We tested the hypotheses that the global incidence of bladder cancer was increasing but its mortality was reducing and its incidence was positively correlated with country-specific socioeconomic development. We retrieved data on age-standardized incidence and mortality rates/100,000 from the GLOBOCAN database in 2012. Temporal patterns were examined for 39 countries from the Cancer Incidence in Five Continents volumes I-X and other national registries. We evaluated the correlation between the incidence/mortality rates and Human Development Index (HDI)/ logarithmic values of Gross Domestic Product per capita (GDP). The average annual percent change of the incidence and mortality rates in the most recent 10 years was examined by joinpoint regression analysis. The highest incidence rates were observed in Southern Europe, Western Europe and North America. The mortality rates were the highest in Western Asia and Northern Africa. The incidence was positively correlated with HDI (r = 0.66 [men]; r = 0.50 [women]) and to a lesser extent logarithmic values of GDP per capita (r = 0.60 [men]; r = 0.50 [women], all p < 0.01). Many European countries experienced incidence rise. A substantial mortality reduction was observed in most countries, yet increases in mortality rates were observed in the Philippines and Iceland. These findings identified countries where more preventive actions are required.

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

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.

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.