Hidekazu Moriya

High Prevalence of Occult Coronary Artery Stenosis in Patients with Chronic Kidney Disease at the Initiation of Renal Replacement Therapy: An Angiographic Examination

The prevalence of coronary artery stenosis (CAS) at the initiation of renal replacement therapy (RRT) in patients with chronic kidney disease (CKD) and no previous history of angina and/or myocardial infarction (MI) has not been fully elucidated. The prevalence of significant CAS was evaluated in 30 asymptomatic stage 5 CKD patients without a history of angina and/or MI by coronary angiography at the initiation of RRT. The correlations of various parameters with the prevalence of CAS were also examined. Atherosclerotic surrogate markers, including intima-media thickness of carotid artery and ankle-brachial BP index (ABI), were also evaluated. Significant CAS (>50% stenosis) was seen in 16 (53.3%) of 30 asymptomatic CKD patients on coronary angiography at the start of RRT. Stress cardiac scintigraphy was not effective for detecting hidden cardiac ischemia among the CKD patients. Univariate analysis showed that diabetes (P = 0.01), left ventricular mass index (P = 0.04), hyperlipidemia (P = 0.04), total cholesterol (P = 0.02), LDL cholesterol (P < 0.01), intima-media thickness (P = 0.04), and fibrinogen (P = 0.01) were positively correlated with the presence of CAS, whereas ABI (P < 0.01) showed a negative correlation with CAS. Stepwise logistic regression analysis revealed that diabetes and fibrinogen were significant and independent risk factors for CAS in asymptomatic CKD patients who started RRT. The results clearly demonstrated that despite the absence of cardiac events, stage 5 CKD patients are already in a very high risk group for CAS at the initiation of RRT, which was also closely associated with a significant decrease in ABI.

Weekly Averaged Blood Pressure Is More Important than a Single-Point Blood Pressure Measurement in the Risk Stratification of Dialysis Patients

BACKGROUND AND OBJECTIVES With regard to monitoring blood pressure in hemodialysis patients, it is important to define clearly the time point at which the blood pressure is measured, because the blood pressure of hemodialysis patients varies with each hemodialysis session as a result of loss of excess fluid. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using weekly averaged blood pressure, 96 hemodialysis patients were studied prospectively for 35 mo. All patients were followed up for cardiovascular events or death from all causes. RESULTS Pulse weekly averaged blood pressure and age at enrollment were significantly higher and parathyroid hormone level was significantly lower in patients with cardiovascular events compared with those without cardiovascular events; however, none of the components of pre- or postdialysis blood pressure was significantly different between patients with and without cardiovascular events. Pulse weekly averaged blood pressure, prepulse pressure, age, and human atrial natriuretic peptide were significantly higher in patients who died than in survivors. Kaplan-Meier method with a log-rank test demonstrated that survival free rate from cardiovascular events and that of all-cause mortality in patients with pulse weekly averaged blood pressure > or =70 mmHg were significantly lower than those in the remaining patients. CONCLUSIONS One-point measurement of blood pressure is insufficient to evaluate hypertension and prognosis of hemodialysis patients, and weekly averaged blood pressure is a useful marker because of averaging fluctuations of blood pressure during 1 wk. Among components of weekly averaged blood pressure, pulse weekly averaged blood pressure could be a good prognostic marker of the incidence of both cardiovascular events and all-cause mortality in hemodialysis patients.

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.

Angiotensin II receptor blockade limits kidney injury in two-kidney, one-clip Goldblatt hypertensive rats with special reference to phenotypic changes

Recent evidence indicates that tubulointerstitial injury plays an important role in hypertensive kidney injury and that phenotypic changes contribute to this pathology. Moreover, angiotensin II is known to be actively involved in the pathogenesis of progressive kidney injury induced by hypertension. The present study was undertaken to see the effect of a newly developed angiotensin II type I receptor (AT1 receptor) antagonist on hypertension-induced kidney injury and to determine the contribution of phenotypic changes to morphologic alterations. Two-kidney, one-clip (2K1C), Goldblatt hypertensive rats (n = 27) were made by clipping the left renal artery. These animals were orally administered 57G709 (a selective non-peptide AT1 receptor antagonist)(10 mg/kg/day), captopril (20 mg/kg/day), or vehicle alone for 23 days beginning 4 weeks after clipping. In the non-clipped kidney of vehicle-treated 2K1 C rats, marked tubulointerstitial injury as well as glomerular sclerosis and/or hyalinosis was found in association with phenotypic changes, as shown by the neoexpression of vimentin in periglomeruli, perivascular walls, distal tubuli, and injured interstitium. Renin expression was markedly suppressed in the non-clipped kidneys of vehicle-treated 2K1C rats as compared with renin expression in normotensive control kidneys of sham-operated rats. Both 57G709 and captopril markedly ameliorated hypertensive kidney injury as reflected by the glomerular sclerosing index and by the tubulointerstitial index as determined by the point-counting method, and this improvement was accompanied by a significant decrease in blood pressure, urinary protein excretion, kidney/body weight ratio, and heart/body weight ratio. In addition, the vimentin neoexpression mentioned above was also suppressed with an inhibition of angiotensin II. These results suggest that in 2K1C Goldblatt hypertensive kidney injury, the AT1 receptor antagonist 57G709 exerts a potent renal protective effect associated with the inhibition of phenotypic changes.

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.

Pathological Regression by Angiotensin II Type 1 Receptor Blockade in Patients with Mesangial Proliferative Glomerulonephritis

Although angiotensin II type 1 receptor blocker (ARB) therapy reduces proteinuria and retards the progression of renal injury in patients with glomerulonephritis, whether these drugs actually ameliorate pathological damages in human glomerulonephritis has not been determined. Fifteen patients with biopsy-proven mild-to-moderate mesangial proliferative glomerulonephritis (10 with immunoglobulin A [IgA] nephropathy and 5 with non-IgA mesangial proliferative glomerulonephritis) received ARB monotherapy. In these patients, repeated renal biopsy was performed after a mean of 28.1 months, and pathological changes (including the mesangial matrix expansion ratio and interstitial fibrosis expansion ratio) were quantitatively examined using an image analyzer. Clinical markers were also evaluated, including the serum creatinine, serum IgA, creatinine clearance (Ccr), 24-h urinary protein excretion, urinary N-acetyl-β-D-glucosaminidase (NAG), and blood pressure. ARB therapy significantly reduced urinary protein excretion (0.68±0.63 to 0.20±0.32 g/day, p=0.016) and the blood pressure (systolic: 133.3±18.2 to 123.4±10.5 mmHg, p=0.041; diastolic: 79.4±11.9 to 72.0±8.2 mmHg, p=0.038). Although the global glomerular sclerosis ratio was unchanged (6.3±8.5% to 10.7±16.1%, p=0.33), the mesangial matrix expansion ratio (33.1±10.8% to 22.7±7.8%, p=0.001) and the interstitial fibrosis ratio (19.9±5.8% to 13.8±4.4%, p=0.034) were significantly reduced by ARB treatment. The levels of pathological improvement were similar between patients with IgA nephropathy and those with non-IgA mesangial proliferative glomerulonephritis. The results of the present study strongly suggest that ARB monotherapy can significantly reverse pathological changes, including mesangial matrix expansion and interstitial fibrosis, in human glomerulonephritis.

Important role of blood rheology in atherosclerosis of patients with hemodialysis

Concerning a role of blood rheology for atherosclerosis in patients with hemodialysis (HD), little data are available. It may be due to the fact that the method for evaluating rheologic properties of circulating blood has been limited. We examined blood rheology in 118 HD patients by using microchannel array flow analyzer that makes it possible to directly observe the flow of blood cell elements through the microchannel. Transit time (TB) of heparinized whole blood through slit pores (7 × 30 µm) was used as an index of rheology and related with various inflammatory biomarkers such as high‐sensitive CRP (hsCRP), monocyte chemotactic protein‐1, osteopontin, or fibrinogen (Fg). Moreover, as a surrogate marker of atherosclerosis, carotid intima‐media thickness (IMT) and aortic stiffness evaluated by brachial‐ankle pulse‐wave velocity (baPWV) were studied. In HD patients, TB had strong positive correlations with hsCRP (r = 0.427; p < 0.00001), Fg (r = 0.452; p < 0.00001), and osteopontin (r = 0.227; p < 0.0134). Further, TB was significantly well correlated with IMT (r = 0.400; p < 0.0001) and PWV (r = 0.470; p < 0.0001). Multivariate regression analysis showed that baPWV, IMT, Fg, hematocrit, white blood cell count, and CRP were chosen as significant explanatory factors for TB. These results suggest that blood rheology may play an important role for atherosclerosis in patients with HD.

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.