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Background: The simultaneous presence of Streptococcus mutans expressing the Cnm protein encoded by cnm (i.e., cnm-positive S. mutans) and Campylobacter rectus in the oral cavity has been associated with proteinuria in patients with IgA nephropathy (IgAN). Objectives: The present study evaluated the relationship between renal function and oral bacteria in patients with IgAN over 5 years of follow-up. Methods: The presence of C. rectus and cnm-positive S. mutans in saliva samples of 117 patients with IgAN was initially evaluated by polymerase chain reaction. Patients were then divided into four groups according to the results of C. rectus and cnm-positive S. mutans detection: group A: C. rectus (−), cnm-positive S. mutans (−); group B: C. rectus (+), cnm-positive S. mutans (−); group C: C. rectus (−), cnm-positive S. mutans (+); and group D: C. rectus (+), cnm-positive S. mutans (+). Clinical characteristics were prospectively followed for 5 years. Results: Serum creatinine levels were significantly higher in group D than in group A over 5 years of follow-up. Additionally, the proportion of patients with an estimated glomerular filtration rate Conclusion: These results suggest that the simultaneous presence of C. rectus and cnm-positive S. mutans in the oral cavity is associated with renal dysfunction in IgAN patients.

Periodontopathic bacteria cause an inflammatory disease localized in the periodontal tissue and are associated with various conditions in other body parts. The distribution of periodontopathic bacterial species in the tonsils is unknown, even though the tonsils are located close to the oral cavity, and inflammation of the tonsils causes various systemic diseases. We detected the major periodontopathic bacterial species residing in saliva and tonsil specimens from 25 subjects undergoing tonsillectomy. Nine of the ten major periodontopathic bacterial species were detected by polymerase chain reaction of tonsil specimens, among which Campylobacter rectus was the most common (80.0%), followed by Porphyromonas gingivalis (36.0%). The other seven types of periodontopathic bacterial species were distributed with 0% to 25.0% abundance in the tonsil specimens. C. rectus had a high detection rate in tonsil specimens ( 75.0%), regardless of whether it was detected in the corresponding saliva specimens. However, the detection rate for P. gingivalis in tonsil specimens was significantly higher in subjects with P. gingivalis-positive saliva (77.8%) than in those with P. gingivalis-negative saliva (6.3%; P 0.001). Furthermore, 75.0% of P. gingivalis in tonsil specimens did not have the known fimA gene that encodes the 41-kDa filamentous appendage protein FimA, which is expressed on the cell surface of the bacteria. Our results suggest that certain periodontopathic bacterial species are detected in the tonsils either independently of or depending on their distribution in the oral cavity and may be involved in tonsil-related diseases.

Purpose Tolvaptan is the first approved treatment for autosomal dominant polycystic kidney disease (ADPKD) that targets a mechanism directly contributing to the development and growth of renal cysts. We investigated the ability of ultrasonography to predict total kidney volume (TKV) of 750 mL or more, which is an indication for tolvaptan therapy in patients with ADPKD. Methods A total of 46 patients with ADPKD were evaluated. The most statistically appropriate measurement based on ultrasonography for predicting TKV determined by computed tomography (CT) was assessed. Results TKV determined by CT was 796.8 (508.8–1,560.3) mL. The median length, anteroposterior distance, and mediolateral distance determined using ultrasonography were 15.7 cm, 7.6 cm, and 7.6 cm in the left kidney, and 13.4 cm, 6.9 cm, and 7.2 cm in the right kidney, respectively. Multivariate regression analysis showed that total kidney length (left and right) [variance inflation factor (VIF), 9.349] and total mediolateral distance (left and right) (VIF, 3.988) were independently associated with TKV. The correlation (r) between the logarithm of TKV determined by CT and total mediolateral distance determined using ultrasonography was 0.915 (p Conclusion Total mediolateral distance determined using ultrasonography can predict TKV in patients with ADPKD.

Previous cohort studies have reported conflicting associations between alcohol consumption and chronic kidney disease, characterized by proteinuria and low glomerular filtration rate (GFR). This systematic review, which included 14,634,940 participants from 11 cohort studies, assessed a dose-dependent association of alcohol consumption and incidence of proteinuria and low estimated GFR (eGFR) of

The presence of Streptococcus mutans expressing Cnm protein encoded by cnm (cnm-positive S. mutans) in the oral cavity is associated with immunoglobulin A (IgA) nephropathy (IgAN). However, the precise mechanism by which cnm-positive S. mutans is involved in the pathogenesis of IgAN remains unclear. The present study evaluated glomerular galactose-deficient IgA1 (Gd-IgA1) to clarify the association between the presence of cnm-positive S. mutans and glomerular Gd-IgA1 in patients with IgAN. The presence of S. mutans and cnm-positive S. mutans was evaluated by polymerase chain reaction in saliva specimens from 74 patients with IgAN or IgA vasculitis. Immunofluorescent staining of IgA and Gd-IgA1 using KM55 antibody in clinical glomerular tissues was then performed. There was no significant association between the glomerular staining intensity of IgA and the positive rate of S. mutans. However, there was a significant association between the glomerular staining intensity of IgA and the positive rate of cnm-positive S. mutans (P < 0.05). There was also a significant association between the glomerular staining intensity of Gd-IgA1 (KM55) and the positive rate of cnm-positive S. mutans (P < 0.05). The glomerular staining intensity of Gd-IgA1 (KM55) was not associated with the positive rate of S. mutans. These results suggest that cnm-positive S. mutans in the oral cavity is associated with the pathogenesis of Gd-IgA1 in patients with IgAN.

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.

The simultaneous presence of Streptococcus mutans expressing the Cnm protein encoded by cnm (i.e., cnm-positive S. mutans) and Campylobacter rectus in the oral cavity has been associated with proteinuria in patients with IgA nephropathy (IgAN).The present study evaluated the relationship between renal function and oral bacteria in patients with IgAN over 5 years of follow-up.The presence of C. rectus and cnm-positive S. mutans in saliva samples of 117 patients with IgAN was initially evaluated by polymerase chain reaction. Patients were then divided into four groups according to the results of C. rectus and cnm-positive S. mutans detection: group A: C. rectus (-), cnm-positive S. mutans (-); group B: C. rectus (+), cnm-positive S. mutans (-); group C: C. rectus (-), cnm-positive S. mutans (+); and group D: C. rectus (+), cnm-positive S. mutans (+). Clinical characteristics were prospectively followed for 5 years.Serum creatinine levels were significantly higher in group D than in group A over 5 years of follow-up. Additionally, the proportion of patients with an estimated glomerular filtration rate45 mL/min increased over time; it was significantly greater in group D than in group A over 5 years of follow-up.These results suggest that the simultaneous presence of C. rectus and cnm-positive S. mutans in the oral cavity is associated with renal dysfunction in IgAN patients.

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.

The mechanisms underlying immunoglobulin A nephropathy (IgAN), the most common chronic form of primary glomerulonephritis, remain poorly understood. Streptococcus mutans, a Gram-positive facultatively anaerobic oral bacterium, is a common cause of dental caries. In previous studies, S. mutans isolates that express Cnm protein on their cell surface were frequently detected in IgAN patients. In the present study, inoculation of Cnm-positive S. mutans in the oral cavities of 2-week-old specific-pathogen free Sprague–Dawley rats fed a high-sucrose diet for 32 weeks produced severe dental caries in all rats. Immunohistochemical analyses of the kidneys using IgA- and complement C3-specific antibodies revealed positive staining in the mesangial region. Scanning electron microscopy revealed a wide distribution of electron dense deposits in the mesangial region and periodic acid-Schiff staining demonstrated prominent proliferation of mesangial cells and mesangial matrix. These results suggest that IgAN-like glomerulonephritis was induced in rats with severe dental caries by Cnm-positive S. mutans.

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.

A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.

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

Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies. We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder.

An arteriovenous fistula (AVF) is considered the gold standard modality of vascular access (VA) for maintenance hemodialysis (HD) because of its superior patency, few complications, provision of high quality of life, and low risk of patient mortality. The rapid growth of the aging population and the high prevalence of comorbidities, particularly diabetes mellitus and peripheral vascular disease, in patients requiring HD inevitably deteriorate the ability to construct and maintain a conventional AVF because of these patients' insufficient vascular adaptability. Furthermore, a substantial proportion of patients undergoing HD encounter non-maturation AVF failure and mis-cannulation-related complications, resulting in the need for a temporary VA procedure. Superficialization of the AVF is an alternative form of VA that facilitates the construction of an autologous fistula by maximizing the availability of a deeply located vein. Superficialization is also utilized in VA revision to improve the cannulability of an arterialized vein.Superficialization involves various approaches, including tunnel transposition, elevation, lipectomy, and liposuction. Tunnel transposition and elevation are prerequisites for construction of an alternative autologous AVF, especially a one- or two-stage transposed brachial-basilic AVF, which is widely recognized as preferential to an arteriovenous graft in patients who cannot undergo conventional AVF installation. Elevation, lipectomy, and liposuction are also employed as revisional interventions for approximating the depth of the arterialized vein and ensuring a sufficient cannulable segment in the forearm and upper arm area. More recently, modified minimally invasive techniques for each superficialization procedure have been introduced to avoid postoperative complications. Amid the growing methodological diversity of superficialization, increasingly more studies have been performed in an attempt to clarify its feasibility and outcomes. On the whole, most superficialization procedures have acceptable patency and safety profiles. However, the preferable superficialization approach varies in accordance with both the influence of the anatomic location and the inherent advantages and limitations of each procedure. Key Messages: Both careful assessment of a patient's vascular adaptability and adequate comprehension of the various superficialization modalities that are available will enable optimal establishment of an autologous AVF in individual patients. This could lead to better outcomes and more successful management of HD.

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.

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.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.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.C. rectus was significantly more prevalent in the IgAN group than in the control group (p0.05). The C. rectus-positive group was significantly associated with proteinuria in the IgAN group (p0.05). 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 (p0.0083).Our results suggest that harbouring C. rectus in the oral cavity could be associated with proteinuria in IgAN patients.

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.