Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Vascular calcification is observed in advanced atherosclerotic lesions. Vascular calcification is considered to increase the risk of intraplaque hemorrhage and subsequent plaque destabilization; however, there is limited pathohistoological evidence of the association between vascular calcification and intraplaque hemorrhage. The aim of this study was to investigate the association between vascular calcification and intraplaque hemorrhage in the coronary arteries. METHODS: We examined 374 coronary arteries obtained from the autopsy samples of 126 deceased individuals. The vascular calcification levels of each artery were categorized into no calcification and quintiles of calcification area size among the arteries with calcification. Macrophage infiltration and neovascularization were also evaluated. The association of the calcification area, macrophage area, or number of vessels with the presence of intraplaque hemorrhage in the coronary arteries was estimated using a logistic regression analysis. RESULTS: Calcification lesions were observed in 149 coronary arteries. Arteries in the fourth quintile of calcification area size had a significantly greater likelihood of intraplaque hemorrhage than the arteries without calcification, after adjusting for confounders: odds ratio 13.13 (95% confidence interval: 2.97-58.16). After evaluating the influence of macrophage infiltration, the highest odds ratio of intraplaque hemorrhage was associated with the combination of large macrophage area and moderately sized calicification areas. The odds ratio of intraplaque hemorrhage additively increased with the combination of calcification and the number of vessels. CONCLUSIONS: The present findings suggest that vascular calcification is significantly associated with intraplaque hemorrhage. The association between vascular calcification and intraplaque hemorrhage may decrease above a certain size of the calcification area.

DOI： 10.5551/jat.64394

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Diabetic kidney disease is a major vascular complication in patients with diabetes mellitus (DM). However, the association between the hemoglobin (Hb)A1c levels, notably the prediabetic levels, and renal pathological changes remains unclear. We investigated the association between the HbA1c levels and renal arteriolar lesions in subjects without any apparent kidney dysfunction using a living kidney donor cohort. METHODS: Between January 2006 and May 2016, 393 living kidney donors underwent a "zero-time" biopsy at Kyushu University Hospital. The patients were divided into four groups (HbA1c levels ＜5.6%, 5.6%-5.7%, 5.8%-6.4%, and ≥ 6.5%, or diagnosed with DM [DM group]). Renal arteriolar hyalinization and wall thickening were assessed using semi-quantitative grading. We then investigated the association between the HbA1c levels and renal pathological changes. RESULTS: 158 (40.2%) patients had arteriolar hyalinization and 148 (37.6%) showed wall thickening. A significant correlation was observed between the HbA1c levels and wall thickening (p for trend ＜0.001). An elevated HbA1c level was significantly associated with wall thickening according to a multivariable logistic analysis in subjects with HbA1c levels of 5.6%-5.7% and 5.8%-6.4%, and the DM group, compared with those with HbA1c levels of ＜5.6% (odds ratio [OR], 1.91; 95% confidence interval [CI]: [1.03-3.54] for 5.6%-5.7%, OR, 1.96; 95% CI: [1.09-3.53] for 5.8%-6.4%, and OR, 2.86; 95% CI: [0.91-9.01] for the DM group), whereas arteriolar hyalinization did not increase within the nondiabetic HbA1c levels. CONCLUSIONS: Elevated high-normal HbA1c levels are considered to be independent risk factors for arteriolar wall thickening. Subclinical renal arteriolar sclerosis may develop in patients with prediabetic HbA1c levels.

DOI： 10.5551/jat.64236

Language：English   Publisher：(一社)日本骨代謝学会  

脆弱性骨折の既往が血液透析を受けている患者の心血管死亡率と関連するかどうかを調査した。Qコホート研究は、末期腎疾患患者の罹患および死亡のリスク因子を特定することを目的とした現在進行中の多施設共同縦断的観察研究であり、北九州の39透析施設で透析を受けている18歳以上の患者3499例(男性59.3%、年齢中央値64歳)を本研究の対象とした。登録時に脆弱性骨折の既往があった患者は346例であった。中央値8.8年の追跡調査中に1730例(49.4%)が死亡し、621例(35.9%)が心血管死を経験した。心血管死の発生率は脆弱性骨折の既往がある患者で有意に高かった。完全調整モデルにおいて、脆弱性骨折の既往は心血管死と関連した。追跡調査期間中に1024例が非致死的心血管疾患イベントを経験した。脆弱性骨折の既往は非致死的心血管疾患イベントとは関連しなかった。以上より、脆弱性骨折の既往は、血液透析を受けている患者の心血管死を予測できる可能性があることが示された。

Language：English   Publishing type：Research paper (scientific journal)  

We previously reported that brain atrophy was more severe and progressed more rapidly in patients with end-stage kidney disease on peritoneal dialysis (PD) than those with non-dialysis-dependent chronic kidney disease. However, it remains unknown whether there is a difference between patients on PD and hemodialysis (HD). In total, 73 PD and 34 HD patients who underwent brain magnetic resonance imaging (MRI) were recruited for a cross-sectional analysis. Among them, 42 PD and 25 HD patients who underwent a second brain MRI after 2 years were recruited for a longitudinal analysis. T1-weighted MRI images were analyzed. Total gray matter volume (GMV), total white matter volume, and cerebrospinal fluid volume were segmented, and each volume was quantified using statistical parametric mapping software. The ratio of GMV (GMR) was calculated by dividing GMV by intracranial volume, to adjust for variations in head size. We compared GMR between PD and HD patients in the cross-sectional analysis and the annual change in GMR (AC-GMR) in the longitudinal analysis. In the cross-sectional analysis, age- and sex-adjusted GMR was significantly lower in PD than HD patients [least square mean (LSM): 39.2% vs. 40.0%, P = 0.018]. AC-GMR was significantly greater in PD than HD patients and this difference remained significant even after adjustment for potential confounding factors (LSM: -0.68 vs. -0.28 percentage-points/year, P = 0.011). In conclusion, the present study demonstrated a more rapid progression of brain atrophy in PD patients compared with HD patients. We demonstrated that decline in GMR progressed significantly more rapidly in PD than HD patients independent of potential confounding factors. GMR gray matter volume ratio, HD hemodialysis, PD peritoneal dialysis.

DOI： 10.1038/s41440-023-01530-5

Publisher：東京医学社  

DOI： 10.24479/kd.0000000874

CiNii Research

Publisher：東京医学社  

DOI： 10.24479/kd.0000000869

CiNii Research

Language：Japanese  

Language：English   Publisher：(一社)日本動脈硬化学会  

日本人の非透析依存性慢性腎臓病(CKD)患者を対象とする前向き観察的コホート研究(福岡腎臓病データベース研究)に登録された3407例のベースラインデータを用いて、心血管リスク因子負荷とCKD重症度に応じた治療的管理を横断的に評価した。KDIGO2012ガイドラインに基づき、推算糸球体濾過量と尿中アルブミン/クレアチニン比によって低リスク群(260例)、中等度リスク群(533例)、高リスク群(647例)、超高リスク群(1099例)、極超高リスク群(868例)に分類した。心血管リスク因子(高血圧、糖尿病、脂質異常症、過体重、現在の喫煙)のうち、高血圧、糖尿病、脂質異常症を有する患者の割合はCKDの進展に伴って有意に上昇したが、すべての心血管リスク因子における治療目標の達成率はCKDの進展に伴って有意に低下した。多変量解析において、極超高リスク群は低リスク群に比べて高血圧の治療目標コントロール不良のリスクが有意に高かった(オッズ比3.68)。非透析依存性CKD患者において、CKDの重症度が上がるにつれて心血管リスク因子負荷が増大することが示された。

Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Acute kidney injury (AKI) is a complex clinical syndrome with a rapid decrease in renal function caused by several different etiologies, including sepsis, ischemia, and the administration of nephrotoxic drugs. Tubular arginase 2 (ARG2), an arginine-metabolic enzyme, is a potential therapeutic target for AKI, but it has not been confirmed under various AKI conditions. The aim of this study was to investigate ARG2 as a therapeutic target for cisplatin-induced AKI. Cisplatin-treated mice with a genetic deficiency in Arg2 had a significant amelioration of renal dysfunction, characterized by decreased acute tubular damage and apoptosis. In contrast, cisplatin-induced tubular toxicity was not ameliorated in proximal tubule cells derived from Arg2-deficient mice. Immunohistochemical analysis demonstrated the increased infiltration of ARG2-positive macrophages in kidneys damaged by cisplatin. Importantly, cisplatin-treated Arg2 knockout mice exhibited a significant reduction in kidney inflammation, characterized by the decreased infiltration of inflammatory macrophages and reduced gene expression of interleukin-6 (IL-6) and interleukin-1β (IL-1β). The secretion of IL-6 and IL-1β induced by lipopolysaccharide was decreased in bone marrow-derived macrophages isolated from Arg2-deficient mice. Furthermore, the lipopolysaccharide-induced elevation of mitochondrial membrane potential and production of reactive oxygen species were reduced in bone marrow-derived macrophages lacking Arg2. These findings indicate that ARG2 promotes the inflammatory responses of macrophages through mitochondrial reactive oxygen species, resulting in the exacerbation of AKI. Therefore, targeting ARG2 in macrophages may constitute a promising therapeutic approach for AKI.

DOI： 10.1016/j.labinv.2023.100227

Language：English   Publisher：(一社)日本腎臓学会  

慢性腎臓病(CKD)患者における、血清尿酸(SUA)や尿酸クリアランス(CUA)等の尿酸代謝マーカーと腎臓病進行との関連にみられる性差を前向きに検討した。当該患者815例(男性523例、女性292例、年齢中央値69歳)を、男女別にSUAまたはCUAの四分位(Q1～Q4)に分け、エンドポイントは血清クレアチニン(SCr)倍増、末期腎疾患(ESKD)、または死亡の複合項目をアウトカム1、SCr倍増またはESKDの複合項目をアウトカム2として検討した。観察期間中(中央値2.5年間)、アウトカム1と2はそれぞれ363例と321例で発生した。男性では、多変量調整Cox比例ハザード分析でQ4と比較したCUAのQ1、Q2、Q3のアウトカム1のハザード比(95%CI)はそれぞれ2.08(1.18～3.70)、2.03(1.22～3.39)、1.85(1.17～2.95)で、CUAの下位四分位とアウトカム2の間にも同様の関連性がみられたが、SUAと両アウトカムとの関連性はみられなかった。女性では、SUA、CUA両者ともアウトカムと関連していなかった。CKD患者では、SUAは男女とも腎転帰と関連していなかったが、男性ではCUAと腎転帰との独立した有意な関連が認められた。

Language：English   Publishing type：Research paper (scientific journal)  

Acute kidney injury is an important global health concern as it is associated with high morbidity and mortality. Polyamines, essential for cell growth and proliferation, are known to inhibit cardiovascular disease. However, under conditions of cellular damage, toxic acrolein is produced from polyamines by the enzyme spermine oxidase (SMOX). We used a mouse renal ischemia-reperfusion model and human proximal tubule cells (HK-2) to investigate whether acrolein exacerbates acute kidney injury by renal tubular cell death. Acrolein visualized by acroleinRED was increased in ischemia-reperfusion kidneys, particularly in tubular cells. When HK-2 cells were cultured under 1% oxygen for 24 h, then switched to 21% oxygen for 24 h (hypoxia-reoxygenation), acrolein accumulated and SMOX mRNA and protein levels were increased. Acrolein induced cell death and fibrosis-related TGFB1 mRNA in HK-2 cells. Administration of the acrolein scavenger cysteamine suppressed the acrolein-induced upregulation of TGFB1 mRNA. Cysteamine also inhibited a decrease in the mitochondrial membrane potential observed by MitoTrackerCMXRos, and cell death induced by hypoxia-reoxygenation. The siRNA-mediated knockdown of SMOX also suppressed hypoxia-reoxygenation-induced acrolein accumulation and cell death. Our study suggests that acrolein exacerbates acute kidney injury by promoting tubular cell death during ischemia-reperfusion injury. Treatment to control the accumulation of acrolein might be an effective therapeutic option for renal ischemia-reperfusion injury.

DOI： 10.1016/j.bbrc.2023.05.029

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Cancer constitutes a major source of morbidity and mortality among people undergoing hemodialysis (HD). A systemic inflammatory response is associated with the incidence and prognosis of cancer in the general population. However, the effect of systemic inflammation on cancer-related mortality in patients undergoing HD remains unclear. METHODS: We analyzed 3,139 patients registered in the Q-Cohort Study, which is a multicenter, observational cohort study of patients on hemodialysis in Japan. The primary outcome was cancer-related mortality during a 10-year follow-up. The covariate of interest was serum C-reactive protein (CRP) concentrations at baseline. The patients were divided into tertiles based on their serum CRP concentrations at baseline (tertile [T] 1: ≤0.07; T2: 0.08-0.24; and T3: ≥0.25). The association between serum CRP concentrations and cancer-related mortality was calculated using the Cox proportional hazards model and the Fine-Gray subdistribution hazards model with non-cancer-related death as a competing risk. RESULTS: During the 10-year follow-up, 216 patients died of cancer. In the multivariable analysis, the risk of cancer-related mortality in the highest tertile (T3) of serum CRP concentrations was significantly higher than that in the lowest tertile (T1) (multivariable-adjusted hazard ratio [95% confidence interval]: 1.68 [1.15-2.44]). This association remained consistent in the competing risk model, in which the subdistribution hazard ratio was 1.47 and the 95% confidence interval was 1.00-2.14 for T3 compared with T1. CONCLUSION: Higher serum CRP concentrations are associated with an increased risk of cancer-related mortality in patients undergoing maintenance HD.

DOI： 10.1159/000530846

Language：English   Publishing type：Research paper (scientific journal)  

Kidney metabolism may be greatly altered in chronic kidney disease. Here we report that arginine metabolism is the most altered in unilateral ureteral obstruction (UUO)-induced fibrosis of the kidneys in metabolomic analysis. Spermidine is the most increased metabolite of arginine. In human glomerulonephritis, the amount of spermidine shown by immunostaining is associated with the amount of fibrosis. In human proximal tubule cells, spermidine induces nuclear factor erythroid 2-related factor 2 (Nrf2). Subsequently, fibrotic signals, such as transforming growth factor β1 secretion, collagen 1 mRNA, and oxidative stress, represented by a decrease in the mitochondrial membrane potential is suppressed by spermidine. UUO kidneys of Arg2 knockout mice show less spermidine and significantly exacerbated fibrosis compared with wild-type mice. Nrf2 activation is reduced in Arg2 knockout UUO kidneys. Spermidine treatment prevents significant fibrotic progression in Arg2 knockout mice. Spermidine is increased in kidney fibrosis, but further increases in spermidine may reduce fibrosis.

DOI： 10.1038/s42003-023-05057-w

Language：Others   Publishing type：Research paper (scientific journal)  

ABSTRACT

Background

Epidemiological studies have identified smoking as an independent risk factor for development of chronic kidney disease. However, the early renal pathological lesions have not been clearly elucidated.

Methods

We investigated time-zero biopsy specimens from 547 living kidney donors and evaluated the relationships between smoking and renal histological changes, including arteriolar hyalinization, intimal thickening of small–medium arteries, global glomerulosclerosis, and interstitial fibrosis and tubular atrophy (IF/TA).

Results

A total of 199 subjects (36.4%) had smoking history; 92 (16.8%) and 107 (19.6%) subjects had <20 pack-years and ≥20 pack-years of smoking, respectively. Cumulative smoking dose was significantly associated with prevalence of arteriolar hyalinization: the multivariable-adjusted odds ratio (OR) per 20 pack-year increase was 1.50 (95% confidence interval 1.15–1.97). The ORs for smokers with <20 pack-years and ≥20 pack-years versus never-smokers were 1.76 (1.01–3.09) and 2.56 (1.48–4.44), respectively. Smoking was also associated with prevalence of >10% global glomerulosclerosis: the OR per 20 pack-year increase was 1.24 (0.96–1.59). The ORs for smokers with <20 pack-years and ≥20 pack-years versus never-smokers were 1.50 (0.98–2.78) and 2.11 (1.18–3.79), respectively. The ORs for these pathological changes increased significantly depending on cumulative smoking dose. Intimal thickening of small–medium arteries and IF/TA were not associated with smoking status. The prevalence of arteriolar hyalinization remained higher in patients with ≥10 years since smoking cessation than in never-smokers [OR 2.23 (1.03–4.83)].

Conclusions

Subclinical pathological injury caused by smoking is potentially associated with renal arteriolar hyalinization and glomerular ischaemia.

DOI： 10.1093/ndt/gfad124

Language：English  

DOI： 10.1007/s13730-023-00793-8

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Background The risk of developing peptic ulcers and gastrointestinal bleeding is high in patients with chronic kidney disease (CKD). Whether or not kidney transplant patients, who are treated with multiple medications, including immunosuppressive drugs, are at an increased risk of developing peptic ulcers is unclear. Methods In this retrospective study, we compared the clinical and endoscopic features of gastroduodenal ulcers between kidney transplant patients and CKD patients. The subjects underwent upper gastrointestinal endoscopy between January 2015 and March 2021. Results Gastroduodenal ulcers were observed more frequently (6.5%) in kidney transplant patients than in CKD patients (2.1%) (p=0.026). Due in part to the lower median age in the kidney transplant ulcer group than in the CKD ulcer group (59 vs. 70 years old, p=0.016), the rates of atrophic gastritis and Helicobacter pylori infection were also lower in the kidney transplant ulcer group than in the CKD ulcer group. Significantly more kidney transplant patients were treated with acid secretion inhibitors than CKD ulcer patients (100% vs. 34.8%, p=0.0005). Peptic ulcers were observed frequently in kidney transplant patients, even though common risk factors for gastroduodenal ulcers other than immunosuppressive drugs were few. All kidney transplant patients were taking immunosuppressive medications, and tacrolimus, mycophenolate mofetil, and methylprednisolone were taken more frequently than others. Conclusion Kidney transplant patients have a high risk of developing gastroduodenal ulcers. All kidney transplant patients take immunosuppressive medications, so there may be an association between immunosuppressive medications and gastroduodenal ulcer development.

DOI： 10.2169/internalmedicine.1508-22

Language：English  

DOI： 10.5551/jat.ED234

Language：English   Publishing type：Research paper (scientific journal)  

Introduction The geriatric nutritional risk index (GNRI) is a widely used tool for nutritional assessment in patients receiving hemodialysis. The simplification of the GNRI calculation would be more useful for easier screening of malnutrition and for providing an intuitive stratification of mortality risk. Methods We retrospectively evaluated 218 Japanese patients receiving maintenance hemodialysis at two hemodialysis centers. The primary outcome was all-cause mortality. The main exposure was a simplified GNRI (sGNRI) calculated as follows: sGNRI = serum albumin (g/dL) + 0.1 x body mass index (kg/m(2)). Results During the median 4.4-year follow-up, 56 patients died. Multivariable-adjusted Cox proportional hazard risk models showed that patients with a lower sGNRI showed a significantly increased mortality risk. No significant difference was observed between the original GNRI and sGNRI regarding mortality predictability. Conclusion sGNRI is as useful as the original GNRI for screening for malnutrition and stratifying hemodialysis patients at increased mortality risk.

DOI： 10.1111/1744-9987.13908

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

維持血液透析(HD)患者の低栄養状態をスクリーニングし、死亡リスクを直観的に層別化することを目的とした高齢者栄養リスク指数(GNRI)の有用性をより向上させるため、GNRIの簡略化を試みその性能を調べる後ろ向き観察研究を施行した。2つのHDセンターで維持HDを受けていた日本人患者218名(男性131名、年齢中央値65歳)を後ろ向きに評価した。オリジナルのGNRIでは体重/理想体重の比を計算する必要があり、式中に現れる係数も小数であって煩雑であるが、その比の代わりにBMIを採用し、BMI(kg/m2)の10分の1の値を血清アルブミン値(g/dL)と加算するだけで計算可能な簡易式GNRIを考案した。主要評価項目は全死因死亡とした。経過観察期間中(中央値4.4年間)に56名の患者が死亡していた。多変量調整済Cox比例ハザードリスクモデルでの解析の結果、簡易式GNRIが低値である患者では死亡リスクが有意に増大していることが示された。死亡予測性に関し、オリジナルのGNRIと簡易式GNRIの間に有意差は観察されなかった。HD患者を対象に低栄養状態をスクリーニングし死亡リスクが高い状態にある患者を層別する目的において、簡易式GNRIはオリジナルのGNRIと同程度に有用なものとなった。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The association between microscopic hematuria (MH) and albuminuria in patients with chronic kidney disease (CKD) caused by diabetes and hypertension remains unclear. METHODS: The Fukuoka Kidney disease Registry Study is a Japanese multicenter prospective cohort study of 4476 patients with non-dialysis-dependent CKD. In this cohort, we conducted a cross-sectional study in 994 patients with diabetic nephropathy and hypertensive nephrosclerosis. Patients were divided into three groups according to erythrocyte count in urine sediment [T1: < 5/high power field (HPF); T2: 5-9/HPF; T3: ≥ 10/HPF]. Macroalbuminuria was defined as urinary albumin-creatinine ratio > 300 mg/g. Associations between the degree of MH (T1-T3) and the prevalence of macroalbuminuria were analyzed using logistic regression. RESULTS: The prevalence of macroalbuminuria was 50.8%, 50.4%, and 67.4% in T1 (n = 725), T2 (n = 226), and T3 (n = 43), respectively. The multivariable-adjusted odds ratios for the presence of macroalbuminuria were 0.95 [95% confidence interval (CI) 0.65-1.39; P = 0.86] and 2.50 (95% CI 1.15-5.47; P = 0.022) for patients in T2 and T3, respectively, compared with patients in T1. CONCLUSIONS: MH with erythrocytes ≥ 10/HPF was significantly associated with increased prevalence of macroalbuminuria in patients with non-dialysis-dependent CKD caused by diabetes and hypertension.

DOI： 10.1007/s10157-022-02298-7

Language：English   Publisher：(一社)日本腎臓学会  

非透析依存性慢性腎臓病(CKD)患者を対象とした多施設前向きコホート研究である福岡腎臓病データベース研究のデータを用いて、高血圧および糖尿病が原因でCKDを発症した患者における顕微鏡的血尿(MH)とアルブミン尿との関連について検討した。福岡腎臓病登録研究における糖尿病性腎症334例および高血圧性腎硬化症660例の合計994例を対象とした。患者を尿沈渣中の赤血球数によって3群に分類した(T1:<5個/強拡大視野(HPF)、T2:5～9個/HPF、T3:≧10個/HPF)。マクロアルブミン尿は、尿中アルブミン-クレアチニン比>300mg/gと定義した。その結果、マクロアルブミン尿の有病率は、T1群725例(年齢中央値73歳)で50.8%、T2群226例(年齢中央値74歳)で50.4%、T3群43例(年齢中央値71歳)で67.4%であった。マクロアルブミン尿の存在に関する多変量調整オッズ比は、T1群と比較して、T2群およびT3群でそれぞれ0.95(95%CI 0.65～1.39、P=0.86)および2.50(95%CI 1.15～5.47、P=0.022)であった。以上より、糖尿病および高血圧による非透析依存性CKD患者において、赤血球数が10個/HPF以上のMHはマクロアルブミン尿の有病率の増加と有意に関連していた。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. METHODS: The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20 years and over, who have received the care of a nephrologist or a diabetologist for more than 3 months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15 g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150 mg/dL and < 1,000 mg/dL) at allocation. In the treatment group, pemafibrate is added to conventional treatment, while conventional treatment is continued with no additional treatment in the control group. Target patient enrollment is 140 patients. The primary endpoint is the change from baseline in the logarithmic urine protein/creatinine ratio at 12 months after study start. CONCLUSION: This study will provide new findings on the renal protective effect of pemafibrate in CKD patients. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN-CTR: UMIN000042284).

DOI： 10.1007/s10157-023-02322-4

Language：English   Publisher：Nature Publishing Group  

慢性腎臓病(CKD)の日本人患者を対象として、腎機能関連形質に関与する遺伝子座をゲノムワイド関連解析(GWAS)で調査した。なお、本調査ではCKD患者475例(男性304例、女性171例、平均年齢68.5±12.0歳)および健常者3471例(男性1358例、女性2113例、平均年齢61.8±8.5歳)から得た患者データと、推算糸球体濾過量(eGFR)が60ml/min/1.73m2未満もしくは尿タンパクが1+以上のCKD疑い患者3664例(男性1837例、女性1827例、平均年齢66.1±6.8歳)ならびに健常者5952例(男性2272例、女性3680例、平均年齢61.8±8.4歳)から得た健診データを用いて解析した。GWASによりCKD、eGFRや尿中アルブミン/クレアチニン比(UACR)に関与する遺伝子座を調べた後、メタ解析を行った結果、CKD、eGFRおよびUACRに関与するそれぞれ10種、9種、22種の遺伝子座が同定された。また、これらのうち22種の遺伝子座は未報告の遺伝子座で、CKD発症に関与する重要な遺伝子座のうち半数はeGFR数値で重要となる遺伝子座と共通していたが、UACRに関与する遺伝子座の多くは、CKDもしくはeGFRに関与する遺伝子座とは異なることが明らかにされた。

Language：English   Publisher：(一社)日本腎臓学会  

透析治療導入には至っていない慢性腎臓病(CKD)患者において、便秘の存在が骨折および心血管疾患の病歴の増加と関連しているか調べた。非透析CKD患者を対象とした多施設共同の前向きコホート研究である福岡腎臓病データベース研究からベースライン時点のデータセットを取得し、3878名を横断解析した。緩下剤を使用していた患者は532名(13.7%)(男性56.8%、年齢中央値76歳)おり、残り3346名(男性55.6%、年齢中央値66歳)は使用していなかった。腎機能が低下するにつれ、緩下剤使用の陽性率、骨折の受傷歴、心血管疾患の病歴はいずれも増高していた。骨折歴の陽性率は、緩下剤使用集団で12.0%、非使用集団で5.1%であった(P<0.001)。心血管疾患歴の陽性率は上記と同順で46.4%と22.5%であった(P<0.001)。多変量調整を行うロジスティック回帰分析の結果、緩下剤使用患者では骨折歴陽性のオッズ比が1.7(95%CI 1.2～2.3)、心血管疾患歴陽性のオッズ比は1.7(95%CI 1.3～2.2)と、いずれも有意に上昇していた。こうした結果から、非透析CKD患者では、緩下剤使用という情報が指し示すところの便秘の存在が、過去に骨折および心血管疾患を経験していた履歴の陽性率上昇と関連していることが示唆された。

Language：English   Publisher：(一社)日本腎臓学会  

大規模前向きコホート研究のデータを用いて、維持血液透析患者におけるエリスロポエチン抵抗性指数(ERI)と脳出血・脳梗塞リスクとの関連性を調査した。Qコホート研究では赤血球造血刺激因子製剤(ESA)で加療された維持血液透析患者2886名(男性1637名、年齢中央値65.0歳)が登録されていた。4年間の前向き追跡中、71名が脳出血を、116名が脳梗塞を発症した。本集団をERIで4層に層別化して多変量解析を施行した。その結果、第4四分位群(ERI≧11.3)の脳出血発症率は第1四分位群(ERI≦4.1)よりも有意に高いことが示された(ハザード比2.2、95%CI 1.08～4.4)。脳梗塞の発症率については、ERIとの関連性は有意とは検出されなかった。以上から、維持血液透析患者ではERI高値は脳出血の重要な危険因子になっていると結論された。

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Cardiovascular disease is a life-threatening chronic kidney disease (CKD) complication. Although cardiovascular risk factor management is significant in patients with CKD, there are few reports that detail the frequency of complications and the treatment of cardiovascular risk factors at different stages of CKD in clinical practice. METHODS: There were a total of 3,407 patients with non-dialysis-dependent CKD who participated in the Fukuoka Kidney disease Registry Study, and they were cross-sectionally analyzed. The patients were classified into five groups based on their estimated glomerular filtration rate and urinary albumin to creatinine ratio according to Kidney Disease: Improving Global Outcomes 2012 guidelines, which recommend low, moderate, high, very high, and extremely high risk groups. The primary outcomes were the cardiovascular risk factor burden and the treatment status of cardiovascular risk factors. Using a logistic regression model, the association between the CKD groups and the treatment status of each risk factor was examined. RESULTS: The proportion of patients with hypertension, diabetes mellitus, and dyslipidemia significantly increased as CKD progressed, whereas the proportion of patients who achieved cardiovascular risk factor treatment targets significantly decreased. In the multivariable analysis, the odds ratios (ORs) of uncontrolled treatment targets were significantly higher for hypertension (OR 3.68) in the extremely high risk group than in the low risk group. CONCLUSIONS: Patients with non-dialysis-dependent CKD demonstrate an increased cardiovascular risk factor burden with greater severity of CKD. Extremely high risk CKD is associated with difficulty in managing hypertension.

DOI： 10.5551/jat.63891

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The accumulation of glucose degradation products (GDPs) during peritoneal dialysis (PD) can lead to immature angiogenesis in the peritoneum. However, the effect of GDPs on angiogenesis, at concentrations observed in dialysate effluent, has not been widely investigated. We do not know how the inflammation observed in PD-related peritonitis affects angiogenesis of the peritoneum. METHODS: Human umbilical vessel endothelial cells (HUVEC) and human umbilical aortic smooth muscle cells (HUASMC) were used to examine the response to the three main GDPs found in peritoneal dialysate (methylglyoxal (MGO), 3-deoxyglucosone (3-DG), and 5-hydroxymethylfurfural (5-HMF). Supernatant from lipopolysaccharide (LPS)-activated murine macrophage cell lines (RAW 264.7 cells) were used to stimulate angiogenesis in the peritoneum. Changes in the expression of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor B (PDGFB) in HUVEC, and PDGF-receptor beta (PDGF-Rβ) in HUASMC, were examined by real-time PCR, Western blot, and ELISA. RESULTS: In HUVECs, the expression of PDGFB mRNA and protein were decreased by exposure to MGO, 3-DG, and 5-HMF at concentrations observed in dialysate effluent. A subsequent decrease in secreted PDGF-BB was observed. In HUASMCs, MGO and 5-HMF increased the expression of VEGF-A mRNA and protein, while 5-HMF decreased the expression of PDGF-Rβ. VEGF-A is upregulated, and PDGF-Rβ is downregulated, by conditioned medium of LPS-stimulated macrophages in HUASMCs. CONCLUSIONS: The GDPs of PD effluent cause an imbalance of angiogenic factors in endothelial cells and vascular smooth muscle cells that may lead to immature angiogenesis in the peritoneum.

DOI： 10.1007/s10157-022-02272-3

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (β coefficient -6.935, 95&#37; confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

DOI： 10.1159/000527900

Language：English   Publisher：(一社)日本腎臓学会  

血管内皮細胞と血管平滑筋細胞を用いたin vitro実験系において、腹膜透析液中のグルコース分解物(GDP)が血管新生に及ぼす影響について検討した。ヒト臍帯静脈内皮細胞(HUVEC)とヒト臍帯動脈平滑筋細胞(HUASMC)において、腹膜透析液に含まれる三つの主要なGDPであるメチルグリオキサール(MGO)、3-デオキシグルコソン(3-DG)、5-ヒドロキシメチルフルフラール(5-HMF)の作用を調べた。HUVECとHUASMCはリポポリサッカライド(LPS)で活性化したマウスマクロファージ細胞株の培養上清で刺激した。その結果、HUVECにおいて、血小板由来増殖因子B(PDGFB)のmRNAとタンパク質の発現は、腹膜透析液で観察される濃度のMGO、3-DG、5-HMFへの曝露により低下し、それに続いて分泌されるPDGF受容体βの減少が観察された。HUASMCでは、MGOと5-HMFにより血管内皮増殖因子A(VEGF-A)のmRNAとタンパク質の発現が増加し、5-HMFによりPDGF受容体βの発現が低下した。HUASMCでは、LPS刺激マクロファージの培養上清により、VEGF-Aの発現が亢進し、PDGF受容体βの発現は低下した。以上より、腹膜透析液中のGDPは、血管内皮細胞や血管平滑筋細胞における血管新生因子の不均衡を引き起こし、腹膜における未熟な血管新生を誘導する可能性が示された。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Constipation is a common complication in patients with chronic kidney disease (CKD) and is involved in the pathogenesis of dysbiosis and progression of CKD. However, little is known about its association with disorders of the bone-cardiovascular axis in patients with CKD. METHODS: We performed a cross-sectional analysis of 3878 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main exposure of interest was constipation defined as use of at least one type of laxative. The main outcomes were the histories of bone fractures and cardiovascular diseases (CVDs) as manifestations of disorders of the bone-cardiovascular axis. RESULTS: The prevalences of laxative use and histories of bone fractures and CVDs increased as kidney function declined. Among the 3878 patients, 532 (13.7%) patients used laxatives, 235 (6.1%) patients had prior bone fractures, and 1001 (25.8%) patients had prior CVDs. Histories of bone fractures and CVDs were significantly more prevalent among laxative users (P < 0.05). Multivariable-adjusted logistic regression analysis revealed that patients with laxatives had a significantly higher odds ratios for histories of bone fractures and CVDs than those without laxatives [adjusted odds ratios (95% confidence intervals) 1.67 (1.20-2.31) and 1.70 (1.30-2.22), respectively, P < 0.05]. CONCLUSIONS: These results suggest that constipation indicated by laxative use is associated with increased prevalences of historical bone fractures and CVDs in pre-dialysis patients with CKD.

DOI： 10.1007/s10157-022-02289-8

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: High serum alkaline phosphatase (ALP) levels are associated with excess all-cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the long-term relationship between serum ALP levels and infection-related mortality remains unclear. METHODS: A total of 3502 maintenance HD patients were registered in the Q-Cohort Study, an observational cohort study in Japan. The primary outcome was infection-related mortality during a 10-year follow-up period. The covariate of interest was serum ALP levels at baseline. The association between serum ALP levels and infection-related mortality was calculated using a Cox proportional hazards model and a Fine-Gray subdistribution hazards model with non-infection-related death as a competing risk. RESULTS: During the follow-up period, 446 patients died of infection. According to their baseline serum ALP levels, the patients were categorized into sex-specific quartiles (Q1-Q4). Compared with patients in the lowest serum ALP quartile (Q1), those in the highest quartile (Q4) had a significantly higher multivariable-adjusted hazard ratio (HR) of 1.70 [95% confidence interval (CI) 1.24-2.32] for infection-related mortality. Furthermore, the HR for every 50 U/L increase in serum ALP levels was 1.24 (95% CI 1.12-1.36) for infection-related mortality. These associations remained consistent in the competing risk model: subdistribution HR, 1.47; 95% CI 1.07-2.03 for Q4 compared with Q1. CONCLUSION: Higher serum ALP levels were significantly associated with a higher risk of infection-related mortality in patients undergoing HD.

DOI： 10.1007/s10157-022-02255-4

Language：English   Publishing type：Research paper (scientific journal)  

Patients with chronic kidney disease (CKD) occasionally need to restrict their consumption of vegetables and fruits. However, recent evidence suggests that plant-based diets have beneficial effects in patients with CKD. We aimed to determine the sufficiency of β carotene and dietary fiber intake in patients with CKD. We conducted a cross-sectional study among 4476 patients registered in the Fukuoka Kidney Disease Registry (FKR) study, a Japanese prospective cohort study of patients with CKD. Data from 3545 patients were analyzed after excluding cases with insufficient information. We evaluated the relationship between CKD stages and the intake of vegetables and fruits. The intake of β carotene and dietary fiber in CKD stages was evaluated using analysis of covariance. As the CKD stage advanced, the intake of vegetables, green leafy vegetables, and fruits significantly decreased (P-value for all trends < 0.01). The intake of vegetables significantly decreased as the CKD stage advanced (P for trend < 0.01). After adjusting for confounding factors, the intake of β carotene and dietary fiber also decreased (both P < 0.01) as the CKD stage advanced. Patients with CKD had insufficient vegetable and fruit intake and a lack of β carotene and dietary fiber from vegetables and fruits.

DOI： 10.1038/s41598-022-24471-4

Language：English   Publishing type：Research paper (scientific journal)  

Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

DOI： 10.1038/s10038-022-01094-1

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hypertension is an important prognostic predictor in patients with chronic kidney disease (CKD), and the recommended target blood pressure has been continuously revised. This study aimed to reveal the current antihypertensive practices in Japanese patients with CKD. METHODS: In the Fukuoka Kidney disease Registry, we extracted 3664 non-dialysis-dependent patients with CKD. Apparent treatment-resistant hypertension (aTRH) was defined as a failure of blood-pressure control treated with three antihypertensive medication classes or a treatment with ≥ 4 classes regardless of blood pressure. The blood-pressure control complied with the target blood pressure recommended by the KDIGO 2012 guideline. RESULTS: The median age of the patients was 67 years, body mass index (BMI) was 23 kg/m2, and estimated glomerular filtration rate (eGFR) was 40 mL/min/1.73 m2. The number of patients with unachieved blood-pressure control was 1933, of whom 26% received ≥ 3 classes of antihypertensive medications. The first choice of medication was renin-angiotensin system inhibitors, followed by calcium-channel blockers. The rate of thiazide use was low in all CKD stages (3-11%). The prevalence of aTRH was 16%, which was significantly associated with BMI (odds ratio [95% confidence interval] per 1-standard deviation change, 1.38 [1.25-1.53]), decreased eGFR (1.87 [1.57-2.23]), as well as age, diabetes mellitus, and chronic heart disease. CONCLUSIONS: Renal dysfunction and obesity are important risk factors of aTRH. Even under nephrologist care, most patients were treated with insufficient antihypertensive medications. It is important to prescribe sufficient classes of antihypertensive medications, including diuretics, and to improve patients' lifestyle habits.

DOI： 10.1007/s10157-022-02250-9

Language：English   Publisher：(一社)日本腎臓学会  

日本人非透析慢性腎臓病(CKD)患者の血圧管理の遵守率と治療抵抗性高血圧症危険因子の重み付けについて検討した。腎臓専門医ケア中の当該CKD患者3664例(男性2065例、女性1599例、年齢中央値67歳)を対象とし、見かけ上の治療抵抗性高血圧症(aTRH)は血圧に関係なく各種降圧薬3クラスの治療で血圧コントロールに失敗した症例または4クラス以上で治療した症例と定義した。患者のBMI中央値は23kg/m2、推算糸球体濾過量(eGFR)中央値は40mL/min/1.73m2であった。血圧コントロールが未達成の患者は1933例で、そのうち26%が3クラス以上の降圧薬で治療されていた。治療の第一選択薬はレニン-アンギオテンシン系阻害剤で、次いでカルシウムチャネル遮断薬であった。aTRHの有病率は16%で、年齢、糖尿病、慢性心臓病とともに、BMI、eGFR減少と有意に関連していた。年齢、腎機能障害、肥満はaTRHの重要な危険因子であり、腎臓専門医のケアを受けていてもCKD患者は降圧薬治療が不十分である可能性が示唆された。

Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は50歳男性で、発熱と全身倦怠感を訴えて入院となった。ヒト免疫不全ウイルス感染の既往や免疫抑制剤による治療歴はなかった。急性腎障害の可能性を考えて腎生検を行った。その結果、間質に炎症細胞の浸潤および肉芽腫様病変を認め、急性肉芽腫性尿細管間質性腎炎と診断した。特発性間質性腎炎が疑われたことからプレドニゾロン40mg/日を投与開始した。またインターフェロン-γ遊離試験で陽性を示したことから潜在性結核感染症に対するイソニアジド投与を開始した。発熱と倦怠感は速やかに消失し、腎機能は改善した。退院後、腎組織・尿培養検査でMycobacterium intracellulareが同定された。プレドニゾロンを漸減し、エタンブトール、クラリスロマイシン、リファンピシンの併用療法を18ヵ月間継続した。2年経過後も慢性腎疾患に対する治療を継続しており、腎代替療法は回避された。

Language：English   Publisher：(一社)日本腎臓学会  

日本人血液透析(HD)患者における、血清アルカリホスファターゼ(ALP)濃度と感染関連死亡率との関係について検討した。観察コホート研究であるQコホート研究に登録された維持HD患者3502例(男性2076例、女性1426例、年齢中央値64.2歳)の10年間のフォローアップデータを用い、主要評価項目として当該期間中の感染関連死亡率、関心共変量をベースラインでの血清ALP濃度として検討した。患者群をALP濃度に従い最低レベルの第1四分位(Q1)から最高レベルの第4四分位群(Q4)まで性別毎に分割し、血清ALP濃度と感染関連死亡率との関連性をCox比例ハザードモデルとFine-Gray部分分布ハザードモデルを用いて検討した。経過観察期間中446例が感染で死亡し、10年間生存率は血清ALP増加とともに減少した。Q1群に比べてQ4群の感染関連死亡率の多変数調整ハザード比(HR)は1.70と有意に高かった。また変数調整後モデルにおける、血清ALP濃度50U/L増加毎の感染関連死亡率HRは1.24であった。HD維持療法施行患者における血清ALP高値は、感染関連および全死因死亡のリスクを増加させた。HD維持療法施行患者における血清ALP高値は、感染関連および全死因死亡のリスクを増加させた。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with increased risks of all cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the impact of the hematopoietic response to ESAs on the development of stroke, including brain hemorrhage and infarction, remains unclear. METHODS: In total, 2886 patients undergoing maintenance HD registered in the Q-Cohort Study who were treated with ESAs were prospectively followed up for 4 years. The hematopoietic response to ESAs was evaluated by the erythropoietin resistance index (ERI), calculated by dividing the weekly dose of ESA by post-HD weight and hemoglobin (U/kg/week/g/dL). The primary outcomes were the incidences of brain hemorrhage and infarction. Patients were divided into quartiles based on their ERI at baseline (Q1, ≤ 4.1; Q2, 4.2-7.0; Q3, 7.1-11.2; and Q4, ≥ 11.3). The risks of brain hemorrhage and infarction were estimated using Cox proportional hazards models, adjusting for potential confounders. RESULTS: During the 4 year follow-up period, 71 patients developed brain hemorrhage and 116 developed brain infarction. In the multivariable analysis, the incidence of brain hemorrhage in the highest quartile (Q4) was significantly higher than that in the lowest quartile (Q1) (hazard ratio [95% confidence interval], 2.18 [1.08-4.42]). However, the association between the ERI and the incidence of brain infarction was not significant. CONCLUSIONS: A higher ERI was associated with an increased risk of brain hemorrhage, but not brain infarction, in patients undergoing maintenance HD. A high ERI is thus an important risk factor for brain hemorrhage in these patients.

DOI： 10.1007/s10157-022-02278-x

Language：English   Publisher：(一社)日本腎臓学会  

日本人非透析依存性慢性腎臓病(CKD)患者における貧血の有病率、赤血球造血刺激因子(ESA)の使用状況、ESA低反応性とその関連因子について、福岡腎臓病データベース研究の横断的解析を実施した。貧血は、ヘモグロビン(Hb)値が11g/dL未満、またはESA療法を受けていることと定義した。ESA低応答性は、1週間あたりのエリスロポエチン投与量を体重とHb値で割ったエリスロポエチン抵抗性指数(ERI;U/kg/week/g/dL)により定義した。非透析依存性患者4460例(年齢中央値67歳)のうち1050例(23.5%)が貧血であった。ESAは626例に投与され、そのうちCKDステージG5の患者は57.5%であった。一方、Hb値が11g/dL未満の患者では、ESA投与率は49.0%であった。また、CKDステージやHb値にかかわらず、鉄分補給を受けている患者の割合はESA投与患者よりも低く、鉄欠乏症の患者でも鉄分補給を受けていない患者がかなりの割合で存在した。ERIはCKDステージの進行と共に増加し、重回帰分析により、年齢、女性、BMI、コレステロール、糸球体濾過量、インタクト副甲状腺ホルモン値がERIの独立した寄与因子であることが示された。以上より、ESAを投与されている多くの日本人非透析依存性CKD患者が適切なHb値を維持できていないことが示された。

Language：English   Publisher：(一社)日本動脈硬化学会  

慢性腎臓病(CKD)患者における心血管リスク特性を含む併存症と腎機能低下の関連を調べ、多疾病罹患の腎機能への影響を評価した。非透析依存性CKD患者4476例(女性44.0%、平均67±15.9歳)に対して23の併発状態と腎機能低下の関連について解析した。腎機能低下は推定糸球体濾過量60mL/分/1.73m2以下と定義した。主要な併存症である高血圧、糖尿病、脂質異常症、心血管疾患(CVD)の既往、がん、骨折の有病率はそれぞれ83.3%、28.7%、45.9%、23.3%、12.7%、6.3%であった。多変量補正分析では年齢、男性、高血圧、脂質異常症、CVDの既往、BMI、尿中蛋白排泄、基礎腎疾患が腎機能低下と関連する独立因子であった。腎機能低下に対するオッズ比(OR)は主要併発状態数の増加に伴って線形に増加した。ORの上昇傾向は心血管併存症でより明白になったが、非心血管併存症では有意ではなかった。心血管併存症およびその危険因子と腎機能低下に独立した関連が認められた。

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Data on the treatment of chronic active T cell-mediated rejection (CA-TCMR) are scarce, and therapeutical strategies for CA-TCMR have not been established. We retrospectively evaluated the outcomes and effects of treatment on pathological and clinical findings in patients with CA-TCMR. METHODS: This study comprised 37 patients who underwent kidney transplantation at our institute who were diagnosed with CA-TCMR between January 2018 and December 2020. Patients were followed until October 2021. RESULTS: A total of 32 of the 37 patients were treated. During the observation period, two patients died (5%), and five patients developed allograft loss (13%). A univariate Cox proportional hazards model showed that indication biopsy, higher spot urine protein/creatinine ratio (UPCR) and Banff ci/ct scores were risk factors for allograft loss. Of the treated patients, 23 underwent follow-up biopsies. The Wilcoxon signed-rank test showed significant improvement in the Baff scores for "ti", "i-IFTA", "t" and "t-IFTA" after treatment. On pathology, 13 (57%) of the patients who underwent follow-up biopsy improved to "no evidence of rejection" or "borderline change." Assuming that improvement in pathology to "borderline change" or "no evidence of rejection" on follow-up biopsy indicates response to treatment, multivariate logistic analysis showed that lower UPCR was a predictive factor for response to treatment. No specific effect of treatment type was observed. CONCLUSIONS: Our results indicate that treatment could improve the pathological findings in CA-TCMR.

DOI： 10.1111/nep.14048

Language：English   Publishing type：Research paper (scientific journal)  

AIM: The Controlling Nutritional Status (CONUT) score and the Prognostic Nutritional Index (PNI) reflect the immunonutritional status of patients. However, the associations of these two indices with cardiovascular disease (CVD) have not been characterized in patients with chronic kidney disease (CKD). Therefore, the current study aimed to determine whether the CONUT score or PNI was associated with prior CVD in patients with CKD. METHODS: A cross-sectional study of 2,751 patients with CKD who were not on dialysis was performed. The patients were grouped into tertiles (T1-T3) of PNI and placed into three groups following their CONUT score: low- (CONUT score, 0), mild- (CONUT score, 1-2), and moderate-to-high- (CONUT score, ≥ 3) risk groups. RESULTS: Prior CVD was present in 655 (24%) of the participants. Multivariable logistic regression analyses, with adjustment for potential confounders, showed that high CONUT score was associated with prior CVD than the low score (mild-risk group: odds ratio [OR]=1.35, 95% confidence interval [CI]=1.04-1.76; moderate-to-high-risk group: OR=1.66, 95% CI=1.19-2.30). In addition, the lower PNI tertiles were independently associated with prior CVD compared with T3 of PNI (T1: OR=1.45, 95% CI=1.09-1.92; T2: OR=1.32, 95% CI=1.01-1.72). CONCLUSIONS: Both CONUT score and PNI were found to be independently associated with prior CVD in patients with CKD in the present cross-sectional study. A longitudinal study is needed to elucidate whether these two indices are associated with subsequent cardiovascular events.

DOI： 10.5551/jat.63501

Language：English   Publishing type：Research paper (scientific journal)  

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

DOI： 10.1007/s00223-022-00947-3

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Elevated serum alkaline phosphatase (ALP) levels have been associated with increased risks of all-cause and cardiovascular mortality in patients receiving hemodialysis. However, little is known about the impact of serum ALP levels on the development of stroke, such as brain hemorrhage and infarction. METHODS: A total of 3,497 patients receiving maintenance hemodialysis registered in the multicenter observational Q-Cohort Study were analyzed. The primary outcomes were the incidences of brain hemorrhage and infarction. The covariate of interest was serum ALP levels. Patients were divided into tertiles based on their serum ALP levels (U/L) at baseline (T1, ＜69.3; T2, 69.3-98.4; T3, ＞98.4). The risks of brain hemorrhage, brain infarction, and composite stroke were estimated using Cox proportional hazards models and competing risk models with all-cause death as a competing risk. RESULTS: A total of 89 patients developed brain hemorrhage and 195 patients developed brain infarction during the 4-year follow-up period. The risk of brain hemorrhage in the highest tertile (T3) was significantly higher than that in the lowest tertile (T1) (multivariable-adjusted hazard ratio [95% confidence interval], 1.93 [1.12-3.35], subdistribution hazard ratio, 1.91 [1.10-3.30]). However, there was no significant association between serum ALP levels and the risk of brain infarction or composite stroke. CONCLUSIONS: Higher serum ALP levels are associated with an increased risk of brain hemorrhage, but not brain infarction, in patients receiving maintenance hemodialysis. High serum ALP level is thus an important risk factor for brain hemorrhage in hemodialysis patients.

DOI： 10.5551/jat.62885

Language：English   Publishing type：Research paper (scientific journal)  

A 73-year-old man receiving hemodialysis and antiplatelets was admitted with a mild case of COVID-19. Heparin was added, and iliopsoas hemorrhage developed. He was successfully treated by interventional radiology. A 76-year-old man receiving hemodialysis and antiplatelets was admitted with mild COVID-19. Heparin was added, and iliacus hemorrhage developed. Despite heparin discontinuation, he died of worsening pneumonia. A 74-year-old man undergoing hemodialysis was admitted with severe COVID-19. Gastrointestinal bleeding developed during continuous hemodiafiltration with heparin. Upon switching to nafamostat and increasing the dose, iliopsoas hemorrhage developed. Despite interventional radiology, he died of infectious complications. Attention to hemorrhagic complications is therefore needed in patients with COVID-19.

DOI： 10.2169/internalmedicine.8976-21

Language：English   Publisher：(一社)日本内科学会  

症例1は73歳男性で、7年前に血液透析と抗血小板薬の服用を開始していた。COVID-19と診断されて入院し、入院1日目にヘパリン追加投与を開始した。入院6日目、造影CTで巨大な左腸腰筋血腫と造影剤溢出が判明した。緊急インターベンショナルラジオロジー(IVR)を行い、完全止血に成功した。症例2は76歳男性で、血液透析を行っており、抗血小板薬を服用していた。COVID-19と診断されて入院したが、無症状で入院時に肺炎は認めなかった。入院4日目に予防的ヘパリン皮下注射を行い、入院6日目にCOVID-19肺炎症状が悪化した。入院9日目、単純CTで左腸骨筋血腫が判明した。呼吸不全が悪化し、入院21日目に死亡した。症例3は74歳男性で、血液透析を行っており、重度COVID-19のために入院した。持続ヘパリン注入とナファモスタットを用いた持続血液透析濾過を開始後、上部消化管出血が出現した。ヘパリンを中止し、ナファモスタットを増量した。造影CTで右腸腰筋血腫と造影剤溢出が判明し、緊急IVRを行って止血した。入院54日目、感染性合併症により死亡した。

Language：English   Publisher：(一社)日本動脈硬化学会  

慢性血液透析患者3497例(男性2073例、女性1424例)を対象に、血清アルカリホスファターゼ(ALP)値が脳出血および脳梗塞に及ぼす影響について検討した。対象は慢性血液透析患者における総死亡、心血管疾患、骨折の危険因子を評価する観察研究(Qコホート研究)の登録患者で、主要評価項目は脳出血および脳梗塞の発症とした。患者を血清ALPの3分位数に基づき、69.3U/L未満の第1三分位群(女性32.6%、年齢中央値60.3歳)、69.3～98.4U/Lの第2三分位群(女性38.5%、年齢中央値65.3歳)、第98.4U/L以上の3三分位群(女性51.0%、年齢中央値66.3歳)の3群に分類した。患者背景はALP高値群の方が高齢で、女性が多く、透析期間が長かった(いずれもP<0.001)。平均追跡期間は4年で、脳出血は89例、脳梗塞は195例で発生した。多変量解析で第1三分位群と比較した第3三分位群における脳出血発症のハザード比は1.93(95%CI:1.12～3.35、P=0.01)であった。ところが脳梗塞とALP値の高値の間に有意な関連はなかった(HR:1.06、95%CI:0.72～1.58、P=0.79)。

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been highlighted as a potential risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). METHODS: We assessed cross-sectionally the prevalence, associated factors, and treatment status of anemia and ESA hyporesponsiveness in 4460 non-dialysis-dependent CKD patients enrolled in a multicenter cohort in Japan. Anemia was defined as a hemoglobin (Hb) level of less than 11 g/dL or receiving ESA therapy. ESA hyporesponsiveness was defined by the erythropoietin-resistance index (ERI), which was the erythropoietin dose per week divided by body weight and Hb level (U/kg/week/g/dl). RESULTS: Of the 4460 patients, 1050 (23.5&#37;) had anemia. ESAs were administered to 626 patients, reaching a percentage of 57.5&#37; of patients with stage G5 CKD. However, the ESA treatment rate was only 49.0&#37; in patients with a hemoglobin level of < 11 g/dL. The proportion of patients receiving iron supplementation was lower than that of patients receiving ESAs regardless of CKD stage or hemoglobin level, and a significant proportion of patients did not receive iron supplementation, even those with iron deficiency. The ERI increased with CKD stage progression, and the multiple regression analysis showed that age, female sex, body mass index, cholesterol, glomerular filtration rate, and intact parathyroid hormone level were independent contributors. CONCLUSIONS: Our findings demonstrate that many Japanese patients with non-dialysis-dependent CKD receiving ESAs fail to maintain adequate hemoglobin levels. These results suggest the need for interventions for ESA hyporesponsiveness factors in addition to iron supplementation.

DOI： 10.1007/s10157-022-02227-8

Language：English  

DOI： 10.1007/s10157-021-02175-9

Language：English   Publishing type：Research paper (scientific journal)  

Dialysate leakage is one of the causes of peritoneal dialysis (PD)-related peritonitis. The rate of catheter removal in PD-related peritonitis caused by dialysate leakage (PDPDL) is high, and the correct treatment is unclear. We experienced a case of PDPDL that was treated with intravenous and intraperitoneal antibiotic therapy. A 44-year-old Japanese man had high glucose discharge from the exit site after 14 days of initiating PD, and he had a fever and cloudy effluent with a high white cell count. We diagnosed him with PDPDL and began to administer vancomycin and ceftazidime intraperitoneally. However, the peritonitis could not be ameliorated. A culture examination showed Staphylococcus aureus from the effluent of peritoneal cavity and exit site cultures. We began intraperitoneal cefazolin administration according to a drug susceptibility test, but the effluent cell count remained high. As we added intravenous cefazolin administration, his symptoms and cloudy effluent improved, and the effluent cell count normalized. He has not developed any recurrence of dialysate leakage or peritonitis. Our findings suggest that PD-related peritonitis accompanied by other infectious sites, such as PDPDL, should be treated with additional intravenous antibiotic therapy to taking effect on the infectious sites except for peritoneum and to keep plasma concentration of antibiotics sufficient especially in cases with preserved residual kidney function.

DOI： 10.1007/s13730-021-00644-4

Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は44歳男性で、腹膜透析開始14日後にダイアライザー出口部で血糖高値を示し、発熱、透析排液混濁、白血球数増加をきたした。透析液漏出に起因する腹膜透析関連腹膜炎と診断し、バンコマイシン(1g/日)およびセフタジジム(1g/日)の腹腔内投与を開始したが、改善は認められなかった。腹腔内および出口部排液の培養検査にて黄色ブドウ球菌を検出し、薬剤感受性試験をもとにセファゾリン(1.5g/日)腹腔内投与を開始したが、排液細胞数は依然として高値を示した。セファゾリン(1g/日)静脈内投与を追加したところ、症状と排液混濁は改善し、排液細胞数は正常化した。腹膜透析開始2年後も透析液漏出または腹膜炎の再発は認めていない。

Language：English   Publishing type：Research paper (scientific journal)  

A 50-year-old man was admitted to our hospital with the complaints of fever and general malaise. He had no history of human immunodeficiency virus (HIV) infection or treatment with immunosuppressive agents. We performed renal biopsy to investigate possible acute kidney injury. Pathological findings showed inflammatory cell infiltration, including granulomatous lesions in the interstitium. We diagnosed the patient with acute granulomatous tubulointerstitial nephritis. We initiated prednisolone (PSL) 40 mg/day (0.6 mg/kg), in combination with isoniazid for a latent tuberculosis infection, because of positive results in interferon-γ release assays. The patient's fever and malaise promptly disappeared, and his renal function improved. After the patient had been discharged, Mycobacterium intracellulare grew in cultures of his renal tissue and urine. We gradually reduced the dose of PSL; we initiated combination therapy with ethambutol, clarithromycin, and rifampin. After 2 years of follow-up, the patient continued treatment for chronic kidney disease; it has since enabled him to avoid renal replacement therapy. This report describes a rare instance of nontuberculous mycobacteria-associated tubulointerstitial nephritis in a patient without a history of HIV infection or organ transplantation. In differential diagnosis of granulomatous tubulointerstitial nephritis, clinicians should consider drugs, sarcoidosis, tubulointerstitial nephritis and uveitis syndrome, vasculitis, and infections (e.g., involving mycobacteria). Prompt microbiological examinations, especially of urine or biopsy cultures, are vital for diagnosis.

DOI： 10.1007/s13730-022-00690-6

Language：English   Publishing type：Research paper (scientific journal)  

Rationale & Objective: Malnutrition-inflammation complex syndrome (MICS) is common in patients receiving hemodialysis and increases the risks of morbidity and mortality. However, few studies have examined the overall impact of MICS on disorders of the bone-cardiovascular axis. Study Design: Prospective, multicenter, observational cohort study. Setting & Participants: A total of 3,030 patients receiving maintenance hemodialysis registered in the Q-Cohort Study. Predictors: A newly developed score for MICS composed of elements chosen from 8 baseline parameters related to nutrition and inflammation by bootstrap resampling, multivariable-adjusted Cox proportional hazard risk analysis for all-cause mortality, and the risk prediction rule. β-coefficients of each element analyzed in the multivariable-adjusted model were used for the creation of the MICS score. Outcomes: Bone fractures, cardiovascular disease events, and the composite outcome of bone fractures and cardiovascular disease events. Analytical Approach: Cox proportional hazard regression and Fine-Gray proportional subdistribution hazards regression. Results: During a median follow-up of 4 years, 140 patients developed bone fractures and 539 developed cardiovascular disease events. Age; serum levels of creatinine, albumin, and C-reactive protein; and body mass index were selected for the creation of the MICS score. The median (IQR) MICS score was 196 (181-212). The multivariable-adjusted Cox proportional hazard risk model and the competing risk model showed that a higher MICS score was incrementally associated with elevated risks of bone fractures, cardiovascular disease events, and the composite outcome; hazard risks (95&#37; CIs) of fractures, cardiovascular disease events, and the composite outcome for each 10-point increase in the MICS score were 1.18 (1.01-1.38), 1.16 (1.07-1.26), and 1.15 (1.07-1.24), respectively. Limitations: One-time measurement of the parameters used for the creation of the MICS score. Conclusions: Malnutrition and inflammation represented by the MICS score were associated with increased risks of bone-cardiovascular axis disorders in patients receiving maintenance hemodialysis.

DOI： 10.1016/j.xkme.2022.100408

Language：English  

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder that affects multiple organs and systems and increases the risk of morbidity and mortality in patients with CKD, especially those receiving dialysis therapy. CKD-MBD is highly prevalent in CKD patients, and its treatment is gaining attention from healthcare providers who manage these patients. Additional important pathologies often observed in CKD patients are chronic inflammation and malnutrition/protein-energy wasting (PEW). These two pathologies coexist to form a vicious cycle that accelerates the progression of various other pathologies in CKD patients. This concept is integrated into the term "malnutrition-inflammation-atherosclerosis syndrome" or "malnutrition-inflammation complex syndrome (MICS)". Recent basic and clinical studies have shown that CKD-MBD directly induces inflammation as well as malnutrition/PEW. Indeed, higher circulating levels of inorganic phosphate, fibroblast growth factor 23, parathyroid hormone, and calciprotein particles, as markers for critical components and effectors of CKD-MBD, were shown to directly induce inflammatory responses, thereby leading to malnutrition/PEW, cardiovascular diseases, and clinically relevant complications. In this short review, we discuss the close interplay between CKD-MBD and MICS and emphasize the significance of simultaneous control of these two seemingly distinct pathologies in patients with CKD, especially those receiving dialysis therapy, for better management of the CKD/hemodialysis population.

DOI： 10.1007/s10157-022-02216-x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Protein-energy wasting (PEW) is a risk factor for mortality in patients undergoing hemodialysis. Recently, a nutritional risk index for Japanese hemodialysis patients (NRI-JH) has been proposed as a surrogate index of PEW. However, no study has determined the association of the NRI-JH with long-term mortality in patients undergoing hemodialysis. Furthermore, the validity of the NRI-JH has not been confirmed. METHODS: In total, 3046 patients undergoing hemodialysis and registered in the Q-Cohort Study were followed up for 10 years. The NRI-JH was calculated on the basis of body mass index and serum levels of albumin, total cholesterol, and creatinine. The patients were divided into four groups according to the NRI-JH scores: 0-3 (G1, n = 1343), 4-7 (G2, n = 1136), 8-10 (G3, n = 321), and 11-13 (G4, n = 246). We examined the association between the NRI-JH and the 4-year and 10-year risks of all-cause, cardiovascular, and infection-related deaths using the Cox proportional hazards model. RESULTS: During the follow-up period, 647 patients died during the first 4 years, and 1503 patients died within 10 years. The 4-year prognosis was analyzed and compared with the lowest NRI-JH score group. Multivariable-adjusted hazard ratios (95% confidence intervals) for all-cause death were 1.93 (1.57-2.38), 2.68 (2.05-3.50), and 3.16 (2.40-4.16) in the G2, G3, and G4 groups, respectively. Similarly, a higher NRI-JH score was associated with an increased risk of cardiovascular and infection-related deaths. CONCLUSION: A higher NRI-JH score was associated with an increased risk of long-term mortality in patients undergoing maintenance hemodialysis. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (UMIN ID: 000000556).

DOI： 10.1007/s10157-021-02124-6

Language：English   Publishing type：Research paper (scientific journal)  

Women have a longer life expectancy than men in the general population. However, it has remained unclear whether this advantage is maintained in patients undergoing maintenance hemodialysis. The aim of this study was to compare the risk of mortality, especially infection-related mortality, between male and female hemodialysis patients. A total of 3065 Japanese hemodialysis patients aged ≥ 18 years old were followed up for 10 years. The primary outcomes were all-cause and infection-related mortality. The associations between sex and these outcomes were examined using Cox proportional hazards models. During the median follow-up of 8.8 years, 1498 patients died of any cause, 387 of whom died of infection. Compared with men, the multivariable-adjusted hazard ratios (95&#37; confidence interval) for all-cause and infection-related mortality in women were 0.51 (0.45-0.58, P < 0.05) and 0.36 (0.27-0.47, P < 0.05), respectively. These findings remained significant even when propensity score-matching or inverse probability of treatment weighting adjustment methods were employed. Furthermore, even when the non-infection-related mortality was considered a competing risk, the infection-related mortality rate in women was still significantly lower than that in men. Regarding all-cause and infection-related deaths, women have a survival advantage compared with men among Japanese patients undergoing maintenance hemodialysis.

DOI： 10.1038/s41598-021-03551-x

Language：English   Publishing type：Research paper (scientific journal)  

In recent years, large cohort studies of patients with chronic kidney disease (CKD) have been established all over the world. These studies have attempted to analyze the pathogenesis of CKD using a large body of published evidence. The design of cohort studies is characterized by the measurement of the exposure prior to the occurrence of the outcome, which has the advantage of clarifying the temporal relationship between predictors and outcomes and estimating the strength of the causal relationship between predictors and multiple outcomes. Recent advances in biostatistical analysis methods, such as propensity scores and risk prediction models, are facilitating causal inference using higher quality evidence with greater precision in observational studies. In this review, we will discuss clinical epidemiological research of kidney disease based on the analysis of observational cohort data sets, with a focus on our previous studies.

DOI： 10.1007/s10157-021-02121-9

Language：English   Publisher：(一社)日本腎臓学会  

日本人血液透析患者の栄養リスク指数(NRI-JH)と長期死亡率との関連性およびNRI-JHの妥当性を検討した。Qコホート研究に登録された血液透析患者3046例(平均64.3歳)を10年間追跡調査した。患者をNRI-JHのスコアに従って、0～3(G1群、1343例)、4～7(G2群、1136例)、8～10(G3群、321例)、11～13(G4群、246例)に分類した。追跡期間中、最初の4年間に647例が死亡し、10年以内に1503例が死亡した。全死因死亡の多変量調整後ハザード比(95%CI)は、G2、G3、G4群でそれぞれ1.93(1.57～2.38)、2.68(2.05～3.50)、3.16(2.40～4.16)であった。同様に、NRI-JHスコアの高さは、心血管死亡および感染症関連死亡のリスク上昇と関連していた。以上より、NRI-JHスコアが高いほど、維持血液透析を受けている患者における長期死亡のリスクが高いことが示された。

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INTRODUCTION: Albuminuria is a clinical hallmark of diabetic nephropathy (DN). Nevertheless, it is controversial whether pathologic DN lesions exist in individuals with diabetes with normoalbuminuria. We investigated the association between albuminuria levels and the frequency of DN lesions in autopsied diabetic cases from a Japanese community. METHODS: A total of 106 autopsied cases with diabetes mellitus (mean age = 76 years, 43.4% male) who died within 6 years after their last health examination were included in the study. Urinary albumin-creatinine ratio (UACR) levels were divided into the following 3 groups: <30.0, 30.0 to 299.9, and ≥300.0 mg/g. The kidney specimens were evaluated with light microscopy. Glomerular DN lesions were categorized into class 0 to I, IIa, IIb, and III glomerular DN lesions according to the criteria of the Renal Pathology Society. A Cochran-Armitage test was used to evaluate the association between the UACR levels and the presence of class IIa or higher glomerular DN lesions. RESULTS: The frequency of class IIa or higher glomerular DN lesions was 63.2% (IIa, 36.8%; IIb, 3.8%; and III, 22.6%) among overall cases. The frequencies increased significantly with higher UACR levels (P for trend = 0.02). The frequency of class IIa or higher glomerular DN lesions was 51.2%, even in individuals with UACR < 30 mg/g. CONCLUSION: This study revealed a positive association of the UACR levels with the presence of class IIa or higher glomerular DN lesions, which were also frequently found even in the normal range of UACR levels, among autopsied diabetic cases from a Japanese community.

DOI： 10.1016/j.ekir.2021.09.007

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A higher urinary sodium-to-potassium (UNa/K) ratio has been reported to be associated with high blood pressure and subsequent cardiovascular events. However, the association between the UNa/K ratio and renal outcomes remains uncertain. We prospectively investigated the association between the UNa/K ratio and renal outcomes in patients with chronic kidney disease (CKD). We enrolled 716 patients with CKD, and 24-h urinary sodium and potassium excretion were measured. Patients were divided into UNa/K ratio tertiles (T1-T3). Endpoints were defined as a composite of doubling of serum creatinine (SCr), end-stage kidney disease (ESKD), or death and a composite of doubling of SCr or ESKD (added as an alternative outcome). We investigated the association between the UNa/K ratio and renal outcomes using a Cox proportional hazards model. During a median follow-up of 2.3 years, doubling of SCr, ESKD, or death and doubling of SCr or ESKD occurred in 332 and 293 patients, respectively. After adjustment for covariates including potentially confounding variables such as plasma renin activity, plasma aldosterone concentration, and B-type natriuretic peptide, the hazard ratios (HRs) (95% confidence intervals [CIs]) for the composite of doubling of SCr, ESKD, or death for T2 and T3 were 1.44 (1.06-1.96) and 1.59 (1.14-2.21), respectively, compared with T1. Additionally, compared with T1, the highest tertile (T3) of the UNa/K ratio was associated with a composite of doubling of SCr or ESKD (HR 1.55, 95% CI 1.09-2.20). A higher UNa/K ratio was independently associated with poor renal outcomes in patients with CKD.

DOI： 10.1038/s41440-021-00741-y

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OBJECTIVE: Randomized controlled trials have shown kidney-protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. RESULTS: At baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m2, and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m2 per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26-0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P heterogeneity ≥ 0.35). CONCLUSIONS: The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.

DOI： 10.2337/dc21-1081

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Receptor-mediated albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. Autophagy is an evolutionarily conserved degradation pathway, and its role in intracellular trafficking through interactions with the endocytic pathway has recently been highlighted. Here, we determined whether autophagy regulates albumin transcytosis in PTECs and suppresses albumin-induced cytotoxicity using human proximal tubule (HK-2) cells. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn was attenuated, and FcRn accumulated in autophagy-related 7 (ATG7) knockdown HK-2 cells. Colocalization of FcRn with RAB7-positive late endosomes and RAB11-positive recycling endosomes was reduced in ATG7 knockdown cells, which decreased recycling of FcRn to the plasma membrane. In ATG7 or autophagy-related 5 (ATG5) knockdown cells and Atg5 or Atg7 knockout mouse embryonic fibroblasts, albumin transcytosis was significantly reduced and intracellular albumin accumulation was increased. Finally, the release of kidney injury molecule-1, a marker of tubule injury, from ATG7 or ATG5 knockdown cells was increased in response to excess albumin. In conclusion, suppression of autophagy in tubules impairs FcRn transport, thereby inhibiting albumin transcytosis. The resulting accumulation of albumin induces cytotoxicity in tubules.NEW & NOTEWORTHY Albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn to the plasma membrane was decreased in autophagy-related 7 (ATG7) knockdown cells. In addition, albumin transcytosis was decreased in ATG7 or autophagy-related 5 (ATG5) knockdown PTECs. Finally, release of kidney injury molecule-1 from ATG7 or ATG5 knockdown cells was increased in response to excess albumin.

DOI： 10.1152/ajprenal.00172.2021

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AIM: Individuals with chronic kidney disease (CKD) have a high prevalence of comorbidities, including cardiovascular disease (CVD) and its risk factors. However, epidemiological results to assess the association between multimorbidity and kidney function among the CKD population remains limited. METHODS: We performed a cross-sectional analysis of the association between 23 comorbid conditions and reduced kidney function in 4,476 patients with non-dialysis-dependent CKD enrolled in a multicenter cohort in Japan. Reduced kidney function was defined as an estimated glomerular filtration rate of ≤ 60 mL/min/1.73 m2. RESULTS: The mean age of patients was 67 years (male, 56.0&#37;). The prevalence of hypertension, diabetes mellitus, dyslipidemia, prior CVD, cancer, and bone fracture, which are the major comorbidities, was 83.3&#37;, 28.7&#37;, 45.9&#37;, 23.3&#37;, 12.7&#37;, and 6.3&#37;, respectively. Multivariable-adjusted analyses revealed that age, male sex, hypertension, dyslipidemia, prior CVD, body mass index, urinary protein excretion, and underlying kidney disease were independent factors associated with reduced kidney function. Importantly, the odds ratios (ORs) for reduced kidney function increased linearly as the number of major comorbid conditions increased (OR for 1-2 conditions: 2.22, 95&#37; confidence interval [CI]: 1.65-2.97; OR for 3-4 conditions: 3.04, 95&#37; CI: 2.12-4.37; OR for ≥ 5 conditions: 4.37, 95&#37; CI: 1.75-10.9). The upward trend in OR was more pronounced with cardiovascular comorbidities but not significant with non-cardiovascular comorbidities. CONCLUSIONS: In conclusion, we observed an independent association between cardiovascular comorbidity and its risk factors and reduced kidney function. The results of this study highlight the importance of managing multimorbidity among patients with CKD.

DOI： 10.5551/jat.62900

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We have been studying the presence of sodium-glucose cotransporter 2 (SGLT2) in mesangial cells and pericytes since 1992. Recent large placebo-controlled studies of SGLT2 inhibitors in patients with type 2 diabetes mellitus have reported desirable effects of the inhibitors on the diabetic kidney and the diabetic heart. Most studies have indicated that these effects of SGLT2 inhibitors could be mediated by the tubuloglomerular feedback system. However, a recent study about urine sodium excretion in the presence of an SGLT2 inhibitor did not show any increases in urine sodium excretion. A very small dose of an SGLT2 inhibitor did not inhibit SGLT2 at the S1 segment of proximal tubules. Moreover, SGLT2 inhibition protects against progression in chronic kidney disease with and without type 2 diabetes. In these circumstances, the tubuloglomerular feedback hypothesis involves several theoretical concerns that must be clarified. The presence of SGLT2 in mesangial cells seems to be very important for diabetic nephropathy. We now propose a novel mechanism by which the desirable effects of SGLT2 inhibitors on diabetic nephropathy are derived from the direct effect on SGLT2 expressed in mesangial cells.

DOI： 10.1210/jendso/bvab083

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Purpose It remains unclear whether subclinical hypothyroidism (SCH) is associated with renal prognosis in patients with chronic kidney disease (CKD). Therefore, we prospectively investigated the association of SCH with renal outcomes in CKD. Methods We conducted a prospective observational study of 480 euthyroid patients and 89 patients with SCH. The endpoints were defined as a composite of doubling of serum creatinine (SCr), end-stage renal disease (ESRD), or death, and a composite of doubling of SCr or ESRD was added as an alternative outcome. Logistic regression analyses were used to identify the factors associated with SCH. In addition, a Cox proportional hazards model was performed to determine whether SCH was associated with poor renal outcomes. Results During a median follow-up period of 26.1 months, doubling of SCr, ESRD, or death and doubling of SCr or ESRD occurred in 244 and 213 patients, respectively. In univariable logistic regression analyses, SCH was significantly associated with older age, lower hemoglobin, higher proteinuria, lower estimated glomerular filtration rate (eGFR), and higher log B-type natriuretic peptide (BNP). Multivariable Cox analyses showed that SCH was associated with poorer renal outcomes after adjustment for covariates, including eGFR and log BNP [doubling of SCr, ESRD, or death: hazard ratio (HR) 1.61, 95% confidence interval (CI), 1.16-2.23; doubling of SCr or ESRD: HR 1.53, 95% CI 1.07-2.20], compared with euthyroidism. Conclusions In CKD, SCH is independently associated with poor renal outcomes, suggesting that screening for SCH might be needed to accurately predict renal prognosis.

DOI： 10.1007/s12020-021-02611-6

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Background Although the mortality rate in patients on hemodialysis remains extremely high, detailed information on causes of death over long-term periods is limited. The aim of this study was to clarify the underlying causes of death in patients undergoing maintenance hemodialysis in Japan. Methods This was a 10-year, multicenter, observational study of 3528 outpatients undergoing maintenance hemodialysis in Japan. Clinical outcomes were analyzed and causes of death were classified into six broad categories including cardiovascular diseases, infectious diseases, malignant neoplasms, cachexia, trauma/accidents, and other diseases, and more detailed subcategories. Results During the 10-year follow-up period, 1748 (49.5%) patients died. The most frequent causes of death were cardiovascular diseases (36.1%), followed by infectious diseases (25.8%) and malignant neoplasms (13.5%). In a detailed classification, sudden death, pulmonary infection, and lung cancer were the most common causes of death in cardiovascular diseases, infectious diseases, and malignant neoplasms, respectively. Conclusion Our study determined details on causes of death in Japanese hemodialysis patients during the 10-year follow-up period. Cardiovascular disease, especially sudden death is noticeable cause of death among patients on hemodialysis.

DOI： 10.1007/s10157-021-02089-6

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HD patients have been reported to have a higher risk of restenosis after percutaneous coronary intervention (PCI). The aim of this study was to investigate the risk factors of coronary restenosis in HD patients. We enrolled 54 HD patients (mean age: 66.5 +/- 10.1 years; 72.2% men; mean HD duration: 3.7 years), who received PCI and follow-up coronary angiography. Of the patients, 22 (40.7%) had restenosis within 3 to 12 months of PCI. Univariate logistic analysis showed low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, LDL-C, non-HDL-C, and history of major adverse cardiovascular events were significantly associated with coronary restenosis (OR]: 1.89, 1.27, 1.22, and 5.79, respectively). Multivariate analysis showed that LDL-C was significantly associated with coronary restenosis (OR: 1.43). These data suggest that LDL-C is an independent risk factor for coronary restenosis in HD patients undergoing PCI, and strict lipid management may be required.

DOI： 10.1111/1744-9987.13558

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Background Clinicopathological significance of light chain deposition in IgA nephropathy and the relation of monotypic IgA deposition to bone marrow abnormalities are important issues to be clarified. Methods We retrospectively investigated light chain deposition in 526 patients with IgA nephropathy. We divided the patients into 5 groups according to the balance of intensity of both light chain deposition: lambda monotypic, lambda dominant, polytypic, kappa dominant and kappa monotypic. Clinicopathological parameters were compared among the groups. The relation of monotypic IgA deposition to hematological malignancy was also evaluated. Results The prevalence of monotypic IgA deposition was 6.3%, 33 patients (21 lambda and 12 kappa). Thirty-two (4.0%) and 10 patients (1.9%) were classified into lambda and kappa dominant groups, respectively. Polytypic IgA deposition was observed in 455 patients (85.7%). Age of onset, age at biopsy, urinary protein creatinine ratio, the percentage of global glomerulosclerosis, and the degree of IgA and C3 deposition were different among the groups. However, there was no gradual difference according to the groups. No patient with monotypic IgA deposition showed hematological abnormality at biopsy and during follow-up. Conclusions The prevalence of IgA monotypic deposition was extremely low. Clinicopathologically, we could not differentiate patients with monotypic IgA deposition from those with polytypic one and no hematological disorder was documented in patients with monotypic IgA deposition. Whether IgA nephropathy with monotypic IgA deposition and that with polytypic one is the same entity or not, and relation between monotypic IgA deposition and hematological malignancy should be clarified by further investigations.

DOI： 10.1007/s10157-021-02026-7

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Backgrounds and aims: The geriatric nutritional risk index (GNRI), which is calculated using the serum albumin level and body mass index, is a nutritional marker associated with an increased risk of cardiovascular events in patients who are receiving hemodialysis. However, no studies have examined the association between the GNRI level and the incidence of stroke in this population.Methods: Three thousand forty-five patients were registered in the Q-Cohort Study, which is a multicenter, observational cohort of hemodialysis patients. The main outcomes were brain infarction and brain hemorrhage. The main exposure was GNRI levels at baseline. Patients were divided into quartiles on the basis of baseline GNRI levels: Q1, <90.7; Q2, 90.7-95.5; Q3, 95.6-99.8; Q4, >99.8. The risk of brain infarction or hemorrhage was estimated using the multivariable-adjusted Cox proportional hazard risk models and restricted cubic spline analyses.Results: During the 10-year follow-up period, 326 patients developed brain infarction and 149 patients developed brain hemorrhage. Cox proportional hazard risk models showed that the risk of brain infarction and hemorrhage in Q1 was significantly higher than that in Q4 group. The hazard ratios [95% confidence intervals] were 1.49 [1.05-2.12] and 1.89 [1.11-3.20], respectively. Restricted cubic spline curves showed that a lower GNRI was incrementally associated with an increased risk for both brain infarction and brain hemorrhage.Conclusions: Our results suggest that a lower GNRI is an independent risk factor for both brain infarction and hemorrhage in patients who are receiving maintenance hemodialysis.

DOI： 10.1016/j.atherosclerosis.2021.03.006

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Background Epidemiological evidence has shown that serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, a diagnostic biomarker for heart failure, are positively associated with cardiovascular risk. Since NT-proBNP in serum is excreted in urine, it is hypothesized that urinary NT-proBNP concentrations are correlated with serum concentrations and linked with cardiovascular risk in the general population. Methods A total of 3060 community-dwelling residents aged >= 40 years without history of cardiovascular disease (CVD) were followed up for a median of 8.3 years (2007-2015). Serum and urinary concentrations of NT-proBNP at baseline were compared. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the association between NT-proBNP concentrations and the risk of developing CVD were computed using the Cox proportional hazards model. Results The median values (interquartile ranges) of serum and urinary NT-proBNP concentrations at baseline were 56 (32-104) pg/mL and 20 (18-25) pg/mL, respectively. There was a strong quadratic correlation between the serum and urinary concentrations of NT-proBNP (coefficient of determination [R-2] = 0.72): urinary concentrations of 20, 27, and 43 pg/mL were equivalent to serum concentrations of 55, 125, and 300 pg/mL, respectively. During the follow-up period, 170 subjects developed CVD. The age- and sex-adjusted risk of CVD increased significantly with higher urinary NT-proBNP levels (P for trend < 0.001). This association remained significant after adjustment for traditional cardiovascular risk factors (P for trend = 0.009). The multivariable-adjusted risk of developing CVD almost doubled in subjects with urinary NT-proBNP of >= 43 pg/mL as compared to those with urinary NT-proBNP of <= 19 pg/mL (HR 2.07, 95% CI 1.20-3.56). Conclusions The present study demonstrated that urinary NT-proBNP concentrations were well-correlated with serum concentrations and were positively associated with cardiovascular risk. Given that urine sampling is noninvasive and does not require specially trained personnel, urinary NT-proBNP concentrations have the potential to be an easy and useful biomarker for detecting people at higher cardiovascular risk.

DOI： 10.1186/s12199-021-00970-0

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Introduction: Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial. Methods: A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR). Results: Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m(2) and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups. Conclusion: A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients.

DOI： 10.1159/000512365

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Background Patients with chronic kidney disease (CKD) have a higher risk of atherosclerotic cardiovascular disease (ASCVD). Dyslipidemia has been established as a risk factor for ASCVD. In the present study, we aimed to determine the prevalence of dyslipidemia at each stage of CKD. Methods We conducted a cross-sectional study among 4476 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese prospective cohort study in patients with non-dialysis-dependent CKD. Outcomes were the prevalence of hyper-low-density lipoprotein (LDL) cholesterolemia, hyper-non-high-density lipoprotein (non-HDL) cholesterolemia, hypertriglyceridemia, and hypo-high-density lipoprotein (hypo-HDL) cholesterolemia at each stage of CKD. We analyzed the relationships between CKD stage and the prevalence of dyslipidemia using logistic regression models. Results Patients in the advanced stages of CKD were more likely to have hypertriglyceridemia [OR 2.16 (95% CI 1.03-4.56), OR 2.24 (95% CI 1.04-4.84), OR 2.62 (95% CI 1.19-5.78), and OR 2.47 (95% CI 1.04-5.88) for CKD stages G3a, G3b, G4, and G5, respectively] and hypo-HDL-cholesterolemia [OR 2.66 (95% CI 1.21-5.82), OR 3.10 (95% CI 1.38-6.95), OR 2.86 (95% CI 1.25-6.53), and OR 3.30 (95% CI 1.35-8.10) for CKD stages G3a, G3b, G4, and G5, respectively] as compared with patients in CKD stage G1. The prevalence of hyper-LDL-cholesterolemia and hyper-non-HDL-cholesterolemia was not related to CKD stage. Conclusion Patients with advanced CKD stages are more likely to have hypertriglyceridemia and hypo-HDL-cholesterolemia than those in early stages. This type of lipid profile may represent a risk factor for ASCVD in patients with CKD.

DOI： 10.1007/s10157-020-02000-9

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Background A growing body of evidence has shown that non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). Non-invasive fibrosis assessments of NAFLD such as Fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS) have been developed to substitute liver biopsy. Little is known about the association between FIB-4 index or NFS and the components of CKD. Methods In the present cross-sectional study, we assessed of 3640 Japanese CKD patients. We examined the association between FIB-4index or NFS and the odds of having low estimated glomerular filtration rate (eGFR) defined as eGFR < 60 mL/min/1.73 m(2) or albuminuria defined as urinary albumin-to-creatinine ratio (UACR) >= 30 mg/g. Patients were divided into quartiles according to their baseline FIB-4 index and NFS levels. Linear and logistic regression analysis were conducted, with adjustment for potential confounding factors. Results FIB-4 index and NFS were negatively associated with eGFR, but not UACR, after adjustment for potential confounding factors. Both FIB-4 index and NFS were significantly associated with low eGFR after adjustment for potential confounding factors. Meanwhile, in the multivariable-adjusted model, no associations were found between FIB-4 index or NFS and albuminuria. The addition of FIB-4 index or NFS to the established clinical CKD risk factors improved diagnostic accuracy of prevalence of low eGFR. We also found that there was a significant trend of higher FIB-4 index and NFS with more advanced renal fibrosis using the kidney biopsy data. Conclusions Higher non-invasive fibrosis assessments of NAFLD were associated with higher odds of decreased eGFR.

DOI： 10.1007/s10157-020-02018-z

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Patients with chronic kidney disease (CKD) are at increased risks of both sarcopenia and fragility fractures. However, information on the association between skeletal muscle mass (SMM) and the risk of bone fractures in patients with CKD is lacking. We performed a cross-sectional analysis of 4146 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry Study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main measure was estimated SMM (eSMM) calculated using an equation validated by bioelectrical impedance analysis with two independent datasets of 100 and 81 CKD patients. The main outcome was historical bone fractures. The associations between sex-specific quartiles (Q1-Q4) of eSMM and fracture history were assessed by logistic regression analyses. The prevalence of a history of fractures increased and eSMM decreased with progressive CKD stages. Among the 4146 patients, 249 had prior bone fractures, including 111 patients in Q1 (lowest quartile), 65 in Q2, 46 in Q3, and 27 in Q4 (highest quartile). A multivariable-adjusted model revealed that patients in Q1 had a significantly higher odds ratio (95&#37; confidence interval) for bone fracture history than those in Q4 (reference): Q1, 2.77 (1.32-5.80); Q2, 1.95 (1.05-3.65); and Q3, 1.57 (0.90-2.75) (P-value for trend < 0.001). Similar associations were obtained when other skeletal muscle surrogates were applied: serum creatinine to serum cystatin C and daily urinary creatinine excretion. These results suggest that a lower eSMM is associated with an increased prevalence of historical bone fractures in pre-dialysis CKD patients.

DOI： 10.1007/s00223-021-00851-2

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Background & aims: Normalized protein catabolic rate (nPCR) is used as a surrogate for daily dietary protein intake and nutritional status in patients receiving maintenance hemodialysis. It remains uncertain whether the nPCR level is associated with the incidence of bone fracture.Methods: A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective, observational study, were followed up for 4 years. The primary outcome was bone fracture at any site. The main exposure was the nPCR level at baseline. Patients were assigned to four groups based on their baseline nPCR levels (G1: <0.85, G2: 0.85<, <0.95, G3: 0.95<, <1.05 [reference], G4: >1.05 g/kg/ day). We examined the relationship between the nPCR levels and the risk for bone fracture using Cox proportional hazards models.Results: During the follow-up period, 136 patients experienced bone fracture at any site. In the multi variable analyses, the risk for bone fracture was significantly higher in the lowest (G1) and highest (G4) nPCR groups than the reference (G3) group (hazard ratio [95% confidence intervals]: G1, 1.93 [1.04-3.58]; G2, 1.27 [0.67-2.40]; G3 1.00 (reference); G4, 2.21 [1.25-3.92]). The association remained almost unchanged, even when patients were divided into sex-specific nPCR quartiles, when analysis was limited to patients with a dialysis vintage >2 years, assumed to have lost residual kidney function, or when a competing risk model was applied.Conclusions: Our results suggest that both lower and higher nPCR levels are associated with an increased risk for bone fracture in hemodialysis patients. 0 2020 Published by Elsevier Ltd.

DOI： 10.1016/j.clnu.2020.07.003

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DOI： 10.1007/s13730-020-00521-6

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Background. Cardiovascular disease (CVD) is a major cause of death in kidney transplant (KT) recipients. To improve their long-term survival, it is clinically important to estimate the risk of CVD after living donor KT via adequate pre-transplant CVD screening.Methods. A derivation cohort containing 331 KT recipients underwent living donor KT at Kyushu University Hospital from January 2006 to December 2012. A prediction model was retrospectively developed and risk scores were investigated via a Cox proportional hazards regression model. The discrimination and calibration capacities of the prediction model were estimated via the c-statistic and the Hosmer-Lemeshow goodness of fit test. External validation was estimated via the same statistical methods by applying the model to a validation cohort of 300 KT recipients who underwent living donor KT at Tokyo Women's Medical University Hospital.Results. In the derivation cohort, 28 patients (8.5%) had CVD events during the observation period. Recipient age, CVD history, diabetic nephropathy, dialysis vintage, serum albumin and proteinuria at 12months after KT were significant predictors of CVD. A prediction model consisting of integer risk scores demonstrated good discrimination (c-statistic 0.88) and goodness of fit (Hosmer-Lemeshow test P=0.18). In a validation cohort, the model demonstrated moderate discrimination (c-statistic 0.77) and goodness of fit (Hosmer-Lemeshow test P=0.15), suggesting external validity.Conclusions. The above-described simple model for predicting CVD after living donor KT was accurate and useful in clinical situations.

DOI： 10.1093/ndt/gfaa275

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A 69-year-old woman with 26-year history of systemic lupus erythematosus and 4-year history of peritoneal dialysis was hospitalized for treatment of bacterial peritonitis. On admission, peritoneal dialysate was collected and subjected to bacterial culture. Cell count in the cloudy peritoneal dialysate was 4194/mu L, and Gram-negative bacilli were detected. Vancomycin (1 g/day) and ceftazidime (1 g/day) were administered intraperitoneally, which resulted in rapid decrease in cell count in the peritoneal dialysate. However, on the 7th hospital day, peritonitis relapsed with abdominal pain and cloudy dialysate. 16S ribosomal RNA gene sequencing analysis identified Stappia indica sp. as the causative bacteria. Although treatment with 1 g/day meropenem for an additional 3 weeks was effective, bacterial peritonitis relapsed 7 days after its discontinuation. Because biofilm formation was suspected, the peritoneal catheter was removed, and she was transferred to maintenance hemodialysis. After removal of the peritoneal catheter, bacterial peritonitis never relapsed. Stappia indica was initially discovered in the deep seawater of the Indian Ocean. The bacterium is rod-shaped, Gram-negative, and oxidase- and catalase-positive. There have been no reports on the clinical effects of genus Stappia. Given the frequent relapse in the present case, Stappia indica sp. may easily form biofilms and are likely resistant to antibiotics. Timely peritoneal catheter removal may be required in some cases of bacterial peritonitis as in the present case. Further case reports are required to further elucidate the clinical effects of Stappia indica on humans.

DOI： 10.1007/s13730-021-00579-w

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Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P < .001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P < .001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

DOI： 10.1111/ajt.16093

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Background Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. Methods This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. Results LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. Conclusion Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia.

DOI： 10.1007/s10157-020-01959-9

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Aim: Most transplant centres use SV40 large T antigen (TAg) staining for the diagnosis and assessment of BK polyomavirus-associated nephropathy (BKPyVAN). This study was performed to evaluate the significance of capsid protein VP1 expression in BKPyVAN. Methods: We performed immunohistochemical staining using anti-SV40 TAg and anti-BKPyV VP1 antibodies in 16 index biopsies and 12 re-biopsies of BKPyVAN and compared the patterns of positivity and the percentage of positive tubules by counting whole specimens. We investigated the correlation between serum creatinine increase from baseline and the percentage of positive tubules for both markers in 16 index biopsies. Results: In VP1 staining, positive findings were observed not only in the nuclei of tubular epithelial cells but also in the cytoplasm, cells shedding into the lumen, intra-tubular casts, and in the interstitium. Two of 28 biopsies (7.1%) showed TAg-positive and VP1-negative results, in which TAg-positive cells were detected only in a single tubule. The median (interquartile range) percentage of positive tubules was 2.8% (0.7-9.8%) for TAg and 1.4% (0.5-3.9%) for VP1 staining (p = 0.2). In 16 index biopsies, serum creatinine increases significantly correlated with the percentage of VP1-positive tubules (r = 0.49, p = 0.02), while this correlation revealed borderline significance with TAg-positive tubules. Conclusions: VP1 expression showed various patterns, but was detected in half as many tubules as TAg staining, which might lead to false negatives in the samples with minimal viral replication. However, increased VP1-positive tubules indicate advanced tubular damage and possible association with graft dysfunction.

DOI： 10.1159/000510967

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Background and aims: Sudden death is one of the most common causes of death among patients on hemodialysis. Although hyperphosphatemia is a well-known risk factor for cardiovascular and all-cause deaths, the studies focusing on the relationship between serum phosphate levels and the risk of sudden death are limited. This study aimed to clarify the relationship between serum phosphate levels and the risk of sudden death in patients on hemodialysis.Methods: This is a multicenter, longitudinal, and observational study. A total of 3505 patients, registered in the Q-Cohort Study, who underwent maintenance hemodialysis, and were followed up for 10 years, were included. Patients were divided into quartiles on the basis of baseline serum phosphate levels: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 908), 4.9-5.6 mg/dL; and Q4 (n = 874), >= 5.7 mg/dL. Associations between baseline serum phosphate levels and sudden death were analyzed using the Cox proportional hazards model and the Fine-Gray regression model.Results: During the follow-up period, 227 patients died from sudden death. The risk for sudden death was significantly higher in the highest quartile (Q4) than in the lowest quartile (Q1) as the reference group (multivariable-adjusted hazard ratios and 95% confidence intervals: Q1, 1.00; Q2, 1.15 [0.77-1.70], Q3, 1.31 [0.89-1.93], and Q4, 1.72 [1.14-2.59]; hazard ratio for every 1-mg/dL increase in the serum phosphate level, 1.23 [1.09-1.39]; p < 0.001).Conclusions: Hyperphosphatemia is independently associated with an elevated risk of sudden death in patients on hemodialysis.

DOI： 10.1016/j.atherosclerosis.2020.11.020

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Background Several large population-based studies have demonstrated that urinary salt excretion (USALT) is associated with albuminuria. However, this relationship has not been assessed in a large cohort study of patients with chronic kidney disease (CKD). Thus, the present study aimed to elucidate whether USALT was independently associated with albuminuria in a large cohort of patients with CKD. Methods This cross-sectional study was conducted in 4075 patients with CKD not on dialysis. USALT (g/day) was estimated from spot urine. Patients were divided into quartiles (Q1-Q4) according to estimated USALT. Multivariable regression models were used to determine whether USALT was independently related to urinary albumin-to-creatinine ratio (UACR) or the presence of macroalbuminuria. Results In multivariable linear regression analyses, 1-g/day increment in USALT was significantly associated with log UACR [coefficient 0.098, 95% confidence interval (CI) 0.075-0.121]. In addition, compared with the first USALT quartile, the third and fourth quartiles exhibited significant associations with log UACR (Q3: coefficient 0.305, 95% CI 0.154-0.456; Q4: coefficient 0.601, 95% CI 0.447-0.756). Furthermore, multivariable logistic regression analyses showed that USALT (1-g/day increment) was significantly associated with the presence of macroalbuminuria [odds ratio (OR) 1.11, 95% CI 1.07-1.14]; the third and fourth USALT quartiles exhibited significantly greater risks of macroalbuminuria, compared with the first quartile (Q3: OR 1.33, 95% CI 1.09-1.62; Q4: OR 1.89, 95% CI 1.54-2.32). Conclusions This significant association of USALT with UACR and macroalbuminuria suggests that higher USALT may cause increased albuminuria, thereby contributing to kidney disease progression.

DOI： 10.1007/s10157-020-01950-4

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The geriatric nutritional risk index (GNRI) and creatinine (Cr) index are indexes often used as nutritional surrogates in patients receiving hemodialysis. However, few studies have directly compared the clinical characteristics of these two indexes. We investigated 3,536 hemodialysis patients enrolled in the Japan DOPPS phases 4 and 5. The primary outcome was all-cause mortality and the main exposures were the GNRI and Cr index. We confirmed and compared the association between these indexes and mortality risk as estimated by a multivariable-adjusted Cox proportional hazards model. During the median 2.2-year follow-up period, 414 patients died of any cause. In the multivariable-adjusted model, lower GNRI and Cr index were both associated with increased risk of all-cause mortality, and these associations were further confirmed by restricted cubic spline curves. The predictability of all-cause mortality, as represented by the c-statistic, was comparable between the two indexes. Furthermore, baseline nutritional surrogates that corresponded with lower GNRI or Cr index values were comparable between the two indexes. Given that calculating the GNRI is simpler than calculating the Cr index, our data suggest that the GNRI may be preferable to the Cr index for predicting clinical outcomes in patients undergoing maintenance hemodialysis.

DOI： 10.1038/s41598-020-62720-6

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Modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr concentration, and Kt/V for urea, is an indicator of skeletal muscle mass in hemodialysis (HD) patients. It remains unknown whether the modified Cr index predicts infection-related mortality in this population. We investigated the association between the modified Cr index and infection-related mortality. A total of 3046 patients registered in the Q-Cohort Study, a multicenter, observational study of HD patients, were analyzed. Associations between sex-specific quartiles (Q1–Q4) of the modified Cr index and the risk for infection-related mortality were analyzed by Cox proportional hazard model. During a median follow-up of 8.8 years, 387 patients died of infection. The estimated risk for infection-related mortality was significantly higher in the lower quartiles (Q1, Q2, and Q3) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals [CI]: Q1, 2.89 [1.70–5.06], Q2, 2.76 [1.72–4.62], and Q3, 1.79 [1.12–2.99]). The hazard ratio (95% CI) for a 1 mg/kg/day decrease in the modified Cr index was 1.18 (1.09–1.27, P < 0.01) for infection-related mortality. In conclusion, a lower modified Cr index is associated with an increased risk for long-term infection-related mortality in the HD population.

DOI： 10.1038/s41598-020-58181-6

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Although hypercalcemia is a risk factor for all-cause mortality in hemodialysis patients, it remains unknown whether hypercalcemia increases the risk of infection-related death. A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective cohort study of hemodialysis patients, were analyzed. The predictor was albumin-corrected serum calcium level at baseline. The main outcome was infection-related death. Death risk were estimated by multivariable-adjusted Cox proportional hazard risk models and competing risk models. During the follow-up period of 4 years, 107 patients died of infection and 473 died of any cause. The patients were divided into four groups by the serum calcium level at baseline (G1, 5.7–8.9 mg/dL; G2, 9.0–9.4 mg/dL; G3, 9.5–9.9 mg/L; G4 10.0–16.5 mg/dL). In the multivariable-adjusted model, the incidence of infection-related death was significantly higher in the highest serum calcium group (G4) compared with the lowest serum calcium group (G1): hazard ratio [95% confidence interval], 2.34 [1.35–4.04], P = 0.002. Furthermore, higher serum calcium level was significantly associated with increased risk of all-cause death. In conclusion, our data suggest that a higher serum calcium level may be a risk factor for infection-related and all-cause death in hemodialysis patients.

DOI： 10.1038/s41598-020-63334-8

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On 31 December 2019, cases of pneumonia whose cause was later identified as SARS-CoV-2 were detected in Wuhan City, Hubei Province of China, and now COVID-19 has spread worldwide. On March 1, 2020, a 69-year-old Japanese man who had been on hemodialysis for 3 years was diagnosed as having COVID-19 pneumonia and hospitalized at our Medical Center. Pulmonary CT revealed bilateral multiple consolidation with bilateral pleural effusion. Aggressive weight reduction was needed to improve the patient's respiratory condition. Hemodialysis therapy was performed in isolation with hydroxychloroquine administration, but the formation of a dialysis membrane clot forced the withdrawal of dialysis therapy. Changing the dialysis membrane material and anticoagulant enabled the resumption of dialysis therapy, allowing the body weight to correct downward. On the 5th hospitalization day, the patient's fever dropped and he showed improved oxygenation and chest X-ray. He was eventually discharged. The hydroxychloroquine and appropriate fluid management may have contributed to the patient's recovery. Clinicians should pay close attention to avoid dialysis-related problems when treating a patient with COVID-19.

DOI： 10.1007/s13730-020-00495-5

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Background: Several experimental studies have indicated that increased plasma osmolarity caused by recurrent dehydration is involved in kidney injury via a mechanism, mediated by vasopressin secretion and activation of the aldose reductase pathway. Epidemiologic evidence linking increased plasma osmolarity and the onset of end-stage kidney disease (ESKD), in patients with primary glomerulonephritis, is lacking. Methods: We retrospectively examined 663 patients with IgA nephropathy (IgAN) diagnosed by kidney biopsy and evaluated the association between estimated plasma osmolarity and ESKD prevalence, using a Cox proportional hazards model. Results: During follow-up (median 80.4 months; interquartile range 22.2–120.1), 73 patients developed ESKD. In a baseline survey, plasma osmolarity was correlated negatively with the mean value of the estimated glomerular filtration rate, but correlated positively with the mean value of urinary protein excretion, systolic blood pressure, and pathologic severity of extracapillary proliferation, in addition to tissue fibrosis and sclerosis. The incidence rate of ESKD increased linearly with increase in plasma osmolarity (P ' 0.05 for trend). In multivariate analyses, plasma osmolarity was an independent risk factor for ESKD (hazard ratio for each increment of 5 mOsm/kg in plasma osmolarity 1.56; 95% confidence interval 1.18–2.07) even after adjustment for potential confounders. Conclusions: Increased plasma osmolarity was associated significantly with an increased risk of ESKD in patients with IgAN. Maintenance of plasma osmolarity by appropriate control of the balance between salt and water may contribute to kidney protection.

DOI： 10.1007/s10157-020-01919-3

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Background Several experimental studies have indicated that increased plasma osmolarity caused by recurrent dehydration is involved in kidney injury via a mechanism, mediated by vasopressin secretion and activation of the aldose reductase pathway. Epidemiologic evidence linking increased plasma osmolarity and the onset of end-stage kidney disease (ESKD), in patients with primary glomerulonephritis, is lacking. Methods We retrospectively examined 663 patients with IgA nephropathy (IgAN) diagnosed by kidney biopsy and evaluated the association between estimated plasma osmolarity and ESKD prevalence, using a Cox proportional hazards model. Results During follow-up (median 80.4 months; interquartile range 22.2-120.1), 73 patients developed ESKD. In a baseline survey, plasma osmolarity was correlated negatively with the mean value of the estimated glomerular filtration rate, but correlated positively with the mean value of urinary protein excretion, systolic blood pressure, and pathologic severity of extracapillary proliferation, in addition to tissue fibrosis and sclerosis. The incidence rate of ESKD increased linearly with increase in plasma osmolarity (P < 0.05 for trend). In multivariate analyses, plasma osmolarity was an independent risk factor for ESKD (hazard ratio for each increment of 5 mOsm/kg in plasma osmolarity 1.56; 95% confidence interval 1.18-2.07) even after adjustment for potential confounders. Conclusions Increased plasma osmolarity was associated significantly with an increased risk of ESKD in patients with IgAN. Maintenance of plasma osmolarity by appropriate control of the balance between salt and water may contribute to kidney protection.

DOI： 10.1007/s10157-020-01919-3

Language：English  

Language：English   Publishing type：Research paper (scientific journal)  

Kidney ischemia–reperfusion injury is a major cause of acute kidney injury (AKI). Following reduced kidney perfusion, the pathological overproduction of reactive oxygen and reactive nitrogen species play a substantial role in the development of kidney ischemia–reperfusion injury. Arginase 2 (ARG2) competes with nitric oxide synthase for the same substrate, L-arginine, and is implicated in the regulation of reactive nitrogen species. Therefore, we investigated the role of ARG2 in kidney ischemia–reperfusion injury using human proximal tubule cells (HK-2) and a mouse model of kidney ischemia–reperfusion injury. ARG2 was predominantly expressed in kidney tubules of the cortex, which was increased after ischemia–reperfusion injury. In HK-2 cells, ARG2 was expressed in punctate form in the cytoplasm and upregulated after hypoxia–reoxygenation. ARG2 knockdown reduced the level of reactive oxygen species and 3-nitrotyrosine after hypoxia–reoxygenation injury compared with control siRNA. Consistent with these results, in Arg2 knockout mice, abnormal kidney function and the increased acute tubular necrosis score induced by ischemia–reperfusion injury was significantly reduced without any obvious blood pressure changes. Additionally, an accumulation of 3-nitrotyrosine and apoptosis of renal tubule cells were attenuated in Arg2 knockout mice compared with wild-type mice. Inhibition of arginase by N^ω-hydroxy-nor-_L-arginine alleviated kidney ischemia–reperfusion injury like the results found in Arg2 knockout mice. Thus, ARG2 plays a pivotal role in ischemia–reperfusion-induced AKI by means of nitrosative stress. Hence, an ARG2-specific inhibitor may effectively treat kidney ischemia–reperfusion injury.

DOI： 10.1016/j.kint.2020.03.032

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Kidney ischemia-reperfusion injury is a major cause of acute kidney injury (AKI). Following reduced kidney perfusion, the pathological overproduction of reactive oxygen and reactive nitrogen species play a substantial role in the development of kidney ischemia-reperfusion injury. Arginase 2 (ARG2) competes with nitric oxide synthase for the same substrate, L-arginine, and is implicated in the regulation of reactive nitrogen species. Therefore, we investigated the role of ARG2 in kidney ischemia-reperfusion injury using human proximal tubule cells (HK-2) and a mouse model of kidney ischemia-reperfusion injury. ARG2 was predominantly expressed in kidney tubules of the cortex, which was increased after ischemia-reperfusion injury. In HK-2 cells, ARG2 was expressed in punctate form in the cytoplasm and upregulated after hypoxia-reoxygenation. ARG2 knockdown reduced the level of reactive oxygen species and 3-nitrotyrosine after hypoxia-reoxygenation injury compared with control siRNA. Consistent with these results, in Arg2 knockout mice, abnormal kidney function and the increased acute tubular necrosis score induced by ischemia-reperfusion injury was significantly reduced without any obvious blood pressure changes. Additionally, an accumulation of 3-nitrotyrosine and apoptosis of renal tubule cells were attenuated in Arg2 knockout mice compared with wild-type mice. Inhibition of arginase by N-omega-hydroxy-nor-L-arginine alleviated kidney ischemia-reperfusion injury like the results found in Arg2 knockout mice. Thus, ARG2 plays a pivotal role in ischemia- reperfusion-induced AKI by means of nitrosative stress. Hence, an ARG2-specific inhibitor may effectively treat kidney ischemia-reperfusion injury.

DOI： 10.1016/j.kint.2020.03.032

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DOI： 10.1111/1744-9987.13442

Language：English   Publishing type：Research paper (scientific journal)  

Background Protein-energy wasting (PEW) is a frequently observed complication that leads to increased mortality in hemodialysis patients. However, a multifaceted assessment of PEW by combined objective nutritional parameters has not yet been established. Methods In total, 144 Japanese patients receiving maintenance hemodialysis at a hemodialysis center were retrospectively followed for 7 years. The primary outcome was all-cause death. The main exposure was a modified simple PEW score (0, 1, 2, 3, or 4), calculated from four parameters: serum albumin and creatinine levels, normalized protein catabolic rate, and body mass index. These parameters are included in the subcategories of PEW as defined by the International Society of Renal Nutrition and Management. The cutoff values of the modified simple PEW score components were based on the receiver operating characteristics curves determined by univariate logistic regression analyses. Risk estimates for all-cause mortality were calculated by the Cox proportional hazards model adjusted for potential confounding factors. Results During the median 5.7-years follow-up period, 37 patients died of any cause. When patients were divided into three subgroups (G1-G3) based on the modified simple PEW score, a multivariable-adjusted analysis showed that the risks of all-cause death in groups G2 and G3 were significantly higher than in the lowest score group (G1), with hazard risk (95% confidence interval) 3.10 (1.16-8.26) (P = 0.024) and 5.68 (1.85-17.45) (P = 0.002), respectively. Conclusions The modified simple PEW score is a useful composite indicator of nutritional status that stratifies the risk of all-cause mortality in patients undergoing maintenance hemodialysis.

DOI： 10.1186/s41100-020-00289-6

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It remains unclear which vascular access provides better survival in hemodialysis patients with heart failure, superficialization of the brachial artery (SBA), or tunneled central venous catheter (TCVC). We retrospectively followed up 60 hemodialysis patients with heart failure who underwent SBA (n = 36) or TCVC placement (n = 24). During the median 2.2-year follow-up period, 36 patients died. The median survival time was significantly longer for the SBA group than for the TCVC group (5.7 vs 1.7 years; P < .05, log-rank test). A multivariate-adjusted Cox regression analysis showed that SBA was associated with a reduced risk of all-cause death (hazard ratio [HR] 0.30; 95% confidence interval [CI] 0.14-0.65). In the cohort of propensity score-matched 15 pairs, patients with SBA experienced fewer all-cause deaths (HR 0.29; 95% CI 0.10-0.77). Our study suggests that SBA is an alternative option in hemodialysis patients with heart failure.

DOI： 10.1111/1744-9987.13457

Language：English  

DOI： 10.1111/1744-9987.13442

Language：English   Publishing type：Research paper (scientific journal)  

The prevalence of atherosclerotic diseases is higher in hemodialysis patients. The aim of the current study was to investigate associations between cholesterol level and the incidences of cardiovascular disease (CVD) and mortality in hemodialysis patients. A total of 3517 participants undergoing maintenance hemodialysis were followed up for 10 years. Total cholesterol (TC) level was divided into quartile in baseline data. The multivariate analyses were calculated by a Cox proportional hazards model. The incidences of ischemic heart disease (IHD), peripheral artery disease (PAD), and CVD were significantly positively associated with higher cholesterol levels after adjustment for confounding factors (P < 0.01, P = 0.04, and P < 0.01, respectively). Furthermore, the incidences of cancer-associated mortality and all-cause mortality were significantly positively associated with lower cholesterol levels after adjustment for confounding factors (both P < 0.01). The lowest TC level at all-cause mortality risk was 179 mg/dL. From these results, higher TC predicts IHD, PAD, and CVD events, and lower TC predicts cancer-associated mortality and all-cause mortality in patients undergoing maintenance hemodialysis.

DOI： 10.1111/1744-9987.13455

Language：English  

A 71-year-old woman was hospitalized for the treatment of fatigue, fever, and cough. On admission, she showed increased serum inflammation markers, severe anemia, pulmonary hemorrhage, and advanced acute kidney injury requiring hemodialysis. Her serum anti-glomerular basement membrane (GBM) antibody titer was found to be extremely high on the 7th hospital day. She was eventually diagnosed with anti-GBM disease. She was treated with a combination of corticosteroid pulse therapy, oral prednisolone and cyclophosphamide, and plasma exchange, but continued to require maintenance hemodialysis for end-stage kidney disease. During her treatment, she suddenly developed headache, blindness, seizure, and consciousness disturbance. She was diagnosed by magnetic resonance imaging with posterior reversible encephalopathy syndrome (PRES) with subcortical cerebral hemorrhage. Both the PRES and cerebral hemorrhage subsided soon after control of her hypertension and reinforcement of immunosuppressive treatment. PRES, particularly when accompanied by cerebral hemorrhage, may cause irreversible and lethal neurological abnormalities, and nephrologists should, therefore, be aware of the potential risk of PRES in patients with anti-GBM disease. We discuss the current case in the light of the previous literature.

DOI： 10.1007/s13730-020-00473-x

Language：English   Publishing type：Research paper (scientific journal)  

It remains unclear which vascular access provides better survival in hemodialysis patients with heart failure, superficialization of the brachial artery (SBA), or tunneled central venous catheter (TCVC). We retrospectively followed up 60 hemodialysis patients with heart failure who underwent SBA (n = 36) or TCVC placement (n = 24). During the median 2.2-year follow-up period, 36 patients died. The median survival time was significantly longer for the SBA group than for the TCVC group (5.7 vs 1.7 years; P <.05, log-rank test). A multivariate-adjusted Cox regression analysis showed that SBA was associated with a reduced risk of all-cause death (hazard ratio [HR] 0.30; 95% confidence interval [CI] 0.14-0.65). In the cohort of propensity score-matched 15 pairs, patients with SBA experienced fewer all-cause deaths (HR 0.29; 95% CI 0.10-0.77). Our study suggests that SBA is an alternative option in hemodialysis patients with heart failure.

DOI： 10.1111/1744-9987.13457

Language：English   Publishing type：Research paper (scientific journal)  

Background and aims: Peripheral artery disease (PAD) is mainly caused by atherosclerosis and is a critical cardiovascular complication in patients undergoing hemodialysis. Although hyperphosphatemia is a risk factor for cardiovascular events, whether serum phosphate concentration is associated with PAD remains unclear. This study was performed to clarify the relationship between serum phosphate concentration and the risk of intervention for PAD in patients undergoing hemodialysis. Methods: In total, 3505 patients undergoing hemodialysis registered in the Q-Cohort Study were followed up for 10 years. The primary outcome was the incidence of major adverse limb events (MALE) as a surrogate endpoint of intervention for PAD. The patients were divided into quartiles according to the baseline serum phosphate concentration: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2–4.8 mg/dL; Q3 (n = 909), 4.9–5.6 mg/dL; and Q4 (n = 873), ≥5.7 mg/dL. A multivariable-adjusted Cox proportional hazards risk model was employed to examine the association between the serum phosphate concentration and the risk of MALE. Results: During a median follow-up period of 8.2 years, 257 patients required intervention with MALE. The Cox proportional hazards risk model showed that the risk of MALE in Q4 was significantly higher than that in Q1 (hazard ratio, 1.81; 95% confidence interval, 1.25–2.63). Every 1-mg/dL increase in serum phosphate concentration was also significantly associated with the increased incidence of MALE (hazard ratio, 1.24; 95% confidence interval, 1.10–1.39). Conclusions: An elevated serum phosphate concentration was associated with an increased risk of MALE in patients undergoing hemodialysis.

DOI： 10.1016/j.atherosclerosis.2020.04.022

Language：English  

DOI： 10.1016/j.stem.2020.05.013

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Background. The utility of the Columbia classification (Colclass) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven.Methods. We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class.Results. The patients were classified into the following variants: not otherwise specified [NOS; n= 121 (60.1%)], perihilar [n= 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n =17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539).Conclusions. The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested.

DOI： 10.1093/ndt/gfy374

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Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), we found that in patients protected from CVD, there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC), in vascular smooth muscle cells (VSMCs). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids and an increase in membrane phospholipids, suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration and proliferation were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein E (Apoe)-knockout mice overexpressing VSMC-specific Aadac showed amelioration of atherosclerotic lesions. Our findings suggest that higher AADAC expression in VSMCs protects T2DM patients from CVD.

DOI： 10.1016/j.stem.2020.04.018

Language：English   Publishing type：Research paper (scientific journal)  

Background and aims: Peripheral artery disease (PAD) is mainly caused by atherosclerosis and is a critical cardiovascular complication in patients undergoing hemodialysis. Although hyperphosphatemia is a risk factor for cardiovascular events, whether serum phosphate concentration is associated with PAD remains unclear. This study was performed to clarify the relationship between serum phosphate concentration and the risk of intervention for PAD in patients undergoing hemodialysis.Methods: In total, 3505 patients undergoing hemodialysis registered in the Q-Cohort Study were followed up for 10 years. The primary outcome was the incidence of major adverse limb events (MALE) as a surrogate endpoint of intervention for PAD. The patients were divided into quartiles according to the baseline serum phosphate concentration: Q1 (n = 886),< 4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 909), 4.9-5.6 mg/dL; and Q4 (n = 873), >= 5.7 mg/dL. A multivariable-adjusted Cox proportional hazards risk model was employed to examine the association between the serum phosphate concentration and the risk of MALE.Results: During a median follow-up period of 8.2 years, 257 patients required intervention with MALE. The Cox proportional hazards risk model showed that the risk of MALE in Q4 was significantly higher than that in Q1 (hazard ratio, 1.81; 95% confidence interval, 1.25-2.63). Every 1-mg/dL increase in serum phosphate concentration was also significantly associated with the increased incidence of MALE (hazard ratio, 1.24; 95% confidence interval, 1.10-1.39).Conclusions: An elevated serum phosphate concentration was associated with an increased risk of MALE in patients undergoing hemodialysis.

DOI： 10.1016/j.atherosclerosis.2020.04.022

Language：English  

DOI： 10.1253/circj.CJ-66-0179

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Background: Parathyroid hormone (PTH) has been associated with cardiovascular disorders; however, it is unknown whether plasma PTH concentrations are associated with atrial fibrillation (AF) in patients with chronic kidney disease (CKD).Methods and Results: The present cross-sectional study analyzed baseline data of 3,384 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese multicenter prospective cohort study of patients with non-dialysis-dependent CKD. The outcome was prevalence of AF, and the main risk factor was plasma intact PTH concentration. Associations between plasma intact PTH concentration quartiles (Q1-Q4, from lowest to highest) and the presence of AF were analyzed using logistic regression. In all, 185 patients had AF; 22, 34, 59, and 70 patients were in Q1, Q2, Q3, and Q4 of PTH concentrations, respectively. The prevalence of AF increased incrementally with increases in plasma intact PTH. In the logistic regression model, patients with higher plasma intact PTH concentrations (Q2-04) had higher adjusted odds ratios (95% confidence intervals) for the prevalence of AF relative to the reference group (Q1), namely 1.33 (0.76-2.34), 1.82 ([1.06-3.13), and 1.99 (1.08-3.64), respectively (P=0.016).Conclusions: Higher plasma intact PTH concentrations were significantly and incrementally associated with an increased prevalence of AF in non-dialysis-dependent CKD patients.

DOI： 10.1253/circj.CJ-19-1201

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven. METHODS: We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class. RESULTS: The patients were classified into the following variants: not otherwise specified [NOS; n = 121 (60.1%)], perihilar [n = 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n = 17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539). CONCLUSIONS: The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested.

DOI： 10.1093/ndt/gfy374

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Why some patients with type 2 diabetes are protected against cardiovascular disease (CVD) has not been clarified. Toyohara et al. reveal that in patients protected from CVD, arylacetamide deacetylase (AADAC) is elevated in vascular smooth muscle cells (VSMCs). AADAC alters lipid metabolism and cellular processes in VSMCs and ameliorates CVD.

DOI： 10.1016/j.stem.2020.04.018

Language：English   Publishing type：Research paper (scientific journal)  

Background: Parathyroid hormone (PTH) has been associated with cardiovascular disorders; however, it is unknown whether plasma PTH concentrations are associated with atrial fibrillation (AF) in patients with chronic kidney disease (CKD). Methods and Results: The present cross-sectional study analyzed baseline data of 3,384 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese multicenter prospective cohort study of patients with non-dialysis-dependent CKD. The outcome was prevalence of AF, and the main risk factor was plasma intact PTH concentration. Associations between plasma intact PTH concentration quartiles (Q1-Q4, from lowest to highest) and the presence of AF were analyzed using logistic regression. In all, 185 patients had AF; 22, 34, 59, and 70 patients were in Q1, Q2, Q3, and Q4 of PTH concentrations, respectively. The prevalence of AF increased incrementally with increases in plasma intact PTH. In the logistic regression model, patients with higher plasma intact PTH concentrations (Q2-Q4) had higher adjusted odds ratios (95% confidence intervals) for the prevalence of AF relative to the reference group (Q1), namely 1.33 (0.76-2.34), 1.82 ([1.06-3.13), and 1.99 (1.08-3.64), respectively (P=0.016). Conclusions: Higher plasma intact PTH concentrations were significantly and incrementally associated with an increased prevalence of AF in non-dialysis-dependent CKD patients.

DOI： 10.1253/circj.CJ-19-1201

Language：English   Publishing type：Research paper (scientific journal)  

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that leads to end-stage kidney disease if only a poor response to plasma exchanges (PEs) or eculizumab therapy is achieved.Case presentationA 58-year-old Japanese man presented with thrombocytopenia, anemia, and kidney failure requiring dialysis without any underlying disease. A kidney biopsy revealed marked mesangiolysis in all glomeruli, compatible with thrombotic microangiopathy (TMA). Based on the positive anti- factor H antibody and negative result for secondary TMA, we diagnosed him as aHUS. Despite eculizumab administration after eight sessions of PE, neither platelet normalization nor kidney recovery was achieved. Eight months later, we discontinued eculizumab therapy due to anaphylactic reaction. At 15months after the onset of TMA, his platelet count increased gradually from 40 to 150x10(3)/mu L with a decreased serum creatinine level and increased urine output, eventually allowing the withdrawal of dialysis therapy. A second kidney biopsy showed mesangial widening compatible with the healing of TMA.ConclusionsThis case indicates that aHUS with PEs and eculizumab therapy has the potential for renal recovery even if over 1year has passed.

DOI： 10.1186/s12882-020-01897-4

Language：English   Publishing type：Research paper (scientific journal)  

Background: Both chronic kidney disease and brain white matter hyperintensities (WMH) are known to be risk factors of dementia and mortality.Methods and Results: In 2012, 1,214 community-dwelling Japanese subjects aged >= 65 years underwent brain magnetic resonance imaging (MRI) scans and a comprehensive health examination. This study investigated associations of the urinary albumin : creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) with the WMH volume to intracranial volume (WMHV : ICV) ratio, and the association of the combination of UACR and the WMHV : ICV ratio with cognitive decline and mortality risk. The geometric mean of the WMHV :ICV ratio was 0.223% in the entire study population, and increased significantly with higher UACR levels after adjusting for potential confounding factors (0.213% for normoalbuminuria, 0.248% for microalbuminuria, and 0.332% for macroalbuminuria; P-trend=0.01). In contrast, there was no clear association between eGFR and the WMHV : ICV ratio. Compared with subjects with normoalbuminuria and a smaller WMHV : ICV ratio (<0.257% [median]), subjects with albuminuria and a larger WMHV : ICV ratio (>= 0.257%) had higher probabilities of cognitive decline at baseline and all-cause death during the follow-up.Conclusions: This study suggests that subjects with albuminuria have a greater risk of WMH enlargement and that the combination of albuminuria and WMH enlargement increases the risk of cognitive decline and all-cause mortality in an elderly Japanese population.

DOI： 10.1253/circj.CJ-19-1069

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that leads to end-stage kidney disease if only a poor response to plasma exchanges (PEs) or eculizumab therapy is achieved. CASE PRESENTATION: A 58-year-old Japanese man presented with thrombocytopenia, anemia, and kidney failure requiring dialysis without any underlying disease. A kidney biopsy revealed marked mesangiolysis in all glomeruli, compatible with thrombotic microangiopathy (TMA). Based on the positive anti- factor H antibody and negative result for secondary TMA, we diagnosed him as aHUS. Despite eculizumab administration after eight sessions of PE, neither platelet normalization nor kidney recovery was achieved. Eight months later, we discontinued eculizumab therapy due to anaphylactic reaction. At 15 months after the onset of TMA, his platelet count increased gradually from 40 to 150 × 103/μL with a decreased serum creatinine level and increased urine output, eventually allowing the withdrawal of dialysis therapy. A second kidney biopsy showed mesangial widening compatible with the healing of TMA. CONCLUSIONS: This case indicates that aHUS with PEs and eculizumab therapy has the potential for renal recovery even if over 1 year has passed.

DOI： 10.1186/s12882-020-01897-4

Language：English   Publishing type：Research paper (scientific journal)  

Background: Patients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis. Methods: In total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC. Results: AVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism (serum calcium, serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23), AVC was significantly associated with the presence of CAP [odds ratio (OR), 3.37; 95% confidence interval (CI), 1.43-7.95], the presence of PAD (OR, 1.76; 95% CI, 1.10-2.81), the CAP score (per 1.0-point increase) (OR, 1.06; 95% CI, 1.02-1.11), and the ankle-brachial blood pressure index (per 0.1-point increase) (OR, 0.83; 95% CI, 0.72-0.95). Conclusions: AVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors.

DOI： 10.1186/s12882-020-01864-z

Language：English   Publishing type：Research paper (scientific journal)  

The accumulation of glucose degradation products (GDPs) can lead to tissue damage in patients with diabetes and those undergoing long-term peritoneal dialysis (PD). Angiogenesis is occasionally observed in the peritoneal membrane of patients undergoing PD, where it is associated with failure of ultrafiltration. To investigate the mechanism underlying the influence of angiogenesis on fluid absorption, we evaluated the effects of accumulation of the glucose degradation product methylglyoxal (MGO) on angiogenesis in vitro, and analyzed the association with angiogenesis in the peritoneal membrane. To this end, we measured the levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)-BB in cultured endothelial and smooth muscle cells after administration of MGO. The expression of PDGF-BB mRNA and protein decreased significantly after exposure to MGO, while the expression of VEGF mRNA increased (both P < 0.01). The expression of PDGF-R beta mRNA in cultured smooth muscle cells did not change after administration of MGO, although the expression of VEGF mRNA increased (P < 0.01). We also evaluated the associations between the number of capillary vessels, peritoneal function, and the degree of MGO deposition using peritoneum samples collected from patients undergoing PD. The number of immature capillary vessels was significantly associated with peritoneal dysfunction and the degree of MGO accumulation (both P < 0.01). In conclusion, MGO enhances the production of VEGF and suppresses the production of PDGF-BB, potentially leading to disturbance of angiogenesis in the peritoneal membrane. Accumulation of MGO in the peritoneum may cause immature angiogenesis and peritoneal dysfunction. (C) 2020 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2020.02.048

Language：English  

A 61-year-old man was hospitalized for creating vascular access for maintenance hemodialysis. Chronic interstitial nephritis was the cause of his end-stage kidney disease. An arteriovenous graft (AVG) was selected because superficial veins in his bilateral upper limbs were not suitable for arteriovenous fistula (AVF). Venography did not show any stenotic lesions in the drainage veins bilaterally. Soon after creation of the AVG, his left arm began to swell. Obstruction of the drainage vessels downstream of the AVG was highly suspected. Magnetic resonance imaging disclosed that the left brachiocephalic vein was compressed at the junction of the superior vena cava by a mediastinal cystic tumor. This tumor was 15 mm in diameter and was tentatively diagnosed as a bronchogenic cyst. While initiating hemodialysis using the AVG, the patient's body weight was decreased by the extracorporeal ultrafiltration method, followed by amelioration of swelling in the left arm. Because the swelling and pain of his left upper limb gradually subsided, we finally decided not to close the AVG and continued hemodialysis using the left AVG. He is currently on maintenance hemodialysis for 3 months with a slightly swollen left upper limb. Central venous obstruction or compression is one of the major causes of ipsilateral limb swelling in patients on hemodialysis. Central venous stenosis caused by previous central catheter insertion is often involved. Our case emphasizes the importance of searching for potential anatomical obstruction of drainage vessels by mediastinal tumors as a potential cause of venous hypertension in hemodialysis patients.

DOI： 10.1007/s13730-019-00433-0

Language：English   Publishing type：Research paper (scientific journal)  

BackgroundPatients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis.MethodsIn total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC.ResultsAVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism (serum calcium, serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23), AVC was significantly associated with the presence of CAP [odds ratio (OR), 3.37; 95% confidence interval (CI), 1.43-7.95], the presence of PAD (OR, 1.76; 95% CI, 1.10-2.81), the CAP score (per 1.0-point increase) (OR, 1.06; 95% CI, 1.02-1.11), and the ankle-brachial blood pressure index (per 0.1-point increase) (OR, 0.83; 95% CI, 0.72-0.95).ConclusionsAVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors.

DOI： 10.1186/s12882-020-01864-z

Language：English   Publishing type：Research paper (scientific journal)  

Bilirubin is recognized as an endogenous antioxidant, and low serum bilirubin is reported to be associated with the progression of kidney disease. However, it is unclear whether serum bilirubin levels are associated with the loss of residual kidney function (RKF) in peritoneal dialysis (PD) patients. This study investigated the relationship between serum total bilirubin and loss of RKF. We prospectively followed 94 PD patients who started PD in our hospital between June 2006 and May 2016. Ten patients who had chronic liver disease or cirrhosis were excluded. Patients were divided into three groups based on serum total bilirubin concentration tertiles: tertile 1 (T1) < 0.3, T2 = 0.3, and T3 ≥ 0.4 mg/dL. We estimated the relationship between serum bilirubin and loss of RKF, defined as daily urine volume (<100 mL) within 3 years after starting PD, using a Cox proportional hazards model. During the 3-year observation period, 22 patients lost RKF. The incidence rate of loss of RKF increased linearly with the decrease in serum total bilirubin levels (P for trend < 0.05). After adjusting for confounding factors, low serum total bilirubin level was shown to be an independent predictor of loss of RKF (hazard ratio [HR] for every 0.1 mg/dL decrease, 1.50; 95% confidence interval [CI], 1.01–2.51; HR [95%CI] for T2 and T1 [vs. T3] 2.03 [0.65–7.88] and 3.70 [1.00–15.9]). This study suggests that low serum total bilirubin levels are associated with the loss of RKF in PD patients.

DOI： 10.1111/1744-9987.12865

Language：English   Publishing type：Research paper (scientific journal)  

Although hypercalcemia is a risk factor for all-cause mortality in hemodialysis patients, it remains unknown whether hypercalcemia increases the risk of infection-related death. A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective cohort study of hemodialysis patients, were analyzed. The predictor was albumin-corrected serum calcium level at baseline. The main outcome was infection-related death. Death risk were estimated by multivariable-adjusted Cox proportional hazard risk models and competing risk models. During the follow-up period of 4 years, 107 patients died of infection and 473 died of any cause. The patients were divided into four groups by the serum calcium level at baseline (G1, 5.7-8.9mg/dL; G2, 9.0-9.4mg/dL; G3, 9.5-9.9mg/L; G4 10.0-16.5mg/dL). In the multivariable-adjusted model, the incidence of infection-related death was significantly higher in the highest serum calcium group (G4) compared with the lowest serum calcium group (G1): hazard ratio [95% confidence interval], 2.34 [1.35-4.04], P=0.002. Furthermore, higher serum calcium level was significantly associated with increased risk of all-cause death. In conclusion, our data suggest that a higher serum calcium level may be a risk factor for infection-related and all-cause death in hemodialysis patients.

DOI： 10.1038/s41598-020-63334-8

Language：English   Publishing type：Research paper (scientific journal)  

The geriatric nutritional risk index (GNRI) and creatinine (Cr) index are indexes often used as nutritional surrogates in patients receiving hemodialysis. However, few studies have directly compared the clinical characteristics of these two indexes. We investigated 3,536 hemodialysis patients enrolled in the Japan DOPPS phases 4 and 5. The primary outcome was all-cause mortality and the main exposures were the GNRI and Cr index. We confirmed and compared the association between these indexes and mortality risk as estimated by a multivariable-adjusted Cox proportional hazards model. During the median 2.2-year follow-up period, 414 patients died of any cause. In the multivariable-adjusted model, lower GNRI and Cr index were both associated with increased risk of all-cause mortality, and these associations were further confirmed by restricted cubic spline curves. The predictability of all-cause mortality, as represented by the c-statistic, was comparable between the two indexes. Furthermore, baseline nutritional surrogates that corresponded with lower GNRI or Cr index values were comparable between the two indexes. Given that calculating the GNRI is simpler than calculating the Cr index, our data suggest that the GNRI may be preferable to the Cr index for predicting clinical outcomes in patients undergoing maintenance hemodialysis.

DOI： 10.1038/s41598-020-62720-6

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Background Renin-angiotensin system blockers (RASBs) reduce end-stage kidney disease and cardiovascular event (CVE) development in chronic kidney disease. However, whether RASBs improve long-term prognosis in kidney transplant (KT) recipients remain unknown. Method We investigated 900 kidney transplant patients in a multicenter retrospective cohort study in Japan and compared death-censored graft survival and CVE (total, cardiac events, stroke) based on RASB use within 12 months after KT. The associations were examined using a Cox hazard model and propensity score-matching analysis. Results The cohort comprised 375 patients treated with RASBs (RASB group) and 525 patients without RASBs (control group). The median observational period was 82 months, with 68 patients reaching graft loss: 79 total CVE, 36 cardiac events, 26 stroke. In a matching cohort comprising 582 patients, death-censored graft survival, total CVE, and cardiac events were not different between the two groups. Only stroke incidence rate was significantly lower in the RASB group compared with the control group (1.4 vs. 6.4 per 1000 patients/year, log-ranked P = 0.005). In a multivariable analysis, stroke events were also significantly lower in the RASB group compared with the control group (Hazard ratio and 95% confidence interval, 0.20 [0.04-0.62]). Conclusion Thus, RASBs potentially reduce stroke events in KT recipients.

DOI： 10.1007/s10157-019-01827-1

Language：English  

DOI： 10.1111/1744-9987.13396

Language：English   Publishing type：Research paper (scientific journal)  

Bilirubin is recognized as an endogenous antioxidant, and low serum bilirubin is reported to be associated with the progression of kidney disease. However, it is unclear whether serum bilirubin levels are associated with the loss of residual kidney function (RKF) in peritoneal dialysis (PD) patients. This study investigated the relationship between serum total bilirubin and loss of RKF. We prospectively followed 94 PD patients who started PD in our hospital between June 2006 and May 2016. Ten patients who had chronic liver disease or cirrhosis were excluded. Patients were divided into three groups based on serum total bilirubin concentration tertiles: tertile 1 (T1) < 0.3, T2 = 0.3, and T3 >= 0.4 mg/dL. We estimated the relationship between serum bilirubin and loss of RKF, defined as daily urine volume (<100 mL) within 3 years after starting PD, using a Cox proportional hazards model. During the 3-year observation period, 22 patients lost RKF. The incidence rate of loss of RKF increased linearly with the decrease in serum total bilirubin levels (P for trend < 0.05). After adjusting for confounding factors, low serum total bilirubin level was shown to be an independent predictor of loss of RKF (hazard ratio [HR] for every 0.1 mg/dL decrease, 1.50; 95% confidence interval [CI], 1.01-2.51; HR [95%CI] for T2 and T1 [vs. T3] 2.03 [0.65-7.88] and 3.70 [1.00-15.9]). This study suggests that low serum total bilirubin levels are associated with the loss of RKF in PD patients.

DOI： 10.1111/1744-9987.12865

Language：English   Publishing type：Research paper (scientific journal)  

Background: Renin–angiotensin system blockers (RASBs) reduce end-stage kidney disease and cardiovascular event (CVE) development in chronic kidney disease. However, whether RASBs improve long-term prognosis in kidney transplant (KT) recipients remain unknown. Method: We investigated 900 kidney transplant patients in a multicenter retrospective cohort study in Japan and compared death-censored graft survival and CVE (total, cardiac events, stroke) based on RASB use within 12 months after KT. The associations were examined using a Cox hazard model and propensity score-matching analysis. Results: The cohort comprised 375 patients treated with RASBs (RASB group) and 525 patients without RASBs (control group). The median observational period was 82 months, with 68 patients reaching graft loss: 79 total CVE, 36 cardiac events, 26 stroke. In a matching cohort comprising 582 patients, death-censored graft survival, total CVE, and cardiac events were not different between the two groups. Only stroke incidence rate was significantly lower in the RASB group compared with the control group (1.4 vs. 6.4 per 1000 patients/year, log-ranked P = 0.005). In a multivariable analysis, stroke events were also significantly lower in the RASB group compared with the control group (Hazard ratio and 95% confidence interval, 0.20 [0.04–0.62]). Conclusion: Thus, RASBs potentially reduce stroke events in KT recipients.

DOI： 10.1007/s10157-019-01827-1

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Vascular access intervention therapy (VAIVT) is necessary to maintain vascular access in patients undergoing hemodialysis. VAIVT-associated vasodilatation is painful. However, few reports have focused on effective pain relief at the time of VAIVT. The present study was performed to determine whether lidocaine-propitocain cream, a eutectic mixture of local anesthetics (EMLA), effectively reduces VAIVT-associated pain in patients undergoing hemodialysis. This placebo-controlled, double-blind, crossover study was conducted in a single center. Among 210 patients who underwent a total of 437 VAIVT procedures from August 2017 to June 2018, 30 patients were randomly allocated to either the EMLA–placebo arm or placebo–EMLA arm at the time of VAIVT. EMLA application significantly reduced the visual analog scale score compared with placebo (47.0 ± 21.1 vs. 68.6 ± 20.7 mm, respectively; P < 0.05). EMLA is a safe and effective treatment for relief of VAIVT-associated pain in patients undergoing hemodialysis.

DOI： 10.1111/1744-9987.12813

Language：English   Publishing type：Research paper (scientific journal)  

Topoisomerase II (TOP2) resolves topologically entwined duplex DNA. It generates a transient DNA double-strand break intermediate, known as TOP2 cleavage complex (TOP2cc) that contains a covalent link between TOP2 and the 5?-terminus of the incised DNA duplex. Etoposide, a frontline anticancer drug, freezes the intermediate and forms irreversible TOP2ccs. Tyrosyl-DNA phosphodiesterase 2 (TDP2) is thought to repair irreversible TOP2ccs by hydrolyzing the phosphodiester bond between TOP2 and DNA after the proteasomal degradation of trapped TOP2ccs. However, the functional cooperation between TOP2 and proteasome in the repair of trapped TOP2ccs in vivo remains unknown. In this study, we analyze the repair of etoposide-induced TOP2ccs in wild-type and TDP2-deficient (TDP2(?/?)) TK6 cells in the absence and presence of MG132, a potent proteasome inhibitor. The results suggested that TOP2ccs were repaired by proteasome-dependent and proteasome-independent pathways. Both proteasome-dependent and proteasome-independent pathways were further subdivided into TDP2-dependent and TDP2-independent pathways, indicating that four pathways operate in the repair of TOP2ccs. In cell survival assays, MG132 increased the etoposide sensitivity of TDP2(?/?) cells, supporting the TDP2-independent and proteasome-dependent pathway among these multiple repair pathways. We also demonstrated that TDP2 released TOP2 from DNA that contained etoposide-induced TOP2cc without proteolytic degradation in vitro. Taken together, the present findings uncover novel proteasome-independent mechanisms for the repair of TOP2ccs.

DOI： 10.1080/15257770.2019.1674332

Language：English  

DOI： 10.1007/s13730-019-00418-z

Language：English   Publishing type：Research paper (scientific journal)  

Preserving residual kidney function (RKF) is important in the management of patients on peritoneal dialysis. However, few studies have examined the association between serum albumin level and the risk of RKF loss. We prospectively recruited 104 patients who began peritoneal dialysis treatment at our hospital between 2006 and 2016. The primary outcome was complete RKF loss, defined as urine volume < 100 mL/day. Serum albumin level at baseline was the main exposure. During a median observation period of 24 months, 33 patients developed RKF loss. A Cox proportional hazards model showed that hypoalbuminemia was associated with an increased risk of RKF, even after adjustments for potential confounding factors. Multivariable-adjusted linear regression analysis also showed that hypoalbuminemia was associated with greater rates of decline in 24-h urine volume and in renal Kt/V urea. Our findings suggest that hypoalbuminemia is associated with an increased risk of RKF loss in patients with peritoneal dialysis.

DOI： 10.1111/1744-9987.12861

Language：English   Publishing type：Research paper (scientific journal)  

Vascular access intervention therapy (VAIVT) is necessary to maintain vascular access in patients undergoing hemodialysis. VAIVT-associated vasodilatation is painful. However, few reports have focused on effective pain relief at the time of VAIVT. The present study was performed to determine whether lidocaine-propitocain cream, a eutectic mixture of local anesthetics (EMLA), effectively reduces VAIVT-associated pain in patients undergoing hemodialysis. This placebo-controlled, double-blind, crossover study was conducted in a single center. Among 210 patients who underwent a total of 437 VAIVT procedures from August 2017 to June 2018, 30 patients were randomly allocated to either the EMLA-placebo arm or placebo-EMLA arm at the time of VAIVT. EMLA application significantly reduced the visual analog scale score compared with placebo (47.0 +/- 21.1 vs. 68.6 +/- 20.7 mm, respectively; P < 0.05). EMLA is a safe and effective treatment for relief of VAIVT-associated pain in patients undergoing hemodialysis.

DOI： 10.1111/1744-9987.12813

Language：English   Publishing type：Research paper (scientific journal)  

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a small vessel vasculitis characterized by hypocomplementemia and urticaria-like exanthema. Some cases also display abdominal pain and membranoproliferative glomerulonephritis (MPGN) with immune complex deposits. We treated a case of HUVS with biopsy-proven gastrointestinal vasculitis and atypical histological findings in a kidney biopsy. The 36-year-old Japanese man, who was previously diagnosed with diffuse panbronchiolitis, visited our hospital due to transient urticaria-like exanthema and rapid deterioration of kidney function. On admission, the skin lesion was found to be only pigmentation, showing no vasculitis by skin biopsy. In laboratory findings, renal dysfunction with hematuria and proteinuria and hypocomplementemia were observed. Gastrointestinal vasculitis was proven by endoscopy and biopsy of the mucosa. Kidney biopsy revealed MPGN with crescents. No immune complex deposits were observed by immunofluorescence or electron microscopy. Additional examination revealed high titers of anti-C1q antibody. The patient was diagnosed with HUVS and treated with corticosteroids and plasma exchange. Although renal function and gastrointestinal vasculitis partially improved, infectious pneumonia frequently recurred. His renal dysfunction began to progress again and reached end-stage kidney disease. This is the first case of HUVS with biopsy-proven gastrointestinal vasculitis and MPGN without immune complex deposits. Notably, in some case of HUVS, anti-C1q antibody may activate the alternative complement pathway without immune complex deposits, resulting in renal injury.

DOI： 10.1007/s13730-019-00421-4

Language：English  

A 54-year-old man was admitted to our hospital with a painful left axillary mass. He had a 27-year history of hemodialysis for end-stage kidney disease because of chronic glomerulonephritis. He had a right radial artery-cephalic vein arteriovenous fistula and left nonfunctioning arteriovenous fistula. Computed tomography imaging showed a left axillary arterial mass with peripheral hematoma and multiple lung tumors. On hospital day 3, he showed disturbances in consciousness as well as enlargement of the axillary mass and hematoma. We performed emergency surgery to resect the left axillary tumor. The patient was diagnosed with angiosarcoma upon histopathological examination of the resected specimen on hospital day 15. Because his condition was extremely poor, we provided supportive care to him, not chemotherapy. He expired on hospital day 25. Angiosarcoma remains a rare disease; however, this case highlights the importance of including angiosarcoma in the differential diagnosis for upper extremity pain in patients undergoing hemodialysis.

DOI： 10.1007/s13730-019-00422-3

Language：English  

Peripheral artery disease (PAD) or arteriosclerosis obliterans is a lethal complication highly prevalent in pre-dialysis CKD and dialyzed patients. PAD is driven by atherosclerotic process and causes ischemia of the affected limb. Given that normal bone metabolism is based on sufficient blood supply and PAD decreases intraosseous blood flow of the affected limb, it is probable that PAD can directly cause ischemic osteopathy or osteoporosis in affected limbs. We herein present a 69-year-old female patient receiving 18 years of maintenance hemodialysis therapy was hospitalized for the treatment of bilateral PAD. Angiography showed a diffuse stenosis of the right superficial femoral artery and total occlusion of the left superficial femoral artery. Right ankle brachial index (ABI) was 0.83, whereas left ABI was unmeasurable. Notably, T score of the bone mineral density (BMD) in the right calcaneus measured by quantitative ultrasound was - 1.4, while that in the left calcaneus was - 2.2, showing a huge difference between BMD in the bilateral calcaneus. Metal stent was inserted to the right superficial femoral artery, whereas femoropopliteal bypass surgery was performed for the left limb. After the surgery, her right and left ABI were 0.96 and 0.92, respectively. Our case typically showed the clinical significance of sufficient blood supply to the bone for the normal bone metabolism and reminds us of the potential need to conduct further research on the association between PAD and ischemic osteopathy in patients with CKD.

DOI： 10.1007/s13730-019-00425-0

Language：English   Publishing type：Research paper (scientific journal)  

Preserving residual kidney function (RKF) is important in the management of patients on peritoneal dialysis. However, few studies have examined the association between serum albumin level and the risk of RKF loss. We prospectively recruited 104 patients who began peritoneal dialysis treatment at our hospital between 2006 and 2016. The primary outcome was complete RKF loss, defined as urine volume < 100 mL/day. Serum albumin level at baseline was the main exposure. During a median observation period of 24 months, 33 patients developed RKF loss. A Cox proportional hazards model showed that hypoalbuminemia was associated with an increased risk of RKF, even after adjustments for potential confounding factors. Multivariable-adjusted linear regression analysis also showed that hypoalbuminemia was associated with greater rates of decline in 24-h urine volume and in renal Kt/V urea. Our findings suggest that hypoalbuminemia is associated with an increased risk of RKF loss in patients with peritoneal dialysis.

DOI： 10.1111/1744-9987.12861

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr concentration, and Kt/V for urea, is an indicator of skeletal muscle mass in hemodialysis (HD) patients. It remains unknown whether the modified Cr index predicts infection-related mortality in this population. We investigated the association between the modified Cr index and infection-related mortality. A total of 3046 patients registered in the Q-Cohort Study, a multicenter, observational study of HD patients, were analyzed. Associations between sex-specific quartiles (Q1-Q4) of the modified Cr index and the risk for infection-related mortality were analyzed by Cox proportional hazard model. During a median follow-up of 8.8 years, 387 patients died of infection. The estimated risk for infection-related mortality was significantly higher in the lower quartiles (Q1, Q2, and Q3) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals [CI]: Q1, 2.89 [1.70-5.06], Q2, 2.76 [1.72-4.62], and Q3, 1.79 [1.12-2.99]). The hazard ratio (95% CI) for a 1mg/kg/day decrease in the modified Cr index was 1.18 (1.09-1.27, P<0.01) for infection-related mortality. In conclusion, a lower modified Cr index is associated with an increased risk for long-term infection-related mortality in the HD population.

DOI： 10.1038/s41598-020-58181-6

Language：English   Publishing type：Research paper (scientific journal)  

Background:Deposition of advanced glycation end products (AGEs) is frequently found in the peritoneum of patients on peritoneal dialysis (PD). Angiogenesis is also observed in the peritoneum. However, the clinical significance of AGEs and angiogenesis in the peritoneum is not fully understood. We evaluated the maturation of capillary vessels and investigated whether AGEs are associated with angiogenesis and peritoneal function in the peritoneal membrane.Methods:Peritoneum obtained when PD catheters were removed from 61 patients with PD was analyzed. The peritoneum was immunohistochemically stained with anti-CD34 (for endothelial cells), anti-alpha smooth muscle actin (alpha SMA) (for pericytes), and anti-AGE antibodies. We defined CD34-positive and alpha SMA-negative vessels as immature capillary vessels in peritoneal membranes using serial sections. We evaluated the associations between vessel density, peritoneal function (dialysate-to-plasma ratio for creatinine (D/P creatinine)), and the degree of AGE deposition.Results:AGE accumulation in the interstitium was positively associated with the duration of PD (p < 0.01). AGE accumulation in the interstitium and vascular wall was positively correlated with the use of acidic solution (p < 0.05) and the maximum value of D/P creatinine (p < 0.05). AGE accumulation in the vascular wall was significantly associated with immature capillary density (CD34+/alpha SMA-) in the peritoneum (p < 0.01). Vessel density was not significantly correlated with the last measurement of D/P creatinine (p = 0.126, r = 0.202), However, immature capillary density was positively correlated with the last measurement of D/P creatinine (p < 0.05, r = 0.278).Conclusions:AGE accumulation is significantly associated with immature angiogenesis and peritoneal dysfunction in patients undergoing PD.

DOI： 10.1177/0896860819878344

Language：English   Publishing type：Research paper (scientific journal)  

Background: Several large population-based studies have demonstrated that urinary salt excretion (USALT) is associated with albuminuria. However, this relationship has not been assessed in a large cohort study of patients with chronic kidney disease (CKD). Thus, the present study aimed to elucidate whether USALT was independently associated with albuminuria in a large cohort of patients with CKD. Methods: This cross-sectional study was conducted in 4075 patients with CKD not on dialysis. USALT (g/day) was estimated from spot urine. Patients were divided into quartiles (Q1–Q4) according to estimated USALT. Multivariable regression models were used to determine whether USALT was independently related to urinary albumin-to-creatinine ratio (UACR) or the presence of macroalbuminuria. Results: In multivariable linear regression analyses, 1-g/day increment in USALT was significantly associated with log UACR [coefficient 0.098, 95% confidence interval (CI) 0.075–0.121]. In addition, compared with the first USALT quartile, the third and fourth quartiles exhibited significant associations with log UACR (Q3: coefficient 0.305, 95% CI 0.154–0.456; Q4: coefficient 0.601, 95% CI 0.447–0.756). Furthermore, multivariable logistic regression analyses showed that USALT (1-g/day increment) was significantly associated with the presence of macroalbuminuria [odds ratio (OR) 1.11, 95% CI 1.07–1.14]; the third and fourth USALT quartiles exhibited significantly greater risks of macroalbuminuria, compared with the first quartile (Q3: OR 1.33, 95% CI 1.09–1.62; Q4: OR 1.89, 95% CI 1.54–2.32). Conclusions: This significant association of USALT with UACR and macroalbuminuria suggests that higher USALT may cause increased albuminuria, thereby contributing to kidney disease progression.

DOI： 10.1007/s10157-020-01950-4

Language：English   Publishing type：Research paper (scientific journal)  

Aim: The incidence of sudden death and its risk factors in patients on hemodialysis remain unclear. This study aimed to clarify the incidence of sudden death and its risk factors in Japanese patients on hemodialysis. Methods: A total of 3505 patients on hemodialysis aged ≥ 18 years were followed for 10 years. Multivariate-adjusted hazard ratio (HR) with 95% confidence interval (95% CI) of each risk factor of sudden death were cal-culated using a Cox proportional hazards model. Results: During the 10-year follow-up, 1735 patients died, including 227 (13%) sudden deaths. The incidence rate of sudden death was 9.13 per 1000 person-years. In multivariable-adjusted Cox analysis, male sex (HR 1.67; 95% CI 1.20–2.33), age (HR 1.44; 95% CI 1.26–1.65 per 10-year higher), the presence of diabetes (HR 2.45; 95% CI 1.82–3.29), history of cardiovascular disease (HR 1.85; 95% CI 1.38–2.46), cardiothoracic ratio (HR 1.21; 95% CI 1.07–1.39 per 5% higher), serum C-reactive protein (HR 1.11; 95% CI 1.03–1.20 per 1-mg/dL higher), and serum phosphate (HR 1.15; 95% CI 1.03–1.30 per 1-mg/dL higher) were independent predictors of sudden death. A subgroup analysis stratified by sex or age showed that lower serum corrected calcium levels, not using vitamin D receptor activators in women, and a shorter dialysis session length in men or older people (≥ 65 years) increased the risk for sudden death. Conclusions: This study clarified the incidence of sudden death and its specific predictors in Japanese patients on hemodialysis.

DOI： 10.5551/jat.49833

Language：English   Publishing type：Research paper (scientific journal)  

Objective Uremic toxins are known risk factors for cancer in patients undergoing hemodialysis (HD). Although adequate removal of uremic toxins might reduce the cancer risk by improving subclinical uremia, the relationship between the dialysis dose and risk of cancer death in patients undergoing HD remains unclear. Methods In this prospective observational study, 3,450 patients undergoing HD were followed up for 4 years. The primary outcome was cancer death. Patients were divided into quartiles according to their baseline Kt/V levels. The association between the Kt/V levels and risk of cancer death was estimated using the Kaplan-Meier method and Cox proportional-hazards model. Results A total of 111 patients (3.2%) died from cancer during the 4-year observational period. The 4-year survival rate decreased linearly with decreasing Kt/V. The multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer death were 2.23 (95% CI, 1.13-4.56), 1.77 (0.88-3.63), and 1.89 (1.04-3.56) in quartile (Q)1, Q2, and Q3, respectively, compared with patients in the highest Kt/V category (Q4) (p for trend = 0.06). Every 0.1 increase in Kt/V was associated with a reduction of 8% in cancer death (HR 0.92, 95% CI, 0.85-0.99). Conclusion A lower dialysis dose might be associated with a higher risk of cancer death in patients undergoing HD. Kt/V is a simple indicator of dialysis dose used in clinical practice and might be a useful modifiable factor for predicting the risk of cancer death. Further basic and interventional studies are needed to confirm the apparent reduction in cancer death associated with increasing the dialysis dose.

DOI： 10.2169/internalmedicine.4027-19

Language：English   Publishing type：Research paper (scientific journal)  

Diagnostic criteria for chronic active T cell–mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P <.001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P <.001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

DOI： 10.1111/ajt.16093

Language：English   Publishing type：Research paper (scientific journal)  

HD patients have been reported to have a higher risk of restenosis after percutaneous coronary intervention (PCI). The aim of this study was to investigate the risk factors of coronary restenosis in HD patients. We enrolled 54 HD patients (mean age: 66.5 ± 10.1 years; 72.2% men; mean HD duration: 3.7 years), who received PCI and follow-up coronary angiography. Of the patients, 22 (40.7%) had restenosis within 3 to 12 months of PCI. Univariate logistic analysis showed low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, LDL-C, non-HDL-C, and history of major adverse cardiovascular events were significantly associated with coronary restenosis (OR]: 1.89, 1.27, 1.22, and 5.79, respectively). Multivariate analysis showed that LDL-C was significantly associated with coronary restenosis (OR: 1.43). These data suggest that LDL-C is an independent risk factor for coronary restenosis in HD patients undergoing PCI, and strict lipid management may be required.

DOI： 10.1111/1744-9987.13558

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1253/circj.CJ-66-0179

Language：English   Publishing type：Research paper (scientific journal)  

Background & aims: Normalized protein catabolic rate (nPCR) is used as a surrogate for daily dietary protein intake and nutritional status in patients receiving maintenance hemodialysis. It remains uncertain whether the nPCR level is associated with the incidence of bone fracture. Methods: A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective, observational study, were followed up for 4 years. The primary outcome was bone fracture at any site. The main exposure was the nPCR level at baseline. Patients were assigned to four groups based on their baseline nPCR levels (G1: <0.85, G2: 0.85≤, <0.95, G3: 0.95≤, <1.05 [reference], G4: ≥1.05 g/kg/day). We examined the relationship between the nPCR levels and the risk for bone fracture using Cox proportional hazards models. Results: During the follow-up period, 136 patients experienced bone fracture at any site. In the multivariable analyses, the risk for bone fracture was significantly higher in the lowest (G1) and highest (G4) nPCR groups than the reference (G3) group (hazard ratio [95% confidence intervals]: G1, 1.93 [1.04–3.58]; G2, 1.27 [0.67–2.40]; G3 1.00 (reference); G4, 2.21 [1.25–3.92]). The association remained almost unchanged, even when patients were divided into sex-specific nPCR quartiles, when analysis was limited to patients with a dialysis vintage ≥2 years, assumed to have lost residual kidney function, or when a competing risk model was applied. Conclusions: Our results suggest that both lower and higher nPCR levels are associated with an increased risk for bone fracture in hemodialysis patients.

DOI： 10.1016/j.clnu.2020.07.003

Language：English   Publishing type：Research paper (scientific journal)  

Background: Both chronic kidney disease and brain white matter hyperintensities (WMH) are known to be risk factors of dementia and mortality. Methods and Results: In 2012, 1,214 community-dwelling Japanese subjects aged ≥65 years underwent brain magnetic resonance imaging (MRI) scans and a comprehensive health examination. This study investigated associations of the urinary albumin: creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) with the WMH volume to intracranial volume (WMHV: ICV) ratio, and the association of the combination of UACR and the WMHV: ICV ratio with cognitive decline and mortality risk. The geometric mean of the WMHV: ICV ratio was 0.223% in the entire study population, and increased significantly with higher UACR levels after adjusting for potential confounding factors (0.213% for normoalbuminuria, 0.248% for microalbuminuria, and 0.332% for macroalbuminuria; Ptrend=0.01). In contrast, there was no clear association between eGFR and the WMHV: ICV ratio. Compared with subjects with normoalbuminuria and a smaller WMHV: ICV ratio (<0.257% [median]), subjects with albuminuria and a larger WMHV: ICV ratio (≥0.257%) had higher probabilities of cognitive decline at baseline and all-cause death during the follow-up. Conclusions: This study suggests that subjects with albuminuria have a greater risk of WMH enlargement and that the combination of albuminuria and WMH enlargement increases the risk of cognitive decline and all-cause mortality in an elderly Japanese population.

DOI： 10.1253/circj.CJ-19-1069

Language：English   Publishing type：Research paper (scientific journal)  

There has been limited data discussing the relationship between apparent treatment-resistant hypertension (ATRH) and cardiovascular disease risk in patients receiving maintenance hemodialysis. We analyzed data for 2999 hypertensive patients on maintenance hemodialysis. ATRH was defined as uncontrolled blood pressure despite the use of three or more classes of antihypertensive medications, or four or more classes of antihypertensive medications regardless of blood pressure level. We examined the relationships between ATRH and cardiovascular events using a Cox proportional hazards model. The proportion of participants with ATRH was 18.0% (539/2999). During follow-up (median: 106.6 months, interquartile range: 51.3–121.8 months), 931 patients experienced cardiovascular events including coronary heart disease (n = 424), hemorrhagic stroke (n = 158), ischemic stroke (n = 344), and peripheral arterial disease (n = 242). Compared with the non-ATRH group, the ATRH group showed a significant increased risk of developing cardiovascular disease (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.08–1.49), coronary heart disease (HR: 1.28; 95% CI: 1.01–1.62), ischemic stroke (HR: 1.31; 95% CI: 1.01–1.69), and peripheral arterial disease (HR: 1.42; 95% CI: 1.06–1.91) even after adjusting for potential confounders. This study demonstrated that ATRH was significantly associated with increased cardiovascular risk in hemodialysis patients.

DOI： 10.1038/s41598-018-37961-1

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Background Recently, living-donor kidney transplantation from marginal donors has been increasing. However, a simple prediction model for graft function including preoperative marginal factors is limited. Here, we developed and validated a new prediction model for graft function using preoperative marginal factors in living-donor kidney transplantation. Methods We retrospectively investigated 343 patients who underwent living-donor kidney transplantation at Kyushu University Hospital (derivation cohort). Low graft function was defined as an estimated glomerular filtration rate of < 45 mL/min/1.73 m(2) at 1 year. A prediction model was developed using a multivariable logistic regression model, and verified using data from 232 patients who underwent living-donor kidney transplantation at Tokyo Women's Medical University Hospital (validation cohort). Results In the derivation cohort, 89 patients (25.9%) had low graft function at 1 year. Donor age, donor-estimated glomerular filtration rate, donor hypertension, and donor/recipient body weight ratio were selected as predictive factors. This model demonstrated modest discrimination (c-statistic = 0.77) and calibration (Hosmer-Lemeshow test, P = 0.83). Furthermore, this model demonstrated good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test, P = 0.54) in the validation cohort. Furthermore, donor age, donor-estimated glomerular filtration rate, and donor hypertension were strongly associated with glomerulosclerosis and atherosclerotic vascular changes in the "zero-time" biopsy. Conclusions This model using four pre-operative variables will be a simple, but useful guide to estimate graft function at 1 year after kidney transplantation, especially in marginal donors, in the clinical setting.

DOI： 10.1007/s10157-019-01774-x

Language：English   Publishing type：Research paper (scientific journal)  

Background: Recently, living-donor kidney transplantation from marginal donors has been increasing. However, a simple prediction model for graft function including preoperative marginal factors is limited. Here, we developed and validated a new prediction model for graft function using preoperative marginal factors in living-donor kidney transplantation. Methods: We retrospectively investigated 343 patients who underwent living-donor kidney transplantation at Kyushu University Hospital (derivation cohort). Low graft function was defined as an estimated glomerular filtration rate of < 45 mL/min/1.73 m² at 1 year. A prediction model was developed using a multivariable logistic regression model, and verified using data from 232 patients who underwent living-donor kidney transplantation at Tokyo Women's Medical University Hospital (validation cohort). Results: In the derivation cohort, 89 patients (25.9%) had low graft function at 1 year. Donor age, donor-estimated glomerular filtration rate, donor hypertension, and donor/recipient body weight ratio were selected as predictive factors. This model demonstrated modest discrimination (c-statistic = 0.77) and calibration (Hosmer–Lemeshow test, P = 0.83). Furthermore, this model demonstrated good discrimination (c-statistic = 0.76) and calibration (Hosmer–Lemeshow test, P = 0.54) in the validation cohort. Furthermore, donor age, donor-estimated glomerular filtration rate, and donor hypertension were strongly associated with glomerulosclerosis and atherosclerotic vascular changes in the “zero-time” biopsy. Conclusions: This model using four pre-operative variables will be a simple, but useful guide to estimate graft function at 1 year after kidney transplantation, especially in marginal donors, in the clinical setting.

DOI： 10.1007/s10157-019-01774-x

Language：English   Publishing type：Research paper (scientific journal)  

Rationale & Objective: Evidence suggests that cardiac remodeling, including left ventricular hypertrophy and myocardial fibrosis, develops with progression of kidney disease. Few studies have examined cardiac pathology across a range of estimated glomerular filtration rates (eGFRs), which was the objective of this investigation. Study Design: Population-based cross-sectional study of deceased patients undergoing autopsy. Setting & Participants: 334 of 694 consecutive deceased patients undergoing autopsy with available cardiac tissue, with a prior health examination within 6 years and without a prior diagnosis of heart disease. Exposure: eGFR. Outcomes: The thickness of the left ventricular wall, sizes of cardiac cells, and percentages of fibrosis, estimated from pathology examination of autopsy samples. Analytical Approach: Generalized estimating equations. Results: Lower eGFRs were associated with greater left ventricular wall thickness. Deceased patients with eGFRs ≥ 60, 45 to 59, 30 to 44, and <30 mL/min/1.73 m² had left ventricular wall thicknesses of 9.1, 9.5, 9.8, and 10.3 mm, respectively (P for trend < 0.05). Lower eGFRs were also significantly associated with greater mean values of cardiac cell size in the left ventricular wall after adjusting for confounders: 15.3, 16.1, 16.4, and 17.4 μm for eGFRs ≥ 60, 45 to 59, 30 to 44, and <30 mL/min/1.73 m² (P for trend < 0.01). Patients with lower eGFRs had significantly higher multivariable-adjusted geometric mean values for fibrosis percentage in the left ventricular wall: 3.22%, 4.33%, 3.83%, and 6.14% for eGFRs ≥ 60, 45 to 59, 30 to 44, and <30 mL/min/1.73 m² (P for trend < 0.001). The negative association of eGFR with multivariable-adjusted mean values of cardiac cell width was stronger among patients with than those without anemia. Limitations: Cross-sectional study with a high proportion of elderly patients, no available information for severity or duration of hypertension and other cardiovascular risk factors, no information for medication use. Conclusions: These findings suggest that reduced eGFR is associated with cardiac hypertrophy and fibrosis of the left ventricle, cardiac cell enlargement, and cardiac fibrosis.

DOI： 10.1053/j.ajkd.2019.02.013

Language：English   Publishing type：Research paper (scientific journal)  

Rationale & Objective: The short- and long-term impact of conversion of dialysate calcium concentration from either 2.5 or 3.0 mEq/L to 2.75 mEq/L on mineral and bone metabolism remains unknown in hemodialysis patients.Study Design: Nonrandomized intervention study.Setting & Population: 12 hemodialysis patients treated at baseline with a 2.5-mEq/L dialysate calcium concentration and another 12 hemodialysis patients treated with a 3.0-mEq/L dialysate calcium concentration.Intervention: Use of 2.75-mEq/L dialysate calcium concentration.Outcomes: Changes in intradialytic calcium and phosphate clearance and changes in predialysis and intradialytic serum and ionized mineral and biochemical parameters over the 24 weeks following dialysate calcium conversion.Results: Conversion of dialysate calcium concentration from 2.5 to 2.75 mEq/L increased intradialytic calcium loading and serum total and ionized calcium levels, whereas conversion of dialysate calcium from 3.0 to 2.75 mEq/L decreased intradialytic calcium loading and serum total and ionized calcium levels. Dialysate calcium concentration conversion did not affect intradialytic serum parathyroid hormone level, intradialytic phosphate elimination, or predialysis serum calcium, phosphate, parathyroid hormone, and fibroblast growth factor 23 levels. Intradialytic calcium influx was determined by dialysate calcium concentration and predialysis serum calcium levels, whereas intradialytic phosphate elimination was determined by predialysis serum phosphate levels.Limitations: Small sample size and no control groups treated with 2.5- and 3.0-mEq/L dialysate calcium concentrations during the 24 weeks of the observation period.Conclusions: Conversion of dialysate calcium concentration from either 3.0 or 2.5 to 2.75 mEq/L results in expected changes in calcium loading based on predialysis calcium concentration. The dialysate calcium concentration should be personalized based on clinical factors.

DOI： 10.1016/j.xkme.2019.08.002

Language：English   Publishing type：Research paper (scientific journal)  

Background Phosphate level is a potent independent risk factor for cardiovascular disease and mortality in patients with chronic kidney disease. The association between hypophosphatemia and kidney function in kidney transplant patients is uncertain. Methods In total, 90 kidney transplant recipients were divided into two groups: one group of patients with hypophosphatemia and the other group without hypophosphatemia. The recipients with hypophosphatemia were identified as having less than or equal to the lowest quartile of serum phosphate levels at 1-, 3-, and 12-month post-transplant. The cumulative kidney survival rates were calculated for each group using the Kaplan-Meier method, and the adjusted hazard ratio (HR) was calculated using the Cox regression model. Results The mean age of patients was 47 years and the median follow-up period was 58 months. During the follow-up period, the following results were demonstrated in 90 transplant patients: graft loss (n = 6), mortality (n = 3). According to the Kaplan-Meier analysis results, the patients with hypophosphatemia demonstrated a significantly lower risk of 30% decline in eGFR compared to those without hypophosphatemia at 1- and 3-month post-transplant, but not at 12-month post-transplant. After adjusting for confounding factors, hypophosphatemia at 1- and 3-month post-transplant was an independent predictor of good kidney survival (HR 0.31, 95% CI 0.10-0.82 and HR 0.31, 95% CI 0.07-0.92, respectively). Conclusions Our findings suggest that hypophosphatemia during the first 3 months after kidney transplantation was associated with better kidney survival.

DOI： 10.1007/s10157-019-01756-z

Language：English   Publishing type：Research paper (scientific journal)  

Rationale & Objective: Evidence suggests that cardiac remodeling, including left ventricular hypertrophy and myocardial fibrosis, develops with progression of kidney disease. Few studies have examined cardiac pathology across a range of estimated glomerular filtration rates (eGFRs), which was the objective of this investigation.Study Design: Population-based cross-sectional study of deceased patients undergoing autopsy.Setting & Participants: 334 of 694 consecutive deceased patients undergoing autopsy with available cardiac tissue, with a prior health examination within 6 years and without a prior diagnosis of heart disease.Exposure: eGFR.Outcomes: The thickness of the left ventricular wall, sizes of cardiac cells, and percentages of fibrosis, estimated from pathology examination of autopsy samples.Analytical Approach: Generalized estimating equations.Results: Lower eGFRs were associated with greater left ventricular wall thickness. Deceased patients with eGFRs >= 60, 45 to 59, 30 to 44, and <30 mL/min/1.73 m(2) had left ventricular wall thicknesses of 9.1, 9.5, 9.8, and 10.3 mm, respectively (P for trend < 0.05). Lower eGFRs were also significantly associated with greater mean values of cardiac cell size in the left ventricular wall after adjusting for confounders: 15.3, 16.1, 16.4, and 17.4 mu m for eGFRs >= 60, 45 to 59, 30 to 44, and <30 mL/min/1.73 m(2) (P for trend < 0.01). Patients with lower eGFRs had significantly higher multivariable-adjusted geometric mean values for fibrosis percentage in the left ventricular wall: 3.22%, 4.33%, 3.83%, and 6.14% for eGFRs >= 60, 45 to 59, 30 to 44, and <30 mL/min/1.73 m(2) (P for trend < 0.001). The negative association of eGFR with multivariable-adjusted mean values of cardiac cell width was stronger among patients with than those without anemia.Limitations: Cross-sectional study with a high proportion of elderly patients, no available information for severity or duration of hypertension and other cardiovascular risk factors, no information for medication use.Conclusions: These findings suggest that reduced eGFR is associated with cardiac hypertrophy and fibrosis of the left ventricle, cardiac cell enlargement, and cardiac fibrosis.

DOI： 10.1053/j.ajkd.2019.02.013

Language：English   Publishing type：Research paper (scientific journal)  

Rationale & Objective: The short- and long-term impact of conversion of dialysate calcium concentration from either 2.5 or 3.0 mEq/L to 2.75 mEq/L on mineral and bone metabolism remains unknown in hemodialysis patients. Study Design: Nonrandomized intervention study. Setting & Population: 12 hemodialysis patients treated at baseline with a 2.5-mEq/L dialysate calcium concentration and another 12 hemodialysis patients treated with a 3.0-mEq/L dialysate calcium concentration. Intervention: Use of 2.75-mEq/L dialysate calcium concentration. Outcomes: Changes in intradialytic calcium and phosphate clearance and changes in predialysis and intradialytic serum and ionized mineral and biochemical parameters over the 24 weeks following dialysate calcium conversion. Results: Conversion of dialysate calcium concentration from 2.5 to 2.75 mEq/L increased intradialytic calcium loading and serum total and ionized calcium levels, whereas conversion of dialysate calcium from 3.0 to 2.75 mEq/L decreased intradialytic calcium loading and serum total and ionized calcium levels. Dialysate calcium concentration conversion did not affect intradialytic serum parathyroid hormone level, intradialytic phosphate elimination, or predialysis serum calcium, phosphate, parathyroid hormone, and fibroblast growth factor 23 levels. Intradialytic calcium influx was determined by dialysate calcium concentration and predialysis serum calcium levels, whereas intradialytic phosphate elimination was determined by predialysis serum phosphate levels. Limitations: Small sample size and no control groups treated with 2.5- and 3.0-mEq/L dialysate calcium concentrations during the 24 weeks of the observation period. Conclusions: Conversion of dialysate calcium concentration from either 3.0 or 2.5 to 2.75 mEq/L results in expected changes in calcium loading based on predialysis calcium concentration. The dialysate calcium concentration should be personalized based on clinical factors. Funding: None. Trial Registration: University Hospital Medical Information Network, www.umin.ac.jp/english/, R000040105, UMIN000035184.

DOI： 10.1016/j.xkme.2019.08.002

Language：English   Publishing type：Research paper (scientific journal)  

Background: Phosphate level is a potent independent risk factor for cardiovascular disease and mortality in patients with chronic kidney disease. The association between hypophosphatemia and kidney function in kidney transplant patients is uncertain. Methods: In total, 90 kidney transplant recipients were divided into two groups: one group of patients with hypophosphatemia and the other group without hypophosphatemia. The recipients with hypophosphatemia were identified as having less than or equal to the lowest quartile of serum phosphate levels at 1-, 3-, and 12-month post-transplant. The cumulative kidney survival rates were calculated for each group using the Kaplan–Meier method, and the adjusted hazard ratio (HR) was calculated using the Cox regression model. Results: The mean age of patients was 47 years and the median follow-up period was 58 months. During the follow-up period, the following results were demonstrated in 90 transplant patients: graft loss (n = 6), mortality (n = 3). According to the Kaplan–Meier analysis results, the patients with hypophosphatemia demonstrated a significantly lower risk of 30% decline in eGFR compared to those without hypophosphatemia at 1- and 3-month post-transplant, but not at 12-month post-transplant. After adjusting for confounding factors, hypophosphatemia at 1- and 3-month post-transplant was an independent predictor of good kidney survival (HR 0.31, 95% CI 0.10–0.82 and HR 0.31, 95% CI 0.07–0.92, respectively). Conclusions: Our findings suggest that hypophosphatemia during the first 3 months after kidney transplantation was associated with better kidney survival.

DOI： 10.1007/s10157-019-01756-z

Language：English   Publishing type：Research paper (scientific journal)  

Background. Graft biopsy is the gold standard for diagnosis of BK polyomavirus-associated nephropathy (BKPyVAN), and polymerase chain reaction is the most specific screening technique. Development of a noninvasive, cost-effective marker for BKPyVAN is important.Methods. We reviewed 492 adult kidney transplant patients. We investigated peripheral blood lymphocyte (PBL) count and urinary cytology at graft biopsy in patients with BKVPyAN (n = 21), acute T-cell-mediated rejection (n = 79), and no evidence of acute rejection (n = 149). We performed univariate and multivariate logistic regression and receiver operating characteristics analyses to compare the test performance of PBL count, urinary cytology, and their combination for diagnosis of BKPyVAN.Results. The PBL count at biopsy was significantly lower in the BKPyVAN group than the acute T-cell-mediated rejection and no acute rejection groups (959 +/- 290/mu AL, 1433 +/- 673/mu L, and 1531 +/- 549/mu L, respectively; P < .01). The PBL count was 959 +/- 290/mu L at diagnosis of BKPyVAN and increased to 1123 +/- 377/mu L, 1238 +/- 419/mu L, and 1292 +/- 491/mu L at 1, 2, and 3 months after treatment, respectively (P <.05). On univariate analysis, the area under the curve was significantly higher for the combined model than for PBL and cytology alone (0.930, 0.797, and 0.875, respectively; P <.01). The improved test performance in the combined model remained significant after multivariate adjustment (0.972, 0.844, and 0.928, respectively; P <.01).Conclusions. Decreased PBL count was found in BKPyVAN, and the predictive performance of the combination of PBL count and urinary cytology was significantly enhanced for diagnosis of BKPyVAN.

DOI： 10.1016/j.transproceed.2019.01.129

Language：English   Publishing type：Research paper (scientific journal)  

Background: Graft biopsy is the gold standard for diagnosis of BK polyomavirus–associated nephropathy (BKPyVAN), and polymerase chain reaction is the most specific screening technique. Development of a noninvasive, cost-effective marker for BKPyVAN is important. Methods: We reviewed 492 adult kidney transplant patients. We investigated peripheral blood lymphocyte (PBL)count and urinary cytology at graft biopsy in patients with BKVPyAN (n = 21), acute T-cell–mediated rejection (n = 79), and no evidence of acute rejection (n = 149). We performed univariate and multivariate logistic regression and receiver operating characteristics analyses to compare the test performance of PBL count, urinary cytology, and their combination for diagnosis of BKPyVAN. Results: The PBL count at biopsy was significantly lower in the BKPyVAN group than the acute T-cell–mediated rejection and no acute rejection groups (959 ± 290/μL, 1433 ± 673/μL, and 1531 ± 549/μL, respectively; P <.01). The PBL count was 959 ± 290/μL at diagnosis of BKPyVAN and increased to 1123 ± 377/μL, 1238 ± 419/μL, and 1292 ± 491/μL at 1, 2, and 3 months after treatment, respectively (P <.05). On univariate analysis, the area under the curve was significantly higher for the combined model than for PBL and cytology alone (0.930, 0.797, and 0.875, respectively; P <.01). The improved test performance in the combined model remained significant after multivariate adjustment (0.972, 0.844, and 0.928, respectively; P <.01). Conclusions: Decreased PBL count was found in BKPyVAN, and the predictive performance of the combination of PBL count and urinary cytology was significantly enhanced for diagnosis of BKPyVAN.

DOI： 10.1016/j.transproceed.2019.01.129

Language：English   Publishing type：Research paper (scientific journal)  

A 57-year-old woman with pre-dialysis chronic kidney disease (CKD) was hospitalized because of fever and fatigue. On admission, increased inflammatory response and pyuria with bacteriuria were observed. Pyelonephritis was successfully treated with antibiotics, whereas her fatigue continued and she developed progressive hypercalcemia and hyponatremia; serum sodium level, 116 mEq/L and corrected serum calcium level, 13.4 mg/dL. Plasma concentrations of adrenocorticotropic hormone and cortisol and serum luteinizing hormone were under the detection level. Although the reaction of other anterior pituitary hormones and the serum antidiuretic hormone (ADH) was preserved, the response of serum luteinizing hormone to administration of luteinizing hormone releasing hormone was impaired. Magnetic resonance imaging showed no structural abnormality in the thalamus, hypothalamus, and pituitary gland. She was diagnosed with adrenal insufficiency caused by partial hypopituitarism in concomitant with pyelonephritis. After starting hydrocortisone replacement, serum levels of sodium and calcium were rapidly normalized. This case highlights the importance of adrenal insufficiency as a differential diagnosis of hypercalcemia in patients with pre-dialysis CKD, especially when hyponatremia was concomitantly observed. Besides, infection should be considered as an important trigger for the development of latent adrenal insufficiency since it could increase the physiological demand of corticosteroid in the body. Also, CKD may enhance the magnitude of hypercalcemia since CKD patients have decreased capacity to increase urinary calcium excretion.

DOI： 10.1007/s13730-018-0371-9

Language：English   Publishing type：Research paper (scientific journal)  

Some peritoneal dialysis (PD)-related peritonitis cases are thought to be caused by the pathogens in the oral cavity; however, the relationship between peritonitis and oral hygiene habits is unclear. In this study, we retrospectively examined the relationship between oral hygiene habits and peritonitis in patients who agreed to a questionnaire survey. Of the 75 patients, 37 patients developed PD-related peritonitis during the observation period. Peritonitis-free survival was significantly higher in patients who spent more time on oral hygiene daily and in patients who replaced their toothbrush more frequently (P < 0.05). According to multivariable analysis, increased daily oral hygiene duration and more frequent toothbrush replacement were associated with a significantly (P < 0.01) lower risk for peritonitis (hazard ratio [HR] 0.37 [95% CI, 0.18–0.77] and HR 0.35 [95% CI, 0.17–0.70], respectively). In conclusion, PD patients with superior oral hygiene habits showed a lower risk for PD-related peritonitis.

DOI： 10.1111/1744-9987.12757

Language：English  

BackgroundThe safety of kidney transplantation (KT) for end-stage kidney disease (ESKD) after haematopoietic stem cell transplantation (HSCT) for haematological disease has not been investigated thoroughly.MethodsIn this retrospective multicentre study, we investigated the clinical courses of six ESKD patients that received KT after HSCT for various haematological diseases. Data for six such patients were obtained from three institutions in our consortium.ResultsTwo patients with chronic myeloid leukaemia, one with refractory aplastic anaemia and another one with acute lymphocytic leukaemia received bone marrow transplantation. One patients with acute lymphocytic leukaemia received umbilical cord blood transplantation, and one with mantle cell lymphoma received peripheral blood stem cell transplantation. The patients developed ESKD at a median of 133 months after HSCT. Two patients who received KT and HSCT from the same donor were temporarily treated with immunosuppressive drugs. The other patients received KT and HSCT from different donors and were treated with antibody induction using our standard regimens. For one patient with ABO-incompatible transplantation, we added rituximab, splenectomy, and plasmapheresis. In the observational period at a median of 51 months after KT, only one patient experienced acute T-cell-mediated rejection. Four patients underwent hospitalization because of infection and fully recovered. No patient experienced recurrence of their original haematological disease. All patients survived throughout the observational periods, and graft functions were preserved.ConclusionsDespite the high infection frequency, survival rates and graft functions were extremely good in patients compared with previous studies. Therefore, current management contributed to favourable outcomes of these patients.

DOI： 10.1007/s10157-018-1672-1

Language：English   Publishing type：Research paper (scientific journal)  

Background: Blood urea nitrogen (BUN) is one of the substances that affects the calculated serum osmolality (cSosm). A previous study demonstrated that BUN and cSosm were independently associated with the development of chronic kidney disease (CKD) in patients with preserved kidney function. In advanced CKD stages, there is a concomitant increase in cSosm and BUN levels. However, it remains unclear whether BUN or cSosm levels are related to renal outcomes in patients with moderate to severe kidney dysfunction. The aim of this study was to clarify whether the BUN or cSosm level is associated with kidney disease progression in patients with advanced CKD.Methods: In this prospective study, we enrolled 459 patients with CKD (stages 3-5). The composite renal endpoint was end-stage renal disease (ESRD) or death, and ESRD alone was added as an alternative outcome. A Cox proportional hazards model was utilized to determine the risk factors for a poor renal outcome. We adjusted for covariates including estimated glomerular filtration rate (eGFR). The cSosm (mOsm/kg) was calculated using the following formula: (2 x sodium) + (BUN/2.8) + (glucose/18).Results: During a median follow-up of 25.8 months, the renal endpoint was observed in 210 patients. Multivariable Cox analysis determined the hazard ratio (HR) [95% confidence interval (CI)] for the composite renal outcome in the second, third, and fourth BUN quartiles were 1.36 (0.72-2.58), 1.87 (0.95-3.66), and 2.66 (1.23-5.76) (P for trend < 0.01), respectively compared with the first BUN quartile. Conversely, by multivariable Cox analysis, the HRs (95% CIs) for poor outcomes in the second, third, and fourth cSosm quartiles, compared with the first cSosm quartile, were 1.13 (0.69-1.87), 0.95 (0.58-1.55), and 1.26 (0.78-2.03), respectively (P for trend = 0.39). In addition, with regard to the renal outcome of ESRD alone, higher BUN quartiles had a significantly increased risk for the outcome, but cSosm levels were not associated with the outcome.Conclusions: Higher BUN levels, but not cSosm levels, were associated with adverse renal outcomes independent of the eGFR, suggesting that BUN may be a useful marker for predicting kidney disease progression.

DOI： 10.1186/s12882-019-1306-1

Language：English   Publishing type：Research paper (scientific journal)  

Some peritoneal dialysis (PD)-related peritonitis cases are thought to be caused by the pathogens in the oral cavity; however, the relationship between peritonitis and oral hygiene habits is unclear. In this study, we retrospectively examined the relationship between oral hygiene habits and peritonitis in patients who agreed to a questionnaire survey. Of the 75 patients, 37 patients developed PD-related peritonitis during the observation period. Peritonitis-free survival was significantly higher in patients who spent more time on oral hygiene daily and in patients who replaced their toothbrush more frequently (P < 0.05). According to multivariable analysis, increased daily oral hygiene duration and more frequent toothbrush replacement were associated with a significantly (P < 0.01) lower risk for peritonitis (hazard ratio [HR] 0.37 [95% CI, 0.18-0.77] and HR 0.35 [95% CI, 0.17-0.70], respectively). In conclusion, PD patients with superior oral hygiene habits showed a lower risk for PD-related peritonitis.

DOI： 10.1111/1744-9987.12757

Language：English   Publishing type：Research paper (scientific journal)  

Background: The safety of kidney transplantation (KT) for end-stage kidney disease (ESKD) after haematopoietic stem cell transplantation (HSCT) for haematological disease has not been investigated thoroughly. Methods: In this retrospective multicentre study, we investigated the clinical courses of six ESKD patients that received KT after HSCT for various haematological diseases. Data for six such patients were obtained from three institutions in our consortium. Results: Two patients with chronic myeloid leukaemia, one with refractory aplastic anaemia and another one with acute lymphocytic leukaemia received bone marrow transplantation. One patients with acute lymphocytic leukaemia received umbilical cord blood transplantation, and one with mantle cell lymphoma received peripheral blood stem cell transplantation. The patients developed ESKD at a median of 133 months after HSCT. Two patients who received KT and HSCT from the same donor were temporarily treated with immunosuppressive drugs. The other patients received KT and HSCT from different donors and were treated with antibody induction using our standard regimens. For one patient with ABO-incompatible transplantation, we added rituximab, splenectomy, and plasmapheresis. In the observational period at a median of 51 months after KT, only one patient experienced acute T-cell-mediated rejection. Four patients underwent hospitalization because of infection and fully recovered. No patient experienced recurrence of their original haematological disease. All patients survived throughout the observational periods, and graft functions were preserved. Conclusions: Despite the high infection frequency, survival rates and graft functions were extremely good in patients compared with previous studies. Therefore, current management contributed to favourable outcomes of these patients.

DOI： 10.1007/s10157-018-1672-1

Language：English   Publishing type：Research paper (scientific journal)  

Background: Blood urea nitrogen (BUN) is one of the substances that affects the calculated serum osmolality (cSosm). A previous study demonstrated that BUN and cSosm were independently associated with the development of chronic kidney disease (CKD) in patients with preserved kidney function. In advanced CKD stages, there is a concomitant increase in cSosm and BUN levels. However, it remains unclear whether BUN or cSosm levels are related to renal outcomes in patients with moderate to severe kidney dysfunction. The aim of this study was to clarify whether the BUN or cSosm level is associated with kidney disease progression in patients with advanced CKD. Methods: In this prospective study, we enrolled 459 patients with CKD (stages 3-5). The composite renal endpoint was end-stage renal disease (ESRD) or death, and ESRD alone was added as an alternative outcome. A Cox proportional hazards model was utilized to determine the risk factors for a poor renal outcome. We adjusted for covariates including estimated glomerular filtration rate (eGFR). The cSosm (mOsm/kg) was calculated using the following formula: (2 × sodium) + (BUN/2.8) + (glucose/18). Results: During a median follow-up of 25.8 months, the renal endpoint was observed in 210 patients. Multivariable Cox analysis determined the hazard ratio (HR) [95% confidence interval (CI)] for the composite renal outcome in the second, third, and fourth BUN quartiles were 1.36 (0.72-2.58), 1.87 (0.95-3.66), and 2.66 (1.23-5.76) (P for trend < 0.01), respectively compared with the first BUN quartile. Conversely, by multivariable Cox analysis, the HRs (95% CIs) for poor outcomes in the second, third, and fourth cSosm quartiles, compared with the first cSosm quartile, were 1.13 (0.69-1.87), 0.95 (0.58-1.55), and 1.26 (0.78-2.03), respectively (P for trend = 0.39). In addition, with regard to the renal outcome of ESRD alone, higher BUN quartiles had a significantly increased risk for the outcome, but cSosm levels were not associated with the outcome. Conclusions: Higher BUN levels, but not cSosm levels, were associated with adverse renal outcomes independent of the eGFR, suggesting that BUN may be a useful marker for predicting kidney disease progression.

DOI： 10.1186/s12882-019-1306-1

Language：English   Publishing type：Research paper (scientific journal)  

Background Assessment of infection-related mortality remains inadequate in patients undergoing peritoneal dialysis. This study was performed to develop a risk model for predicting the 2-year infection-related mortality risk in patients undergoing peritoneal dialysis. Methods The study cohort comprised 606 patients who started and continued peritoneal dialysis for 90 at least days and was drawn from the Fukuoka Peritoneal Dialysis Database Registry Study in Japan. The patients were registered from 1 January 2006 to 31 December 2016 and followed up until 31 December 2017. To generate a prediction rule, the score for each variable was weighted by the regression coefficients calculated using a Cox proportional hazard model adjusted by risk factors for infection-related mortality, including patient characteristics, comorbidities, and laboratory data. Results During the follow-up period (median, 2.2 years), 138 patients died; 58 of them of infectious disease. The final model for infection-related mortality comprises six factors: age, sex, serum albumin, serum creatinine, total cholesterol, and weekly renal Kt/V. The incidence of infection-related mortality increased linearly with increasing total risk score (P for trend <0.001). Furthermore, the prediction model showed adequate discrimination (c-statistic = 0.79 [0.72–0.86]) and calibration (Hosmer–Lemeshow test, P = 0.47). Conclusion In this study, we developed a new model using clinical measures for predicting infection-related mortality in patients undergoing peritoneal dialysis.

DOI： 10.1371/journal.pone.0213922

Language：English   Publishing type：Research paper (scientific journal)  

BackgroundAcute kidney injury (AKI) is one of the most severe complications after cardiothoracic surgery (CTS). However, diagnosis of AKI by elevation of serum creatinine (SCr) misses a critical time period for prevention and treatment of AKI. We have observed that patients who develop AKI show a smaller SCr decrease after CTS than those without AKI. Hence, we hypothesized that the magnitude of the SCr change (SCr) measured early after CTS can predict subsequent AKI.MethodsWe conducted a retrospective analysis from January 2014 to December 2016 to examine the association of SCr with AKI. SCr was calculated as follows: (early postoperative SCr on intensive care unit [ICU] admission) - (preoperative SCr). Established risk factors and demographics were included in the multivariate-adjusted logistic regression model. AKI was defined by SCr criteria of the Kidney Disease: Improving Global Outcomes group.ResultsAmong 252 patients who underwent CTS, 69 developed AKI. The median SCr was -0.14mg/dL (range -0.96-0.45). Patients were divided into three groups based on SCr: Group 1, -0.2mg/dL (n=84); Group 2, >-0.2 to <-0.1mg/dL (n=76); and Group 3, -0.1mg/dL (n=92). In the multivariate analysis, Group 3 had a significantly higher incidence of AKI than Group 1 (odds ratio, 7.34; 95% confidence interval 2.55-23.3). SCr was an independent risk factor for AKI (odds ratio for every 0.1-mg/dL increase in SCr, 1.55; 95% confidence interval 1.23-1.97).ConclusionsA minor change in the SCr level early after CTS can predict subsequent AKI just after ICU admission.

DOI： 10.1007/s10157-018-1638-3

Language：English   Publishing type：Research paper (scientific journal)  

BackgroundAssessment of infection-related mortality remains inadequate in patients undergoing peritoneal dialysis. This study was performed to develop a risk model for predicting the 2-year infection-related mortality risk in patients undergoing peritoneal dialysis.MethodsThe study cohort comprised 606 patients who started and continued peritoneal dialysis for 90 at least days and was drawn from the Fukuoka Peritoneal Dialysis Database Registry Study in Japan. The patients were registered from 1 January 2006 to 31 December 2016 and followed up until 31 December 2017. To generate a prediction rule, the score for each variable was weighted by the regression coefficients calculated using a Cox proportional hazard model adjusted by risk factors for infection-related mortality, including patient characteristics, comorbidities, and laboratory data.ResultsDuring the follow-up period (median, 2.2 years), 138 patients died; 58 of them of infectious disease. The final model for infection-related mortality comprises six factors: age, sex, serum albumin, serum creatinine, total cholesterol, and weekly renal Kt/V. The incidence of infection-related mortality increased linearly with increasing total risk score (P for trend < 0.001). Furthermore, the prediction model showed adequate discrimination (c-statistic = 0.79 [ 0.72-0.86]) and calibration (Hosmer-Lemeshow test, P = 0.47).ConclusionIn this study, we developed a new model using clinical measures for predicting infection-related mortality in patients undergoing peritoneal dialysis.

DOI： 10.1371/journal.pone.0213922

Language：English  

DOI： 10.1007/s10157-018-1671-2

Language：English   Publishing type：Research paper (scientific journal)  

Background: Acute kidney injury (AKI) is one of the most severe complications after cardiothoracic surgery (CTS). However, diagnosis of AKI by elevation of serum creatinine (SCr) misses a critical time period for prevention and treatment of AKI. We have observed that patients who develop AKI show a smaller SCr decrease after CTS than those without AKI. Hence, we hypothesized that the magnitude of the SCr change (ΔSCr) measured early after CTS can predict subsequent AKI. Methods: We conducted a retrospective analysis from January 2014 to December 2016 to examine the association of ΔSCr with AKI. ΔSCr was calculated as follows: (early postoperative SCr on intensive care unit [ICU] admission) − (preoperative SCr). Established risk factors and demographics were included in the multivariate-adjusted logistic regression model. AKI was defined by SCr criteria of the Kidney Disease: Improving Global Outcomes group. Results: Among 252 patients who underwent CTS, 69 developed AKI. The median ΔSCr was − 0.14 mg/dL (range − 0.96–0.45). Patients were divided into three groups based on ΔSCr: Group 1, ≤ − 0.2 mg/dL (n = 84); Group 2, > − 0.2 to < − 0.1 mg/dL (n = 76); and Group 3, ≥ − 0.1 mg/dL (n = 92). In the multivariate analysis, Group 3 had a significantly higher incidence of AKI than Group 1 (odds ratio, 7.34; 95% confidence interval 2.55–23.3). ΔSCr was an independent risk factor for AKI (odds ratio for every 0.1-mg/dL increase in ΔSCr, 1.55; 95% confidence interval 1.23–1.97). Conclusions: A minor change in the SCr level early after CTS can predict subsequent AKI just after ICU admission.

DOI： 10.1007/s10157-018-1638-3

Language：English   Publishing type：Research paper (scientific journal)  

Background & aims: The geriatric nutritional risk index (GNRI) is a simple but useful nutritional marker for all-cause mortality and cardiovascular mortality in patients undergoing hemodialysis (HD). However, whether the GNRI can predict infection-related mortality in patients undergoing HD remains unclear, and there is insufficient evidence regarding whether the GNRI improves the predictive value for risk assessment beyond the existing conventional nutritional markers. Here, we investigated the association between the GNRI and infection-related mortality in patients undergoing HD and evaluated the predictive value of GNRI. Methods: A prospective cohort study was performed on a total of 3436 Japanese HD patients aged ≥18 years. Patients were divided into four groups by quartiles of GNRI: (Quartile 1 [Q1], >100.2; Q2, 95.9–100.2; Q3, 90.8–95.8; Q4, <90.8). We estimated the relationship between GNRI and all-cause mortality and infection-related mortality using a Cox proportional hazards model. To assess the additional predictive value of the GNRI in risk assessment, we compared the c-statistic, net reclassification improvement, and integrated discrimination improvement among serum albumin, serum creatinine, and the GNRI. Results: During follow-up period (median, 4.0 years), a total of 564 patients died; 120 of these patients died of infectious disease. All-cause mortality and infection-related mortality increased linearly with lower GNRI levels. After adjusting for confounding risk factors, the GNRI was an independent predictor of infection-related mortality as well as all-cause mortality (hazard ratio [HR], 5.89; 95% confidence interval [CI], 2.85–13.8; P < 0.001 for Q4 vs. Q1, HR, 2.62; 95% CI, 1.23–6.24; P = 0.01 for Q3 vs. Q1). Additionally, when the GNRI was incorporated into a model with potential risk factors instead of serum albumin, the c-statistic increased significantly (0.811 vs. 0.821, P = 0.03), and the net reclassification improvement and integrated discrimination improvement was 0.26 (P = 0.005) and 0.005 (P = 0.01). This association was more apparent in the older patients (0.739 vs. 0.760, P = 0.02) than in the younger patients (0.916 vs. 0.912, P = 0.35). Similar results were observed between serum creatinine and the GNRI, but the difference did not reach statistical significance. Conclusions: Lower GNRI levels are an independent risk factor for infection-related mortality in patients undergoing HD. Moreover, addition of the GNRI to models with standard risk factors significantly improves the predictive ability of infection-related mortality, especially in older patients.

DOI： 10.1016/j.clnu.2018.01.019

Language：English   Publishing type：Research paper (scientific journal)  

Thrombotic microangiopathy (TMA) develops from various etiologies, and it is often difficult to distinguish the etiology of TMA in kidney transplantation. Antiphospholipid syndrome (APS) is one of the differential diagnoses for TMA that may cause acute loss of graft function or fatal thrombotic complications. This report details a 66-year-old male patient with polycythemia after ABO-incompatible kidney transplantation. Antibody screening tests were negative before transplant. Despite administration of an adequate desensitization therapy including plasmapheresis and rituximab, he developed acute graft dysfunction on postoperative day 112 and graft biopsy revealed prominent microvascular inflammation in the glomerular capillaries without immunoglobulin deposits. Flow cytometric panel-reactive antibody screening failed to detect donor-specific antibodies at both pre-transplant and episode biopsies. Anticardiolipin antibody was repeatedly positive, but neither thrombosis nor previous thrombotic episodes were detected. After excluding several differential diagnoses, the graft dysfunction with unexplained TMA was treated with steroid pulse, plasmapheresis and rituximab re-induction. Anticardiolipin antibody disappeared after this intensive treatment and graft function recovered gradually and stabilized for 52months. This report suggests that asymptomatic anticardiolipin antibody may be associated with acute graft dysfunction. Even if thrombotic episodes are not observed, an exist of anticardiolipin antibody may be one of the risk factors of renal TMA after kidney transplantation.

DOI： 10.1007/s13730-018-0354-x

Language：English   Publishing type：Research paper (scientific journal)  

Background & aims: The geriatric nutritional risk index (GNRI) is a simple but useful nutritional marker for all-cause mortality and cardiovascular mortality in patients undergoing hemodialysis (HD). However, whether the GNRI can predict infection-related mortality in patients undergoing HD remains unclear, and there is insufficient evidence regarding whether the GNRI improves the predictive value for risk assessment beyond the existing conventional nutritional markers. Here, we investigated the association between the GNRI and infection-related mortality in patients undergoing HD and evaluated the predictive value of GNRI.Methods: A prospective cohort study was performed on a total of 3436 Japanese HD patients aged >= 18 years. Patients were divided into four groups by quartiles of GNRI: (Quartile 1 [Q1], >100.2; Q2, 95.9 -100.2; Q3, 90.8-95.8; Q4, <90.8). We estimated the relationship between GNRI and all-cause mortality and infection-related mortality using a Cox proportional hazards model. To assess the additional predictive value of the GNRI in risk assessment, we compared the c-statistic, net reclassification improvement, and integrated discrimination improvement among serum albumin, serum creatinine, and the GNRI.Results: During follow-up period (median, 4.0 years), a total of 564 patients died; 120 of these patients died of infectious disease. All-cause mortality and infection-related mortality increased linearly with lower GNRI levels. After adjusting for confounding risk factors, the GNRI was an independent predictor of infection-related mortality as well as all-cause mortality (hazard ratio [HR], 5.89; 95% confidence interval [Cl], 2.85-13.8; P < 0.001 for Q4 vs. Q1, HR, 2.62; 95% CI, 1.23-6.24; P = 0.01 for Q3 vs. Q1). Additionally, when the GNRI was incorporated into a model with potential risk factors instead of serum albumin, the c-statistic increased significantly (0.811 vs. 0.821, P = 0.03), and the net reclassification improvement and integrated discrimination improvement was 0.26 (P = 0.005) and 0.005 (P = 0.01). This association was more apparent in the older patients (0.739 vs. 0.760, P = 0.02) than in the younger patients (0.916 vs. 0.912, P = 0.35). Similar results were observed between serum creatinine and the GNRI, but the difference did not reach statistical significance.Conclusions: Lower GNRI levels are an independent risk factor for infection-related mortality in patients undergoing HD. Moreover, addition of the GNRI to models with standard risk factors significantly improves the predictive ability of infection-related mortality, especially in older patients. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

DOI： 10.1016/j.clnu.2018.01.019

Language：English   Publishing type：Research paper (scientific journal)  

Background: Several studies have shown that the neutrophil/lymphocyte ratio (NLR) is a marker that reflects the state of systemic inflammation. A high NLR was reported to be associated with cardiovascular events and mortality. However, little is known about the association between NLR and kidney disease progression in patients with chronic kidney disease (CKD). Therefore, the aim of the present study was to determine whether NLR is associated with renal outcomes in CKD patients. Methods: This prospective observational study included 350 consecutive patients with stage 1–4 CKD treated between June 2009 and November 2016. Data were collected until June 2017. The endpoint was the composite of end-stage renal disease requiring dialysis or death. Subjects were divided into two groups according to high and low NLR levels. A Cox proportional hazards model was used to determine the risk factors for composite outcomes. Results: The composite endpoint was observed in 83 patients during the median follow-up period of 31.8 months: 29 in the low NLR group and 54 in the high NLR group. Multivariable analysis showed that the high NLR group had a significant increase in the hazard ratio (HR) for composite outcomes (HR 1.67, 95% confidence interval 1.02–2.77) compared with the low NLR group. Conclusion: The present study demonstrated that a high NLR was associated with poor renal outcomes, suggesting that NLR may be a useful marker for prognostic prediction in patients with CKD.

DOI： 10.1080/0886022X.2019.1595645

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent cardiovascular risk factor in CKD. We explored the potential impact of indoxyl sulfate on proinflammatory activation of macrophages and its underlying mechanisms.METHODS: We examined in vitro the effects of clinically relevant concentrations of indoxyl sulfate on proinflammatory responses of macrophages and the roles of organic anion transporters and organic anion transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics, bioinformatics, and network analysis, then explored potential key pathways. To address the role of Delta-like 4 (Dll4) in indoxyl sulfate-induced macrophage activation and atherogenesis in CKD in vivo, we used 5/6 nephrectomy and Dll4 antibody in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. To further determine the relative contribution of OATP2B1 or Dll4 to proinflammatory activation of macrophages and atherogenesis in vivo, we used siRNA delivered by macrophage-targeted lipid nanoparticles in mice.RESULTS: We found that indoxyl sulfate-induced proinflammatory macrophage activation is mediated by its uptake through transporters, including OATP2B1, encoded by the SLCO2B1 gene. The global proteomics identified potential mechanisms, including Notch signaling and the ubiquitin-proteasome pathway, that mediate indoxyl sulfate-triggered proinflammatory macrophage activation. We chose the Notch pathway as an example of key candidates for validation of our target discovery platform and for further mechanistic studies. As predicted computationally, indoxyl sulfate triggered Notch signaling, which was preceded by the rapid induction of Dll4 protein. Dll4 induction may result from inhibition of the ubiquitin-proteasome pathway, via the deubiquitinating enzyme USP5. In mice, macrophage-targeted OATP2B1/Slco2b1 silencing and Dll4 antibody inhibited proinflammatory activation of peritoneal macrophages induced by indoxyl sulfate. In low-density lipoprotein receptor-deficient mice, Dll4 antibody abolished atherosclerotic lesion development accelerated in Ldlr-/- mice. Moreover, coadministration of indoxyl sulfate and OATP2B1/Slco2b1 or Dll4 siRNA encapsulated in macrophage-targeted lipid nanoparticles in Ldlr-/- mice suppressed lesion development.CONCLUSIONS: These results suggest that novel crosstalk between OATP2B1 and Dll4-Notch signaling in macrophages mediates indoxyl sulfate-induced vascular inflammation in CKD.

DOI： 10.1161/CIRCULATIONAHA.118.034588

Language：English   Publishing type：Research paper (scientific journal)  

Background: Eldecalcitol (ELD) is an active vitamin D-3 analog that is widely used in Japan for the treatment of osteoporosis. The most common adverse drug reaction of ELD is hypercalcemia. However, few reports have focused on acute kidney injury (AKI) associated with ELD-induced hypercalcemia. Materials and methods: We retrospectively reviewed the medical records at our hospital for cases of hypercalcemia-induced AKI between April 2013 and February 2018. Among them, we focused on patients who developed AKI secondary to ELD-induced hypercalcemia. Results: Among 69 patients who developed hypercalcemia-induced AKI, 32 patients (46.4%) developed AKI associated with ELD-induced hypercalcemia. Their mean age was 82 +/- 5 years, 97% of them were female, mean corrected serum calcium level was 12.2 +/- 1.5 mg/dL, serum creatinine level was 2.5 +/- 2.2 mg/dL, and estimated glomerular filtration rate was 23.9 +/- 14.4 ml/min/1.73 m(2) on admission. ELD administration was discontinued in all patients and some of them were treated with hydration with or without calcitonin, which was followed by a normalization of serum calcium level. Corrected serum calcium level on admission was significantly higher (p < .05) in patients treated with magnesium oxide. Although there were no significant differences, serum calcium and creatine levels on admission tended to be higher in patients who were treated with other drugs that affect renal hemodynamics and renal calcium metabolism than those not taking these drugs. Conclusions: Prescribers of ELD should regularly monitor serum calcium levels and kidney function to prevent hypercalcemia and AKI associated with ELD and pay more attention to concomitant drugs especially magnesium oxide.

DOI： 10.1080/0886022X.2019.1578667

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Background: Several studies have shown that the neutrophil/lymphocyte ratio (NLR) is a marker that reflects the state of systemic inflammation. A high NLR was reported to be associated with cardiovascular events and mortality. However, little is known about the association between NLR and kidney disease progression in patients with chronic kidney disease (CKD). Therefore, the aim of the present study was to determine whether NLR is associated with renal outcomes in CKD patients. Methods: This prospective observational study included 350 consecutive patients with stage 1-4 CKD treated between June 2009 and November 2016. Data were collected until June 2017. The endpoint was the composite of end-stage renal disease requiring dialysis or death. Subjects were divided into two groups according to high and low NLR levels. A Cox proportional hazards model was used to determine the risk factors for composite outcomes. Results: The composite endpoint was observed in 83 patients during the median follow-up period of 31.8 months: 29 in the low NLR group and 54 in the high NLR group. Multivariable analysis showed that the high NLR group had a significant increase in the hazard ratio (HR) for composite outcomes (HR 1.67, 95% confidence interval 1.02-2.77) compared with the low NLR group. Conclusion: The present study demonstrated that a high NLR was associated with poor renal outcomes, suggesting that NLR may be a useful marker for prognostic prediction in patients with CKD.

DOI： 10.1080/0886022X.2019.1595645

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There has been limited data discussing the relationship between apparent treatment-resistant hypertension (ATRH) and cardiovascular disease risk in patients receiving maintenance hemodialysis. We analyzed data for 2999 hypertensive patients on maintenance hemodialysis. ATRH was defined as uncontrolled blood pressure despite the use of three or more classes of antihypertensive medications, or four or more classes of antihypertensive medications regardless of blood pressure level. We examined the relationships between ATRH and cardiovascular events using a Cox proportional hazards model. The proportion of participants with ATRH was 18.0% (539/2999). During follow-up (median: 106.6 months, interquartile range: 51.3-121.8 months), 931 patients experienced cardiovascular events including coronary heart disease (n = 424), hemorrhagic stroke (n = 158), ischemic stroke (n = 344), and peripheral arterial disease (n = 242). Compared with the non-ATRH group, the ATRH group showed a significant increased risk of developing cardiovascular disease (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.08-1.49), coronary heart disease (HR: 1.28; 95% CI: 1.01-1.62), ischemic stroke (HR: 1.31; 95% CI: 1.01-1.69), and peripheral arterial disease (HR: 1.42; 95% CI: 1.06-1.91) even after adjusting for potential confounders. This study demonstrated that ATRH was significantly associated with increased cardiovascular risk in hemodialysis patients.

DOI： 10.1038/s41598-018-37961-1

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The influence of pre-dialysis blood pressure (BP) on the prognosis of hemodialysis (HD) patients is still inconclusive. A total of 3436 HD patients were prospectively followed up for 4 years. The patients were divided into quintiles of pre-dialysis systolic BP (SBP) and diastolic BP (DBP) levels [mm Hg]: Quintile 1 (Q1), SBP <134, DBP <66; Q2, SBP 134 to 147, DBP 66 to 72; Q3, SBP 148 to 158, DBP 73 to 79; Q4, SBP 159 to 171, DBP 80 to 85; Q5, SBP ≥172, DBP ≥86. The association between the pre-dialysis BP and outcomes were examined using a Cox proportional hazards model. During a 4-year follow-up period, 564 (16.4%) patients died of any cause and 590 (17.2%) developed cardiovascular (CV) events. The lowest level of pre-dialysis SBP group (Q1) showed a significantly increased risk of all-cause mortality (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.40–2.39) and the highest group (Q5) significantly increased risk of CV events (HR 1.31, 95% CI 1.02–1.68) compared with the reference group (Q3), respectively. The highest level of pre-dialysis DBP group was significantly associated with increased risk for both all-cause mortality and CV events. Restricted cubic spline analysis for BP and outcomes suggested the optimal pre-dialysis BP value associated with the lowest risk of outcomes was SBP 152 mm Hg for all-cause mortality, SBP 143 mm Hg for CV events, and DBP 68 mm Hg for all-cause mortality. Our results suggested that pre-dialysis BP was independently associated with all-cause mortality and CV events among Japanese HD patients.

DOI： 10.1097/MD.0000000000013485

Language：English   Publishing type：Research paper (scientific journal)  

The influence of pre-dialysis blood pressure (BP) on the prognosis of hemodialysis (HD) patients is still inconclusive.A total of 3436 HD patients were prospectively followed up for 4 years. The patients were divided into quintiles of pre-dialysis systolic BP (SBP) and diastolic BP (DBP) levels [mm Hg]: Quintile 1 (Q1), SBP <134. DBP <66; 02, SBP 134 to 147. DBP 66 to 72; Q3, SBP 148 to 158, DBP 73 to 79; 04, SBP 159 to 171, DBP 80 to 85; Q5, SBP >= 172, DBP >= 86. The association between the pre-dialysis BP and outcomes were examined using a Cox proportional hazards model.During a 4-year follow-up period, 564 (16.4%) patients died of any cause and 590 (17.2%) developed cardiovascular (CV) events. The lowest level of pre-dialysis SBP group (Q1) showed a significantly increased risk of all-cause mortality (hazard ratio [HR] 1.83. 95% confidence interval [CI] 1.40-2.39) and the highest group (Q5) significantly increased risk of CV events (HR 1.31, 95% CI 1.02-1.68) compared with the reference group (Q3), respectively. The highest level of pre-dialysis DBP group was significantly associated with increased risk for both all-cause mortality and CV events. Restricted cubic spline analysis for BP and outcomes suggested the optimal pre-dialysis BP value associated with the lowest risk of outcomes was SBP 152 mm Hg for all-cause mortality, SBP 143 mm Hg for CV events, and DBP 68 mm Hg for all-cause mortality.Our results suggested that pre-dialysis BP was independently associated with all-cause mortality and CV events among Japanese HD patients.

DOI： 10.1097/MD.0000000000013485

Language：English   Publishing type：Research paper (scientific journal)  

A 40-year-old woman had been followed as an outpatient to manage chronic kidney disease secondary to autosomal dominant polycystic kidney disease (ADPKD). Atrial premature contraction was found incidentally on an electrocardiogram during her regular follow-up examination. Subsequent transthoracic echocardiography detected an abnormal structure located very close to the left ventricular outflow tract (23 mm long x 15 mm wide in diastole). The structure was finally diagnosed as congenital left ventricular diverticulum (CLVD) using transesophageal echocardiography, contrast-enhanced computed tomography, and magnetic resonance imaging. Although CLVD occasionally causes intraventricular coagulation, lethal arrhythmia, and congestive heart failure, the size and location of her diverticulum remained unchanged over time and a 24-h Holter electrocardiogram showed no lethal arrhythmias. Accordingly, neither anticoagulation therapy nor surgical resection of the diverticulum was performed. To the best of our knowledge, ours is the first case of CLVD in a patient with ADPKD. Because gene abnormalities in polycystin coding are mechanistically related to the development of colonic diverticulum and abnormal cyst formation in ADPKD patients, we suspected that CLVD and abnormal cyst formation were related to the same gene abnormality in ADPKD. More case reports, case series studies, and basic research are required to determine whether CLVD in ADPKD is mechanistically associated with abnormal polycystin or just a coincidence.

DOI： 10.1007/s13730-018-0335-0

Language：English  

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DOI： 10.1111/nep.13246

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Background and aims: The modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr levels, and Kt/V for urea, reflects skeletal muscle mass in patients on hemodialysis. Whether the modified Cr index is associated with cardiovascular events and all-cause mortality remains unknown. Methods: A total of 3027 patients registered in the Q-Cohort Study, a multicenter, prospective study of patients on hemodialysis in Japan, were analyzed. The main outcomes were cardiovascular events and all-cause mortality. Associations between sex-specific quartiles of the modified Cr index and outcomes were analyzed by the Cox proportional hazard models and the Fine–Gray proportional subdistribution hazards model. Results: The modified Cr index was correlated with known nutritional and inflammatory markers. During a 4-year follow-up, 499 patients died of any cause, 372 experienced heart disease, and 194 developed stroke. The risk for all-cause mortality was significantly higher in the lower quartiles (Q1 and Q2) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals: Q1, 2.65 [1.69–4.25], Q2, 1.92 [1.27–2.94], and Q3, 1.31 [0.87–2.02]). The risk of heart disease was significantly higher in Q1 than in Q4 (hazard ratios and 95% confidence intervals: Q1, 1.64 [1.04–2.61], Q2, 1.34 [0.91–2.00], and Q3, 1.04 [0.71–1.52]). The risk of stroke was not associated with the modified Cr index. Conclusions: A lower modified Cr index is associated with an increased risk for heart disease and all-cause mortality, but not with the risk for stroke in patients on hemodialysis.

DOI： 10.1016/j.atherosclerosis.2018.06.001

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Background and aims: The modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr levels, and Kt/V for urea, reflects skeletal muscle mass in patients on hemodialysis. Whether the modified Cr index is associated with cardiovascular events and all-cause mortality remains unknown.Methods: A total of 3027 patients registered in the Q-Cohort Study, a multicenter, prospective study of patients on hemodialysis in Japan, were analyzed. The main outcomes were cardiovascular events and all-cause mortality. Associations between sex-specific quartiles of the modified Cr index and outcomes were analyzed by the Cox proportional hazard models and the Fine-Gray proportional subdistribution hazards model.Results: The modified Cr index was correlated with known nutritional and inflammatory markers. During a 4-year follow-up, 499 patients died of any cause, 372 experienced heart disease, and 194 developed stroke. The risk for all-cause mortality was significantly higher in the lower quartiles (Q1 and Q2) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals: Q1, 2.65 [1.69-4.25], Q2, 1.92 [1.27-2.94], and Q3, 1.31 [0.87-2.02]). The risk of heart disease was significantly higher in Q1 than in Q4 (hazard ratios and 95% confidence intervals: Ql, 1.64 [1.04-2.61], Q2, 1.34 [0.91-2.00], and Q3, 1.04 [0.71-1.52]). The risk of stroke was not associated with the modified Cr index.Conclusions: A lower modified Cr index is associated with an increased risk for heart disease and all-cause mortality, but not with the risk for stroke in patients on hemodialysis. (C) 2018 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2018.06.001

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Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-β1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

DOI： 10.1038/labinvest.2017.77

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Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+ VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-beta 1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

DOI： 10.1038/labinvest.2017.77

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Background: Lymphangiogenesis occurs in diseased native kidneys and kidney allografts, and correlates with histological injury; however, the clinical significance of lymphatic vessels in kidney allografts is unclear. Methods: This study retrospectively reviewed 63 kidney transplant patients who underwent protocol biopsies. Lymphatic vessels were identified by immunohistochemical staining for podoplanin, and were classified according to their location as perivascular or interstitial lymphatic vessels. The associations between perivascular lymphatic density and kidney allograft function and pathological findings were analyzed. Results: There were no significant differences in perivascular lymphatic densities in kidney allograft biopsy specimens obtained at 0 h, 3 months and 12 months. The groups with higher perivascular lymphatic density showed a lower proportion of progression of interstitial fibrosis/tubular atrophy grade from 3 to 12 months (P for trend = 0.039). Perivascular lymphatic density was significantly associated with annual decline of estimated glomerular filtration rate after 12 months (r = −0.31, P = 0.017), even after adjusting for multiple confounders (standardized β = −0.30, P = 0.019). Conclusions: High perivascular lymphatic density is associated with favourable kidney allograft function. The perivascular lymphatic network may be involved in inhibition of allograft fibrosis and stabilization of graft function.

DOI： 10.1007/s10157-016-1338-9

Language：English   Publishing type：Research paper (scientific journal)  

Background Lymphangiogenesis occurs in diseased native kidneys and kidney allografts, and correlates with histological injury; however, the clinical significance of lymphatic vessels in kidney allografts is unclear.Methods This study retrospectively reviewed 63 kidney transplant patients who underwent protocol biopsies. Lymphatic vessels were identified by immunohistochemical staining for podoplanin, and were classified according to their location as perivascular or interstitial lymphatic vessels. The associations between perivascular lymphatic density and kidney allograft function and pathological findings were analyzed.Results There were no significant differences in perivascular lymphatic densities in kidney allograft biopsy specimens obtained at 0 h, 3 months and 12 months. The groups with higher perivascular lymphatic density showed a lower proportion of progression of interstitial fibrosis/tubular atrophy grade from 3 to 12 months P for trend = 0.039). Perivascular lymphatic density was significantly associated with annual decline of estimated glomerular filtration rate after 12 months r = -0.31, P = 0.017), even after adjusting for multiple confounders standardized beta = -0.30, P = 0.019).Conclusions High perivascular lymphatic density is associated with favourable kidney allograft function. The perivascular lymphatic network may be involved in inhibition of allograft fibrosis and stabilization of graft function.

DOI： 10.1007/s10157-016-1338-9

Language：English  

The Notch signaling pathway regulates the development of various cell types and organs, and also contributes to disease mechanisms in adults. Accumulating evidence suggests its role in cardiovascular and metabolic diseases. Notch signaling components also control the phenotype of immune cells. Delta-like ligand 4 (Dll4) of the Notch pathway promotes proinflammatory activation of macrophages in vitro and in vivo. Dll4 blockade attenuates chronic atherosclerosis, vein graft disease, vascular calcification, insulin resistance, and fatty liver in mice. The Dll4-Notch axis may, thus, participate in the shared mechanisms for cardiometabolic disorders, serving as a potential therapeutic target for ameliorating these global health problems.

DOI： 10.1161/ATVBAHA.116.306926

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 61-year-old woman, with a 25-year history of maintenance hemodialysis due to end-stage renal disease of unknown causes, was admitted because of systemic joint pain and inflammatory response of unknown etiology that persisted for 1 month. Laboratory data on admission revealed leukocytopenia, lymphocytopenia, high serum C-reactive protein, and positivity for antinuclear antibody (ANA) and anti-double strand DNA. After admission, she progressively developed cough and dyspnea. A chest radiograph revealed bilateral ground glass opacity and pleural effusion. A thoracentesis revealed lupus erythematosus cells, suggesting lupus pleuritis. A chest computed tomography showed a pattern of diffuse alveolar damage compatible with acute lupus pneumonitis. She fulfilled the American Rheumatism Association diagnostic criteria for systemic lupus erythematosus (SLE). Methylprednisolone pulse therapy followed by oral prednisone treatment improved the clinical symptoms and laboratory abnormalities. ANA was negative 25 years earlier when she first started hemodialysis and she had neither clinical nor serological abnormalities related to SLE during the last 25 years. Further, she had neither received drugs that can cause drug-induced SLE, nor had a history of ultraviolet ray exposure, pregnancy, blood transfusion, trauma and smoking. This report suggests that new-onset SLE can develop in patients undergoing long-term dialysis. Hence, when we encounter dialysis patients with arthralgia and/or respiratory disorders, we should consider the possibility of new-onset SLE.

DOI： 10.1007/s13730-014-0155-9

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Objective Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease.Approach and Results We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage- or endothelial cell (EC)-targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion development in low-density lipoprotein (LDL) receptor-deficient (Ldlr(-/-)) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation.Conclusions These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4-Notch axis as a novel therapeutic target.

DOI： 10.1161/ATVBAHA.115.305516

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Fibroblast growth factor (FGF) 23 plays an important role in regulation of renal phosphate excretion in patients with chronic kidney disease. However, it remains undetermined whether FGF23 is closely linked to renal phosphate handling in patients with low glomerular filtration rate (GFR). The present cross-sectional study included 52 outpatients undergoing peritoneal dialysis with urine volume≥100mL/day. The primary outcome was level of urinary phosphate excretion, and the secondary outcomes were tubular maximal reabsorption of phosphate normalized to GFR (TmP/GFR), an index of the renal threshold for phosphate excretion, and level of peritoneal phosphate excretion. Variates of interest were serum FGF23 and parathyroid hormone (PTH) levels. The median and interquartile range of serum FGF23 level, TmP/GFR, and total urinary and peritoneal phosphate excretion were 5610 (1493-11430) ng/mL, 1.30 (0.44-1.86) mg/dL, 117 (40-234) mg/day, and 208 (156-250) mg/day, respectively. Multivariate linear regression analysis revealed that serum FGF23 level was significantly (P<0.05) associated with TmP/GFR negatively and significantly (P<0.05) associated with urinary phosphate excretion positively, even after adjusting for confounders. In contrast, none of the three outcome variates was associated with serum PTH level. Neither serum FGF23 nor PTH level was associated with peritoneal phosphate excretion. The present study indicates that FGF23, but not PTH, is involved in urinary phosphate regulation, even in patients on peritoneal dialysis with residual renal function.

DOI： 10.1111/1744-9987.12221

Language：English   Publishing type：Research paper (scientific journal)  

Fibroblast growth factor (FGF) 23 plays an important role in regulation of renal phosphate excretion in patients with chronic kidney disease. However, it remains undetermined whether FGF23 is closely linked to renal phosphate handling in patients with low glomerular filtration rate (GFR). The present cross-sectional study included 52 outpatients undergoing peritoneal dialysis with urine volume100mL/day. The primary outcome was level of urinary phosphate excretion, and the secondary outcomes were tubular maximal reabsorption of phosphate normalized to GFR (TmP/GFR), an index of the renal threshold for phosphate excretion, and level of peritoneal phosphate excretion. Variates of interest were serum FGF23 and parathyroid hormone (PTH) levels. The median and interquartile range of serum FGF23 level, TmP/GFR, and total urinary and peritoneal phosphate excretion were 5610 (1493-11430) ng/mL, 1.30 (0.44-1.86) mg/dL, 117 (40-234) mg/day, and 208 (156-250) mg/day, respectively. Multivariate linear regression analysis revealed that serum FGF23 level was significantly (P<0.05) associated with TmP/GFR negatively and significantly (P<0.05) associated with urinary phosphate excretion positively, even after adjusting for confounders. In contrast, none of the three outcome variates was associated with serum PTH level. Neither serum FGF23 nor PTH level was associated with peritoneal phosphate excretion. The present study indicates that FGF23, but not PTH, is involved in urinary phosphate regulation, even in patients on peritoneal dialysis with residual renal function.

DOI： 10.1111/1744-9987.12221

Language：English   Publishing type：Research paper (scientific journal)  

It is unknown whether the use of diuretics is optimal over other antihypertensive agents in patients with chronic kidney disease (CKD) whose blood pressure remains uncontrolled despite treatment with renin-angiotensin system (RAS) inhibitors. In this study, we assessed the additive effects of hydrochlorothiazide (HCTZ) on reducing proteinuria in CKD patients under treatment with losartan (LS). We conducted a multicenter, open-labeled, randomized trial. One hundred and two CKD patients with hypertension and overt proteinuria were recruited from nine centers and randomly assigned to receive either LS (50 mg, n=51) or a combination of LS (50 mg per day) and HCTZ (12.5 mg per day) (LS/HCTZ, n=51). The primary outcome was a decrease in the urinary protein-to-creatinine ratio (UPCR). The target blood pressure was <130/80 mm Hg, and antihypertensive agents (other than RAS inhibitors and diuretics) were added if the target was not attained. Baseline characteristics of the two groups were similar. After 12 months of treatment, decreases in the UPCR were significantly greater in the LS/HCTZ group than in the LS group. There were no significant differences in blood pressure or the estimated glomerular filtration rate between the two groups. LS/HCTZ led to a greater reduction in proteinuria than treatment with LS, even though blood pressure in the LS group was similar to that in the LS/HCTZ group following the administration of additive antihypertensive agents throughout the observation period. This finding suggests that LS/HCTZ exerts renoprotective effects through a mechanism independent of blood pressure reduction.

DOI： 10.1038/hr.2014.110

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It is unknown whether the use of diuretics is optimal over other antihypertensive agents in patients with chronic kidney disease (CKD) whose blood pressure remains uncontrolled despite treatment with renin-angiotensin system (RAS) inhibitors. In this study, we assessed the additive effects of hydrochlorothiazide (HCTZ) on reducing proteinuria in CKD patients under treatment with losartan (LS). We conducted a multicenter, open-labeled, randomized trial. One hundred and two CKD patients with hypertension and overt proteinuria were recruited from nine centers and randomly assigned to receive either LS (50 mg, n = 51) or a combination of LS (50mg per day) and HCTZ (12.5 mg per day) (LS/HCTZ, n = 51). The primary outcome was a decrease in the urinary protein-to-creatinine ratio (UPCR). The target blood pressure was <130/80 mmHg, and antihypertensive agents (other than RAS inhibitors and diuretics) were added if the target was not attained. Baseline characteristics of the two groups were similar. After 12 months of treatment, decreases in the UPCR were significantly greater in the LS/HCTZ group than in the LS group. There were no significant differences in blood pressure or the estimated glomerular filtration rate between the two groups. LS/HCTZ led to a greater reduction in proteinuria than treatment with LS, even though blood pressure in the LS group was similar to that in the LS/HCTZ group following the administration of additive antihypertensive agents throughout the observation period. This finding suggests that LS/HCTZ exerts renoprotective effects through a mechanism independent of blood pressure reduction.

DOI： 10.1038/hr.2014.110

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Fibroblast growth factor 23 (FGF23) levels in dialysis patients are influenced by various factors, including phosphorus load. However, the clinical parameters that determine serum FGF23 levels in patients on peritoneal dialysis (PD) remain unclear. The aim of the present study was to examine the effects of clinical factors, on serum FGF23 levels, with an emphasis on residual renal function (RRF). This cross-sectional study included 56 outpatients undergoing PD therapy. Urine volume ≥100mL/day or renal creatinine (Cr) clearance was used as a surrogate marker for RRF. Clinical characteristics were compared between patients with and without RRF. Linear regression analysis was conducted with serum FGF23 level as the dependent variable and renal Cr clearance as the main independent variable. The median and interquartile range of serum FGF23 levels were 5970 (1451-11688) pg/mL. Patients with RRF showed higher urinary and total phosphate eliminations, and lower serum FGF23 and phosphate levels than patients without RRF. Multivariate linear regression analysis showed that the renal Cr clearance and serum phosphate and dialysis history were negatively associated with serum FGF23 levels, even after adjusting for potential confounders including peritoneal Cr clearance. Further, the predictabilities of serum FGF23 were comparable among renal Cr clearance, Kt/V for urea, and renal phosphate clearance. RRF determined by renal Cr clearance or residual urine volume is an independent negative determinant of serum FGF23 levels in PD patients.

DOI： 10.1111/1744-9987.12170

Language：English   Publishing type：Research paper (scientific journal)  

Fibroblast growth factor 23 (FGF23) levels in dialysis patients are influenced by various factors, including phosphorus load. However, the clinical parameters that determine serum FGF23 levels in patients on peritoneal dialysis (PD) remain unclear. The aim of the present study was to examine the effects of clinical factors, on serum FGF23 levels, with an emphasis on residual renal function (RRF). This cross-sectional study included 56 outpatients undergoing PD therapy. Urine volume 100mL/day or renal creatinine (Cr) clearance was used as a surrogate marker for RRF. Clinical characteristics were compared between patients with and without RRF. Linear regression analysis was conducted with serum FGF23 level as the dependent variable and renal Cr clearance as the main independent variable. The median and interquartile range of serum FGF23 levels were 5970 (1451-11688) pg/mL. Patients with RRF showed higher urinary and total phosphate eliminations, and lower serum FGF23 and phosphate levels than patients without RRF. Multivariate linear regression analysis showed that the renal Cr clearance and serum phosphate and dialysis history were negatively associated with serum FGF23 levels, even after adjusting for potential confounders including peritoneal Cr clearance. Further, the predictabilities of serum FGF23 were comparable among renal Cr clearance, Kt/V for urea, and renal phosphate clearance. RRF determined by renal Cr clearance or residual urine volume is an independent negative determinant of serum FGF23 levels in PD patients.

DOI： 10.1111/1744-9987.12170

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Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of P_i overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary P_i loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different P_i concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary P_i concentration-dependent increases in serum and tissue levels of TNF-α and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by P_i overload. Regression analysis showed that serum P_ilevels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-P_i medium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary P_i overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of P_i loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.

DOI： 10.1152/ajprenal.00633.2013

Language：English   Publishing type：Research paper (scientific journal)  

Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of P-i overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary P-i loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different P-i concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary P-i concentration-dependent increases in serum and tissue levels of TNF-alpha and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by P-i overload. Regression analysis showed that serum P-i levels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-P-i medium directly increased the expression of TNF-alpha in advance of the increase in osteochondrogenic markers. Our data suggest that dietary P-i overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of P-i loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.

DOI： 10.1152/ajprenal.00633.2013

Language：English  

Language：English   Publishing type：Research paper (scientific journal)  

BackgroundChronic kidney disease (CKD) is frequently associated with uremic encephalopathy and cognitive impairment. Recent studies have demonstrated that cerebral oxidative stress contributes to cognitive dysfunction. Although oxidative stress has been reported to increase in the uremic rat brain, the relationship between increased oxidative stress and cognitive impairment in uremia is unclear. In the present study, the effects of tempol (TMP), an antioxidant drug, were investigated in uremic mice.MethodsCKD was induced in male C57BL/6 mice (n = 8) by left nephrectomy and 2/3 electrocoagulation of the right renal cortex. Working memory performance was tested by the radial arm water maze test. We have prepared two protocols ('time course study' and 'treatment study'). First, we examined the working memory test and histological examination of mouse brains after 4 and 8 weeks. Next, we investigated the effect of TMP (3 mM) against uremia-induced neurodegeneration and oxidative stress in the mouse brain.ResultsEight weeks after CKD induction, vehicle-treated mice made significantly more errors than sham-operated control mice, while TMP improved working memory performance in CKD mice. CKD was associated with accumulation of 8-hydroxy-2′-deoxyguanosine in the hippocampal neuronal cells, but not in TMP-treated CKD mice. Increased numbers of pyknotic neuronal cells were observed in the hippocampus of CKD mice at 8 weeks, but pyknotic neuronal cell numbers were decreased under the influence of TMP in uremic mice.ConclusionsThe present study provided evidence that uremia is associated with spatial working memory dysfunction in mice and that treatment with TMP protects against cerebral oxidative stress and improves cognitive dysfunction in uremic mice, suggesting their potential usefulness for the treatment of cognitive dysfunction in uremia.

DOI： 10.1093/ndt/gft327

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Background. Chronic kidney disease (CKD) is frequently associated with uremic encephalopathy and cognitive impairment. Recent studies have demonstrated that cerebral oxidative stress contributes to cognitive dysfunction. Although oxidative stress has been reported to increase in the uremic rat brain, the relationship between increased oxidative stress and cognitive impairment in uremia is unclear. In the present study, the effects of tempol (TMP), an antioxidant drug, were investigated in uremic mice.Methods. CKD was induced in male C57BL/6 mice (n = 8) by left nephrectomy and 2/3 electrocoagulation of the right renal cortex. Working memory performance was tested by the radial arm water maze test. We have prepared two protocols ('time course study' and 'treatment study'). First, we examined the working memory test and histological examination of mouse brains after 4 and 8 weeks. Next, we investigated the effect of TMP (3 mM) against uremia-induced neurodegeneration and oxidative stress in the mouse brain.Results. Eight weeks after CKD induction, vehicle-treated mice made significantly more errors than sham-operated control mice, while TMP improved working memory performance in CKD mice. CKD was associated with accumulation of 8-hydroxy-2'-deoxyguanosine in the hippocampal neuronal cells, but not in TMP-treated CKD mice. Increased numbers of pyknotic neuronal cells were observed in the hippocampus of CKD mice at 8 weeks, but pyknotic neuronal cell numbers were decreased under the influence of TMP in uremic mice.Conclusions. The present study provided evidence that uremia is associated with spatial working memory dysfunction in mice and that treatment with TMP protects against cerebral oxidative stress and improves cognitive dysfunction in uremic mice, suggesting their potential usefulness for the treatment of cognitive dysfunction in uremia.

DOI： 10.1093/ndt/gft327

Language：English   Publishing type：Research paper (scientific journal)  

There is little information regarding whether patients with chronic kidney disease (CKD) have a high incidence of vulnerable plaques in their coronary arteries. To gain additional evidence on this, we conducted a population-based study by randomly selecting 126 subjects from 844 consecutive autopsies of elderly residents of Hisayama, Japan. We then determined the relationships of CKD with neovascularization and intraplaque hemorrhage in coronary atherosclerosis with the subjects classified into four categories based on their estimated glomerular filtration rate (eGFR). Areas of oxidized low-density lipoprotein (oxLDL) and vascular endothelial growth factor (VEGF) expression, assessed by immunohistochemistry in a total of 375 coronary arteries, increased significantly with decreasing eGFR. A lower eGFR was also associated with increased numbers of newly formed blood vessels. These relationships remained substantially unchanged after adjustment for confounding factors. The multivariate-adjusted odds ratio of the presence of intraplaque hemorrhages was 6.2 (95% confidence interval, 1.1-35.0) in patients with an eGFR <30 ml/min/1.73 m(2) compared with those with an eGFR of >= 60 ml/min/1.73 m(2). Thus, elderly patients with CKD have intimal neoangiogenesis and an increased risk of intraplaque hemorrhage in coronary arteries, possibly favored by local accumulation of oxLDL and VEGF.

DOI： 10.1038/ki.2013.111

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Objectives Serum tartrate-resistant acid phosphatase 5b (TRACP5b) is a bone resorption marker used in the assessment of bone metabolic status. The present study was designed to determine the clinical characteristics and utility of measuring serum TRACP5b levels in peritoneal dialysis (PD) patients. Design Cross-sectional study. Patients Forty-one patients receiving PD treatment in a single centre. Measurement Serum levels of the bone turnover markers TRACP5b, N-terminal cross-linking telopeptide of type 1 collagen (NTX), bone-specific alkaline phosphatase (BAP), and parathyroid hormone (PTH) were simultaneously measured. The correlation of serum TRACP5b with other established bone markers was analysed after logarithmic transformation. Multivariate linear regression analysis was performed to examine the effects of both renal and peritoneal Kt/V (an index for solute clearance) for urea on bone markers using age, sex, body mass index, and PTH as covariates. Bone markers were also measured in three patients before and after treatment with cinacalcet hydrochloride, alphacalcidol, and raloxifene hydrochloride. Results Log TRACP5b was significantly correlated with log NTX, log BAP and log PTH. In the multivariate analysis, peritoneal Kt/V was not correlated with log NTX, log BAP or log TRACP5b. In contrast, renal Kt/V was significantly correlated with log NTX only. Responses to drug treatment were more accurately determined from serum TRACP5b and BAP than from serum NTX. Conclusions Serum TRACP5b and BAP are potentially useful biomarkers for the evaluation of bone turnover in PD patients because they correlate well with other established bone markers and they are not influenced by renal and peritoneal clearances.

DOI： 10.1111/cen.12070

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Objectives Serum tartrate-resistant acid phosphatase 5b (TRACP5b) is a bone resorption marker used in the assessment of bone metabolic status. The present study was designed to determine the clinical characteristics and utility of measuring serum TRACP5b levels in peritoneal dialysis (PD) patients. Design Cross-sectional study. Patients Forty-one patients receiving PD treatment in a single centre. Measurement Serum levels of the bone turnover markers TRACP5b, N-terminal cross-linking telopeptide of type 1 collagen (NTX), bone-specific alkaline phosphatase (BAP), and parathyroid hormone (PTH) were simultaneously measured. The correlation of serum TRACP5b with other established bone markers was analysed after logarithmic transformation. Multivariate linear regression analysis was performed to examine the effects of both renal and peritoneal Kt/V (an index for solute clearance) for urea on bone markers using age, sex, body mass index, and PTH as covariates. Bone markers were also measured in three patients before and after treatment with cinacalcet hydrochloride, alphacalcidol, and raloxifene hydrochloride. Results Log TRACP5b was significantly correlated with log NTX, log BAP and log PTH. In the multivariate analysis, peritoneal Kt/V was not correlated with log NTX, log BAP or log TRACP5b. In contrast, renal Kt/V was significantly correlated with log NTX only. Responses to drug treatment were more accurately determined from serum TRACP5b and BAP than from serum NTX. Conclusions Serum TRACP5b and BAP are potentially useful biomarkers for the evaluation of bone turnover in PD patients because they correlate well with other established bone markers and they are not influenced by renal and peritoneal clearances.

DOI： 10.1111/cen.12070

Language：English  

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Objective Phosphate binders are used in the treatment of hyperphosphatemia in peritoneal dialysis (PD) patients. An ideal phosphate binder for long-term use must be effective with little or no side effects. We evaluated the long-term efficacy and side effects of lanthanum carbonate (LaC) used in combination with other phosphate binders in PD patients. Patients The subjects of this retrospective study were 30 PD patients who received LaC at Kyushu University. The effect of LaC on various biochemical parameters (serum phosphate, calcium and parathyroid hormone), daily dose of other phosphate binders, gastrointestinal side effects, and nutritional status were determined during the 24-week treatment. We also evaluated the rate of achievement of the Japanese Society of Dialysis Treatment guidelines for secondary hyperparathyroidism and used multivariate analysis to determine the factors associated with the efficacy of LaC. Results LaC (960±412 mg/day) reduced serum phosphate from 6.2 to 5.3 mg/dL. The rate of achievement of the guideline target improved after 24 weeks of LaC treatment. The dose of other phosphate binders and dialysis volume remained unchanged during the treatment. Although 53% of patients experienced at least one gastrointestinal side effect, LaC treatment did not affect the nutritional status, and none of the patients discontinued LaC. Multivariate analysis identified low stature, old age and high baseline total creatinine clearance as significant factors that determine the effectiveness of LaC in PD patients. Conclusion Low dose LaC treatment used in combination with other phosphate binders improved serum phosphate control with tolerable gastrointestinal symptoms in PD patients.

DOI： 10.2169/internalmedicine.51.6814

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3747/pdi.2010.00287

Language：English   Publishing type：Research paper (scientific journal)  

Background: Chronic kidney disease (CKD) is associated with increased risk of coronary heart disease. However, information regarding the histopathologic characteristics of coronary atherosclerosis in individuals with CKD is scarce. This study investigated the relationship between CKD and severity of coronary atherosclerosis in population-based autopsy samples.Study Design: Cross-sectional study.Setting & Participants: 126 individuals randomly selected from 844 consecutive population-based autopsy samples.Predictor: Estimated glomerular filtration rate (eGFR) calculated using the 6-variable Modification of Diet in Renal Disease (MDRD) Study equation.Outcomes: Severity of atherosclerosis in 3 main coronary arteries, including atherosclerotic lesion types defined using the American Heart Association classification; stenosis rates; and coronary calcified lesions.Measurements: The relationship between CKD and severity of coronary atherosclerosis was evaluated using generalized estimating equation methods.Results: Frequencies of advanced atherosclerotic lesions increased gradually as eGFR decreased (33.6%, 41.7%, 52.3%, and 52.8% for eGFRs >= 60, 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively; P for trend = 0.006). This relationship was substantially unchanged even after adjustment for potential confounding factors (ORs, 1.40 [95% CI, 0.76-2.55], 2.02 [95% CI, 0.99-4.15], and 3.02 [95% CI, 1.22-7.49] for eGFRs of 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively). Frequencies of calcified lesions of coronary arteries also increased gradually with lower eGFRs (P for trend = 0.02). Hypertension and diabetes were associated with increased risk of advanced coronary atherosclerosis and calcification of coronary arteries in individuals with decreased eGFR.Limitations: Cross-sectional study, absence of data for proteinuria, and extremely high proportion of aged people.Conclusions: The autopsy findings presented here suggest that CKD is associated significantly with severity of coronary atherosclerosis. Patients with CKD should be considered a high-risk population for advanced coronary atherosclerosis. Am J Kidney Dis 55:21-30. (C) 2009 by the National Kidney Foundation, Inc.

DOI： 10.1053/j.ajkd.2009.06.034

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Emerging evidence indicates that the tight communication between vascular endothelial cells and mural cells using platelet-derived growth factor (PDGF)-BB is essential for capillary stabilization during the angiogenic process. However, little is known about the related regulator that determines PDGF-BB expression. Using murine models of therapeutic neovascularization, we here show that a typical lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, is an essential regulator determining PDGF-BB expression for vascular stabilization via a paracrine mode of action. The blockade of VEGF type 3 receptor (VEGFR3) using neutralizing antibody AFL-4 abrogated FGF-2-mediated limb salvage and blood flow recovery in severely ischemic hindlimb. Interestingly, inhibition of VEGFR3 activity not only diminished lymphangiogenesis, but induced marked dilatation of capillary vessels, showing mural cell dissociation. In these mice, VEGF-C and PDGF-B were upregulated in the later phase after induced ischemia, on day 7, when exogenous FGF-2 expression had already declined, and blockade of VEGFR3 or PDGF-BB activities diminished PDGF-B or VEGF-C expression, respectively. These results clearly indicate that VEGF-C is a critical mediator, not only for lymphangiogenesis, but also for capillary stabilization, the essential molecular mechanism of communication between endothelial cells and mural cells during neovascularization.

DOI： 10.1152/ajpheart.00015.2009

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Onimaru M, Yonemitsu Y, Fujii T, Tanii M, Nakano T, Nakagawa K, Kohno R, Hasegawa M, Nishikawa S, Sueishi K. VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. Am J Physiol Heart Circ Physiol 297: H1685-H1696, 2009. First published September 4, 2009; doi:10.1152/ajpheart.00015.2009.-Emerging evidence indicates that the tight communication between vascular endothelial cells and mural cells using platelet-derived growth factor (PDGF)-BB is essential for capillary stabilization during the angiogenic process. However, little is known about the related regulator that determines PDGF-BB expression. Using murine models of therapeutic neovascularization, we here show that a typical lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, is an essential regulator determining PDGF-BB expression for vascular stabilization via a paracrine mode of action. The blockade of VEGF type 3 receptor (VEGFR3) using neutralizing antibody AFL-4 abrogated FGF-2-mediated limb salvage and blood flow recovery in severely ischemic hindlimb. Interestingly, inhibition of VEGFR3 activity not only diminished lymphangiogenesis, but induced marked dilatation of capillary vessels, showing mural cell dissociation. In these mice, VEGF-C and PDGF-B were upregulated in the later phase after induced ischemia, on day 7, when exogenous FGF-2 expression had already declined, and blockade of VEGFR3 or PDGF-BB activities diminished PDGF-B or VEGF-C expression, respectively. These results clearly indicate that VEGF-C is a critical mediator, not only for lymphangiogenesis, but also for capillary stabilization, the essential molecular mechanism of communication between endothelial cells and mural cells during neovascularization.

DOI： 10.1152/ajpheart.00015.2009

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Numerous past studies have suggested a critical role of the paracrine effect between tumor vascular endothelial growth factor (VEGF)-C and lymphatic FLT-4 in solid tumor-associated lymphangiogenesis. In contrast, the pathophysiological role of tumor cell-associated FLT-4 in tumor progression remains to be elucidated. Here, we investigated this role using a tumor implantation model. SAS cells, an oral squamous; carcinoma cell line expressing both VEGF-C and FLT-4 but neither FLK-1/KDR nor VEGF-D were adopted for experiments. Stable transformants of dominant-negative (dn) SAS cells were established in which the cytoplasmic domain-deleted FLT-4 was exogenously overexpressed, which can lead to inactivation of endogenous FLT-4 through competitive antagonism and is associated with down-activation of endogenous FLT-4-related intracellular signals. In vitro and in vivo proliferation assays showed lower proliferative activity of dn-SAS cells. An immunobistochemical study revealed that the tumor lymphangiogenesis was significantly suppressed, and the level of human VEGF-C mRNA was significantly lower in dn-SAS cell-derived tumor tissues. Moreover, in vitro studies demonstrated that the significant suppression of VEGF-C and VEGF-A expression was evident in dn-SAS cells or wild-type SAS cells treated with either the FLT-4 kinase inhibitor MAZ51 or the inhibitor of FLT-4-related signals. These findings together suggested that the VEGF-C/FLT-4 autocrine loop in tumor cells was a potential enhancer system to promote cancer progression, and FLT-4 in tumor tissue might become an effective target for cancer therapy. (Am J Pathol 2009, 175:1709-1721; DOI: 10.2353/ajpath.2009.081139)

DOI： 10.2353/ajpath.2009.081139

Language：English   Publishing type：Research paper (scientific journal)  

Numerous past studies have suggested a critical role of the paracrine effect between tumor vascular endothelial growth factor (VEGF)-C and lymphatic FLT-4 in solid tumor-associated lymphangiogenesis. In contrast, the pathophysiological role of tumor cell-associated FLT-4 in tumor progression remains to be elucidated. Here, we investigated this role using a tumor implantation model. SAS cells, an oral squamous carcinoma cell line expressing both VEGF-C and FLT-4 but neither FLK-1/KDR nor VEGF-D were adopted for experiments. Stable transformants of dominant-negative (dn) SAS cells were established in which the cytoplasmic domain-deleted FLT-4 was exogenously overexpressed, which can lead to inactivation of endogenous FLT-4 through competitive antagonism and is associated with down-activation of endogenous FLT-4-related intracellular signals. In vitro and in vivo proliferation assays showed lower proliferative activity of dn-SAS cells. An immunohistochemical study revealed that the tumor lymphangiogenesis was significantly suppressed, and the level of human VEGF-C mRNA was significantly lower in dn-SAS cell-derived tumor tissues. Moreover, in vitro studies demonstrated that the significant suppression of VEGF-C and VEGF-A expression was evident in dn-SAS cells or wild-type SAS cells treated with either the FLT-4 kinase inhibitor MAZ51 or the inhibitor of FLT-4-related signals. These findings together suggested that the VEGF-C/FLT-4 autocrine loop in tumor cells was a potential enhancer system to promote cancer progression, and FLT-4 in tumor tissue might become an effective target for cancer therapy.

DOI： 10.2353/ajpath.2009.081139

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Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 × 10^-7, crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCη was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

DOI： 10.1038/ng1945

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Cerebral infarction is the most common type of stroke an often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C ( PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples ( P =5.1 X 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14- year follow- up cohort study in Hisayama ( Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction ( P =0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKC eta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

DOI： 10.1038/ng1945

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Background and purpose: ATP-sensitive K ⁺ channels (K _ATP channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel K _ATP channel opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated. Experimental approach: Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle. Key results: ZD0947 (≥ 0.1 μM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil>ZD0947>diazoxide. In conventional whole-cell configuration, ZD0947 (≥ 0.1 μM) caused a concentration-dependent inward K ⁺ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K ⁺ current at -60 mV. Gliclazide (≤ 1 μM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (K _i = 4.0 μM) and the diazoxide-induced currents (high-affinity site, K _i1 = 42.4 nM; low-affinity site, K _i2 = 84.5 μM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of K _ATP channels, in the bundles of human detrusor smooth muscle. Conclusions and Implications: These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive K _ATP channels in human urinary bladder.

DOI： 10.1038/sj.bjp.0706893

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Background and purpose: ATP-sensitive K+ channels (K-ATP channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel (KATP) channel opener, on both carbachol (CCh)induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated.
Experimental approach: Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle.
Key results: ZD0947 (>= 0.1 mu M) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil > ZD0947 > diazoxide. In conventional whole-cell configuration, ZD0947 (>= 1 mu M) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (>= 1 mu M), a selective SUR1 blocker, inhibited the ZD0947-induced currents (K-i = 4.0 mu M) and the diazoxide-induced currents (high-affinity site, K-i1=42.4 nM; low-affinity site, K-i2=84.5 mu M) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of K-ATP channels, in the bundles of human detrusor smooth muscle.
Conclusions and Implications: These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive K-ATP channels in human urinary bladder.

DOI： 10.1038/sj.bjp.0706893

Language：English   Publishing type：Research paper (scientific journal)  

The vascular endothelial growth factor (VEGF) family plays an essential role in vascular development, angiogenesis and lymphangiogenesis. VEGF-A is a key regulator of endothelial cell functions and VEGF-C and VEGF-D are known to stimulate both angiogenesis and lymphangiogenesis. In a surgically removed subretinal vascular membrane of an age-related macular degeneration (AMD) patient, both VEGF-C and VEGF-D were confirmed. in addition to VEGF-A, to be markedly positive in the retinal pigment epithelium (RPE). There is no lymph vessel in ocular tissue, so it is possible that VEGF-C and VEGF-D expression in the RPE play some role in ocular angiogenesis, as well as VEGF-A. Next, we assessed the transition of VEGF-A, -C, and -D expression on several conditions, in human RPE. Hypoxia proverbially induced VEGF-A mRNA expression, meanwhile VEGF-C and VEGF-D mRNA expression was down-regulated. The Ca2+ deprivation from culture medium strongly up-regulated VEGF-A and VEGF-D mRNA expression. Culture on plastic flasks precoated with poly-2-hydroxyethyl methacrylate up-regulated VEGF-D expression. Meanwhile, no significant change of VEGF-C mRNA expression was found in the blockade of cell-cell and/or cell-matrix adhesion. These findings suggest the possibility that VEGF-C and VEGF-D expression in RPE modify the ocular angiogenesis as angiogenic stimulators. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.exer.2006.05.007

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Objective - Monocyte chemoattractant protein- 1 ( MCP- 1) is a C-C chemokine that is known as an inflammatory/ arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated.Methods and Results - Using murine models of fibroblast growth factor-2 ( FGF- 2) - mediated therapeutic neovascularization, we here show that FGF- 2 targets nonendothelial mesenchymal cells ( NEMCs) enhancing both angiogenic ( vascular endothelial growth factor [ VEGF]) and arteriogenic ( MCP- 1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP- 1 expression that was strongly enhanced by FGF- 2 gene transfer, and a blockade of MCP- 1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor ( TNF)-alpha stimulated MCP- 1 expression in all cell types tested, whereas FGF- 2 - mediated upregulation of MCP- 1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo.Conclusions - These results indicate that FGF- 2 targets NEMCs independently, enhancing both angiogenic ( VEGF) as well as inflammatory/ arteriogenic ( MCP- 1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF- 2 - mediated therapeutic neovascularization.

DOI： 10.1161/01.ATV.0000244684.23499.bf

Language：English   Publishing type：Research paper (scientific journal)  

The vascular endothelial growth factor (VEGF) family plays an essential role in vascular development, angiogenesis and lymphangiogenesis. VEGF-A is a key regulator of endothelial cell functions and VEGF-C and VEGF-D are known to stimulate both angiogenesis and lymphangiogenesis. In a surgically removed subretinal vascular membrane of an age-related macular degeneration (AMD) patient, both VEGF-C and VEGF-D were confirmed, in addition to VEGF-A, to be markedly positive in the retinal pigment epithelium (RPE). There is no lymph vessel in ocular tissue, so it is possible that VEGF-C and VEGF-D expression in the RPE play some role in ocular angiogenesis, as well as VEGF-A. Next, we assessed the transition of VEGF-A, -C, and -D expression on several conditions, in human RPE. Hypoxia proverbially induced VEGF-A mRNA expression, meanwhile VEGF-C and VEGF-D mRNA expression was down-regulated. The Ca²⁺ deprivation from culture medium strongly up-regulated VEGF-A and VEGF-D mRNA expression. Culture on plastic flasks precoated with poly-2-hydroxyethyl methacrylate up-regulated VEGF-D expression. Meanwhile, no significant change of VEGF-C mRNA expression was found in the blockade of cell-cell and/or cell-matrix adhesion. These findings suggest the possibility that VEGF-C and VEGF-D expression in RPE modify the ocular angiogenesis as angiogenic stimulators.

DOI： 10.1016/j.exer.2006.05.007

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE - Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated. METHODS AND RESULTS - Using murine models of fibroblast growth factor-2 (FGF-2)-mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-α stimulated MCP-1 expression in all cell types tested, whereas FGF-2-mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo. CONCLUSIONS - These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2-mediated therapeutic neovascularization.

DOI： 10.1161/01.ATV.0000244684.23499.bf

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Objective - To assess the expression and distribution of a neurotrophic/antiangiogenic factor, pigment epithelium-derived factor (PEDF), related to angiogenesis that is a possibly key event during atherogenesis in human atherosclerotic plaques. Methods and Results - Twenty fresh aortic samples were used for reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry (IHC). In addition, 80 stocked paraffin blocks of coronary arteries from 40 autopsy cases were also used. IHC revealed divergent staining patterns for PEDF in both the aortas and the coronary arteries tested, ie, "cytoplasmic staining" or "extracellular deposition," were observed, respectively. In the areas showing cytoplasmic staining, double PEDF was expressed in a majority of the foamy macrophages and in some smooth muscle cells, and the PEDF-positive cell frequency was positively correlated with that of microvessels in a cell-rich area in the coronary arteries (P<0.0001). Inversely, extracellular deposition of PEDF was seen in acellular areas and was negatively correlated with the number of microvessels (P=0.0003). Conclusions - These results suggest that PEDF may function as an antiangiogenic factor when it is deposited onto the extracellular matrix. Thus, PEDF may play a significant role in determining the balance of angiogenesis/antiangiogenesis during atherogenesis.

DOI： 10.1161/01.ATV.0000175759.78338.1e

Language：English   Publishing type：Research paper (scientific journal)  

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non-small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.

DOI： 10.1158/0008-5472.CAN-04-4171

Language：English   Publishing type：Research paper (scientific journal)  

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non-small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.

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The effects of flavoxate hydrochloride (Bladderon®, piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba ²⁺ currents in human detrusor myocytes were investigated using a conventional whole-cell patch-clamp. Tension measurement was also performed to study the effects of flavoxate on K ⁺-induced contraction in human urinary bladder. Flavoxate caused a concentration-dependent reduction of the K ⁺-induced contraction of human urinary bladder. In human detrusor myocytes, flavoxate inhibited the peak amplitude of voltage-dependent nifedipine-sensitive inward Ba ²⁺ currents in a voltage- and concentration-dependent manner (K _i = 10 μM), and shifted the steady-state inactivation curve of Ba ²⁺ currents to the left at a holding potential of -90mV. Immunohistochemical studies indicated the presence of the α _1c subunit protein, which is a constituent of human L-type Ca ²⁺ channels (Ca _v1-2), in the bundles of human detrusor smooth muscle. These results suggest that flavoxate caused muscle relaxation through the inhibition of L-type Ca ²⁺ channels in human detrusor.

DOI： 10.1038/sj.bjp.0706284

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Event date： 2022.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸   Country：Japan  

Event date： 2021.8

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Venue：Thailand   Country：Thailand  

Event date： 2021.6

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Venue：横浜   Country：Japan  

Event date： 2021.6

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Venue：横浜   Country：Japan  

Event date： 2021.6

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Venue：横浜   Country：Japan  

Event date： 2021.6

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Venue：横浜   Country：Japan  

Event date： 2020.11

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Venue：大阪   Country：Japan  

Event date： 2020.10

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Venue：和歌山   Country：Japan  

Event date： 2020.9

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Venue：東京   Country：Japan  

Event date： 2020.8

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Venue：横浜   Country：Japan  

Event date： 2020.7

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Venue：福岡   Country：Japan  

Event date： 2020.7

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Venue：名古屋   Country：Japan  

Event date： 2019.11

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Venue：Washington DC   Country：United States  

Event date： 2019.10

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Venue：高知   Country：Japan  

Event date： 2019.6

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Venue：横浜   Country：Japan  

Event date： 2019.6

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Venue：名古屋   Country：Japan  

Event date： 2012.9

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Venue：徳島県徳島市   Country：Japan  

Event date： 2011.11

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Venue：Philadelphia   Country：Japan  

Event date： 2011.6

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Venue：横浜   Country：Japan  

Event date： 2010.11

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Venue：大分   Country：Japan  

Event date： 2010.6

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Venue：神戸   Country：Japan  

Event date： 2010.6

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Venue：神戸   Country：Japan  

Event date： 2010.5

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Venue：Kyoto   Country：Japan  

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Language：English   Publisher：(一社)日本腎臓学会  

Language：Japanese   Publisher：(一社)筑紫医師会  

Language：English   Publisher：(一社)日本腎臓学会  

Language：English   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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レニン・アンジオテンシン系阻害薬による腎移植レシピエントの心血管病発症の抑制効果

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地域高齢住民における慢性腎臓病と大脳白質病変の関連 久山町研究

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血液透析患者における全身性動脈硬化性疾患と心血管リスクの関係 Qコホート研究10年予後

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IgA腎症患者における血漿浸透圧と末期腎不全発症リスクの関連

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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一般住民の連続剖検例における腎機能低下と左室肥大の関係 久山町研究

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腎機能障害による冠状動脈内新生血管と内膜内出血への影響

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腎機能と冠状動脈硬化病変における酸化LDL、慢性炎症との関連

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久山町剖検例における慢性腎臓病の冠状動脈硬化進展に与える影響

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久山町剖検例における慢性腎臓病の冠状動脈硬化進展に与える影響

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全身性疾患と腎障害up to date 一般住民における慢性腎臓病と動脈硬化の関係 久山町研究

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Objective - To assess the expression and distribution of a neurotrophic/ antiangiogenic factor, pigment epithelium-derived factor ( PEDF), related to angiogenesis that is a possibly key event during atherogenesis in human atherosclerotic plaques.
Methods and Results - Twenty fresh aortic samples were used for reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry (IHC). In addition, 80 stocked paraffin blocks of coronary arteries from 40 autopsy cases were also used. IHC revealed divergent staining patterns for PEDF in both the aortas and the coronary arteries tested, ie, "cytoplasmic staining" or "extracellular deposition," were observed, respectively. In the areas showing cytoplasmic staining, double PEDF was expressed in a majority of the foamy macrophages and in some smooth muscle cells, and the PEDF-positive cell frequency was positively correlated with that of microvessels in a cell-rich area in the coronary arteries ( P < 0.0001). Inversely, extracellular deposition of PEDF was seen in acellular areas and was negatively correlated with the number of microvessels ( P = 0.0003).
Conclusions - These results suggest that PEDF may function as an antiangiogenic factor when it is deposited onto the extracellular matrix. Thus, PEDF may play a significant role in determining the balance of angiogenesis/ antiangiogenesis during atherogenesis.

DOI： 10.1161/01.ATV.0000175759.78338.1e

Language：English  

1 The effects of flavoxate hydrochloride (Bladderon((R)), piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba2+ currents in human detrusor myocytes were investigated using a conventional whole-cell patch-clamp. Tension measurement was also performed to study the effects of flavoxate on K+-induced contraction in human urinary bladder.
2 Flavoxate caused a concentration-dependent reduction of the K+-induced contraction of human urinary bladder.
3 In human detrusor myocytes, flavoxate inhibited the peak amplitude of voltage-dependent nifedipine-sensitive inward Ba2+ currents in a voltage- and concentration-dependent manner (K-i = 10 mu M), and shifted the steady-state inactivation curve of Ba2+ currents to the left at a holding potential of -90 mV.
4 Immunohistochemical studies indicated the presence of the alpha(1C) subunit protein, which is a constituent of human L-type Ca2+ channels (Ca(V)1.2), in the bundles of human detrusor smooth muscle.
5 These results suggest that flavoxate caused muscle relaxation through the inhibition of L-type Ca2+ channels in human detrusor.

DOI： 10.1038/sj.bjp.0706284

Language：English  

Type：Academic society, research group, etc. 

Type：Academic society, research group, etc. 

Type：Competition, symposium, etc.