Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body's iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (-0.459, -0.643 to -0.276, p = 0.000; -0.648, -1.099 to -0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (-1.392, -1.749 to -1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

Low parathyroid hormone levels after parathyroidectomy reduce cardiovascular mortality in chronic hemodialysis patients.

BACKGROUND: The aim of the study is to elucidate whether parathyroid hormone (PTH) levels after parathyroidectomy affect the prognosis of patients with secondary hyperparathyroidism. SUBJECTS AND METHODS: Two hundred and ninety-five patients, who underwent PTx without autotransplantation from July 1998 to December 2011, were divided into the low (n = 148) and high (n = 147) PTH groups, using the median value of each mean value of intact PTH after surgery (16.6 pg/mL). After observation for 5.00 years, we evaluated demographic factors, influences of postoperative mineral metabolism, magnitude of uremia, and vitamin D receptor activators on their prognosis, with the multivariate Cox proportional hazard model. RESULTS: While overall survival rates in the high and low PTH groups were 54.9 and 74.2 %, respectively (P = 0.1500), cardiovascular survival rates were 71.6 and 94.4 %, respectively (P = 0.0256). The hazard ratio for cardiovascular mortality in the high PTH group (≥16.6 pg/mL) was 3.132 (P = 0.0470), and those in groups with the median age more than 59 years and with cardiovascular disease were 2.654 (P = 0.0589) and 3.377 (P = 0.0317), respectively. The intact PTH level 6 days after surgery and the mean postoperative intact PTH value showed a strong correlation (Spearman ρ = 0.9007, P < 0.0001, y = 0.4725x + 30.395, R 2 = 0.51798). CONCLUSION: The present study suggests that maintaining low PTH levels after parathyroidectomy reduces cardiovascular mortality and improves the prognosis. Total parathyroidectomy (more than 4 glands) without autotransplantation seems to be one of the treatment options for managing severe secondary hyperparathyroidism.

Circulating Aminoterminal Propeptide of Type III Procollagen as a Biomarker of Cardiovascular Events in Patients Undergoing Hemodialysis.

AIM: Type Ⅲ collagen abundantly exists in the cardiovascular system, including the aorta and heart. We prospectively investigated whether serum levels of aminoterminal propeptide of type Ⅲ procollagen (PⅢNP), a circulating biomarker of cardiovascular fibrosis, could predict cardiovascular events in patients undergoing hemodialysis. METHODS: Serum PⅢNP concentrations were measured in 244 patients undergoing maintenance hemodialysis (men, 126; women, 118; mean age, 64±11 years; dialysis duration, 11.5±7.8 years) by immunoradiometric assay in February 2005. The endpoint was cardiovascular events, and the patients were followed up until the endpoint was reached, or until January 31, 2011. RESULTS: During the follow-up for 4.7±1.8 years, cardiovascular events occurred in 78 (30.3%) of 244 patients. Stepwise Cox hazard analysis revealed that cardiovascular events were associated with increased serum PⅢNP concentration (1 U/mL; hazard ratio, 1.616; P=0.0001). The median serum PⅢNP concentrations were higher in patients with cardiovascular events than in those without (2.30±0.19 U/mL vs 1.30±0.03 U/mL; P＜0.0001). When the patients were assigned to subgroups based on serum PⅢNP cut-off value for cardiovascular events of 1.75 U/mL, defined by receiver operating characteristic analysis, cardiovascular event-free survival rates at 5 years were lower (P=0.0001) in the subgroup of serum PⅢNP ≥1.75 U/mL than in that of serum PⅢNP ＜1.75 U/mL (31.9% vs 88.2%). CONCLUSIONS: Serum PⅢNP could be a new biomarker for predicting the cardiovascular events in patients undergoing hemodialysis.

Similarities between N-glycan glycoform of tonsillar IgA1 and that of aberrant IgA1 abundant in IgA nephropathy patient serum.

BACKGROUND: There are many reports on the presence of an incompletely glycosylated O-linked oligosaccharide(s) in the IgA1 hinge region of some IgA nephropathy patients. As the candidates of such IgA1, tonsillar IgA1 and aberrant IgA1, which are abundant in an IgA nephropathy patient, were proposed. On the other hand, in mice, the abnormality of the N-linked oligosaccharide chain of IgA induced the IgA nephropathy. Therefore, analyses of the N-glycan glycoform on serum IgA1, aberrant IgA1 and tonsillar IgA1 were carried out using the 3-dimensional mapping method. RESULTS: The sugar chain composition was almost the same in these 3 IgA1 preparations. However, the structural characteristics for the aberrant IgA1 showed a drastic increase in the neutral N-glycans; in particular, 25% of the sugar chains in the aberrant IgA1 were the high mannose-type as compared with approximately 5%-6% in the serum IgA1 and tonsillar IgA1. The neutral complex-type N-glycan chain with fucose was higher in both the aberrant IgA1 and tonsillar IgA1 than in the serum IgA1. A typical component in the aberrant IgA1 was the fully galactosylated biantenna with the fucose residue. CONCLUSIONS: We found an abnormality in the N-linked oligosaccharides of the aberrant IgA1. In addition to our previous report about the abundance of asialo-O-linked oligosaccharide in both the tonsillar IgA and aberrant IgA, our results concerning the N-glycan glycoform of the aberrant IgA showed the possible promotion of its self-aggregation and its glomerular deposition by the synergistic difference in the O- and N-linked carbohydrate chains, and also the derivation of the aberrant IgA1 in the sera from the tonsillar tissue.

Possible Inhibitory Effect of Erythropoiesis-Stimulating Agents at the Predialysis Stage on Early-Phase Coronary Events after Hemodialysis Initiation.

BACKGROUND: We examined whether the use of erythropoiesis-stimulating agents (ESAs) to correct anemia at the predialysis stage could inhibit early-phase coronary events after hemodialysis initiation. METHODS: We enrolled 242 patients with chronic kidney disease who had received continued medical treatments and initiated maintenance hemodialysis from 1 September 2000 to 31 December 2014 at Toujinkai Hospital. Patients with a previous history of blood transfusion or any cardiovascular events or interventions were excluded. The coronary events were followed for 1 year after initiation of hemodialysis. RESULTS: Coronary events occurred in 51 of 242 patients: 10 patients had acute coronary syndrome [9 with percutaneous coronary intervention (PCI), 1 without intervention], and 41 had elective coronary revascularization (38 PCI and 3 coronary artery bypass graft). ESA was administered in 118 of 242 patients (48.8%). In stepwise logistic analysis, coronary events were positively associated with nonuse of ESA at the predialysis stage (odds ratio 2.66, p = 0.005) and diabetes mellitus (odds ratio 5.33, p < 0.001). When dividing the patients into 4 subgroups by blood hemoglobin (Hb) level (8.5 g/dl) and the use/nonuse of ESA, coronary event-free survival rates were higher (p = 0.005) in those with Hb ≥8.5 g/dl, ESA+ (86.6%, n = 82) and tended to be higher (p = 0.055) in those with Hb <8.5 g/dl, ESA+ (86.1%, n = 36) than in patients with Hb <8.5 g/dl, ESA- (68.6%, n = 86) in a Kaplan-Meier analysis. CONCLUSIONS: The use of ESA to correct anemia at the predialysis stage may inhibit early-phase coronary events after hemodialysis initiation.

Disordered balance of IgA subclass production in the tonsils of some IgA nephropathy patients.

BACKGROUND: There are reports concerning the relationship between tonsillectomy and immunoglobulin A nephropathy (IgAN). Two reports on the biochemical analysis of over-produced IgA1 from IgAN patients were recently published. On the other hand, histochemical analysis of tonsillar tissue indicated the disordered balance in IgG and IgA producing cells and in the IgA subclass producing cells in IgAN patients. METHODS: IgA in tonsillar extracts and serum was separated into passed fraction (IgA2) and bound fraction (IgA1) by a jacalin-agarose column. Isoelectric focusing (IEF) analysis was carried out using an IPGphor instrument. The IgA content in each sample was analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The IgA1/IgA2 ratio of the tonsillar extracts from controls and IgAN patients was compared. The ratio distribution indicated statistically significant differences. The mean ratio for the control tonsil was 61/39. However, the ratio from eight out of thirty-two IgAN patients exhibited a higher value than the mean + 2SD (standard deviation) of the controls. Among them, three patients exhibited 92/8. Meanwhile, the ratios for serum by this method were close to the previously reported 89/11. There were no differences in the IgA1 IEF profile between the representative lowand high-IgA1 producing patients. CONCLUSIONS: This is the first report concerning IgA subclass distribution in tonsillar tissue. The ratio 61/39 for tonsillar IgA differ from the value (>90% of IgA1) in the previous histochemical report. The value is similar to the previous report for colostrum, whole saliva, jejunal fluid and bronchial fluid. The IgA1/IgA2 ratio distribution in the tonsillar extracts from the patients with chronic tonsillitis is significantly different from that of the IgAN patients.

Improvement of myocardial fatty acid metabolism by oral nicorandil in hemodialysis patients without coronary artery disease.

BACKGROUND: We investigated the potential of oral nicorandil to improve myocardial fatty acid metabolism assessed by single-photon emission computed tomography (SPECT) using (123)I-ß-methyliodophenyl pentadecanoic acid (BMIPP) in hemodialysis patients without obstructive coronary artery disease (CAD). METHODS: This study was based on a cohort study of 155 hemodialysis patients with angiographic absence of obstructive CAD, with analysis performed in 100 propensity-matched patients (54 men and 46 women, 64 ± 10 years); 50 with oral administration of nicorandil (15 mg/d, nicorandil group) and 50 without (control). BMIPP SPECT was performed every year after angiography. Uptake on SPECT was graded in 17 segments on a five-point scale (0 normal, 4 absent) and assessed as BMIPP summed scores (SS). RESULTS: Over a mean follow-up period of 5.3 ± 1.9 years, we observed 25 cardiac deaths among 100 propensity-matched patients. Myocardial uptake of BMIPP in SPECT improved in the nicorandil group compared with the control group from 2 years of administration. In Kaplan-Meier survival analyses, free survival rate from cardiac death was higher in patients with a BMIPP SS improvement rate of ≥20% compared to those with ≥0% <20% or with <0% BMIPP SS improvement rate. At multiple logistic analysis, a ≥20% BMIPP SS improvement rate was positively associated with serum albumin concentration and oral nicorandil. CONCLUSIONS: Long-term oral nicorandil may inhibit cardiac death by improving myocardial fatty acid metabolism in hemodialysis patients without obstructive CAD.

Effects of intravenous l-carnitine on myocardial fatty acid imaging in hemodialysis patients: responders or non-responders to l-carnitine.

We investigated whether chronic intravenous administration of l-carnitine could improve myocardial fatty acid imaging in patients on maintenance hemodialysis. We enrolled 72 hemodialysis patients who had impaired myocardial fatty acid imaging and left ventricular dysfunction not based on coronary lesion. l-Carnitine (1,000 mg) was intravenously administered after dialysis for 1 year to 36 participants (Carnitine group), while not in the other 36 participants (Control group). Single-photon emission computed tomography (SPECT) using an iodinated fatty acid analogue, BMIPP, was performed. Uptake on SPECT images was graded in 17 segments on a five-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores. During follow-up, 19 participants were discontinued from the study, and 53 participants (65 ± 12 years: 27 carnitine, 26 control) were analyzed. The mean BMIPP summed scores 1 year after carnitine administration did not differ from that before in the carnitine group, nor from that in the control group. However, improved SPECT (Changes in BMIPP summed scores <-20%) was found in 7 (25.9%) participants in the carnitine, whereas in 2 (7.7%) in the control group. Multivariate logistic analysis showed the improved SPECT was inversely associated with baseline serum albumin levels (1 g/L: odds ratio, 0.669); the cut-off was 35 g/L. Chronic intravenous l-carnitine might improve myocardial fatty acid imaging in a selected group of hemodialysis patients with hypoalbuminemia.

Detection of enriched Thomsen-Friedenrich antigen on IgA1 from IgA nephropathy patients.

BACKGROUND: Human serum IgA1 has a mucin-like structure on its hinge portion which is composed of a mucin-type sugar chain and amino acid sequence rich in proline, serine and threonine. There are incompletely glycosylated O-linked oligosaccharide(s) on the IgA1 hinge region in some nephropathy patients. METHODS: We made a detailed analysis of the incompleteness of the sugar chain by digesting IgA1 with various glycosidases. To verify the incompleteness of the sugar chains, the galactosamine/glucosamine ratio (O/N ratio) was introduced as a specific value for each IgA1 preparation. RESULTS: When IgA1 from serum was treated with alpha-N-acetylgalactosaminidase and/or neuraminidase or endo-beta-N-acetylglucosaminidase H (Endo-H), the O/N ratio did not change. However, endo-alpha-N-acetylgalactosaminidase (Endo-A) reduced the O/N ratio of IgA1 from the IgA nephropathy patient whereas before treatment, the O/N ratio had been similar in the normal control and IgA nephropathy. CONCLUSIONS: This result means there is a small amount of the unsubstituted and the sialylated N-acetylgalactosamine residues (Tn and sialyl Tn antigen, respectively), and abundant asialo Galbeta1,3GalNAc (TF antigen) in the IgA1 molecule. In view of the incompleteness of the IgA1 sugar chain, the decrease in the sialic acid content of the mucin-type sugar chain on IgA1 from an IgA nephropathy patient became obvious in this experiment.

Compositional similarity between immunoglobulins binding to asialo-, agalacto-IgA1-Sepharose and those deposited in glomeruli in IgA nephropathy.

BACKGROUND: It has been found that the immunoglobulin A1-binding protein (IgA1-BP) can be separated from human serum using an asialo-, agalacto-IgA1 (aglyco-IgA1)-Sepharose column (13). As the IgA content in IgA1-BP was significantly higher in IgA nephropathy patients than that in other nephropathy patients, the relationship between IgA in IgA1-BP and glomerular deposited IgA was predicted. METHODS: IgA1-BP was separated from serum using the aglyco-IgA1-Sepharose column and the aglyco-IgA1-HPLC column. A jacalin-agarose column fractionated the IgA. The immunoglobulins were analyzed by the enzyme-linked immunosorbent assay (ELISA). RESULTS: A rapid separation method of IgA1-BP from serum by the aglyco-IgA1-HPLC column was developed and this column confirmed the reproduction of the IgA1-BP separation. The following similarities between IgA in IgA1-BP and glomerular deposited IgA were detected. A major portion of IgA in IgA1-BP was the IgA1 subclass. The IgA was rich in medium-size IgA and in the jacalin-high-affinity IgA1 fraction. The IgA showed a statistically significant lower kappa/lambda ratio in its light-chain composition than that of serum IgA, i.e. abundance in IgA bearing the lambda light chain. Other immunoglobulin classes (IgG and IgM) in IgA1-BP also exhibited a significantly low kappa/lambda ratio. CONCLUSIONS: In this experiment, preferential bindings of the IgA1 subclass, the medium-size IgA and the IgA with the lambda light chain to the aglyco-IgA1-column were observed. Based on previous reports concerning aglyco-IgA1 self-aggregation, the interaction of aglyco-IgA1 with matrix proteins and the rat glomerular deposition of artificially deglycosylated IgA1, IgA in IgA1-BP is thought to be partially the same molecule as the IgA deposited on the mesangial matrix in the IgA nephropathy patient.

Tonsillar IgA1 as a possible source of hypoglycosylated IgA1 in the serum of IgA nephropathy patients.

BACKGROUND: There are many reports of incompletely glycosylated O-linked oligosaccharides on the IgA1 hinge region in certain IgA nephropathy patients. In addition, other reports have noted a relationship between tonsillectomy and IgA nephropathy. METHODS: Immunoglobulins from extracts of tonsillectomized tissue and other sources were analysed by isoelectric focusing (IEF) and by enzyme-linked immunosorbent assay (ELISA). RESULTS: The IEF profile of tonsillar IgA differed from that of serum IgA and it was enriched in cationic IgA. However, extracts from tonsillitis controls and IgA nephropathy patients exhibited profiles that were very similar. Enzymatic removal of sialic acid induced a shift of the peaks to the cathode side. The profiles of IgA from treated tonsillar extract and treated serum were closely overlapped. In addition, asialo Galbeta1,3GalNAc was clearly present in cationic IgA from tonsillar extract and in aberrant IgA1 from serum following enzymatic transfer of sialic acid to IgA1. Serum IgA also contained partly sialylated IgA1. Quantitative analysis of IgA and IgG in the extracts indicated that IgA was significantly higher, whereas IgG was significantly lower in IgA nephropathy patients. CONCLUSIONS: We found that the IgA1 produced in tonsillar tissue differed from serum IgA1. Furthermore, an overproduction of asialo IgA1 resulted from the disordered balance between IgA- and IgG-producing cells in the tonsils from the IgA nephropathy patient. Although it is unclear how such asialo IgA1 molecules are transferred from tonsil tissue to serum, a tonsillar source may produce a few micrograms of aberrant IgA1 that then appears in serum.