Dysregulated iron metabolism in patients on hemodialysis.

The two main causes of death in patients on maintenance hemodialysis (MHD) are cardiovascular disease and infection. In the current report, we discuss the association of the iron-catalyzed Fenton reaction and iron sequestration with complications in MHD patients. In particular, we have studied the deregulation of several iron transport systems of polymorphonuclear leukocytes (PMNLs) and the effects of TNF-α on human umbilical vein endothelial cells or PMNLs obtained from MHD patients and controls, and the following results were obtained.

Hemodialysis restored iron distribution that was sequestered in the spleen by bilateral nephrectomy.

Acute kidney injury (AKI) is associated with dysregulated iron metabolism, which may play a significant role in cellular injury. The effect of hemodialysis (HD) on iron metabolism in AKI therapy has not been well defined. The effects of HD on iron parameters were tested in control rats and bilateral nephrectomy (BNx) rats.

The removal of serum hepcidin by different dialysis membranes.

Purpose: Hepcidin has been suspected to be associated with anemia of chronic disease, which is commonly observed in patients with maintenance hemodialysis (MHD). As almost of hepcidin is bounded to protein, it is essential to clarify which kind of dialysis membrane can remove it efficiently.

Methods: Ex vivo study: 50 mL of whole blood from healthy volunteers were circulated for 2 h in a microcircuit with mini-dialyzers (acrylonitrile-co-methallyl sulfonate (AN69) or polysulfone (PS)) without ultrafiltration.

Acetate free citrate-containing dialysate increase intact-PTH and BAP levels in the patients with low intact-PTH.

Background: Recently, acetate-free citrate containing dialysate (A(-)D) was developed. We have already reported about the significant effect of A(-)D on metabolic acidosis, anemia, and malnutrition in maintenance hemodialysis (MHD) patients. In this study, we compared the effect of A(-)D and acetate containing dialysate (A(+)D) on serum calcium and intact-parathyroid hormone (int-PTH) levels.

The mitochondrial protein frataxin is downregulated in hemodialysis patients.

Background: The mitochondrial protein frataxin regulates iron metabolism for heme and iron sulfur cluster synthesis in the mitochondria and could be associated with the regulation of oxidative stress. To clarify the expression of frataxin and its association with uremia, we evaluated the mRNA and protein levels of frataxin in the polymorphonuclear leukocytes (PMNLs) of patients on hemodialysis (HD).

Methods: Uremic patients on HD (n = 18) and healthy control subjects (n = 18) were investigated.

Vasopressin V1a receptor is required for nucleocytoplasmic transport of mineralocorticoid receptor.

We previously reported that a deficiency in the vasopressin V1a receptor (V1aR) results in type 4 renal tubular acidosis, which suggests that vasopressin exerts direct effects on the physiological actions of aldosterone. We investigated the role of vasopressin for nucleocytoplasmic transport of mineralocorticoid receptor (MR) in the intercalated cells. Vasopressin V1aR-deficient (V1aR(-/-)) mice showed largely decreased expression of MR and 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) in the medulla of the kidney, which was partially ameliorated by fludrocortisone treatment.

High levels of tumor necrosis factor-α downregulate antimicrobial iron transport protein, Nramp1, in chronic hemodialysis patients: a key factor for infection risk.

Background/aims: The susceptibility of patients on maintenance hemodialysis (MHD) to infections is a major cause of mortality and morbidity. Natural resistance-associated macrophage protein 1 (Nramp1) regulates intracellular pathogen proliferation, and its mRNA expression is highest in polymorphonuclear leukocytes (PMNLs). The purpose of this study was to determine the level of Nramp1 in PMNLs from MHD patients and the factors affecting its expression.

The impact of ferritin fluctuations on stable hemoglobin levels in hemodialysis patients.

Background: Hemoglobin (Hb) cycling in patients with renal anemia might be associated with a higher mortality rate. We investigated the association of factors relating serum ferritin and dose of erythropoiesis-stimulating agents (ESAs) with Hb levels.

Methods: We measured Hb and ferritin levels every month in 266 hemodialysis (HD) patients for 12 months.

Effects of acetate-free citrate-containing dialysate on metabolic acidosis, anemia, and malnutrition in hemodialysis patients.

Previously, dialysate contained small amounts of acetate as an alkaline buffer. Recently, acetate-free dialysate (A[-]D) has been available. We evaluated the clinical effect of A(-)D over acetate-containing dialysate (A(+)D) on acid-base balance, anemia, and nutritional status in maintenance hemodialysis (MHD) patients.

Hepcidin: another culprit for complications in patients with chronic kidney disease?

Hepcidin has been established as a central regulator of iron metabolism. In most patients with chronic kidney disease (CKD), serum hepcidin levels are relatively high, favoring iron sequestration in several cell types and organs and thereby leading to iron-related complications. In the absence of overt inflammation, serum hepcidin has been found to be most closely associated with serum ferritin in healthy subjects and in CKD patients.

Persistent homocysteine metabolism abnormality accelerates cardiovascular disease in hemodialyzed patients--the Nishinomiya Study.

Objective: Homocysteine (Hcy) is an intermediate in sulfur amino acid metabolism and may induce oxidative stress. Several studies have reported that elevated Hcy in end-stage renal failure may contribute to cardiovascular disease (CVD). The purpose of this study is to investigate whether the changes in Hcy levels correlate better with the CVD outcomes than baseline Hcy level.

A crossover study of the acrylonitrile-co-methallyl sulfonate and polysulfone membranes for elderly hemodialysis patients: the effect on hemodynamic, nutritional, and inflammatory conditions.

Many maintenance hemodialysis (MHD) patients have recently been treated with high flux (HF) dialysis membranes such as polysulfone (PSu) membranes. However, the appropriateness of HF for elderly MHD remains to be elucidated. In order to estimate hemodialysis (HD) efficiency, the hemodynamic condition during HD, and the nutritional status, 28 elderly MHD patients were treated with PSu for 3 months.

Aldosterone requires vasopressin V1a receptors on intercalated cells to mediate acid-base homeostasis.

Both aldosterone and luminal vasopressin may contribute to the maintenance of acid-base homeostasis, but the functional relationship between these hormones is not well understood. The effects of luminal vasopressin likely result from its interaction with V1a receptors on the luminal membranes of intercalated cells in the collecting duct. Here, we found that mice lacking the V1a receptor exhibit type 4 renal tubular acidosis.

Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis.

Multiple sclerosis (MS) in Asian countries, including Japan, is classified into two types: conventional MS (C-MS), characterized mainly by cerebral lesions, and opticospinal MS (OS-MS) or neuromyelitis optica (NMO), characterized by selective involvement of the optic nerve and spinal cord. Recently, a serum immunoglobulin-G-antibody was discovered in patients with NMO that targets aquaporin-4 (AQP4). The existence of the anti-AQP4 antibody shows the pathogenetic role of humoral immune factors in OS-MS/NMO.

Pathological role of aminolevulinate in uremic patients.

Previous reports have demonstrated that δ-aminolevulinate (ALA) can promote iron release from horse spleen ferritin under conditions of high serum ALA levels in uremia; therefore, we speculated that the accumulated ALA in uremic patients would stimulate iron release from ferritin, resulting in accelerated oxidative stress and uremic complications. We measured the plasma ALA of uremic patients and examined the ALA-induced iron release from human ferritin. The participants consisted of 30 hemodialysis patients and 14 healthy subjects.

Hepcidin as well as TNF-α are significant predictors of arterial stiffness in patients on maintenance hemodialysis.

Background: Dysregulated iron metabolism has been suspected to be linked to anemia of chronic disease and to cardiovascular disease (CVD). For the purpose of clarifying the factors affecting arterial stiffness, we evaluated the relationship between iron metabolism, brachial-ankle (ba)-pulse wave velocity (PWV) and several risk factors for CVD in maintenance hemodialysis (MHD) patients.

Methods: A total of 168 MHD patients were recruited, and the levels of iron parameters, hepcidin, CVD risk factors and ba-PWV were evaluated.

Importance of ferritin for optimizing anemia therapy in chronic kidney disease.

The clinical significance of serum ferritin in monitoring the iron status of patients on maintenance hemodialysis (MHD) has become suspected. In this review, we reassess the interpretation of high serum ferritin values in such patients, with the goal of treating their anemia in a safe way. From the observations that (1) H-ferritin gene transcription is predominantly active in inflammatory conditions, whereas L-ferritin is induced only after exposure to very high iron concentrations and is preferentially secreted to plasma from hepatocytes; (2) the expression of both types of ferritin proteins are exclusively dependent on intracellular free iron, which is often sequestered by LPS or cytokines in several cell types, and (3) splenic iron is depleted and serum ferritin does not increase in the combined conditions of both inflammation and iron deficiency, it is deduced that elevated serum ferritin levels are caused by the accumulation of intracellular iron, especially reticuloendothelial cells or macrophages, hepatocytes, and other cells, while cytokines or inflammation might modulate the relative ratio of ferritin to body iron storage.

A case of a maintenance hemodialysis patient in whom a change of sensitivity to acetate was suspected.

Sodium acetate, which is a buffering agent in dialysates, has a vasodilatation effect as well as effects for depression of myocardial contractility even in low dosages. Also, it is presumed to be one of the causes of hypotension during hemodialysis (HD). In recent years, acetate-free dialysates [A(-)D] have been developed.

Determinants of hepcidin in patients on maintenance hemodialysis: role of inflammation.

Background/aim: Hepcidin could be one of the most important regulators for iron metabolism in patients on maintenance hemodialysis (MHD). The factors affecting serum hepcidin levels were evaluated among indexes of anemia, iron metabolism, or inflammation, as well as the dose of erythropoietin.

Methods: 198 MHD patients treated with recombinant human erythropoietin were recruited and serum hepcidin-25 levels were specifically measured by liquid chromatography tandem mass spectrometry.

Serum ferritin predicts prognosis in hemodialysis patients: the Nishinomiya study.

Background: The mortality in end-stage renal disease patients with dialysis remains high. Serum ferritin is a useful surrogated marker of iron storage. It has not been elucidated whether the ferritin level can predict the prognosis of patients with dialysis but without obvious inflammation.

The impact of beta2-microglobulin clearance on the risk factors of cardiovascular disease in hemodialysis patients.

beta2-Microglobulin (beta2M) is an independent predictor of outcome for hemodialysis (HD) patients and a representative substance of middle molecules. We tested the relationship among serum beta2M levels and cardiovascular disease (CVD) risk factors in HD patients. A total of 132 HD patients were divided according to the dialysis membrane used [property; cellulose and synthetic or beta2M clearance; low filtration (LF), middle filtration (MF), and high filtration (HF)].

Interleukin-6 is a predictor of mortality in stable hemodialysis patients.

Background/aims: Mortality in end-stage renal disease patients with dialysis remains high. A high percentage of dialysis patients display signs of chronic microinflammation. To clarify whether microinflammation is involved in the high incidence of poor prognosis in dialysis patients, we investigated the association of inflammatory markers with mortality in a prospective observational cohort study.

Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells.

Objective: Tumor necrosis factor (TNF)-alpha-induced endothelial injury, which is associated with atherosclerosis, is mediated by intracellular reactive oxygen species. Iron is essential for the amplification of oxidative stress. We tested whether TNF-alpha accelerated iron accumulation in vascular endothelium, favoring synthesis of hydroxyl radical.