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Advanced glycation end products (AGEs), produced by the Maillard reaction between carbohydrates and proteins, may be involved in diabetes and its complications. Accurate quantification of AGEs

Background The Pandemic of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has critically impacted the spread of infection within nursing facilities. We evaluated the usefulness of genetic and serological tests conducted during a COVID-19 outbreak in a nursing facility in Japan. Methods After the first identification of SARS-CoV-2 infection, a comprehensive, facility- and/or unit-wide PCR testing from nasopharyngeal swabs was repeatedly performed in a three-unit facility including 99 residents with dementia and 53 healthcare personnel. Additionally, PCR testing was conducted separately for residents and staff with fever of ≥37.5 °C. Facility-wide serological testing, including rapid kit testing and quantitative assay, was conducted twice over 1 month apart. Results A total of 322 PCR and 257 antibody tests were performed. 37 (24.3%) of the 152 individuals (25/99 residents, 25.3%; 12/53 staff, 22.6%) were identified as PCR-positive. Seven residents died with a mortality of 7.1% (7/99). Among the 37 individuals, 10 (27.0%) were asymptomatic at the time of testing. PCR positivity was concentrated on one unit (Unit 1) (20/30 residents, 66.7%; 9/14 staff, 64.3%). The other units showed a limited spread of infection. In unit-wide and separate tests, PCR positivity detection was highly prevalent (22.9 and 44.4%, respectively) in Unit 1, compared with that in the other units. Serological testing identified two additional infected residents with a negative PCR result and showed that no staff was newly identified as infected. Conclusions Thorough PCR testing, in combination with comprehensive and separate tests, is critical for managing COVID-19 outbreaks in nursing facilities, particularly, in units considered an epicenter. Serological testing is also beneficial for tracing contacts, confirming the number of infected individuals, and authorizing the termination of the outbreak.

A 54-year-old Japanese woman developed simultaneous abdominal distension and bilateral leg edema. Her medical history and results of periodic medical check-up were unremarkable. Blood tests revealed severe hypoproteinemia and acute kidney injury, and urinalysis revealed 4+ proteinuria and 2+ hematuria. Abdominal computed tomography revealed a large intra-abdominal mass with fat tissue density. She underwent emergency tumor excision, splenectomy, and distal pancreatectomy. However, hypoproteinemia and acute kidney injury worsened. Therefore, she was transferred to the nephrology division for confirmation of diagnosis and for treatment of acute kidney injury and nephrotic syndrome. We conducted percutaneous kidney biopsy and diagnosed minimal change disease (MCD). Intravenous prednisolone was started, and heavy proteinuria and systemic edema were gradually alleviated. She achieved complete remission 2 months later, and oral prednisolone was tapered. Histopathological diagnosis of abdominal tumor was dedifferentiated liposarcoma of retroperitoneal origin. Immunohistochemical staining revealed strong expression of vascular endothelial growth factor in the tumor cells in the dedifferentiated component. Currently, her clinical course is stable without recurrence of liposarcoma and nephrotic syndrome. MCD develops in patients with Hodgkin’s lymphoma, solid organ cancers, hematological malignancies, and thymoma, whereas concurrent MCD and liposarcoma are rare. Remission of nephrotic syndrome and normalized kidney function induced by steroid therapy are important for better management of patients with malignancy.

Combined computed tomography-derived myocardial blood flow (CTP-MBF) and computed tomography angiography (CTA) has shown good diagnostic performance for detection of coronary artery disease (CAD). However, fractal analysis might provide additional insight into ischemia pathophysiology by characterizing multiscale perfusion patterns and, therefore, may be useful in diagnosing hemodynamically significant CAD.The purpose of this study was to investigate, in a multicenter setting, whether fractal analysis of perfusion improves detection of hemodynamically relevant CAD over myocardial blood flow quantification (CTP-MBF) using dynamic, 4-dimensional, dynamic stress myocardial computed tomography perfusion (CTP) imaging.In total, 7 centers participating in the prospective AMPLIFiED (Assessment of Myocardial Perfusion Linked to Infarction and Fibrosis Explored with Dual-source CT) study acquired CTP and CTA data in patients with suspected or known CAD. Hemodynamically relevant CAD was defined as ≥90% stenosis on invasive coronary angiography or fractional flow reserve 0.80. Both fractal analysis and CTP-MBF quantification were performed on CTP images and were combined with CTA results.This study population included 127 participants, among them 61 patients, or 79 vessels, with CAD as per invasive reference standard. Compared with the combination of CTP-MBF and CTA, combined fractal analysis and CTA improved sensitivity on the per-patient level from 84% (95% CI: 72%-92%) to 95% (95% CI: 86%-99%; P = 0.01) and specificity from 70% (95% CI: 57%-82%) to 89% (95% CI: 78%-96%; P = 0.02). The area under the receiver-operating characteristic curve improved from 0.83 (95% CI: 0.75-0.90) to 0.92 (95% CI: 0.86-0.98; P = 0.01).Fractal analysis constitutes a quantitative and pathophysiologically meaningful approach to myocardial perfusion analysis using dynamic stress CTP, which improved diagnostic performance over CTP-MBF when combined with anatomical information from CTA.

Fractal analysis of dynamic, four-dimensional computed tomography myocardial perfusion (4D-CTP) imaging might have potential for noninvasive differentiation of microvascular ischemia and macrovascular coronary artery disease (CAD) using fractal dimension (FD) as quantitative parameter for perfusion complexity. This multi-center proof-of-concept study included 30 rigorously characterized patients from the AMPLIFiED trial with nonoverlapping and confirmed microvascular ischemia (nmicro = 10), macrovascular CAD (nmacro = 10), or normal myocardial perfusion (nnormal = 10) with invasive coronary angiography and fractional flow reserve (FFR) measurements as reference standard. Perfusion complexity was comparatively high in normal perfusion (FDnormal = 4.49, interquartile range [IQR]:4.46–4.53), moderately reduced in microvascular ischemia (FDmicro = 4.37, IQR:4.36–4.37), and strongly reduced in macrovascular CAD (FDmacro = 4.26, IQR:4.24–4.27), which allowed to differentiate both ischemia types, p

This study measured the fume particle size distribution and fume generation rate during arc welding of cast iron and estimated the generation rate of respirable dust. In addition, the generation rate of particles with a diameter of 0.3 µm or less was estimated. In this experiment, three types of filler materials (mild steel wire, stainless steel wire, and mild steel covered electrodes) with main constituents of Fe or Fe-Cr-Ni, as proposed previously by the authors, were used. The welding methods were gas metal arc welding and shielded metal arc welding. The fumes measured in this research contained 73–91% respirable dust, and the fume generation rates were in the range of 1.96–12.2 mg/s. The results of this study were as follows: (i) the welding current affects the generation rate of respirable dust, and it is highly likely that the higher the fume generation rate, the more respirable dust is generated; (ii) the generation rates of respirable dust at low and high current were highest when mild steel covered electrodes and stainless steel wire was used, respectively; and (iii) the generation rate of particles with a diameter of 0.3 µm or less was highest when stainless steel wire is used.

Background There is uncertainty surrounding the causal relationship between serum uric acid and hypertension. The aim was to investigate the association between serum uric acid and prevalence of hypertension in a general population of Japanese. Methods This was a population-based cross-sectional study using health check-up data of the residents of the Iki City, Nagasaki Prefecture, Japan. A total of 7,484 participants aged 30 years or older were included in this study. Serum uric acid was classified into four groups: group 1 (< 357 µmol/L (< 6 mg/dL)), group 2 (357 - 415 µmol/L (6 - 6.9 mg/dL)), group 3 (416 - 475 µmol/L (7 - 7.9 mg/dL)) and group 4 (≥ 476 µmol/L (≥ 8 mg/dL)). Hypertension was defined as blood pressure (BP) levels of ≥ 140/90 mm Hg or use of BP lowering medications. Results Hypertension was observed among 3,467 participants (prevalence 46.3%). The prevalence of hypertension increased with elevation of serum uric acid levels: 42.8% in group 1, 55.0% in group 2, 57.6% in group 3 and 59.8% in group 4 (P < 0.001 for trend). This association was significant even after adjustment for other risk factors including age, sex, current smoking, current alcohol intake, obesity, diabetes, dyslipidemia, estimated glomerular filtration rate and proteinuria: odds ratios (95% confidence intervals) were 1.50 (1.28 - 1.77) for group 2, 1.58 (1.25 - 1.99) for group 3 and 1.89 (1.36 - 2.64) for group 4 compared with the reference group of group 1 (P < 0.001 for trend). Conclusions Serum uric acid was clearly associated with prevalence of hypertension in a general population of Japanese.

Background: We investigated whether eating speed was associated with the incidence of diabetes in a Japanese general population. Methods: A total of 4853 Japanese individuals without diabetes at baseline were analyzed. Self-reported eating speed was categorized as slow, medium, and fast on the basis of questionnaire responses. The study outcome was the incidence of diabetes. Results: After an average follow-up period of 5.1 years, 234 individuals developed diabetes. The incidence of diabetes per 1000 person-years was 4.9 in the slow eating speed group, 8.8 in the medium eating speed group, and 12.5 in the fast eating speed group, respectively (*** p &lt, 0.001 for trend). The HRs were 1.69 (95%CI 0.94–3.06) for the medium eating speed and 2.08 (95%CI 1.13–3.84) for the fast eating speed, compared to the slow eating speed (* p = 0.014 for trend) after adjustment for age, gender, smoking status, drinking, exercise, obesity, hypertension, and dyslipidemia. Conclusion: Faster eating speed increased a risk for the incidence of diabetes in a general Japanese population.

Background and Aims Diabetic nephropathy (DN) is currently a leading cause of end-stage kidney disease worldwide. Kidney biopsy is generally performed in diabetic patients to discriminate between DN and non-diabetic kidney disease (NDKD), and to provide more specific treatments. In addition to conventional predicting factors of DN, recent studies suggested the predictive value of anemia in the diagnosis of DN, however detailed pathophysiology and the significance of anemia in renal pathology are not fully understood. This study aimed to investigate the impact of anemia on renal pathology and clinical course in patients who underwent kidney biopsy. Method We reviewed 81 patients (60.4 ± 13.7 years, 54 men and 27 women) with type 2 diabetes who underwent percutaneous kidney biopsy in Fukuoka University Hospital from January 2001 through March 2020. DN was diagnosed by mesangial expansion or nodular glomerulosclerosis observed under a light microscope, and immunofluorescence assisted in differentiating NDKD from DN. Anemia was defined as hemoglobin level Results According to their pathological findings, patients were classified into two groups: isolated DN (DN group, n=30) and NDKD alone or concurrent DN (NDKD group, n=51). There were 11 types of NDKD. Of these, membranous nephropathy was the most common (23.5%), followed by IgA nephropathy (17.6%), and crescentic glomerulonephritis (13.7%). In multiple logistic regression analysis, absence of severe hematuria (odds ratio (OR) 11.66, 95% confidence interval (CI) 1.68 - 89.9) and presence of anemia (OR 11.38, 95% CI 2.51 - 51.52) were significantly related with the diagnosis of DN. Akaike’s information criterion (AIC) and net reclassification improvement (NRI) analyses revealed improved predictive performance by adding anemia to the conventional factors (AIC 100.152 to 91.844; NRI 27.0%). The tissues of patients in the DN group demonstrated more severe interstitial fibrosis and tubular atrophy (IF/TA) than the NDKD group (p Conclusion DN is associated with anemia because of severe IF/TA regardless of renal function, and anemia helps clinician discriminate clinically between isolated DN and NDKD.

Single-center studies indicated a high diagnostic accuracy of dynamic computed tomography perfusion (CTP) imaging in the diagnosis of coronary artery disease (CAD).This prospective multicenter study determined the diagnostic performance of combined coronary computed tomography angiography (CTA) and CTP for detecting hemodynamically significant CAD defined by invasive coronary angiography (ICA) with fractional flow reserve (FFR).Seven centers enrolled 174 patients with suspected or known CAD who were clinically referred for ICA. CTA and dynamic CTP were performed using dual-source CT before ICA. FFR was done as part of ICA in the case of 26% to 90% coronary diameter stenosis. Hemodynamically significant stenosis was defined as FFR of 0.8 or90% stenosis on ICA.The study protocol was completed in 157 participants, and hemodynamically significant stenosis was detected in 76 of 157 patients (48%) and 112 of 442 vessels (25%). According to receiver-operating characteristic curve analysis, adding dynamic CTP to CTA significantly increased the area under the curve from 0.65 (95% CI: 0.57-0.72) to 0.74 (95% CI: 0.66-0.81; P = 0.011) on the patient level, with decreased sensitivity (93% vs 72%; P 0.001), improved specificity (36% vs 75%; P 0.001), and improved overall accuracy (64% vs 74%; P 0.001).In this prospective multicenter study on dynamic CTP, the combination of anatomic assessment with coronary CTA and functional evaluation with dynamic CTP allowed more accurate identification of hemodynamically significant CAD compared with CTA alone. However, the clinical significance of this approach needs to be further investigated, including its usefulness in improving prognosis. (Assessment of Myocardial Perfusion Linked to Infarction and Fibrosis Explored With Dual-Source CT [AMPLIFiED]; UMIN000016353).

Objectives This study aimed to clarify the relationship between the white blood cell (WBC) count and hypertension in the general Japanese population. Methods We conducted a population-based retrospective cohort study using annual health check-up data of residents of Iki City, Nagasaki Prefecture, Japan. A total of 2935 participants without hypertension at baseline were included in the present analysis. WBC counts were classified as tertile 1 ( Result During an average follow-up of 4.5 years, 908 participants developed hypertension. The incidence (per 100 person-years) of hypertension increased with an elevation in the WBC count (6.3 in tertile 1, 7.0 in tertile 2, and 7.4 in tertile 3). This association was significant, even after adjustment for other risk factors, including age, sex, current smoking habits, current alcohol intake, exercise habits, obesity, elevated blood pressure, diabetes mellitus, and dyslipidemia. The hazard ratios were 1.07 for tertile 2 (95% CI 0.90–1.26) and 1.27 for tertile 3 (95% CI 1.06–1.51) compared with the reference group of tertile 1 (p = 0.009). Conclusion The WBC count was associated with future development of hypertension in the general Japanese population.

Introduction: Single-center studies indicated a high diagnostic accuracy of dynamic computed tomography perfusion (CTP) imaging in the diagnosis of hemodynamically significant coronary artery disease (CAD). However, no prospective multicenter study has assessed the performance of combined coronary computed tomography angiography (CTA) and dynamic CTP. Hypothesis: In this prospective multicenter study, we assessed the hypothesis that dynamic CTP can provide an incremental diagnostic value over CTA detecting hemodynamically significant CAD defined by invasive coronary angiography (ICA) with fractional flow reserve (FFR). Methods: Seven centers enrolled 165 patients with suspected or known CAD, who were clinically referred for ICA. CTA and dynamic CTP were performed using dual-source CT prior to ICA. FFR was done as part of ICA in case of 26-90% coronary diameter stenosis. Hemodynamically significant stenosis was defined as of FFR Results: The study protocol was completed in 157 participants and hemodynamically significant stenosis was detected in 112 of 442 vessels (25%) and 123 of 157 patients (78%). According to receiver operating characteristic curve analysis, CTA showed an area under the curve (AUC) of 0.81 (95% confidence interval [CI], 0.73-0.86) on the patient level and 0.80 (95% CI, 0.76-0.84) on the vessel level. Adding dynamic CTP to CTA significantly increased the AUC to 0.85 (95% CI, 0.78-0.90; p=0.027) on the patient level and to 0.84 (95% CI, 0.80-0.87; p=0.002) on the vessel level. In the subgroups of patients with 1-, 2- and 3-vessel disease by CTA, the addition of dynamic CTP to CTA significantly increased AUC from 0.80 to 0.84 (p=0.041) in 2-vessel disease and from 0.65 to 0.73 (p=0.022) in 3-vessel disease, but not in 1-vessel disease (from 0.84 to 0.87, p=0.265). Conclusion: In this first prospective multicenter study on dynamic CTP, the combination of anatomical assessment with coronary CTA and functional evaluation with dynamic CTP allowed more accurate detection of hemodynamically significant coronary artery stenosis. Improved diagnostic performance with dynamic CTP was mainly obtained when multivessel disease was suspected by CTA.

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect various organs. The kidney is one of the organs most frequently affected and IgG4-related tubulointerstitial nephritis (TIN) is the most dominant feature.1 However, several radiologically characteristic lesions within the kidney have also been shown to be diagnostic for IgG4-RD affecting the kidney, in the setting of definitively diagnosed IgG4-related lesions in extrarenal organs.2 Therefore the term ‘IgG4-related kidney disease (IgG4-RKD)’ has been proposed as a comprehensive term for the renal lesions associated with IgG4-RD.2 3 In 2011, the IgG4-RKD working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD.4 Recently, we validated those criteria in a Japanese kidney cohort and developed a revised version.5 On the other hand, the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-RD (the ACR/EULAR criteria) were proposed in 2019.6 According to the latter criteria, exclusion criteria should be applied first to any potential IgG4-RD case. Then, inclusion criteria consisting of eight weighted domains are applied to any case that does not satisfy any of the exclusion criteria, and if …

Background In 2011, the IgG4-related kidney disease (IgG4-RKD) working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD. The aim of the present study was to validate those criteria and develop a revised version. Methods Between April 2012 and May 2019, we retrospectively collected Japanese patients with kidney disease, for whom data on serum IgG4 values and/or immunohistological staining for IgG4 in renal biopsy samples were available. These patients were classified as IgG4-RKD or non-IgG4-RKD based on the diagnostic criteria for IgG4-RKD 2011, and the results were evaluated by expert opinion. Accordingly, we developed some revised versions of the criteria, and the version showing the best performance in the present cohort was proposed as the IgG4-RKD criteria for 2020. Results Of 105 included patients, the expert panel diagnosed 55 as having true IgG4-RKD and 50 as mimickers. The diagnostic criteria for IgG4-RKD 2011 had a sensitivity of 72.7% and a specificity of 90.0% in this cohort. Of the 15 patients with true IgG4-RKD who were classified as non-IgG4-RKD, all lacked biopsy-proven extra-renal lesions, although many had clinical findings highly suggestive of IgG4-RD. The revised version to which “bilateral lacrimal, submandibular or parotid swelling, imaging findings compatible with type 1 autoimmune pancreatitis or retroperitoneal fibrosis” was added as an item pertaining to extra-renal organ(s) improved the sensitivity to 90.9% while the specificity remained at 90.0%. Conclusion The revised version has considerably improved test performance after addition of the new extra-renal organ item (imaging and clinical findings).

Background and Aims Chronic kidney disease is one of the most urgent public health issue in Japan as well as other countries. Many risk factors for development and progression of CKD have been recognized, such as hypertension, diabetes, obesity. However, it is still unclear whether increase of serum uric acid has negative impact on kidney function. The aim of this study is to investigate how serum uric acid influences the new-onset and progression of CKD in Japanese general population. Method The Iki epidemiological Study of atherosclerosis And Chronic Kidney Disease (ISSA-CKD) is a population-based retrospective cohort study using annual health check-up data in the Iki Island (Nagasaki Prefecture, Japan), which has approximately 27,000 residents. A total of 7,645 residents underwent annual health check-ups from fiscal year 2008 to 2016. After excluding residents who visited only 1 health check-up and those with missing information of serum creatinine or serum uric acid, a total of 5507 adults were included in the present analysis. The outcome of the present analysis was new-onset of CKD (reduction in estimated glomerular filtration rate [eGFR] less than 60mL/min/1.73m2 or development of proteinuria among participants without CKD at baseline) and CKD progression (worsening of the stages of eGFR or proteinuria according to the KDIGO guideline among participants with CKD at baseline). Results During a mean follow-up of 4.6 years, 757 (16.7%) new-onset CKD and 193 (19.7%) progression of CKD were observed. Serum uric acid had significant relationship with new-onset CKD even after adjustment for sex, age, obese, hypertension, dyslipidemia, and diabetes mellitus: hazard ratio 1.14 per 1 mg/dL increase, 95% confidence interval 1.07-1.21, P Conclusion The findings of the present analysis show that serum uric acid was significantly associated with increased risks of new onset of CKD, but was not associated with progression of CKD in Japanese general population.

Here, we present a 67-year-old Japanese man who developed insidious-onset nephrotic syndrome. He had a history of occupational asbestos exposure for about 8 years during his 30s, and was found to have pleural effusion 3 years before his present illness. At that time, repeated cytology testing of his pleural effusion found no malignant cells, and pleural biopsy found fibrous pleuritis without evidence of malignant mesothelioma. Percutaneous kidney biopsy found massive deposits of AA-type amyloid in the glomeruli, small arteries, and medulla. Computed tomography showed a calcified mass in the right lower lung that was positive for (67)Ga uptake, but transbronchial lung biopsy and bronchoalveolar lavage found no evidence of malignancy. He was diagnosed with rounded atelectasis and diffuse pleural thickening. As these benign asbestos-related diseases have no standard treatment, we administered low-dose angiotensin II receptor blocker to preserve kidney function. Unfortunately, his nephrotic syndrome persists, with progressive chronic kidney failure. Kidney involvement in patients with asbestos-related disease is rare. To our knowledge, this is the first case to present with secondary amyloidosis. Kidney biopsy should be considered for patients with existing asbestos-related pleuropulmonary diseases who have urinary abnormalities or renal dysfunction, to clarify the incidence and pathophysiology of renal manifestations.

Objectives Ultraviolet radiation (UVR) emitted during arc welding frequently causes keratoconjunctivitis and skin erythema. The extent of the hazard of UVR varies depending on the welding process and conditions. Therefore, it is important to identify the levels of UVR present under different conditions. The purpose of this study was to investigate the degree of hazard of UVR emitted by the different types of arc welding of cast iron frequently used in industry. Methods In this study, we experimentally measured the UVR emitted during gas tungsten arc welding (GTAW), shielded metal arc welding (SMAW), and gas metal arc welding (GMAW) of cast iron. The degree of hazard of UVR was quantitatively evaluated in accordance with the guidelines of the American Conference of Governmental Industrial Hygienists. Results Effective irradiances measured in this study were in the range 0.045‐2.2 mW/cm2 at a distance of 500 mm from the welding arc. The maximum allowable exposure times corresponding to these levels were only 1.4‐67 s/day. Conclusions UVR emitted during arc welding of cast iron has the following characteristics: (a) It is more hazardous at higher welding currents. (b) The magnitude of the hazard, which depends on the welding process, increases in the order of GMAW > SMAW > GTAW. (c) It is influenced by the filler material used; that is, the components contained in the filler material affect the hazard of UVR. The effect is Fe > Ni, Cr

The aim of this study was to investigate the effects of long-term weight gain from the age of 20 on incidence of hyper-low-density-lipoprotein (LDL) cholesterolemia in the general population of Japanese people. Methods: We conducted a population-based retrospective cohort study using annual health checkup data for residents of Iki City, Nagasaki Prefecture, Japan. A total of 3179 adult (≥30 years old) men and women without hyper-LDL cholesterolemia at baseline, who underwent two or more health checkups were included in the analysis. Information on weight gain (≥10 kg) after 20 years of age was obtained using questionnaire. The outcome of this study was development of hyper-LDL cholesterolemia defined as LDL-cholesterol level ≥3.62 mmol/L and/or initiation of lipid-lowering medications. Results: During a mean follow-up period of 4.53 years, 665 of the 3179 participants developed hyper-LDL cholesterolemia (46.5/1000 person-years). The incidence of hyper-LDL cholesterolemia was higher in participants with a weight gain of ≥10 kg (55.3/1000 person-years) than among those with a weight gain of &lt, 10 kg (41.8/1000 person-years). This association remained statistically significant even after adjustment for age, sex, smoking, daily drinking, exercise, obesity, hypertension, and diabetes (multivariable hazard ratio 1.31, 95% confidence interval 1.08–1.58, p = 0.006). Conclusion: A weight gain of ≥10 after 20 years of age affected the development of hyper-LDL cholesterol regardless of age, sex, and obesity in a general population of Japanese.

Background More than 2 years have passed since the proposal of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD). The aim of this study was to estimate the number of histological diagnosis for IgG4-RKD throughout Japan and to clarify the regional distribution of the development of this disease. Methods A questionnaire was supplied to 140 research facilities registered in the Japan Renal Biopsy Registry (J-RBR). The items of the questionnaire were the total number of renal biopsies performed and the number of cases diagnosed as IgG4-RKD in 2012 and 2013 at each facility. Age, sex, and diagnosis category were also included for the IgG4-RKD cases. The geographic distribution of the disease development was evaluated using clinical case reports presented at the Eastern/Western regional meeting of the Japanese Society of Nephrology during the 15 years following 2001. Results Forty-seven facilities completed the questionnaire, resulting in a collection rate of 34 %. The total numbers of renal biopsies in 2012 and 2013 were 3387 and 3591, respectively. Forty-seven of these cases (24 in 2012 and 23 in 2013) were diagnosed as IgG4-RKD. The frequency of development of IgG4-RKD per one million over 40-year-old individuals during these 15 years varied between 0.9 and 3.1, depending on Japanese geographic region of Japan. Conclusion The results of the present survey indicate that the number of diagnosis for IgG4-RKD is approximately 130 cases per year throughout Japan, and no regional differences in disease frequency appear to exist.

Objectives: Ultraviolet radiation (UVR) emitted during arc welding frequently causes keratoconjunctivitis and erythema in the workplace. The degree of hazard from UVR exposure depends on the welding method and conditions. Therefore, it is important to identify the UVR levels present under various conditions. Methods: We experimentally evaluated the UVR levels emitted in gas metal arc welding (GMAW) of mild steel. We used both a pulsed welding current and a non-pulsed welding current. The shielding gases were 80% Ar + 20% CO2 and 100% CO2. The effective irradiance defined in the American Conference of Governmental Industrial Hygienists guidelines was used to quantify the UVR hazard. Results: The effective irradiance measured in this study was in the range of 0.51-12.9 mW/cm2 at a distance of 500 mm from the arc. The maximum allowable exposure times at these levels are only 0.23-5.9 s/day. Conclusions: The following conclusions were made regarding the degree of hazard from UVR exposure during the GMAW of mild steel: (1) It is more hazardous at higher welding currents than at lower welding currents. (2) At higher welding currents, it is more hazardous when 80% Ar + 20% CO2 is used as a shielding gas than when 100% CO2 is used. (3) It is more hazardous for pulsed welding currents than for non-pulsed welding currents. (4) It appears to be very hazardous when metal transfer is the spray type. This study demonstrates that unprotected exposure to UVR emitted by the GMAW of mild steel is quite hazardous.

Background:The 2019 ACR/EULAR classification criteria for IgG4-RD have recently been published1). In the criteria, patients with an inclusion criteria score of >20 without exclusion criteria are classified as having IgG4-RD.Objectives:To validate the 2019 ACR/EULAR classification criteria for IgG4-RD in a Japanese kidney disease cohort.Methods:The study involved Japanese patients diagnosed as having kidney disease between April 2012 and May 2019, for whom sufficient clinical information and data on serum IgG4 values and/or immunohistological staining for IgG4 in renal biopsy samples were known. These patients were classified as having IgG4-RKD or non-IgG4-RKD (mimickers) based on the 2019 ACR/EULAR classification criteria for IgG4-RD, and the results were evaluated by expert opinion.Results:Among 105 included patients, the expert panel diagnosed 55 as having true IgG4-RKD and 50 as mimickers. The final diagnoses among the mimickers were vasculitis (n=11), idiopathic tubulointerstitial nephritis (TIN) (n=5), drug-induced TIN (n=5), Sjögren’s syndrome (n=4) and others. Among the 55 true IgG4-RKD patients, 4 had exclusion criteria, and 50 of the remaining 51 had an inclusion criteria score of ≥20 points (sensitivity 90.9%). On the other hand, 49 of the 50 mimickers were classified as having non-IgG4-RKD (specificity 98.0%) (Table 1).Table 1.General characteristics and prevalence of individual items of true IgG4-RKD and non-IgG4-RKD (mimicker)IgG4-RKD(true IgG4-RKD)(n=55)Non-IgG4-RKD(mimicker)(n=50)PAge at diagnosis,mean ±SD (years)69.9 ± 9.456.7 ± 17.4Male (%)76.4440.001Elevated serum IgG454/55 (98.2%)18/50 (36.0%)Serum IgG4 (mg/dl), mean±SD1028 ± 796226 ± 261Dense IgG4+Plasma cells (>10/hpf) in the kidney biopsy48/51 (94.1%)13/40 (32.5%)Storiform fibrosis in the kidney biopsy28/51 (54.9%)3/50 (6%)Hypocomplementemia39/55 (70.1%)7/42 (16.7%)Renal pelvis thickening/soft tissue5/55 (9%)1/50 (2%)0.20Bilateral renal cortex low-density areas29/55 (52.7%)7/50 (14.0%)Exclusion criteria present4/55 (7.3%)22/50 (44%)Total inclusion criteria points >20 without exclusion criteria50/55 (90.9%)1/50 (2%)Conclusion:The 2019 ACR/EULAR classification criteria for IgG4-RD showed good agreement with expert classification in this Japanese kidney disease cohort.References:[1] Wallace ZS, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 79:77-87, 2020Disclosure of Interests:None declared

The most representative kidney lesion of IgG4-related disease (IgG4-RD) is plasma cell-rich tubulointerstitial nephritis (TIN) with distinctive imaging findings including multiple low-density lesions on contrast-enhanced computed tomography. In addition, membranous glomerulonephritis is a representative glomerular lesion of this disease. Recent advances have clarified that inflammation with IgG4-positive plasma cell infiltrates is not restricted to the renal parenchyma, but can be seen in outside the renal capsule, around medium-sized arteries such as lobar arteries, around nerves, and in the renal pelvis and periureter. Hypocomplementemia is a very important feature of IgG4-TIN, and serum complement level might serve as a convenient biomarker to predict relapse. Although good responsiveness to glucocorticoid has been considered characteristic of IgG4-RD, delayed start of treatment is associated with partial scarring in the kidneys on imaging study. Therefore, steroid therapy should be immediately initiated as soon as the diagnosis of IgG4-TIN is made. Future analyses of pathogenesis will be needed to more precisely define the optimal therapeutic strategies for the various subsets of Ig4-RD patients.

Ultraviolet radiation (UVR) emitted during arc welding frequently causes keratoconjunctivitis and erythema. The extent of the hazard of UVR varies depending on the welding method and conditions. Therefore, it is important to identify the levels of UVR that are present under various conditions. In this study, we experimentally evaluated the hazard of UVR emitted in gas tungsten arc welding (GTAW) of aluminum alloys. The degree of hazard of UVR is measured by the effective irradiance defined in the American Conference of Governmental Industrial Hygienists guidelines. The effective irradiances measured in this study are in the range 0.10-0.91 mW/cm(2) at a distance of 500 mm from the welding arc. The maximum allowable exposure times corresponding to these levels are only 3.3-33 s/day. This demonstrates that unprotected exposure to UVR emitted by GTAW of aluminum alloys is quite hazardous in practice. In addition, we found the following properties of the hazard of UVR. (1) It is more hazardous at higher welding currents than at lower welding currents. (2) It is more hazardous when magnesium is included in the welding materials than when it is not. (3) The hazard depends on the direction of emission from the arc.

Immunoglobulin G4-related disease is a rare immune-mediated disease characterized by the infiltration of IgG4-positive plasma cells and unique storiform fibrosis of multiple organs. The majority of IgG4-related disease patients respond to glucocorticoids, yet the precise mechanism of their action remains unclear. Pathological sections of the submaxillary gland, kidney, and retroperitoneum from 20 patients in total diagnosed with IgG4-related disease were analyzed for glucocorticoid receptor expression and the cell types expressing glucocorticoid receptor. Strong and abundant expression of glucocorticoid receptor was observed in the submaxillary gland, kidney, and retroperitoneum of IgG4-related disease patients, while glucocorticoid receptor was rarely or only faintly observed in the submaxillary gland of patients with Sjogren's syndrome, radicular cysts and sialolithiasis or in the healthy kidney. Glucocorticoid receptor was mainly expressed in fibro/myofibroblasts, CD4-positive T cells and IgG4-positive plasma cells in the submandibular glands and kidneys of IgG4-related disease patients. The abundant expression of glucocorticoid receptor in various types of cells, including resident fibro/myofibroblasts in IgG4-related disease patients might provide clues to the mechanism of steroid responsiveness in IgG4-related disease patients.

Background Although vascular endothelial growth factor (VEGF) is elevated in patients with acute myocardial infarction (AMI), the clinical significance of its elevation remains unclear. The present study was designed to determine the relationship between VEGF and left ventricular dimension in patients with AMI. Methods and results Plasma VEGF levels were examined by enzyme-linked immunosorbent assay daily for one week and then weekly for four weeks in 38 patients with AMI (65.4 ± 1.7 years). Left ventriculography was performed at 14 days, 6 months, and 2 years after the onset of AMI. Plasma VEGF levels were significantly elevated and reached a peak on day 6. Peak plasma VEGF levels positively correlated with both end-diastolic and end-systolic volume indices at 14 days after the onset of AMI. When patients with AMI were divided into two groups according to plasma VEGF levels on admission, left ventricular volume indices were higher in the high VEGF group than in the low VEGF group at the subacute phase of AMI (14 days). These differences were no longer present in the chronic phase of AMI. Conclusion Plasma VEGF levels were increased in patients with AMI, and peak levels were associated with left ventricular volume indices in the subacute phase, suggesting an important role of endogenous VEGF in the left ventricular dimension in patients with AMI.

Background— Noncardiac surgery after percutaneous coronary intervention (PCI) has been reported to be carrying high risk for both ischemic and bleeding complications. However, there has been no report comparing the incidence and outcomes of surgical procedures after coronary artery bypass grafting (CABG) with those after PCI. Methods and Results— Among 14 383 patients undergoing first coronary revascularization (PCI, n=12 207; CABG, n=2176) enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG Registry Cohort-2, surgical procedures were performed more frequently after CABG (n=560) than after PCI (n=2398; cumulative 3-year incidence: 27% versus 22%; unadjusted P P =0.9; adjusted hazard ratio, 0.97; 95% confidence interval, 0.47–1.89; P =0.9). The risk for the primary bleeding outcome measure (moderate or severe bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification) was lower in the CABG groups than in the PCI group (cumulative incidence: 1.3% versus 2.6%; unadjusted P =0.07; adjusted hazard ratio, 0.36; 95% confidence interval, 0.12–0.87; P =0.02). There were no interactions between the timing of surgery and the types of coronary revascularization (CABG/PCI) for both ischemic and bleeding outcomes. Conclusions— Surgical procedures were performed significantly more frequently after CABG than after PCI, particularly

IgG4-related disease (IgG4-RD) is a systemic disease characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in multiple target organs, including the pancreas, kidney, biliary tract and salivary glands. In contrast, Mikulicz's disease (MD) has been considered a subtype of Sjögren's syndrome (SS) based on histopathological similarities. However, it is now recognized that MD is an IgG4-RD distinguishable from SS and called as IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS). Regarding immunological aspects, it is generally accepted that CD4+ T helper (Th) cells play a crucial role in the pathogenesis of SS. Since it is well known that IgG4 is induced by Th2 cytokines such as interleukin (IL)-4 and IL-13, IgG4-DS is speculated to be a unique inflammatory disorder characterized by Th2 immune reactions. However, the involvement of Th cells in the pathogenesis of IgG4-DS remains to be clarified. Exploring the role of Th cell subsets in IgG4-DS is a highly promising field of investigation. In this review, we focus on the selective localization and respective functions of Th cell subsets and discuss the differences between SS and IgG4-DS to clarify the pathogenic mechanisms of these diseases.

Introduction Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving β-oxidation of long-chain fatty acids (FAO), which leads to rhabdomyolysis and subsequent acute renal failure. The detailed mechanisms of disease pathogenesis remain unknown; however, the availability of relevant human cell types for investigation, such as skeletal muscle cells, is limited, and the development of novel disease models is required. Methods We generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of a Japanese patient with CPT II deficiency. Mature myocytes were differentiated from the patient-derived hiPSCs by introducing myogenic differentiation 1 (MYOD1), the master transcriptional regulator of myocyte differentiation. Using an in vitro acylcarnitine profiling assay, we investigated the effects of a hypolipidemic drug, bezafibrate, and heat stress on mitochondrial FAO in CPT II-deficient myocytes and controls. Results CPT II-deficient myocytes accumulated more palmitoylcarnitine (C16) than did control myocytes. Heat stress, induced by incubation at 38 °C, leads to a robust increase of C16 in CPT II-deficient myocytes, but not in controls. Bezafibrate reduced the amount of C16 in control and CPT II-deficient myocytes. Discussion In this study, we induced differentiation of CPT II-deficient hiPSCs into mature myocytes in a highly efficient and reproducible manner and recapitulated some aspects of the disease phenotypes of CPT II deficiency in the myocyte disease models. This approach addresses the challenges of modeling the abnormality of FAO in CPT II deficiency using iPSC technology and has the potential to revolutionize translational research in this field.

Immune-checkpoint inhibitor nivolumab (anti-PD-1 antibody) blocks T cell inhibition and stimulate immunologic response toward cancer cells. It was also revealed that PD-1/PD-L1 interaction crucially controls the effector differentiation of auto-reactive T cells to maintain self-tolerance. Therefore, potential autoimmunological side-effect can occur in any organ. Here, we report a case of 67-year-old Japanese male with lung adenocarcinoma treated with nivolumab who developed acute tubulointerstitial nephritis after the third infusion of nivolumab. Kidney biopsy showed distinct histological findings: Proliferation of CD38 positive and IgG positive plasma cells, and affluent infiltration of FoxP3+ regulatory T cells. Herein, we do pathological discussion concerning acute tubulointerstitial nephritis occurred in this case based on these histological findings.

IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and marked infiltration of IgG4-positive cells in multiple organs. Interleukin-33 (IL-33) is a recently described cytokine that is secreted by damaged epithelial cells, macrophages, and dendritic cells, and potently activates helper T type 2 (Th2) immune responses, which have been suggested to play a major role in IgG4 production of IgG4-RD. Here, we assessed the expression of IL-33 and related molecules in the salivary glands (SGs) of patients with IgG4-RD versus that in patients with Sjögren’s syndrome (SS) and controls. Expression of IL-33 and its receptor (ST2) was strongly detected around ectopic germinal centers (GCs) in the SGs from patients with IgG4-RD, whereas IL-33 was expressed only in epithelial cells in patients with SS and controls. Moreover, IL-33 and CD68+/CD163+ macrophages were mainly distributed around ectopic GCs in patients with IgG4-RD. Double immunofluorescence staining showed that IL-33 expression co-localized with CD68+/CD163+ macrophages. Finally, mRNA expression levels of IL-33 showed a positive correlation to those of Th2 cytokines (IL-4 and IL-13) in patients with IgG4-RD. Our data suggest that IL-33 produced by M2 macrophages might contribute to the pathogenesis of IgG4-RD via aberrant activation of Th2 immune responses.

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that is characterized by the production of multiple autoantibodies and immune complex formation. Lupus nephritis (LN), which has various histological patterns and variable clinical outcomes, is one of the most important complications of SLE. Although this pathogenetic mechanism in each histologically different type of nephritis remains unclear, recent findings in LN elucidate an essential role for the Th1, IL-17 producing T cells and Th17 cells in the development of diffuse lupus nephritis (DLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of LN. Therefore the suppression of pivotal role cytokines in each pathological condition may support immunosuppressant strategy for LN.

Background In immunoglobulin G4-related kidney disease (IgG4-RKD), focal or diffuse renal cortical atrophy is often observed in the clinical course after glucocorticoid therapy. This study aimed to clarify the factors related to renal atrophy after glucocorticoid therapy in IgG4-RKD. Methods We retrospectively evaluated clinical features including laboratory data and computed tomography (CT) findings before and after glucocorticoid therapy in 23 patients diagnosed with IgG4-RKD, all of whom were followed up for more than 24 months. Results Seventeen patients were men, and six were women (average age 62.0 years). Average follow-up period was 54.9 months. The average estimated glomerular filtration rate (eGFR) at diagnosis was 81.7 mL/min/1.73 m2. All patients had had multiple low-density lesions on contrast-enhanced CT before glucocorticoid therapy, and showed disappearance or reduction of these lesions after it. Pre-treatment eGFR and serum IgE level in 11 patients in whom renal cortical atrophy developed 24 months after the start of glucocorticoid therapy were significantly different from those in 12 patients in whom no obvious atrophy was found at that time (68.9 ± 30.1 vs 93.5 ± 14.1 mL/min/1.73 m2, P = 0.036, and 587 ± 254 vs 284 ± 263 IU/mL, P = 0.008, respectively). Pre-treatment eGFR and serum IgE level were also significant risk factors for renal atrophy development 24 months after the start of therapy with an odds ratio of 0.520 (per 10 mL/min/1.73 m2, 95% confidence interval (CI) 0.273–0.993, P = 0.048) and 1.090 (per 10 IU/mL, 95% CI: 1.013–1.174, P = 0.022), respectively, in age-adjusted, sex-adjusted, serum IgG4 level-adjusted logistic regression analysis. Receiver operating characteristic curve analysis showed that eGFR of less than 71.0 mL/min/1.73 m2 and serum IgE of more than 436.5 IU/mL were the most appropriate cutoffs and yielded sensitivity of 63.6% and specificity of 100%, and sensitivity of 90.9% and specificity of 75.0%, respectively, in predicting renal atrophy development. Conclusions This study suggests that pre-treatment renal insufficiency and serum IgE elevation predict renal atrophy development after glucocorticoid therapy in IgG4-RKD. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1175-y) contains supplementary material, which is available to authorized users.

Clopidogrel was administered to a 67-year-old Japanese man to prevent the recurrence of cerebral infarction. Twelve weeks later, he was admitted to our hospital with acute renal failure, hemolytic anemia and thrombocytopenia, and was diagnosed with clopidogrel-induced thrombotic microangiopathy. Clopidogrel was immediately discontinued and corticosteroid and plasma exchange therapy were administered simultaneously. Thereafter, the patient's condition gradually improved. The patient had a decreased serum complement C3 level. This suggests that the activated alternative pathway is related to thrombotic microangiopathy (TMA). TMA is a critical drug-associated adverse reaction that clinicians should always be vigilant about, because clopidogrel is widely prescribed.

BACKGROUND To obtain a clear understanding of the pathogenesis of lipoprotein glomerulopathy (LPG), we studied the role of the deficiency of Fc receptor gamma chain (FcRγ) for the development of LPG in concert with apolipoprotein E (apoE) abnormalities. METHODS We generated apoE and FcRγ double-knockout (FcRγ/apoE-KO) mice, and subsequently introduced several kinds of human recombinant apoE genes. At 21 days after infection, the mice were sacrificed and histologically examined. Peritoneal macrophages were evaluated for their response to modified lipids. RESULTS In the FcRγ/apoE-KO mice, the human apoE3-injected mice showed the most drastic LPG-like changes, as well as prominent hypertriglyceridemia. Meanwhile, relative to the human apoE3-injected mice, the FcRγ/apoE-KO mice showed greater lipoprotein deposition and less macrophage infiltration into the mesangial area. Moreover, the peritoneal macrophages in the apoE/FcRγ-KO mice were impaired in lipid uptake and secretion of the cytokines monocyte chemotactic protein-1 and regulated upon activation, normal T-cell expressed and secreted, after the uptake of oxidized low-density lipoprotein. CONCLUSIONS These results suggest that the impairment of macrophage function resulting from FcRγ deficiency plays a principal role in the development of LPG in the presence of apoE abnormalities.

Background— There still remain safety concerns on surgical procedures after coronary drug-eluting stents (DES) implantation, and optimal management of perioperative antiplatelet therapy (APT) has not been yet established. Methods and Results— During 3-year follow-up of 12 207 patients (DES=6802 patients and bare-metal stent [BMS] only=5405 patients) who underwent coronary stent implantation in the CREDO-Kyoto registry cohort-2, surgical procedures were performed in 2398 patients (DES=1295 patients and BMS=1103 patients). Surgical procedures (early surgery in particular) were more frequently performed in the BMS group than in the DES group (4.4% versus 1.9% at 42-day and 23% versus 21% at 3-year, log-rank P =0.0007). Cumulative incidences of death/myocardial infarction (MI)/stent thrombosis (ST) and bleeding at 30 days after surgery were low, without differences between BMS and DES (3.5% versus 2.9%, P =0.4 and 3.2% versus 2.1%, P =0.2, respectively). The adjusted risks of DES use relative to BMS use for death/MI/ST and bleeding were not significant (hazard ratio: 1.63, 95% confidence interval: 0.93 to 2.87, P =0.09 and hazard ratio: 0.6, 95% confidence interval: 0.34 to 1.06, P =0.08, respectively). The risks of perioperative single- and no-APT relative to dual-APT for both death/MI/ST and bleeding were not significant; single-APT as compared with dual-APT tended to be associated with lower risk for death/MI/ST (hazard ratio: 0.4, 95% confidence interval: 0.13 to 1.01, P =0.053). Conclusions— Surgical procedures were commonly performed after coronary stent implantation, and the risk of ischemic and bleeding complications in surgical procedures was low. In patients selected to receive DES or BMS, there were no differences in outcomes. Perioperative administration of dual-APT was not associated with lower risk for ischemic events.

IgG4-related disease has attracted wide attention recently. It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. Although several sets of diagnostic criteria for autoimmune pancreatitis (AIP) are available and renal lesion is recognized as an extra-pancreatic manifestation of AIP, it is difficult to differentiate IgG4-related tubulointerstitial nephritis (TIN) without AIP from other types of TIN. To clarify the entity of IgG4-related kidney disease (IgG4-RKD) and support in-depth studies, the Japanese Society of Nephrology has established a working group to prepare diagnostic criteria for IgG4-RKD.The working group analyzed 41 patients with IgG4-RKD, and collected the following data to devise a diagnostic algorithm and diagnostic criteria for IgG4-RKD: clinical features including extra-renal organ involvement, urinalysis and serological features including serum IgG4 levels, imaging findings demonstrated by computed tomography (CT), renal histology with IgG4 immunostaining, and response to steroid therapy.The conditions for criteria are as follows. (1) Presence of some kidney damage, as manifested by abnormal urinalysis or urine marker(s) and/or decreased kidney function with either elevated serum IgG level, hypocomplementemia, or elevated serum IgE level. (2) Kidney imaging studies showing abnormal renal imaging findings, i.e., multiple low density lesions on enhanced CT, diffuse kidney enlargement, hypovascular solitary mass in the kidney, and hypertrophic lesion of the renal pelvic wall without irregularity of the renal pelvic surface. (3) Serum IgG4 level exceeding 135 mg/dl. (4) Renal histology showing two abnormal findings: (a) dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells10/high power field (HPF) and/or ratio of IgG4-positive plasma cells/IgG positive plasma cells40%. (b) Characteristic 'storiform' fibrosis surrounding nests of lymphocytes and/or plasma cells. (5) Extra-renal histology showing dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells10/HPF and/or ratio of IgG4-positive plasma cells/IgG-positive plasma cells40%. The diagnosis is classified into 3 stages of definite, probable and possible according to the combinations of the above conditions. Thirty-nine cases (95.1%) were diagnosed with IgG4-RKD according to the criteria.The provisional criteria and algorithm appear to be useful for clarifying the entity of IgG4-RKD and seeking underlying IgG4-RKD cases; however, further experience is needed to confirm the validity of these criteria.