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1.
Contrib Nephrol ; 185: 22-31, 2015.
Article in English | MEDLINE | ID: mdl-26023012

ABSTRACT

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. (1) Iron was sequestered in MHD-PMNLs, in which the protein governing iron transport was dysregulated. (2) TNF-α accelerated iron accumulation and oxidative stress in human umbilical vein endothelial cells in a manner similar to that in MHD-PMNLs. (3) An endosomal iron transport protein, or natural resistance-associated macrophage protein 1, was decreased in PMNLs from MHD patients, and TNF-α caused a decline in this protein's expression in control PMNLs. (4) The mitochondrial iron chaperone protein frataxin was decreased in MHD-PMNLs, which was linked to the acceleration of oxidative stress and hypercytokinemia. (5) The index of arterial stiffness was aggravated in MHD patients and was associated with serum hepcidin and TNF-α levels, which could inhibit iron exit from cells. With regard to bacterial infections, iron availability to these intracellular pathogens is critical for their growth. In particular, iron accumulation in cells and endosomes may accelerate the spread of infection. Cardiovascular disease has been shown to be linked to oxidative stress caused by iron sequestration in vascular cells and macrophages as well as by the alteration of iron metabolism in mitochondria, and the observed increase in hepcidin and TNF-α may accelerate these crucial steps of oxidative stress in vascular disease. Thus, because surplus iron in the body may escalate the dysregulation of iron metabolism, as observed in MHD patients, iron supplementation for renal anemia treatment should be prudent.


Subject(s)
Iron/metabolism , Kidney Failure, Chronic/physiopathology , Renal Dialysis/adverse effects , Tumor Necrosis Factor-alpha/pharmacology , Atherosclerosis/etiology , Atherosclerosis/mortality , Cation Transport Proteins/metabolism , Cause of Death , Cells, Cultured , Endosomes/metabolism , Hepcidins/blood , Human Umbilical Vein Endothelial Cells , Humans , Infections/etiology , Infections/mortality , Iron-Binding Proteins/metabolism , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/therapy , Neutrophils/metabolism , Oxidative Stress , Tumor Necrosis Factor-alpha/blood , Vascular Stiffness , Frataxin
2.
Am J Physiol Renal Physiol ; 306(12): F1393-9, 2014 Jun 15.
Article in English | MEDLINE | ID: mdl-24740789

ABSTRACT

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 BNx rats were divided into the following three groups: 1) the sham-operated group (BNx-Sham), 2) the BNx group, and 3) the HD group (BNx-HD), which received HD therapy 40-45 h after BNx. Sections of the liver or spleen were stained with Berlin blue to examine the accumulation of iron. The mRNA levels of hepcidin and ferroportin 1 in the spleen and liver were also quantified using RT-PCR. In the BNx group, the plasma iron and hematocrit levels were decreased, and hepcidin levels were increased. The iron staining in the spleen in the BNx group was significantly more intense than that in the BNx-Sham group; however, after an HD session, splenic iron staining diminished to the level of the sham group along with an increase in plasma iron and a decrease in hepcidin. BNx moved iron from hemoglobin and the plasma to the spleen, which is associated with an increase in plasma hepcidin. A single HD session accelerated the release of iron from the spleen, and the increased plasma iron was linked to the removal of hepcidin. Our data suggested that hepcidin might dynamically modulate the iron metabolism in BNx as well as in HD.


Subject(s)
Erythropoiesis/physiology , Iron/metabolism , Nephrectomy , Renal Dialysis , Spleen/metabolism , Animals , Cation Transport Proteins/metabolism , Hepcidins/metabolism , Kidney/surgery , Liver/metabolism , Male , Models, Animal , Rats , Rats, Sprague-Dawley
3.
Int J Artif Organs ; 36(9): 633-9, 2013 Oct 03.
Article in English | MEDLINE | ID: mdl-23918276

ABSTRACT

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. We measured hepcidin-25 levels at 0, 60, and 120 min in the blood samples. In vivo study: Blood samples were taken from 28 MHD patients at the start and end of HD sessions with PS or AN69. We measured serum levels of hepcidin 20, 22, and 25 by liquid chromatography tandem mass spectrometry, and also measured serum levels of urea nitrogen (UN), ß2microglobulin (MG). RESULTS: Ex vivo study: Although serum hepcidin 25 levels increased after the ex vivo session with PS, they significantly decreased with AN69. In vivo study: The reduction ratio of ß2MG by PS was significantly higher than that of AN69. On the other hand, there was no significant difference in the reduction ratio of hepcidin 20, 22, and 25 between PS and AN69. CONCLUSIONS: Both super-flux PS and AN69 similarly removed hepcidin 20 22, and 25. HD with PS might achieve a high removal ratio of hepcidin by enhanced diffusion performance and an increased clearance of small molecule solutes. On the other hand, AN69 might remove hepcidin by adsorption.


Subject(s)
Hepcidins/blood , Membranes, Artificial , Renal Dialysis/methods , Renal Insufficiency, Chronic/therapy , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Renal Insufficiency, Chronic/blood
4.
BMC Nephrol ; 14: 18, 2013 Jan 18.
Article in English | MEDLINE | ID: mdl-23327614

ABSTRACT

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. METHOD: Single session study: Seventeen patients were treated with A(+)D in one session and also treated with A(-)D in another session. Serum levels of pH, HCO3-, total (t)-calcium, ionized (i)-calcium, and int-PTH were evaluated at the beginning and the end of each session. Cross over study: A total of 29 patients with MHD were treated with A(+)D for 4 months, switched to A(-)D for next 4 months, and returned to A(+)D for the final 4 months. RESULTS: In single session study, serum i-calcium and t-calcium levels significantly increased, and int-PTH levels decreased after HD with A(+)D, whereas HD with A(-)D did not affect iCa and int-PTH. In cross over study, if all patients were analyzed, there was no significant difference in serum int-PTH or bone alkaline phosphatase (BAP) levels during each study period. In contrast, in the patients with low int-PTH (<60 pg/mL), serum levels of int-PTH and BAP were significantly increased during the A(-)D, without significant changes in serum t-calcium or i-calcium levels. CONCLUSION: A(-)D containing citrate could affect calcium and PTH levels, and, in 4 month period of crossover study, increased int-PTH levels pararelled with increasing BAP levels, exclusively in MHD patients with low int-PTH levels.


Subject(s)
Acidosis/chemically induced , Acidosis/prevention & control , Alkaline Phosphatase/blood , Citric Acid/chemistry , Hemodialysis Solutions/adverse effects , Hemodialysis Solutions/chemistry , Parathyroid Hormone/blood , Acetates/adverse effects , Acetates/chemistry , Acidosis/blood , Calcium/blood , Citric Acid/adverse effects , Female , Humans , Male , Middle Aged
5.
Clin Exp Nephrol ; 17(3): 424-30, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23180044

ABSTRACT

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. PMNLs were isolated by differential centrifugation. The mRNA levels of frataxin in isolated leukocytes were quantified by TaqMan real-time polymerase chain reaction. Frataxin protein expression in the cell lysate was evaluated using SDS-polyacrylamide gel electrophoresis and Western blotting. RESULTS: The frataxin/glyceraldehyde-3-phosphate dehydrogenase mRNA ratio in PMNLs from uremic patients was significantly lower than that in control subjects. Frataxin protein expression in uremic patients was also significantly lower than that in controls. Multiple regression analysis showed that frataxin mRNA levels were independently associated with the serum levels of both the oxidative stress marker malondialdehyde and the proinflammatory cytokine tumor necrosis factor-α. CONCLUSION: The downregulation of frataxin seems to be linked with uremic status, which is usually associated with chronic inflammation and the acceleration of oxidative stress. Mitochondrial iron regulation may play a role in several comorbidities and in the poor prognosis in uremic patients. Further investigation is needed to elucidate whether reduced frataxin levels are linked to the pathological status of uremic patients and whether uremic substances affect frataxin expression.


Subject(s)
Iron-Binding Proteins/biosynthesis , Renal Dialysis , Uremia/metabolism , Aged , Down-Regulation , Female , Humans , Kidney Failure, Chronic/metabolism , Male , Middle Aged , Mitochondrial Proteins/metabolism , Neutrophils/metabolism , RNA, Messenger/metabolism , Tumor Necrosis Factor-alpha/blood , Frataxin
6.
Am J Physiol Renal Physiol ; 303(7): F1080-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22811487

ABSTRACT

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 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) in the medulla of the kidney, which was partially ameliorated by fludrocortisone treatment. The incubation of IN-IC cells, an intercalated cell line established from temperature-sensitive SV40 large T antigen-expressing rats, with aldosterone or vasopressin increased the nuclear-to-cytoplasmic ratio of the MR from 11.2 to 47.2% and from 18.7 to 61.2%, respectively, in 30 min without any changes in MR expression from the whole cell extract. The immunohistochemistry analysis of the IN-IC cells revealed the nuclear accumulation of MRs after a 30-min incubation with aldosterone or vasopressin. These effects were accompanied by an increase in regulator of chromosome condensation-1 (RCC-1) due to aldosterone and a decrease in Ran GTPase-activating protein 1 (Ran Gap1) due to vasopressin. RNA interference against V1aR abolished the nuclear accumulation of MR induced by aldosterone or vasopressin. Vasopressin increased PKCα and -ß(1) expression, and aldosterone increased PKCδ and -ζ expression, but these effects were abolished with a V1aR knockdown. These results suggest that vasopressin directly regulates the nucleocytoplasmic transport of MRs via the V1aR in the intercalated cells of the collecting ducts.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Kidney Medulla/metabolism , Receptors, Mineralocorticoid/metabolism , Receptors, Vasopressin/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics , Animals , Cell Line , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cytoplasm/genetics , Cytoplasm/metabolism , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Mice , Mice, Knockout , Protein Transport/genetics , RNA Interference , Rats , Receptors, Mineralocorticoid/genetics , Receptors, Vasopressin/metabolism , Vasopressins/metabolism
7.
Am J Nephrol ; 35(4): 372-8, 2012.
Article in English | MEDLINE | ID: mdl-22508410

ABSTRACT

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. METHODS: Twenty MHD patients and 24 healthy volunteers (controls) were recruited. Relative quantitative PCR was used to measure Nramp1 mRNA, and protein levels were semiquantified by means of real-time PCR and Western blot analysis or immunohistochemistry. The effect of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) on Nramp1 expression in PMNLs from controls was also examined. RESULTS: Nramp1 mRNA and protein levels were substantially lower in PMNLs from MHD than control subjects. Serum TNF-α levels were significantly higher in the MHD group and were inversely correlated with Nramp1 mRNA levels. The addition of TNF-α to PMNLs from control subjects decreased mRNA and protein levels of Nramp1. IL-6 did not alter Nramp1 mRNA or protein expression. CONCLUSION: We found that Nramp1 was downregulated in the PMNLs of MHD patients, which constitute the first defense barrier against bacterial challenges. High levels of TNF-α may be associated with the downregulation of Nramp1. Our findings indicate that the susceptibility to infection observed in MHD patients could be partly due to the impairment of the intracellular handling of iron and the donation of more iron to the bacteria.


Subject(s)
Cation Transport Proteins/metabolism , Down-Regulation , Renal Insufficiency, Chronic/blood , Tumor Necrosis Factor-alpha/blood , Aged , Cation Transport Proteins/drug effects , Cation Transport Proteins/genetics , Cells, Cultured , Female , Humans , Interleukin-6/blood , Interleukin-6/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Renal Dialysis , Renal Insufficiency, Chronic/therapy , Tumor Necrosis Factor-alpha/pharmacology
8.
Clin Exp Nephrol ; 16(3): 448-55, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22270185

ABSTRACT

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. RESULTS: The standard deviation (SD) and residual SD (RSD) (liner regression of Hb or ferritin SD values) values of Hb were significantly correlated with ferritin SD or RSD values, respectively. The percentage achievement of target Hb in the target-ferritin group was significantly higher than in the high-amplitude fluctuation ferritin group. Ferritin SD and RSD values in patients with oral or no iron supplementation were significantly lower than those who received intravenous iron. CONCLUSION: Iron storage varies over a relatively wide range in HD patients, and this variation is closely associated with Hb cycling. The stability of iron storage and ESA dosage is important for maintaining stable Hb levels.


Subject(s)
Ferritins/blood , Hemoglobins/metabolism , Kidney Failure, Chronic/drug therapy , Renal Dialysis , Aged , Anemia/drug therapy , Female , Ferrous Compounds/therapeutic use , Hematinics/therapeutic use , Humans , Male , Middle Aged
9.
Artif Organs ; 36(3): 282-90, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21954915

ABSTRACT

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. Twenty-nine patients on MHD were treated with A(+)D for 4 months (first A(+)D), switched to A(-)D for 4 months, and returned to A(+)D for the next 4-month period (second A(+)D). Metabolic acidosis: Serum bicarbonate (HCO3(-) ) levels did not change in patients with normal HCO3(-) levels (≥20 mEq/L) throughout the study. Meanwhile, in patients with initially low HCO3(-) levels, it was significantly increased during the A(-)D period only. Anemia: In patients with target hemoglobin (Hb) ≥10 g/dL, Hb levels were maintained during the study period, even if the dose of erythropoiesis-stimulating agents (ESAs) decreased. In patients with low Hb levels, it was significantly increased in the A(-)D period without increasing ESA or iron doses. Nutritional Condition: In patients with normal albumin levels (≥3.8 g/dL), albumin did not change throughout the study period. However, in patients with lower albumin levels, it was significantly increased during the A(-)D period. These improvements in metabolic acidosis, anemia, and nutrition in the A(-)D period completely dissipated during the second A(+)D period. Hemodialysis (HD) with A(-)D may improve a patient's clinical status with intractable metabolic acidosis, hyporesponsiveness to ESA, and malnutrition that were not normalized in HD with A(+)D.


Subject(s)
Acidosis/therapy , Anemia/therapy , Citric Acid/therapeutic use , Dialysis Solutions/therapeutic use , Malnutrition/therapy , Renal Dialysis , Acetates/therapeutic use , Acid-Base Equilibrium , Acidosis/blood , Aged , Anemia/blood , Female , Humans , Male , Malnutrition/blood , Middle Aged , Renal Dialysis/methods
10.
J Ren Nutr ; 22(1): 12-8.e1, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21752669

ABSTRACT

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. METHODS: A total of 187 patients on dialysis participated in the present prospective observational study and were followed up for 107 months. Baseline cross-sectional analysis of the relationship between Hcy and several factors related to its metabolism was performed, along with survival analysis for the occurrence of CVD. All subjects were divided into the Increase or Decrease of Hcy group on the basis of changes in Hcy from baseline to year 3. RESULTS: The occurrence of CVD was higher in the Increase (30.1%) than in the Decrease group (9.0%). Greater change of Hcy was associated with risk of CVD (hazard ratio: 3.658) after adjusting basic factors and nutritional status. In stepwise multiple analyses, serum folate, vitamin B(12), cysteine, creatinine, and body mass index were considered to be independent predictors of Hcy. CONCLUSIONS: These data show that increase in Hcy is a powerful predictor of the occurrence of CVD in patients on dialysis.


Subject(s)
Cardiovascular Diseases/epidemiology , Homocysteine/blood , Renal Dialysis , Body Mass Index , Cardiovascular Diseases/etiology , Creatinine/blood , Cross-Sectional Studies , Folic Acid/blood , Homocysteine/metabolism , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Middle Aged , Prospective Studies , Vitamin B 12/blood
12.
Nephrol Dial Transplant ; 26(10): 3092-100, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21785039

ABSTRACT

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. Intestinal iron absorption is tightly regulated by both iron stores and hepcidin. The expression of the mammalian iron exporter, ferroportin (FPN), limits the growth of intracellular bacteria by depleting cytosolic iron. An upregulation of hepcidin could diminish FPN and favor bacterial growth. Of note, in patients with hyperferritinemia impaired hepcidin expression caused by a mutation in the hemochromatosis gene associates with an attenuation of atherosclerosis. Thus, hepcidin might accelerate atherosclerosis by preventing iron exit from macrophages or other cells in the arterial wall. High hepcidin levels have also been found to be linked to good erythropoiesis-stimulating agents (ESAs) response, in conjunction with the strong hepcidin-ferritin correlation. Finally, hepcidin may also play a significant role by itself in the pathogenesis of CKD complications associated with disturbed iron metabolism, i.e. unrelated to ESA hyporesponsiveness, such as bacterial infections and atherosclerosis.


Subject(s)
Anti-Bacterial Agents/adverse effects , Antimicrobial Cationic Peptides/adverse effects , Iron Overload/etiology , Kidney Failure, Chronic/complications , Hepcidins , Humans
13.
ASAIO J ; 57(4): 293-9, 2011.
Article in English | MEDLINE | ID: mdl-21499075

ABSTRACT

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. After this, the patients were switched to acrylonitrile-co-methallyl sulfonate (AN69) membranes for the next 3 months and then returned to PSu for another 3 months. Reduction ratio of inflammatory cytokines (interleukin [IL]-6) by AN69 was significantly higher than the reduction ratio by PSu. After 3 months with AN69, the serum total protein, albumin, and cholesterol levels significantly increased, and after switching back to PSu, the levels returned to baseline. Furthermore, the frequency of saline used to treat episodes of hypotension during HD significantly decreased in the AN69 period. In elderly MHD patients, it was possible to achieve improvements in both malnutrition and chronic inflammatory conditions with AN69. This suggests that AN69 may be the preferred membrane for elderly MHD, because it stabilizes the hemodynamic condition and demonstrates a higher removal of inflammatory cytokines during HD.


Subject(s)
Acrylic Resins/chemistry , Acrylonitrile/analogs & derivatives , Acrylonitrile/chemistry , Alkanesulfonates/chemistry , Polymers/chemistry , Sulfones/chemistry , Aged , Cardiovascular System , Cross-Over Studies , Female , Hemodynamics , Humans , Inflammation , Interleukin-6/metabolism , Male , Membranes, Artificial , Middle Aged , Nutritional Sciences , Renal Dialysis
14.
J Am Soc Nephrol ; 22(4): 673-80, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21415155

ABSTRACT

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. The administration of the mineralocorticoid agonist fludrocortisone ameliorated the acidosis by restoring excretion of urinary ammonium via increased expression of Rhcg and H-K-ATPase and decreased expression of H-ATPase. In a cell line of intercalated cells established from transgenic rats expressing the mineralocorticoid and V1a receptors, but not V2 receptors, knockdown of the V1a receptor gene abrogated the effects of aldosterone on H-K-ATPase, Rhcg, and H-ATPase expression. These data suggest that defects in the vasopressin V1a receptor in intercalated cells can cause type 4 renal tubular acidosis and that the tubular effects of aldosterone depend on a functional V1a receptor in the intercalated cells.


Subject(s)
Acid-Base Equilibrium/physiology , Aldosterone/metabolism , Homeostasis/physiology , Kidney Tubules, Collecting/metabolism , Receptors, Vasopressin/metabolism , Acid-Base Equilibrium/drug effects , Aldosterone/pharmacology , Animals , Cation Transport Proteins/metabolism , Cell Line , Fludrocortisone/pharmacology , Homeostasis/drug effects , Kidney Tubules, Collecting/cytology , Kidney Tubules, Collecting/drug effects , Membrane Glycoproteins/metabolism , Mice , Mice, Knockout , Mineralocorticoids/agonists , Models, Animal , Proton-Translocating ATPases/metabolism , RNA Interference , Rats , Rats, Transgenic , Receptors, Vasopressin/deficiency , Receptors, Vasopressin/genetics
15.
J Clin Neurosci ; 18(4): 478-80, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21315606

ABSTRACT

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. We treated eight patients with anti-AQP4 antibody-positive MS with double filtration plasmapheresis (DFPP) to remove the antibody. Improvement of vision was observed in two patients. Motion improvement was seen in seven patients. Sensory improvement was observed in four patients. In total, six out of eight patients (75%) showed therapeutic improvement after DFPP treatment. We propose that DFPP might be an effective therapeutic option for patients with anti-AQP4 antibody-positive MS.


Subject(s)
Neuromyelitis Optica/therapy , Plasmapheresis/methods , Adult , Aged , Aquaporin 4/immunology , Autoantibodies/immunology , Autoantigens/immunology , Female , Humans , Male , Middle Aged , Neuromyelitis Optica/immunology
16.
Ther Apher Dial ; 15(1): 28-33, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21272249

ABSTRACT

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. Plasma malondialdehyde was measured as a surrogate marker of lipid peroxidation. The plasma exchange effluent from two patients who had undergone plasma exchange (for the treatment of systemic lupus erythematosus and acute myeloblastic leukemia) was collected and treated to obtain the human ferritin-rich fraction. Iron release from ferritin was examined using bathophenanthroline sulfate. The influence of antioxidants and different pH levels on iron release were investigated. Plasma ALA and malondialdehyde concentration in the hemodialysis patient was significantly higher than that in healthy subjects. ALA was positively correlated with malondialdehyde. The abundance of iron release was dependent on the ALA concentration and incubation time. Iron release at the high pH of 7.6 was decreased compared with that at pH 7.4. Citrate increased iron release at pH 7.4, but citrate-stimulated iron release was totally abolished at pH 7.6. Our study suggests that ALA accumulation may have a role to play in certain complications in uremic patients, such as oxidative stress, by releasing iron from ferritin.


Subject(s)
Aminolevulinic Acid/blood , Ferritins/metabolism , Kidney Failure, Chronic/metabolism , Antioxidants , Female , Humans , Hydrogen-Ion Concentration , Iron/metabolism , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/therapy , Male , Middle Aged , Oxidative Stress , Renal Dialysis , Uremia
17.
Nephrol Dial Transplant ; 26(8): 2663-7, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21245128

ABSTRACT

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. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. RESULTS: Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and hepcidin were higher in MHD patients, which was consistent with results from our previous study. ba-PWV significantly correlated with age (P < 0.01, R = 0.34), total cholesterol (T-CHO; P = 0.02, R = 0.21), TNF-α (P < 0.01, R = 0.24) and hepcidin (P < 0.01, R = 0.25) but not with other iron parameters and CVD risk factors. According to multiple regression analysis, age (ß = 0.30), T-CHO (ß = 0.24) TNF-α (ß = 0.19) and hepcidin (ß = 0.23) were selected as the significant predictors of ba-PWV in MHD patients. CONCLUSION: Serum levels of both hepcidin and TNF-α are independently associated with arterial stiffness in MHD patients, suggesting that microinflammation and iron metabolism might affect the integrity of arterial walls.


Subject(s)
Antimicrobial Cationic Peptides/blood , Biomarkers/metabolism , Renal Dialysis/adverse effects , Tumor Necrosis Factor-alpha/blood , Vascular Stiffness , Blood Flow Velocity , Female , Follow-Up Studies , Glomerular Filtration Rate , Hepcidins , Humans , Interleukin-6/blood , Kidney Failure, Chronic/therapy , Kidney Function Tests , Male , Middle Aged , Prognosis , Pulsatile Flow , Risk Factors , Survival Rate
18.
Am J Nephrol ; 32(5): 439-46, 2010.
Article in English | MEDLINE | ID: mdl-20881381

ABSTRACT

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. Therefore, high levels of serum ferritin in patients on MHD can be used to indicate iron deposition in most cells, including vascular and immunocompetent cells, and is still a reliable indicator of the need to withhold iron administration.


Subject(s)
Anemia, Iron-Deficiency/drug therapy , Ferritins/blood , Kidney Failure, Chronic/physiopathology , Renal Dialysis/adverse effects , Anemia, Iron-Deficiency/etiology , Antimicrobial Cationic Peptides/blood , Cytokines/physiology , Hepcidins , Humans , Iron/therapeutic use , Kidney Failure, Chronic/complications
19.
ASAIO J ; 56(5): 488-90, 2010.
Article in English | MEDLINE | ID: mdl-20811173

ABSTRACT

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. In this case, although it was possible to maintain a relatively stable hemodynamic condition during HD using 10 mEq/L of acetate-containing dialysate [A(+)D], after HD using A(-)D for 4 months and then switched back to A(+)D, the patient complained of several symptoms such as nausea, vomiting, and headache, and severe hypotension episodes increased during HD. Furthermore, stabilization of the hemodynamic condition was obtained after switching back to A(-)D. Moreover, the nutritional state and anemia were improved. Conventionally, it has been considered that cases referred to as acetate intolerance have various symptoms with increasing blood acetate levels; however, this case suggests the possibility that tolerance to acetate was acquired by using the A(+)D over time, and the tolerance dissipated after using the A(-)D for 4 months. The number of cases involving broadly defined acetate intolerance as in this case was higher than expected. These findings suggest that using A(-)D for such cases, it may therefore be possible to maintain stable hemodynamic conditions during HD and improve the nutritional state and anemia.


Subject(s)
Acetates/adverse effects , Hemodialysis Solutions/adverse effects , Hemodialysis Solutions/chemistry , Renal Dialysis/adverse effects , Renal Dialysis/methods , Aged , Clinical Trials as Topic , Diabetic Nephropathies/therapy , Headache/etiology , Humans , Hypotension/etiology , Male , Nausea/etiology , Vomiting/etiology
20.
Am J Nephrol ; 31(6): 534-40, 2010.
Article in English | MEDLINE | ID: mdl-20484891

ABSTRACT

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. RESULTS: In multivariate analysis, only transferrin and ferritin were selected as significant predictors of hepcidin in all patients. In the selected patients with highly sensitive C-reactive protein of >0.3 mg/dl, however, ferritin as well as the IL-6 level were found to be significant predictors for serum hepcidin. The serum ferritin/hepcidin ratio was very similar among MHD and healthy volunteers, suggesting that uremic conditions do not affect the ratio. Serum hepcidin levels decreased by only 27% after a single hemodialysis session, but returned to basal levels 1 h after and remained so until the next hemodialysis session. CONCLUSIONS: In the absence of apparent inflammation, the serum hepcidin level could be exclusively associated with ferritin in MHD patients and was independent of inflammatory cytokines. Only in the presence of microinflammation, however, might IL-6 also affect hepcidin expression.


Subject(s)
Antimicrobial Cationic Peptides/blood , Renal Dialysis , Adult , Aged , Case-Control Studies , Chromatography, Liquid , Female , Hepcidins , Humans , Male , Middle Aged
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