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Background and Objectives Research on racial and gender disparities in end-of-life care quality has burgeoned over the past few decades, but few studies have incorporated the theory of intersectionality, which posits that membership in 2 or more vulnerable groups may result in increased hardships across the life span. As such, this study aimed to examine the intersectional effect of race and gender on the quality of care received at the end of life among older adults. Research Design and Methods Data were derived from the combined Round 3 to Round 10 of the National Health and Aging Trends Study. For multivariate analyses, 2 logistic regression models were run; Model 1 included the main effects of race and gender and Model 2 included an interaction term for race and gender. Results Results revealed that White men were the most likely to have excellent or good care at the end of life, followed by White women, Black men, and Black women, who were the least likely to have excellent or good care at the end of life. Discussion and Implications These results point to a significant disadvantage for Black women, who had worse end-of-life care quality than their gender and racial peers. Practice interventions may include cultural humility training and a cultural match between patients and providers. From a policy standpoint, a universal health insurance plan would reduce the gap in end-of-life service access and quality for Black women, who are less likely to have supplemental health care coverage. [ABSTRACT FROM AUTHOR]

Nearly 700,000 suicide deaths occur each year. One in every five suicide death occurs among adults over 60 years of age or older. As the aging population increases rapidly, there is a need to understand protective factors to prevent older adult suicide. This study used the rapid review methodology to search literature from 1997 to 2022, examining whether resilience was a protective factor. The literature search was conducted over the following six databases for peer-reviewed journals and gray literature including Abstracts in Social Gerontology, Academic Search Premier, APA PsycInfo, CINAHL Complete, MEDLINE, and SocINDEX with Full Text. A total of six peer-reviewed journal articles met the inclusion criteria. The conclusion of the articles suggested resilience may be a protective factor in older adult suicide. Despite its underpinning, resilience in suicide prevention literature is lacking. More studies should examine resilience and its constructs as part of the effort to prevent older adult suicide. [ABSTRACT FROM AUTHOR]

The purpose of this systematic review was to provide a comprehensive account of racial and ethnic differences in retrospective end-of-life outcomes. Studies were searched from the following databases: Abstracts in Social Gerontology, Academic Search Premier, CINAHL Plus with Full Text, ERIC, MEDLINE, PsycINFO, PubMED, and SocIndex. Studies were included if they were published in English, included people from groups who have been minoritized, included adults aged 18 and older, used retrospective data, and examined end-of-life outcomes. Results from most of the 29 included studies showed that people from groups who have been minoritized had more aggressive/intensive care, had less hospice care, were more likely to die in a hospital, less likely to engage in advance care planning, less likely to have good quality of care, and experienced more financial burden at the end of life. Implications for practice (timely referrals), policy (health insurance access), and research (intervention studies) are provided. [ABSTRACT FROM AUTHOR]

Background/Objective: Compared to existing studies on end-of-life care of mid- to older-aged patients diagnosed with cancer, there is a paucity of research on adolescents and young adult (AYA) patients. Guided by the Anderson's Behavioral Model for Healthcare Utilization, this study examined predisposing/enabling/need factors associated with hospice referral/enrollment among AYA patients diagnosed with cancer. Methods: Data were drawn from medical records of AYA patients who died of cancer between January 2013 and December 2016 at three academic sites in the United States and were 15–39 years old at the time of death. Logistic regression was conducted (N = 224). Results: Findings showed that hospice referral was strongly associated with hospice enrollment (odds ratio [OR] = 69.68, p < 0.0001). White patients were more likely to be referred to hospice care than non-White patients; the effect was, however, significant only among patients with private insurance (OR = 3.44, p = 0.040). Patients with public insurance were more likely to be referred to hospice than those with private insurance; the effect was, however, significant only among non-White patients (OR = 5.66, p = 0.005). Among those not receiving cancer treatment in the last month of life (LML), patients with hematologic malignancies were less likely to be referred to hospice than those with solid tumors (OR = 0.19). Among patients with solid tumors, receiving cancer treatment in the LML lowered the odds of hospice referral (OR = 0.50, p = 0.043). Conclusion: Further research efforts are needed to investigate the role of race, insurance, cancer types, and treatments in hospice use among bigger samples of AYA patients diagnosed with cancer. [ABSTRACT FROM AUTHOR]

Prior research reported lower engagement in end‐of‐life discussions and planning among Korean American (KA) immigrants; however, there is a dearth of research investigating factors associated with their willingness to discuss their end‐of‐life care wishes. This study aimed to examine the willingness to have end‐of‐life discussions with family and doctors among KA immigrants and social determinants of health (SDH) associated with willingness. A self‐administered, cross‐sectional survey was conducted with a convenience sample of 259 KA immigrants recruited from two counties in Alabama. Demographic, health, acculturation and SDH information were collected. Logistic regression analyses were conducted to examine associations between SDH and willingness for end‐of‐life discussion with family and doctors, respectively. The majority of the sample was willing to discuss end‐of‐life care with family (94%) and doctors (82%). Those with hospice awareness were more likely to have willingness for discussion with family (OR = 27.70, p < 0.001) and doctors (OR = 5.01, p < 0.001). Those who could not see a doctor because of cost (OR = 0.03, p < 0.01) and who had higher threats to interpersonal safety (OR = 0.74, p < 0.05) were less likely to have willingness for discussion with family. Those who had more chronic conditions (OR = 0.60, p < 0.05) and higher levels of social isolation (OR = 0.77, p < 0.05) were less likely to have willingness for discussion with doctors. The SDH identified in this study should be considered in developing interventions to promote end‐of‐life discussions in the KA immigrant community. Future research should investigate the associations explored in this study in a larger and more representative sample. [ABSTRACT FROM AUTHOR]

Advanced care planning (ACP) utilization remains very limited in rural communities compared to urban areas. ACP earlier in the disease trajectory is particularly important for people with dementia (PWD) due to its progressive nature affecting their decision-making ability. Considering the well-documented benefits of ACP in improving the quality of end-of-life (EOL) care, the rural vs. urban disparity may indicate poorer EOL quality for rural PWD. This study aimed to explore barriers and current resources for ACP of PWD from the perspectives of health or social service providers serving rural communities. Using a qualitative approach, semi-structured face-to-face interviews were conducted with 11 health or social service professionals serving older adults and their caregivers in rural Alabama. Thematic analysis revealed three major barriers: (1) lack of knowledge, (2) psychosocial barriers, and (3) limited access to healthcare. Participants also showed misconception that a lawyer or a notary is required for ACP. Two themes arose in the participants' recommendations to address the barriers: (1) providing ACP-relevant information and (2) addressing psychosocial stressors about ACP. This study highlighted an urgent need for social policy in ACP education for caregivers and service providers in rural settings. [ABSTRACT FROM AUTHOR]

Although residential geographic health disparities have been noted in the previous literature, studies are specifically lacking on intra-group health comparisons of African American older adults by residential geography. The purpose of this study was to determine if health-related characteristics of African American older adults varied by residential geography. Socioeconomic demographics, medical conditions, primary care use, and self-ratings of general health, social activity, and physical activity were compared in a community-dwelling sample of 327 urban and non-urban African American older adults. Urban and non-urban African American older adults were compared on health-related factors. Compared to urban African American older adults, those in non-urban areas had lower incomes, lower self-ratings of general health, social activity, and physical activity, and a higher frequency of arthritis and gastroenterological and urological conditions. Despite poorer general health and medical conditions, non-urban African American older adults were less likely to visit the doctor when needed. Study findings suggest residential geography may be an underappreciated underlying contributing factor to inter-group health disparities between African American and white older adults and not race alone. Therefore, social workers in public health, health care, and clinical settings should be aware of the interaction between race and residential geography. [ABSTRACT FROM AUTHOR]

Knowledge of patient end-of-life (EOL) wishes and discussions are vital for family caregivers, including children and youth who may be in caregiving roles (“young carers” or “caregiving youth”). However, little is known about caregiving youth awareness and perceptions of EOL issues. This study sought to explore caregiving youth knowledge of EOL wishes and their willingness for EOL discussions. Face-to-face interviews with 40 caregiving youth ages 10–20, who have a parent with Huntington’s disease (HD), provided information about their knowledge of the presence of their ill parent’s living will (LW) and durable power of attorney for health care (DPAHC), and willingness to talk with the parent about EOL choices and possibility of death. Less than one-half of the participants were aware of the parent’s LW or DPAHC. Content analysis revealed themes in reasons to want or not want EOL discussion with the parent: respect for the parent’s wishes, caregiving youths’ opinion not valued, and avoidance of EOL issues. Themes also included reasons to not want discussion with the parent about possibility of death: protecting the parent, parent in denial, parent not ready, and realization of the terminal outcome. Findings suggest HD patients and their caregiving youth need support for open EOL discussions, and could benefit from educational programs and support groups around EOL issues. [ABSTRACT FROM PUBLISHER]

While racial disparity in the use of hospice care by older African Americans is widely acknowledged, little is known about the values that they consider as important in receiving health care services along with direct experiences with having these values respected by hospice care providers. Using individual, face-to-face interviews, data were collected directly from 28 African American hospice patients about their experiences in hospice care. Content analysis was used to identify and categorize themes from multiple readings of the qualitative data. Resulting themes included: dying at home, open communications, independent decision-making, autonomy in daily life, unwillingness to be a burden, and relationships. Through the initial assessment, value preferences can be explored and then shared with hospice team members to ensure that services are provided in such a way that their values and preferences are respected. [ABSTRACT FROM AUTHOR]

Background. Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]. Methods. We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice. Results. Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs. Conclusion. These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD. [ABSTRACT FROM PUBLISHER]

This study explored terminally ill elders' anticipation of future support, which may be particularly important due to their vulnerable state and resulting support needs. Qualitative data was gathered from face-to-face interviews with 100 elders receiving hospice care; 85 of whom discussed anticipating future support. Content analysis revealed that anticipating support was based on current experiences of received support and that the definition of future extended beyond death for some who anticipated surviving loved ones receiving grief support. Not all anticipation of support evoked positive feelings. Some respondents anticipated receiving unhelpful support or felt guilty about anticipating support from overburdened caregivers. Implications are discussed regarding the role of social workers in working with caregivers to insure that the terminally ill elders they care for can anticipate future support in their dying process and after death. [ABSTRACT FROM AUTHOR]

Purpose: This study explored the role control plays in the dying process of terminally ill elders by investigating the aspects of the dying process over which they seek to exercise control, the strategies they use, and whether they desire to exercise more control. Design and Methods: In-depth face-to-face interviews were conducted with 84 terminally ill elders receiving hospice care. Directed and conventional content analysis methods were used to identify main themes and patterns. Results: The results revealed that all 84 elders were using at least 1 primary control strategy in their dying process, 83 of whom did so in combination with another primary or compensatory secondary control strategy. Decision making, independence, mental attitude, instrumental activities of daily living, activities of daily living, and relationships were aspects of the dying process over which the respondents sought to exercise control. Over half of the respondents wanted more control; however, they felt their illness prevented it. Implications: The findings highlight the importance of terminally ill elders’ having opportunities to exercise control in their dying process. Practitioners need to ensure that these opportunities exist and to be aware that elders are adaptive and use multiple strategies in exercising control. [ABSTRACT FROM PUBLISHER]

Background and Objectives In long-term care facilities in the United States, certified nursing assistants (CNAs) provide mealtime assistance to residents with dementia, a task that substantially increases caregiver burden due to the time and attention required. The aim of this qualitative study was to explore the individual and interpersonal barriers and facilitators CNAs experience when providing mealtime assistance to residents with dementia. Research Design and Methods Focus group questions were developed based on the corresponding levels of the Social Ecological Model. Using purposive sampling, 9 focus groups were conducted with 53 CNAs who had at least 1 year of experience as a CNA working with older adults. Focus groups were audio-recorded and transcribed verbatim. Data were analyzed using the directed content analysis approach. Results CNAs reported individual skills, training, and personal characteristics that affected their ability to provide mealtime assistance. At the interpersonal level, CNAs identified their relationships with residents, residents' family members, and other health care professionals as factors that affect their ability to provide mealtime assistance. Discussion and Implications These findings provide evidence for strategies that administrators can utilize to reduce caregiver burden by improving the mealtime experience. First, CNAs need adequate training, particularly to develop communication skills. Developing verbal communication skills may improve interpersonal relationships between CNAs and residents' family members and other coworkers. Developing nonverbal communication skills may foster an improved relationship between CNAs and their residents with dementia. Future research should evaluate interventions that seek to improve these skills to determine their impact on the mealtime experience. [ABSTRACT FROM AUTHOR]

Aim: The objectives of the present study were to estimate the prevalence of co‐occurring diabetes and hypertension among older adults, examine predictors of co‐occurring diabetes and hypertension, and ascertain whether predictors varied by race. Methods: A retrospective analysis was carried out using a statewide survey of Alabama community‐dwelling older adults (n = 1204). Measures of central tendency and frequency distributions were used for univariate analysis. Logistic regression was used to predict co‐occurring diabetes and hypertension. Results: The prevalence of co‐occurring diabetes and hypertension among older adults was 17%. African American race (OR 2.28, 95% CI 1.596–3.255), body mass index ≥30 (OR 2.45, 95% CI 1.732–3.463), heart disease (OR 1.93, 95% CI 1.355–2.756) and eye disease (OR 1.44, 95% CI 1.018–2.024) were associated positively with co‐occurring diabetes and hypertension. Conclusions: The prevalence of co‐occurring diabetes and hypertension among older adults was alarmingly high. The notable difference in the likelihood of co‐occurring diabetes and hypertension is representative of a racial health disparity that largely disfavors African American older adults. Findings from the present study highlight a need for identification of older adults who have and who are at risk of co‐occurring diabetes and hypertension in the general population and in clinical settings, and the development and implementation of suitable interventions, particularly targeting older African American adults. Geriatr Gerontol Int 2018; 18: 1356–1360. [ABSTRACT FROM AUTHOR]

Glomerular hyperfiltration (GHF) is a hemodynamic change of the kidney as an adaptive response to nephron loss. Although GHF is associated with metabolic risk factors and cardiovascular disease (CVD), the mechanisms that explain these relationships remain largely unknown. This is partially caused by a non-unified definition of GHF based on pathophysiologic vascular changes. Thus, the objective of this study was to evaluate the association between various definitions of GHF and carotid plaque in a health checkup cohort. A total of 4493 individuals without history of CVD who had carotid ultrasonography (USG) results available between January 2016 and June 2018 were enrolled. GHF was defined as >90th percentile of eGFR residuals after adjusting for confounding factors. Carotid plaque score was calculated based on carotid USG results. Of 4493 individuals (mean age, 52.3 ± 10.1 years; 3224 [71.8%] males), 449 subjects were included in the GHF group (mean eGFR, 107.0 ± 7.1 ml/min/1.73 m2) and 4044 subjects were included in the non-GHF group (mean eGFR, 92.5 ± 12.3 ml/min/1.73 m2). When the GHF group was compared to the non-GHF group, GHF was associated with the presence of significant carotid plaque (carotid plaque score ≥2) (adjusted OR: 1.46; 95% CI: 1.16 to 1.83; p = 0.001). GHF defined in this study showed higher sensitivity to the presence of carotid plaque than other definitions of GHF. GHF status was associated with risk of carotid plaque in individuals without history of CVD. Presence of subclinical carotid plaque was associated with risk of future CVD. Therefore, GHF based on creatinine could be a useful surrogate marker for surveillance of CVD in asymptomatic individuals. [Display omitted] • Although glomerular hyperfiltration (GHF) was associated with metabolic risk and CVD, its role has been underrated because definition was not unified. • GHF with adjustment for confounding factors was associated with the presence of significant carotid plaque (plaque score ≥2). • Carotid plaque is associated with the risk of cardiovascular disease (CVD). GHF can be a useful surrogate for surveillance of CVD. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes in type 2 diabetes mellitus (T2DM) patients. However, the mechanisms by which SGLT2 inhibitors improve the clinical outcomes remain elusive. We evaluated whether empagliflozin, an SGLT2 inhibitor, ameliorates mitochondrial dysfunction and inflammatory milieu of the kidneys in T2DM patients. We prospectively measured copy numbers of urinary and serum mitochondrial DNA (mtDNA) nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND-1) and cytochrome-c oxidase 3 (mtCOX-3) and urinary interleukin-1β (IL-1β) in healthy volunteers (n = 22), in SGLT2 inhibitor-naïve T2DM patients (n = 21) at baseline, and in T2DM patients after 3 months of treatment with empagliflozin (10 mg, n = 17 or 25 mg, n = 4). Both urinary mtDNA copy numbers and IL-1β levels were higher in the T2DM group than in healthy volunteers. Baseline copy numbers of serum mtCOX-3 in the T2DM group were lower than those in healthy volunteers. Empagliflozin induced marked reduction in both urinary and serum mtND-1 and mtCOX-3 copy numbers, as well as in urinary IL-1β. Empagliflozin could attenuate mitochondrial damage and inhibit inflammatory response in T2DM patients. This would explain the beneficial effects of SGLT2 inhibitors on cardiovascular and renal outcomes. [ABSTRACT FROM AUTHOR]

This study explored next-of-kin's retrospective accounts of hospice and palliative care discussions for hospitalized veterans. In-depth, face-to-face interviews were used to generate narrative accounts of 78 next-of-kin's experience of their loved one's hospital care during the last days of the patient's life. One-third of participants reported taking part in a hospice or palliative care discussion during the patient's final hospitalization. In over one-half of those cases, the patients died before discharge or transfer to hospice or palliative care was accomplished. Hospice and palliative care discussions in the hospital setting shaped family perceptions of the patients’ care, directed family efforts in the days prior to death, and engendered anticipation of remaining quality time with the patient. Discussions about hospice or palliative care have meaning, emotional impact, practical effects, and unintended consequences for next-of-kin. Social workers in hospital settings can play a critical role in supporting family members through the hospice and palliative care discussion process and facilitate timely care transitions. They also can attend to the psychosocial concerns of family members, particularly when death occurs prior to discharge to hospice or transfer to an inpatient palliative care service. [ABSTRACT FROM AUTHOR]

This study explored next-of-kin's retrospective accounts of hospice and palliative care discussions for hospitalized veterans. In-depth, face-to-face interviews were used to generate narrative accounts of 78 next-of-kin's experience of their loved one's hospital care during the last days of the patient's life. One-third of participants reported taking part in a hospice or palliative care discussion during the patient's final hospitalization. In over one-half of those cases, the patients died before discharge or transfer to hospice or palliative care was accomplished. Hospice and palliative care discussions in the hospital setting shaped family perceptions of the patients’ care, directed family efforts in the days prior to death, and engendered anticipation of remaining quality time with the patient. Discussions about hospice or palliative care have meaning, emotional impact, practical effects, and unintended consequences for next-of-kin. Social workers in hospital settings can play a critical role in supporting family members through the hospice and palliative care discussion process and facilitate timely care transitions. They also can attend to the psychosocial concerns of family members, particularly when death occurs prior to discharge to hospice or transfer to an inpatient palliative care service. [ABSTRACT FROM PUBLISHER]

Background: Extracellular vesicle (EV)-microRNAs (miRNAs) are potential biomarkers for various renal diseases. This study attempted to identify the circulating EV-miRNA signature not only for discriminating idiopathic membranous nephropathy (IMN) from idiopathic nephrotic syndrome (INS), but also to predict the treatment response of patients with IMN.Methods: We prospectively enrolled 60 participants, including those with IMN (n = 19) and INS (n = 21) and healthy volunteers (HVs; n = 20) in this study. Using RNA sequencing, we assessed the serum EV-miRNA profiles of all participants. To identify the EV-miRNAs predictive of treatment response in IMN, we also analyzed EV-miRNAs among patients with IMN with and without clinical remission.Results: The expression levels of 3 miRNAs differed between IMN patients, INS patients and HVs. In addition, compared to HVs, RNA sequencing revealed differential expression of 77 and 44 EV-miRNAs in patients with IMN without and with remission, respectively. We also identified statistically significant (|fold change ≥ 2, p < 0.05) differences in the expression levels of 23 miRNAs in IMN without remission. Biological pathway analysis of miRNAs in IMN without remission indicated that they are likely involved in various pathways, including renal fibrosis.Conclusion: Our study identified EV-miRNAs associated with IMN as well as those associations with therapeutic response. Therefore, these circulating EV-miRNAs may be used as potential markers for the diagnosis and prediction of treatment response in patients with IMN. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between abdominal periaortic (APA) and renal sinus (RS) fat attenuation index (FAI) measured on MDCT and metabolic syndrome in non-obese and obese individuals. Methods: Visceral, subcutaneous, RS, and APA adipose tissue were measured in preoperative abdominal CT scans of individuals who underwent donor nephrectomy (n = 84) or bariatric surgery (n = 155). FAI was defined as the mean attenuation of measured fat volume. Participants were categorized into four groups: non-obese without metabolic syndrome (n = 64), non-obese with metabolic syndrome (n = 25), obese without metabolic syndrome (n = 21), and obese with metabolic syndrome (n = 129). The volume and FAI of each fat segment were compared among the groups. Receiver operator characteristics curve analysis was used to assess the association between the FAIs and metabolic syndrome. Results: FAIs of all abdominal fat segments were significantly lower in the obese group than in the non-obese group (p < 0.001). RS, APA, and the visceral adipose tissue FAIs were significantly lower in participants with metabolic syndrome than in those without metabolic syndrome in the non-obese group (p < 0.001, p = 0.006, and p < 0.001, respectively). The area under the curve for predicting metabolic syndrome was significantly higher for APA FAI (0.790) than subcutaneous, visceral, and RS FAI in all groups (0.649, 0.647, and 0.655, respectively). Conclusion: Both metabolic syndrome and obesity were associated with lower RS and APA adipose tissue FAI, and APA FAI performed best for predicting metabolic syndrome. Key Points: • The volume and FAI of RS, APA, and visceral adipose tissue showed opposite trends with regard to metabolic syndrome or obesity. • Both metabolic syndrome and obesity were associated with lower RS FAI and APA FAI. • APA FAI performed best for predicting metabolic syndrome among FAIs of abdominal fat segments. [ABSTRACT FROM AUTHOR]

Background. It is well established that the survival rate of diabetic end-stage renal disease patients remains the lowest among all primary diagnoses probably because of higher prevalence of cardiovascular diseases (CVD) associated with diabetes. This study was designed to evaluate the impact of CVD and other risk factors individually or in combination on mortality in diabetic peritoneal dialysis (PD) patients.Methods. In a retrospective study, 213 incident PD patients [118 had diabetes mellitus (DM), 94 were female, mean age 55 ± 13 years] underwent initial assessment of nutritional status, comorbid disease (CMD) survey, residual renal function (RRF), dialysis adequacy and peritoneal transport characteristics at a mean of 9 days (range, 3–24 days) after start of PD and were then followed for 30 ± 24 months (range, 3–115 months). Of 213 patients, 154 patients were reassessed after a mean of 11 months (range, 6–19 months). Nutritional status was assessed by subjective global assessment and other methods. CMD was graded by Davies index and included DM, CVD, liver disease and respiratory disease.Results. On Kaplan–Meier analysis, patient survival was significantly lower in female DM patients compared to other groups. The 3-year patient survival rate was 46, 70, 82 and 83% for female DM, male DM, male non-DM and female non-DM, respectively (P = 0.003). On Cox proportional hazards multivariate analysis including all patients, old age, presence of CVD or protein-energy wasting (PEW), low serum albumin concentration and low RRF were independent predictors of mortality but not DM per se or female gender. In DM patients, old age, female gender, presence of CVD or PEW and low RRF were independent predictors of mortality while old age was the only risk factor in non-DM patients. After adjustment for age, gender and RRF, DM patients with both CVD and PEW had a risk of mortality that was 3.3 times that of DM patients without CVD and PEW. In DM patients without CVD and PEW, patient survival was not different from that of non-DM patients without CVD and PEW.Conclusions. DM per se was not a risk factor for mortality in this group of PD patients. Instead, the higher mortality rate in diabetic PD patients, in particular among female patients, was mainly attributable to concurrent morbidity such as CVD and PEW, together with low RRF. [ABSTRACT FROM AUTHOR]

The radiodensity and volume of epicardial adipose tissue (EAT) on computed tomography angiography (CTA) may provide information regarding cardiovascular risk and long-term outcomes. EAT volume is associated with mortality in patients undergoing incident hemodialysis. However, the relationship between EAT radiodensity/volume and all-cause mortality in patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis remains elusive. In this retrospective study, EAT radiodensity (in Hounsfield units) and volume (in cm3) on coronary CTA were quantified for patients with ESRD using automatic, quantitative measurement software between January 2012 and December 2018. All-cause mortality data (up to December 2019) were obtained from the Korean National Statistical Office. The prognostic values of EAT radiodensity and volume for predicting long-term mortality were assessed using multivariable Cox regression models, which were adjusted for potential confounders. A total of 221 patients (mean age: 64.88 ± 11.09 years; 114 women and 107 men) with ESRD were included. The median follow-up duration (interquartile range) after coronary CTA was 29.63 (range 16.67–44.7) months. During follow-up, 82 (37.1%) deaths occurred. In the multivariable analysis, EAT radiodensity (hazard ratio [HR] 1.055; 95% confidence interval [CI] 1.015–1.095; p = 0.006) was an independent predictor of all-cause mortality in patients with ESRD. However, EAT volume was not associated with mortality. Higher EAT radiodensity on CTA is associated with higher long-term all-cause mortality in patients undergoing prevalent hemodialysis, highlighting its potential as a prognostic imaging biomarker in patients undergoing hemodialysis. [ABSTRACT FROM AUTHOR]

Background: Recently, a new international risk prediction model including the Oxford classification was published which was validated in a large multi‐ethnic cohort. Therefore, we aimed to validate this risk prediction model in Korean patients with IgA nephropathy. Methods: This retrospective cohort study was conducted with 545 patients who diagnosed IgA nephropathy with renal biopsy in three medical centers. The primary outcome was defined as a reduction in estimated glomerular filtration rate (eGFR) of >50% or incident end‐stage renal disease (ESRD). Continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) were used to validate models. Results: During the median 3.6 years of follow‐up period, 53 (9.7%) renal events occurred. In multivariable Cox regression model, M1 (hazard ratio [HR], 2.22; 95% confidence interval [CI], 1.02–4.82; p =.043), T1 (HR, 2.98; 95% CI, 1.39–6.39; p =.005) and T2 (HR, 4.80; 95% CI, 2.06–11.18; p <.001) lesions were associated with increased risk of renal outcome. When applied the international prediction model, the area under curve (AUC) for 5‐year risk of renal outcome was 0.69, which was lower than previous validation and internally derived models. Moreover, cNRI and IDI analyses showed that discrimination and reclassification performance of the international model was inferior to the internally derived models. Conclusion: The international risk prediction model for IgA nephropathy showed not as good performance in Korean patients as previous validation in other ethnic group. Further validation of risk prediction model is needed for Korean patients with IgA nephropathy. SUMMARY AT A GLANCE: Prediction models for IgA nephropathy using clinical variables and the Oxford MEST scores were developed and may be utilised to individualise risk of progression. This study evaluates the performance of these prediction models in an external cohort of Korean patients. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are promising source of cell‐based regenerative therapy. In consideration of the risk of allosensitization, autologous MSC‐based therapy is preferred over allogenic transplantation in patients with chronic kidney disease (CKD). However, it remains uncertain whether adequate cell functionality is maintained under uremic conditions. As chronic inflammation and oxidative stress in CKD may lead to the accumulation of senescent cells, we investigated cellular senescence of CKD MSCs and determined the effects of metformin on CKD‐associated cellular senescence in bone marrow MSCs from sham‐operated and subtotal nephrectomized mice and further explored in adipose tissue‐derived MSCs from healthy kidney donors and patients with CKD. CKD MSCs showed reduced proliferation, accelerated senescence, and increased DNA damage as compared to control MSCs. These changes were significantly attenuated following metformin treatment. Lipopolysaccharide and transforming growth factor β1‐treated HK2 cells showed lower tubular expression of proinflammatory and fibrogenesis markers upon co‐culture with metformin‐treated CKD MSCs than with untreated CKD MSCs, suggestive of enhanced paracrine action of CKD MSCs mediated by metformin. In unilateral ureteral obstruction kidneys, metformin‐treated CKD MSCs more effectively attenuated inflammation and fibrosis as compared to untreated CKD MSCs. Thus, metformin preconditioning may exhibit a therapeutic benefit by targeting accelerated senescence of CKD MSCs. [ABSTRACT FROM AUTHOR]

The time at which hypertension treatment should be initiated for different age groups and sexes remains controversial. We aimed to determine whether the association between blood pressure (BP) and major adverse cardiovascular events (MACE) varies with age and sex. This study enrolled 327,328 subjects who had not taken antihypertensive medication in the Korean National Health Service-National Health Screening Cohort between 2002 and 2003. Participants were categorized into four groups according to 2017 American College of Cardiology/American Heart Association hypertension guideline. Primary outcome was MACE characterized by cardiovascular mortality, myocardial infarction, unstable angina, and stroke. During a 10-year follow-up, a significant increase in MACE risk was observed from the stage 1 hypertension group (hazard ratio [HR], 1.23; 95% CI 1.15–1.32; P < 0.001) in time-varying Cox analysis. This relationship was persistent in subjects aged < 70 years, but increased MACE risk was observed only in the stage 2 hypertension group in ≥ 70 years (HR, 1.52; 95% CI 1.32–1.76, P < 0.001). When categorized as per sex, both men and women showed significant MACE risk from stage 1 hypertension. However, on comparing the sexes after stratifying by age, a significantly increased risk of MACE was shown from stage 1 hypertension in men aged < 50 years, but from stage 2 hypertension in men aged ≥ 50 years. Meanwhile, increased MACE risk was observed from stage 2 hypertension in women aged < 60 years, but from stage 1 hypertension in women aged ≥ 60 years. Thus, young male subjects had higher MACE risk than young female subjects, but this difference gradually decreased with age and there was no difference between sexes in subjects aged ≥ 70 years. Therefore, our results suggest that hypertension treatment initiation may need to be individualized depending on age and sex. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is caused by dysfunctional kidneys, which result in complications like cardiovascular diseases. Chronic kidney disease‐induced pathophysiological conditions decrease efficacy of autologous mesenchymal stem/stromal cell (MSC)‐based therapy by reducing MSC functionality. To enhance therapeutic potential in patients with CKD, we isolated exosomes derived from melatonin‐treated healthy MSCs (MT exosomes) and assessed the biological functions of MT exosome–treated MSCs isolated from patients with CKD (CKD‐MSCs). Treatment with melatonin increased the expression of cellular prion protein (PrPC) in exosomes isolated from MSCs through the upregulation of miR‐4516. Treatment with MT exosomes protected mitochondrial function, cellular senescence, and proliferative potential of CKD‐MSCs. MT exosomes significantly increased the level of angiogenesis‐associated proteins in CKD‐MSCs. In a murine hindlimb ischemia model with CKD, MT exosome–treated CKD‐MSCs improved functional recovery and vessel repair. These findings elucidate the regenerative potential of MT exosome–treated CKD‐MSCs via the miR‐4516‐PrPC signaling axis. This study suggests that the treatment of CKD‐MSCs with MT exosomes might be a powerful strategy for developing autologous MSC‐based therapeutics for patients with CKD. Furthermore, miR‐4516 and PrPC could be key molecules for enhancing the regenerative potential of MSCs in ischemic diseases. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are a popular cell source for stem cell‐based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin‐induced HSPA1L binds to cellular prion protein (PrPC), resulting in the recruitment of PrPC into the mitochondria. The HSPA1L‐PrPC complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti‐oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin‐treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control. [ABSTRACT FROM AUTHOR]

Although it is known that the expression and activity of sirtuin 1 (Sirt1) decrease in the aged kidney, the role of interaction between Sirt1 and hypoxia‐inducible factor (HIF)‐1α is largely unknown. In this study, we investigated whether HIF‐1α could be a deacetylation target of Sirt1 and the effect of their interaction on age‐associated renal injury. Five‐week‐old (young) and 24‐month‐old (old) C57Bl/6J mice were assessed for their age‐associated changes. Kidneys from aged mice showed increased infiltration of CD68‐positive macrophages, higher expression of extracellular matrix (ECM) proteins, and more apoptosis than young controls. They also showed decreased Sirt1 expression along with increased acetylated HIF‐1α. The level of Bcl‐2/adenovirus E1B‐interacting protein 3, carbonic anhydrase 9, Snail, and transforming growth factor‐β1, which are regulated by HIF‐1α, was significantly higher in aged mice suggesting that HIF‐1α activity was increased. In HK‐2 cells, Sirt1 inhibitor sirtinol and siRNA‐mediated knockdown of Sirt1 enhanced apoptosis and ECM accumulation. During hypoxia, Sirt1 was down‐regulated, which allowed the acetylation and activation of HIF‐1α. Resveratrol, a Sirt1 activator, effectively prevented hypoxia‐induced production of ECM proteins, mitochondrial damage, reactive oxygen species generation, and apoptosis. The inhibition of HIF‐1α activity by Sirt1‐induced deacetylation of HIF‐1α was confirmed by Sirt1 overexpression under hypoxic conditions and by resveratrol treatment or Sirt1 overexpression in HIF‐1α‐transfected HK‐2 cells. Finally, we confirmed that chronic activation of HIF‐1α promoted apoptosis and fibrosis, using tubular cell‐specific HIF‐1α transgenic mice. Taken together, our data suggest that Sirt1‐induced deacetylation of HIF‐1α may have protective effects against tubulointerstitial damage in aged kidney. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitor use is associated with incident chronic kidney disease, chronic kidney disease progression and end-stage renal disease. However, the extent of proton pump inhibitor prescriptions to chronic kidney disease patients is still unclear. Method: In a retrospective study, we enrolled patients (>18 years old) who received proton pump inhibitor in the out-patient setting from 2014 through 2015. All data was obtained from electronical medical records of Soonchunhyang Medical Center. The prescription patterns and characteristics of proton pump inhibitors were analyzed according to individual estimated glomerular filtration rate of the patients. Result: During the study period 178,228 patients visited the out-patient clinic. Proton pump inhibitors were prescribed to 9,109 (5.11%) patients. In our sample, 50% were females and 9.8% were chronic kidney disease (eGFR<60mL/min/1.73 m2) patients. Among the patients with chronic kidney disease, 730 (8.0%) were categorized as stage 3 or 4 and 166 (1.8%) were categorized as stage 5 or end-stage renal disease. The prevalence of proton pump inhibitors prescription among chronic kidney disease patients was higher than in the non-chronic kidney disease group (p<0.001). Median duration of usage was 120 [interquartile range 63–273] days in the stage 3–4 group, 106 [56–266] days in the stage 5-end-stage renal disease group and 90 [56–176] days in the non-chronic kidney disease group. Patients in stage 3–4 group were prescribed longer duration of proton pump inhibitors than the non-chronic kidney disease group even after adjusting for age and sex (p<0.001). The main departments of medicine which prescribed proton pump inhibitors for the stage 3–4 group were gastroenterology (40.0%), cardiology (29.6%), nephrology (9.5%) and neurology (4.8%). Compared to the non-chronic kidney disease group, the stage 3–4 and stage 5-end-stage renal disease group were taking larger number of drugs simultaneously (6.90±4.17 vs4.54±2.43; p<0.001, 5.64±2.87 vs 4.54±2.34; p<0.001, respectively). Conclusion: Chronic kidney disease patients are taking proton pump inhibitors for a much longer duration compared to non-chronic kidney disease patients. Physicians should pay careful attention when prescribing proton pump inhibitors to high risk groups. [ABSTRACT FROM AUTHOR]

Background: The elevation of serum creatinine (SCr), acute kidney injury (AKI), is associated with an increase of mortality in critically ill patients. However, it is uncertain whether a decrease in SCr in the intensive care unit (ICU) has an effect on outcomes. Methods: In a retrospective study, we enrolled 486 patients who had been admitted to an urban tertiary center ICU between Jan 2014 and Dec 2014. The effect of changes in SCr after ICU admission on 90 day mortality was analyzed. Patients were classified into 3 groups based on change in SCr after ICU admission: a stable SCr group (Δ SCr < 0.3mg/dL during ICU stay), a decreased SCr group (Δ SCr ≥ -0.3 mg/dL during ICU stay) and an increased SCr group with criteria based on the KDIGO AKI criteria. Results: In total, 486 patients were identified. SCr decreased in 123 (25.3%) patients after ICU admission. AKI developed in 125 (24.4%) patients. The overall 90-day mortality rate was 29.0%. In a Kaplan-Meyer analysis, the mortality of the AKI group was higher than that of other groups (p<0.0001). Patients with a decrease in SCr had a higher mortality rate than those with stable SCr (p<0.0001). A Cox analysis showed that both a decrease in SCR (HR, 3.56; 95% CI, 1.59–7.97; p = 0.002) and an increase in SCr (AKI stage 1, HR, 9.35; 95% CI, 4.18–20.9; p<0.0001; AKI stage 2, HR, 11.82; 95% CI, 3.85–36.28; p<0.0001; AKI stage 3, HR, 17.41; 95% CI, 5.50–55.04; p<0.0001) were independent risk factors for death compared to stable SCr. Conclusion: Not only an increase in SCr, but also a decrease in SCr was associated with mortality in critically ill patients. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a significant risk factor for cardiovascular and peripheral vascular disease. Although mesenchymal stem cell (MSC)-based therapy is a promising strategy for treatment of ischemic diseases associated with CKD, the associated pathophysiological conditions lead to low survival and proliferation of transplanted MSCs. To address these limitations, we investigated the effects of fucoidan, a sulfated polysaccharide, on the bioactivity of adipose tissue-derived MSCs and the potential of fucoidan-treated MSCs to improve neovascularization in ischemic tissues of CKD mice. Treatment of MSCs with fucoidan increased their proliferative potential and the expression of cell cycle-associated proteins, such as cyclin E, cyclin dependent kinase (CDK) 2, cyclin D1, and CDK4, via focal adhesion kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt axis. Moreover, fucoidan enhanced the immunomodulatory activity of MSCs through the ERK-IDO-1 signal cascade. Fucoidan was found to augment the proliferation, incorporation, and endothelial differentiation of transplanted MSCs at ischemic sites in CKD mice hind limbs. In addition, transplantation of fucoidan-treated MSCs enhanced the ratio of blood flow and limb salvage in CKD mice with hind limb ischemia. To our knowledge, our findings are the first to reveal that fucoidan enhances the bioactivity of MSCs and improves their neovascularization in ischemic injured tissues of CKD. In conclusion, fucoidan-treated MSCs may provide an important pathway toward therapeutic neovascularization in patients with CKD. [ABSTRACT FROM AUTHOR]

Background and Objectives: Glucose control is a significant predictor of mortality in diabetic peritoneal dialysis (PD) patients. During PD, the local toxic effects of intra-peritoneal glucose are well recognized, but despite large amounts of glucose being absorbed, the systemic effects of this in non-diabetic patients are not clear. We sought to clarify whether dialysate glucose has an effect upon systemic glucose metabolism. Methods and Materials: We analysed the Global Fluid Study cohort, a prospective, observational cohort study initiated in 2002. A subset of 10 centres from 3 countries with high data quality were selected (368 incident and 272 prevalent non-diabetic patients), with multilevel, multivariable analysis of the reciprocal of random glucose levels, and a stratified-by-centre Cox survival analysis. Results: The median follow up was 5.6 and 6.4 years respectively in incident and prevalent patients. On multivariate analysis, serum glucose increased with age (β = -0.007, 95%CI -0.010, -0.004) and decreased with higher serum sodium (β = 0.002, 95%CI 0.0005, 0.003) in incident patients and increased with dialysate glucose (β = -0.0002, 95%CI -0.0004, -0.00006) in prevalent patients. Levels suggested undiagnosed diabetes in 5.4% of prevalent patients. Glucose levels predicted death in unadjusted analyses of both incident and prevalent groups but in an adjusted survival analysis they did not (for random glucose 6–10 compared with <6, Incident group HR 0.92, 95%CI 0.58, 1.46, Prevalent group HR 1.42, 95%CI 0.86, 2.34). Conclusions: In prevalent non-diabetic patients, random glucose levels at a diabetic level are under-recognised and increase with dialysate glucose load. Random glucose levels predict mortality in unadjusted analyses, but this association has not been proven in adjusted analyses. [ABSTRACT FROM AUTHOR]

Background: Racial differences exist for a number of health conditions, services, and outcomes, including end-of-life (EOL) care. Objective: The aim of the study was to examine differences in processes of care in the last 7 days of life between African American and white inpatients. Methods: Secondary analysis was conducted of data collected in the Best Practices for End-of-Life Care for Our Nation's Veterans (BEACON) trial (conducted 2005-2011). Subjects were 4891 inpatient decedents in six Veterans Administration Medical Centers. Data were abstracted from decedents' medical records. Multi-variable analyses were conducted to examine the relationship between race and each of 18 EOL processes of care controlling for patient characteristics, study site, year of death, and whether the observation was pre- or post-intervention. Results: The sample consisted of 1690 African American patients (34.6%) and 3201 white patients (65.4%). African Americans were less likely to have: do not resuscitate (DNR) orders (odds ratio [OR]: 0.67; p = 0.004), advance directives (OR: 0.71; p = 0.023), active opioid orders (OR: 0.64, p = 0.0008), opioid medications administered (OR: 0.61, p = 0.004), benzodiazepine orders (OR: 0.68, p < 0.0001), benzodiazepines administered (OR: 0.61, p < 0.0001), antipsychotics administered (OR: 0.73, p = 0.004), and steroids administered (OR: 0.76, p = 0.020). Racial differences were not found for other processes of care, including palliative care consultation, pastoral care, antipsychotic and steroid orders, and location of death. Conclusions: Racial differences exist in some but not all aspects of EOL care. Further study is needed to understand the extent to which racial differences reflect different patient needs and preferences and whether interventions are needed to reduce disparities in patient/family education or access to quality EOL care. [ABSTRACT FROM AUTHOR]

Background Mesenchymal stem cells (MSCs) have the potential to differentiate into multiple cell lineages. Given this potential for tissue regeneration, MSC-based therapeutic applications have been considered in recent years. However, ischemia-induced apoptosis has been reported to be one of the main causes of MSC death following transplantation. The primary objective of this study was to determine whether a natural antioxidant, fucoidan, could protect MSCs from ischemia-induced apoptosis in vitro and in vivo. Furthermore, we investigated the mechanism of action of fucoidan's anti-ischemic effect in MSCs. Methods and result Pre-treatment with fucoidan (10 μg/mL) suppressed the increase in H 2 O 2 -induced reactive oxygen species (ROS) levels and drastically reduced apoptotic cell death in MSCs. Fucoidan inhibited the activation of the pro-apoptotic proteins p38-mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and caspase-3, and augmented the expression of the anti-apoptosis protein cellular inhibitor of apoptosis (cIAP). Moreover, fucoidan significantly increased manganese superoxide dismutase (MnSOD) expression and decreased cellular ROS levels via the Akt pathway, resulting in enhanced cell survival. In a murine hindlimb ischemia model, transplanted fucoidan-treated MSCs showed significantly enhanced cell survival and proliferation in ischemic tissues. Functional recovery and limb salvage also remarkably improved in mice injected with fucoidan-stimulated MSCs compared with mice injected with non-stimulated MSCs. Conclusion Taken together, these results show that fucoidan protects MSCs from ischemia-induced cell death by modulation of apoptosis-associated proteins and cellular ROS levels through regulation of the MnSOD and Akt pathways, suggesting that fucoidan could be powerful therapeutic adjuvant for MSC-based therapy in ischemic diseases. [ABSTRACT FROM AUTHOR]

Previous studies have shown that induction of immune tolerance by mesenchymal stem cells (MSCs) is partially mediated via monocytes or dendritic cells (DCs). The purpose of this study was to determine the role of CD11c+ cells in MSC-induced effects on ischemia/reperfusion injury (IRI). IRI was induced in wildtype (WT) mice and CD11c+-depleted mice following pretreatment with or without MSCs. In the in-vitro experiments, the MSC-treated CD11c+ cells acquired regulatory phenotype with increased intracellular IL-10 production. Although splenocytes cocultured with MSCs showed reduced T cell proliferation and expansion of CD4+FoxP3+ regulatory T cells (Tregs), depletion of CD11c+ cells was associated with partial loss of MSCs effect on T cells. In in-vivo experiment, MSCs’ renoprotective effect was also associated with induction of more immature CD11c+ cells and increased FoxP3 expression in I/R kidneys. However all these effects induced by the MSCs were partially abrogated when CD11c+ cells were depleted in the CD11c+-DTR transgenic mice. In addition, the observation that adoptive transfer of WT CD11c+ cells partially restored the beneficial effect of the MSCs, while transferring IL-10 deficient CD11c+ cells did not, strongly suggest the important contribution of IL-10 producing CD11c+ cells in attenuating kidney injury by MSCs. Our results suggest that the CD11c+ cell-Tregs play critical role in mediating renoprotective effect of MSCs. [ABSTRACT FROM AUTHOR]

Background: Kidney injury molecule-1 (KIM-1) is a sensitive biomarker for proximal tubular injury. Recently, a few studies have shown that urinary KIM-1 has clinical implications in IgA nephropathy (IgAN). We performed this study to determine whether tissue KIM-1 has clinical implications for predicting long-term outcome and whether urinary KIM-1 is correlated with tissue KIM-1 and kidney injury in IgAN patients. Methods: We assessed the prognostic prediction capability of tissue KIM-1 expression in 69 adult patients with IgAN retrospectively. Renal biopsies from all patients were scored by a pathologist who was blinded to the clinical data for the pathologic variables. The primary outcome was the composite of a 50 % reduction in eGFR or end-stage renal disease. Tissue KIM-1 expression was assessed semiquantitatively by counting the stained tubules per 100× power field; 0 tubule indicates grade 0; 1-5 tubules, grade 1; 6-10 tubules, grade 2; and more than 10 tubules, grade 3. Comparing urinary KIM-1 and tissue KIM-1 expression, 50 consecutive IgAN patients were prospectively enrolled to measure urinary KIM-1 levels and examine their biopsy specimens by KIM-1 immunohistochemistry. Results: Univariate analysis showed that tissue KIM-1 expression was associated with the renal outcome in IgAN. Multivariate regression analysis, as the relationship of tissue KIM-1 with prognosis, was consistent. Proteinuria at biopsy and tissue KIM-1 grade 3 were shown to have a prognostic value. The concentration of urinary KIM-1/Cr in patients with IgAN was significantly higher than that in the normal controls. Conclusion: Tissue KIM-1 expression is an independent predictor of adverse renal outcomes in IgA nephropathy patients. [ABSTRACT FROM AUTHOR]

Tubular injury and fibrosis are associated with progressive kidney dysfunction in advanced glomerular disease. Glomerulotubular crosstalk is thought to contribute to tubular injury. microRNAs (miRNAs) in extracellular vesicles (EVs) can modulate distant cells. We hypothesized that miRNAs in EVs derived from injured podocytes lead to tubular epithelial cell damage. As proof of this concept, tubular epithelial (HK2) cells were cultured with exosomes from puromycin-treated or healthy human podocytes, and damage was assessed. Sequencing analysis revealed the miRNA repertoire of podocyte EVs. RNA sequencing identified 63 upregulated miRNAs in EVs from puromycin-treated podocytes. Among them, five miRNAs (miR-149, -424, -542, -582, and -874) were selected as candidates for inducing tubular apoptosis according to a literature-based search. To validate the effect of the miRNAs, HK2 cells were treated with miRNA mimics. EVs from injured podocytes induced apoptosis and p38 phosphorylation of HK2 cells. The miRNA-424 and 149 mimics led to apoptosis of HK2 cells. These results show that miRNAs in EVs from injured podocytes lead to damage to tubular epithelial cells, which may contribute to the development of tubular injury in glomerular disease. [ABSTRACT FROM AUTHOR]

Minor glomerular abnormalities (MGAs) are unclassified glomerular lesions indicated by the presence of minor structural abnormalities that are insufficient for a specific pathological diagnosis. The long-term clinical outcomes and pathogenesis have not been examined. We hypothesized that MGAs would be associated with the deterioration of long-term kidney function and increased urinary mitochondrial DNA (mtDNA) copy numbers. We retrospectively enrolled patients with MGAs, age-/sex-/estimated glomerular filtration rate (eGFR)-matched patients with immunoglobulin A nephropathy (IgAN), and similarly matched healthy controls (MHCs; n = 49 each). We analyzed the time × group interaction effects of the eGFR and compared mean annual eGFR decline rates between the groups. We prospectively enrolled patients with MGAs, age- and sex-matched patients with IgAN, and MHCs (n = 15 each) and compared their urinary mtDNA copy numbers. Compared to the MHC group, the MGA and IgAN groups displayed differences in the time × group effects of eGFR, higher mean annual rates of eGFR decline, and higher urinary mtDNA copy numbers; however, these groups did not significantly differ from each other. The results indicate that MGAs are associated with deteriorating long-term kidney function, and mitochondrial injury, despite few additional pathological changes. We suggest that clinicians conduct close long-term follow-up of patients with MGAs. [ABSTRACT FROM AUTHOR]

Mitochondrial injury plays important roles in the pathogenesis of various kidney diseases. However, mitochondrial injury in IgA nephropathy (IgAN) remains largely unexplored. Here, we examined the associations among mitochondrial injury, IgAN, and treatment outcomes. We prospectively enrolled patients with IgAN and age-/sex-matched healthy volunteers (HVs) as controls (n = 31 each). Urinary copy numbers of the mitochondrial DNA (mtDNA) genes cytochrome-c oxidase-3 (COX3) and nicotinamide adenine dinucleotide dehydrogenase subunit-1 (ND1) were measured. Urinary mtDNA levels were elevated in the IgAN group compared with that in HVs (p < 0.001). Urinary ND1 levels were significantly higher in the low proteinuria group than in the high proteinuria group (p = 0.027). Changes in urinary levels of ND1 and COX3 were positively correlated with changes in proteinuria (p = 0.038 and 0.024, respectively) and inversely correlated with changes in the estimated glomerular filtration rate (p = 0.033 and 0.017, respectively) after medical treatment. Mitochondrial injury played important roles in IgAN pathogenesis and may be involved in early-stage glomerular inflammation, prior to pathological changes and increased proteinuria. The correlation between changes in urinary mtDNA and proteinuria suggest that these factors may be promising biomarkers for treatment outcomes in IgAN. [ABSTRACT FROM AUTHOR]

Beta2-adrenergic receptor (β2AR) agonists can have protective effects targeting macrophage activation, but research on human subjects has not been done. This study was designed to assess the relationship between the use of β2AR agonists and diabetic vascular complications. Using data from the Korean National Health Insurance Service, adults first diagnosed with diabetes in 2004 (n = 249,222) were followed up until 31 December 2015. Propensity score matching was performed between case and control groups (n = 5179 in each), and multivariate analysis was conducted. The β2AR agonist group was divided into quartiles according to the duration of β2AR agonist use. During the follow-up, the incidence of vascular complications gradually decreased as the duration of β2AR agonist administration increased. Multivariate analysis revealed that the hazard ratio for all composite vascular complications was 0.80 (95% CI, 0.75–0.86, p < 0.001) in the longest quartile of β2AR agonist use as compared with the control group after adjusting for confounding variables. The association between the duration of β2AR agonist use and the risk of each vascular complication including cerebrovascular, peripheral vascular, peripheral neural, renal, and ophthalmic complications was consistent, and the risks were significantly lower in the longest users than the control group. Long-term use of β2AR agonists may exert a protective effect against diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy (DN) is associated with high risk of cardiovascular disease and mortality. Exosomal microRNAs (miRNAs) regulate gene expression in a variety of tissues and play important roles in the pathology of various diseases. We hypothesized that the exosomal miRNA profile would differ between DN patients and patients without nephropathy.Methods: We prospectively enrolled 74 participants, including healthy volunteers (HVs), diabetic patients without nephropathy, and those with DN. The serum exosomal miRNA profiles of participants were examined using RNA sequencing.Results: The expression levels of 107 miRNAs differed between HVs and patients without DN, whereas the expression levels of 95 miRNAs differed between HVs and patients with DN. Among these miRNAs, we found 7 miRNAs (miR-1246, miR-642a-3p, let-7c-5p, miR-1255b-5p, let-7i-3p, miR-5010-5p, miR-150-3p) that were uniquely up-regulated in DN patients compared to HVs, and miR-4449 that was highly expressed in DN patients compared to patients without DN. A pathway analysis revealed that these eight miRNAs are likely involved in MAPK signaling, integrin function in angiogenesis, and regulation of the AP-1 transcription factor. Moreover, they were all significantly correlated with the degree of albuminuria.Conclusions: Patients with DN have a different serum exosomal miRNA profile compared to HVs. These miRNAs may be promising candidates for the diagnosis and treatment of DN and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Although mesenchymal stem cell (MSC)‐based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H2O2 to induce oxidative stress. CKD‐derived MSCs exhibited greater oxidative stress‐induced senescence than normal‐mMSCs, while melatonin protected CKD‐mMSCs from H2O2 and associated excessive senescence. The latter was mediated by PrPC‐dependent mitochondrial functional enhancement; melatonin upregulated PrPC, which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin‐treated CKD‐mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD‐mMSCs are more susceptible to H2O2‐induced senescence than normal‐mMSCs, and melatonin administration protects CKD‐mMSCs from excessive senescence by upregulating PrPC and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD‐mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell‐based therapies using mouse‐derived CKD‐mMSCs. [ABSTRACT FROM AUTHOR]

Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway. [ABSTRACT FROM AUTHOR]

Macrophage activation has been well recognized in the pathogenesis of cardiovascular complications of diabetes and insulin resistance. We have previously shown that increased activity of protein kinase C(PKC), commonly observed in diabetes potentiated insulin's action in monocytic THP-1 cells on Erkl/2 phosphorylation, cell adhesion and surface expression of Mac-1, a surrogate marker for macrophage activation. In this study, we have characterized PKC isoform-specific action mediating these effects. THP-1 cells, following exposure to 25 mM of D-glucose for 3 days, increased membraneous translocation of several PKC isoforms including α, δ2, and ε, similar to those stimulated by PMA, a PKC activator. In addition, GF109203X (1µM), a general PKC inhibitor suppressed PMA-induced PKC activation and cell adhesion in THP-1 cells by 100% (p<0.01 vs PMA). This is likely due to the inhibition of PKCδ isoform since 10 µM Rottlerin, a PKCδ inhibitor aborogated PMA-induced cell adhesion completely. Interestingly, both hyperglycemia and PMA-induced PKC activation increased the membraneous levels of p47[sup phox], a cytosolic subunit of NADPH oxidase which translocates to membrane when activated. Thus, we hypothesized that the hyperglycemia-induced PKCδactivity will promote the generation of superoxide via NADPH oxidase that subsequently contribute to the activation of macrophages. We showed that PMA-induced activation/adhesion of floating THP-1 cells to culture plates were completely inhibited by NADPH oxidase inhibitor Diphenyleneiodonium (DPI, 10 µM, p<0.01 vs PMA). In addition, PKC activation synergistically increased and prolonged insulin's action on Erk½ phosphorylation that is critical to macrophage activation. We have also shown that the sustained activation of Erk½ pathway might be due the reduced expression of a phosphotase MKP-1 which modulate Erk½ phosphorylation following PKCδ activation. Thus, our study has provided a molecular link suggesting that the PKCδ may lead to macrophage activation via NADPH oxidase-dependent superoxide generation. These alterations can potentiate and prolong the action of insulin on MEK/Erk½ pathway via changes in phosphatase expression that accelerate atherogenesis. [ABSTRACT FROM AUTHOR]