Myofibroblastic differentiation in simple peritoneal sclerosis

OBJECTIVE: To analyze the presence of myofibroblasts in a series of peritoneal dialysis (PD) patients with simple sclerosis and non-PD, uremic patients. Since there is a close correlation between active fibrosis and myofibroblastic differentiation we wanted to test if myofibroblasts are present in uremic, non-PD peritoneal samples. To determine if there are correlations between myofibroblastic presence and other functional and morphologic peritoneal parameters. METHODS: Biopsies were collected from three patient groups: 1) Normal control samples (n = 15) of parietal and visceral peritoneum 2) non-PD uremic patients (n = 16); and 3) uremic patients on PD (n = 32). Peritoneal morphologic and functional parameters and immunohistochemical expression of alfa-smooth muscle actin was analyzed in each case. Vascular endothelial growth factor (VEGF), bcl-2 anti-apoptotic protein, and progesterone receptor was evaluated in a subset of cases. RESULTS: Myofibroblasts were present in 56.3% of the patients with PD-related simple sclerosis. In most cases they were distributed in the upper submesothelial area. None of the biopsies from normal controls and uremic, non-PD patients showed myofibroblasts. Within the group of PD patients, myofibroblasts showed no correlation with time on dialysis, urea/creatinine MTAC, episodes of peritonitis, submesothelial thickening, hyalinizing vasculopathy or mesothelial status. In a subset of PD patients VEGF expression was observed in submesothelial fibroblastic cells. No expression of progesterone receptor or bcl-2 was observed. CONCLUSIONS: Myofibroblasts are a reliable and simple indicator of fibrosis since they appear in early stages of PD treatment and in patients with minor morphologic anomalies. They are not exclusive of patients with sclerosing peritonitis, ultrafiltration loss or long standing treatment. Their absence in non-PD, uremic patients suggest that uremia-related fibrosis takes place without a significant participation of myofibroblasts.     

Immunohistochemical characterization of fibroblast subpopulations in normal peritoneal tissue and in peritoneal dialysis-induced fibrosis

Peritoneal fibrosis is one of the most common morphological changes observed in continuous ambulatory peritoneal dialysis (CAPD) patients. Both resident fibroblasts and new fibroblast-like cells derived from the mesothelium by epithelial-to-mesenchymal transition are the main cells involved fibrogenesis. In order to establish markers of peritoneal impairment and pathogenic clues to explain the fibrogenic process, we conducted an immunohistochemical study focused on peritoneal fibroblasts. Parietal peritoneal biopsies were collected from four patient groups: normal controls (n=15), non-CAPD uremic patients (n=17), uremic patients on CAPD (n=27) and non-renal patients with inguinal hernia (n=12). To study myofibroblastic conversion of mesothelial cells, -smooth muscle actin (SMA), desmin, cytokeratins and E-cadherin were analyzed. The expression of CD34 by fibroblasts was also analyzed. Fibroblasts from controls and non-CAPD uremic patients showed expression of CD34, but no myofibroblastic or mesothelial markers. The opposite pattern was present during CAPD-related fibrosis. Expression of cytokeratins and E-cadherin by fibroblast-like cells and -SMA by mesothelial and stromal cells supports that mesothelial-to-myofibroblast transition occurs during CAPD. Loss of CD34 expression correlated with the degree of peritoneal fibrosis. The immunophenotype of fibroblasts varies during the progression of fibrosis. Myofibroblasts seem to derive from both activation of resident fibroblasts and local conversion of mesothelial cells.Manuel López-Cabrera and Rafael Selgas contributed equally to the article.     

Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease

Background and Objective High levels of some adipocytokines have been reported in patients with chronic renal failure, but little information is available on adipocytokine concentrations in uraemic patients under different modalities of therapy. Our aims were (1) to quantify the serum concentrations of leptin, adiponectin and resistin in uraemic patients on peritoneal dialysis (PD) and haemodialysis (HD), in comparison with patients on conservative management, and (2) to study the relationships between adipocytokine levels and previous atherosclerotic vascular disease. Patients and Measurements We studied 82 dialysis patients treated by PD (n = 44, 23 males and 21 females, mean age 54·4 ± 1·8 years) or HD (n = 38, 22 males and 16 females, age 60·8 ± 1·6 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of leptin, adiponectin and resistin were measured in all subjects. Information on vascular disease (cerebral vascular, peripheral vascular and heart disease) was obtained from a detailed medical history. Results PD patients showed significantly higher serum leptin concentrations [median (interquartile range), 28·7 (13·0–71·9) µg/l] than those found in patients on HD [9·7 (4·7–31·9) µg/l, P < 0·01] or in conservative management [5·9 (4·3–38·6) µg/l, P < 0·05]. Adiponectin concentrations were similar in the three groups of patients (mean ± SEM, 48·0 ± 4·5 mg/l in PD, 57·7 ± 4·4 mg/l in HD, and 44·4 ± 7·0 mg/l in controls, NS). Patients treated by both PD and HD exhibited resistin concentrations significantly higher than those found in controls (26·3 ± 0·99 and 27·5 ± 1·4 µg/l, respectively, vs. 17·3 ± 1·0 µg/l, P < 0·001). Leptin concentrations were positively correlated with body mass index (BMI) (r = 0·287, P < 0·01) and adiponectin levels were negatively related to BMI (r = ?0·416, P < 0·001) and the homeostatic model assessment (HOMA‐R) index (r =?0·216, P < 0·05). Leptin, adiponectin and resistin levels in patients with previous vascular events were similar to those found in patients without these complications. Logistic regression analysis did not demonstrate any relationship between serum adipocytokine concentrations and the presence of vascular disease of any type. A significant relationship between resistin and heart disease [odds ratio (OR) 1·80 (1·03–3·15), P = 0·039] was found when analysing subgroups of patients. Conclusions These data suggest that leptin levels are higher in PD patients, and resistin levels are higher in PD and HD patients in relation to patients on conservative management, whereas adiponectin concentrations are similar in the three groups. These results do not support the presence of a clinically relevant relationship between adipocytokines and previous episodes of vascular disease in the whole population or in patients classified in subgroups, with the only exception of a relationship between resistin levels and heart disease.     

Use of icodextrin for diurnal exchange in patients undergoing automatic peritoneal dialysis. Comparison with glucose solutions

Icodextrin (IC) is an osmotic agent that produces sustained ultrafiltration (UF) during long dwell time periods in peritoneal dialysis patients. The aim of this study was to evaluate the effects of 7.5% IC for the diurnal exchange in automated peritoneal dialysis (APD) patients and to compare them with that of 2.27% glucose solutions. Seventeen patients treated on APD during 13.9 +/- 12.7 months were included. The study was divided into three eight weeks phases. During the baseline period patients used 2.27% glucose for the daytime, second, IC 7.5% was prescribed for the day-exchange, and finally 2.27% glucose solution was used for the last eight weeks. Daytime UF increased in all patients during IC use (-53 +/- 22 to 270 +/- 304 ml/day, p < 0.01). Patients with higher peritoneal permeability capacity obtained more benefits. Daytime urea KT/V and weekly creatinine clearance (WCC) augmented significantly during IC use, but the increase of weekly urea KT/V and WCC was not significant (2.18 +/- 0.45 to 2.26 +/- 0.41 and 62.7 +/- 18 to 66.6 +/- 15 l/week/1.73 m2; respectively). On IC, nightly glucose load significantly decreased (289 +/- 82 to 266 +/- 94 g, p < 0.05), returning to previous value after withdrawal. Plasma osmolality did not change, although plasma sodium levels decreased during IC use (140 +/- 3 to 136 +/- 2, p < 0.001). Serum amylase levels significantly declined during IC use (279 +/- 151 to 29 +/- 9 U/l), returning to previous values after transfer to glucose. Peritoneal function transport parameters and peritoneal protein losses did not change. IC metabolite plasma levels increased during the use of this solution, returning to previous values after withdrawal. In conclusion, IC dialysate is an excellent alternative to glucose dialysate for the day-exchange in APD patients. Daytime UF increased in all patients, but those with higher peritoneal permeability capacity obtained more benefits. The decrease of the glucose peritoneal load overnight and the reduction for more than 50% of exposure time of the peritoneal membrane to glucose solutions, probably make IC solution a more biocompatible fluid.     

MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.     

Effect of hemodialysis schedules and membranes on hepatocyte growth factor and hepatitis C virus RNA levels

Hemodialysis induces production of the hepatocyte growth factor (HGF) and decrease of serum hepatitis C virus (HCV) RNA in patients with HCV infection, but it is not known if the hemodialysis schedule or type of membrane affect both the HGF production and HCV viremia. The effects on both parameters of alternate‐day intermittent hemodialysis and short‐daily hemodialysis and high and low flux membranes were investigated in 41 patients treated by hemodialysis. Sixteen (39%) patients were anti‐HCV positive and 11 (69%) had HCV RNA. Twenty‐six patients were on alternate‐day intermittent and 15 on short‐daily hemodialysis. High flux membranes were used for 29 patients and low flux membranes for 12 patients. A decrease in HCV RNA was observed at the end of hemodialysis (8.6 × 10⁵ ± 1.1 × 10⁶ IU/ml vs. 4.4 × 10⁵ ± 7.3 × 10⁵ IU/ml, P = 0.003). The proportion of HCV RNA decrease was similar in patients dialyzed with both schedules and with both types of membranes. The HGF levels increased from 2,605.9 ± 1,428.7 to >8,000 pg/ml at 15 min. At the end of the session, the HGF levels decreased to 5,106.7 ± 2,533.9 pg/ml. The HGF levels at the start of the next session were similar to those at baseline (2,680.0 ± 1,209.3 pg/ml). The increase and dynamics of the HGF levels were similar in patient's hemodialyzed with both schedules and with both types of membranes. These results suggest that changes in HCV RNA and HGF levels during hemodialysis are not influenced by the schedule or type of membrane used. J. Med. Virol. 82: 763–767, 2010. © 2010 Wiley‐Liss, Inc.