Sumi Hidaka

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.

Lanthanum Carbonate Delays Progression of Coronary Artery Calcification Compared With Calcium-Based Phosphate Binders in Patients on Hemodialysis A Pilot Study

Background and Objectives: Coronary artery calcification (CAC) is associated with future cardiovascular events and/or death of patients on hemodialysis (HD). We investigated whether progression of CAC in patients on HD could be delayed by switching from a calcium (Ca)-based phosphate (Pi) binder to lanthanum carbonate. Design, Setting, Participants, and Measurements: The CAC scores were evaluated at study enrollment and after 6 months in 52 patients on HD using calcium carbonate (CC) as a Pi binder. Patients were randomly divided into 2 groups assigned to receive either CC or lanthanum carbonate (LC), and the CAC scores were evaluated after a 6-month treatment period. Progression of CAC was assessed, as were serum levels of Ca, Pi, and intact parathyroid hormone (iPTH). Results: Forty-two patients completed the study (23 receiving CC and 19 receiving LC). In the 6 months prior to randomization, all patients were treated with CC. During this 6-month period, the CAC scores increased significantly in all 42 patients. Once randomized, there was significantly less progression in the group treated with LC than with CC. Changes in CAC scores from 6 to 12 months were significantly smaller in the LC group than the CC group (−288.9 ± 1176.4 vs 107.1 ± 559.6, P = .036), and percentage changes were also significantly different (−6.4% vs 41.2%, P = .024). Serum Ca, Pi, and iPTH levels were similar in both groups during the study period. Conclusions: This pilot study suggested that LC delayed progression of CAC in patients on HD compared with CC.

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.

Serum Biological Antioxidant Potential Predicts the Prognosis of Hemodialysis Patients

Background: It is well known that oxidative stress is enhanced in patients with end-stage renal disease. However, little is known about the relationship between serum antioxidant capacity and clinical outcome in hemodialysis (HD) patients. Methods: We examined the relationship between serum biomarkers of oxidative stress and clinical outcomes including all-cause mortality, hospitalization rate and incidence of cardiovascular events in HD patients. As biomarkers of oxidative stress, we measured serum levels of coenzyme Q10 (CoQ10) and biological antioxidant potential (BAP). Results: 108 patients were observed for 30 months as the follow-up periods. The survival group (n = 83) showed significantly higher BAP values compared with those in death groups (n = 25; p < 0.05). When serum BAP levels were divided into two groups by their median value, the group with higher BAP values had a better survival rate than that with lower BAP values on the Kaplan-Meier survival analysis (p = 0.05). Although serum levels of CoQ10 did not show any association with clinical outcomes, lower BAP was selected as an independent risk factor for all-cause mortality as well as the absence of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers therapy by age-adjusted Cox regression analysis. Conclusions: This study indicated that BAP could predict the prognosis of HD patients.

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.

Correlation of Coronary Artery Calcification With Pre‐Hemodialysis Bicarbonate Levels in Patients on Hemodialysis

Coronary artery calcification (CAC) leads to a significant increase in cardiovascular morbidity and mortality in hemodialysis (HD) patients. Metabolic acidosis, which is common in HD patients, promotes bone resorption in human and animals as a result of buffer function of bone, and calcium and phosphate elute from bone into blood stream. However, the effect of acidosis on CAC in HD patients has never been precisely investigated. This is a cross‐sectional observational study performed in a single center. One hundred and seven prevalent HD patients (35 women and 72 men) underwent electron‐beam computed tomography (EBCT) to evaluate CAC score (CACS), and then we evaluated associated factors of CACS with clinical and laboratory parameters including pre‐HD pH and bicarbonate levels. Pre‐HD pH and bicarbonate levels were 7.35 ± 0.04, and 17.6 ± 1.8mmol/L, respectively. The pre‐HD pH had no significant correlation to CACS (r = −0.025, P = 0.81). CACS was significantly negatively correlated with pre‐HD bicarbonate levels (r = −0.329, P = 0.0009) and serum albumin levels (r = −0.298, P = 0.0467), while it was positively correlated with age (r = 0.319, P = 0.0008) and HD duration (r = 0.385, P = 0.0004). Serum levels of calcium, phosphorus, intact parathyroid hormone, and use of phosphorus binders were not related to CACS. Multivariate analysis indicated that plasma pre‐HD bicarbonate level was independently associated with CACS. The present study showed that blood levels of pre‐HD bicarbonate were significantly associated with CAC in HD patients. Further studies are needed to confirm these results and to determine whether correction of metabolic acidosis prevents the development of CAC, one of the features of accelerated atherosclerosis in HD patients.

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.

Hepatitis B virus-related membranous nephropathy treated with entecavir.

In January 2007, a 57 year old woman with a 3 year history of hypertension was referred to our department because of proteinuria and microscopic haematuria. HBV infection was proved in 1997, and serological tests showed that hepatitis B e-antigen (HBeAg) was negative and hepatitis B e-antibody (HBeAb) was positive in 2003. In the summer of 2005, slight elevation of liver enzymes was observed, and in December of 2005, HBeAg was positive and HBeAb was negative (HBeAg reverse seroconversion). On admission, the findings of physical examination were unremarkable except pitting oedema in the lower extremities. The results of peripheral blood count were normal. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 61 IU/L and 43 IU/L, respectively. Serum creatinine was 63 mmol/L (0.71 mg/dL). Immunoglobulins and complements were within normal range. The HBV-DNA level was 7.5 LGE/mL. Urinary protein excretion was 3.72 g/ day, and serum albumin decreased to 33 g/L. A renal biopsy led to a diagnosis of HBV-related MN. Entecavir was commenced at 0.5 mg/day without angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Two months after treatment, virological tests showed HBeAg seroconversion. Four months after treatment, HBV-DNA was not detected in the blood. Entecavir treatment was continued for 1 year more, and finally resulted in complete remission of proteinuria. However, 3 months after cessation of entecavir, HBV was detected again. We are observing the patient without entecavir, because HBeAg remains negative.

Randomized Pilot Trial Between Prostaglandin I2 Analog and Anti-Platelet Drugs on Peripheral Arterial Disease in Hemodialysis Patients

The effect of the prostaglandin I2 analog, beraprost sodium (BPS), on hemodialysis (HD) patients with peripheral arterial disease (PAD) has not been fully elucidated. The effect of BPS was compared to that of PAD drugs in HD patients with PAD in a multicenter randomized prospective interventional pilot study (J‐PADD). Seventy‐two PAD patients on HD were entered and randomly divided into two groups; that is, BPS group (Group A: n = 35) and PAD drug (cilostazol or sarpogrelate) group (Group B: n = 37). Primary endpoint was changes in skin perfusion pressure (SPP). Kidney Disease Quality of Life (KDQOL) score, cardiovascular events, PAD events, and adverse events were also evaluated. SPP increased significantly in both groups at 24 weeks from their basal levels. The absolute increase of SPP in Group A and Group B were 15.4 ± 30.0 mm Hg (P < 0.0001) and 20.2 ± 22.1 mm Hg (P = 0.025) (instep), and 13.8 ± 19.3 mm Hg (P < 0.0001) and 9.2 ± 16.3 mm Hg (P = 0.041) (sole), respectively. Changes of KDQOL score showed significantly better result in the role of physical score in Group A compared with Group B. Although heart rate was unchanged in Group A, 9.3/min increase was seen in Group B patients who received cilostazol. There was no intergroup difference in cardiovascular events and/or PAD events between the two groups during the study period. This exploratory pilot study suggested BPS was as effective as anti‐platelet drugs in improving microcirculation in HD patients.

Sarpogrelate Hydrochloride, a Selective 5-HT 2A Receptor Antagonist, Improves Skin Perfusion Pressure of the Lower Extremities in Hemodialysis Patients with Peripheral Arterial Disease

Background: Peripheral arterial disease (PAD) frequently occurs in patients on hemodialysis (HD); however, little is known about the effectiveness of drugs. We compare the effects of sarpogrelate and cilostazol in HD patients with PAD. Methods: We conducted a prospective, randomized, open-label, and multicenter trial for 24 weeks in HD patients with PAD. Thirty-five patients were divided into two groups: sarpogrelate (n = 17) and cilostazol (n = 18). We analyzed changes in skin perfusion pressure (SPP), levels of oxidative stress biomarkers, and adverse events. Results: At 24 weeks, SPP was increased in both groups (sarpogrelate, 43 ± 17 to 55 ± 15 mmHg; cilostazol, 49 ± 21 to 66 ± 29 mmHg; p < 0.05), and no difference was observed between the groups. Plasma pentosidine levels decreased in both groups (sarpogrelate, 0.65 ± 0.24 to 0.48 ± 0.12 mg/mL; cilostazol, 0.58 ± 0.22 to 0.47 ± 0.17 mg/mL; p < 0.05), and there were no differences between the groups. Serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels significantly increased only in cilostazol group (p < 0.05). There were no clinically significant safety concerns linked to the both drugs. Although blood pressure did not differ in both groups, heart rate increased only in cilostazol group from 77 ± 13 to 83 ± 16 beats per minute (p < 0.05). Conclusion: Sarpogrelate improves SPP in HD patients with PAD without increasing heart rate and serum MDA-LDL levels. We demonstrated that sarpogrelate is an effective and safe drug for the treatment of HD patients with PAD.