Identification of circulating microbial DNA and its association with kidney function in patients with diabetic kidney disease.

AIM: Recently, substantial studies have been accumulated to indicate the important role of gut microbiota in diabetic kidney disease (DKD). The abnormal change of bacterial-derived products could imply specific injuries or play beneficial or harmful roles in DKD progression. In this study, we examined the presence and contribution of the Klebsiella oxytoca gene in the circulation of patients with DKD. METHOD: We enrolled a total of 16 healthy participants, 17 patients with DKD, 5 patients with DKD requiring haemodialysis (HD), and 7 patients with CKD without diabetes. Bacterial-derived DNA (16S rDNA and a specific K. oxytoca gene) in the blood was detected using droplet digital PCR, then investigated the relationship with clinical characteristics. RESULTS: We identified an increase in K. oxytoca genes in the blood of DKD patients. Interestingly, blood K. oxytoca copies and K. oxytoca/ 16S DNA ratio correlated with higher blood creatinine and BUN levels together with lower eGFR in DKD patients. K. oxytoca levels were also associated with higher neutrophil percentage, lower lymphocyte frequency, and increased neutrophil-to-lymphocyte ratio. CONCLUSION: Collectively, the presence of the K. oxytoca gene in the circulation could serve as a biomarker reflecting reduced renal function in DKD patients.

Autotaxin concentrations in peritoneal dialysis effluent reflect peritoneal function.

INTRODUCTION: Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function. METHODS: This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET. RESULTS: Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05). CONCLUSIONS: Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function.

Effects of d-alanine Intake on Amino Acid Metabolism and Kidney Function in Healthy Adults: A Multicenter, Randomized Pilot Study.

Background: d-alanine administration prevented kidney damage in a murine acute kidney injury model. Further data are needed on the influence of d-alanine on kidney function in humans. Objective: This study investigated the effects of d-alanine intake on amino acid metabolism and kidney function in healthy volunteers. Methods: This multicenter pilot study randomly assigned individuals from the general Japanese population to receive 3 g or 6 g of d-alanine intake per day for 7 d in a 1:1 ratio. The primary endpoint was the mean change in plasma and urine d-alanine levels from baseline to 7 d after intake. The secondary endpoints were mean changes in kidney function and other clinical factors. Safety was assessed by evaluating adverse events and clinical parameters. Results: We randomly assigned 24 participants to the 3-g (n = 12) and 6-g d-alanine (n = 12) groups. The mean baseline estimated glomerular filtration rate (eGFR) was 73 mL/min/1.73 m2. The mean plasma d-alanine concentration increased from baseline by 77.5 ± 34.3 and 192.1 ± 80.9 nmol/mL in the 3-g and 6-g d-alanine groups (both p < 0.0001), respectively, in a dose-dependent manner (between-group difference: 114.6 nmol/mL; 95% CI: 62.1-167.2; P = 0.0002). A similar increase was observed for the urine d-alanine to creatinine ratio. The mean eGFR was elevated by 5.7 ± 8.8 mL/min/1.73 m2 in the 6-g d-alanine group (P = 0.045) but did not significantly change in the 3-g d-alanine group. Nonserious adverse events were reported in 11 participants. Conclusions: d-alanine intake increased plasma and urine d-alanine levels and was well tolerated in participants with normal kidney function. These results will be useful in future trials investigating the effects of d-alanine intake on kidney disease progression in patients with chronic kidney disease.This trial was registered at the UMIN Clinical Trials Registry as UMIN000051466.

Myocardin-related transcription factor contributes to renal fibrosis through the regulation of extracellular microenvironment surrounding fibroblasts.

Fibroblast accumulation and extracellular matrix (ECM) deposition are common critical steps for the progression of organ fibrosis, but the precise molecular mechanisms remain to be fully investigated. We have previously demonstrated that lysophosphatidic acid contributes to organ fibrosis through the production of connective tissue growth factor (CTGF) via actin cytoskeleton-dependent signaling, myocardin-related transcription factor family (MRTF) consisting of MRTF-A and MRTF-B-serum response factor (SRF) pathway. In this study, we investigated the role of the MRTF-SRF pathway in the development of renal fibrosis, focusing on the regulation of ECM-focal adhesions (FA) in renal fibroblasts. Here we showed that both MRTF-A and -B were required for the expressions of ECM-related molecules such as lysyl oxidase family members, type I procollagen and fibronectin in response to transforming growth factor (TGF)-ß1 . TGF-ß1 -MRTF-SRF pathway induced the expressions of various components of FA such as integrin α subunits (αv , α2 , α11 ) and ß subunits (ß1 , ß3 , ß5 ) as well as integrin-linked kinase (ILK). On the other hand, the blockade of ILK suppressed TGF-ß1 -induced MRTF-SRF transcriptional activity, indicating a mutual relationship between MRTF-SRF and FA. Myofibroblast differentiation along with CTGF expression was also dependent on MRTF-SRF and FA components. Finally, global MRTF-A deficient and inducible fibroblast-specific MRTF-B deficient mice (MRTF-AKO BiFBKO mice) are protected from renal fibrosis with adenine administration. Renal expressions of ECM-FA components and CTGF as well as myofibroblast accumulation were suppressed in MRTF-AKO BiFBKO mice. These results suggest that the MRTF-SRF pathway might be a therapeutic target for renal fibrosis through the regulation of components forming ECM-FA in fibroblasts.

Trehalose ameliorates peritoneal fibrosis by promoting Snail degradation and inhibiting mesothelial-to-mesenchymal transition in mesothelial cells.

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA+ myofibroblasts that was reduced by trehalose. The number of Wt1+ α-SMA+ cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA+ myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1+ α-SMA+ cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα1 mRNA expression induced by TGF-ß1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs.

Factors related to dementia patients' length of day-care clinic attendance.

BACKGROUND: In our previous study, we reported that patients using a day-care clinic for less than 1 year were older than those who continued day-care activities for more than 1 year. We found that dementia symptoms, as assessed by caregivers using the initial Assessment Scale for Symptoms of Dementia score, influenced the length of day-care clinic attendance (LDC). However, these results were obtained by univariate analysis. In this study, we investigated the factors that influenced LDC using multivariate analysis. METHODS: We studied data from 457 patients with dementia who attended our day-care clinic for dementia patients from 1 April 2000 to 31 March 2012 and continued intervention until 31 March 2013. We evaluated the factors that influenced LDC using Cox's proportional hazards model for each sex. RESULTS: Kaplan-Meier analysis showed a gender difference in LDC. The median LDC was 18 months (interquartile range: 3-37 months) for men and 21 months (interquartile range: 5-53 months) for women (P = 0.027). In model 1, the low initial Assessment Scale for Symptoms of Dementia score for each sex and high initial scores for Hasegawa's Dementia Scale-Revised and Nishimura's activity of daily living scale in women were related to the long-term use of day care. Model 2 indicated that a low final score for Nishimura's activity of daily living scale increased LDC for each sex. LDC was not affected by variables related to the caregiving system except for the number of cohabitants in men. CONCLUSIONS: It was suggested that patients with high cognitive and physical functions attend the day-care clinic for a long time. It was necessary to control the behavioural and psychological symptoms of dementia for those using day care in the long term. However, patients with low physical function at the end of day-care attendance may also attend our day-care service in the long term if they receive favourable assistance.

[BPSD from the Perspective of the New Orange Plan].

I have discussed BPSD, especially who should treat BPSD and who can treat them, from the viewpoint of the New Orange Plan. It is desirable for all the doctors to have extensive knowledge about dementia and engage in treatment in cooperation with other departments and, more comprehensively, with nursing-care insurance fields. During the period when a patient has mild BPSD and the burden on caretakers is light, it is possible for his or her family doctor to treat BPSD. However, when a patient has severe BPSD and is in a situation where care is difficult, non-drug therapy often becomes the first choice for the treatment and drug therapy second. In the case that neither of them are effective enough for treatment, short- term hospitalization on a dementia treatment ward (closed ward) in the psychiatric depart- ment is necessary. The doctors who are specialists in dementia consist mainly of psychiatrists, neurophysicians, brain surgeons, geriatricians, and doctors who belong to the Department of General Medicine. If we consider the characteristics of the role psychiatrists play in treating dementia, it can be said that psychiatrists are specialists in treating psychic symptoms, which constitute the core of BPSD. Since psychiatrists use antipsychotics far more often than doctors in other departments, they are specialized in prescribing an antipsychotic according to the symptom. In the case of severe BPSD, psychiatrists can hospitalize the patient on a closed ward and give treatment to him or her if necessary but at the minimum. In other words, psy- chiatrists are in an important position in treating dementia that is different from doctors of other departments, and a psychiatric department seems to be the only department which can follow dementia patients through all the stages of their dementia. I strongly hope that not only dementia-specialized doctors but also all other doctors will develop an interst in dementia, and that dementia patients can access effective services any- where in Japan. The problem of dementia concerns not only people engaged in medical and care businesses but also all people in the community, and I think that it is the most important for the whole of society to try to treat dementia.

Factors related to day-care clinic outcomes for dementia patients: differences between hospitalization in the dementia ward and institutionalization.

BACKGROUND: Few reports have investigated factors related to the outcomes of day-care attendance. The aim of this retrospective study was to investigate the factors related to the outcomes of patients who attended day-care clinics, with special attention to the differences between hospitalization in the dementia ward and institutionalization. METHODS: We analyzed data from 333 patients in consecutive cases who attended day care between 1 April 2000 and 31 March 2010 and then followed them until 31 March 2011. For univariate and multivariate analyses, patients were divided into seven groups characterized by their outcomes: (i) patients who continued day-care attendance (continued); (ii) those hospitalized for physical problems (hospital (physical)); (iii) those hospitalized in the dementia ward (ward (dementia)); (iv) those hospitalized in the psychiatric ward for psychiatric problems (ward (psychiatric)); (v) those institutionalized (institution); (vi) those who stopped day-care attendance by choice (intention); and (vii) those who stopped day-care attendance for other or unknown reasons (others). RESULTS: Behavioural and psychological symptoms of dementia were the main reasons for hospitalization and institutionalization. Men were easier to hospitalize in the dementia ward. Patients who applied for insurance were more likely to be institutionalized. The differences between patients who were hospitalized (dementia ward) and institutionalized were age and cognitive function. CONCLUSIONS: Patients who were older and had high cognitive function were institutionalized rather than hospitalized in the dementia ward. Patients with severe dementia symptoms were advised to be treated in the dementia ward.

Longitudinal study of the cognitive, behavioral and physical status of day care service users with dementia: factors associated with long-term day care use.

AIM: The aim of the present retrospective study was to investigate the time-courses of the cognitive, behavioral and physical status of day care service users with dementia, and to determine the factors associated with the long-term use of day care in order to aid the development of better interventions. METHODS: We analyzed the data of 162 consecutive patients who attended our day care clinic for 1 year or more between 1 April 2000 and 31 March 2010. The patients were divided into three groups according to the length of their day care attendance (the 1-year, 3-year and 5-year groups). Then, we investigated the time-courses of their cognitive, behavioral and physical status. Logistic regression analysis was used to detect the factors that affect the duration of day care service attendance in dementia patients. RESULTS: The Hasegawa Dementia Scale-Revised (HDS-R), Assessment Scale for Symptoms of Dementia (ASSD) and Nishimura's Activities of Daily Living (N-ADL) scores of the three groups all significantly deteriorated during the study period except for the HDS-R score of the 3-year group. Higher age and a high ASSD score were associated with a short period of day care service attendance, whereas the patients' daughters-in-law acting as a caregiver was related to the long-term use of day care services in model 1. CONCLUSIONS: It is better to control behavioral and psychological symptoms in order to improve the utilities of day care for dementia patients. The caregiving environment of dementia patients might be associated with the length of day care attendance.

Factors related to readmission to a ward for dementia patients: sex differences.

AIM: The aim of this study was to investigate the factors related to readmission to a ward for dementia patients with special attention to sex-related issues. METHODS: We reviewed the data of 326 patients who were hospitalized in a ward for dementia patients between 1 April 2000 and 31 March 2008, and followed up for 24 months after discharge. For univariate and multivariate analyses, patients were divided into: (i) patients who were not readmitted to our ward within 24 months (control); (ii) patients who were readmitted to our ward within 3 months (early readmission); and (iii) patients readmitted within 4 to 24 months (late readmission). RESULTS: Factors related to readmission differed between sexes as well as between the early and late stage. A small number of cohabitants and outcome (hospital) were factors related to early readmission in men, while outcome (hospital) and long stay in the ward were related to early readmission in women. High physical function, care distress and short stay in the ward were the factors related to late readmission in women. CONCLUSIONS: Most patients who were transferred to another hospital were readmitted within 3 months. Some women were readmitted in the late stage. They had relatively high cognitive and physical functions and most of their caregivers had care distress. The causes of readmission were not due to a decline in cognitive function. It is important to prevent complications in dementia patients and to establish a caregiving system for dementia patients that decreases the burden on caregivers in order to reduce the rate of readmission.

Predictors of length of stay in a ward for demented elderly: gender differences.

BACKGROUND: In our previous studies, we found both gender differences among care recipients and predictors that influenced outcomes after discharge from a ward for demented elderly. Here, we investigate predictors that influence the length of stay for each sex. METHODS: We studied the data of 390 patients with dementia who were hospitalized in a ward for demented elderly between 1 April 2000 and 31 March 2008, and treated until 31 March 2009. The patients were divided into groups classified by gender. We analyzed the gender differences of characteristics and evaluated the predictors that influenced the length of stay in the ward for demented elderly using Cox's proportional hazards model. A model using the initial scores of the Revised Hasegawa Dementia Scale (HDS-R), Assessment Scale for Symptoms of Dementia (ASSD) and Nishimura's activity of daily living scale (N-ADL), which were examined on admission, was named Model 1. In Model 1, we checked the effect of each patient's characteristics, except for complications and destinations, on their length of stay. Model 2 used the final scores of HDS-R, ASSD and N-ADL including complications and destinations. RESULTS: There was a clear gender difference in the length of stay. The length of stay of women was longer than that of men. It was difficult to predict the length of stay in Model 1. Age was the only predictor in women and no predictor was identified in men. In Model 2, complications and the final HDS-R and N-ADL scores were predictors of the length of stay in men. Age, complications and destinations were predictors of the length of stay in women. CONCLUSIONS: It was observed that there were gender differences among predictors of the length of stay. However, it was difficult to predict the length of stay on admission. Retrospectively, the length of stay was determined by physical and psychological conditions, not by the social variables in men. In women, it was supposed that the caregiver's wish to give care at home reduced the length of stay. Besides, complication was a common predictor of the extension of stay in each sex. We have to decrease the number of complications as much as possible to reduce the length of stay.

Predictors of outcomes from a ward for demented elderly: gender differences.

BACKGROUND: In a previous study, we found gender differences among care recipients and suggested that elderly women living alone have difficulty receiving care from their families. We investigated the gender differences among predictors which influenced outcomes after discharge from a ward for treatment of demented elderly with severe psychotic symptoms. METHODS: We enrolled the data of 325 patients with dementia who were hospitalized between 1 April 2000 and 31 March 2007, and discharged by 31 March 2008. Two hundred and ninety-four patients were divided into men and women. We checked the gender differences of their characteristics. After that, they were subdivided into three groups to analyze the effect of each patient's characteristics and care situation on their outcomes: (i) given home care (home); (ii) became institutionalized (institution); and (iii) transferred to another hospital (hospital). RESULTS: In the hospital groups, the incidence of complications was high for each sex. The differences between the institution group and home group were shown by N-ADL score in men. In contrast, the predictors in women were the HDS-R score, the number of cohabitants and the caregiver. CONCLUSIONS: It was observed that there were gender differences among outcome predictors. The outcomes of demented patients were predicted by both complications and condition on admission. Most women did not return to their homes because of the situation in which they received care. It is necessary to establish a clear system for providing care for the demented elderly, especially for women.