LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts.

BACKGROUND: As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI. METHODS: LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed. RESULTS: LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells. CONCLUSIONS: Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.

Association of plasma ceramide with decline in kidney function in patients with type 2 diabetes.

Circulating ceramide levels are dysregulated in kidney disease. However, their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0, and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5 ml/min/1.73 m2 per year or greater, and ESKD defined as eGFR <15/min/1.73 m2 for at least 3 months, on dialysis or renal death at follow-up. During a median follow-up period of 7.7 years, 197 patients experienced RDKF. Ceramide Cer24:0 (odds ratio [OR] = 0.71, 95% CI 0.56-0.90) and ratios Cer16:0/Cer24:0 (OR = 3.54 [1.70-7.35]), Cer18:0/Cer24:0 (OR = 1.89 [1.10-3.25]), and Cer24:1/Cer24:0 (OR = 4.01 [1.93-8.31]) significantly associated with RDKF in multivariable analysis; 124 patients developed ESKD. The ratios Cer16:0/Cer24:0 (hazard ratio [HR] = 3.10 [1.44-6.64]) and Cer24:1/Cer24:0 (HR = 4.66 [1.93-11.24]) significantly associated with a higher risk of ESKD. The Cer24:1/Cer24:0 ratio improved risk discrimination for ESKD beyond traditional risk factors by small but statistically significant margin (Harrell C-index difference: 0.01; P = 0.022). A high ceramide risk score also associated with RDKF (OR = 2.28 [1.26-4.13]) compared to lower risk score. In conclusion, specific ceramide levels and their ratios are associated with RDKF and conferred an increased risk of ESKD, independently of traditional risk factors, including baseline renal functions in patients with T2D.

Incident heart failure and the subsequent risk of progression to end stage kidney disease in individuals with type 2 diabetes.

BACKGROUND: Diabetic kidney disease is an established risk factor for heart failure. However, the impact of incident heart failure on the subsequent risk of renal failure has not been systematically assessed in diabetic population. We sought to study the risk of progression to end stage kidney disease (ESKD) after incident heart failure in Asian patients with type 2 diabetes. METHODS: In this prospective cohort study, 1985 outpatients with type 2 diabetes from a regional hospital and a primary care facility in Singapore were followed for a median of 8.6 (interquartile range 6.2-9.6) years. ESKD was defined as a composite of progression to sustained eGFR below 15 ml/min/1.73m2, maintenance dialysis or renal death, whichever occurred first. RESULTS: 180 incident heart failure events and 181 incident ESKD events were identified during follow-up. Of 181 ESKD events, 38 (21%) occurred after incident heart failure. Compared to those did not progress to ESKD after incident heart failure (n = 142), participants who progressed to ESKD after heart failure occurrence were younger, had higher HbA1c and higher urine albumin-to-creatinine ratio at baseline. The excess risk of ESKD manifested immediately after heart failure occurrence, persisted for two years and was moderated thereafter. Cox regression suggested that, compared to counterparts with no heart failure event, participants with heart failure occurrence had 9.6 (95% CI 5.0- 18.3) fold increased risk for incident ESKD after adjustment for baseline cardio-renal risk factors including eGFR and albuminuria. It appeared that heart failure with preserved ejection fraction had a higher risk for ESKD as compared to those with reduced ejection fraction (adjusted HR 13.7 [6.3-29.5] versus 6.5 [2.3-18.6]). CONCLUSION: Incident heart failure impinges a high risk for progression to ESKD in individuals with type 2 diabetes. Our data highlight the need for intensive surveillance of kidney function after incident heart failure, especially within the first two years after heart failure diagnosis.

Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes.

BACKGROUND: Angiogenin, an enzyme belonging to the ribonucleases A superfamily, plays an important role in vascular biology. Here, we sought to study the association of plasma angiogenin and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes (T2D). METHODS: This prospective study included 1083 T2D individuals recruited from a secondary hospital and a primary care facility. The primary outcome was a composite of four-point MACE (nonfatal myocardial infarction, stroke, unstable angina pectoris leading to hospitalization and cardiovascular death). Circulating angiogenin was measured by a proximity extension assay. Cox regression models were used to evaluate the association of baseline plasma angiogenin with the risk of MACE. RESULTS: During a median follow-up of 9.3 years, 109 (10%) MACE were identified. Plasma angiogenin was significantly higher in participants with MACE than in those without MACE (P < 0.001). Doubling of plasma angiogenin concentration was associated with a 3.10-fold (95% CI 1.84-5.22) increased risk for MACE. The association was only moderately attenuated after adjustment for demographic and cardiometabolic risk factors (adjusted HR 2.38, 95% CI 1.34-4.23) and remained statistically significant after additional adjustment for estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (uACR) (adjusted HR 1.90, 95% CI 1.02-3.53). A consistent outcome was obtained when plasma angiogenin was analysed as a categorical variable in tertiles. CONCLUSIONS: Plasma angiogenin was associated with the risk of future cardiovascular events in patients with T2D and may be a promising novel biomarker for identifying high-risk T2D patients for early management.

Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy.

Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.

Asylee perspectives on psychotherapies for posttraumatic stress.

Asylees (i.e., asylum seekers) have a higher prevalence of mental health concerns, particularly posttraumatic distress, than the general population due to both their exposure to traumatic experiences and prolonged uncertain status in a new country. Meta-analyses of randomized controlled trials with asylees have found that culturally adapted cognitive behavioral therapy (CA-CBT), eye movement desensitization and reprocessing (EMDR), and narrative exposure therapy (NET) are efficacious in treating trauma-related symptoms and posttraumatic stress disorder (PTSD); however, treatment utilization remains low. Thus, it is imperative to determine what PTSD interventions are effective, credible, and acceptable for asylees. We employed structured virtual interviews with 40 U.S. asylees from diverse countries living with one or more symptoms of PTSD. Participants were asked about treatment engagement, perceived barriers to treatment, goals for psychotherapy, and perceptions of the effectiveness and difficulty of engaging in CA-CBT, EMDR, NET, and (non-exposure-based) interpersonal therapy (IPT) for PTSD. Participants perceived IPT to be significantly less difficult than all exposure-based treatments, with medium effect sizes, ds = 0.55-0.71. A qualitative analysis of asylees' comments provided valuable insights into how they think about these treatments. Ways in which these results can be considered when informing recommendations for improving interventions for asylees are discussed.

Efficacy and safety of intraurethral Erbium:YAG laser treatment in women with stress urinary incontinence following failed intravaginal laser therapy: a retrospective study.

Urinary incontinence (UI) is a prevalent condition affecting 25-45% of women and is linked to factors such as menopause, parity, high body mass index, and radical pelvic surgery. Among the three types of UI, stress incontinence (SUI) is the most common, accounting for almost 50% of cases, followed by urgency and overflow incontinence. UI has been found to be associated with reduced quality of life and mental stress. Non-invasive laser treatment is the safest and most effective option for managing SUI, with intraurethral Erbium SMOOTHTM laser treatment holding promise for patients experiencing SUI even after undergoing previous failed intravaginal Erbium:YAG laser treatment. The study recruited 93 female patients with mild to moderate SUI who had received two courses of intravaginal Erbium:YAG laser between January 2015 and June 2018. Of these, 22 patients (23%) who continued to experience SUI after a four-week interval for a second intravaginal Erbium:YAG laser were selected for intraurethral laser treatment in January 2019. The efficacy of the treatment was evaluated by comparing the pre- and post-treatment ICIQ-UI SF score. The urethral length was measured before the procedure. The main procedure involved delivering non-ablative laser energy using Erbium SMOOTHTM technology 2940 nm via a 4-mm cannula with personalized length and fluence was 1.5 J/cm. The 22 female patients with persistent SUI received intraurethral Erbium:YAG laser treatment. Their average age was 47.5 years, with an average of 2 parities and a mean body mass index of 20.97. All patients completed the ICIQ-SF questionnaire before and 3 months after the procedure. Of the patients, 77% reported improvement in symptoms, with 6 reporting strong improvement and 11 reporting improvement. The treatment was well-tolerated, with mild and transient adverse effects such as urinary infection in 1 patient (4.5%) and mild pain in 7 patients (31.8%). Intraurethral laser treatment may be helpful for Taiwanese women with persistent SUI after vaginal laser treatment. However, patients with prior pelvic surgery or pelvic organ prolapse history may limit the efficacy of intraurethral laser. Additional research is necessary to comprehensively investigate the advantages of intraurethral laser therapy. However, using intraurethral Erbium SMOOTHTM laser treatments to rejuvenate tissues and enhance structural support could be a promising avenue for managing stress urinary incontinence in Taiwanese women.

Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes.

AIMS/HYPOTHESIS: We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks. METHODS: Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery-validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis. RESULTS: Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression. CONCLUSIONS/INTERPRETATION: Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine.

A head-to-head comparison between Guardian Connect and FreeStyle Libre systems and an evaluation of user acceptability of sensors in patients with type 1 diabetes.

AIMS: A user-calibrated real-time continuous glucose monitoring (rt-CGM) system is compared to a factory-calibrated flash glucose monitoring (FGM) system and assessed in terms of accuracy and acceptability in patients with type 1 diabetes (T1D). METHODS: Ten participants with T1D were enroled from a specialist diabetes centre in Singapore and provided with the Guardian Connect with Enlite Sensor (Medtronic, Northridge, CA, USA) and first-generation Freestyle Libre System (Abbott Diabetes Care, Witney, UK), worn simultaneously. Participants had to check capillary blood glucose four times per day. At the end of week 1 and week 2, participants returned for data download and were given a user evaluation survey. RESULTS: Accuracy evaluation between Guardian Connect and Freestyle Libre includes the overall mean absolute relative difference value (9.7 ± 11.0% vs. 17.5 ± 10.9%), Clarke Error Grid zones A + B (98.6% vs. 98.1%), sensitivity (78.9% vs. 63.4%), and specificity (93.4% vs. 81.0%). Notably, time below range (<3.9 mmol/L) was 10.5% for FGM versus 2% for rt-CGM. From the evaluation survey, 90% of participants perceived rt-CGM to be accurate versus 40% for FGM, although the majority found both devices to be easy to use, educational, and useful in improving glycaemic control. However, due to the cost of sensors, only 30% were keen to use either device for continuous monitoring. CONCLUSIONS: Although rt-CGM was superior to FGM in terms of accuracy, the value of glucose trends in both devices is still useful in diabetes self-management. Patients and clinicians may consider either technology depending on their requirements.

Glucose Awareness to Motivate and Enable Solutions (GAMES) in diabetes mellitus using flash glucose monitoring: A clinical programme.

AIMS: This real-world observational clinical programme evaluated short and medium-term effects of intermittent flash glucose monitoring on HbA1c, glycaemic variability and lifestyle behavioural changes. METHODS: Two first-generation Libre flash glucose monitoring sensors were provided 3-4 months apart with a food, activity diary, user evaluation survey and treatment modification after each sensor wear. T-tests were used to compare glucose variables within each sensor (week 1 vs. week 2) and between sensors (1st sensor vs. 2nd sensor). EasyGV software was used to calculate glycaemic variability. RESULTS: From 42 type 1 diabetes and 120 type 2 diabetes participants, there was no statistically significant change in mean HbA1c for participants with type 1 diabetes at 3-4 months after the 1st sensor but there was a statistically significant HbA1c reduction for participants with type 2 diabetes [-4 mmol/mol (-0.4%), p = 0.008], despite no statistically significant differences in carbohydrate intake, exercise frequency and duration. Greater reduction was seen in those with baseline HbA1c> 86 mmol/mol (10%) in both type 1 [-12 mmol/mol (-1.1%), p = 0.009] and type 2 diabetes [-11 mmol/mol (-1.0%), p = 0.001). Both type 1 and type 2 diabetes showed improvements in Glucose Management Indicator and percentage time-above-range when comparing week 1 versus week 2 of the same sensor. Higher scan frequency resulted in improved glycaemic parameters and certain measures of glycaemic variability. The majority of participants (85%) agreed that flash glucose monitoring is a useful device but only 60% were keen to use it for daily monitoring. CONCLUSION: Constant feedback from flash glucose monitoring improves glycaemic parameters within the first week of wear. Intermittent use 3-4 months apart resulted in greater improvements for those with higher baseline HbA1c.

Examining the behaviour of energy prices to COVID-19 uncertainty: A quantile on quantile approach.

The energy market is extremely vulnerable to the uncertainty caused by the pandemic and leads to global lockdowns and stagnant economic activity. This study is important because energy prices (EPs) experience a dramatic decline due to the pandemic, which has negative consequences for the global economy. We aim to analyze EPs behaviour to coronavirus (COVID-19) from 2020:01 to 2021:05. The finding shows that EPs are extremely vulnerable to the uncertainty produced by the pandemic in the short run. The COVID-19 has a negative effect on EPs in the medium to upper quantile, which suggests that higher uncertainty caused by the pandemic results in rapid decline. However, the impact of the COVID-19 is greater on the oil prices (OPs) as compared to the natural gas (NGP) and the heating oil price (HOP). Moreover, the finding reveals that COVID-19 impact on EPs are consistently negative across all the quantile. The degree of the impact increases when the relationship changes from short to long run. The pandemic has affected the energy price in the short run, which needs prudent policies to fully grasp the magnitude of the COVID-19 impact on energy prices.

COVID-19 impact on multifractality of energy prices: Asymmetric multifractality analysis.

This article assesses the asymmetric multifractality of the energy prices in the different periods during the coronavirus pandemic (COVID-19) through asymmetric multifractality detrended fluctuation analysis. The higher (lower) multifractality shows a rapid rise (fall), which has different consequences for the energy prices. The findings explore strong multifractality in the downward movements for crude oil, heating oil, diesel, gasoline, propane and kerosene oil returns. The upside multifractality for coal and natural gas returns are bigger than the downside in both periods. Furthermore, the access asymmetry is more pronounced during the COVID-19, implying increased market inefficiency. The outcomes explore if energy prices are inefficient during the pandemic. A special attention is required in order to observe such unexpected fluctuations in the price dynamic and guidelines are vital. The level of efficiency can be improved by a greater transference in information while the government must play its role in regulations. Such aspects can increase stability and decrease the expected risks and price movements.

Save the environment, get financing! How China is protecting the environment with green credit policies?

Green credit policy (GCP) can achieve economic growth and environmental conservation, notably by lowering air pollutants (PM2.5). Green credit is a significant component of China's green financing for environmental regulation and achieving carbon neutrality. In this paper, to understand the causal relationship between GCP and PM2.5, we apply a bootstrap full-sample Granger causality test, parameter stability test, and quantile-on-quantile test for the period between 2003:M01 to 2019:M12. The result shows a bidirectional relationship and reveals that GCP has varied environmental implications in its early and mature stages because of a low percentage of green credit and a lack of motivation for financial institutions. In the long run, GCP and PM2.5 interaction confirm the favorable effects of GCP on PM2.5 as the green credit system improves. For robustness, we used quantile-based granger causality to evaluate the causative link between GCP and PM2.5. In light of the findings, this research advises legislative reforms and stresses the relevance of green credit in improving air quality. This study adds additional evidence that air pollution affects green credit policies. Air quality being a leading indicator helps firms anticipate changes in bank credit preferences and alter financing techniques.

The race to zero emissions: Can renewable energy be the path to carbon neutrality?

When taking into account the general terms on which the global green and low-carbon transition takes place, it can be affirmed that the use of clean and renewable energy, including wind, hydro, solar, etc., is an alternative to the traditional energy sources. The renewable energy industry possesses considerable potential, and has recently become the centre of the global energy landscape. Therefore, this article refers to the rolling-window Granger causality test, in order to explore the role of renewable energy (RE) in reducing the greenhouse gas emissions. By studying the interactions that take place between RE consumption and carbon dioxide (CO2) emissions, we find that the negative impact of RE on CO2 indicates that the replacement role of RE has become increasingly prominent, for it to effectively contribute towards the realization of carbon emission reduction. The results in this regard are consistent with the energy-environment model, suggesting that RE has an excellent performance in achieving carbon neutrality. In fact, CO2 usually exhibits a negative effect on RE, which indicates towards the predictability of environmental quality to the development potential of renewable energy. Carbon emission reduction has become a game of interest among the countries around the world. And hence, in relation to these turn of events in the last few decades, RE is now expected to usher in the required acceleration. While eventually it is believed that the green energy competition will reshape the geopolitics of the world.

Sustainable finance and renewable energy: Promoters of carbon neutrality in the United States.

This investigation explores whether sustainable finance and renewable energy could facilitate U.S. carbon neutrality. We perform the time-varying parameter-stochastic volatility-vector auto-regression (TVP-SV-VAR) model to obtain the changing relations among U.S. sustainable finance (SF), renewable energy (RE) and carbon dioxide emission (CO2). The empirical outcomes reveal a short-term negative effect from RE to CO2, indicating that renewable energy consumption could promote U.S. carbon neutrality. This effect is asymmetrical, and it could be observed that RE increase has a greater effect on CO2 than RE reduction. Also, the development of sustainable finance could facilitate U.S. carbon neutrality, and the direct impact is longer and more significant than RE, but the indirect effect of SF on CO2 by influencing RE is hysteretic. Besides, the asymmetric effect reveals that the negative direct impact of SF increase on CO2 is smaller than SF reduction, and the latter's indirect effect is more rapid than the former. Against the backdrop of global warming and frequent extreme weather, the above conclusions have meaningful practical applications for the U.S. to achieve carbon neutrality targets through developing sustainable finance and renewable energy.

COVID19: A blessing in disguise for European stock markets?

This study aims to bridge the gap that has remained unfilled after the initial scrutiny and reporting of the damaging effects of Covid-19 on financial markets. The study analyzes 10 European stock markets and compares their pre and post covid return dynamics. Our findings are surprisingly pleasant, albeit counterintuitive to some. We observe a quick and unprecedented recovery in the European stock market, yielding significantly higher returns post covid, given a reasonably large holding period. We also observe an alteration and change in the status quo of countries while transmitting or receiving cross-market spillovers.

Obesity and risk of age-related eye diseases: a systematic review of prospective population-based studies.

BACKGROUND: Obesity is a public health challenge worldwide. The relationship between obesity and age-related eye diseases including cataract, glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR) have remained elusive. DESIGN AND METHODS: We conducted a systematic review of three electronic databases for longitudinal population-based studies that described associations between measures of obesity including body mass index (BMI), waist-circumference (WC), and waist-to-hip ratio (WHR), and age-related eye diseases. RESULTS: Our search yielded 1731 articles, of which 14, 10, 16 and 8 articles met our eligibility criteria for cataract, glaucoma, AMD and DR, respectively. BMI-defined obesity was positively associated with incident cataract, incident AMD and incident DR in Western populations, but in Asian populations associations for incident AMD were not significant and associations for incident DR were inverse. WC-defined obesity was associated with incident glaucoma in non-Western populations. WHR-defined obesity but not BMI-defined obesity was associated with the incidence or progression of AMD in two Western studies. CONCLUSIONS: Overall, we found strong evidence supporting associations between obesity and age-related eye diseases. Further research on the association of abdominal obesity and effect of weight loss and physical activity on age-related eye diseases is warranted to support clinical and public health recommendations.

Association of Plasma Leucine-Rich Alpha-2 Glycoprotein 1 (LRG1) with All-Cause and Cause-Specific Mortality in Individuals with Type 2 Diabetes.

BACKGROUND: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein in the transforming growth factor-beta superfamily. We sought to study whether LRG1 might predict risk for all-cause and cause-specific mortality in individuals with type 2 diabetes. METHODS: 2012 outpatients with type 2 diabetes were followed for a median of 7.2 years and 188 death events were identified. Association of LRG1 with risk for mortality was assessed by multivariable Cox regression models. RESULTS: Participants with a higher concentration of LRG1 had an increased risk for all-cause mortality [HR (95% CI), 1.76 (1.03-3.01), 1.75 (1.03-2.98), and 4.37 (2.72-7.02) for quartiles 2, 3, and 4, respectively, compared to quartile 1]. The association remained significant after adjustment for known cardio-renal risk factors including estimated glomerular filtration rate and albuminuria [adjusted HR 2.76 (1.66-4.59), quartile 4 versus 1]. As a continuous variable, a 1-SD increment in LRG1 was associated with 1.34 (1.14-1.57)-fold adjusted risk for all-cause mortality. High plasma LRG1 was independently associated with mortality attributable to cardiovascular disease, infection, and renal diseases. Adding LRG1 into a clinical variable-based model improved discrimination (c statistics from 0.828 to 0.842, P = 0.006) and reclassification (net reclassification improvement 0.47, 95% CI 0.28-0.67) for prediction of 5-year all-cause mortality. CONCLUSION: Plasma LRG1 predicts risk for all-cause mortality and mortality attributable to cardiovascular disease, infection, and renal disease independent of known cardio-renal risk factors. It may be a potential novel biomarker to improve risk stratification in individuals with type 2 diabetes.

The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease.

BACKGROUND: The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. SUMMARY: This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.

Association between depressive symptoms and pulse wave velocity is mediated by increased adiposity in older adults with type 2 diabetes.

Background: Studies investigating the association between depression and aortic stiffness in older patients with type 2 diabetes are lacking. We postulated an association between depressive symptoms and aortic stiffness, and this relationship may be mediated by increased adiposity. Methods: We analyzed participants with type 2 diabetes aged 55 years or older (n = 958). We measured aortic stiffness using carotid-femoral pulse wave velocity (cut-off ≥ 12 m/s) using the tonometry method. We defined depressive symptoms as a score of greater than 5 on the Geriatric Depression Scale-15 (GDS-15). Adiposity indices we assessed were body mass index, waist circumference, waistto-height ratio, visceral fat area and fat mass. Results: Among the participants, 27.2% had aortic stiffness, of whom 6.5% had depressive symptoms. Score on the GDS-15 was correlated with pulse wave velocity, and both variables were correlated with the adiposity markers we analyzed (all p < 0.05). Depressive symptoms were associated with pulse wave velocity (B = 1.79, 95% confidence interval [CI] 0.83-2.75) or aortic stiffness (risk ratio 1.60, 95% CI 1.10-2.33) in the unadjusted model. The association persisted after controlling for demographics, duration of diabetes, glycated hemoglobin, comorbidities and medications. Further adjustment for visceral fat area and fat mass in separate models reduced the association between depressive symptoms and pulse wave velocity or aortic stiffness. Mediation models revealed that the mediation proportions of fat mass and visceral fat area on the association between depressive symptoms and pulse wave velocity were 11.8% and 9.7%, respectively. A preliminary analysis of longitudinal data (n = 184) showed similar findings. Limitations: Causality cannot be inferred from the associations we observed. Conclusion: Depressive symptoms are associated with elevated pulse wave velocity in older people with type 2 diabetes, and this relationship may be partially mediated by increased adiposity.