Kumeo Ono

Ankle-Brachial Blood Pressure Index Predicts All-Cause and Cardiovascular Mortality in Hemodialysis Patients

A reduction in ankle-brachial BP index (ABPI) is associated with generalized atherosclerotic diseases and predicts cardiovascular mortality and morbidity in several patient populations. However, a large-scale analysis of ABPI is lacking for hemodialysis (HD) patients, and its use in this population is not fully validated. A cohort of 1010 Japanese patients undergoing chronic hemodialysis was studied between November 1999 and May 2002. Mean age at entry was 60.6 +/- 12.5 yr, and duration of follow-up was 22.3 +/- 5.6 mo. Patients were stratified into five groups (< 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.1, > or = 1.1 to < 1.3, and > or = 1.3) by ABPI measured at entry by an oscillometric method. The frequency distribution of ABPI was 16.5% of patients < 0.9, 8.6% of patients > or = 0.9 to < 1.0, 16.9% of patients 1.0 > or = to < 1.1, and 47.0% of patients > or 1.1 to < 1.3, whereas 10.9% of patients had an abnormally high ABPI (> or = 1.3). The relative risk of a history of diabetes mellitus (DM), cardiovascular, and cerebrovascular disease was significantly higher in patients with lower ABPI than those with ABPI > or = 1.1 to <1.3. During the study period, 77 cardiovascular and 41 noncardiovascular fatal events occurred. On the basis of Cox proportional hazards regression analysis, ABPI emerged as a strong independent predictor of all-cause and cardiovascular mortality. After adjustment for confounding variables, the hazard ratio (HR) for ABPI < 0.9 was 4.04 (95% confidence interval, 2.38 to 6.95) for all-cause mortality and 5.90 (2.83 to 12.29) for cardiovascular mortality. Even those with modest reductions in the ABPI (> or = 0.9 to <1.1) appeared to be at increased risk. Patients having abnormally high ABPI (> or = 1.3) also had poor prognosis (HR, 2.33 [1.11 to 4.89] and 3.04 [1.14 to 8.12] for all-cause and cardiovascular mortality, respectively). Thus, the present findings validate ABPI as a powerful and independent predictor for all-cause and cardiovascular mortality among hemodialysis patients.

Increased excretion of urinary transforming growth factor beta in patients with focal glomerular sclerosis.

The urinary transforming growth factor beta (TGF-beta) excretion was measured in 33 patients including 10 with systemic lupus erythematosus (SLE), 8 with focal glomerular sclerosis (FGS), 9 with IgA nephropathy (IgAN), and 6 with membranous nephropathy (MN), and in 7 healthy subjects by enzyme-linked immunosorbent assay using a monoclonal antibody specific for TGF-beta 1 + 2 + 3. A significantly increased urinary TGF-beta excretion was observed in FGS patients (555.5 +/- 458.4 ng/mg Cr) as compared with normal controls (46.9 +/- 43.9 ng/mg Cr) (p < 0.05) and a relative increase in SLE patients (96.4 +/- 58.2 ng/mg Cr) and a decrease in MN patients (24.8 +/- 13.3 ng/mg Cr). In contrast, there was no difference in TGF-beta excretion between IgAN patients (54.1 +/- 37.4 ng/mg Cr) and normal controls. A correlation between the amount of proteinuria and TGF-beta was not found. As has been previously demonstrated in experimental studies, TGF-beta may play a similar role in human glomerular diseases. The results obtained in this study raised the possibility that extracellular matrix might be produced by glomerular cells in vivo under the control of TGF-beta and that TGF-beta might act as a stimulator for the development of glomerulosclerosis.

FK506, a novel immunosuppressive agent, induces antigen-specific immunotolerance in active Heymann's nephritis and in the autologous phase of Masugi nephritis.

FK506 is a new drug which has potent immunosuppressive activity. We studied its immunosuppressive effects on active Heymanns nephritis and the aulologous phase of Masugi nephritis. The induction of active Heymanns nephritis was completely suppressed by FK506 injected simultaneously with the antigen (day 1) and then daily for 14 days at a dose of 0.64 mg/kg per day or more. With a lower dosage of this agent, antibody production and immune deposits in the glomerular basement membrane occurred despite the suppression of proteinuria. Similar results were obtained in rats on other treatment schedules (1–7 days or day 8–14 days duration). Rats that were prevented from developing Heymanns nephritis or the autologous phase of nephrotoxic antiserum nephritis by FK506 treatment exhibited a suppressed immune response to a second immunization of the same antigen even 4 weeks after cessation of drug administration; however, they developed antibodies when inoculated with other antigens. Rat peripheral leucocyte counts and scrum creatinin were not remarkably influenced by the administration of FK506. These results indicate that FK506 has potent immunosuppressive activity, and it is suggested that it is able to induce an antigen‐specific immunotolerance.

Active Inhibitory Effect of Nafamostat Mesylate against the Elevation of Plasma Myeloperoxidase during Hemodialysis

Plasma levels of myeloperoxidase (MPO) were compared between hemodialysis (HD) sessions using heparin and those using nafamostat mesylate (NM) as an anticoagulant by an enzyme immunoassay established in our laboratory. MPO levels were markedly elevated during the entire HD procedure with heparin. In contrast, MPO levels were scarcely elevated during the HD with NM. On the other hand, polymorphonuclear leukocyte-elastase was markedly elevated during both of these HD procedures. These observations indicated that NM selectively attenuated MPO elevation in vivo during HD. This inhibitory effect of NM was further investigated ex vivo. Blood samples from a normal subject were collected with heparin alone, NM alone and a mixture of heparin and NM. Each sample was then circulated in a closed circuit composed of a dialyzer with a cuprophane membrane. MPO levels with heparin alone were shown to markedly rise in the closed system. In contrast, levels of MPO in the blood samples mixed with NM were not elevated even in the presence of heparin. These ex vivo results indicate that NM has an active inhibitory effect on the elevation of plasma MPO induced by granulocyte activation through a dialysis membrane. Our results demonstrate that clinical use of NM as an anticoagulant serves to selectively suppress MPO elevation considered as a consequence of granulocyte activation during HD.

Hypercalcemia associated with osteolytic lesions in the extramedullary blastic crisis of chronic myelogenous leukemia: Report of a case

SummaryA 43-year-old male patient with hypercalcemia and osteolytic lesions complicating chronic myelogenous leukemia is presented. Extramedullary myeloid blastic crisis was diagnosed by the histological finding of the specimen biopsied from a osteolytic lesion in the right femur. As the serum levels of parathyroid hormone, 1,25 (OH)2 vitamin D, prostaglandin E2 and interleukin 1, and the urinary excretion of cyclic AMP were all normal, it was considered that the hypercalcemia was attributed to the bone destruction by the invasion of leukemic myeloblasts.

The elevation of plasma levels of myeloperoxidase and polymorphonuclear leukocyte elastase as an index of bioincompatibility of the column during hemodialysis using with a β2-microglobulin-selective adsorbent column

AbstractBackground. It is well known that dialysis-related amyloidosis (DRA) is a serious major complication in long-term hemodialysis (HD) patients, and β2-microglobulin (MG) accumulation is recognized to be the major cause of DRA. Recently, a β2-MG selective adsorbent column has been developed for eliminating β2-MG from the circulating blood.We developed a novel enzyme immunoassay (EIA) method to measure myeloperoxidase (MPO), and observed the course of plasma MPO and polymorphonuclear leukocyte (PMN)-elastase concentrations as an index of the bioincompatibility of this column during treatment. Methods. Six patients undergoing maintenance HD participated in this study. Both proteins (MPO and PMN-elastase) were compared in patients receiving HD without this column and HD with this column. The concentrations were measured by EIA. The MPO assay was established in our laboratory, using our monoclonal anti-MPO antibody. Results. Both proteins were markedly elevated during HD with this column, compared with their concentrations in patients receiving HD without this column. Conclusion. Marked elevation of both MPO and PMN-elastase, indicating excessive granulocyte activation, was caused by the use of this column. It is possible that this phenomenon may lead to serious pathogenic conditions and progress to DRA in HD patients with long-term use of this column. At present, we have no data for long-term use. In future, the advantages and disadvantages of long-term use of this column should be investigated.

A major pathogenic antigen of Heymann nephritis is present exclusively in the renal proximal tubule brush border—studies with a monoclonal antibody against pronase‐digested tubular antigen

We have isolated a nephritogenic 120‐kD antigen from rat renal tubule brush border that induces rat Heymann nephritis. A MoAb that recognized this antigen reacted exclusively with the brush border on indirect immunofluorescence and immunoelectron microscopy. Rabbit antiserum against this antigen also reacted exclusively with the brush border. With the injection of this antiserum, rabbit IgG became detectable along the glomerular basement membrane (GBM) after 3 days. Our 120‐kD antigen was shown to have a close relationship with gp330 based on the following: (i) this antigen can induce active Heymann nephritis as gp330: (ii) our MoAb reacted with the immune deposits of nephritic kidneys induced not only by the 120‐kD antigen but also by gp330, and conversely, rabbit antiserum against gp330 reacted with those induced by the 120‐kD antigen as well as gp330; and (iii) by immunoblotting, polyclonal antibodies against the 120‐kD antigen reacted with gp330 and polyclonal antibodies against gp330 reacted with the 120‐kD antigen. These observations indicate that antigen present exclusively in the brush border can induce active Heymann nephritis, and the common antigenic determinants shared by brush border and the coated pits of glomerular epithelium may not be a prerequisite to induce nephritis. A more precise relationship between the 120‐kD antigen and reported C14 fusion protein or 40‐kD α2MRAP remains to be established.

Detection of heterogeneity of Cu, Zn-superoxide dismutase with monoclonal antibodies and the establishment of a highly sensitive fluorescence sandwich enzyme-linked immunosorbent assay.

Murine monoclonal antibodies directed against a native form of Cu, Zn‐superoxide dismutase (SOD) were produced by immunizing SOD purified from human erythrocytes. The monoclonal antibodies able to bind SOD were further screened for their ability to absorb SOD activity using antimouse 1gG conjugated iron beads as solid supports in magnetic separation. This new screening method revealed the heterogeneity of native SOD in the reactivity with the antibodies. One monoclonal antibody succesfully absorbed the entire activity of SOD detected by an inhibition assay of cypridina luciferin analog (MCLA)‐dependent chemilluminescence induced by superoxide anion production, while others absorbed only a part of the SOD activity. The evidence that all of the latter antibodies failed to react with recombinant artificial SOD free of charge isomers suggested correlation of the heterogeneity with the presence of charge isomeric forms. The former antibody was further used to establish a fluorescence sandwich enzyme immunoassay, and this provided a very sensitive detection limit as low as 100 pg/ml.