Hiroaki Oda

Effect of lipoproteins on cultured human mesangial cells

It was recently reported that low-density lipoprotein (LDL) promotes mesangial cell proliferation, and oxidized LDL is cytotoxic for mesangial cells. However, there have been few studies about the effects of other lipoproteins on mesangial cells. Accordingly, we investigated the effect of various lipoproteins on cultured human mesangial cells using 3H-thymidine (3H-TdR) incorporation and cell counting assays. We also investigated the levels of several cytokines in mesangial cell culture supernatants after stimulation by the lipoproteins. Addition of very-low-density lipoprotein (VLDL) at concentrations up to 100 micrograms/mL, intermediate-density lipoprotein (IDL) at up to 50 micrograms/mL, and LDL at up to 50 micrograms/mL induced the proliferation of cultured human mesangial cells, whereas cell growth was inhibited at higher concentrations. Oxidized LDL caused a concentration-dependent decrease of 3H-TdR incorporation. High-density lipoprotein (HDL) had no proliferative effective effect at any concentration. Exposure to VLDL, IDL, LDL, or a high concentration of HDL enhanced the secretion of interleukin-6, platelet-derived growth factor, and transforming growth factor-beta by mesangial cells, whereas tumor necrosis factor-alpha secretion was stimulated by oxidized LDL. These finding indicate that triglyceride (TG)-rich lipoproteins (VLDL and IDL) promote mesangial cell proliferation as well as LDL, whereas oxidized LDL has the reverse effect. These effects of lipoproteins may be related to modulation of various cytokines. Accordingly, TG-rich lipoproteins, LDL, and oxidized LDL may be involved in mesangial cell proliferation and injury in patients with mesangial proliferative glomerulonephritis.

Platelet-derived growth factor, interleukin (IL)-1 beta, IL-6R and tumor necrosis factor-alpha in IgA nephropathy. An immunohistochemical study.

We clarified the presence of platelet-derived growth factor (PDGF), interleukin (IL)-1 beta, IL-6, IL-6 receptor (IL-6R) and tumor necrosis factor-alpha (TNF-alpha) in renal biopsy specimens from 62 patients with IgA nephropathy, and discuss their relationship with mesangial cell proliferation, degree of histological damage and various clinical factors. Mesangial proliferation was determined histologically by PAS staining and the positive rate of proliferating cell nuclear antigen (PCNA). Renal biopsy specimens were stained using an enzyme-antibody method to determine the presence of cytokines and the receptor. PCNA-positive cells in the glomeruli significantly increased in patients positive for PDGF, IL-6, IL-6R and TNF-alpha. The degree of histological damage increased with the positive rates of PDGF, IL-6 or IL-6R and the number of PCNA-positive cells in the glomeruli. In the PDGF-A-positive patients, total urinary protein (TUP), urinary beta2-microglobulin (u-beta2-m) and systolic and diastolic blood pressure were significantly higher, and creatinine clearance (Ccr) was significantly lower than in the PDGF-A-negative patients. In the PDGF-B-positive patients, TUP, serum creatinine (s-Cr) and urinary and serum beta2-m increased significantly and Ccr decreased significantly. Il-1beta was not related to any clinical factors. In the IL-6-positive patients, TUP was significantly higher than in the IL-6-negative patients. In the IL-6R-positive patients, TUP, s-Cr, urinary beta2-m and systolic blood pressure were significantly higher than in the IL-6R-negative patients. In conclusion, PDGF, IL-6 and IL-6R may be closely related to mesangial cell proliferation, histological changes and deterioration of various clinical factors in patients with IgA nephropathy.

Frequency of Complications with Prolonged Femoral Vein Catheterization for Hemodialysis Access

Analysis of 120 cases of femoral vein catheterization for > or = 2 days for hemodialysis in 89 hospitalized patients was performed to determine the frequency of catheter-related complications including infection and venous thrombosis. The rate of clinically significant complications was < 3.5% and compared favorably with published complication rates of central vein catheters. We conclude that prolonged femoral vein catheterization for hemodialysis is associated with an acceptably low rate of complications when appropriate techniques for placement and catheter care are followed and should be considered a reasonable option for vascular access in hospitalized patients.

Remnant-Like Particle Cholesterol May Indicate Atherogenic Risk in Patients on Chronic Hemodialysis

Recently, involvement of remnant-like particle cholesterol (RLP-C) in atherosclerosis was reported, but this parameter has not been adequately investigated in hemodialysis (HD) patients. The present study investigated the relationship between the RLP-C level and total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), lipid peroxides (malone dialdehyde, MDA), apolipoprotein (Apo) A-I, and ApoB. In addition, the fractions of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), LDL, and HDL in serum lipoproteins were determined by disk polyacrylamide gel electrophoresis. The relationship between the RLP-C level and three atherogenic indices was also studied. The RLP-C level in HD patients (8.2 +/- 6.7 mg/dl) was significantly higher than that in normal controls (2.7 +/- 1.3 mg/dl). The RLP-C level showed a significant positive correlation with the levels of TC, TG, LDL-C, MDA, ApoB, VLDL(%), and IDL(%), as well as a negative correlation with HDL(%). However, there was no correlation with age or the duration of HD. RLP-C also showed significant positive correlations with the (TC -HDL-C)/HDL-C ratio and the (VLDL + LDL)/HDL ratio, as well as a negative correlation with the ApoA-I/ApoB ratio. These results suggest that RLP-C may be a potential indicator of atherogenic risk in HD patients.

Lipid-lowering therapy and coagulation/fibrinolysis parameters in patients on peritoneal dialysis.

Patients on continuous ambulatory peritoneal dialysis (CAPD) often have abnormalities of lipid metabolism or coagulation and fibrinolysis, these patients may thus be more susceptible to atherosclerosis than those on hemodialysis. It has been reported that hypercoagulability and hyperfibrinolysis are correlated with abnormalities of lipid metabolism. Therefore, we investigated the effect of a decrease in lipids on the coagulation and fibrinolysis system in CAPD patients with hyperlipidemia who received lipid-lowering therapy. The patients included 5 men and 13 women, with a mean age of 52.5 years. Pravastatin sodium (10 mg/day) and ethyl icosapentate (1800 mg/day) were administered concomitantly for 8 weeks. Lipid levels and coagulation/fibrinolysis parameters were measured before and after therapy. The patients were divided into two groups depending on their response to therapy: responders showed a decrease in total cholesterol or triglycerides by at least 20% and non-responders showed less improvement. In the responders, the levels of protein C, tissue plasminogen activator/plasminogen activator inhibitor-I complex, factor XIII, α2-plasmin inhibitor, and D-dimer were significantly lower after therapy than before therapy. Protein C, factor XIII, and α2-plasmin inhibitor were also significantly decreased after therapy in non-responders, but the extent of the decrease was smaller. The plasminogen level was significantly increased after therapy in non-responders. These findings suggest that a decrease in lipid levels and/or some other action by lipid-lowering agents may correct abnormalities of coagulation and fibrinolysis in CAPD patients. (Int J Artif Organs 2000; 23: 27–32)

Apolipoprotein E Polymorphism in IgA Nephropathy

Background/Aim: To clarify the role of the apolipoprotein E (Apo E) phenotype in IgA nephropathy, we investigated its relationship with histological damage and clinical factors. Methods: The subjects were 104 consecutive patients (41 men and 63 women) with IgA nephropathy. The Apo E phenotype was identified by plasma isoelectric focusing and immunoblotting, and the frequencies of Apo E alleles were calculated. Results: The frequencies of the phenotypes and the alleles were as follows: 2/2 = 0, 2/3 = 0.086, 3/3 = 0.654, 2/4 = 0.010, 4/3 = 0.211, 4/4 = 0.010, 3/5 = 0.029, Ε2 = 0.048, Ε3 = 0.817, Ε4 = 0.120, and others = 0.015. There were no significant differences between the IgA nephropathy patients and healthy individuals in the frequencies of Apo E phenotypes and the alleles. However, the Apo E2 phenotype was significantly more common among patients with severe histological damage than in those with mild damage. The serum triglyceride levels were significantly elevated, and the Apo E2 phenotype was significantly more prevalent in patients with severe histological damage as compared with those with mild damage. Conclusion: The Apo E2 phenotype appears to be associated with the severity of histological damage in IgA nephropathy.

Serum soluble interleukin-2 receptor in patients with glomerulonephritis

Serum soluble interleukin-2 receptor (IL-2R) concentrations were determined using the ELISA method in 55 cases of glomerulonephritis. These patients can be classified as 29 cases of IgA nephropathy, 10 cases of membranous glomerulonephritis and 16 cases of mesangial proliferative glomerulonephritis. Our results showed that serum soluble IL-2R concentrations in glomerulonephritis cases were significantly higher than those in healthy controls. Among the different types of glomerulonephritis cases, however, no significant differences in serum soluble IL-2R were observed. While we found a significant positive correlation of serum soluble IL-2R to BUN and creatinine, we also found a significant negative correlation between serum soluble IL-2R and creatinine clearance. These findings suggest that serum soluble IL-2R can serve as an indicator of exacerbation of glomerulonephritis.

Continuous Ambulatory Peritoneal Dialysis Is Superior to Hemodialysis in Chronic Dialysis Patients with Cerebral Hemorrhage

Continuous Ambulatory Peritoneal Dialysis Is Superior to Hemodialysis in Chronic Dialysis Patients with Cerebral Hemorrhage N. Noriaki Yorioka H. Hiroaki Oda T. Takahiko Ogawa Y. Yoshihiko Taniguchi S. Shigeyuki Kushihata A. Atsuo Takemasa K. Koji Usui K. Kenichiro Shigemoto S. Satoru Harada M. Michio Yamakido 2nd Department of Internal Medicine, Hiroshima University School of Medicine, and Ichiyokai Harada Hospital, Hiroshima, Japan

Localization of Hepatocyte Growth Factor and Tubulointerstitial Lesions in IgA Nephropathy

To investigate the relationship between localization of hepatocyte growth factor (HGF) and tubulointerstitial lesions (TILs) in the cortical area of renal biopsy specimens, a clinicopathological study was performed in 35 patients with IgA nephropathy. HGF was detected by an enzyme-antibody method and TILs were assessed semiquantitatively by light microscopy. HGF was observed mainly on epithelial cells in the tubules, but not in the glomeruli. Fourteen patients had biopsies that were positive for HGF. There was a correlation between HGF positivity and histological damage, the TIL grade, and several clinical parameters determined at biopsy. Thus, HGF is related to TILs in IgA nephropathy, and may be a factor in the exacerbation of this disease.

Role of secondary hyperparathyroidism in the development of post-transplant acute tubular necrosis.

Post-transplant cure tubular necrosis (ATN) represents the most frequent cause of delayed graft function in the immediate post-transplant period. Several causes have been associated with the development of post-transplant ATN such as donor and recipient ages, cold-warm ischemia times, HLA mismatches, and postoperative hypotension. In the present study, we retrospectively evaluated the role of secondary hyperparathyroidism and high parathyroid hormone (PTHi) blood levels in the development of post-transplant ATN. One hundred patients submitted to cadaveric renal transplant between January 1992 and March 1993 in our unit were included. Twenty-seven patients (27%) developed post-transplant ATN and seventy-three (73%) did not. Post-transplant ATN was significantly associated with gender (p < 0.01), recipient age (p < 0.01), number of transplantations (p < 0.01), time on hemodialysis (p < 0.001), cold ischemic time (p < 0.05) and PTHi levels (p < 0.001). The bivariate and multivariate statistical analyses demonstrated that the development of post-transplant ATN was significantly more frequent in females; retransplanted patients, patients with a time on dialysis of more than 5 years, recipients over 60 years old, patients with a PTHi blood level higher than 240 pg/ml (4 times normal level) and a cold ischemia time of more than 18 h. Based on these results, we conclude that high PTHi blood levels in the renal transplant recipients represent a relevant factor in the development of post-transplant ATN. The administration of intravenous pulsed of 1,25(OH)2D3 and/or a calcium channel blocker in the perioperative period could be useful to decrease the incidence and severity of post-transplant ATN in these patients.