The influence of uremic toxins on low bone turnover disease in chronic kidney disease.

Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to ß-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.

Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease.

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-ß1 (TGF-ß1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-ß1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.

Glycemic control with insulin attenuates sepsis-associated encephalopathy by inhibiting glial activation via the suppression of the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways in septic rats.

Sepsis-associated encephalopathy (SAE) is frequently encountered in critically ill patients. Hyperglycemia is a common phenomenon among patients with sepsis, and glycemic control improves patient outcomes. Therefore, here, we aimed to explore whether glycemic control using insulin inhibits the pro-inflammatory cytokine response and glial activation in the cerebrum and is concomitantly associated with the relief of SAE. Using cecal ligation and puncture (CLP), sepsis was induced in male Sprague-Dawley rats. The CLP rats were administered intravenous glucose or subjected to subcutaneous insulin implant within the first hour after CLP. The survival rate, blood glucose (BG) values, and behavioral expression were assessed daily for 5 days after CLP. At day 5 after CLP, electroencephalography (EEG) recordings and blood-brain barrier (BBB) permeability testing were performed. Immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assays were used to evaluate glial activation and the pro-inflammatory cytokine response qualitatively and quantitatively, respectively. The glucose-treated CLP rats (BG > 390 mg/dL) exhibited a decline in survival rate; insensitivity to mechanical and thermal stimuli; slowed EEG activity; and an increase in BBB permeability, pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) levels, and glial activation (astrocytes and microglia) in the cerebral tissues compared with CLP rats (BG ~ 270 mg/dL). Double-immunofluorescence showed that activated astrocytes and microglia co-expressed phosphorylated nuclear factor kappa B and mitogen-activated protein kinases, respectively. Furthermore, glycemic control using insulin therapy maintained the BG at 120-160 mg/dL and inhibited the production of pro-inflammatory cytokines and glial activation in the cerebrum of septic rats. In addition, the survival rate, sensory threshold, EEG activity, and BBB permeability recovered to near-normal levels in septic rats after insulin therapy. Taken together, the results of this study elucidated the pathophysiological alterations in brains subjected to sepsis, especially regarding glycemic control. These findings improve our understanding of SAE and support the importance of glycemic control in sepsis.

Bronchiolitis obliterans organizing pneumonia due to titanium nanoparticles in paint.

We present a case of a 58-year-old man who experienced Bronchiolitis obliterans organizing pneumonia after a 3-month exposure to polyester powder paint. Mineralogical analysis by transmission electron microscopy of a pulmonary sample and the polyester powder paint he was exposed to showed the presence of titanium dioxide nanoparticles in both. We suggest that exposure to titanium dioxide nanoparticles should be added to the etiology of Bronchiolitis obliterans organizing pneumonia.