Hemodiafiltration Improves Low Levels of Health-Related Quality Of Life (Qol) and Nutritional Conditions of Hemodialysis Patients.

We compared the effects on the nutritional condition and health-related quality of life (HR-QoL) of the treatment of patients with on-line hemodiafiltration (OL-HDF) and conventional hemodialysis (CHD) using a superflux dialyzer. In total, 47 maintenance (M) HD patients were treated by CHD with a high-flux dialyzer for the first 4 months (1st CHD) and were then switched to predilution OL-HDF for the next 4 months (OL-HDF), after which CHD was resumed for the last 4 months (2nd CHD). We assessed the clinical parameters, fat mass value, muscle mass value, and HR-QoL. In patients with low serum albumin levels, these levels significantly (p < 0.05) increased in the OL-HDF period. Moreover, the fat mass values significantly (p < 0.05) increased in patients with decreased fat mass values in the OL-HDF period. Although there was no significant difference in the patients with higher scores of physical functioning, role physical, vitality, and social functioning, patients with lower scores in the 1st CHD period had significantly increased (p < 0.05) in the OL-HDF period. In this crossover study, we revealed that OL-HDF treatment significantly improved the nutritional conditions and HR-QoL scores compared with the improvement observed after CHD with a superflux dialyzer, especially for maintenance hemodialysis patients with malnutrition and a low QoL.

Long-acting erythropoiesis-stimulating agent (ESA) induces physiological erythropoiesis via improvement of iron availability.

PURPOSE: Previous studies reported that the long-acting erythropoiesis-stimulating agent (ESA) significantly suppresses the expression of hepcidin, which regulates iron availability. In this study, we compared the iron availability for erythropoiesis between short and long-acting ESA over a long period. METHODS: We enrolled 69 hemodialysis patients in this study. All patients were treated with short-acting ESA (epoetin-α or epoetin-ß) for the first 30 months. Then, all patients switched to long-acting ESA (continuous erythropoietin receptor activator-methoxy polyethylene glycol-epoetin beta) for the next 30 months. We measured their blood levels of Hb, ferritin, iron, total iron-binding capacity, intact-parathyroid hormone, calcium, phosphate, albumin, and highly sensitive CRP level. RESULTS: There was no significant change in the dose of short or long-acting ESA during the study period. Compared with the short-acting ESA period, the mean hemoglobin (Hb) and transferrin saturation levels were significantly increased in the long-acting ESA period (from 10.3 ± 0.2 to 10.6 ± 0.3 g/dL). On the other hand, the mean serum ferritin level (from 72 ± 22.2 to 56.3 ± 14 ng/mL) and the dose of IV iron (from 108 ± 63 to 53 ± 27 mg/month) were significantly decreased in the long-acting ESA period. CONCLUSION: In this study, we found that anemia treatment with long-acting ESA attenuated the iron utilization for erythropoiesis and maintained target Hb levels without requiring a higher dose of IV iron or ESA.

The pharmacokinetics of oral metronidazole in patients with metronidazole-induced encephalopathy undergoing maintenance hemodialysis.

BACKGROUND: Metronidazole-induced encephalopathy (MIE) is a rare disease caused by an adverse reaction to metronidazole (MNZ). Furthermore, the pharmacokinetics of MNZ during hemodialysis (HD) treatment have not been revealed. CASE PRESENTATION: In a 70-year-old woman undergoing maintenance HD, MNZ was administered intermittently for the treatment of recurrent hepatic cyst infections. She complained of vomiting, dizziness, and dysarthria after 65 consecutive days of MNZ administration. In brain fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), we found a high signal intensity in the cerebellar dentate nuclei and splenium of the corpus callosum. We diagnosed the patient with MIE. MNZ administration was withdrawn immediately, and HD treatment was performed for 3 consecutive days. Accompanying the remarkable decrease in serum MNZ levels, MIE symptoms were attenuated after three consecutive days of HD. In a brain MRI at 9 days, the high-intensity areas in the cerebellar dentate nuclei and splenium of the corpus callosum had disappeared. CONCLUSION: In this patient, we diagnosed MIE in the early stage using MRI, and 3 consecutive days of HD rapidly attenuated the symptoms associated with MIE, accompanied by a significant decrease in serum MNZ levels.

Clinical Benefit of an Adsorptive Technique for Elderly Long-Term Hemodialysis Patients.

BACKGROUND: With the advancement of technology, a dialysis membrane has been developed to achieve the efficient removal of beta-2 microglobulin (ß2MG), which could not be removed with previous hemodialysis (HD) membranes. Recently, there has been an increase in the population of elderly chronic kidney disease (CKD) patients with chronic inflammation and malnutrition. The optimal extracorporeal circulation treatment for elderly CKD patients is not certain. SUMMARY: We have reported the clinical advantages, such as improvements in nutritional, inflammatory, and hemodynamic conditions, of the adsorptive HD membrane for elderly HD patients. We have also reported that the use of ß2MG adsorption columns improved the symptoms of dialysis-related amyloidosis and the number of bone cysts, which could not be improved by the high-flux hemodialyzer. Both the adsorptive HD membrane and ß2MG adsorption columns remove uremic toxins and inflammatory cytokines via adsorption without aggravating the nutritional condition of these patients. Key Messages: We should reconsider the mechanisms of adsorption, in addition to diffusion and convection, in the extracorporeal circulation treatment of elderly HD patients.

Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis-Effect on Fibroblast Growth Factor-23 Metabolism.

OBJECTIVE: Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. DESIGN AND METHODS: A prospective randomized study. SUBJECTS: Participants on MHD with severe iron deficiency (n = 61). INTERVENTION: Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32). MAIN OUTCOME MEASURE: Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. RESULTS: Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. CONCLUSION: Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

Novel iron-containing phosphate binders and anemia treatment in CKD: oral iron intake revisited.

Recent reports have shown that novel phosphate binders containing iron are not only efficacious for the treatment of hyperphosphatemia but also may reduce the need for erythropoiesis-stimulating agents and intravenous (IV) iron for anemia management in patients on maintenance hemodialysis (MHD). Possible healthcare cost savings, which have not been demonstrated in a long-term study, may be an additional advantage of using such multi-pronged treatment strategies for the control of both hyperphosphatemia and iron needs. It is currently assumed that oral iron supplementation is less efficient than the IV route in patients with chronic kidney disease (CKD). The unexpected efficacy of novel iron-containing phosphate binders, such as ferric citrate, in repleting insufficient iron stores and improving the anemia of CKD could change this view. Previous assumptions of self-controlled iron uptake by 'mucosal block' or hepcidin, or else by impaired intestinal iron absorption due to CKD-associated inflammation cannot be reconciled with recent observations of the effects of ferric citrate administration. Citrate in the intestinal lumen may partly contribute to the acceleration of iron absorption. Animal experiments and clinical studies have also shown that oral iron overload can cause excessive iron accumulation despite high hepcidin levels, which are not able to block iron absorption completely. However, like with IV iron agents, no long-term safety data exist with respect to the effects of iron-containing phosphate binders on 'hard' patient outcomes. Future randomized prospective studies in patients with CKD are necessary to establish the safety of oral iron-containing phosphate binders for the control of both hyperphosphatemia and renal anemia.

Effect of protoconized therapy for renal anemia on adverse events of patients with maintenance hemodialysis.

PURPOSE: We evaluate the effect of the protoconized anemia therapy on adverse events using the Hb and ferritin levels of individual patients undergoing maintenance hemodialysis (MHD). METHODS: Design: A randomized, parallel group, multi-center study. PATIENTS: Two hundred sixty-six MHD patients. Intervention group: The doses of erythropoietin, iron, and vitamin C were adjusted every month based on the ferritin and hemoglobin (Hb) levels according to the protocol. Non-intervention group: The attending physician determined the doses of erythropoietin and iron. RESULTS: The maintenance rate of target Hb and ferritin levels were significantly higher in the Intervention group than in the Non-intervention group. The frequency of hospitalization was significantly lower for patients with a higher maintenance rate of target Hb levels than for those with a lower maintenance rate. CONCLUSIONS: Using an anemia treatment protocol according to the individual Hb and ferritin levels of hemodialysis patients might stabilize the Hb and ferritin levels, which in turn could contribute to the lower frequency of adverse events in MHD patients.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. To clarify whether the ferritin level is involved in the prognosis in dialyzed patients, we investigated the relation between ferritin level and mortality in hemodialyzed patients during long-term follow-up. METHODS: Ninety stable hemodialyzed patients were enrolled and followed for 107 months. Serum ferritin and related factors (dialysis, nutrition, iron metabolism, inflammation and oxidative stress) were measured and used for statistical analysis. Survival analysis of death for ferritin as a predictive variable was performed. RESULTS: A relatively high level of serum ferritin (> or =100 ng/ml) was associated with poor prognosis after adjustment for basic factors and C reactive protein (hazard ratio, 4.18). Hemoglobin-stratified Kaplan-Meier analysis showed that the prognosis for the high ferritin-low hemoglobin group was significantly poor. CONCLUSION: This study suggests that the ferritin level is closely associated with high mortality in hemodialyzed patients. Further studies investigating the pathological role of iron storage on survival of hemodialyzed patients with large populations are needed.