Aritoshi Kida

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. 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.

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 (β = 0.30), T-CHO (β = 0.24) TNF-α (β = 0.19) and hepcidin (β = 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.

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. Methods: 120 patients undergoing hemodialysis were enrolled. Baseline cross-sectional analysis of the relationship between inflammatory markers [interleukin-6 (IL-6), tumor necrosis factor-α and high-sensitivity C-reactive protein] and other factors, along with a survival analysis for death, were performed. All subjects were divided into 2 groups according to the median value of IL-6. Results: The mortality rate was significantly higher in the high (20.0%) compared with the low IL-6 group (3.3%, p = 0.0046). Receiver-operating characteristic curves indicated high mortality to be closely associated with a high IL-6 level rather than tumor necrosis factor-α. In stepwise multiple regression analyses, age, phosphorus and high-sensitivity C-reactive protein were independent predictors of IL-6 (R2 = 0.466, p < 0.0001). Conclusions: These data clearly show that plasma IL-6 is a powerful predictor of all-cause mortality in dialysis 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. 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.

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 patients clinical status with intractable metabolic acidosis, hyporesponsiveness to ESA, and malnutrition that were not normalized in HD with A(+)D.

The Impact of β2-Microglobulin Clearance on the Risk Factors of Cardiovascular Disease in Hemodialysis Patients

&bgr;2-Microglobulin (&bgr;2M) is an independent predictor of outcome for hemodialysis (HD) patients and a representative substance of middle molecules. We tested the relationship among serum &bgr;2M 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 &bgr;2M clearance; low filtration (LF), middle filtration (MF), and high filtration (HF)]. There was no significant difference in CVD risk factors between cellulose and synthetic groups. On the other hand, serum &bgr;2M, highly-sensitive C-reactive protein (hCRP), troponin-T (TnT), and myeloperoxidase (MPO) levels of LF were significantly higher and those of prealbumin (PA) were lower than the MF and HF. Serum &bgr;2M level was positively correlated with hCRP, interleukin-6 (IL-6), tumor necrosis factor-&agr; (TNF-&agr;), MPO, TnT, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and inversely correlated with PA and ankle-brachial index (ABI). There was a significant correlation between serum &bgr;2M levels and various CVD risk factors in HD. Cardiovascular disease risk factors in HD patients were dependent on the &bgr;2M clearance but not membrane property.

The beneficial effect of effective control of anemia on hyperinsulinemia and hypoxemia in a hemodialysis patient with corrected transposition of the great arteries

We report the beneficial effect of control of anemia on hyperinsulinemia and hypoxemia in a hemodialysis patient with corrected transposition of the great arteries. The patient’s hemoglobin (Hb) level of 10.3 g/dl on admission represents good control for hemodialysis (HD) patients, but it was too low for this patient with secondary polycythemia because of a right-to-left shunt. Control of anemia for a 10-month period was followed by a marked increase in Hb level (from 10.3 g/dl to 13.9 g/dl) and in aerobic work capacity, while the fasted insulin level decreased from 36.7 µU/ml to 8.0 µU/ml, without changes in leptin level, body mass index (BMI), fat mass, Kt/V, or protein catabolic rate (PCR). Additionally, hypoxemia was ameliorated, from PO2 33.1 mmHg to PO2 56.2 mmHg, and the hyperdynamic cardiac state was improved. The degree of anemia, together with deteriorating tissue oxygenation, may have predisposed this patient to developing insulin resistance and consequent hyperinsulinemia. The most appropriate target Hb concentration should be tailored for the clinical condition of each individual patient, bearing in mind an insulin-resistance state, especially in hemodialysis patients with hypoxemia. A more complete understanding of what regulates insulin resistance and consequent hyperinsulinemia in endstage renal disease (ESRD) awaits the elucidation of carbohydrate and insulin metabolism.

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 chro-matography tandem mass spectrometry, and also measured serum levels of urea nitrogen (UN), P2microglobulin (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 β2MG 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.

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. 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.

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

BackgroundRecently, 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.MethodSingle 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.ResultsIn 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.ConclusionA(−)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.