Addition of IV iron to darbepoetin alpha Q3W in patients with chemotherapy-induced anemia was well tolerated, resulting in an improved hematopoietic response rate and lower incidence of transfusions compared with darbepoetin alpha alone.

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TGF-beta has been considered as the key regulator in the generation of glomerulosclerosis. Despite abundant descriptive data, it still remains undetermined whether sustained, local expression of TGF-beta leads to irreversible glomerulosclerosis. There is no doubt that TGF-beta stimulates ECM production in the glomerulus, but this molecule has several anti-inflammatory properties as well. Towards a better understanding of the pathogenesis of glomerulonephritis and for the development of novel and efficient therapeutic interventions, extensive efforts should be made to clarify the 'bright side' of TGF-beta as well as its 'dark side' in individual experimental and human diseases, focusing especially on the concentration and the time-point at which its anti-inflammatory properties spill over into its prosclerotic actions.

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NO2 + NO3 (NOx), the stable oxidation products of NO, and cGMP are widely accepted as indices of in vivo NO production. Whether acute changes in urinary excretion of nitrite + nitrate (UNOXV) can be taken to reflect acute changes in renal and/or systemic NO production is not known. The present studies were conducted in the conscious rat to investigate the effect on acute changes in UNOxV, of maneuvers that (a) enhance NO production and (b) act as diuretics. L-arginine (L-arg) and acetylcholine (Ach) produce equivalent NO dependent falls in renal vascular resistance (RVR), but a much greater increase in UNOX V is seen with L-arg. D-arg does not stimulate NO and has no renal vasodilatory effect, but produces a large rise in UNOX V, and SNP lowers BP but not RVR and results in a reduced UNOX V. None of the diuretics employed should stimulate the NO system or lower RVR; however, the proximally acting agents, acetazolamide and D-arg increased UNOx V, while the loop diuretic furosemide had little effect. H2O diuresis (a distal event) led to a fall in UNOx V. These data suggest that NOx is reabsorbed extensively in the proximal tubule and that inhibition of proximal reabsorption leads to an increase in UNOx V. Also, our results show that the relationship between UNOx V and UcGMP V is unpredictable. Therefore, we conclude that measurements of acute changes in UNOxV and/or UcGMP V should be interpreted cautiously, since they may reflect altered tubular handling of NOx rather than the acute activity of the systemic and/or renal NO systems.

Background and Aim: The role of IV iron supplementation during treatment with erythropoiesis-stimulating agents (ESAs) in patients with CIA is of increasing interest as a possible means of improving response. This randomized, open-label, multicenter study was designed to evaluate the safety and efficacy of IV iron vs standard practice in CIA patients receiving darbepoetin alfa. Interim efficacy analyses showed a higher response rate for darbepoetin alfa with IV iron compared to darbepoetin alfa with standard iron practice with no difference in the safety profile between the treatment arms (Vanderbroek et al, EHA 2006). Iron parameters are reported here. Methods: Eligible patients were diagnosed with a non-myeloid malignancy and had CIA with a baseline hemoglobin (Hb) value < 11g/dL. All patients received darbepoetin alfa 500 mcg administered Q3W with the SureClick™ prefilled autoinjector. Patients were randomized 1:1 to IV iron 200 mg (single dose Q3W at the same time as darbepoetin alfa or in 2 doses of 100 mg within 3 weeks) or standard practice (oral iron or no iron). Randomization was stratified by tumor type and baseline Hb category (< 10 or ≥10 g/dL). Results: A total of 400 patients were randomized. Mean (SD) age of the study population was 61.4 (11.5) years; range, 20–86. Sixty percent (n=241) of participants were women; 28% (n=114) had lung or gynecological tumors; and 52% (n=208) had a baseline Hb value ≥10 g/dL. In the interim analysis population (n=196), the mean (SD) weekly dose of IV iron was 64.8 (6.6) mg in the IV iron group (n=100). In the standard practice group, 28 of 96 patients (29%) received oral iron and 2 (2%) received IV iron (these patients were analyzed as randomized). Mean (standard error) serum ferritin concentrations and percent transferrin saturation (TSAT) in the 2 groups from baseline (BL) to end of study (EOS) are shown in the figure. Conclusions: The combination of darbepoetin alfa Q3W and IV iron appeared to be associated with a trend toward increased mean serum ferritin levels compared to the standard practice control arm. In contrast, mean TSAT surprisingly appeared to be similar in the 2 groups for most of the study period, perhaps suggesting that TSAT is influenced by other factors. Iron management appears to be an important factor in the response to ESAs and the findings presented here suggest the need for additional exploration into iron uptake and demand in cancer patients treated with darbepoetin alfa. Serum Ferritin Concentration Serum Ferritin Concentration Transferrin Saturation (%) Transferrin Saturation (%)

Adhesion of macrophages is a crucial event that determines the number and function of macrophages at inflammatory sites. The aim of this study was to elucidate the role of mesangial cells in the regulation of macrophage adhesiveness. J774.2 macrophages were suspended in serial dilutions of mesangial cell conditioned medium (MC medium) and seeded on plastic tissue culture plates. MC medium did not affect the initial adhesion of macrophages but induced subsequent detachment in a concentration-dependent manner. A similar effect was observed when macrophages were plated on plastic coated with laminin, collagen type IV or Matrigel. The reduced adhesiveness was reversible, and cell viability was unaffected by MC medium, indicating that the effect is not due to cytotoxicity. Conditioned media from fibroblastic, epithelial and endothelial cell lines did not induce macrophage detachment. To identify the active component in MC medium, we examined the involvement of transforming growth factor-beta 1 (TGF-beta 1) in the process. Mesangial cells constitutively expressed TGF-beta 1 mRNA, and MC medium contained the active form of TGF-beta 1. Exogenously added TGF-beta 1 induced macrophage detachment in a dose-dependent manner, and an anti-TGF-beta 1 neutralizing antibody partially abolished the activity of MC medium, indicating the involvement of TGF-beta 1 as an active component. Compared to adherent cells, detached macrophages showed reduced mitogenic activity and blunted induction of IL-1 beta and IL-6 in response to lipopolysaccharide. These data demonstrate that TGF-beta 1 is a mesangial cell-derived factor that impairs adhesiveness of macrophages and confers blunted responses to a specific stimulus. These findings suggest one potential mechanism for macrophage clearance from inflamed glomeruli.