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Several randomized controlled trials (RCTs) have demonstrated the cardiometabolic effects of aerobic exercise in the general population and in patients with cardiovascular diseases. However, the efficacy of aerobic exercise in patients with chronic kidney disease (CKD) remains to be elucidated. RCTs comparing aerobic exercise with no aerobic exercise in patients with CKD not requiring kidney replacement therapy were identified through PubMed using RobotAnalyst, a web-based software system that combines text-mining and machine learning algorithms for organizing references. Cardiometabolic and renal outcomes of interest included body mass index (BMI); systolic blood pressure (SBP); hemoglobin A1c (HbA1c), total cholesterol (TCHO), low- and high- density lipoprotein cholesterol (LDLC and HDLC, respectively), and urinary protein (UP) levels/concentration; peak oxygen uptake (Vo2peak); and glomerular filtration rate (GFR) at the end of the follow-up period. The standardized mean difference (SMD) of each outcome was estimated using the DerSimonian-Laird random-effect model with inverse-variance weighting. A total of 15 trials, including 622 patients, were included. Their follow-up periods were 3–4, 6–12, and > 12-months in 7 (46.7%), 7 (46.7%), and 1 (6.7%) trial(s), respectively. Meta-analyses showed that aerobic exercise significantly decreased BMI (SMD, -0.19 [95% confidence interval, −0.38, −0.00]) and SBP (−0.75 [−1.24, −0.26]) and increased Vo2peak (0.54 [0.29, 0.78]); however, no significant association was observed in HbA1c, TCHO, HDLC, LDLC, GFR, and UP. Meta-regression models suggested that aerobic exercise was more likely to improve Vo2peak in patients with younger age, no diabetes, and lower BMI. Aerobic exercise of 3–12 months’ duration improved obesity, high blood pressure, and low exercise capacity in overweight/obese patients with CKD, but it had no significant effect on GFR and proteinuria. Well-designed large RCTs with a longer follow-up period are needed to evaluate the efficacy of aerobic exercise in patients with CKD.

ObjectiveTo evaluate the effect of triglyceride deposit cardiomyovasculopathy (TGCV) on the cardiovascular outcomes in haemodialysis (HD) patients with suspected coronary artery disease (CAD).MethodsThis retrospective single-centre observational study included data from the cardiac catheter database of Narita Memorial Hospital between April 2011 and March 2017. Among 654 consecutive patients on HD, the data for 83 patients with suspected CAD who underwent both [123I]-β-methyl-iodophenyl-pentadecanoic acid scintigraphy and coronary angiography were analysed. Patients were divided into three groups: definite TGCV (17 patients), probable TGCV (22 patients) and non-TGCV control group (44 patients). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke assessed for up to 5 years of follow-up.ResultsThe prevalence of definite TGCV was approximately 20% and 2.6% among consecutive HD patients with suspected CAD and among all HD patients, respectively. At the end of the median follow-up period of 4.7 years, the primary endpoint was achieved in 52.9% of the definite TGCV patients (HR, 7.45; 95% CI: 2.28 to 24.3; pConclusionsTGCV is not uncommon in HD patients and is associated with an increased risk of cardiovascular events including cardiovascular death. Thus, TGCV might be a potential therapeutic target.

Steroid therapy is one of the important therapies for IgA nephropathy (IgAN), but the features of the IgAN patients who have the benefit from this therapy remained unclear. This retrospective observational study, using data of 874 patients with IgAN analyzed the proteinuria and kidney function of IgAN patients who had beneficial effect by steroid therapy. Two advantages of the present study were a large cohort and a long observational period. Corticosteroid therapy had ameliorated the kidney prognosis [incident rate ratio (IRR) 0.57 (95%CI 0.34–0.92), P = 0.029]. Because of interaction between kidney function and use of corticosteroid (P = 0.047), stratification analysis by kidney function revealed that prognosis of kidney function in IgAN patients whose eGFR was less than 60 ml/min/1.73m2 was ameliorated by corticosteroid therapy [IRR 0.50 (95%CI 0.26–0.97), P = 0.015); while, there was no change of kidney prognosis in IgAN patients whose eGFR was above 60 ml/min/1.73 m2. To make the target of corticosteroid therapy for IgAN patients more clear, IgAN patients, whose eGFR were less than 60 ml/min/1.73 m2, were stratified by proteinuria (1 g/day). In IgAN patients whose eGFR were under 60 ml/min/1.73 m2 and whose proteinuria were over 1.0 g/day, corticosteroid therapy seemed to ameliorate kidney function [IRR 0.39 (95%CI 0.19–0.86), P

Streptococcus mutans is known to be a major causative agent of dental caries, and strains expressing the cell surface collagen-binding Cnm protein contribute to the development of several systemic diseases. A relationship between tonsillar immunity and glomerulonephritis has been recognized in IgA nephropathy (IgAN), and specific pathogens may have effects on tonsillar immunity (mucosal immunity). Here, we present findings showing a relationship between the presence of Cnm-positive S. mutans strains in the tonsils of IgAN patients and IgAN condition/pathogenesis. Analyses of tonsillar specimens obtained from patients with IgAN (n = 61) and chronic tonsillitis (controls; n = 40) showed that the Cnm protein-positive rate was significantly higher in IgAN patients. Among IgAN patients, the tonsillar Cnm-positive group (n = 15) had a significantly higher proportion of patients with high urinary protein (>1.5 g/gCr) and lower serum albumin level than the Cnm-negative group (n = 46). Additionally, Cnm protein and CD68, a common human macrophage marker, were shown to be merged in the tonsils of IgAN patients. These findings suggest that Cnm-positive S. mutans strains in the tonsils may be associated with severe IgAN.

IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN.

Chronic kidney disease (CKD) patients have an extremely high risk of developing cardiovascular diseases (CVD) compared to the general population. Systemic inflammation associated with oxidative stress could be an important determinant of morbidity and mortality associated with CVD. We suspected that dysregulation of iron metabolism should be considered in these patients. Anemia is prevalent in CKD patients and is often treated with erythropoiesis-stimulating agents (ESAs) and iron. In addition, iron administration sometimes causes iron overdose. Excessive iron in the cytosol and mitochondria can accelerate the formation of a highly toxic reactive oxygen species, hydroxyl radicals, which damage lipids, proteins, and DNA. In this review, we propose the following four major reasons for oxidative stress in CKD patients: 1) iron is sequestered in cells by proinflammatory cytokines and hepcidin; 2) the reduction in frataxin increases "free" iron in mitochondria; 3) the accumulation of 5-aminolevulinic acid, a heme precursor, has toxic effects on iron and mitochondrial metabolism; and 4) the elevated levels of the metabolic hormone, leptin, promote hepatic hepcidin production. Although an efficient therapy for preventing oxidative stress in these patients has not yet been well defined, we propose that ESAs for renal anemia may ameliorate these causes of oxidative stress. Further clinical trials are necessary to clarify the effectiveness of ESAs on oxidative stress in CKD patients.

Sodium intake theoretically has dual effects on both non-dialysis chronic kidney disease (CKD) patients and dialysis patients. One negatively affects mortality by increasing proteinuria and blood pressure. The other positively affects mortality by ameliorating nutritional status through appetite induced by salt intake and the amount of food itself, which is proportional to the amount of salt under the same salty taste. Sodium restriction with enough water intake easily causes hyponatremia in CKD and dialysis patients. Moreover, the balance of these dual effects in dialysis patients is likely different from their balance in non-dialysis CKD patients because dialysis patients lose kidney function. Sodium intake is strongly related to water intake via the thirst center. Therefore, sodium intake is strongly related to extracellular fluid volume, blood pressure, appetite, nutritional status, and mortality. To decrease mortality in both non-dialysis and dialysis CKD patients, sodium restriction is an essential and important factor that can be changed by the patients themselves. However, under sodium restriction, it is important to maintain the balance of negative and positive effects from sodium intake not only in dialysis and non-dialysis CKD patients but also in the general population.

Introduction: Hemodialysis (HD) has been reported as a strong prognostic factor in patients with cardiovascular disease. It is unknown how much triglyceride deposit cardiomyovasculopathy (TGCV), a novel identified rare cardiovascular disorder, is associated with cardiovascular mortality among HD patients. Hypothesis: We hypothesized that comorbidity of TGCV in HD patients who suspected of CAD plays a critical role for cardiovascular outcomes in this population. Methods: We examined the data obtained from 83 consecutive HD patients suspected of coronary artery disease who underwent both [123I]-β-methyl-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy and subsequent coronary angiography (CAG). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke up to 5 years of follow-up. The key secondary endpoint was a composite of cardiovascular death, non-fatal MI, non-fatal stroke, target vessel revascularization, or any hospitalization for heart failure. Results: A total of 83 HD patients were grouped into either the definite TGCV (17 patients), the probable TGCV (22 patients), or the non-TGCV control group (44 patients). At the end of the follow-up period for a median of 4.7 years, a primary endpoint event occurred in 58.8% of the definite TGCV patients (hazard ratio, 8.06; 95% confidence interval [CI], 2.52-25.8, Log-rank p Conclusions: Comorbidity of TGCV in patients on HD was associated with increased risk of cardiovascular events including cardiovascular death, which might highlight the potential therapeutic target.

Background IgA nephropathy (IgAN) is one of the most frequently occurring types of chronic glomerulonephritis. Previous analyses have revealed that a major pathogen of dental caries, Streptococcus mutans [which expresses collagen-binding protein (Cnm) on its surface], is involved in the pathogenesis of IgAN. Methods Cnm-positive S. mutans isolated from a patient with IgAN was intravenously administered to specific pathogen-free Sprague–Dawley rats to evaluate their kidney conditions. Results The urinary protein level of the S. mutans group reached a plateau at 30 days, with increased numbers of mesangial cells and an increased mesangial matrix. The numbers of rats with IgA-positive and/or C3-positive glomeruli were significantly greater in the S. mutans group than in the control group at 45 days (P S. mutans group. There were significantly more CD68-positive cells (macrophages) in the glomeruli of the S. mutans group than in the glomeruli of the control group during the late phase (P Conclusion Our results suggested that intravenous administration of Cnm-positive S. mutans caused transient induction of IgAN-like lesions in rats.

Background and Aims Several factors, such as anemia, hypertension, hyperuricemia, metabolic acidosis, and chronic kidney disease (CKD)-mineral and bone disorder (MBD), are associated with the progression of CKD or adverse events in CKD patients. However, the significant factors associated with the progression of CKD or adverse events in patients under the condition of appropriate control according to guidelines have not been clarified. Method The study was a 3-year observational study conducted in a single center. In 88 patients with various stages of CKD (not on renal replacement therapy (RRT)) who were treated by nephrologists, blood levels of Hb, ferritin, iron, total iron-binding capacity, and albumin were measured every 3 months, and high-sensitivity C reactive protein (hCRP), β2-microglobulin (MG), HCO3-, and intact-parathyroid hormone (int-PTH), in addition to urinary sodium, potassium, calcium, phosphorus, protein, and β2-MG levels, were measured every 6 months. We also evaluated the doses of iron, erythropoiesis-stimulating agent (ESA), vitamin D, phosphate binder, anti-hypertensive agents, and anti-hyperuricemic agents. All patients were treated according to the clinical practice guidelines for CKD (Japanese Society of Nephrology 2013). A time-dependent Cox hazard model was applied to evaluate the associations between clinical parameters and adverse events (initiation of RRT and hospitalization resulting in cardiovascular disease or infection). Results Unexpectedly, under the condition of appropriate control by nephrologists, hypertension, hyperuricemia, metabolic acidosis, iron metabolism, and inflammation were not selected as significant predictors of the progression of renal dysfunction or adverse events. (Factors associated with the progression of renal dysfunction) In multiple regression analysis, lower baseline blood levels of Hb (β=0.497, P Conclusion In this study, we found that among several factors, anemia and CKD-MBD-related factors (phosphate, calcium, vitamin D, int-PTH) were selected as significant predictors of the progression of renal dysfunction. Furthermore, although phosphate binders or vitamin D analogs were administered appropriately, CKD-MBD-related factors (phosphate, calcium, vitamin D, and int-PTH) were associated with RRT initiation or adverse events in these patients. From these results, we presumed that early intervention or strict control of CKD-MBD factors might attenuate the risk for adverse events in CKD patients.

Background and Aims IgA nephropathy (IgAN) is one of most common primary glomerulonephritis, whose pathogenesis had remained unclear. We had reported that Cnm-(+)Streptococcus mutans, a kinds of major dental caries bacteria. Cnm-(+)S. mutans had strong collagen binding ability, resulting in high pathogenicity. We reported that the prevalence of Cnm-(+)S. mutans in IgA nephropathy is significantly higher than that in control (Misaki-T et al, Clin Exp Nephrol 2015; 19:844-50), and that Cnm-(+)S. mutans in IgA nephropathy was associated with proteinuria (Misaki-T et al, Sci Rep 2016). We also reported C.rectus and S. mutans increased proteinuria synergistically (Misaki-T et al, Nephron, 2018). In this point, there is no direct evidence that Cnm-(+)S. mutans could induce IgA nephropathy. In this study, we evaluated the renal lesions in rats which had dental caries induced by Cnm-(+)S. mutans derived from IgA nephropathy patient to confirm the pathogenesis of IgA nephropathy like lesions induced by Cnm-(+)S mutans. Method Cmn-(+)S. mutans from saliva of IgA nephropathy patients was orally administrated into 4 weeks old male Sprague-Dawley rats. Addition of sugar to water had been kept during study period to develop dental carits. At week 34 after the infection, blood, urine, and kidney samples were evaluated. Kidney samples were stained by Periodic Acid-Schiff (PAS), IgA, C3. Historical evaluation by electron microscope analysis was also performed. Results At week 34, plaque score and dental caries score in infectious rats significantly elevated, compared with control rats (P Conclusion Cmn-(+)S. mutans from saliva of IgA nephropathy patients could induce IgA-dominant infection-associated glomerulonephritis, or IgA nephropathy.

Background and Aims Cigarette Smoking is one of important risks for cardiovascular diseases, and also smoking had been reported to have harmful effect upon Choric kidney Diseases. Our group had reported that smoking canceled the beneficial effect caused by alcohol drinking using Japanese Nationwide Survey cross-sectional data (Matsumoto-A et al Hypertension Res, 2017). In this cohort study, we aimed to reveal the effect of smoking upon incidence of proteinuria and decline of kidney function using longitudinal large cohort of general population in Japan. Method The present nationwide longitudial survey included members of the general Japanese population who underwent the Specific Health Check and Guidance in Japan between April 2008 and March 2014. 149,260 who were not lack of essential data without chronic kidney diseases and whose kidney function was 60≦eGFR Results Smoker had significantly higher incidence rate of proteinuria than non-smoker (p Conclusion Smoking was risk for proteinuria and decline of kidney function. Moreover, smoker with incident proteinuria had worst kidney prognosis.

Background and Aims IgA nephropathy (IgAN) is one of most common primary glomerulonephritis, whose pathogenesis had remained unclear. We had reported that C.rectus and T.denticola, kinds of major periodontal disease bacteria, in tonsils with IgA nephropathy patients were specific to IgAN patients compared with chronic tonsillitis (Nagasawa-Y et al, Plos One, 2014). We also reported C.rectus and S.mutans increased proteinuria synergistically (Misaki-T et al, Nephron, 2018). Red complex of bacteria related with periodontal disease consists of P.gingivalis, T.denticola, and Tannerella forsythia, which has strongest pathogenicity of periodontal disease (Figure 1). But, in this point there were no report of prevalence of red complex of periodontal bacteria in IgA nephropathy. In this study, we evaluated the periodontal disease bacteria including P.gingivalis, T.denticola, and Tannerella forsythia in tonsils of IgAN patients, and the relationship between these periodontal bacteria clinical features in IgAN patients. Method Tonsils were obtained from 23 IgAN patients and 63 chronic tonsillitis patients when the tonsillectomy was operated. mRNAs were extracted from tonsils and the prevalences of P.gingivalis, T.denticola, and Tannerella forsythia were evaluated by RT-PCR using bacteria specific primers. All patients gave the written informed consent which was approved by Hyogo College of medicine. Results Average age was 33+-14 in IgAN patients, and the age in control patients was 27+-7. The average proteinuria in IgAN patietns was 0.9+-1.1g/gcre, and average hematuria was (2+). The prevalence of T.denticola was very low in both groups (0%, 1.6% respectively). The prevalence of P.gingivalis in IgA patients was significantly higher than that in control patients (33% vs 3.2%, respectively, P Conclusion Prevalence of red complex of periodontal disease bacteria, especially P.gingivalis, Tannerella forsythia in IgAN patient was higher than that in control. Red complex of periodontal disease bacteria might have some relationship with pathogenesis of IgAN

Triglyceride deposit cardiomyovasculopathy (TGCV) is a newly identified disease that was discovered in individuals who required cardiac transplantation in Japan in 2008. Defective intracellular lipolysis causes triglyceride (TG) accumulation in the myocardium and coronary artery vascular smooth muscle cells, which results in severe heart failure and coronary artery disease with poor prognosis. A known cause of TGCV is a genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in the intracellular hydrolysis of TG. TGCV is classified into primary TGCV with ATGL mutations and idiopathic TGCV without ATGL mutations. Since its discovery, the Japan TGCV Study Group has attempted to elucidate its pathophysiology, develop diagnostic procedures, and specific treatment. Myocardial scintigraphy with iodine-123-β-methyl iodophenyl-pentadecanoic acid ((123)I-BMIPP) is a unique imaging modality for evaluating myocardial lipolysis in vivo. The washout rate of (123)I-BMIPP is an essential indicator for the diagnosis of TGCV. Along with our efforts to provide awareness of and insights into this disease concept, we found that the cumulative number of clinically diagnosed patients has reached >200 and the cases are distributed throughout Japan. In addition, we successfully completed three investigator-initiated clinical trials of a potential therapeutic agent (CNT-01) for TGCV, which was assigned by the Ministry of Health, Labour, and Welfare, Japan, under the SAKIGAKE Designation System in June 2020. Here, we provide the Diagnostic Criteria 2020 for TGCV in order to further promote this “rare and intractable disease” project.

Recently, dialysis patients are often suffering from frailty, protein energy wasting, and sarcopenia. Nutritional intervention is one of the important treatments to these statuses. Japanese Society of Dialysis Therapy published the standard nutrition intake in dialysis patients, which basically indicated the minimum nutritional requirements to avoid the dialysis complication, such as calcification, atherosclerosis, hypotension during dialysis therapy. But, theoretically maximum nutritional intake is much larger than the standard intake. Indeed, 60 kg dialysis patients could take 12.6 g/day at maximum, according to the relationship between body weight increase between dialysis sessions and mortality. Moreover, recent improvement of phosphate binders and dialysis therapy itself enlarged the allowance of nutritional intake. Under these circumstances, more aggressive nutritional intervention had become available for dialysis patients. Nutritional intervention could improve not only protein energy wasting, but also sarcopenia, or frailty itself, because these three concepts measured the same condition that aged patients are fragile from another aspect. Dual intervention (nutritional intervention and exercise intervention) had reported to improve not only nutritional or physical factors, but also quality of life, which indicating that dual intervention could ameliorate frailty itself. Multiple interventions to Frailty including aggressive nutritional intervention are expected to improve the mortality of dialysis patients.

Background: Periodontitis-related pathogens, such as Campylobacter or Treponema species, have recently been shown to be associated with immunoglobulin A nephropathy (IgAN). Some strains of Streptococcus mutans, a major pathogen of dental caries, harbour the cnm gene that encodes a collagen-binding protein (Cnm). This has also been demonstrated to be associated with urinary protein levels in IgAN patients. Objectives: The purpose of the present study was to analyse the association of IgAN with C. rectus, Treponema denticola and cnm-positive S. mutans in the oral cavity of humans. Methods: The presence of C. rectus, T. denticola and cnm-positive S. mutans strains in saliva samples of 117 IgAN patients and 56 healthy controls was evaluated by PCR, and the subjects’ clinical parameters were analysed. Results: C. rectus was significantly more prevalent in the IgAN group than in the control group (p < 0.05). The C. rectus-positive group was significantly associated with proteinuria in the IgAN group (p < 0.05). In addition, the C. rectus-positive and cnm-positive S. mutans group was shown to be more closely associated with urinary protein levels than the other groups (p < 0.0083). Conclusion: Our results suggest that harbouring C. rectus in the oral cavity could be associated with proteinuria in IgAN patients.

Chronic kidney disease (CKD) is characterized by a reduced glomerular filtration rate (GFR) and proteinuria. Modifiable lifestyle factors such as smoking and alcohol contribute to CKD. Recent cohort studies have shown that moderate alcohol consumption attenuates the decline of the GFR and smoking has been previously shown to be associated with CKD. However, the association of smoking and alcohol consumption on CKD is not entirely clear. To examine whether there is evidence to assume that smoking is an effective modifier of the association between CKD and alcohol consumption, we conducted a cross-sectional study of a population of people who presented for a health checkup under a program that targets the insured population aged ≧40 years using data from the Specific Health Check and Guidance in Japan between April 2008 and March 2009. Of the 506 807 participants aged ⩾40 years, 292 013 (57.6%) were included in the present analysis. Outcomes were kidney dysfunction, as an eGFR of

Background/Aims: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. Methods: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. Results: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). Conclusion: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.

Circulating lymphocytes infiltrate into local foci at the inflammatory phase of acute wound healing for activation of the immune system and express an immune checkpoint protein programmed cell death 1 (PD-1) at the resolution phase for inactivation of the immune system. Conversely, the PD-1 expression was still found even on circulating lymphocytes of the elder patients with chronic tonsillitis at the palliative stage. Recently, an adhesion G protein coupled receptor 56 (GPR56) was reported to at least work as a proliferation factor for infiltrated lymphocytes into local foci at the resolution phase of acute wound healing. To preliminary examine a similar role of PD-1 and GPR56 at local foci at chronic inflammation, palate tonsils were prepared from small amounts of patients with chronic tonsillitis and tonsillar hypertrophy. A positive relationship of RNA expression might be observed between PD-1 and GPR56 in the elder patients with chronic tonsillitis. In regard to immunohistopathological findings, there were huge and small amounts of PD-1 and GPR56 expression at the marginal zone of lymphoid follicles of palate tonsils with chronic tonsillitis. Moreover, the positive relationship of RNA expression between PD-1 and GPR56 confirmed in large numbers of the elder patients with chronic tonsillitis. Probably, GPR56 participates in a supplement of PD-1+ lymphocytes to circulating bloods of the elder patients with chronic tonsillitis through a lymphocyte cell maintenance system at the marginal zone of the lymphoid follicles of palate tonsils., Highlights • Accumulation of PD-1+ lymphocytes at the marginal zone of palate tonsils. • Expression of GPR56 transcript at palate tonsils. • Co-localization of GPR56+ lymphocytes besides PD-1+ lymphocytes. • Positive relationship between GPR56 and PD-1 in palate tonsils of chronic tonsillitis-patients.

AIM Regular exercise habits are well-known to exert a favorable effect on the metabolic syndrome, which may cause proteinuria and chronic kidney disease (CKD). However, it remains unknown if exercise exerts a favorable effect on proteinuria and kidney dysfunction. The aim of this study was to reveal the association between exercise and the prevalence of proteinuria and kidney dysfunction and the attenuation by obesity. METHODS This study was a cross-sectional cohort study that included 292,013 participants who underwent the Specific Health Check and Guidance in Japan. The exercise score (range 0-3) was based on the number of positive answers to three questions regarding exercise habits. The outcome was defined as urinary protein detected by a dipstick test and kidney dysfunction [estimated glomerular filtration rate (GFR) less than 45 ml/min/1.73 m(2)]. RESULTS The exercise score was significantly associated with the prevalence of proteinuria in both males [vs. exercise score 0; exercise score 1, multivariate-adjusted odds ratio 0.86 (95% confidence interval 0.81-0.92), P

In CKD patients, arteriosclerotic lesions, including calcification, can occur in vascular smooth muscle cells in a process called Moenckeberg’s medial arteriosclerosis. Iron overload induces several complications, including the acceleration of arteriosclerosis. However, the relationship between Moenckeberg’s arteriosclerosis in vascular smooth muscle cells and iron accumulation has remained unknown. We tested the accelerated effect of iron on calcification in cultured human aortic vascular smooth muscle cells (HASMCs). After establishment of this model, we performed a microarray analysis using mRNA from early stage culture HASMCs after iron stimulation with or without TNF-alpha stimulation. The role of interleukin-24 (IL-24) was confirmed from candidate genes that might contribute to calcification. HASMCs demonstrated calcification induced by iron and TNF-alpha. Calcification of HASMCs was synergistically enhanced by stimulation with both iron and TNF-alpha. In the early phase of calcification, microarray analysis revealed up-regulation of IL-24. Stimulation of HASMCs by IL-24 instead of iron induced calcification. The anti-IL-24 antibody reversed the effect of IL-24, supporting the important role of IL-24 in HASMCs calcification. In conclusion, iron-induced calcification in vascular smooth muscle cells occurred via IL-24, IL-24 was increased during the calcification process induced by iron, and IL-24 itself caused calcification in the absence of iron.

Objective Salt loading induces renal damage independently of blood pressure (BP) elevation via reactive oxygen species and sympathetic activity. Melatonin, a hormone that regulates the circadian rhythm, has multiple functions, including anti-oxidant effects and the inhibition of sympathetic activity. We have shown that impaired melatonin secretion is associated with renal damage in chronic kidney disease (CKD) patients. However, the associations between salt loading, melatonin secretion, and urinary albumin and protein have not been clarified. Methods We recruited 32 CKD patients, conducted 24-hour ambulatory BP monitoring and collected daytime and nighttime urine while the patients were consuming a standard salt (10 g/day) or low salt (6 g/day) diet. The excretion levels of albumin, protein and 6-sulfatoxymelatonin (aMT6s), a metabolite of melatonin, in daytime and nighttime urine were investigated in patients consuming standard salt and low salt diets. Results The urinary aMT6s levels in daytime and nighttime of the patients consuming standard salt and low salt diets did not differ to a statistically significant extent. However, the urinary aMT6s levels in patients consuming a standard salt diet-but not patients consuming a low salt diet-were significantly and negatively correlated with the daytime and nighttime urinary albumin and protein levels. Contrarily, no significant correlations were found between the urinary aMT6s levels and the BP levels, renal function, and plasma angiotensin II levels in patients consuming either a standard salt or low salt diet. A multiple regression analysis adjusted for age, sex, and body mass index revealed that the urinary albumin and protein levels were significantly and negatively associated with the urinary aMT6s levels in patients consuming a standard salt diet, but not in patients consuming a low salt diet. Conclusion Salt loading aggravates the relationship between melatonin secretion and albuminuria or proteinuria.

Objective Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. Design and Methods A prospective randomized study. Subjects Participants on MHD with severe iron deficiency (n = 61). Intervention Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32). Main Outcome Measure Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. Results Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. Conclusion Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

Purpose We evaluate the effect of the protoconized anemia therapy on adverse events using the Hb and ferritin levels of individual patients undergoing maintenance hemodialysis (MHD). Methods Design: A randomized, parallel group, multi-center study. Patients Two hundred sixty-six MHD patients. Intervention group: The doses of erythropoietin, iron, and vitamin C were adjusted every month based on the ferritin and hemoglobin (Hb) levels according to the protocol. Non-intervention group: The attending physician determined the doses of erythropoietin and iron. Results The maintenance rate of target Hb and ferritin levels were significantly higher in the Intervention group than in the Non-intervention group. The frequency of hospitalization was significantly lower for patients with a higher maintenance rate of target Hb levels than for those with a lower maintenance rate. Conclusions Using an anemia treatment protocol according to the individual Hb and ferritin levels of hemodialysis patients might stabilize the Hb and ferritin levels, which in turn could contribute to the lower frequency of adverse events in MHD patients.

Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown.This multicenter retrospective cohort study included 125 adult-onset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models.During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant difference was observed in incidence of adverse events, including infection, aseptic osteonecrosis, cataract, diabetes, and gastrointestinal bleeding.Initial use of methylprednisolone was associated with earlier remission and lower incidence of relapse in adult-onset minimal change disease patients. Efficacy of methylprednisolone should be evaluated in randomized controlled trials.

Hematuria is the first manifestation of urinary abnormality in immunoglobulin A nephropathy (IgAN). Hematuria has recently been reported as a risk factor for deterioration of renal function; however, its cause remains unknown.We analyzed the surface marker of peripheral blood mononuclear cells before and immediately after tonsillectomy in IgAN patients and controls (chronic tonsillitis or tonsillar hypertrophy) by flow cytometry and investigated the association with hematuria. To prove our hypothesis that NK cells induce hematuria, we administered IL-12, activator of NK cells, to HIGA mice. In addition, we transferred cultured NK cells to nude rats and transferred the CD16(+)CD56(+) cells, including NK cells, that are derived from the peripheral blood of IgAN patients immediately after tonsillectomy to nude rats to assess the hematuria level and renal histology of the recipients. We also performed cytotoxicity assays against glomerular endothelial cells by NK cells.We found that IgAN patients who showed rapid deterioration of hematuria after tonsillectomy also displayed a significant increase in CD16(+)CD56(+) cells in the peripheral blood immediately after tonsillectomy. Exogenous administration of IL-12 to HIGA mice induced hematuria. Adoptive transfer of either cells of an NK cell line, or of CD16(+)CD56(+) cells derived from IgAN patients, into nude rats induced hematuria in the recipients. In vitro analysis showed that NK cells exert cytotoxic activity toward human glomerular endothelial cells in a dose-dependent manner.CD16(+)CD56(+) cells seem to be responsible for hematuria in IgAN.

The association between alcohol consumption and chronic kidney disease (CKD), characterized by reduced glomerular filtration rate and proteinuria, is controversial. Recent studies suggest that serum γ-glutamyltransferase (GGT) level, a conventional marker of excessive alcohol consumption, predicts the CKD incidence. Little information is available on the difference in the clinical impact of alcohol consumption and GGT on proteinuria.The present cross-sectional survey included 332,296 Japanese people aged ≥40 years in 2008. To examine the associations of GGT and alcohol consumption with proteinuria, 134,600 men and 197,696 women were classified into 20 categories based on GGT quartiles and alcohol consumption categories, and their prevalence rate ratios (PRR) of proteinuria defined as ≥1+ of dipstick urinary protein were calculated after adjusting for clinically relevant factors.Prevalence of proteinuria was 7.5 and 3.7 % in men and women, respectively. In both gender an association between alcohol consumption and proteinuria was in a J-shaped fashion with the lowest PRR of mild drinkers with ≤19 g/day of ethanol consumption, whereas an association between serum GGT level and proteinuria was linear. Compared with rare drinkers in the lowest GGT quartile, the subjects in higher GGT quartiles had a higher probability of proteinuria, irrespective of alcohol consumption. An optimal cutoff level of serum GGT was 43.6 and 23.2 IU/L in men and women, respectively.The subjects with higher serum GGT level had a higher probability of proteinuria, regardless of alcohol consumption, suggesting that GGT has a clinically greater impact on CKD than alcohol consumption.

Introduction: Little is known about genetic predictors that modify the renoprotective effect of renin-angiotensin system (RAS) blockade in IgA nephropathy (IgAN). Materials and methods: The present multicenter retrospective observational study examined effect modification between RAS blockade and three RAS-related gene polymorphisms in 237 IgAN patients, including ACE I/D (rs1799752), AT1R A1166C (rs5186) and AGT T704C (rs699). Results: During 9.9 ± 4.2 years of observation, 63 patients progressed to a 50% increase in serum creatinine level. Only ACE I/D predicted the outcome ( ACE DD vs ID/II, hazard ratio 1.86 (95% confidence interval 1.03, 3.33)) and modified the renoprotective effect of RAS blockade ( p for interaction between ACE DD and RAS blockade = 0.087). RAS blockade suppressed progression in ACE DD patients but not in ID/II patients ( ACE ID/II with RAS blockade as a reference; ID/II without RAS blockade 1.45 (0.72, 2.92); DD without RAS blockade 3.06 (1.39, 6.73); DD with RAS blockade 1.51 (0.54, 4.19)), which was ascertained in a model with the outcome of slope of estimated glomerular filtration rate ( p = 0.045 for interaction). Conclusion: ACE I/D predicted the IgAN progression and the renoprotective effect of RAS blockade in IgAN patients whereas neither AT1R A1166C nor AGT T704C did.

Objective For patients with end-stage renal disease on hemodialysis, the durability of vascular access (VA) is still far from optimal, and access survival after intervention for access failure is an important aspect. Procoagulant status is a leading cause of access failure. Coagulation-fibrinolysis imbalance can occur in hemodialyzed patients, but the influence of the imbalance has not been fully elucidated. Methods We prospectively examined coagulation-fibrinolysis balance to assess the risk of access failure after the intervention of revascularization in a cohort of 462 hemodialysis patients. Thrombin-antithrombin complex (TAT) and plasmin-α2-plasmin inhibitor complex (PIC) are markers for coagulation and fibrinolysis. Median follow-up was 243 days. The end point was clinical access failure: revascularization or access revision. The survival curve for VA patency was assessed using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression models that allowed adjustment for baseline differences in age, sex, dialysis vintage, diabetes mellitus, and various factors (quantity of blood flow, prothrombin time-international normalized ratio, fibrin degradation products, C-reactive protein, interleukin-6, tumor necrosis factor-α, and pentraxin-3) were used. Results The 162 patients who reached an end point had smaller access flow volume and smaller percentage of arteriovenous fistula and higher TAT/PIC ratio. Kaplan-Meier analysis indicated that the patients with elevated TAT/PIC ratio showed poorer outcome (P Conclusions Our results suggest that coagulation-fibrinolysis imbalance is a significant risk factor for access failure and may predict VA failure in hemodialyzed patients after access intervention.

Patients with chronic kidney disease on dialysis are at higher risk for cardiovascular disease (CVD), which is the greatest cause of mortality. The target range of serum intact parathyroid hormone (iPTH) for prognosis, 60 to 240 pg/mL, was recommended by the Japanese Society for Dialysis Therapy guidelines. To investigate the impact of this iPTH target on CVD, dialysis patients were enrolled. A total 287 participants were observed. At the start of the study, serum iPTH levels, routine laboratory parameters, and certain factors related to CVD were evaluated. A survival analysis (Kaplan-Meier curve) was used. After 10 years of follow-up, 19.2% of patients had CVD. The subjects were divided into three groups according to their iPTH level at baseline based on the target range of 60 to 240 pg/mL: Low, Middle, and High groups. CVD was more common in the High and Low groups compared to the Middle group. A lower risk of CVD was evident in the extended dialysis patients with a range of 60 to 240 pg/mL iPTH. Further studies are needed to evaluate the impact of the iPTH level on poor outcome.