Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surface molecule HAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1–related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC. Cancer Res; 74(5); 1416–28. ©2014 AACR.

White adipose tissue has long been considered a mere storage site for lipids and therefore an energetic reservoir for the maintenance of vital cell functions. When a fall in glucose occurs, lipolysis leads to the release of fatty acids for use by a variety of tissues such as muscle, liver and kidney. Partial oxidation of fatty acids also generates ketones, which serve as an alternate fuel source for the brain and other tissues. Conversely, an increase in glucose and lipids results in increased adipose fatty acid transport and lipogenesis. Fat metabolism depends on energy requirements and is regulated by nutrient, neural and hormonal signals [ 1 ]. Obesity and its adverse health consequences constitute an upcoming global epidemic in developed countries that has attracted the attention of the biomedical research community and national health care systems for both scientific and economic reasons. Although it is well-known that obesity prejudices health, it has been recognised that not all patients develop the same metabolic risk profile. While this profile is quite normal in some individuals, severe complications such as insulin resistance, atherogenic dyslipidaemia, type 2 diabetes, hypertension and cardiovascular disease may develop in others. Many studies conducted in the last 20 years have revealed that considerable metabolic heterogeneity exists among various adipose tissue depots, with abdominally obese patients being the subgroup with the highest risk of complications. The discovery of leptin in the mid-1990s [ 2 ] [ 3 ] changed the view of adipose tissue to that of a tissue with significant endocrine functions. This secreted circulating factor, known as leptin, is encoded by the ob gene [ 2 ], and functions as the signal that reports the state of the body’s energy stores to the brain. Although it is mainly expressed in adipose tissue, low levels of leptin have also been detected in the placenta, skeletal muscle, gastric and mammary epithelium, as well as brain [ 4 ] [ 5 ] [ 6 ]. Leptin has a relative mass of 16 kDa, a helical structure similar to cytokines, and is highly conserved among mammals. Adipose tissue and plasma leptin concentrations are dependent on the amount of energy stored as fat, as well as energy balance status. Leptin is up-regulated by insulin, glucocorticoids, acute infection and pro-inflammatory cytokines, and down-regulated by cold exposure, adrenergic stimulation, GH, thyroid hormone, melatonin and smoking [ 4 ] [ 5 ] [ 6 ]. Leptin expression displays a dimorphic pattern by gender since it is higher in females than in males, due in part to its inhibition by androgens and stimulation by oestrogens [ 7 ]. Mutations in the ob gene causing total leptin deficiency may produce hyperphagia, morbid obesity, diabetes, a variety of neuroendocrine abnormalities and autonomic and immune dysfunction [ 4 ]. Adipose tissue functions as the major storage depot for triglycerides, but is also an active endocrine organ that senses metabolic signals and secretes hormones that affect the whole body’s energy homeostasis [ 8 ] [ 9 ] [ 10 ]. Apart from leptin, adipocytes are able to secrete tumour necrosis factor alpha [ 11 ], plasminogen activator inhibitor (PAI-1) [ 12 ], adipsin [ 13 ], resistin [ 14 ] and adiponectin [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ], collectively known as adipocytokines [ 20 ]. Other hormones such as angiotensinogen [ 21 ] and angiotensin II (AII) [ 22 ] have also been described in adipose tissue. Some authors have related the presence of AII with control of adiposity through regulation of lipid synthesis and storage in adipocytes [ 23 ]. Others have described the expression of AII receptors in human preadipocytes, claiming that AII has early, receptor-mediated effects on cell cycle progression in human preadipocytes that may contribute to their differentiation to the adipocyte phenotype [ 24 ]. Since all these products have been implicated in metabolic, neuroendocrine, immune and cardiovascular regulation [ 25 ], it is of great interest to understand the endocrine actions of products secreted by adipose tissue and their potential role in disease.

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) following kidney transplantation occurs in a large percentage of patients. Accurate prediction of recurrence and elucidation of its pathogenesis are major therapeutic goals. To detect differential proteins related to FSGS recurrence, proteomic analysis was performed on plasma and urine samples from 35 transplanted idiopathic FSGS patients, divided into relapsing and nonrelapsing. Several proteins were detected increased in urine of relapsing FSGS patients, including a high molecular weight form of apolipoprotein A‐I, named ApoA‐Ib, found exclusively in relapsing patients. This finding was verified by Western blot individually in the 35 patients and validated in an independent group of 40 patients with relapsing or nonrelapsing FSGS, plus two additional groups: FSGS‐unrelated patients showing different proteinuria levels (n = 30), and familial FSGS transplanted patients (n = 14). In the total of 119 patients studied, the ApoA‐Ib form was detected in 13 of the 14 relapsing FSGS patients, and in one of the 61 nonrelapsing patients. Only one of the 30 patients with FSGS‐unrelated proteinuria tested positive for ApoA‐Ib, and was not detected in familial patients. Urinary ApoA‐Ib is associated with relapses in idiopathic FSGS and warrants additional investigation to determine its usefulness as biomarker of relapse following transplantation.

In 2001, the authors described the clinical features of a genetically distinct autosomal dominant limb-girdle muscular dystrophy (LGMD; LGMD 1F). Using a genome-wide screen with more than 400 microsatellite markers, the authors identified a novel LGMD disease locus at chromosome 7q32.1-32.2. Within this chromosomal region, filamin C, a gene encoding actin binding protein highly expressed in muscle, was an obvious candidate gene; however, the authors did not detect any defects in filamin C or its protein product.

Mutations in the thymidine kinase 2 (TK2) gene cause a myopathic form of the mitochondrial DNA depletion syndrome (MDS). Here, the authors report the unusual clinical, biochemical, and molecular findings in a 14-year-old patient in whom pathogenic mutations were identified in the TK2 gene. This report extends the phenotypic expression of primary TK2 deficiency and suggests that factors other than TK2 may modify expression of the clinical phenotype in patients with MDS syndrome.