Gestational Exposure to Maternal Systemic Glucocorticoids and Childhood Risk of CKD.

RATIONALE & OBJECTIVE: The potential effects of antenatal glucocorticoid exposure on the health of children are unclear. We examined the association of gestational exposure to maternal systemic glucocorticoids and the risk of developing chronic kidney disease (CKD) in childhood. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Newborns cared for at the largest health care delivery system in Taiwan between 2004 and 2018. EXPOSURE: Maternal prescriptions for systemic glucocorticoids between the last menstrual period and birth as a proxy for gestational exposure. OUTCOME: Incidence of childhood CKD, including congenital anomalies of the kidney and urinary tract (CAKUT) and other kidney diseases (non-CAKUT), over 10 years. ANALYTICAL APPROACH: Cox proportional hazards models with stabilized inverse probability of treatment weighting and robust sandwich estimator were used to estimate the average association between systemic glucocorticoids and incident CKD after adjustment for offspring characteristics (adjusted HR: AHR). RESULTS: Among 23,363 singleton-born children, gestational systemic glucocorticoid exposure was significantly associated with a higher risk of childhood CKD (AHR, 1.69 [95% CI, 1.01-2.84]). Stratified analyses showed stronger associations between systemic glucocorticoids and childhood CKD within the strata of birth<37 weeks' gestational age (AHR, 2.38 [95% CI, 1.19-4.78]), male sex (AHR, 1.89 [95% CI, 1.00-3.55]), gestational exposure in the second trimester (AHR, 6.70 [95% CI, 2.17-20.64]), and total dose of>24mg hydrocortisone equivalent (AHR, 1.91 [95% CI, 1.05-3.47]). LIMITATIONS: Study was limited to the Taiwan health care delivery system and childhood CKD events through the age of 10 years. CONCLUSIONS: The findings of this study suggest that gestational exposure to systemic glucocorticoids is associated with the occurrence of kidney disease in childhood. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy. PLAIN-LANGUAGE SUMMARY: In a singleton-born cohort of neonates, maternal exposure to antenatal systemic glucocorticoids was significantly associated with a 1.7-fold increased risk of the children developing chronic kidney disease over the first 10 years of life. Children of mothers who received>24mg of hydrocortisone equivalent, systemic glucocorticoid treatment in second trimester of gestation, and children born at<37 weeks of gestational age had a higher risk of childhood kidney disease after gestational systemic glucocorticoid exposure. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy.

Impact of Sirolimus versus Mycophenolate Mofetil on Kidney Function after Calcineurin Inhibitor Dose Reduction in Liver Transplant Recipients.

Impaired kidney function is associated with increased morbidity and mortality in patients undergoing liver transplantation. Although immunosuppressants are essential in these patients, they impair kidney function. This study aimed to compare adverse kidney outcomes between patients treated with a reduced dose of tacrolimus (calcineurin inhibitor) plus sirolimus or mycophenolate mofetil (MMF) in the liver transplant center at Kaohsiung Chang Gung Memorial Hospital between April 2011 and December 2017. Propensity score matching was used to identify 232 patients. The risk of adverse kidney outcomes was estimated using Cox proportional hazards regression, and changes in kidney function over time were analyzed using linear mixed modeling. Acute kidney disease risks in this study cohort were not significantly different for the two immunosuppressants (aHR 1.04; 95% CI: 0.70-1.55, p = 0.8328). However, sirolimus use was significantly associated with a higher risk of estimated glomerular filtration rate decline > 30% than MMF (aHR, 2.09; 95% CI: 1.33-3.28; p = 0.0014). Our results demonstrate that sirolimus use may have worsened long-term kidney outcomes compared to MMF. Close monitoring of kidney function, dose adjustment, and timely transition to MMF is necessary for LT patients receiving sirolimus.

Guideline-Adherent Hypertension in Children and Adolescents: A Multi-Institutional Database Analysis from Taiwan.

BACKGROUND/AIMS: Childhood-onset hypertension is associated with cardiovascular morbidity and adult mortality. This study aimed to assess guideline-adherent hypertension among Taiwanese youth and the agreement on hypertension between the 2017 American Academy of Pediatrics guidelines and the 2004 Fourth Report. METHODS: In this cross-sectional study, we collected outpatient blood pressure (OBP) measurements obtained during routine care visits from a large healthcare delivery system between 2009 and 2018 to evaluate the rate of guideline-adherent hypertension and assess patient-related factors of pediatric hypertension. RESULTS: In total, 12,469 children and adolescents who underwent three separate ≥3 OBP measurements over 33,369 person-years with a total of 95,608 BP measurements in an outpatient setting were analyzed. According to the 2017 American Academy of Pediatrics (AAP) guidelines, the rate of pediatric hypertension in the study setting, which included participants aged 1 to 17 years, ranged from 0.78 to 5.95 per 1000 persons. Although there was perfect agreement between the thresholds of the two guidelines for defining hypertension in the age groups of 1-7, 8-12, and 13-17 years (all κ statistic ≥ 0.85), the use of the AAP threshold classified more adolescents as having hypertension. Children and adolescents with hypertension often had complex chronic diseases and required substantial healthcare services in outpatient, emergency, and inpatient settings. CONCLUSIONS: The present study provides evidence of guideline-adherent pediatric hypertension and highlights the importance of regularly monitoring blood pressure to identify and manage hypertension in children and adolescents. Further research is required to determine the impact of new thresholds on the detection of target organ damage at a pediatric age.

Denosumab Is Superior to Raloxifene in Lowering Risks of Mortality and Ischemic Stroke in Osteoporotic Women.

Both osteoporosis and cardiovascular disease (CVD) share similar pathways in pathophysiology and are intercorrelated with increased morbidity and mortality in elderly women. Although denosumab and raloxifene are the current guideline-based pharmacological treatments, their impacts on cardiovascular protection are yet to be examined. This study aimed to compare mortality rate and cardiovascular events between denosumab and raloxifene in osteoporotic women. Risks of CVD development and all-cause mortality were estimated using Cox proportional hazard regression. A total of 7972 (3986 in each group) women were recruited between January 2003 and December 2018. No significant difference between denosumab and raloxifene was observed in composite CVDs, myocardial infarction, or congestive heart failure. However, comparison of the propensity score matched cohorts revealed that patients with proportion of days covered (PDC) ≥60% had lower incidence of ischemic stroke in the denosumab group than that in the raloxifene group (aHR 0.68; 95% CI 0.47-0.98; p = 0.0399). In addition, all-cause mortality was lower in the denosumab group than in the raloxifene group (aHR 0.59; 95% CI 0.48-0.72; p = 0.001), except in patients aged <65 y/o in this cohort study. We concluded that denosumab is superior to raloxifene in lowering risks of all-cause mortality and certain ischemic strokes in osteoporotic women.

Cardiovascular diseases morbidity and mortality among children, adolescents and young adults with dialysis therapy.

Background: The age-specific burden of cardiovascular disease (CVD) and mortality in pediatric and young adult patients with end-stage kidney disease (ESKD) remains unclear. We aimed to examine the prevalence and incidence of CVD and all-cause mortality in children and adolescents compared with adults with dialysis in Taiwan. Methods: This retrospective observational cohort study comprised 3,910 patients with more than 2 time point receipts of dialysis therapy in a year, including 156 aged <12 years (children), 250 aged 13-20 years (adolescents), 1,036 aged 21-30 years (young adults) and 2,468 aged 31-40 years (adults) in a large healthcare delivery system in Taiwan (2003-2017). Age groups were classified by the date of first receipt of dialysis therapy. The outcomes include the composite of CVD events and any cause of death. Death-censored Cox proportional hazard models were used to evaluate the composite outcome risk of CVD in the four age groups. Results: Among patients receiving dialysis treatment, the risk of composite CVD events [HR, 1.63 (1.22-2.19)] and mortality [HR, 1.76 (1.38-2.25)] was greater in children than the dialysis initiated in older patients. Non-atherosclerotic CVD was more prevalent, especially in younger patients, within the first 6 months after the initiation of dialysis. After 6 months of initial dialysis, the risk of atherosclerotic CVD was higher in adults than those for adolescents and children. The magnitude of CVD risk in adolescents who initiated dialysis therapy was higher in females [HR, 2.08 (1.50-2.88)] than in males [HR, 0.75 (0.52-1.10)]. Conclusion: Younger patients undergoing chronic dialysis with a higher risk of CVD events than older patients are associated with a faster onset of non-atherosclerotic CVD and a higher risk of both CVD- and non-CVD-related mortality.

Trajectory of low-density lipoprotein cholesterol in patients with chronic kidney disease and its association with cardiovascular disease.

Background: The role of longitudinal temporal trends in LDL-C in cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and diabetes is unclear. This study categorized the long-term LDL-C trajectory and determined its association with the incidence of atherosclerotic CVD in patients with CKD according to diabetes status and estimated glomerular filtration rate (eGFR). Methods: The risk of atherosclerotic CVD was estimated in 137,127 Taiwanese patients with CKD using six LDL-C trajectory classes determined by the latent class mixed model as optimal, near optimal, above optimal, borderline, sustained high, and declined high over 5 years. Results: The risk of CVD was higher in the sustained high LDL-C [>160 mg/dL over time; adjusted hazard ratio (aHR) = 1.68, 95% CI = 1.45-1.94], declined high LDL-C (>160 to <100 mg/dL; aHR = 1.23, 95% CI = 1.11-1.38), and borderline LDL-C (approximately 140 mg/dL over time; aHR = 1.16, 95% CI = 1.07-1.26) groups than in the optimal LDL-C group (<100 mg/dL over time). There was no such association in patients with an eGFR <15 mL/min/1.73 m2. Persistent diabetes was associated with a 1.15-2.47-fold increase in CVD in patients with high LDL-C (>120 mg/dL). Conclusion: The LDL-C trajectory pattern was associated with the phenotype of CVD risk. The degree of risk varied according to eGFR and diabetes status. A stable low LDL-C over time was potentially beneficial for prevention of CVD. Intensive lipid management and periodic assessment of LDL-C is essential to reduce the risk of CVD in patients with CKD and diabetes.

Comparative Adverse Kidney Outcomes in Women Receiving Raloxifene and Denosumab in a Real-World Setting.

Both osteoporosis and kidney diseases are common and intercorrelate to increase morbidity and mortality in elderly women. This study aimed to compare adverse kidney outcome between women initiated with denosumab and a matched group of raloxifene initiators using propensity score matching methods in a large healthcare delivery system in Taiwan. The risks of adverse kidney outcomes were estimated using Cox proportional hazard regression and the change in kidney function over time was analyzed using the linear mixed model. A total of 9444 (4722 in each group) women were identified who matched the inclusion criteria between January 2003 and December, 2018. Denosumab use was significantly associated with higher risk of eGFR decline ≥ 30% from baseline than raloxifene use (aHR: 1.26; 95% CI: 1.16−1.36, p < 0.0001). The mean change in eGFR over time was 1.24 mL/min/1.73 m2 per year in the denosumab group and 0.45 mL/min/1.73 m2 per year in the raloxifene group (p = 0.0004). However, the risks of acute kidney injury (10.53%) and chronic dialysis (0.66%) in this study cohort were not significantly different for the two anti-osteoporosis treatments. Close monitoring of the residual kidney function and treatment effect is needed in those with denosumab.

A Profile of Nanoparticle-Based Plasma Neurodegenerative Biomarkers for Cognitive Function Among Patients Undergoing Hemodialysis.

Purpose: This study aimed to compare the plasma levels of nanoparticle-based neurodegenerative biomarkers between hemodialysis (HD) participants with grossly normal cognitive function and healthy controls. Patients and Methods: A cohort of participants undergoing maintenance HD and healthy controls were enrolled for comparison between July and October 2021. The immunomagnetic reduction method was used to measure plasma neurodegenerative biomarkers Aß1-40, Aß1-42, tau protein, and neurofilament light chain (NfL). The clinical dementia rating (CDR) was used to evaluate cognitive function. A receiver operating characteristic curve was used to discriminate between HD participants and healthy controls. Results: There were 52 and 18 participants in the HD and healthy control groups, respectively. The mean age of the HD participants was 62 years, and that of the healthy controls was 57 years. The mean HD vintage in the HD cohort was 11.8 years. HD participants demonstrated significantly higher plasma levels of Aß1-42, tau protein, Aß1-42 × tau, and NfL and Aß1-42/Aß1-40 ratio and significantly lower plasma Aß1-40 levels than healthy controls. The measured plasma biomarkers could not discriminate between CDR0 and CDR0.5 HD participants. The area under the curve of the study biomarkers to discriminate HD participants from healthy controls ranged from 0.987 (Aß1-42 × tau) to 0.889 (NfL). Conclusion: The plasma levels of nanoparticle-based neurodegenerative biomarkers were higher in HD participants with grossly normal cognitive function than in healthy controls. These findings imply that neurodegenerative changes appear in HD participants. A profile of plasma neurodegenerative biomarkers could be considered a potential surrogate for evaluating long-term cognitive function in HD participants.

Excess Risk of Major Adverse Cardiovascular and Kidney Events after Acute Kidney Injury following Living Donor Liver Transplantation.

Acute kidney injury (AKI) is a well-known risk factor for major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE) in nontransplant settings. However, the association between AKI after liver transplantation (LT) and MACE/MAKE is not established. A retrospective cohort analysis including 512 LT recipients was conducted. The incidence of post-LT AKI was 35.0% (n = 179). In total, 13 patients (2.5%) developed de novo coronary artery disease (CAD), 3 patients (0.6%) diagnosed with heart failure (HF), and 11 patients (2.1%) had stroke. The post-LT AKI group showed a higher incidence of CAD and HF than the no post-LT AKI group (4.5% versus 1.5%, p = 0.042; 1.7% versus 0%, p = 0.018; respectively), while there was no significant difference in the stroke events (2.8% versus 1.8%, p = 0.461). Through Cox regression analysis, history of cardiovascular disease (HR 6.51, 95% CI 2.43-17.46), post-LT AKI (HR 3.06, 95% CI 1.39-6.75), and pre-LT diabetes (HR 2.37, 95% CI 1.09-5.17) were identified as independent predictors of MACE; pre-LT chronic kidney disease (HR 9.54, 95% CI 3.49-26.10), pre-LT diabetes (HR 3.51, 95% CI 1.25-9.86), and post-LT AKI (HR 6.76, 95% CI 2.19-20.91) were risk factors for end-stage renal disease. Post-LT AKI is predictive for the development of MACE and MAKE.

Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice.

High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.

Apixaban vs. Warfarin in Atrial Fibrillation Patients With Chronic Kidney Disease.

Background and Objectives: Real-world evidence of apixaban treatment in patients with chronic kidney disease remains scarce. This study aimed to compare the relative risk of stroke or systemic embolism (SE) and major bleeding between apixaban and warfarin in atrial fibrillation (AF) patients with different degrees of kidney function. Design, Setting, Participants, and Measurements: We evaluated newly diagnosed AF patients between 2004 and 2018, who were receiving apixaban or warfarin. Electronic medical record data were collected from a large healthcare delivery network in Taiwan. The outcomes of hospitalization for stroke/SE and major bleeding were compared with propensity-score matched apixaban and warfarin cohorts. Stratified analyses according to initial apixaban dose (standard dose of 10 mg/day vs. lower dose of 2.5-5.0 mg/day) and baseline estimated glomerular filtration rate were performed. Results: Each cohort involved 1,625 matched patients. Apixaban was significantly associated with a lower risk of stroke/SE (adjusted hazard ratio [aHR]: 0.74; 95% confidence interval [CI]:0.57-0.97; p = 0.03). The risk of major bleeding was not increased whether in standard doses (aHR: 0.66; 95% CI: 0.45-0.96; p = 0.03) or reduced doses (aHR, 0.84; 95% CI, 0.63-1.12; p = 0.23) of apixaban. Regarding kidney function, apixaban reduced the risk of stroke/SE by 37% in those with an eGFR of <30 ml/min/1.73 m2 (aHR: 0.63; 95% CI: 0.40-0.98; p = 0.04). Conclusions: Compared to warfarin, apixaban is associated with a reduced risk of stroke/SE and is consistent with a subset of AF patients with eGFR <30 ml/min/1.73 m2. Both standard and reduced doses of apixaban showed lower risk of major bleeding than those of warfarin.

The AST-120 Recovers Uremic Toxin-Induced Cognitive Deficit via NLRP3 Inflammasome Pathway in Astrocytes and Microglia.

Chronic kidney disease (CKD) is characterized by the progressive loss of renal function; moreover, CKD progression commonly leads to multiple comorbidities, including neurological dysfunction and immune disorders. CKD-triggered neuroinflammation significantly contributes to cognitive impairment. This study aimed to investigate the contribution of uremic toxins to cognitive impairment. Serum creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels were measured using an enzyme-linked immunosorbent assay and high-performance liquid chromatography. The creatinine, BUN, IS, and PCS levels were increased from 4 weeks after 5/6-nephrectomy in mice, which suggested that 5/6-nephrectomy could yield a CKD animal model. Further, CKD mice showed significantly increased brain and serum indoxyl sulfate levels. Immunohistochemistry analysis revealed hippocampal inflammation and NLRP3-inflammasomes in astrocytes. Further, the Y-maze and Morris water maze tests revealed learning and memory defects in CKD mice. AST-120, which is also an IS absorbent, effectively reduced serum and hippocampal IS levels as well as reversed the cognitive impairment in CKD mice. Additionally, NLRP3-knockout mice that underwent 5/6-nephrectomy showed no change in cognitive function. These findings suggested that IS is an important uremic toxin that induces NLRP3 inflammasome-mediated not only in microglia, but it also occurred in astrocytic inflammation, which subsequently causes cognitive impairment.

Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral glucose-lowering agents. Apart from their glucose-lowering effects, large clinical trials assessing certain SGLT2 inhibitors have revealed cardiac and renal protective effects in non-diabetic patients. These excellent outcomes motivated scientists and clinical professionals to revisit their underlying mechanisms. In addition to the heart and kidney, redox homeostasis is crucial in several human diseases, including liver diseases, neural disorders, and cancers, with accumulating preclinical studies demonstrating the therapeutic benefits of SGLT2 inhibitors. In the present review, we aimed to update recent advances in the antioxidant roles of SGLT2 inhibitors in common but debilitating human diseases. We anticipate that this review will guide new research directions and novel therapeutic strategies for diabetes, cardiovascular diseases, nephropathies, liver diseases, neural disorders, and cancers in the era of SGLT2 inhibitors.

Recent Advances in Microfluidic Devices for Contamination Detection and Quality Inspection of Milk.

Milk is a necessity for human life. However, it is susceptible to contamination and adulteration. Microfluidic analysis devices have attracted significant attention for the high-throughput quality inspection and contaminant analysis of milk samples in recent years. This review describes the major proposals presented in the literature for the pretreatment, contaminant detection, and quality inspection of milk samples using microfluidic lab-on-a-chip and lab-on-paper platforms in the past five years. The review focuses on the sample separation, sample extraction, and sample preconcentration/amplification steps of the pretreatment process and the determination of aflatoxins, antibiotics, drugs, melamine, and foodborne pathogens in the detection process. Recent proposals for the general quality inspection of milk samples, including the viscosity and presence of adulteration, are also discussed. The review concludes with a brief perspective on the challenges facing the future development of microfluidic devices for the analysis of milk samples in the coming years.

Lack of association between erythropoietin treatment and risk of depression in patients with end-stage kidney disease on maintenance dialysis: a nationwide database study in Taiwan.

BACKGROUND: Patients with end-stage kidney disease (ESKD), have been associated with higher risk of developing depression. Erythropoietin (EPO), frequently used for the treatment of anemia in ESKD patients, has been shown to have neuroprotective and antidepressant effects. In this study, we examined whether EPO treatment changed the risk of depression in ESKD patients. METHODS: In a nationwide population-based cohort in Taiwan from 1998 to 2013, patients with a diagnosis of ESKD on maintenance dialysis and aged greater than 18 years were classified into EPO treatment group or non-EPO treatment group. All patients were followed up until the diagnosis of depressive disorder or the end of the study period. RESULTS: In this cohort (13,067 patients in the EPO and 67,258 patients in the non-EPO group), 5569 patients were diagnosed as depressive disorder in the follow-up period. We found the risk of depression in EPO group was not significantly different from that in non-EPO group (adjusted hazard ratio = 0.98, 95% confidence interval 0.92-1.04, p = 0.499) after adjusting for sex, age, certification year of catastrophic illness for ESKD, physical co-morbidities, and use of benzodiazepines. CONCLUSION: In summary, using the nationwide reimbursement data in Taiwan, we found that EPO treatment in ESKD patients was not associated with their general risk of developing depression.

Group 2 innate lymphoid cells contribute to IL-33-mediated alleviation of cardiac fibrosis.

Rationale: The major cause of heart failure is myocardium death consequent to detrimental cardiac remodeling and fibrosis following myocardial infarction. The cardiac protective cytokine interleukin (IL)-33, which signals by ST2 receptor binding, is associated with group 2 innate lymphoid cell (ILC2) activation and regulates tissue homeostasis and repair following tissue injury in various tissues. However, the distribution and role of IL-33-responsive ILC2s in cardiac fibrosis remain unclear. In this study, we elucidated the roles of IL-33-responsive cardiac-resident ILC2s and IL-33-mediated immunomodulatory functions in cardiac fibrosis. Methods: We examined the distribution of cardiac ILC2s by using flow cytometry. The roles of IL-33-mediated ILC2 expansion in cardiac fibrosis was evaluated in the mouse model of catecholamine-induced cardiac fibrosis. ILC-deficient Rag2‒/‒IL2Rγc‒/‒ mice were implemented to determine the contribution of endogenous ILC in the progression of cardiac fibrosis. Histopathological assessments, speckle tracking echocardiography, and transcriptome profile analysis were performed to determine the effects of IL-33-mediated cardiac protective functions. Results: We identified the resident cardiac ILC2s, which share similar cell surface marker and transcriptional factor expression characteristics as peripheral blood and lung tissue ILC2s. IL-33 treatment induced ILC2 expansion via ST2. In vivo, ILC-deficient Rag2‒/‒IL2Rγc‒/‒ mice developed exacerbated cardiac fibrosis following catecholamine-induced stress cardiac injury. IL-33 treatment expanded cardiac ILC2s and revealed protective effects against cardiac tissue damage with reduced cardiomyocyte death, immune cell infiltration, tissue fibrosis, and improved myocardial function. Transcriptome analysis revealed that IL-33 attenuated extracellular matrix synthesis- and fibroblast activation-associated gene expressions. IL13-knockout or epidermal growth factor receptor (EGFR) inhibition abolished IL-33-mediated cardiac protective function, confirming IL-13 and EGFR signaling as crucial for IL-33-mediated cardioprotective responses. Moreover, ILC2-produced BMP-7 served as a novel anti-fibrotic factor to inhibit TGF-ß1-induced cardiac fibroblast activation. Conclusion: Our findings indicate the presence of IL-33-responsive ILC2s in cardiac tissue and that IL-33-mediated ILC2 expansion affords optimal cardioprotective function via ILC2-derived factors. IL-33-mediated immunomodulation is thus a promising strategy to promote tissue repair and alleviate cardiac fibrosis following acute cardiac injury.

Comparison of Adverse Kidney Outcomes With Empagliflozin and Linagliptin Use in Patients With Type 2 Diabetic Patients in a Real-World Setting.

Background: To compare the effects of empagliflozin and linagliptin use on kidney outcomes of type 2 diabetes mellitus (T2DM) patients in a real-world setting. Methods: The study involved a propensity score-matched cohort comprising new users of empagliflozin or linagliptin with T2DM between January 1, 2013 and December 31, 2018 from a large healthcare delivery system in Taiwan. Clinical outcomes assessed: acute kidney injury (AKI), post-AKI dialysis, and mortality. Cox proportional hazard model was used to estimate the relative risk of empagliflozin or linagliptin use; a linear mixed model was used to compare the average change in estimated glomerular filtration rate (eGFR) over time. Results: Of the 7,042 individuals, 67 of 3,521 (1.9%) in the empagliflozin group and 144 of 3,521 (4.1%) in the linagliptin group developed AKI during the 2 years follow-up. Patients in the empagliflozin group were at a 40% lower risk of developing AKI compared to those in the linagliptin group (adjusted hazard ratio [aHR], 0.60; 95% confidence interval [CI], 0.45-0.82, p = 0.001). Stratified analysis showed that empagliflozin users ≥65 years of age (aHR, 0.70; 95% CI, 0.43-1.13, p = 0.148), or with a baseline eGFR <60 ml/min/1.73 m2 (aHR, 0.97; 95% CI, 0.57-1.65, p = 0.899), or with a baseline glycohemoglobin ≦7% (aHR, 1.01; 95% CI, 0.51-2.00, p =0.973) experienced attenuated benefits with respect to AKI risk. A smaller decline in eGFR was observed in empagliflozin users compared to linagliptin users regardless of AKI occurrence (adjusted ß = 1.51; 95% CI, 0.30-2.72 ml/min/1.73 m2, p = 0.014). Conclusion: Empagliflozin users were at a lower risk of developing AKI and exhibited a smaller eGFR decline than linagliptin users. Thus, empagliflozin may be a safer alternative to linagliptin for T2DM patients.

Effect of clinical factors on trajectory of functional performance in patients undergoing hemodialysis.

PURPOSE: This study aimed to investigate the association between clinical factors and temporary changes in functional performance in patients undergoing hemodialysis. METHODS: This was a retrospective, longitudinal observational study conducted from 2015 to 2017. Eight-two patients undergoing hemodialysis in the outpatient clinic were enrolled. Functional performance was measured using the Karnofsky Performance Status (KPS) scale. Collected data for analysis included demographics, laboratory parameters, and KPS scale scores. All participants were grouped into a high KPS cluster and a low KPS cluster based on dynamic changes in KPS scales from 2015 to 2017. RESULTS: Participants in the high KPS cluster demonstrated an approximate trend, and those in the low KPS cluster demonstrated a low pattern. By stepwise selection model analysis, age (OR 1.12, 95% CI 1.03-1.23, p = 0.011), serum BUN (OR 1.08, 95% CI 1.02-1.16, p = 0.015), calcium levels (OR 3.24, 95% CI 1.2-8.73, p = 0.02), and beta-2-microglobulin (OR > 1.0, CI >1.00-<1.01, p = 0.031) showed risk for the low KPS cluster. Male sex (OR 0.20, 95% CI 0.04-0.96, p = 0.045) and albumin level (OR 0.02, 95% CI 0-0.4, p = 0.009) showed a low risk for the low KPS cluster. CONCLUSIONS: A different trajectory pattern was observed between the high and low KPS clusters in a 3-year period. Risk factors for the low KPS cluster were age, serum BUN, calcium, and beta-2-microglobulin levels. Male sex and serum albumin levels reduced the risk for the low KPS cluster.

Mutual Interaction of Clinical Factors and Specific microRNAs to Predict Mild Cognitive Impairment in Patients Receiving Hemodialysis.

Cognitive impairment (CI) is not uncommon in dialysis patients. Various factors have been implicated. This study aims to examine mutual interaction of various clinical factors for CI in patients receiving hemodialysis. A total of 48 hemodialysis patients in outpatient clinic were recruited from 2015 to 2017. Demographics, circulating uremic toxin concentrations, miRNA concentrations, and nerve injury protein concentrations were collected. Clinical dementia rating (CDR) scores were used to stratify the functional scores of the patients. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic test performance for predicting dichotomous results, and cumulative ROC analysis was used to examine the combined contribution of clinical factors. CDR scale 0 included 15 patients (mean age, 59.1 years); CDR > 0.5 included 33 patients (mean age, 64.0 years). On cumulative ROC analysis, the major predictors of mild CI were hemoglobin, age, sex, homocysteine, neuron-specific enolase (NSE), and miR-486. The cumulative area under the curve (AUC) on combining hemoglobin, age, and miR-486 was the highest (0.897, 95% confidence interval 0.806-0.988). Two dichotomized variables reached 81.82% sensitivity and 86.67% specificity, with the likelihood ratio for positive and negative results being 6.14 and 0.21, respectively. In conclusion, hemoglobin, age, and miR-486 display high-degree combined effects on mild CI in patients receiving hemodialysis.

Urinary Exosomal MicroRNA Signatures in Nephrotic, Biopsy-Proven Diabetic Nephropathy.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD). Elucidating the mechanisms underlying proteinuria in DKD is crucial because it is a common problem in DKD-related mortality and morbidity. MicroRNAs (miRs) associated with DKD have been detected in experimental diabetes models and in patients with both diabetes and CKD. Here, we aimed to investigate pathologic miRs in diabetic nephropathy (DN) by prospectively following six nephrotic, biopsy-proven isolated DN patients (enrolled between August 2015 and July 2017) for one year. The urinary exosomes were isolated at the time of the biopsy and the contained miRs were analyzed by next-generation sequencing. The results were compared to the control group, composed of age-, gender-, and CKD stage-matched patients with proteinuric CKD who did not present diabetes. Among the 72 identified miRs, we investigated eight (miR-188-5p, miR-150-3p, miR-760, miR-3677-3p, miR-548ah-3p, miR-548p, miR-320e, and miR-23c) exhibiting the strongest upregulation (13-15 fold) and two (miR-133a-3p and miR-153-3p) with the strongest downregulation (7-9 fold). The functional analysis of these miRs showed that they were involved in known and novel pathways of DN, supporting their pathologic roles. The bioinformatics-based prediction of the target genes of these miRs will inspire future research on the mechanisms underlying DN pathogenesis.