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Table of Contents
Vol. 114, No. 1, 2010
Issue release date: February 2010
Section title: Original Paper
Nephron Clin Pract 2010;114:c29–c37
(DOI:10.1159/000245067)

A Small Reduction in the Ankle-Brachial Index Is Associated with Increased Mortality in Patients on Chronic Hemodialysis

Kato A.a · Takita T.c · Furuhashi M.c · Kumagai H.d · Hishida A.b
aDivision of Blood Purification and bFirst Department of Medicine, Hamamatsu University School of Medicine, cMaruyama Hospital, Hamamatsu, and dDepartment of Clinical Nutrition and Sciences, University of Shizuoka, Shizuoka, Japan
email Corresponding Author

Abstract

Background: High pulse wave velocity (PWV) and a low ankle-brachial index (ABI) are associated with mortality in hemodialysis (HD) patients. Recently, the cardio-ankle vascular index (CAVI) was developed as a novel index of arterial stiffness independent of blood pressure. Methods: We compared brachial-ankle PWV (baPWV), the ABI and the CAVI as predictors of mortality in 194 HD patients (age 64 ± 12 years; time on HD 111 ± 96 months) during a follow-up period of 39 ± 4 months (range 31–46). Results: The ABI was significantly positively correlated with serum albumin and negatively with log-transformed highly sensitive C-reactive protein (p < 0.01), while baPWV and the CAVI were not. Of 194 patients, 39 patients (20.1%) died during the follow-up, 25 (64.1%) of cardiovascular causes. Kaplan-Meier analysis revealed that the patients with an ABI in the lowest tertile (<1.0) had a significantly lower survival rate (p < 0.01). Cox hazards analysis after adjustment for the conventional risk factors revealed that an ABI value in the lowest tertile was a determinant of total mortality when compared with ABI values in the highest tertile [>1.1; hazard ratio 3.50 (95% confidence interval 1.20–10.20); p = 0.02]. In contrast, baPWV and the CAVI were not associated with mortality. Conclusion: These findings suggest that a small reduction in the ABI (<1.0) is an independent predictor of all-cause mortality in chronic HD patients.

© 2009 S. Karger AG, Basel


  

Key Words

  • Ankle-brachial index
  • Brachial-ankle pulse wave velocity
  • Cardio-ankle vascular index
  • Mortality
  • Hemodialysis

 Introduction

Cardiovascular disease (CVD) is the main cause of death in hemodialysis (HD) patients. To identify patients with a high risk of CVD, several markers have been suggested as potential predictors of morbidity and mortality, including noninvasive measures of subclinical atherosclerosis, such as pulse wave velocity (PWV) and the ankle-brachial index (ABI). PWV is useful for evaluating arterial stiffness, while ABI (the ratio of systolic blood pressure in the ankle to that in the arm) is a marker of general atherosclerosis, but is now used clinically in the assessment of peripheral arterial occlusive disease (PAD) in the lower limbs.

Carotid-femoral (aortic) PWV increases with more advanced chronic kidney disease [1]. Aortic PWV is known to be a predictor of mortality in HD patients [2,3]. However, measurement of aortic PWV requires a high degree of technical expertise. Thus, brachial-ankle PWV (baPWV), a simple and convenient test, has been used to screen for arterial stiffness. baPWV has been shown to be an independent determinant of carotid atherosclerosis [4] and diastolic left ventricular dysfunction in HD patients [5]. Unfortunately, PWV is essentially influenced by changes in systemic blood pressure during measurement, thereby sometimes leading to unreliable data. In addition, the HD procedure itself affects baPWV measurement [6]. Thus, the individual relevance of PWV measurement remains controversial.

Recently, to overcome these limitations, the cardio-ankle vascular index (CAVI) was developed as a new index of arterial stiffness. CAVI is measured from an electrocardiogram, phonocardiogram, brachial artery waveform and ankle artery waveform, and is adjusted for blood pressure based on the stiffness parameter β [7]. CAVI is superior to baPWV as an index of arterial stiffness in patients who have undergone coronary angiography [8]. However, there are no studies that show CAVI as an early predictor of mortality and/or events in any population.

The ABI is another good predictor of all-cause and cardiovascular mortality. A 0.10 reduction in ABI increased the risk of coronary heart disease by 20–34% in subjects recruited from the general population [9]. A meta-analysis found that a low ABI (≤0.9) is associated with approximately twice the 10-year mortality and major coronary artery event rate [10]. Ono et al. [11] first demonstrated that in HD patients, a low ABI (<0.9) and an abnormally high ABI (≧1.3) are both associated with total and cardiovascular mortality, during a mean follow-up of 22.3 months. However, there is no study that has compared PWV, CAVI and ABI as predictors of mortality in HD patients.

In the present study, we measured baPWV, CAVI and ABI simultaneously using a new clinical device, a VaSera VS-1000 (Fukuda Denshi, Tokyo, Japan), and compared these noninvasive tests as predictors of mortality and cardiovascular events in chronic HD patients.

 

 Patients and Methods


 Study Population

The patient population was selected from 424 patients who had been undergoing regular HD both at Maruyama Hospital and Maruyama Clinic (Hamamatsu, Japan). A diagnosis of CVD (history of myocardial infarction, angina pectoris, stroke or PAD) or diabetes mellitus, the presence of traditional major cardiovascular risk factors and drug prescriptions were recorded from medical charts and analyzed. Since it takes almost 20 min to complete the measurement of ABI, PWV and CAVI, we obtained consent from only 200 of these 424 patients (47%) and enrolled them in the study. After determining basal parameters, we followed them up for the next 39 ± 4 months (range 31–46). During the follow-up, we treated patients to achieve target levels of hemoglobin of more than 10 g/dl, serum phosphorus lower than 5.5 mg/dl, intact parathyroid hormone below 300 pg/ml and systolic blood pressure below 140/90 mm Hg.

 HD Procedures

All patients underwent regular HD for 3.5–4.5 h 3 times a week at a blood flow rate of 160–220 ml/min. All patients used bicarbonate dialysate at a dialysate flow rate of 500 ml/min. All HD treatments were performed using one of the following membranes: high-flux polysulfone synthetic hollow fiber (BS-U, Toray Medical, Japan; APS, Asahi Medical, Japan, or FPX, Fresenius Medical Care, Japan), cellulose triacetate hollow fiber (FB-U, Nipro Medical, Japan) or ethylene-vinyl alcohol hollow fiber (Kf-m, Kuraray Medical, Japan). No patient received hemodiafiltration. None of the patients reused the dialyzer. Neither bacteria nor pyrogens were detected in the dialysate prepared from water obtained by reverse osmosis. Using an endotoxin removal filter, the endotoxin concentration in dialysate was found to be below 20 EU/liter by routine analysis with a Limulus amebocyte lysate assay (endotoxin measurement kit, Wako Junyaku, Tokyo, Japan).

 Blood Samples

Blood samples were drawn from the arterial site of the arteriovenous fistula at the start of each dialysis session after the 2-day interval. Serum electrolytes, urea nitrogen, creatinine, albumin, total cholesterol and triglycerides were measured by standard laboratory techniques using an autoanalyzer. Absolute whole blood cell subtype counts were calculated by multiplying total whole blood cells quantitated as cells per microliter of blood by the percentage of each subtype. Intact parathyroid hormone was determined by immunoradiometric assay. Serum ferritin was measured by the latex agglutination method. Highly sensitive C-reactive protein (hs-CRP) was measured by latex photometric immunoassay (Wako Junyaku). The efficacy of dialysis was assessed based on the delivered dose of dialysis (Kt/Vurea) using a single-pool urea kinetic model. The normalized protein catabolic rate was calculated from dialysis urea removal and serum urea levels.

 Assessment of baPWV, CAVI and ABI

Measurements of baPWV, CAVI and ABI were conducted before the midweek HD cycle with the patient in a supine position after resting for at least 10 min. We applied cuffs at the 4 extremities and monitored the electrocardiogram and heart sounds during the measurement. PWV from the heart to the ankle was obtained by calculating the superficial path lengths from the elbow to the suprasternal notch (Da) and from the suprasternal notch to the femur to the ankle (Db) based on anthropometric data for the Japanese population. To detect the brachial and ankle pulse waves with cuffs, the pressure of the cuffs was kept low at 30–50 mm Hg to ensure a minimal effect of cuff pressure on the hemodynamics. We measured the time interval between the initial increase in brachial and tibial waveforms (Ta), and obtained baPWV as follows: baPWV = (Db – Da)/Ta.

CAVI was calculated using the formula a [ρ/ΔP [ln Ps/Pd] × PWV2] +b, where a and b are constants, ρ is blood density, ΔP is the difference in systolic and diastolic pressure, Ps is systolic pressure, Pd is diastolic pressure, and PWV is heart-ankle PWV. The average coefficient of variation for 2 measurements in 10 HD patients was 4.3%, which was almost identical to that in a previous study [12]. The reproducibility scores for baPWV and ABI were also within 5% (baPWV 4.5%; ABI 4.3%) in these patients.

All measurements and calculations were made together and automatically using a CAVI-VaSera VS-1000 (Fukuda Denshi). We repeatedly measured these parameters in both legs in each patient and expressed the results as means.

 Statistical Analysis

Values are expressed as means ± standard deviation (SD). The χ2 test was used for categorical variables including gender, underlying kidney disease, prevalence of CVD and smoking habits. Univariate correlations between baPWV, CAVI and ABI and laboratory variables were tested using a nonparametric Spearman rank analysis. ABI, baPWV and CAVI values were each divided into 3 tertiles and analyzed as categorical variables (ABI: <1.0, 1.0 ≤ ABI <1.1, ≧1.1; baPWV: <14.5 m/s, 14.5 ≤ baPWV < 17.5 m/s, ≧17.5 m/s; CAVI: <8.3, 8.3 ≤ CAVI < 10.7, ≧10.7).

The primary outcome studied was all-cause mortality. We also assessed fatal and nonfatal cardiovascular events as a secondary outcome. Survival was estimated using Kaplan-Meier curves and compared using the log-rank test. Cox proportional hazards models were applied to calculate hazard ratios and adjusted survival curves for time to death. Three models were applied, i.e. no adjustment (model 1), adjustment for age, gender and diabetes mellitus (model 2), and adjustment for age, gender, diabetes mellitus and other classical risk factors (i.e. serum albumin, log-transformed hs-CRP, current smoking and time on HD; model 3). Results of the Cox proportional hazards analysis are presented as hazard ratios and 95% confidence intervals. A p value less than 0.05 was considered statistically significant. All statistical calculations were performed with StatView 5J software (SAS Institute, Cary, N.C., USA).

 

 Results


 Baseline Characteristics

During the follow-up, 5 patients had transferred away from our institute and 1 patient had received a kidney transplant. Thus, in the final analysis there were 194 patients. The underlying kidney diseases found in these patients were chronic glomerulonephritis (n = 107), diabetic nephropathy (n = 39), polycystic kidney disease (n = 11), nephrosclerosis (n = 11), others (n = 13) and unknown (n = 13).

Table 1 presents the baseline characteristics of the study population. ABI was lower in patients with a history of CVD (n = 39) than in those without (n = 155) (0.96 ± 0.19 vs. 1.02 ± 0.19; p = 0.05). We recorded higher baPWV (19.5 ± 7.8 vs. 15.9 ± 3.8 m/s; p < 0.01) and CAVI (10.7 ± 3.3 vs. 9.7 ± 2.8; p = 0.07) in patients with prevalent CVD than in those without. A significantly higher ABI was also found in patients with angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) treatment than in those without (1.06 ± 0.14 vs. 0.99 ± 0.20; p < 0.02). In contrast, both baPWV (16.3 ± 4.3 vs. 16.5 ± 5.2 m/s) and CAVI (10.1 ± 2.9 vs. 9.7 ± 2.7) were similar in the patients with and without RAS inhibition. Use of statins or antiplatelet agents was also not associated with ABI (data not shown).

TAB01
Table 1. Baseline characteristics of the study population

Table 2 shows univariate correlations between ABI, baPWV and CAVI and laboratory variables using a Spearman rank test. ABI was significantly correlated with age, serum creatinine, intact parathyroid hormone, albumin, total cholesterol and log-transformed hs-CRP (p < 0.01). There were also significant associations between baPWV and CAVI, respectively, and age, time on HD, serum phosphorus, normalized protein catabolic rate and mean blood pressure (p < 0.01).

TAB02
Table 2. Univariate correlations between ABI, baPWV and CAVI and laboratory variables

 Total Mortality and CVD Events

Information on total mortality and fatal and nonfatal cardiovascular events was gathered during outpatient follow-up visits or hospitalization of patients in Maruyama Hospital, by reviewing hospital records or by directly contacting the referring physicians. During the follow-up period, 39 patients (20.1%) died, 25 of them due to CVD. The causes of death in the CVD-related deaths were chronic heart failure in 6 cases, cerebrovascular disease in 6, sudden death in 5, myocardial infarction in 4 and intestinal ischemia in 4. Non-CVD causes of death consisted of malignancies in 5 patients, infections in 4 and other causes in 5. There were another 15 patients who were admitted to hospital due to nonfatal cardiovascular events during the follow-up. The reasons for admission were chronic heart failure in 6 patients, PAD in 4, coronary artery disease in 4 and cerebrovascular disease in 1. Two patients had undergone limb amputation, while no patients had received a coronary artery bypass graft during the observation period. Thus, a total of 39 patients experienced fatal or nonfatal cardiovascular events during the study.

Table 3 shows the differences in baseline characteristics between the deceased and surviving patients. In the deceased group, basal ABI was significantly lower, while baPWV was significantly higher (p < 0.01). In contrast, there was no difference in CAVI between the 2 groups. There was a significant difference in ABI (0.90 ± 0.22 vs. 1.03 ± 0.17; p < 0.01) and baPWV (18.9 ± 7.7 vs. 16.1 ± 3.9; p < 0.01) between the patients with cardiovascular events and those without.

TAB03
Table 3. Baseline characteristics in the groups of deceased and surviving patients

Kaplan-Meier analysis revealed that the survival rate was significantly lower in patients with an ABI less than 1.0 (64.2%; n = 67) compared to those with an ABI between 1.0 and 1.1 (85.2%; n = 61) and those with an ABI higher than 1.1 (90.9%; n = 66) (p < 0.01; fig. 1). Patients with baPWV values in the highest tertile (≧17.5 m/s; n = 66) had a significantly lower survival rate (69.7%) than those with values in the middle tertile (14.5–17.5 m/s; n = 64; 85.9%) and the lowest tertile (<14.5 m/s; n = 64; 84.4%) (p < 0.03). In contrast, CAVI did not predict survival (fig. 2).

FIG01
Fig. 1. Kaplan-Meier analysis for overall survival according to the levels of ABI.

FIG02
Fig. 2. Probability of survival of 194 HD patients according to tertiles of baPWV and CAVI.

The lowest tertile of ABI (<1.0) was also associated with increased cardiovascular events (33.8%) when compared with the middle tertile (1.0 ≤ ABI ≤ 1.1; 18.7%) and the highest tertile (>1.1; 6.1%; p < 0.01, log-rank test). Patients with baPWV values in the highest tertile also had a significantly higher rate of CVD events (30.3%) compared to those with values in the middle tertile (14.1%) and the lowest tertile (17.2%; p < 0.02, log-rank test).

 Predictors of Total Mortality and Cardiovascular Events

Cox regression analysis not adjusted for risk factors (model 1) revealed that the patients with ABI values in the lowest and middle tertiles had a significantly higher risk of mortality and cardiovascular events compared with those with ABI values in the highest tertile. A higher risk of mortality and cardiovascular events was also found in patients with baPWV values in the highest tertile compared with those with values in the lowest tertile. In contrast, CAVI was not associated with either total mortality or cardiovascular events.

When adjusted for age, gender and diabetes mellitus (model 2), Cox regression analysis showed that the patients with ABI values in the lowest tertile had a 3.33- and 4.34-fold higher risk of total mortality and cardiovascular events, respectively, compared with those with ABI values in the highest tertile. In contrast, baPWV and CAVI were not indicators for total mortality or cardiovascular events in model 2.

When finally further adjusted for current smoking habit, serum albumin, log-transformed hs-CRP and time on HD therapy (model 3), patients with ABI values in the lowest tertile (<1.0) had a 3.50-fold higher risk of total mortality. In contrast, the lowest ABI tertile was not a predictor of fatal and nonfatal cardiovascular events.

The results of the Cox hazards analysis are shown in table 4.

TAB04
Table 4. Cox hazards analysis for total mortality and fatal and nonfatal cardiovascular events during the follow-up

 

 Discussion

Recently, CAVI has been used as a test to assess arterial distensibility. CAVI is associated with carotid and coronary arteriosclerosis in general and diabetic subjects [13,14,15]. In HD patients, CAVI is increased, and CAVI over 7.6 predicts the presence of CVD with both sensitivity and specificity of 79% [16]. CAVI is also related to arterial wall fibrosis of the brachial artery due to vascular access surgery [17]. However, there has been no study examining the significance of CAVI for subsequent mortality and cardiovascular events in dialysis patients.

In this study, we compared baPWV, CAVI and ABI as predictors of all-cause mortality and cardiovascular events during a follow-up period of 39 ± 4 months. We found that the lowest tertile of ABI (<1.0) was a significant determinant of total mortality when compared with the highest tertile (>1.1). In contrast, baPWV and CAVI were not associated with all-cause mortality and cardiovascular events.

ABI is known to be an independent predictor of cardiovascular morbidity and mortality in general subjects [9,10]. For levels of ABI below 1.1, the hazard ratios for total mortality increase constantly with decreasing ABI both in men and women [10]. In a previous study, decreases in ABI of more than 0.15 were associated with a higher risk of CVD events during a 3-year observation period [18]. A low ABI (<0.9) indicates a risk of death in predialysis chronic kidney disease patients [19]. In HD patients, Kitahara et al. [20] reported that ABI (<0.9), but not baPWV, was a significant predictor of mortality during a follow-up of 34 ± 11 months. In this study, we showed that a modest reduction in ABI (<1.0) was also an independent predictor of total mortality in HD patients.

There are some probable explanations why measurement of ABI is superior to arterial stiffness parameters as a predictor of mortality. Firstly, ABI represents stenosis or obstruction of peripheral arteries, while baPWV and CAVI indicate arterial stiffness. Thus, a decrease in ABI may reflect a more advanced stage of arteriosclerosis. Secondly, since the presence of severe PAD can reduce blood flow and internal pressure in the lower limbs, a low ABI may mask an increase in baPWV. In this study, however, baPWV was not associated with total mortality in patients without overt PAD (ABI >1.0; data not shown). Pannier et al. [21] reported that aortic PWV, but neither brachial nor femoral PWV, predicts cardiovascular outcome. Since baPWV includes the properties of the aorta and peripheral conduit arteries, its predictive power may be weak compared to aortic PWV. Finally, since baPWV was inversely correlated with time on HD, a nonatherosclerotic mechanism of dialysis such as characteristics of the dialyzer membrane may influence arterial stiffness [22].

There is growing evidence that chronic inflammation plays an important role in the pathogenesis of accelerated atherosclerosis and malnutrition. A strong and positive relationship between inflammation and PAD has been demonstrated [23]. In nondiabetic HD patients, ABI but not aortic PWV is reported to be positively correlated with serum albumin but negatively with CRP [24]. We previously found an inverse association between ABI and the peripheral blood monocyte count, a marker of inflammation [25]. CRP has been demonstrated to be a predictor of mortality in diabetic HD patients with advanced PAD [26]. In this study, we confirmed that ABI was positively correlated with albumin but negatively with log-transformed hs-CRP. In contrast, baPWV and CAVI were not associated with nutritional and inflammatory markers. It follows from these findings that ABI is a good marker of the malnutrition, inflammation and atherosclerosis (MIA) syndrome.

An abnormally high ABI (≧1.3) is another predictor of mortality in chronic HD patients [11]. Falsely elevated ABI or incompressible arteries at the ankle are interpreted as indicating the presence of medial arterial calcification. In this study, however, there was no patient whose baseline ABI exceeded 1.3.

Low doses of ACEIs and ARBs improve arterial stiffness in HD patients [22,27]. An increased ABI is also found in HD patients taking ACEIs or ARBs [28]. Long-term use of statins and ACEIs reduced the risk of all-cause mortality and cardiac events in a general PAD population not on dialysis [29]. In this study, we confirmed a significantly higher level of ABI in patients using ACEIs and/or ARBs than in those not on such treatment.

There are several limitations of this study. Firstly, the study subjects were recruited from only two dialysis units and thus the selection of patients was limited. Secondly, we only assessed the parameters at baseline. We also did not measure other markers of central and peripheral arteriosclerosis such as the augmentation index and skin perfusion pressure. However, the augmentation index is reported not to be predictive of mortality in HD patients [30]. Thirdly, since we only assessed clinical parameters at entry, we could not exclude the possibility that the management of renal anemia, bone mineral disease and hypertension during the study period may have influenced our patients’ prognosis. Finally, the time point of the assessment differed from that in the previous studies. In this study, we only conducted the measurements before the dialysis cycle, as described previously [17,24]. However, other studies performed measurements 30–60 min after the start of HD [12] or after the completion of HD [16,20]. Although we did not compare the timing of measurement of baPWV, CAVI and ABI, it has been reported that removal of excess fluid during an HD session increases PWV [6], leaves it unchanged [31] or decreases it [32]. In contrast, ABI does not change due to HD alone [6], suggesting that the measurement time relative to HD is not a matter of concern when using ABI as a predictor of arterial disease.

In summary, we compared the 3 noninvasive parameters of ABI, baPWV and CAVI as predictors of all-cause mortality and cardiovascular events in HD patients and found that an ABI lower than 1.0 was an independent predictor of total mortality. A decreased ABI is also associated with low albuminemia and inflammation. These findings suggest that ABI is useful as a marker of the malnutrition, inflammation and atherosclerosis syndrome among noninvasive atherosclerotic parameters in predicting poor outcome in chronic HD patients.


References

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    External Resources

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Author Contacts

Akihiko Kato, MD
Division of Blood Purification, Hamamatsu University School of Medicine
1-20-1 Handayama, Higashi-ku, Hamamatsu
Shizuoka 431-3192 (Japan)
Tel./Fax +81 53 435 2756, E-Mail a.kato@hama-med.ac.jp

  

Article Information

Received: April 6, 2009
Accepted: June 26, 2009
Published online: October 9, 2009
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 4, Number of References : 32

  

Publication Details

Nephron Clinical Practice

Vol. 114, No. 1, Year 2010 (Cover Date: February 2010)

Journal Editor: El Nahas M. (Sheffield)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


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Abstract

Background: High pulse wave velocity (PWV) and a low ankle-brachial index (ABI) are associated with mortality in hemodialysis (HD) patients. Recently, the cardio-ankle vascular index (CAVI) was developed as a novel index of arterial stiffness independent of blood pressure. Methods: We compared brachial-ankle PWV (baPWV), the ABI and the CAVI as predictors of mortality in 194 HD patients (age 64 ± 12 years; time on HD 111 ± 96 months) during a follow-up period of 39 ± 4 months (range 31–46). Results: The ABI was significantly positively correlated with serum albumin and negatively with log-transformed highly sensitive C-reactive protein (p < 0.01), while baPWV and the CAVI were not. Of 194 patients, 39 patients (20.1%) died during the follow-up, 25 (64.1%) of cardiovascular causes. Kaplan-Meier analysis revealed that the patients with an ABI in the lowest tertile (<1.0) had a significantly lower survival rate (p < 0.01). Cox hazards analysis after adjustment for the conventional risk factors revealed that an ABI value in the lowest tertile was a determinant of total mortality when compared with ABI values in the highest tertile [>1.1; hazard ratio 3.50 (95% confidence interval 1.20–10.20); p = 0.02]. In contrast, baPWV and the CAVI were not associated with mortality. Conclusion: These findings suggest that a small reduction in the ABI (<1.0) is an independent predictor of all-cause mortality in chronic HD patients.

© 2009 S. Karger AG, Basel


  

Author Contacts

Akihiko Kato, MD
Division of Blood Purification, Hamamatsu University School of Medicine
1-20-1 Handayama, Higashi-ku, Hamamatsu
Shizuoka 431-3192 (Japan)
Tel./Fax +81 53 435 2756, E-Mail a.kato@hama-med.ac.jp

  

Article Information

Received: April 6, 2009
Accepted: June 26, 2009
Published online: October 9, 2009
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 4, Number of References : 32

  

Publication Details

Nephron Clinical Practice

Vol. 114, No. 1, Year 2010 (Cover Date: February 2010)

Journal Editor: El Nahas M. (Sheffield)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 4/6/2009
Accepted: 6/26/2009
Published online: 10/9/2009
Issue release date: February 2010

Number of Print Pages: 1
Number of Figures: 2
Number of Tables: 4

ISSN: (Print)
eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


Copyright / Drug Dosage

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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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