-analyses have not demonstrated convincing evidence that vitamin D therapy improves cardiovascular outcomes. Some evidence suggests that vitamin D status is a biomarker of lifestyle, since unhealthy and sedentary lifestyles are associated with vitamin D insufficiency or deficiency and are also risk factors for cardiovascular complications.

Ghrelin and leptin pathophysiology in chronic kidney disease.

Ghrelin is an orexigenic hormone with additional effects on the regulation of inflammation and the cardiovascular system. It may play an important role in the pathogenesis of cachexia/protein-energy wasting (PEW), inflammation and cardiovascular complications in chronic kidney disease (CKD). There are three circulating gene products of ghrelin, namely, acyl ghrelin, des-acyl ghrelin and obestatin, each with individual distinct functions. Perturbations of these circulating ghrelin proteins impact the overall milieu of CKD. Leptin is an anorexigenic hormone which is secreted from the adipocytes and interacts with ghrelin and other appetite-regulating hormones. Leptin also plays a role in regulating inflammation and the cardiovascular system. Indeed, ghrelin and leptin may play yin-and-yang roles in CKD pathophysiology. Clinical trials involving the use of the mimetics or antagonists of these hormones are limited to short-term phase I/II studies. Further understanding of their interactions in CKD pathophysiology is needed for potential large-scale clinical trials, which may impact the quality of life and survival of patients with CKD.

Is obesity a risk factor for chronic kidney disease in children?

There is a rapid increase worldwide in the prevalence of obesity in adults and children. Obesity is not only a comorbidity for chronic kidney disease (CKD) but may also be a risk factor for CKD. Epidemiological correlations and pathophysiological changes have been observed associating obesity with CKD. Low birth weight may be associated with both obesity and low nephron mass, leading to CKD later in life. Elevated levels of adipokines, such as leptin and adiponectin, in obesity may be factors in CKD pathogenesis and progression. Furthermore, various other factors, such as hypertension, increased cardiovascular morbidity, insulin resistance, dyslipidemia, and lipotoxicity, may play significant roles in the pathogenesis of CKD in obesity. Reduction in obesity, which is a potentially modifiable risk factor, might help decrease the burden of CKD in the population. Apart from individualized options, community-based interventions have the potential to create a strong impact in this condition.

A case of pulmonary embolism and stroke in a 16-year-old girl.

A 16-year-old girl arrived intubated to the emergency department. She had shortness of breath and cough for 2 days with leg pain. On arrival, she was hemodynamically stable with an unremarkable physical exam. Electrocardiogram revealed a prolonged QT interval; laboratory work-up was normal except for an elevated dimerized plasmin fragment D. Acute pulmonary embolism was confirmed by a chest computed tomography scan. A lower extremity duplex scan was negative and echocardiogram revealed a patent foramen ovale with bidirectional shunting. An inferior vena cava filter was placed to prevent acute recurrence and unfractionated heparin was initiated. The next day she was noted to have right hemiparesis. Stroke was confirmed by magnetic resonance imaging. The patient underwent mechanical clot retrieval and was discharged on anticoagulation therapy to a brain rehabilitation unit.