Norishi Ueda

Oxidant mechanisms in toxic acute renal failure

Over the last decade, there has been accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown in both in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, the results of recent studies suggest that cytochrome P-450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Cyclosporine A has been shown to enhance the generation of hydrogen peroxide in vitro and lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

Apoptotic mechanisms in acute renal failure

It has been generally accepted that a catastrophic breakdown of regulated cellular homeostasis, known as necrosis, is the mode of cellular injury in various forms of acute renal failure. One of the major advances in our understanding of cell death has been the recognition that the pathways traditionally associated with apoptosis as described in the landmark study by Kerr, Wyllie, and Currie in 1972 maybe very critical in the form of cell injury associated with necrosis. The pathway that is followed by the cell varies with both nature and severity of insults and may evolve from an apoptotic to a necrotic form of cell death. It is also likely that there are some common pathways that are shared and regulated in the two modes of cell death. In this review, we first describe evidence for the role of apoptotic pathways in ischemic acute renal failure, and then consider the potential mechanisms that may participate in this model of acute renal tubular injury. We then summarize the current information of apoptotic pathways related to other common causes of acute renal failure including endotoxin-induced, toxic acute renal failure and transplant rejection. A better understanding of the mechanisms of apoptosis could lead to safer and more specific therapeutic interventions for acute renal failure.

Role of Endonucleases in Renal Tubular Epithelial Cell Injury

The study of cell death has emerged as an important and exciting area of research in cell biology. Although two kinds of cell death, apoptosis and necrosis, are recognized, one of the major advances in our understanding of cell death has been the recognition that the pathways traditionally associated with apoptosis may be very critical in the form of cell injury associated with necrosis. Renal tubular epithelial cell injury from ischemia or toxins has generally been regarded as a result of a necrotic form of cell death. We briefly describe recent evidence indicating apoptotic mechanisms including endonuclease activation in renal tubular injury and some mediators (oxidants, caspases and ceramide) which regulate this process. The pathway that is followed by the cell is dependent on both the nature and severity of insults, and it is likely that the cascades that lead to the apoptotic or necrotic mode of cell death are activated almost simultaneously and may share some common pathways.

Role of Hepcidin-25 in Chronic Kidney Disease: Anemia and Beyond

Iron is an essential element for all living organisms, but produces toxic oxidants. Thus, iron homeostasis is tightly regulated in mammals. Hepcidin-25 (hepcidin) has emerged as a molecule that regulates iron metabolism. Binding of hepcidin to its receptor, ferroportin, inhibits intestinal iron absorption and iron efflux from hepatocytes and macrophages. Decreased hepcidin enhances iron absorption and efflux. Hepcidin could be predictive of iron status and the response to iron supplementation or erythropoietin-stimulating agents. Monitoring hepcidin is helpful for the management of anemia. Thus, it is urgent to obtain normal reference values in a large population of healthy subjects and to standardize various hepcidin assays, which enables to compare the data measured by different methods. Anemia is an important and common problem associated with chronic kidney disease (CKD), which is caused by erythropoietin deficiency, iron-restricted erythropoiesis, inflammation, hypoxia, vitamin D deficiency, hyperparathyroidism, and obesity. Anemia causes poor quality of life, progression of CKD, increased risk of cardiovascular events, and mortality. Besides its role in anemia, recent evidence suggests that hepcidin-25 plays a role in the pathogenesis and progression of kidney injury via modulation of iron-mediated oxidant injury. Despite accumulating experimental data, information about clinical significance of hepcidin-25 for anemia and kidney injury in CKD patients is scarce, especially in children. This review summarizes the current knowledge of the role of hepcidin-25 in the regulation of anemia and kidney injury in children and adults with CKD. Strategy for modulating hepcidin-25 to prevent anemia and kidney injury associated with CKD is also discussed.

Sphingolipids in Genetic and Acquired Forms of Chronic Kidney Diseases

Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs. A balancing role of apoptotic SLs and anti-apoptotic S1P is crucial in the regulation of glomerular injury and complications associated with CKDs. Interaction between SLs, endothelial function and reninangiotensin- aldosterone system (RAAS) plays an important role in the regulation of glomerular injury. SLs affect mitochondrial function that regulate the opening of mitochondrial permeability transition (MPT) pore, mitochondrial outer membrane permeability (MOMP), generation of reactive oxygen species (ROS), and expression of BcL-2 family proteins, which result in cytochrome c release and caspase activation, leading to apoptosis, and regulate glomerular cell proliferation or renal fibrosis. This review article summarizes the current evidence supporting a role of SLs metabolism defects in the pathogenesis and progression of glomerular injury and discusses a role of mitochondria, including MPT pore, MOMP, ROS generation, BcL-2 family proteins, interaction between SLs, endothelial function and RAAS, and SLs-induced downstream signaling events in CKDs. Crosstalk between these factors plays a role in the pathogenesis and progression of CKDs. Therapeutic strategy of targeting SLs metabolism defects for CKDs through modulation of the enzymes responsible for SLs metabolism defects is also discussed.

Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease

Iron deficiency anemia (IDA) is a major problem in chronic kidney disease (CKD), causing increased mortality. Ferritin stores iron, representing iron status. Hepcidin binds to ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin and hepcidin independent of iron status, which reduce iron availability. While intravenous iron therapy (IIT) is superior to oral iron therapy (OIT) in CKD patients with inflammation, OIT is as effective as IIT in those without. Inflammation reduces predictive values of ferritin and hepcidin for iron status and responsiveness to iron therapy. Upper limit of ferritin to predict iron overload is higher in CKD patients with inflammation than in those without. However, magnetic resonance imaging studies show lower cutoff levels of serum ferritin to predict iron overload in dialysis patients with apparent inflammation than upper limit of ferritin proposed by international guidelines. Compared to CKD patients with inflammation, optimal ferritin levels for IDA are lower in those without, requiring reduced iron dose and leading to decreased mortality. The management of IDA should differ between CKD patients with and without inflammation and include minimization of inflammation. Further studies are needed to determine the impact of inflammation on ferritin, hepcidin and therapeutic strategy for IDA in CKD.

Optimal Serum Ferritin Levels for Iron Deficiency Anemia during Oral Iron Therapy (OIT) in Japanese Hemodialysis Patients with Minor Inflammation and Benefit of Intravenous Iron Therapy for OIT-Nonresponders

Background: We determined optimal serum ferritin for oral iron therapy (OIT) in hemodialysis (HD) patients with iron deficiency anemia (IDA)/minor inflammation, and benefit of intravenous iron therapy (IIT) for OIT-nonresponders. Methods: Inclusion criteria were IDA (Hb <120 g/L, serum ferritin <227.4 pmol/L). Exclusion criteria were inflammation (C-reactive protein (CRP) ≥ 5 mg/L), bleeding, or cancer. IIT was withheld >3 months before the study. ΔHb ≥ 20 g/L above baseline or maintaining target Hb (tHB; 120–130 g/L) was considered responsive. Fifty-one patients received OIT (ferrous fumarate, 50 mg/day) for 3 months; this continued in OIT-responders but was switched to IIT (saccharated ferric oxide, 40 mg/week) in OIT-nonresponders for 4 months. All received continuous erythropoietin receptor activator (CERA). Hb, ferritin, hepcidin-25, and CERA dose were measured. Results: Demographics before OIT were similar between OIT-responders and OIT-nonresponders except low Hb and high triglycerides in OIT-nonresponders. Thirty-nine were OIT-responders with reduced CERA dose. Hb rose with a peak at 5 months. Ferritin and hepcidin-25 continuously increased. Hb positively correlated with ferritin in OIT-responders (r = 0.913, p = 0.03) till 5 months after OIT. The correlation equation estimated optimal ferritin of 30–40 ng/mL using tHb (120–130 g/L). Seven OIT-nonresponders were IIT-responders. Conclusions: Optimal serum ferritin for OIT is 67.4–89.9 pmol/L in HD patients with IDA/minor inflammation. IIT may be a second line of treatment for OIT-nonreponders.