International variation in histologic grading is large, and persistent feedback does not improve reproducibility.

Histologic grading systems are used to guide diagnosis, therapy, and audit on an international basis. The reproducibility of grading systems is usually tested within small groups of pathologists who have previously worked or trained together. This may underestimate the international variation of scoring systems. We therefore evaluated the reproducibility of an established system, the Banff classification of renal allograft pathology, throughout Europe. We also sought to improve reproducibility by providing individual feedback after each of 14 small groups of cases. Kappa values for all features studied were lower than any previously published, confirming that international variation is greater than interobserver variation as previously assessed. A prolonged attempt to improve reproducibility, using numeric or graphical feedback, failed to produce any detectable improvement. We then asked participants to grade selected photographs, to eliminate variation induced by pathologists viewing different areas of the slide. This produced improved kappa values only for some features. Improvement was influenced by the nature of the grade definitions. Definitions based on "area affected" by a process were not improved. The results indicate the danger of basing decisions on grading systems that may be applied very differently in different institutions.

Modulation of chemokine production and expression of adhesion molecules in renal tubular epithelial and endothelial cells by catecholamines.

BACKGROUND: The present study was conducted to investigate whether catecholamines influence the production of chemokines and adhesion molecules in proximal tubular epithelial cells (PTECs) and endothelial cells. METHODS: PTECs and human umbilical vein endothelial cells (HUVECs) were stimulated with various concentrations of dopamine (DA), adrenaline (AD), or noradrenaline (NA), and the production of interleukin (IL)-8, ENA-78, and Gro-alpha was assessed by ELISA. The influence of catecholamine pretreatment on tumor necrosis factor (TNF)-alpha-mediated production of these chemokines and the expression of adhesion molecules was also tested. RESULTS: In PTECs, DA inhibited the production of all three chemokines in a dose-dependent fashion. Although inhibition in ENA-78 and Gro-alpha production was also found in HUVECs, IL-8 production was up-regulated in these cells. Increased IL-8 secretion was predominantly observed at the apical site of the cells. In AD or NA stimulated cells, the production of Gro-alpha was increased in PTECs and decreased in HUVECs. Down-regulation in IL-8 production was also observed after AD but not after NA stimulation of both cell types. Interestingly, TNF-alpha-mediated up-regulation in intercellular adhesion molecule 1, vascular cell adhesion molecule (VCAM), and E-selectin was delayed in DA-pretreated HUVECs but not in PTECs. The influence of DA, but not AD or NA, on chemokine production was completely prevented by the addition of N-acetylcysteine. CONCLUSIONS: This study demonstrates that catecholamines differentially influence chemokine production and indicates that DA may have anti-inflammatory properties because it delays the expression of adhesion molecules and inhibits the production of chemokines in PTECs and endothelial cells under basal and inflammatory conditions.