Tomoki Asai

Tokyo Medical and Dental University, Edo, Tōkyō, Japan

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Publications (8)28.05 Total impact

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    ABSTRACT: Chronic kidney disease (CKD) increases the risk of developing cardiovascular diseases such as heart failure (HF) and ischemic heart disease (IHD). The characteristics of patients with CKD complicated with HF at the time of starting hemodialysis have not yet been evaluated. We enrolled 347 patients in this study and compared gender, age, body mass index, laboratory data, causative disease, complications, and echocardiographic findings between groups with (n = 105) and without (n = 242) HF. Type II diabetic nephropathy and estimated glomerular filtration rate (eGFR; mL/min/1.73 m(2) ) were the independent factors for HF (OR: 3.004, 95% CI: 1.754 to 5.146 and OR: 1.215, 95% CI: 1.101 to 1.330, [per 1 mL/min/1.73 m(2) increase], respectively). The higher GFR appeared to be not a risk factor for HF, probably because the HF group included patients who required periodic dialysis to prevent fatal HF, even if their renal function was not extremely deteriorated. The prevalence of hypertension, IHD and values of body mass index, triglycerides, and LDL-cholesterol did not differ between these two groups. Echocardiographic data showed that left ventricular mass index was an independent risk factor for HF (OR: 1.006, 95% CI: 1.001 to 1.012, per 1 g/m(2) increase) and more than half of the patients appeared to have left ventricular diastolic dysfunction. Our findings suggest that not only CKD, but also type II DM, is a potent risk for left ventricular dysfunction, which causes HF and IHD in pre-dialysis patients with CKD.
    Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 12/2012; 16(6):541-7. · 1.53 Impact Factor
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    ABSTRACT: BACKGROUND: Hyporesponsiveness to a large dose of erythropoietin-stimulating agents (ESA) could increase mortality risk among chronic kidney disease patients. This study aimed to assess a safe dose of ESA and the impact of hyporesponsiveness to ESA on mortality risk among hemodialyzed patients. METHODS: Patients on hemodialysis were enrolled in this cohort study. The first year was used to assess the longitudinal dialysis status of patients; the subsequent 2 years were used to assess the time-dependent risk of mortality. RESULTS: Of the 349 subjects enrolled, 40 died within 2 years. When subjects were stratified by epoetin dose and hemoglobin level into four groups, those who had low hemoglobin despite a high dose of epoetin were associated with the highest risk of mortality among the four groups (adjusted hazard ratio 2.73; 95 % confidence interval 1.20-6.24). These highest-risk subjects had lower serum albumin and higher serum ferritin than any of the other subjects. The impact of serum albumin and serum ferritin on mortality risk in an unadjusted Cox proportional hazards model was attenuated in an adjusted model which included factors of low hemoglobin and higher ESA. A dose of epoetin up to 9000 U/week had no impact on mortality risk as long as hemoglobin levels stayed above 10 g/dL. CONCLUSIONS: Hyporesponsiveness to ESA was associated with an increased risk of mortality. There was no sign of increased mortality risk associated with epoetin itself up to a total dose of 9000 U/week.
    Clinical and Experimental Nephrology 07/2012; · 1.25 Impact Factor
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    ABSTRACT: BACKGROUND: Cause-and-effect associations between sevelamer hydrochloride (HCl) and mortality have yet to be clarified. The effects of sevelamer HCl on mortality, lipid abnormality and arterial stiffness were examined in patients with chronic kidney disease stage 5D. METHODS: The effects of sevelamer HCl were studied by a single-center cohort study that was conducted from January 1, 2005 to December 31, 2008 (n = 483). By the end of the study, 172 patients (Sevelamer group) had succeeded in continuing sevelamer HCl for >6 months (median 37 months), and 300 patients (Control group) had received calcium carbonate (n = 264) or no phosphate binder (n = 36). The mortality and other outcomes were compared between these two groups after matching by a propensity score calculated using age, gender, diabetes prevalence, and dialysis vintage. RESULTS: All-cause [hazard ratio (HR) 0.4, P = 0.02] and cardiovascular (CV)-cause [HR 0.29, P = 0.03] cumulative mortality were significantly lower in the matched Sevelamer group than in the matched Control group. The matched Sevelamer group showed increased high-density lipoprotein cholesterol (P = 0.003) and no change in pulse wave velocity (PWV) and ankle-brachial index (ABI), whereas the matched Control group showed increased serum low-density lipoprotein (LDL) cholesterol (P = 0.003), increased PWV (P = 0.03), and decreased ABI (P = 0.0009). Change in serum LDL cholesterol level correlated inversely with sevelamer HCl dosage (P = 0.02). CONCLUSIONS: Reduced mortality in patients with sevelamer HCl may, at least in part, be explained by an improvement in dyslipidemia and arterial stiffness by sevelamer HCl.
    Clinical and Experimental Nephrology 05/2012; · 1.25 Impact Factor
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    ABSTRACT: In chronic kidney disease stage 5D, diagnostic usefulness of bone mineral density (BMD) in predicting fracture has not been established because of variable results in previous studies. The reason for this may be the heterogeneity of underlying pathogenesis of the fracture. BMD was measured annually and serum biochemistry monthly for 485 hemodialyzed patients from April 2003 to March 2008, and all fractures were recorded. Forty-six new episodes of any type of fracture and 29 cases of prevalent spine fracture were recorded. Serum bone-specific alkaline phosphatase (b-AP) was a very useful surrogate marker for any type of incident fracture risk [area under curve (AUC) = 0.766, P < 0.0001]. A significantly greater risk of any type of incident fracture was associated with parathyroid hormone (PTH) levels either <150 pg/mL [hazard ratio (HR) = 3.47, P < 0.01] or >300 pg/mL (HR = 5.88, P < 0.0001) compared with 150-300 pg/mL. Receiver-operating characteristic analysis demonstrated a significant predictive power for incident of any type of fracture by BMD at the total hip (AUC = 0.760, P < 0.0001) and other hip regions in females in the lower PTH group (PTH < 204 pg/mL). BMDs at every site but whole body or lumbar spine had significant power to discriminate prevalent spine fracture regardless of gender or PTH. Hemodialyzed patients with low or high PTH or increased b-AP had a high fracture risk. BMD by Dual Energy X-ray Absorptiometry (DEXA), especially at the total hip region, was useful to predict any type of incident of fracture for females with low PTH or to discriminate prevalent spine fracture for every patient.
    Nephrology Dialysis Transplantation 06/2011; 27(1):345-51. · 3.37 Impact Factor
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    ABSTRACT: Anemia is a common complication of patients with chronic kidney disease (CKD), which not only lowers their quality of life but also potentially causes cardiovascular diseases such as congestive heart failure and coronary heart disease, and accelerates the progression of renal dysfunction. Pre-dialysis patients were assigned to groups A, B, C or D based on hemoglobin levels of ≤ 8.9 (n = 48), 9.0-9.9 (n = 63), 10-10.9 (n = 53), and ≥ 11.0 g/dL (n = 39), respectively. Cardiac function was estimated using echocardiography to clarify the relationship between anemia and cardiac disorders in patients with CKD immediately before starting hemodialysis. Left ventricular ejection fraction (LVEF) was significantly higher in group D than in groups A and B. The fractions with an LVEF of less than 50% were 16.7, 4.8, 1.9, and 0% in groups A, B, C, and D, respectively. Posterior wall thickness was statistically thicker and the deceleration time of the early diastolic wave was longer in groups A and B, respectively, than in groups C and D. The left ventricular mass index in group D was significantly lower than in any other groups. Anemia in pre-dialysis patients with CKD is a probable cause of impaired left ventricular systolic function and progressive left ventricular hypertrophy. Our results suggest that Hb levels should be maintained at >11 g/dL by EPO administration from the perspective of protecting cardiac function, although the upper limit of the target Hb level was undetermined.
    Clinical and Experimental Nephrology 11/2010; 15(1):121-5. · 1.25 Impact Factor
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    ABSTRACT: Aquaporin-2 (AQP-2) proteins are mainly expressed at the apical region of the collecting duct cells. We previously reported three different mutations in the C-terminus of AQP-2 that all-cause autosomal-dominant nephrogenic diabetes insipidus. When one of these mutant AQP-2s was expressed in Madin-Darby canine kidney (MDCK) cells, it was mistargeted to the basolateral membrane, suggesting a critical role of the C-terminal tail in the apical trafficking of AQP-2. Portions of the AQP-2 C-terminal tail (residues 226-271) were mutated by the polymerase chain reaction (PCR) technique and inserted into the pcDNA3.1 vector. Constructs were transfected into MDCK cells to examine the localization of mutated AQP-2 proteins by immunofluorescence microscopy. Cell surface expression was detected by biotinylation assay. The wild-type AQP-2 was localized at the apical membrane, whereas mutants lacking residues 262-271 (the last 10 amino acids) were predominantly distributed in the endoplasmic reticulum. Deletion mutants of the initial (226-240del) and middle (241-252del) portions of the C-terminal tail were identified at the apical membrane, suggesting that residues 226-252 have no involvement in apical targeting. An AQP-4-AQP-2 chimera in which a portion of the AQP-4 C-terminal tail was replaced by the corresponding site in AQP-2 (residues 256-271) was found at the apical membrane. The sequence of the last 4 amino acids of AQP-2 (G-T-K-A) corresponds to a PDZ-interacting motif. Our investigations identified a mutant of this portion mostly localized to the subapical region. Further, apical expression was found to be significantly decreased in mutants lacking a consensus sequence for cyclic adenosine monophosphate (cAMP)-dependent phosphorylation (residues 253-256). The sequence at 256-271 is sufficient for apical trafficking in AQP-2. The putative PDZ-interacting motif (G-T-K-A, residues 268-271) plays a key role in apical membrane expression. In addition, cAMP-dependent phosphorylation was found to be critical for apical targeting.
    Kidney International 12/2005; 68(5):1999-2009. · 7.92 Impact Factor
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    ABSTRACT: Targeted positioning of water channel aquaporin-2 (AQP2) strictly regulates body water homeostasis. Trafficking of AQP2 to the apical membrane is critical to the reabsorption of water in renal collecting ducts. Controlled apical positioning of AQP2 suggests the existence of proteins that interact with AQP2. A biochemical search for AQP2-interacting proteins led to the identification of PDZ-domain containing protein, signal-induced proliferation-associated gene-1 (SPA-1) which is a GTPase-activating protein (GAP) for Rap1. The distribution of SPA-1 coincided with that of AQP2 in renal collecting ducts. The site of colocalization was concomitantly relocated by hydration status. AQP2 trafficking to the apical membrane was inhibited by the SPA-1 mutant lacking Rap1GAP activity and by the constitutively active mutant of Rap1. AQP2 trafficking was impaired in SPA-1-deficient mice. Our results show that SPA-1 directly binds to AQP2 and regulates at least in part AQP2 trafficking.
    FEBS Letters 07/2004; 568(1-3):139-45. · 3.58 Impact Factor
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    ABSTRACT: We previously reported three aquaporin-2 (AQP2) gene mutations known to cause autosomal-dominant nephrogenic diabetes insipidus (NDI) (Am J Hum Genet 69:738, 2001). The mutations were found in the C-terminus of AQP2 (721delG, 763 to 772del, and 812 to 818del). The wild-type AQP2 is a 271 amino acid protein, whereas these mutant genes were predicted to encode 330 to 333 amino acid proteins due to the frameshift mutations leading to the creation of a new stop codon 180 nucleotides downstream. The Xenopus oocyte expression study suggested that the trafficking of the mutant AQP2s was impaired. To determine the cellular pathogenesis of these NDI-causing mutations in mammalian epithelial cells, Madin-Darby canine kidney (MDCK) cells were stably transfected with the wild-type AQP2, or the 763 to 772del mutant AQP2, or both. Cells were grown on the membrane support to examine the localization of AQP2 proteins by immunofluorescence microscopy. Confocal immunofluorescence microscopy showed that the wild-type AQP2 was expressed in the apical region, whereas the mutant AQP2 was apparently located at the basolateral region. Furthermore, the wild-type and mutant AQP2s were colocalized at the basolateral region when they were cotransfected, suggesting the formation of mixed oligomers and thereby mistargeting. Mixed oligomers of the wild-type and the 763 to 772del mutant AQP2s are mistargeted to the basolateral membrane due to the dominant-negative effect of the mutant. This defect is very likely to explain the pathogenesis of autosomal-dominant NDI. The mistargeting of the apical membrane protein to the basolateral membrane is a novel molecular pathogenesis of congenital NDI.
    Kidney International 08/2003; 64(1):2-10. · 7.92 Impact Factor