Kenjiro Honda

Impact of coronary artery calcification in hemodialysis patients: Risk factors and associations with prognosis.

The risk factors of coronary artery calcification (CAC) and the impact of CAC on cardiovascular events, cardiovascular deaths, and all‐cause deaths in hemodialysis (HD) patients have not been fully elucidated. We examined the CAC score (CACS) in 74 HD patients using electron‐beam computed tomography. Fifty‐six patients underwent a second electron‐beam computed tomography after a 15‐month interval to evaluate CAC progression. We evaluated (1) the risk factors for CAC and its progression and (2) the impact of CAC on the prognosis. In the cross‐sectional study, HD vintage and high‐sensitive C‐reactive protein (hsCRP) were the independent risk factors for CAC. In the prospective cohort study, delta CACS (progression of CAC) was significantly correlated with hsCRP, fibrinogen, and serum calcium level in the univariate analysis. Stepwise multiple regression analysis revealed that only hsCRP was the independent risk factor for CAC progression in HD patients. Kaplan‐Meier survival analysis revealed that cardiovascular events (P<0.0001), cardiovascular deaths (P=0.039), and all‐cause deaths (P=0.026) were significantly associated with CACS. In conclusion, CAC had significantly progressed in HD patients during the 15‐month observation period. Microinflammation was the only independent risk factor for CAC progression in HD patients. The advanced CAC was a significant prognostic factor in HD patients, i.e., which was strongly associated with future cardiovascular events, cardiovascular deaths, and all‐cause deaths.

Photoelectrochemistry of metallochlorophylls

Abstract Photoinduced electron transfer from eleven metallochlorophyll a (MChl a) monolayers to a SnO2 substrate was investigated photoelectrochemically. Six MChl as [M = Pd(II), Cu(II), Hg(II), H2(II), Mg(II), and Zn(II)] gave measurable photoeffects. For the latter three pigments, two-dimensional dilution of the monolayer led to an enhancement of the photocurrent quantum yield. The highest quantum yield was attained with MgChl a at sufficient dilution. Five MChl as [M = Ni(II), Co(II), Ag(II), Mn(III), and Fe(III)] showed no photoresponse, due probably to a rapid intramolecular deactivation of the excited state. Some kinetic aspects of the interfacial photoprocess were clarified by experiments with mixed monolayers composed of a photoactive MChl a and photo-inactive NiChl a (quencher).

Cardiovascular Protective Effects of On‐Line Hemodiafiltration: Comparison With Conventional Hemodialysis

Atherosclerotic complications have a significant effect on mortality in patients undergoing hemodialysis (HD) therapy. However, anti‐atherosclerotic and cardioprotective effects of on‐line hemodiafiltration (HDF) remain to be elucidated. We prospectively compared the anti‐atherosclerotic and cardioprotective effects in two randomly divided groups, i.e. on‐line HDF group (n = 13) and conventional HD group (n = 9) for 1 year. Surrogate markers were brachial‐ankle pulse wave velocity (baPWV), intima‐media thickness (IMT) of carotid artery as an atherosclerosis marker, and cardiac functional surrogate markers included left ventricular mass index (LVMI), ejection fraction (EF), and LV diastolic capacity represented as E/A and deceleration time (DT). LVMI in on‐line HDF patients showed significant regression after 1 year of treatment (131.9 ± 25.8 to 116.5 ± 24.7 g/m2, P = 0.03), while LVMI in HD patients did not show any significant change (148.0 ± 47.1 to 142.3 ± 35.5 g/m2). Levels of baPWV in HD patients showed a significant increase (11.4%) from basal levels, while on‐line HDF groups showed no significant increase. Furthermore, HD patients showed significant worsening of LV diastolic capacity (E/A: from 0.87 ± 0.12 to 0.79 ± 0.08, P = 0.03), while it was not shown in on‐line HDF patients. Ejection fraction and IMT did not show any significant change in both groups. Serum albumin, C‐reactive protein, β2 microglobulin, blood pressure, and anti‐hypertensive drug use did not change in both groups. On‐line HDF showed a significant improvement in LVMI and prevented a significant worsening of baPWV or LV diastolic capacity compared with patients on conventional HD therapy.

High-throughput screening identified disease-causing mutants and functional variants of α-galactosidase A gene in Japanese male hemodialysis patients

Fabry disease is a genetic disorder caused by deficient activity of lysosomal enzyme α-galactosidase A (GLA) and end-stage renal disease (ESRD) will be present after accumulation of glycosphingolipids within the kidney. Undiagnosed atypical variants of Fabry disease, which are limited to renal involvement, were found in several ESRD patient populations. On the other hand, unexpectedly high frequencies of male subjects having the c.196G>C nucleotide change (p.E66Q) showing low α-GLA activity have been reported on Japanese and Korean screening for Fabry disease. However, several evidences indicate the c.196G>C is not a pathogenic mutation but is a functional polymorphism. In the present study, high-throughput screening of serum GLA could successfully indentify two Fabry disease patients in a cohort consisted of 1080 male hemodialysis patients. Moreover, our serum assay was able to distinguish two patients with disease-causing genetic mutations (p.G195V and p.M296I) from eight functional variants that showed relatively decreased enzyme activity (p.E66Q). In conclusion, high-throughput serum enzyme assay distinctly identified disease-causing mutants and functional variants of GLA gene in Japanese male hemodialysis patients. In addition, our results underscore the high prevalence of not only undiagnosed Fabry patients but functional variants of p.E66Q among the ESRD population.

A novel mechanism in maggot debridement therapy: protease in excretion/secretion promotes hepatocyte growth factor production

Maggot debridement therapy (MDT) is effective for treating intractable wounds, but its precise molecular mechanism, including the association between MDT and growth factors, remains unknown. We administered MDT to nine patients (66.3 ± 11.8 yr, 5 male and 4 female) with intractable wounds of lower extremities because they did not respond to conventional therapies. Significant increases of hepatocyte growth factor (HGF) levels were observed in femoral vein blood during 48 h of MDT (P < 0.05), but no significant change was found for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-β1 (TGF-β1), or tumor necrosis factor-α (TNF-α). We conducted NIH-3T3 cell stimulation assay to evaluate the relation between HGF and protease activity in excretion/secretion (ES) derived from maggots. Compared with the control group, HGF was significantly higher in the 0.05 μg/ml ES group (P < 0.01). Furthermore, protease inhibitors suppressed the increase of HGF (P < 0.05). The HGF expression was increased in proportion to the ES protein concentration of 0.025 to 0.5 μg/ml. In fact, ES showed stronger capability of promoting HGF production and less cytotoxicity than chymotrypsin or bromelain. HGF is an important factor involved in cutaneous wound healing. Therefore, these results suggest that formation of healthy granulation tissue observed during MDT results from the increased HGF. Further investigation to identify molecules enhancing HGF expression by MDT will contribute greatly to drug target discovery for intractable wound healing therapy.

Differences in associated factors between aortic and mitral valve calcification in hemodialysis

Increased prevalence of aortic and mitral valve calcification has been reported in patients on hemodialysis, but it remains unknown whether aortic and mitral valve calcification arise from similar pathogenesis. We detected heart valve calcification using two-dimensional echocardiography, and we related valve calcification to various clinical parameters in patients treated with hemodialysis three times a week for more than 1 year. In 112 patients (77 men and 35 women, age 67±10 years, duration on hemodialysis 95±67 months), aortic and mitral valve calcification were observed in 84 (75.0%) and 58 (51.7%) patients, respectively. Aortic valve calcification was associated with increased age, higher serum calcium, lower serum albumin, lower total cholesterol and higher high-sensitivity C-reactive protein. Multivariate analysis showed that increased age and higher serum calcium were independently associated with aortic valve calcification. Conversely, mitral valve calcification was associated with increased age, higher high-sensitivity C-reactive protein and higher serum β2-microglobulin, but not with higher serum calcium. In multivariate analysis, increased age and higher serum β2-microglobulin were independently associated with mitral valve calcification. Serum β2-microglobulin was associated with longer duration on hemodialysis, malnutrition inflammation (lower serum albumin and higher high-sensitivity C-reactive protein) and dyslipidemia. Considering the results in previous studies showing that the distribution of β2-microglobulin amyloid deposition was consistent with that of tissue calcification in patients on hemodialysis, β2-microglobulin may have pathogenic roles in valve calcification.

Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1α expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.

High-density Association Mapping and Interaction Analysis of PLA2R1 and HLA Regions with Idiopathic Membranous Nephropathy in Japanese

Although recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. We genotyped across the PLA2R1 gene and the HLA region, using 183 IMN patients and 811 healthy controls. Five SNPs around the PLA2R1 gene were significantly associated with IMN. In addition to the two SNPs previously reported to be strongly associated with IMN, rs3749119 and rs35771982 (OR 3.02 and 2.93, P = 3.24E-14 and 4.64E-14, respectively), two novel intronic SNPs (rs2715928 and rs16844715) were also identified as IMN-associated SNPs (OR = 2.30 and 2.51, P = 3.15E-10 and 5.66E-13, respectively). In the HLA gene analysis, DRB1*1501 and DQB1*0602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). The interaction was strongest between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the intronic SNP rs2715928 (OR = 17.53, P = 4.26E-26). Furthermore, positive interaction was also observed between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the missense SNP rs35771982 (OR = 15.91, P = 2.76E-29), which is in strong linkage disequilibrium with 5′UTR SNP rs3749119, and intronic SNP rs16844715 (OR = 15.91, P = 2.30E-26) for IMN. Neither HLA-DRB1*15:01 nor HLA-DQB1*06:02 was associated with steroid responsiveness, overall survival and renal survival during the observation period of mean 11 years though limited number of analysis.

Successful treatment with cyclosporine of thrombotic thrombocytopenic purpura refractory to corticosteroids and plasma exchange.

tions, as recommended in the instruction manual. We consider that this catheter malfunction of the Soft Cell was caused by poor connection between the catheter and the cuff that occurred in the manufacturing process. This malfunction results in the cuff remaining under the skin and detachment of the catheter from the vein. This not only results in discontinuation of dialysis therapy, but can cause complications such as massive bleeding or infection. At present,we are using anotherTCC instead of the Soft Cell, since the reason for its malfunction has not been clarified.The Soft Cell is commonly used; therefore, the causes of detachment should be promptly investigated, and countermeasures taken as soon as possible in order to prevent serious complications.

Beraprost Sodium, an Orally Active Prostaglandin I2 Analog, Improves Renal Anemia in Hemodialysis Patients With Peripheral Arterial Disease

Beraprost sodium (BPS) is a stable, orally active prostaglandin I2 (PGI2) analog with antiplatelet and vasodilating properties. It has been reported that PGI2 has pleiotropic effects that are anti‐inflammatory and anti‐atherogenic. In this study, we aim to determine the relationship between PGI2 and renal anemia. We conducted a prospective randomized trial including 20 hemodialysis patients. Ten patients were assigned to be treated with 120 µg/day of BPS and the other patients were assigned to a control group. After six months, the titer of hemoglobin had significantly increased in the BPS group compared to the baseline (11.1 ± 0.3 g/dL vs. 10.3 ± 1.4 g/dL, respectively), and there was a significant difference between the BPS group and the control group. The level of ferritin was lower in the BPS group compared to the control group, but the average dose of erythropoietin did not significantly change. These findings suggest that BPS may improve renal anemia in hemodialysis patients.