Megalin-related mechanism of hemolysis-induced acute kidney injury and the therapeutic strategy.

Hemolysis-induced acute kidney injury (AKI) is attributed to heme-mediated proximal tubule epithelial cell (PTEC) injury and tubular cast formation due to intratubular protein condensation. Megalin is a multiligand endocytic receptor for proteins, peptides, and drugs in PTECs and mediates the uptake of free hemoglobin and the heme-scavenging protein α1-microglobulin. However, understanding of how megalin is involved in the development of hemolysis-induced AKI remains elusive. Here, we investigated the megalin-related pathogenesis of hemolysis-induced AKI and a therapeutic strategy using cilastatin, a megalin blocker. A phenylhydrazine-induced hemolysis model developed in kidney-specific mosaic megalin knockout (MegKO) mice confirmed megalin-dependent PTEC injury revealed by the co-expression of kidney injury molecule-1 (KIM-1). In the hemolysis model in kidney-specific conditional MegKO mice, the uptake of hemoglobin and α1-microglobulin as well as KIM-1 expression in PTECs was suppressed, but tubular cast formation was augmented, likely due to the nonselective inhibition of protein reabsorption in PTECs. Quartz crystal microbalance analysis revealed that cilastatin suppressed the binding of megalin with hemoglobin and α1-microglobulin. Cilastatin also inhibited the specific uptake of fluorescent hemoglobin by megalin-expressing rat yolk sac tumor-derived L2 cells. In a mouse model of hemolysis-induced AKI, repeated cilastatin administration suppressed PTEC injury by inhibiting the uptake of hemoglobin and α1-microglobulin and also prevented cast formation. Hemopexin, another heme-scavenging protein, was also found to be a novel ligand of megalin, and its binding to megalin and uptake by PTECs in the hemolysis model were suppressed by cilastatin. Mass spectrometry-based semiquantitative analysis of urinary proteins in cilastatin-treated C57BL/6J mice indicated that cilastatin suppressed the reabsorption of a limited number of megalin ligands in PTECs, including α1-microglobulin and hemopexin. Collectively, cilastatin-mediated selective megalin blockade is an effective therapeutic strategy to prevent both heme-mediated PTEC injury and cast formation in hemolysis-induced AKI. © 2024 The Pathological Society of Great Britain and Ireland.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Protein intake and its relationship with frailty in chronic kidney disease.

INTRODUCTION: Patients with chronic kidney disease (CKD) are susceptible to frailty because of a range of nutrition-related factors. While protein restriction is commonly advised to preserve kidney function in patients with CKD, insufficient protein intake could potentially exacerbate frailty risk. This study aimed to elucidate the relationship between frailty and protein intake in patients with CKD. METHODS: This cross-sectional study enrolled patients with CKD stage 3-5. Frailty and prefrailty were assessed using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria. To estimate dietary protein intake, Maroni's formula based on 24-h urine collection was used. The potential association between frailty/pre-frailty and protein intake was investigated using a logistic regression analysis. RESULTS: Ninety-seven individuals with CKD were included in the study, with a median age of 73.0 years (interquartile range: 67.0, 82.0). Among them, 34 were women (35.1%), and the estimated glomerular filtration rate (eGFR) was 36.3 mL/min/1.73 m2 (interquartile range: 26.9, 44.1). Frailty and pre-frailty were identified in 13.4% and 55.7% of participants, respectively. Comparing the groups, protein intake in the frailty/pre-frailty group (0.83 g/kgBW/day [0.72, 0.93]) was lower than that in the robust group (0.89 g/kgBW/day [0.84, 1.19], p = 0.002). Upon logistic regression analysis, protein intake exhibited an independent association with frailty/pre-frailty (odds ratio: 0.72, 95% confidence interval: 0.59-0.89, p = 0.003). CONCLUSION: Reduced protein intake in patients with CKD is associated with frailty and pre-frailty. It is advisable to ensure that patients with CKD who are at risk of frailty consume an adequate amount of protein.

Survey of Japanese nephrologists' use of clinical practice guidelines for rapidly progressive glomerulonephritis.

BACKGROUND: The guidelines in Japan for the treatment of rapidly progressive glomerulonephritis (RPGN) have been revised; the latest update was released in 2020. We investigated the actual usage of the new guidelines in Japan. METHODS: We distributed a survey electronically to board-certified nephrologists throughout Japan from December 15, 2021 to January 31, 2022. The survey focused on anti-neutrophil cytoplasmic antibody (ANCA)-associated RPGN and anti-glomerular basement membrane (GBM)-antibody RPGN, plus the treatment strategies and infection-prevention measures used. RESULTS: The survey was completed by 155 certified nephrologists from medical facilities across Japan. Their responses regarding treatment procedures revealed that ANCA-associated RPGN was treated with immunosuppressants and/or biologics by 58.1% of the survey respondents, and with plasma exchange (PE) in combination with corticosteroids by 21.3%. Regarding anti-GBM-antibody RPGN, 78.1% of the respondents used corticosteroids in combination with PE (63.2%), cyclophosphamide (CY) (23.9%), or rituximab (RTX) (8.4%), suggesting a discrepancy between clinical practice and the actual use of the guidelines. Trimethoprim-sulfamethoxazole was prescribed as prophylaxis by 94.8% of the respondents, reflecting the widespread recognition of the need to prevent infectious disease in patients with RPGN. CONCLUSIONS: The survey responses revealed how Japan's new RPGN guidelines are used in actual clinical practice. Our findings will contribute to the guidelines' dissemination and implementation.

Association of serum magnesium levels with renal prognosis in patients with chronic kidney disease.

BACKGROUND: Magnesium deficiency is associated with various health conditions, but its impact on the progression of chronic kidney disease (CKD) remains unclear. This study aimed to investigate the association between serum magnesium levels and prognosis of renal function in CKD patients. METHODS: This is an analysis of the Japan Chronic Kidney Disease Database Ex　(J-CKD-DB-Ex), which is a multicenter prospective cohort including CKD patients enrolled from January 1, 2014 to December 31, 2020. We included adult outpatients with CKD stage G3 and G4 at the time of initial magnesium measurement. Patients were classified by magnesium levels as low (<1.7 mg/dl), normal (1.7-2.6 mg/dl), or high (>2.6 mg/dl). The primary outcomes were the composite of an eGFR < 15 ml/min/1.73 m2 or a ≥30% reduction in eGFR from the initial measurement, which was defined as CKD progression. We applied the Kaplan-Meier analysis and Cox regression hazard model to examine the association between magnesium levels and CKD progression. RESULTS: The analysis included 9868 outpatients during the follow-up period. The low magnesium group was significantly more likely to reach CKD progression. Cox regression, adjusting for covariates and using the normal magnesium group as the reference, showed that the hazard ratio for the low magnesium group was 1.20 (1.08-1.34). High magnesium was not significantly associated with poor renal outcomes compared with normal magnesium. CONCLUSION: Based on large real-world data, this study demonstrated that low magnesium levels are associated with poorer renal outcomes.

Cigarette smoking and progression of kidney dysfunction: a longitudinal cohort study.

INTRODUCTION: Cigarette smoking is one of the most important life-modifiable risk factors for CVD events. The effect on CKD progression caused by smoking remained uncertain, while the effect on CVD had been established. METHOD: The study population included participants from the specific health check and specific health guidance, an annual health check-up for all inhabitants of Japan who were aged between 40 and 74 years. 149,260 subjects (male, 37.1%; female, 62.9%) were included in this analysis. RESULTS: The relationship between smoking status along with new-onset proteinuria and eGFR deterioration more than 15 mL/min/1.73 m2 was examined. Median observation periods were 1427 days [738, 1813] in males and 1437 days [729, 1816] in females. In male participants, the strongest factor upon kidney dysfunction was new-onset proteinuria (1.41 [1.31 1.51], P < 0.001). The second strongest factor on kidney deterioration was smoking (1.24 [1.16 1.31], P < 0.001). In female participants, strongest factor upon kidney dysfunction was smoking (1.27 [1.16-1.39], P < 0.001). The second strongest factor on kidney deterioration was new-onset proteinuria (1.26 [1.17 1.36], P < 0.001). To reveal the relationship of effects from new-onset proteinuria and smoking on the kidney function, the participants were divided into four groups with and without new-onset proteinuria and smoking. The group with both proteinuria and smoking had significantly worst renal prognosis (P for trend < 0.001). CONCLUSION: Large longitudinal observation study revealed smoking has an evil effect on the progression of CKD. This evil effect could be observed in CKD patients with proteinuria as well as in general population without new-onset proteinuria.

Appropriate Anthropometric Indices for Geriatric Nutritional Risk Index in Predicting Mortality in Older Japanese Patients: A Comparison of the Lorentz Formula and Body Mass Index.

The Geriatric Nutritional Risk Index (GNRI) is a popular nutritional screening tool. However, the calculation of ideal body weight (IBW) differs among studies. We aimed to compare GNRI calculated using the Lorentz formula (LF) with a body mass index (BMI) and to investigate the cutoffs based on original or quartile criteria for the association with mortality in elderly patients in Japan. This retrospective study enrolled patients aged 65 and older in a long-term care hospital. The GNRI was calculated using two different IBW methods: the LF and a BMI of 22 kg/m2. We categorized GNRI results based on the original criteria or quartile criteria. Mortality outcomes were analyzed using the GNRI based on IBW (LF or BMI) and its classification (original criteria or quartile) through Cox proportional hazard regression. There were 262 participants, including 160 women, with a median age of 86. There was a notable difference between GNRI-BMI and GNRI-LF. The GNRI-LF original and quartile criteria did not show an association with mortality. A significant association with mortality was found between Q1 and Q4 in the GNRI-BMI quartile criteria (hazard ratio: 2.60; 95% confidence interval: 1.66-4.07, p < 0.01), but not the GNRI-BMI original criteria. The GNRI calculated using BMI with quartile criteria proved to be a reliable predictor of mortality for Japanese elderly inpatients. The calculation method of GNRI and the appropriate cutoff point should be considered based on the patient's background.

Association between dry eye and periodontal disease in community-dwelling Japanese adults: data from the Uonoma cohort study.

BACKGROUND: While research has explored the risk of periodontal disease in various eye conditions, the link between dry eye and periodontal disease remains underexplored, especially in Japanese adults. This study aims to investigate the association between dry eye and periodontal disease in community-dwelling Japanese adults. METHODS: This study is a subset of the Uonuma cohort study, which includes Japanese adults aged 40 years and older residing in the Uonuma area of Niigata Prefecture, Japan. Participants completed a self-administered, paper-based questionnaire. Statistical analyses, including the chi-square test, independent t test, ANOVA test, and logistic regressions, were employed to assess the association of periodontal disease with independent variables. RESULTS: Among 36,488 participants (average age 63.3 years, 47.4% men), 39.3% had a history of periodontal disease, and gender differences were statistically significant (p < 0.001). Significant associations were found between periodontal disease and dry eye diagnosis or symptoms. Univariable logistic regression revealed links between periodontal disease and age, gender, living status, alcohol consumption, remaining teeth, bite molar availability, and history of dry eye disease or symptoms. Multiple-adjusted regression found that doctor-diagnosed dry eye was associated with a higher likelihood of periodontal disease (odds ratio, 1.12; 95% confidence interval, 1.03-1.22). Participants who never experienced dryness or foreign body sensation had lower ORs of periodontal disease than those who always experienced such symptoms across all models. CONCLUSION: A significant correlation was found between dry eye and periodontal disease in Japanese adults. Regular check-ups, early detection, and effective management of both conditions are strongly recommended.

Trends in the Incidence of Renal Replacement Therapy due to Rapidly Progressive Glomerulonephritis in Japan, 2006-2021.

Objective Patients with rapidly progressive glomerulonephritis (RPGN) are at a high risk of progression to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT). The present study examined recent trends in the incidence of RRT due to RPGN in Japan. Methods The number of patients with incident RRT due to RPGN by sex from 2006 to 2021 was extracted from the Japanese Society of Dialysis Therapy Registry. The incidence rates of RRT were calculated for four-year periods with the census population as the denominator. Standardized incidence ratios (SIRs) and age-specific incidence rates were also calculated. Results From 2006 to 2021, the crude number of patients with incident RRT due to RPGN increased by 34% and 58% in men and women, respectively. The SIRs decreased significantly in 2010-2013 relative to the first period (2006-2009) for both men (0.90 [95% confidence interval {CI} 0.85-0.96]) and women (0.92 [0.86-0.99]) but then increased to 1.01 (0.96-1.07) for men and 1.20 (1.13-1.27) for women in 2018-2021. In the older age groups (≥70 years old), age-specific incidence rates initially decreased in 2010-2013 but increased thereafter, peaking in 2018-2021. Conclusion From 2006 to 2021, the number of patients with incident RRT due to RPGN increased, with an increase in the age-specific incidence of RRT due to RPGN in the older age groups (≥70 years old), suggesting that the number of patients with incident RRT due to RPGN will continue to increase as the population ages in Japan.

A case of non-lupus full-house nephropathy diagnosed by kidney biopsy but observed IgA nephropathy on second biopsy.

We describe a case of full-house nephropathy without any underlying disease, including systemic lupus erythematosus. A 40-year-old woman was referred to our hospital with mild proteinuria and microscopic hematuria. The patient was diagnosed with immune complex-mediated glomerulonephritis with a predominant mesangioproliferative pattern based on renal histopathological results using full-house immunofluorescence staining. She showed no clinical criteria for the diagnosis of systemic lupus erythematosus, except for kidney disorders, and tested negative for antinuclear antibodies throughout her clinical course. However, in the second kidney biopsy, no C1q or C4 were detected in the immunofluorescence study, suggesting an immunoglobulin A nephropathy-like pattern. The patient responded favorably to corticosteroid treatment. We found a heterozygous CFHR3-CFHR1 deletion. The association between full-house nephropathy and CFHR3-CFHR1 deletion is unknown, but its influence on the histological pattern in our case is suspected. This indicates the diversity in the pathogenesis of non-lupus full-house nephropathy and warrants further investigation.

Impact of transferrin saturation on cardiovascular events in non-dialysis-dependent chronic kidney disease patients treated with darbepoetin alfa.

BACKGROUND: Although the widespread use of long-acting erythropoiesis-stimulating agents (ESAs) has facilitated the improvement of anemia in patients with chronic kidney disease (CKD), the improvement in prognosis has not been fully demonstrated. Iron deficiency is associated with the development of cardiovascular diseases (CVDs), and the relative iron deficiency induced by erythropoiesis-stimulating agents may prevent the improvement of prognosis. Therefore, we investigated the association between iron deficiency and cardiovascular events during long-acting erythropoiesis-stimulating agent therapy using transferrin saturation (TSAT), which is less susceptible to inflammation than ferritin. METHODS: This study included 1040 patients with non-dialysis-dependent CKD, aged ≥ 20 years, with a glomerular filtration rate < 60 mL/min/1.73 m2 and hemoglobin < 11 g/dL, who were treated with darbepoetin alfa for 96 weeks. The patients were recruited in the BRIGHTEN Trial, a multicenter, prospective, observational study conducted to evaluate erythropoiesis-stimulating agent resistance to darbepoetin alfa in treating anemia in non-dialysis-dependent CKD in a clinical setting. The association between transferrin saturation and the cumulative incidence of cardiovascular events was evaluated using the Kaplan-Meier method. To calculate the hazard ratio (HR), 95% confidence intervals (CI) and the Cox proportional hazards model were used. RESULTS: Survival curve analysis for cardiovascular events indicated that patients with transferrin saturation ≥ 30% had a significantly better prognosis, with an adjusted hazard ratio of 0.34 (95% confidence interval 0.22-0.52). Stratified analysis revealed that patients with transferrin saturation of 30-40% had a significantly lower risk of cardiovascular events than those with transferrin saturation of 20-30%, even after a multivariate-adjusted hazard ratio of 0.33 (95% confidence interval 0.21-0.54). CONCLUSION: Patients with CKD and transferrin saturation of 30-40% had significantly fewer cardiovascular events than those with transferrin saturation of 20-30% among patients treated with long-acting erythropoiesis-stimulating agents. Therefore, it may be useful to maintain higher transferrin saturation from the viewpoint of erythropoiesis-stimulating agent responsiveness and the reduction of cardiovascular events.

Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis.

Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD.

Individual dipeptidyl peptidase-4 inhibitors and acute kidney injury in patients with type 2 diabetes: A systematic review and network meta-analysis.

This network meta-analysis of randomized controlled trials aimed to determine whether any individual dipeptidyl peptidase-4 (DPP-4) inhibitors increase the risk of acute kidney injury (AKI). The Medical Literature Analysis and Retrieval System Online via PubMed, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were systematically searched to identify relevant studies. The primary outcome was AKI. A frequentist network meta-analysis was performed using a random-effects model to account for heterogeneity. Twenty-nine studies involving 56 117 participants were included. There were 918 cases of AKI (1.63%). The risk of bias was generally considered to be low. The only DPP-4 inhibitor that significantly increased the frequency of AKI when compared with placebo was sitagliptin (risk ratio 1.65, 95% confidence interval 1.22-2.23). However, because one study showed significant outliers in the funnel plot, in a highly heterogeneous population composed solely of patients undergoing surgery for coronary artery bypass graft, we conducted a post-hoc sensitivity analysis to exclude this study. The results showed no statistically significant difference in the risk of AKI between sitagliptin and placebo. Individual DPP-4 inhibitors do not appear to increase the risk of AKI. However, sitagliptin may be associated with AKI in patients with underlying severe cardiovascular disease.

Effect of proteinuria on the rapid kidney function decline in chronic kidney disease depends on the underlying disease: A post hoc analysis of the BRIGHTEN study.

AIMS: It is unclear whether the effect of proteinuria on rapid kidney function decline is equivalent among diabetic kidney disease (DKD), non-DKD with diabetes (NDKD+DM), and nephrosclerosis without diabetes (NS-DM), particularly in advanced chronic kidney disease patients. METHODS: In total, 1038 chronic kidney disease patients who participated in the BRIGHTEN study were included in the present study. A linear mixed effect model was applied to estimate the annual estimated glomerular filtration rate decline in each disease group. RESULTS: The prevalence of rapid decliners (rapid kidney function decline, defined as an eGFR loss of > 5 mL/min/1.73 m2/year) in the DKD group (44.6 %) was significantly higher compared with the NDKD+DM (27.9 %) and NS-DM (27.0 %) groups. By contrast, the prevalence of rapid decliners in different urine total protein to creatinine ratio (UPCR) categories (<0.5, 0.5 to < 1.0, 1.0 to < 3.5, and ≥ 3.5 g/g) were equivalent between the DKD and NS-DM groups. Moreover, the prevalence of a UPCR < 1.0 g/g in rapid decliners of the NS-DM group was more than double than in those of the DKD and NDKD+DM groups. CONCLUSIONS: The risk of rapid kidney function decline in NS-DM patients with low levels of proteinuria may be greater than initially predicted.

A Case of Adult-Onset Still's Disease With Hypocomplementemia.

Adult-onset Still's disease (AOSD) causes fever, rash, pharyngalgia, and arthralgia through autoinflammation. Its complement titer has not previously received attention because this usually increases during the inflammatory process. Our female patient in her 60s was admitted to the hospital with fever, rash, arthralgia, and pharyngalgia. Her white blood cell count was 19,130/µL, hemoglobin was 11.0 g/dL, platelet count was 26.0 × 104/µL, and ferritin titer was 6,175 ng/mL. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. The presence of infectious diseases and malignancies was excluded. She was diagnosed with hypocomplementemia at the onset of AOSD because of her low complement component 4 (C4) titer (<5.0 mg/dL). Her complement component 3 (C3) titer was 104.5 mg/dL, which was within normal limits. There was no sign of thrombotic microangiopathy (TMA) or hemophagocytosis. She was treated with high-dose corticosteroids, including pulse methylprednisolone therapy, cyclosporine, methotrexate, and intravenous immunoglobulin, but was resistant to these, and her disease repeatedly flared up. Treatment with intravenous cyclophosphamide eventually led to remission. Post-treatment, her C4 titer increased to within the normal range. Although hypocomplementemia with TMA or hemophagocytosis has been reported in AOSD patients, our patient showed no sign of either at disease onset. Hypocomplementemia of AOSD may be a sign of high disease activity and could be a predictive marker for resistance to standard therapy.

Exercise instruction during haemodialysis treatment after changes to the insurance regime: a nationwide questionnaire survey in Japan.

In April 2022, an additional medical fee for exercise instruction during haemodialysis treatment was approved for insurance claims in Japan. We conducted a questionnaire survey to investigate the current situation regarding exercise therapy during haemodialysis treatment after this change. Questionnaires were mailed to 4257 haemodialysis facilities, almost all the haemodialysis facilities in Japan, on January 31, 2023. In total, 1657 facilities responded, of which 550 (33%) provided exercise instruction during haemodialysis treatment, and 65% of these claimed the new fee. Of the 550 facilities that had claimed the fee at the time of survey, 245 (55%) started exercise instruction in April 2022 or later. Exercise instruction focused on resistance training (81%) and aerobic exercise (62%) for 20-30 min (66%) three times a week (80%). The instructors included physicians in 45% of facilities, nurses in 74%, and physical therapists in 36%. Efficacy was evaluated in 76% of the facilities providing instruction, mainly by assessing change in muscle strength (49%). Overall, 39% of facilities had experienced some adverse events, but none were life-threatening. In conclusion, after the change in the insurance regime, exercise instruction during haemodialysis treatment has become more popular, and more patients on haemodialysis are undergoing exercise therapy.

A case of multiorgan failure due to carbamazepine intoxication successfully treated with multimodal blood purification therapy.

Carbamazepine (CBZ) intoxication can occur due to various factors, including drug interactions and over-ingestion. Extracorporeal elimination, particularly through hemodialysis and hemoperfusion, is effective in treating severe carbamazepine intoxication. However, as the effectiveness of various modalities can differ, method selection may be based on a specific clinical situation. A 47-year-old woman who took CBZ for schizophrenia presented to our hospital with episodes of vomiting and consciousness disorder. As the CBZ concentration was > 20 µg/mL, she was admitted to the intensive care unit with a diagnosis of acute CBZ poisoning. She underwent one session of hemoperfusion for 2 h, and her CBZ level decreased from > 20 µg/mL to 6.4 µg/mL. However, she developed acute kidney and liver injuries 2 days after admission and underwent intermittent hemodialysis, plasma exchange, continuous hemodiafiltration (CHDF), and online HDF, depending on her condition. Her general condition improved, and she was transferred to the psychiatric department. To our knowledge, no case reports have described severe acute CBZ poisoning in a patient who developed multiorgan failure to date, which was successfully treated with multimodal blood purification therapy. When treating severe CBZ intoxication, blood purification therapy should be tailored to the changing pathophysiology of the condition.

Correction: Determination of specific life changes on psychological distress during the COVID-19 pandemic.

[This corrects the article DOI: 10.1371/journal.pone.0256481.].

Changes in daily intake of nutrients and foods including confectionery after the initiation of empagliflozin in Japanese patients with type 2 diabetes: a pilot study.

INTRODUCTION: It is unclear how dietary intake changes after sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is started in patients with type 2 diabetes. METHODS: We performed a non-controlled, open-label study that enrolled 51 patients with type 2 diabetes. The patients were newly administered empagliflozin, and their dietary habits were examined using a self-administered diet history questionnaire at the beginning of the study and after 24 weeks. We investigated the association of changes in HbA1c and body weight with changes in energy, nutrient, and food group intakes. RESULTS: At 24 weeks after the start of the study, HbA1c improved significantly and body weight decreased. In the food group, only the intake of confectionery increased, and there were no significant differences in the association between changes in HbA1c and body weight and changes in energy, nutrient, and food group intakes after 24 weeks. However, a significant negative correlation was found between change in HbA1c after 4 weeks and change in energy intake after 24 weeks, and principal component analysis showed an association between change in HbA1c levels after 4 weeks and change in energy intake and some food group intakes including confectionery after 24 weeks. CONCLUSION: In this study, after 24 weeks of treatment with empagliflozin, only intake of confectionery increased. Early assessment by dietitians after initiation of SGLT2i treatment might be important because our data suggested that the reduction in blood glucose levels after the start of empagliflozin was associated with a subsequent increase in energy intake. TRIAL REGISTRATION: University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on September 5, 2016 (registration ID, UMIN000002309|| http://www.umin.ac.jp/ctr/ ).