Takashi Ishizu

Reduced serum hydroxyl radical scavenging activity in erythropoietin therapy resistant renal anemia

Relation between anemia resistant to recombinant human erythropoietin (rHuEPO) therapy and the oxidative stress in hemodialysis (HD) patients was investigated. Stable HD patients who had consistent hemoglobin concentrations on a constant dose of rHuEPO were studied. Patients were excluded if there were factors that might affect hemopoiesis or administration of antioxidant supplements. Patients were classified into three groups: High (9000 U/week), Low (1500-4500 U/week) and No rHuEPO group. Thiobarbituric acid reactive substances (TBARS) of sera and erythrocyte were examined. Serum superoxide and hydroxyl radical scavenging activities were measured using electron spin resonance. TBARS in the erythrocyte was higher in High rHuEPO group compared with No rHuEPO group, though the serum TBARS were similar. A diminution of serum hydroxyl radical scavenging activity was observed in High rHuEPO group. Hydroxyl radical signal intensity showed a strong correlation with the serum ferritin in High rHuEPO group, although ferritin concentrations were not different among the 3 groups. Superoxide scavenging activity showed no differences. These results indicate that increased lipid peroxidation in erythrocyte, raised by decreased serum hydroxyl radical scavenging activity, is one cause of rHuEPO resistant anemia. Serum ferritin may be involved in this hydroxyl radical production.

Elimination of Lipid Peroxide during Hemodialysis

Background/Aims: This study is aimed to show the antioxidative effect of hemodialysis (HD) by demonstrating the elimination of toxic lipid peroxides. Methods: Blood samples were obtained from patients on regular maintenance HD before and 15, 30, 60, 120 and 240 min after the start of each HD session. Plasma cholesteryl ester hydroperoxide (CE-OOH), phosphatidylcholine hydroperoxide (PC-OOH), and eliminators of lipid peroxides (LOOH) such as apolipoprotein A-I (apoA-I) and lecithin:cholesterol acyltransferase (LCAT) were investigated. The hydroxyl radical scavenging activity was measured for the evaluation of the pro-oxidative side. Results: CE-OOH and PC-OOH were elevated in patients with chronic kidney disease both on and not on HD, while these values were much higher in HD patients. CE-OOH quickly dropped during the first 30 min of HD, then gradually decreased until 240 min. CE-OOH concentrations were related to those of apoA-I. In contrast, PC-OOH showed an increase 30 min after the start of HD, a change which resembled that of LCAT and was the reverse of the hydroxyl radical scavenging activity. Conclusion: These results demonstrate the antioxidative action through CE-OOH elimination involving apoA-I. The pro- and antioxidative effects of HD on LOOH are not uniform but PC-OOH is mainly influenced prooxidatively.

Temporal Changes in Post-Infectious Glomerulonephritis in Japan (1976-2009)

Background The incidence of post-infectious glomerulonephritis (PIGN) in developed countries has decreased over the last 50 years. Here we identified the trends of the incidence of PIGN in Japan during the past four decades. Methods We explored the frequency, clinicopathological findings, and prognosis of PIGN based on 6,369 cases from the Renal Biopsy Database of our institute in the Kanto region of Japan, diagnosed histologically from 1976 to 2009. Results The numbers of PIGN cases were 131 (2.1%) in total, and 2.4%, 1.1%, 2.6% and 2.1% identified in the 1970s, 1980s, 1990s, and 2000s, respectively. Acute glomerulonephritis (AGN), including post-streptococcal glomerulonephritis (PSGN), accounted for almost all of the PIGN cases in the 1970s, but decreased to approx. 40%–50% since the 1990s. In the 1990s, Staphylococcus aureus infection-related nephritis (SARN) showed a rapid increase in rate, reaching 30%. The incidence of hepatitis C virus infection-associated GN (HCVGN) has increased since the 1990s. The average age at onset rose from 33 to 51 years over the study period. These transitions can be summarized as increases in SARN and HCVGN and decreases in PSGN and other types of AGN, since SARN and HCVGN have older onsets compared to PSGN and other AGN types. The clinicopathological features were marked for each PIGN. Regarding the prognosis, the renal death rates of both the SARN and HCVGN groups were significantly higher than those of other PIGN. Conclusion Based on our analysis of the Renal Biopsy Database, the incidence of PIGN in Japan reached its peak in the 1990s. The temporal changes in the incidence of PIGN reflected the trends in infectious diseases of each decade and the continual aging of the population, with a related higher susceptibility to infections.

Efficacy of Continuous Oral Administration of Lanthanum Carbonate over 24 months

To examine the efficacy of long‐term administration of lanthanum carbonate, changes in serum Ca, phosphate, whole parathyroid hormone (wPTH), and ALP were examined in 40 patients who were able to tolerate dosage of lanthanum carbonate over a continuous period of 24 months. Concurrently, concomitant administration of other phosphate binders, cinacalcet, vitamin D, etc., was also examined. After 24 months, serum phosphorus levels (P levels) had decreased to within management target of guidelines, from 6.16 ± 1.44 mg/dL to 5.58 ± 1.15 mg/dL, and this effect was maintained for 2 years. There were no changes in Ca level. wPTH did not change significantly but tended to increase at 12 months. The dose of concomitantly administered calcium carbonate and sevelamer hydrochloride was reduced. The P‐lowering function of lanthanum carbonate still held steady at 24 months following the start of dosage. Because of the rising trend seen in wPTH, dose of cinacalcet and/or vitamin D need to be modulated. Reducing the number of concomitantly administered phosphate binder tablets was desirable from the standpoint of patient adherence.

Analysis of T-cell receptor usage in myeloperoxidase−antineutrophil cytoplasmic antibody-associated renal vasculitis

BackgroundBacterial superantigens produced by Staphylococcus aureus may be associated with the onset of proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, including Wegener’s granulomatosis. We investigated T-cell subsets to assess the superantigens present in patients with myeloperoxidase−antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis.MethodsPeripheral-blood mononuclear cells (PBMC) obtained from 40 normal controls and ten patients with MPO-ANCA-associated vasculitis were stained with fluorescence-labeled monoclonal antibodies against T-cell markers, including 17 variable regions of T-cell receptor β-chains (TCR-Vβ) and were then analyzed using flow cytometry.ResultsAmong PBMCs, the percentage of CD3+ cells from patients with MPO-ANCA-associated vasculitis was significantly lower than that from normal controls, but there were no differences between the two groups in the percentage of CD19+ cells or CD16+ cells. Although there were no differences regarding the overall percentage of CD4+ cells between the two groups, the percentage of CD4+CD45RO+ cells in patients with MPO-ANCA-associated vasculitis was significantly higher than that in normal controls, and percentages of CD4+CD45RO+HLA-DR+ and CD4+CD45RO+CD62Llow cells in patients with MPO-ANCA-associated vasculitis were also significantly increased. There was no significant difference between the two groups in terms of the usage of the 17 different TCR-Vβ regions.ConclusionThere was no difference in bacterial superantigens between controls and MPO-ANCA-associated vasculitis patients because of the absence of specific usage of TCR-Vβ regions. Given the elevated levels of memory T cells, conventional antigens rather than superantigens may be associated with the pathogenesis of MPO-ANCA-associated vasculitis.

Effect of different dialyzers on defensins during hemodialysis

AbstractBackground. Defensins are antimicrobial peptides that constitute 30% to 50% of total azurophil granule proteins. Although the activation of azurophils during hemodialysis has been reported, including the release of granulocyte lactoferrin, myeloperoxidase, and elastase, the release of defensins during hemodialysis has not been investigated. The purpose of this study was to determine the effects of hemodialysis on defensin release. Methods. Plasma defensin levels and excreted defensins in dialyzer eluates and dialysates during hemodialysis were determined by radioimmunoassay. Thirty hemodialysis patients were divided into three groups, each group using a different dialyzer membrane: cuprophan (CU), polymethylmethacrylate (PMMA), or polysulfone (PS). Results. The postdialysis plasma defensin level in the CU group was significantly increased compared with the predialysis level. In contrast, defensin levels in the PMMA and PS groups showed significant decreases postdialysis. The predialysis neutrophil count and defensin level exhibited a significant positive correlation in all groups. However, postdialysis, a significant positive correlation was found only in the CU group. Interestingly, defensin excretion in the dialyzer eluates of the PMMA group and in the dialysates of the PS group was higher than that in each of the other two groups respectively. Conclusions. No significant statistical correlation between postdialysis neutrophil count and defensin level was observed in the PMMA and PS groups, a finding that may be explained by the increased excretion of defensins during hemodialysis in these groups. These results suggested that plasma defensin level may be a marker for granulocyte activation in patients dialyzed with membranes showing lower levels of excreted defensins. This study also revealed the importance of determining both plasma changes and excreted volumes of granule proteins to define neutrophil degranulation during hemodialysis.

Subclavian steal syndrome in a hemodialysis patient after percutaneous transluminal angioplasty of arteriovenous access

Introduction: We describe a hemodialysis patient who developed subclavian steal syndrome via an arteriovenous fistula after percutaneous transluminal angioplasty. Case description: A 55-year-old female with end-stage renal failure due to polycystic kidney disease had been treated with hemodialysis for 10 years. Because of an autologous arteriovenous fistula stenosis, percutaneous transluminal angioplasty was performed. After successful treatment with percutaneous transluminal angioplasty, the patient developed dizziness. Magnetic resonance imaging with angiography of the brain and neck revealed normal bilateral subclavian and carotid arteries. However, flow in the left vertebral artery was not detected in time-of-flight magnetic resonance angiography. The left vertebral artery showed completely reversed blood flow as detected by color duplex ultrasound. We also confirmed anterograde flow in the left vertebral artery by color duplex ultrasound with arteriovenous fistula compression. Arteriovenous flows before the arteriovenous fistula stenosis and post-percutaneous transluminal angioplasty were 1146 and 2239 mL/min, respectively. These findings suggested high-flow arteriovenous fistula led to the subclavian steal syndrome. The patient was subsequently treated by a flow reduction in the high-flow arteriovenous access using a modified graft inclusion technique. We decreased the arteriovenous fistula flow to 851 mL/min, which remained under 850 mL/min, 1 year later. The brain natriuretic peptide level and right-ventricular pressure also decreased after treatment. A modified graft inclusion technique was successful in decreasing the high flow of the arteriovenous fistula, and improved subclavian steal syndrome symptom and cardiac overload. Conclusion: This case shows that percutaneous transluminal angioplasty for an arteriovenous fistula may induce subclavian steal syndrome, and a modified graft inclusion technique was useful in improving the high flow of an arteriovenous fistula.