Tsutomu Mano

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.

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.

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.

Increased leukocyte aggregates are associated with atherosclerosis in patients with hemodialysis.

Little data are available on the role of blood rheology in atherosclerosis in hemodialysis (HD) patients. This study sought to assess the relationship between leukocytes conjugated with platelets (leukocyte aggregates [LA]) and atherosclerosis in patients with HD. The present study included 118 patients on HD. As surrogate markers of atherosclerosis, aortic stiffness measured by brachial‐ankle pulse wave velocity, and carotid intima‐media thickness (IMT) were measured. As an assessment of LA, a method, microchannel array flow analyzer, which makes it possible to directly observe the flow of blood cell elements through the microchannel, was used. We measured a number of LA during 50 μL flow of whole blood through microchannels. In 12 age‐matched healthy individuals, a number of LA during 50 μL flow of whole blood was 25.7±5.4, whereas in HD patients it was significantly increased up to 48.2±16.4 (P<0.001). Flow cytometry demonstrated that LA were predominantly monocytes. Leukocyte aggregates were positively associated with plasma levels of fibrinogen (P<0.01), or serum high‐sensitive C‐reactive protein (P<0.01). Moreover, LA had highly significant associations with brachial‐ankle pulse wave velocity (P<0.001) and IMT (P<0.001). In conclusion, we demonstrated hemorheologically that monocyte‐platelet conjugates play an important role in aortic stiffness and IMT in HD patients.

Glucose metabolism, insulin resistance, and renal pathology in non-diabetic chronic kidney disease.

Background: The relation between insulin resistance and atherosclerosis is widely recognized, but it remains unknown whether glucose metabolism/insulin resistance is related to renal pathology in humans. Methods: We quantitatively evaluated pathological changes in the glomeruli, tubulointerstitium, and vessels in renal biopsy specimens from 23 patients with non-diabetic chronic kidney disease (CKD), all of whom took a 75-gram oral glucose tolerance test. We correlated the renal pathological changes with fasting plasma glucose (FPG), fasting plasma insulin, 2-hour plasma glucose (2-h PG), 2-hour plasma insulin (2-h PI), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index. Results: HOMA-IR exceeded 1.73 in 11 patients (47.8%), and 2-h PI exceeded 64.0 µU/ml in 14 (60.9%). FPG significantly correlated with interstitial fibrosis (r = 0.532, p = 0.009). The significance was marginal in the correlation between FPG and tubular atrophy and arterio-arteriolosclerosis. Statistically significant correlation was also found between 2-h PG and arterio-arteriolosclerosis (r = 0.422, p = 0.04) and between HOMA-IR and interstitial fibrosis (r = 0.416, p = 0.04). Conclusion: Although precise mechanisms remain unknown, glucose metabolism/insulin resistance seem to play pathogenic roles in formation and progression of renal pathological changes, especially tubulointerstitial and vascular lesions, in non-diabetic CKD.