Takayasu Ohtake

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.

Associations of Renal Vascular Resistance With Albuminuria and Other Macroangiopathy in Type 2 Diabetic Patients

OBJECTIVE—Albuminuria can be caused by endothelial dysfunction as a result of ischemic nephropathy rather than classic diabetic nephropathy. We studied whether renal vascular resistance (resistive index [RI]) of the main renal arteries could be associated with albuminuria and further assessed the relationship between RI and aorta stiffness measured by brachial-ankle pulse-wave velocity (baPWV). RESEARCH DESIGN AND METHODS—We consecutively studied 150 patients with type 2 diabetes and the absence of clinically overt renal artery stenosis. Renal function expressed as the estimated glomerular filtration rate (eGFR) was calculated using the modified formula of modification of diet in renal disease (MDRD). The RI [(peak systolic velocity –end-diastolic velocity)/peak systolic velocity] was measured with duplex Doppler ultrasonography. RESULTS—When the presence of albuminuria (uAlb) was defined as urinary albumin-to-creatinine ratio (μg/mg · creatinine) >30, mean RI [(left RI + right RI)/2] was significantly higher in uAlb, compared with that in patients without uAlb. RI had significant associations with age (r = 0.398, P < 0.0001), diastolic blood pressure (r = −0.398, P < 0.0001), eGFR (r = −0.373, P < 0.0001), and baPWV (r = 0.223, P < 0.05), respectively. Multivariate logistic regression analysis showed that increased RI when defined as RI >0.72 (median) was significantly associated with age (P < 0.01, 95%CI 1.02–1.19), diastolic blood pressure (P < 0.01, 0.86–0.97), and uAlb (P < 0.01, 1.53–15.46), respectively. Moreover, RI was an independent risk factor for uAlb after adjustment of both diastolic blood pressure and eGFR. CONCLUSIONS—Renal vascular resistance was associated with albuminuria and aorta stiffness. Increased RI may imply the presence of any type of underlying renal damage, including ischemic nephropathy.

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.

Coronary Artery Calcification, ADMA, and Insulin Resistance in CKD Patients

BACKGROUND AND OBJECTIVES It is known that coronary artery calcification (CAC) develops in chronic kidney disease (CKD) before initiation of renal replacement therapy, and factors associated with CKD mineral and bone disorders (CKD-MBDs) are involved. However, little information is available about any association between plasma levels of asymmetric dimethylarginine (ADMA), insulin resistance, and CAC. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 111 CKD patients (79 men, 32 women; glomerular filtration rate [GFR] median, 33.7 ml/min per 1.73 m(2)), free of cardiovascular disease, were consecutively recruited along with 30 age-matched healthy subjects. Coronary artery calcification scores (CACS) were measured by multidetector-row CT according to Agatston score. RESULTS In CKD patients, CACS was distributed widely from 0 to 2901, while in age-matched, healthy control subjects (n = 30), CACS showed a range from 0 to 307. GFR had a significant negative correlation with CACS. Plasma ADMA levels were negatively correlated with GFR and positively correlated with CACS. When CACS was divided into quartiles (<50, n = 56; 50 to 300, n = 24; 300 to 600, n = 14; >600, n = 17), the patients with CACS >600 had significantly higher values of HOMA-IR, plasma ADMA levels, and fibrinogen along with serum levels of phosphorus, compared with those in patients having CACS <50. Multivariate regression analysis determined HOMA-IR as an independent contributing factor to CACS. CONCLUSIONS CAC becomes more prevalent and severe with a decline in GFR, and plasma ADMA levels and insulin resistance, independent of factors associated with CKD-MBD, are correlated with CAC.

Roles of reactive oxygen species and antioxidant enzymes in murine daunomycin-induced nephropathy

We evaluated the roles of reactive oxygen species and intrinsic antioxidant enzymes in the development of daunomycin (DM)-induced nephropathy in mice. A single dose of DM (20 mg/kg intravenously) induced proteinuria by day 7 and the nephrotic syndrome by day 14 in DM-sensitive strain (A/J) but not in DM-resistant strain (C57BL/6J) (B6). Renal cortical lipid peroxide levels in the A/J mice significantly increased at days 2, 4, and 7 after DM injection, whereas no increase was observed in the B6 mice. The resistance to DM in B6 mice was associated with higher activities in renal cortical superoxide dismutase and glutathione peroxidase. The administration of superoxide dismutase or of dimethylthiourea significantly suppressed the DM-induced proteinuria in the A/J mice. Four days of superoxide dismutase or dimethylthiourea administration suppressed the proteinuria. These findings suggested that murine DM-nephropathy appeared to be mediated by reactive oxygen species and that intrinsic antioxidant enzyme activities may play an important role in the susceptibility to DM-induced nephropathy in mice.

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.

LDL-Apheresis Reduces P-Selectin, CRP and Fibrinogen— Possible Important Implications for Improving Atherosclerosis

Abstract:  Although it is known that LDL‐apheresis improves coronary artery stenosis (CAS) as well as ischemic limbs seen in patients with peripheral arterial occlusive disease (PAOD), the underlying mechanisms remain still unknown. LDL‐apheresis might exert its favorable action through anti‐inflammatory effects. We studied whether or not serum or plasma levels of P‐selectin, high sensitivity C‐reactive protein (hsCRP), monocyte chemotractant protein‐1 (MCP‐1) or fibrinogen could be reduced in patients with PAOD before and after 10 sessions of LDL‐apheresis. Sixteen patients (12 patients with hemodialysis, HD) with PAOD were enrolled in the present study. LDL‐apheresis was carried out 10 times (treated plasma of 3000 mL) over 5 weeks. Serum levels of P‐selectin were significantly reduced from 516 ± 153 to 290 ± 52 ng/mL before and after 10‐sessions of LDL‐apheresis, respectively (P < 0.05). Likewise, serum levels of hsCRP decreased from 9.118 ± 2.649 to 5.587 ± 2.445 mg/L (P < 0.01); and plasma fibrinogen levels statistically decreased from 196 ± 9.82 to 149 ± 7.97 mg/dL (P < 0.01), whereas serum levels of MCP‐1 were not significantly changed. The favorable actions of LDL‐apheresis might include anti‐inflammatory effects, which could lead to an improvement of CAS and PAOD. Moreover, this intervention might be applicable for patients with atherosclerotic cardiovascular disorders, particularly in patients with HD.

Interstrain Differences in Murine Daunomycin-Induced Nephrosis

Examining 8 inbred murine strains [A/J, BALB/c, SM/J, C3H/J, SWR/J, C57BL/6J (B6), DBA-2, B10D2/old (B10D2/o)] for urinary albumin excretion after a single daunomycin (DM) injection (20 mg/kg), we found strain specificity in susceptibility to DM nephrosis. This specificity did not relate to the serum disappearance rate of this drug. A/J and BALB/c were highly susceptible to the nephrosis while C57BL/6J, DBA-2 and B10D2/o were completely resistant to it. Chronological observation revealed that A/J mice had significant proteinuria at 2 weeks after injection, and it persisted for the remaining 4 weeks of this experiment, while C57BL/6J showed no increase over the experimental period. Using segregants obtained from an A/J and B6 backcross, it has been shown that susceptibility is inherited as an autosomal recessive trait and involves approximately three genes. Neither a C5 deficiency, H-2 type nor coat color gene (c-locus) was related to this susceptibility. This strain difference in nephrotoxicity would be a promising way to investigate its subcellular mechanism.