Impaired endotoxin-induced interleukin-1β secretion, not total production, of mononuclear cells from ESRD patients

Impaired endotoxin-induced interleukin-1β secretion, not total production, of mononuclear cells from ESRD patients. Lipopolysaccharide (LPS)-induced interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) production and secretion from peripheral blood mononuclear cells (PBMC) were determined in a longitudinal study with repeated measurements in PBMC from patients with chronic uremia not on hemodialysis (N = 8), end-stage renal disease (ESRD) patients (N = 8), and healthy controls (N = 7). ESRD patients were studied while using low-flux Cuprophan dialyzers and again using high-flux AN 69 dialyzers. Total (cell-associated plus secreted) LPS-induced IL-1β production was enhanced in uremic patients, but similar to controls in ESRD patients on Cuprophan. In contrast, LPS-induced IL-1β secretion (secreted amounts in % of total production) was similar to controls in uremic patients, but significantly reduced in ESRD patients on Cuprophan (P < 0.01). During AN 69 hemodialysis, LPS-induced total IL-1β production remained unchanged but IL-1β secretion increased significantly (P < 0.05) compared to Cuprophan dialysis. Increased IL-1β secretion coincided with a suppression in PGE2 synthesis (P < 0.02). Similarly, blockade of endogenous PGE2 by indomethacin increased LPS-induced IL-1β secretion (P < 0.01) but did not enhance total IL-1β production in PBMC from controls and patients on Cuprophan hemodialysis. Neither total production nor secretion of TNFα was different comparing the three study groups. We conclude that LPS-induced IL-1β secretion, but not total production, is impaired in PBMC from ESRD patients on long-term Cuprophan hemodialysis. This functional change in the PBMC response is specific for IL-1β, not due to uremia per se but hemodialysis-dependent and reversible. Hemodialysis with AN 69 suppresses endogenous PGE2 synthesis in PBMC which is associated with increased LPS-induced IL-1β secretion in the presence of unchanged total IL-1β production. We speculate that PGE2 could inactivate the IL-1β converting enzyme which is essential for processing and secretion of mature IL-1β

Cadherin-9 Is a Novel Cell Surface Marker for the Heterogeneous Pool of Renal Fibroblasts

BACKGROUND: Interstitial fibroblasts are a minor, but nevertheless very important, component of the kidney. They secrete and remodel extracellular matrix and they produce active compounds such as erythropoietin. However, studying human renal fibroblasts has been hampered by the lack of appropriate surface markers. METHODS AND FINDINGS: The expression of cadherin-9 in various human renal cell lines and tissues was studied on the mRNA level by RT-PCR and on the protein level with the help of newly generated cadherin-9 antibodies. The classical type II cadherin-9, so far only described in the neural system, was identified as a reliable surface marker for renal fibroblasts. Compared to FSP1, a widely-used cytosolic renal fibroblast marker, cadherin-9 showed a more restricted expression pattern in human kidney. Under pathological conditions, cadherin-9 was expressed in the stroma of renal cell carcinoma, but not in the tumor cells themselves, and in renal fibrosis the percentage of cadherin-9-positive cells was clearly elevated 3 to 5 times compared to healthy kidney tissue. Induction of epithelial mesenchymal transition in renal epithelial cells with cyclosporin-A, which causes renal fibrosis as a side effect, induced cadherin-9 expression. Functional studies following siRNA-mediated knockdown of cadherin-9 revealed that it acts in the kidney like a typical classical cadherin. It was found to be associated with catenins and to mediate homophilic but not heterophilic cell interactions. CONCLUSIONS: Cadherin-9 represents a novel and reliable cell surface marker for fibroblasts in healthy and diseased kidneys. Together with the established marker molecules FSP1, CD45 and alpha smooth muscle actin, cadherin-9 can now be used to differentiate the heterogenic pool of renal fibroblasts into resident and activated fibroblasts, immigrated bone marrow derived fibroblast precursors and cells in different stages of epithelial mesenchymal transition

The influence of visual-spatial skills on the association between processing of nonsymbolic numerical magnitude and number word sequence skills

Nonsymbolic numerical magnitude processing skills are assumed to be fundamental to mathematical learning. Recent findings suggest that visual-spatial skills account for associations between children\u27s performance in visually presented nonsymbolic numerical magnitude comparison tasks and their performance in visually presented arithmetic tasks. The aim of the current study was to examine whether associations between children\u27s performance in visually presented tasks assessing nonsymbolic numerical magnitude processing skills and their performance in tasks assessing early mathematical skills, which do not involve visual stimulation, may also be mediated by visual-spatial skills. This line of reasoning is based on the assumption that children make use of mental visualization processes when working on tasks assessing early mathematical skills, such as knowledge of the sequence of number words, even when these tasks do not involve visual stimulation. We assessed 4- to 6-year-old children\u27s performance in a nonsymbolic numerical magnitude comparison task, in tasks concerning knowledge of the sequence of number words, and in a developmental test to assess visual-spatial skills. Children\u27s nonsymbolic numerical magnitude processing skills were found to be associated with their number word sequence skills. This association was fully mediated by interindividual differences in visual-spatial skills. The effect size of this mediation effect was small. We assume that the ability to construct mental visualizations constitutes the key factor underlying this mediation effect. (DIPF/Orig.

Timely Referral to Outpatient Nephrology Care Slows Progression and Reduces Treatment Costs of Chronic Kidney Diseases

IntroductionWe present a new approach to evaluate the importance of ambulatory nephrology care in patients with chronic kidney disease (CKD).MethodsAn anonymized health claims database of German insurance companies was searched in a retrospective analysis for patients with CKD using the codes of the International Classification of Diseases, 10th German modification. A total of 105,219 patients with CKD were identified. Patients were assigned to the group “timely referral,” when nephrology care was present in the starting year 2009, or initiated during the following 3 years in CKD1–4. Using frequency matching for age and gender, 21,024 of the late referral group were matched with the equal number of patients in the timely referral group. Hospital admission rates, total treatment costs, and kidney function (change in CKD stages, start of dialysis, mortality) were documented each year during the 4-year follow-up.ResultsHospital admission rates (110%–186%) and total treatment costs (119%–160%) were significantly higher (P < 0.03) in late referral compared with timely referral. In the timely referral group, significantly more patients did not change their CKD stage (65%–72.9% vs. 52%–64.6%, P < 0.05) compared with late referral. Starting in CKD3 more patients tended to start dialysis in 1 year in timely referral (1.9 ± 0.6 vs. 1.0 ± 0.4, P = 0.1). In contrast, death rates were significantly higher in the late referral group (18.8 ± 1.8% vs. 6.7 ± 0.4%, P = 0.0001).DiscussionTimely referral to outpatient nephrology care is associated with slowed disease progression, less hospital admissions, reduced total treatment costs, and improved survival in patients with CKD

Detection of endotoxin-like interleukin-1-inducing activity during in vitro dialysis

Detection of endotoxin-like interleukin-1-inducing activity during in vitro dialysis. In order to study the integrity of dialysis membranes to pyrogens, the dialysate side of a closed loop hemodialysis (HD) circuit was challenged with E. coli microfiltrate containing 500 ng/ml endotoxin. Three solutions, a) tissue culture medium/saline, b) 5% human serum albumin, and c) 10% fresh human plasma, were circulated in the blood loop for five hours. Samples drawn from the blood side were assayed for interleukin-1 (IL-1)-inducing activity on human mononuclear cells (MNC) in vitro. No IL-1-inducing substances were detected when saline or culture medium was circulated in the blood loop. Circulating 5% human serum albumin revealed IL-1-inducing activity in the samples drawn only after five hours of HD. However, the addition of 10% fresh human plasma to the blood side resulted in the appearance of an IL-1-inducing substance(s) after 15 minutes of HD. After 30 minutes, maximum IL-1-inducing activity was observed (control stimulation index, 3.30 ± 0.67 SEM VS. 7.59 ± 1.50, (P < 0.02). The IL-1-inducing activity of the samples was completely inhibited by polymyxin B, a cationic antibiotic which blocks the IL-1-inducing activity of endotoxin. Additional experiments demonstrated that in vitro MNC IL-1-production induced by the same E. coli microfiltrate is enhanced in the presence of 10% plasma. These studies demonstrate that: (a) in the presence of plasma, IL-1-inducing factors pass into the blood compartment of a dialysis system challenged with bacterial pyrogen; and (b) MNC production of IL-1 is enhanced in the presence of plasma. Since the Limulus test is influenced by plasma, in vitro MNC-IL-1-production provides a more reliable and relevant assay to determine dialysis membrane permeability for pyrogens