Kunihiro Nabeshima

Accumulation of bisphenol A in hemodialysis patients.

Bisphenol A [BPA, 2,2-bis(4-hydoxyphenyl)propane], an industrial chemical used in the production of polycarbonate, epoxide resin, and polyarylate, is considered to be an endocrine-disrupting chemical. BPA may be present in some hollow-fiber dialyzers used in hemodialysis. In this study, we tested the amounts of BPA eluted from various hollow fibers. Furthermore, we measured the BPA concentration in the sera of 22 renal disease predialysis patients, as well as 15 patients who were receiving hemodialysis, to see if there is BPA accumulation in these patients. The elution test of BPA showed that a much larger amount of BPA was eluted from polysulfone (PS), and polyester-polymeralloy hollow fibers. Among renal disease patients who had not undergone hemodialysis, the serum BPA concentration increased as the renal function deteriorated, showing a significant negative association. In a crossover test between PS and cellulose (Ce) dialyzers, the predialysis serum BPA concentration of PS dialyzer users decreased after changing to a Ce dialyzer, and the serum BPA increased again after switching back to PS dialyzers. In patients who were using PS dialyzers, the BPA level significantly increased after a dialysis session. However, in the Ce dialyzer users, the BPA level decreased. Since accumulation of BPA could affect the endocrine or metabolic system of the human body, it is important to perform further investigations on dialysis patients.

Evaluation of blood purification and bortezomib plus dexamethasone therapy for the treatment of acute renal failure due to myeloma cast nephropathy.

Aggressive removal of circulating free light chains (FLC) by blood purification accompanied by chemotherapy is a promising approach for the treatment of acute renal failure due to myeloma cast nephropathy. Plasma exchange has been performed to remove serum FLC; in order to examine an alternative strategy we performed hemodiafiltration using protein‐leaking dialyzers for the treatment of dialysis‐dependent acute renal failure due to myeloma cast nephropathy. In the first case with κ‐light chain cast nephropathy, the pre‐treatment serum creatinine was 9.65 mg/dL, and the serum κ‐FLC was 27 100 mg/L. Plasma exchange or hemodiafiltration was performed from Monday to Friday during the first several weeks. Chemotherapy was started with high‐dose dexamethasone and then switched to bortezomib plus dexamethasone. The mean removal rates of κ‐FLC were 45.8% (one plasma volume) and 66.9% (one‐and‐a‐half plasma volumes) by plasma exchange. The removal rates of κ‐FLC by hemodiafiltration (66.9%, FB210UHβ; 71.6%, PES210Dα; 75.2%, FXS220) were comparable to those by plasma exchange. In the second case with λ‐light chain cast nephropathy, the pre‐treatment serum creatinine was 4.14 mg/dL, and the serum λ‐FLC was 4140 mg/L. The mean removal rates of λ‐FLC were 60.2% (FXS140) and 64.2% (FB210UHβ) by hemodiafiltration. Both cases became dialysis‐independent. The combination of an intense blood purification regimen and bortezomib plus dexamethasone therapy appears to be an efficient approach to renal recovery. Hemodiafiltration using protein‐leaking dialyzers could become an alternative to plasma exchange as a method of removing FLC.

Expression of Tumor Necrosis Factor Receptors on Granulocytes in Patients with Myeloperoxidase Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis

Background/Aims: To clarify the clinical significance of tumor necrosis factor (TNF) receptors in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, we evaluated the cell surface expression of TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Patients and Methods: 43 patients with MPO-ANCA-associated vasculitis, 16 patients with chronic renal failure, 10 patients with sepsis, 15 patients with systemic lupus erythematosus, and 18 healthy controls were enrolled in this study, and the surface expression levels of TNFR1, TNFR2, CD63, and CD64 on granulocytes were assessed. In 21 patients with MPO-ANCA-associated vasculitis, soluble TNFR1 (sTNFR1), soluble TNFR2(sTNFR2), and TNF-α in the serum were also measured. Results: The surface expression levels of TNFR1 and TNFR2 on granulocytes were significantly higher in patients with MPO-ANCA-associated vasculitis than in the healthy controls, and positively correlated with the Birmingham Vasculitis Activity Score (BVAS). The levels of sTNFR1, sTNFR2, and TNF-α in the serum were also significantly higher in patients with MPO-ANCA-associated vasculitis than in the healthy controls. Serum levels of sTNFR1 and sTNFR2 correlated with serum creatinine, while the surface expression of TNFR1 and TNFR2 on the granulocytes did not. There was no significant correlation between the BVAS and CD63 or BVAS and CD64. Conclusion: The surface expression levels of TNFR1 and TNFR2 on granulocytes were upregulated in patients with MPO-ANCA-associated vasculitis and reflected disease activity.

Complement C4d deposition in transplanted kidneys : preliminary report on long-term graft survival

Abstract:  The effects of antibody‐mediated rejection on long‐term graft survival have not been fully investigated. The aim of this study is to clarify the influence on long‐term survival of deposition of the complement split product C4d in allografts using polyclonal anti‐C4d antibody. Inclusion criteria were recipients who underwent graft biopsy during acute deterioration of graft function within the first 2 yr after transplantation. Patients whose graft did not survive more than 1 yr and who received graft from an human leucocyte antigen (HLA)‐identical sibling or an ABO‐incompatible donor were excluded. Among the 92 recipients investigated, 22 (23.9%) had peritubular capillary C4d deposition, 15 (16.3%) had glomerular capillary C4d deposition and seven (7.6%) had both peritubular and glomerular capillary C4d deposition. Twenty of these 22 patients revealed acute cellular rejection, including borderline changes. There was no significant relationship between pathological severity of acute rejection and presence or absence of peritubular capillary C4d deposition. Graft survival was inferior in patients with peritubular capillary C4d deposition to that in patients without C4d deposition (p = 0.0419). Graft survival in patients with glomerular C4d deposition did not differ from that in patients without C4d deposition. In conclusion, C4d deposition in peritubular capillaries has a substantial impact on long‐term graft survival.

Severe metabolic acidosis and hypokalemia in a patient with enterovesical fistula

We report a case of a 59-year-old woman who had severe metabolic acidosis and hypokalemia due to an enterovesical fistula. The patient came to our hospital complaining of systemic weakness and numbness of the fingers. She was found to have hyperchloremic metabolic acidosis (arterial bicarbonate, 2.8 mEq/l) and hypokalemia (serum potassium, 1.9 mEq/l) and was admitted for treatment. Following the correction of metabolic acidosis and hypokalemia, the patient was examined for the underlying cause of these electrolyte and acid-base disorders. She had a history of total hysterectomy followed by radiotherapy due to uterine cancer 30 years previously. After the surgery, she had suffered postoperative neurogenic bladder dysfunction, necessitating intermittent self-catheterization. Two years before admission, she had begun to experience watery diarrhea. A radiographic study after recovery from the acid-base and electrolyte disorders revealed the presence of an enterovesical fistula. The fistula was surgically resected and the metabolic acidosis completely cleared. Unexplained hyperchloremic metabolic acidosis with hypokalemia may suggest the presence of an enterovesical fistula in patients with a surgical history of malignant pelvic tumor and neurogenic bladder dysfunction.

Treatment With Cytapheresis for Antineutrophil Cytoplasmic Antibody‐associated Renal Vasculitis and Its Effect on Anti‐inflammatory Factors

Abstract:  To evaluate the efficacy of cytapheresis for the treatment of rapidly progressive glomerulonephritis (RPGN) caused by myeloperoxidase antineutrophil cytoplasmic antibody (MPO‐ANCA)‐associated vasculitis, the renal prognosis and the mortality rate at 1 year after treatment were compared between a Cytapheresis Group and a Steroid Pulse Group. The Cytapheresis Group included 10 patients who were treated with cytapheresis and oral corticosteroids. Five had granulocytapheresis with the Adacolumn (Japan Immuno Research Laboratories Co. Ltd, Takasaki, Japan) and the remaining five had leukocytapheresis with the leukocyte removal filter, Cellsorba (Asahi Medical Co. Ltd, Tokyo, Japan). The Steroid Pulse Group was comprised of 12 patients who were treated with methylprednisolone pulse therapy and oral corticosteroids. In the Cytapheresis Group, renal function recovered in 70% of the patients and the mortality rate was 10%. In the Steroid Pulse Group, renal function recovered in 66.7% and the mortality rate was 33.3%, with infection as the cause of death. Total doses of corticosteroids converted to prednisolone dose during a 1 month period, ranged from 280 mg to 1226 mg in the Cytapheresis Group. On the other hand, these dosages ranged from 2375 mg to 8380 mg in the Steroid Pulse Group. These results indicated that the mortality rate by infection could be reduced by adding cytapheresis therapy. Concerning the mechanism of cytapheresis, anti‐inflammatory factors such as soluble tumor necrosis factor receptor, and interleukin‐10 reduced after cytapheresis. These changes might be responsible for the efficacy of cytapheresis. In conclusion, cytapheresis is thought to be one of the effective treatments for RPGN caused by MPO‐ANCA‐associated vasculitis, reducing the levels of anti‐inflammatory factors.

Cytapheresis for the treatment of myeloperoxidase antineutrophil cytoplasmic autoantibody-associated vasculitis: a pilot study of 21 patients.

Abstract:  Twenty‐one patients with myeloperoxidase‐antineutrophil cytoplasmic autoantibody (MPO‐ANCA)‐associated vasculitis were treated using cytapheresis. Of these, 17 were treated for glomerulonephritis and four were treated for pulmonary hemorrhage. The overall survival rate was 85.7% with a follow‐up duration of 24.0 ± 13.8 months. In the 17 patients with MPO‐ANCA‐associated glomerulonephritis, pretreatment creatinine was 3.2 ± 1.6 mg/dL, and renal function recovered in 76.5%. Pulmonary hemorrhage was ameliorated in all four patients. Abdominal pain occurred in three of the 21 patients but symptoms resolved soon after the cytapheresis procedure was completed. No other adverse effects occurred during cytapheresis. From these results, cytapheresis can be considered a safe and effective treatment for MPO‐ANCA‐associated vasculitis. As for the mechanism of its action, soluble tumor necrosis factor receptor 1 (sTNFR), sTNFR2 and interleukin 1 receptor antagonist were elevated soon after cytapheresis and those levels 2 h after the cytapheresis procedure were higher than before the procedure in some cases. These elevations might be related to the efficacy of cytapheresis.

Effects of Cytapheresis on Tumor Necrosis Factor Receptor and on Expression of CD63 in Myeloperoxidase–Antineutrophil Cytoplasmic Autoantibody-associated Vasculitis

Abstract:  To evaluate the therapeutic potential of cytapheresis in myeloperoxidase–antineutrophil cytoplasmic autoantibody (MPO–ANCA)‐associated vasculitis, plasma levels of soluble tumor necrosis factor receptors (sTNFR1, sTNFR2) and the expression of TNFR1, TNFR2, and CD63 on granulocytes were measured. The levels of sTNFR1 and sTNFR2, and the expression of TNFR1 and TNFR2 were significantly higher in MPO–ANCA‐associated vasculitis patients than in normal controls. The levels of sTNFR1 and sTNFR2 increased significantly after cytapheresis (P < 0.001). The expression of TNFR1 showed a tendency to decrease after cytapheresis (P = 0.0535). The expression of CD63 decreased significantly after cytapheresis (P < 0.05). Because sTNFR1 and sTNFR2 act as TNF‐antagonists, the increases of sTNFR1 and sTNFR2 after cytapheresis might contribute to inhibit the action of TNF‐α. The decreased expression of TNFR1, which mediates the signal for polymorphonuclear cell respiratory burst, might also contribute to the reduction of inflammation. From these results, the inhibition of TNF action and removal of degranulated granulocytes appear to be related to the mechanism whereby cytapheresis can exert a beneficial and therapeutic function in the treatment of MPO–ANCA‐associated vasculitis.

Serum levels of 5-s-cysteinyldopa are correlated with skin colors in hemodialysis patients but not in peritoneal dialysis patients.

Background: Diffuse hyperpigmentation is common in patients with chronic renal failure undergoing hemodialysis (HD) or peritoneal dialysis (PD). We previously reported that serum levels of 5-S-cysteinyldopa (5SCD, a pheomelanin precursor) and pheomelanin were significantly elevated in HD patients. Methods: Skin color was assessed using a Mexameter that measures the melanin index (MI) and the erythema index (EI). The upper inner arms (non-sun-exposed site) and the foreheads (sun-exposed site) of HD and PD patients and control subjects were analyzed. Results: MI values on the upper inner arms and on the foreheads of HD and PD patients were significantly higher than in controls. In HD patients, significant correlations were found for serum 5SCD levels with MI and EI on the upper inner arm, and for EI on the forehead. In PD patients, no such correlations were found. Conclusions: Hyperpigmentation in HD patients results partly from accumulation of pheomelanin in the skin.